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Syntheses of heterocyclic compounds via diversity-oriented approach and microwave-assisted solid -phase combinatorial chemistry

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Syntheses of Heterocyclic Compounds via
Diversity-Oriented Approach and Microwave-Assisted
Solid-Phase Combinatorial Chemistry
by
Sun Li-Ping
M.Sc., Lanzhou Institute of Chemical Physics (1991)
A Thesis Presented to
The Hong Kong University of Science and Technology
in Partial Fulfdlment of the Requirements for the Degree
of Doctor of Philosophy in Chemistry
July 2004, Hong Kong
Copyright© by Sun Li-Ping 2004
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
UMI Number: 3148585
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Authorization
I hereby declare that I am the sole author of the thesis.
I authorize The Hong Kong University of Science and Technology to lend this
thesis to other institutions or individuals for the purpose of scholarly research.
I further authorize The Hong Kong University of Science and Technology to
reproduce the thesis by photocopying or by any other means, in total or parts, at the
request of other institution or individuals for the purpose of scholarly research.
ii
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Syntheses of Heterocyclic Compounds via
Diversity-Oriented Approach and Microwave-Assisted Solid-Phase
Combinatorial Chemistry
by
Sun Li-Ping
M.Sc., Lanzhou Institute of Chemical Physics (1991)
This doctoral thesis has been examined by the committee o f the University as
follows:
/—
„
LCU-
________
Prof. Tony R EASTHAM, Chairman
Prof. Wei-Min DAI
Dept, o f Electrical & Electronic
Thesis Supervisor
Engineering (HKUST)
Dept, o f Chemistry (HKUST)
Prof. Dan YANG, External Examiner
Prof. Zhihong G U € H -^
Dept, o f Chemistry
Dept, o f Chemistry (HKUST)
(The University o f Hong Kong)
Prof. Zhenyang LIN
Prof. Zhenguo WU
Dept, o f Chemistry (HKUST)
Dept, o f Biochemistry (HKUST)
L.
C
Prof. Chi Kwong CHANG
(/
Department o f Chemistry
Departm ent Head
July 2004
Dept, o f Chemistry (HKUST)
iii
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Acknowledgments
First of all, I would like to express my deepest appreciation and gratitude to my
supervisor,
Prof.
Wei-Min Dai,
for his
financial
support,
guidance
and
encouragement in the past few years. His profound knowledge, enormous enthusiasm
and keen insight in organic chemistry will continue to be a profound influence to my
research.
I would also like to acknowledge all the members of my examination committee,
Prof. Tony R Eastham, Prof. Zhenyang Lin, Prof. Dan Yang, Prof. Zhihong Guo, Prof.
Zhenguo Wu, for their kindness to spend their precious time for my thesis
examination.
I would like to thank a number of people for their technical support. Ms. Yee
Lai Chan, for her help with the Bruker AFX-300 MHz and Varian EX-300 MHz
NMR spectrometers; Dr. Lora Cao, for her assistant on MS spectra; Mrs. Bobby Wai
Hing Cheng for his help in carrying out the LC-MS experiments; Ms. Judy Tse and
Disney Lau for their help in chemicals purchasing and delivery. All the staffs in the
Department of Chemistry are also acknowledged.
I would like to acknowledge all the past and present members of Prof. Dai’s
research group: Dr. Anxin Wu, Dr. Dian-Shun Guo, Dr. Jin-Ting Liu, Mr.Yukihiro
Tachi, Dr. Kelly Ka Yim Yueng, Dr. Tommy Kong Wah Lai, Mr. Huafeng Wu, Miss
Ye Zhang, Miss Xuan Wang, Dr. Yan Zhang, Ms. Xianghong Huang, Dr. Chen Ma,
Dr Yongqiang Wang and Mr. Feng Cai for their assistance, encouragement and
support in the past few years. I would especially like to thank Dr. Dian-Shun Guo
and Ms. Xianghong Huang for their assistance in some of experiments.
I wish to thank all friends on the 7/F, especially, I would also like to express my
iv
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thanks to the past and present labmates in laboratory 7152 for their kind help and
friendship.
Finally, I am greatly indebted to my family for their enormous support and
encouragement in spirit for me. Without their love and support, this thesis would not
be completed.
v
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L ist o f A bbreviation
Ac
acetyl
Ar
Aryl
Bn
benzyl
Boc
ferf-butoxycarbonyl
Bpoc
biphenylisopropoxycarbonyl
°C
tem perature in degree Centigrade
DBU
l,8-diazobicyclo[5.4.0]-7-ene
DIC
A,A-diisopropylcarbodiimide
DCE
dichloroethane
DCM
dichloromethane
DIEA
A A^-diisopropyl ethyl amine
DM AP
4-dim ethylaminopyridine
DMF
A,A-dimethylformamide
DM SO
dimethyl sulfoxide
eq
equivalent (equivalents)
ESPCS
encoded split-pool combinatorial synthesis
Et
ethyl
et al.
and others
Fmoc
(9-fluorenylmethyloxy)carbonyl
h
hour (hours)
HATU
azabenzotriazolyl-A,A A'-tetram ethyluronium hexafluorophosphate
HPLC
high performance liquid chromatography
HRM S
high solution mass spectroscopy
Hz
hertz(s_1)
vi
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HOBt
iV-hydroxybenzotriazole
i-Pr
isopropyl
IR
infrared
J
coupling constant in Hz
m-
meta
[M]+
molecule ion
Me
methyl
MeCN
acetonitrile
MeOH
methanol
MASPOS
microwave-assisted solid-phase organic synthesis
min
minute (minutes)
mol
mole(s)
mmol
millimole(s)
mL
milliliter(s)
MS
mass spectrum
MW
molecular weight
m/z
mass-to-charge ratio
n-
normal
Naph
naphthyl
NBS
yV-bromosuccinimide
NIS
A-iodosuccinimide
NMP
A-methylpyrrolidinone
NMR
nuclear magnetic resonance
Nu
nucleophile
0-
ortho
Ph
phenyl
vii
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PhMe
toluene
Pr
propyl
PS
polystyrene
PEG
poly(ethylene glycol)
PEG-PS
polystyrene-polyethylene glycol graft copolymer
PPTS
pyridinium p-toluenesulfonate
ppm
part per million
Py
pyridine
PyBOP
benzotriazol-1-yloxy trispyrrolidinophosphonium hexafluorophosphate
PyBroP
bromobispyrrolidinophosphonium hexafluorophosphate
R
alkyl
Rink
linker derived from 4-[[(2,4-dimethoxyphenyl)-amino]methyl]phenol
rt
room temperature (20 °C)
5-
secondary
SPOS
solid-phase organic synthesis
t-
tertiary
i-Bu
tert- butyl
TBAF
tetrabutylammonium fluoride
TBTU
N- [(1 H-benzotriazol-1-yl)(dimethylamino)methylene] -N methylmethanaminium tetrafluoroborate N-oxide
TentaGel
PEG-PS polymer marketed by Rapp Polymere
TFA
trifluoroacetic acid
THF
tetrahydrofuran
THP
3,4-dihydro-2//-pyran or linker derived from
6-(hydroxymethyl)-3,4-dihydro-2//-pyran
TLC
thin-layer-chromatography
viii
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TMG
1,1,3,3 -tetramethylguanidine
TMS
trimethylsilyl
TMS-C1
trimethylsilyl chloride
Wang
linker derived from (hydroxymethyl)phenol
ix
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Tabic of Contents
Title Page.............................................................................................................................. i
Authorization....................................................................................................................... ii
Signature Page.................................................................................................................... iii
Acknowledgments..............................................................................................................iv
List of Abbreviations..........................................................................................................vi
Table of Contents.................................................................................................................x
List of Figures.................................................................................................................. xiv
List of Selected Schemes..................................................................................................xv
List of Tables.................................................................................................................. xviii
Abstract..............................................................................................................................xix
Chapter 1
Brief Introduction to Diversity-Oriented Synthesis of
Small Molecules and Solid-Phase Organic Synthesis
1.1.
Introduction................................................................................................. 1
1.2.
Target-oriented synthesis...........................................................................1
1.3.
Solid-phase organic synthesis................................................................... 3
1.4.
Diversity-oriented synthesis.....................................................................4
1.5.
Diversity-oriented approach to solid-phase synthesis of
heterocyclic small m olecules................................................................ 12
1.6.
Chapter 2
Planned studies of this thesis research ................................................ 19
Novel Synthesis of Indoles via Sonogashira
Cross-Coupling of 2-Carboxamidoaryl Triflates
X
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2.1.
Introduction.............................................................................................. 22
2.2
Synthetic methodologies toward 2-substituted indoles......................... 24
2.2.1.
Metal-catalyzed intermolecular annulation ofhaloanilides
with alkynes............................................................................. 24
2.2.2.
Metal-catalyzed intramolecular cyclization of
2-alkynylanilines
28
2.3.
Results and discussion............................................................................ 34
2.4.
Conclusion................................................................................................43
C hapter 3
Palladium-Catalyzed Synthesis of C4, C5, C6, C7
Nitrogen Substituted Indoles
3.1.
Introduction.............................................................................................. 44
3.2.
Results and discussion.............................................................................47
3.2.1.
Synthesis of arenesulfamoylindole derivatives at C4, C5, C6,
and C7 positions........................................................................ 47
3.3.
Chapter 4
3.2.2.
One-pot palladium-catalyzed synthesisof nitroindoles
53
3.2.3.
Synthesis of 4- and 7-azaindoles.............................................. 57
Conclusion................................................................................................61
A Novel Solid-Phase Synthesis of Indole
Library under Microwave Irradiation
4.1.
Introduction.............................................................................................. 62
4.2.
Recent advances in palladium-catalyzed indolesynthesis
on solid -p h a se.......................................................................................................... 63
4.3.
Microwave-assisted solid-phase synthesisof heterocycles..................68
4.4.
Results and discussion............................................................................ 74
xi
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4.4.1.
Synthesis of 5-nitroindoles on solid-phase............................. 75
4.4.2.
Microwave-assisted cyclization of 2-alkynylanilides on
solid-phase.................................................................................. 78
4.4.3.
4.5.
Chapter 5
Construction of a 96-member indole library........................... 82
Conclusion................................................................................................ 90
Microwave-Assisted Traceless Solid-Phase
Synthesis of Indoles
5.1.
Introduction...............................................................................................91
5.2.
Traceless solid-phase organic synthesis................................................. 92
5.2.1.
Usage of traceless linkers.........................................................93
5.2.2.
Cyclative cleavage...................................................................94
5.2.3.
Post-cleavage modification..................................................... 96
5.3.
Traceless solid-phase synthetic methodologies toward indoles........... 97
5.4.
Results and discussion........................................................................... 100
5.4.1.
Spacer effect on cyclization of 2-alkynylanilides under
microwave irradiation..........................................
5.4.2.
5.5.
Chapter 6
100
Traceless synthesis of an indole library.............................. 107
Conclusion...............................................................................................112
Microwave-Assisted Solid-Phase Synthesis of
a Benzimidazole Library
6.1.
Introduction.............................................................................................113
6.2.
R ecent advances in the solid-phase synthesis o f b en zim id a zo les
6.3.
Results and discussion...........................................................................120
6.4.
Conclusion...............................................................................................128
xii
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114
Summary......................................................................................................................... 129
Experimental Section.....................................................................................................131
References and Notes.................................................................................................... 247
List of Publications........................................................................................................268
Appendix.........................................................................................................................269
xiii
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List of Figures
Figure 1.
Several complex natural products synthesized by TOS.
Figure 2.
Planning synthetic strategies in target-oriented synthesis (a) and
diversity-oriented synthesis (b).
Figure 3.
Building blocks used in the Galanthamine library synthesis.
Figure 4.
Approaches to the diversity-oriented synthesis of functional
heterocyclic compounds.
Figure 5.
Bioactive compounds containing 2-substituted indole scaffolds.
Figure 6.
Selected examples of bioactive nitrogen substituted indoles.
Figure 7.
Structures of synthesized C4, C5, C6, and C7 arenesulfamoylindoles.
Figure 8.
X-ray crystal structure of 106b-l.
Figure 9.
Structures of an indole library.
Figure 10. LC-MS data of la (n = 3, Ar = m-CF3C6H4).
Figure 11.
LC-MS data of lb (n = 3, Ar = 4-F3COC6H4).
Figure 12. LC-MS data of 220a.
Figure 13. LC-MS data of 220c.
Figure 14. Structures of drugs based on the benzimidazole scaffold.
Figure 15. LC-MS data of the benzimidazole 251b-C.
Figure 16. Comparison of two strategies for integration of MASPOS into ESPCS.
xiv
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List of Selected Schemes
Scheme 1.
Solid-phase synthesis of 7-5-5-7 polycyclic ring system using
complexity-generating reactions by Schreiber et al.
Scheme 2.
DOS based on galanthamine-like molecules on solid-phase
by Shair et al.
Scheme 5.
Solid-phase synthesis of quinoxalin-2-ones by Purandare et al.
Scheme 6.
Solid-phase synthesis of diverse heterocycles by Purandare et al.
Scheme 7.
Strategy for the construction of resin-bound 2,2-dimethylbenzopyran scaffolds by Nicolaou et al.
Scheme 11.
Larock indole synthesis.
Scheme 12.
Sonogashira coupling and cyclization on alumina.
Scheme 13.
Pd(II)-Cu(I)-catalyzed cyclization toward indole synthesis.
Scheme 14.
One-pot multi-component coupling approach to indoles.
Scheme 15.
A domino copper-catalyzed coupling-cyclization process to indoles.
Scheme 16.
A base-catalyzed approach to indoles by Yamanaka et al.
Scheme 17.
Pd(II)-catalyzed cyclization of 2-alkynylanilines.
Scheme 18.
IPy2 BF4 -promoted intramolecular cyclization to indoles.
Scheme 19.
Cu(II) salts-catalyzed cyclization of 2-alkynylanilines.
Scheme 20.
Cacchi’s approach to indole synthesis.
Scheme 21.
Synthetic approach of substituted indoles.
Scheme 22.
Cross-coupling reaction of phenylacetylene with
3-carboxamidophenyl triflate 92.
Scheme 23.
Cross-coupling reaction of 94 possessing different TV-protecting
groups.
Scheme 24.
Synthesis 5, 6, and 7-arenesulfamoyl indoles starting from
xv
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2-amino nitrophenols.
Scheme 25.
Synthetic approach to 4-aminoindoles and C4 arenesulfamoylindoles.
Scheme 26.
One-pot synthetic approach toward nitroindoles.
Scheme 27.
Synthesis of azaindoles by palladium-catalyzed heteroannulation and
Bartoli cyclization..
Scheme 28.
Synthesis of 4-azaindoles.
Scheme 29.
Synthesis of 2,5-disubstituted 7-azaindoles.
Scheme 30.
Intramolecular Heck reaction for the synthesis of indoles on
solid-phase.
Scheme 31.
Solid-phase synthesis of indoles by Zhang et al.
Scheme 32.
Synthesis of indoles on solid-phase by Kondo et al.
Scheme 33.
Synthesis of indoles on solid-phase by Bedeschi et al.
Scheme 34.
Microwave-assisted Cu-mediated iV-arylation of heterocycles.
Scheme 35.
Microwave-assisted solid-phase synthesis of bicyclic
dihydropyrimidones.
Scheme 36.
Microwave-assisted solid-phase synthesis of melatoninergic
analogues.
Scheme 37.
Microwave-assisted cellulose-supported synthesis of pyrazoles and
isoxazoles.
Scheme 38.
Microwave-assisted solid-phase synthesis of 1,3,4-oxadiazoles using
polymer-supported Burgess reagent.
Scheme 39.
Synthetic approach to nitroindoles on solid-phase.
Scheme 40.
Microwave-assisted solid-phase synthesis of indoles.
Scheme 41.
B ase-m ediated cleavage o f A'-acylindoles.
Scheme 42.
1,4-benzodiazepine synthesis based on silicon traceless linker.
Scheme 44.
Traceless synthesis of quinazoline-2,4-diones on solid-phase by
xvi
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cyclative cleavage.
Scheme 45.
Traceless synthesis of l,4-benzodiazepine-2,5-diones by cyclative
cleavage.
Scheme 46.
Traceless solid-phase synthesis of quinazolinones by post-cleavage
modification.
Scheme 47.
Traceless synthesis of 2,3-disubstituted indoles using a THP linker.
Scheme 48.
Traceless solid-phase synthesis by sulfonyl linker.
Scheme 49.
Traceless solid-phase synthesis by chameleon catches approach.
Scheme 50.
Synthesis of resin-bound 2-bromo-4-nitroanilides.
Scheme 51.
Pd-catalyzed cross-coupling of the resin-bound 2-bromoanilide.
Scheme 52.
Attempted Cu(II)-catalyzed heteroannulation to indoles via
MASPOS.
Scheme 53.
Microwave-assisted modification of Rink amide resin by glycine
units.
Scheme 54.
Effect of the peptide-modified spacers on indole formation via
MASPOS.
Scheme 55.
Traceless solid-phase synthesis of indole library.
Scheme 56.
Synthetic routes to benzimidazoles.
Scheme 57.
Solid- phase synthesis of benzimidazoles by Wei et al.
Scheme 59.
Traceless solid-phase synthesis of benzimidazoles by Huang et al.
Scheme 60.
Synthesis of benzimidazole N-oxides by Wu et al.
Scheme 61.
Microwave-assisted liquid-phase combinatorial synthesis of
2-(arylamino)benzimidazoles.
Scheme 62.
S ynthesis o f a 50 m em ber b en zim id azole library.
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List of Tables
Table 1.
A-acylation of 2-aminophenols and formation of triflates
Table 2.
Effects o f additives on the cross-coupling o f triflate with
phenylacetylene
Table 3.
Effects of additive on the cross-coupling reaction of triflates
Table 4.
Influence of N-protected group on cross-coupling reaction
Table 5.
Synthesis 2- alkynylanilides from 2-carboxamidophenyl triflates
Table 6.
Synthesis of indole from 2-alkynylanilides
Table 7.
Some results of acylation of aminophenols and their triflates
Table 8.
Yields of cross-coupling products, nitroindoles and aminoindoles
Table 9.
One-pot synthesis of nitroindoles
Table 10. Results for the synthesis of 4-azaindoles
Table 11. Some results of cyclization mediated by f-BuOK in NMP
Table 12.
Cyclization results of resin-bound 2-alkynylanilides 173 with or without
microwave irradiation
Table 13.
Synthesis of indoles la via microwave-assisted cyclization of
resin-bound 2-alkynylanilides 173
Table 14. Results of the 96-member indole library
Table 15. A 16-member indole library
Table 16.
Optimization of amination conditions on solid-phase under microwave
irradiation
Table 17.
Purity (%) and yield (%) of a library of 50 benzimidazoles
xviii
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Syntheses of Heterocyclic Compounds via
Diversity-Oriented Approach and Microwave-Assisted
Solid-Phase Combinatorial Chemistry
by
Sun Li-Ping
A thesis presented to the Department of Chemistry
For the degree of Doctor of Philosophy
At The Hong Kong University of Science and Technology
July 2004
Abstract
Diversity-oriented synthesis is a novel subject emerging from genomics and
proteomics research in recent years, which aims to synthesize small molecules with
structural complexity and diversity for use in a systematic exploration in biology. By
coupling with split-pool solid-phase technology, diversity-oriented synthesis offers a
powerful means to access structurally complex and diverse small molecules by
considering three distinct diversity elements: building blocks, stereochemistry, and
skeletons.
This
thesis
research
addresses
diversity-oriented
synthesis
of
functionalized indole and benzimidazole skeletons starting from readily available and
diverse building blocks.
After a brief overview in Chapter 1 on diversity-oriented synthesis and applications
to heterocycle synthesis from recent literature, Chapter 2 describes the development
of a novel methodology for the synthesis of indoles using commercially available
xix
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and
inexpensive
2-aminophenols.
The
Pd(0)-Cu(I)-catalyzed
Sonogashira
cross-coupling reaction of 2-carboxamidoaryl triflates with 1-alkynes, where a
remarkable additive effect was observed, afforded 2-alkynylanilides. The latter
underwent the base-mediated intramolecular heteroannulation, providing substituted
indoles in good overall yields with two points of diversification originated from
2-aminophenols and 1-alkynes. This cross-coupling-heteroannulation approach, in
both stepwise and one-pot fashion, was successfully extended to the general
synthesis of C4, C5, C6, and C7 nitrogen-substituted indoles, and 4- and
7-azaindoles. These results are documented in Chapter 3.
Solid-phase organic synthesis (SPOS) in combination with encoded split-pool
technology provides a powerful means for the preparation of small molecule libraries.
In Chapter 4, a 96-member indole library was synthesized using radio-frequency
(7?/)-encoded MicroKan reactors based on the developed solution chemistry. The key
step to indole ring formation was accomplished by Cu(II)- or Pd(II)-catalyzed
heteroannulation of 2-alkynylsulfonamides under controlled microwave irradiation.
This synthetic method allows facile introduction of three points of diversity through
(i) functional groups in the sulfonamide subunit, (ii) carbon chain length at C2
position, and (iii) substituent at N1 position of indole. A traceless version of the
microwave-assisted solid-phase indole library synthesis was established as given in
Chapter 5. A remarkable effect of the
glycine-based peptide spacer on
microwave-assisted heteroannulation was observed and accounted by a possible
binding of the peptide sub-unit with Cu(II). This finding seems very useful for
designing suitable spacer/linker for metal-catalyzed reactions on solid supports.
The final chapter outlines a new approach to the solid-phase synthesis of a
50-member
benzimidazole
library
from
commercially
available
4-chloro-3-nitrobenzoic acid. The key step is the microwave-assisted transition
xx
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metal-free amination reaction of the resin-bound o-chloronitrobenzene with
benzylamines. As the consequence of the above library syntheses, we established an
efficient strategy for integration of microwave-assisted solid-phase organic synthesis
(MASPOS) with encoded split-pool combinatorial synthesis (ESPCS).
xxi
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Chapter 1
Brief Introduction to DiversityOriented Synthesis of Small Molecules
and Sol id-Phase Organic Synthesis
1.1.
Introduction
Synthetic organic chemistry is not only a tool for obtaining compounds or behavior
o f materials, but it also leads to the creation o f novel drug or drug-like candidates
and novel materials with interesting properties.
Small molecules are known to play an important role in drug discovery. They can
exert powerful effects on the functions o f macromolecules that comprise living
systems.1 Small molecules-based natural products can serve as useful chemical
probes for understanding the roles and functions o f biological targets and most of
them are known to be an important source to modulate (i.e. promote or inhibit)
protein-protein interactions by interaction with enzymes and proteins.2 This
remarkable ability makes them useful, both as research tools for understanding life
processes and pharmacologic agents for promoting and restoring health.1Challenges
in the synthesis of these small molecules, natural product-like compounds have been
drawing a intense attention of chemists during the last few years.2 Synthetic organic
chemists aim to generate these compounds through three general approaches, that is,
(i) target-oriented synthesis; (ii) combinatorial chemistry; and (iii) diversity-oriented
synthesis.
1.2.
Target-oriented synthesis (TOS)
1
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In a classic manner, synthesis o f small molecules uses target-oriented approach
(TOS)3 and relies primarily on nature to discover useful specific compounds. Lead
compounds are derived from the extraction o f plants, animals, insects, or
microorganisms. After isolation o f the chemical entities responsible for the biological
activity, the structures are characterized by spectroscopic techniques. Once such a
structure has been identified, it becomes a target for chemical synthesis. Targetoriented synthesis (TOS) can be planned efficiently through retrosynthetic analysis,
which breaks down the complex natural product into single construction unit in the
reverse direction starting from simple materials while the implementation of the
synthesis is carried out.
AcO
P t r ^ NH
o
.0
Me,
HO'
BzO
0Ac
OMe
2: Cephalotaxine
1: Taxol
MeO.
Me
H
Me.
HO
Me
Me
H'1':
HQ.
OH
O
,OMe
Me
Me
MeOOC jl
MeO
OAc
N H COOMe
Me
'OH
3: FK506
Figure 1. Examples of complex natural products synthesized by TOS.
2
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Target-oriented synthesis (TOS) has provided a great driving force in developing
efficient synthetic methods in organic chemistry, especially in the development of
stereo- and enantio-selective methods through the use of chiral reagents and catalytic
asymmetric reactions.4 A number o f structurally complex natural drugs have been
synthesized, such as total synthesis o f taxol,5 FK506,6 cephalotaxine,7 and
vinblastine8 (Figure 1). However, this traditional method has been very timeconsuming and very expensive.
1.3.
Solid-phase organic synthesis
By applying combinatorial chemistry, especially solid-phase organic synthesis, it is
possible to obtain large sets o f organic compounds over short periods o f time. Since
solid-phase synthesis was first developed by Merrifield10afor the peptide synthesis in
1963, it has been widely used in the synthesis of peptides and remained mainstay in
this field nearly 40 years. Until 1992, Bunin and Ellman10b reported the synthesis of
the library of 1,4-benzodiazepines on solid-phase, which is the turning point in the
progress o f solid-phase organic synthesis. In the last decade, solid-phase organic
synthesis for small organic molecules has drawn considerable attention and has
become a cornerstone in the combinatorial synthesis of drug-like small organic
molecule library in medicinal chemistry.13b
The advantages of solid-phase organic synthesis are displayed strikingly, including
the following aspects: (i) The ease o f chemistry. The reaction can be accomplished in
a simple repetitive process o f the addition o f regents, filtering, and washing o f resin;
(ii) In a solid-phase synthesis, high concentration of reagents can be used to drive
reactions to completion and achieve high yields. It should be mentioned that the high
concentration o f reagents plays the key role rather than the excess o f reagents; (iii)
The straightforward nature o f parallel solid-phase synthesis; and (iv) Some
3
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innovative methods are available for the manipulation o f discrete compounds and for
“tracking” the identity of compounds when compounds are attached to a solid
support.9 Most importantly, solid-phase synthesis can be applied to the elegant and
powerful “split-pool” synthetic strategy for combinatorial chemistry.100 Split-pool
synthesis is referred to as “one-bead-one-compound approach”, and, in this method,
a collection o f beads is split into reaction vessels that subsequently each receive a
unique set o f reagents, for example, one of a collection of building blocks.15' 17 This
solid-phase, parallel synthetic technique, is most commonly used by medicinal
chemists to synthesize a “focused libraries” of related compounds sharing structural
features necessary for binding to a preselected protein target, allowing the general
principles of retrosynthetic analysis to be applied readily. Over the past few years,
we have observed the impact of solid-phase parallel organic synthesis in the
development o f
high-throughput synthesis of focused libraries in drug
discovery.130,0
More recently, the solid-phase organic synthesis combined with split-pool strategy
has been used to efficiently generate structurally complex and diverse libraries of
synthetic small molecules.21,24,25
1.4.
Diversity-oriented synthesis (DOS)
The third synthetic method of small molecules is diversity-oriented synthesis (DOS),
which is proposed firstly by Schreiberin 2000.19 As described by Schreiber, DOS is
not focused on a given target. It is used for identifying new targets or for
understanding biological functions of new targets. In contrast to target-oriented
synthesis (TOS), diversity-oriented synthesis (DOS) is not aimed at one particular
target and retrosynthetic analysis can therefore not be effective in this context
(Figure 2). It is based upon the forward synthetic analysis and aims to develop novel
4
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methods for efficiently obtaining small molecule libraries with structural complexity
and diversity beginning with simple starting materials and reactions.
(a) Target-oriented synthesis
i— S
a?
o
Begin with: complex structures
End with: simple starting materials
(b) Diversty-oriented synthesis
Retrosynthetic analysis
--------►- Forward synthetic analysis
Begin with: simple starting materials
End with: large collection of structurally complex and diverse compounds
Figure 2. Planning synthetic strategies in target-oriented synthesis (a)
and diversity-oriented synthesis (b).
In contrast to mutation-derived research approach to understand the functions o f a
given target protein, Schreiber defined the technique as chemical genetics approach
in which small molecules can be directly used to modulate (that is, active or inactive)
protein.20 In the genomics and proteomics research, the small molecules will be in
great demand in order to discover novel genes and proteins. Therefore, diversityoriented synthesis leading to small molecule libraries will play an important role in
this area and chemical genetics is providing a driving force for the development of
diversity-oriented synthesis (DOS).
In diversity-oriented synthesis, the goal of achieving structural complexity is o f the
same importance as that of structural diversity in synthetic pathways. Structural
5
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complexity and diversity can be analyzed separately, but these analyses eventually
should be melded . 1 ,2 0
Structural complexity can be achieved via tandem complexity-generating reactions
and conformation analysis. In this planning strategy, the identification o f pairwise
relationships o f complexity-generation reactions, where the product o f one
complexity-generation reaction is the substrate for the second reaction , 2 1 can lead to
high levels o f molecular complexity in a very efficient manner with just a few
synthetic steps. Schreiber et al.21e described the first example of the pairwise use of
complexity-generating reactions as shown in Scheme 1.
H O O C ^ S K ^ N ^ A r , M eO H , TH F
if
48 h (67%)
6
KHMDS
allyl
brom ide
9
8
OM
7
Scheme 1. Solid-phase synthesis o f 7-5-5-7 polycyclic ring system using
complexity-generating reactions by Schreiber et al.
6
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The key step in this strategy is the use o f a tandem Ugi-4 component reaction to give
the product capable of undergoing an intramolecular cycloaddition reaction followed
by the ring closing metathesis. The resin-bound amine 5 was treated with excess
furfural, benzylisocyanide, and fumaric acid (3-bromobenzyl) monocarboxamide to
give the complex Ugi product 7, after an intramolecular Diels-Alder reaction via the
intermediate 6 . Bis-allylation o f the secondary amides was achieved by reaction with
allyl bromide and potassium hexamethyldisilazane. This was then subjected to ring
opening-closing metathesis reaction in the presence of the ruthenium catalyst. The
resin was treated subsequently with HF-pyridine to give the desired poly cyclic
compound 9 in high yield.
The goal o f structural diversity can be achieved through three distinct diversity
elements, that is, appendages (such as building block diversity), stereochemistry, and
molecular skeleton . 1 Incorporating diverse building blocks is the most obvious one.
The simplest diversity-generating process is the central feature o f combinatorial
chemistry and involves the use o f coupling reactions to attach different appendages
to a common molecular skeleton. If a molecular skeleton has multiple reactive sites
with potential for orthogonal functionalities, then the technique of split-pool
synthesis can be used to harness the power of combinatorics (a multiplicative
increase in the number o f products with an additive increase in the number of
reaction conditions), and thereby generate all possible combinations o f appendages
(that is, the complete matrix) efficiently. In this method, cycles o f pooling, respliting,
and further chemistry result in large collection of compounds that are spatially
segregated on unique beads. Split-pool synthesis is analogous to the genetic
recombination. Encoding methods, which are analogous to the genetic code, have
been developed that record the chemical history o f the synthetic compounds,
allowing the structures o f compounds selected in screens to be inferred . 1 9 Therefore,
7
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in genomics and proteomics research, diversity-oriented synthesis will play an
important role.
Structural diversity is one important aspect in diversity. Combinatorial chemistry,
especially split-pool solid-phase synthesis has proven to be a very important strategy
for generating structural diversity in diversity-oriented synthesis (DOS ) . 1 ,1 9 ' 21
Demonstrating the efficient generation of building-block diversity, Shair et al.22
recently reported the synthesis of a library of ~3000 unique small molecules in which
a core skeleton resembling the structure of the natural product Galanthamine was
orthogonally functionalized with four diverse sets of building blocks.
HQ
i- P r
Si— /-Pi
h 2n
1. C H(OCH3)3-CH2CI2,
NaBH 3C N, AcOH
2. allylchloroform ate
3. piperidine, THF
Si—/-Pr
1. Phl(O A c)2
2. P d (P P h 3)4
CHO
11
-<
R4
R3
-<----
O/.
R2
/-Pr
S i—/-Pr
HO'
14
13
Scheme 2. DOS based on galanthamine-like molecules on solid-phase
by Shair et al.
As shown in Scheme 2, the library started with the attachment o f a tyrosine
derivative to 500-600 pM high capacity polystyrene resin through a Si— O bond to
8
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generate 10. Reductive animation and protecting-group adjustments produced 12.
Treatment o f 12 to PhI(OAc ) 2
followed by Pd-mediated deprotection and
spontaneous cyclization afforded 13. Then, four diversity-generating reactions with
various building blocks were performed by ( 1 ) phenolic hydroxyl group alkylation;
(2) an intermolecular Michael-type reaction with thiols in the presence o f «-BuLi; (3)
the secondary amine alkylation or acylation; and (4) an imine formation from the
carbonyl group, to complete a small molecule, natural product-like library with 2527
members of 14 (Figure 3).
OTBS
Figure 3. Building blocks used in the Galanthamine library synthesis.
It was interesting to note that a consecutive series o f four product-equal-substrate
relationships enabled the efficient generation o f a complex molecular library with
four building blocks (Figure 3). After biological screening, one molecule was
identified as a potent inhibitor of VSVG-GFP movement from Golgi apparatus to the
9
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plasma membrane, which was unrelated to the acetylcholinesterase inhibitory
activity o f the natural product, Galanthamine.
Stereochemical diversity increases the number of relative orientations of potential
macromolecule-interacting elements in small molecules. It can be achieved by using
stereo-specific reactions that proceed with enantio- or diastereo-selectivity.
Schreiber et al, 2 3 described an example of combinatorial stereochemical diversity
synthesis o f dihydropyrancarboxamides (Scheme 3), in which both stereo-specific
and enantio-selective stereochemical diversity-generation processes were generated
by a combinatorial matrix o f four stereoiosomeric products.
O
M
'
*
'rTV0Me
3
steps
►
Et°Y°Y^R3
R1'"' T
OM
=2
/-Pr /-Pr
15
16a
O
B0Y ° y A Rs
f I
OM
r2
16b
o
EtO/,, . O ^ A r 3
r 1^
OM
T
p2
O
E t O ^ ( x J l . R3
r a"
16c
OM
Y
r 2 16d
Scheme 3. Asymmetric diversity-oriented synthesis of dihydropyrancarboxamides.
Generating high levels o f skeletal diversity is especially challenging . 1 9 , 2 0 The design
o f branching reaction pathways that result in structures with widely varying
connectivity are highly desirable. In this process, regents are added to reaction
vessels following a split step that causes the skeletal backbone to be altered, rather
than the simple process o f adding regents that couple building blocks to a common
skeletal backbone. There are two different strategies for planning skeletal diversity in
DOS . 1 ,1 9 ,2 0 One involves use o f different regents to transform a common substrate
10
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with the potential for diverse reactivity into a collection of products having distinct
molecular skeletons (regent-based strategy). Another one involves substrate-based
approach, namely
diverse
skeletons
o f small molecules can be accessed
combinatorially by transforming a collection o f substrates having different
appendage. The latter pre-encode skeletal information into a collection o f products
having distinct molecular skeletons using common reaction conditions (substratebased strategy).
Schreiber et al.lA,2lg reported a reagent-based strategy example for the diversityoriented synthesis o f a small molecule library on a tetracyclic template. Using splitpool solid-phase synthesis, combined with the encoding technology, they designed a
large library containing 2.18 million members.
O
o
HO
"'N
PyBOP, DIPEA
NMP, rt
18
17
substituents
\
0
1+
H O O C -^ h k
nucleophilic
attack i
R
1
HATU, DIPEA, rt
electrophilic
capping
capping
I
— reductive N-O
N-0 bond
x -------- ^ cleavage
O
H
\
-
electrophilic
capping
1
O
electrophilic
W
\electrophilic
capping
nucleophilic
attack
nucleophilic attack
capping
Scheme 4. Tetracyclic template from Shikimic acid for the synthesis
o f small molecule libraries.
11
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As shown in Scheme 4, the epoxide derivative o f shikimic acid was attached to
TentaGel-S resin, followed by reaction with various nitrone carboxylic acid
derivatives to give the resin bound tetracyclic template 19. The latter possesses a
high degree of rigidity and multiple reaction centers. It could further be subjected to
a variety o f organic and organometallic reactions for the generation of small
molecule libraries.
As described above, two goals of diversity-oriented synthesis, namely, generating
structural complexity and structural diversity in an efficient manner can be
considered independently. However, achieving high levels o f both complexity and
diversity requires new advances in strategic thinking, integrated forward-synthetic
planning, for example, the incorporation of complexity-generating reactions into
stereochemical and skeletal diversity-generating process.
In genomics and proteomic research, the demand o f small molecules is growing
constantly and largely because these small molecule-based structurally complex and
diverse agents serve as smart, powerful tools both in understanding the roles and
functions of emerging biological targets and in validating their biological responses.
Diversity-oriented organic synthesis, especially coupled with an economical and
efficient technology such as solid-phase organic synthesis (split-pool technique)
offers the means to synthesize complex and diverse small molecules efficiently.
Diversity-oriented synthesis is central to chemical genetics, which aims to explore
biology with small molecules in a systematic way. Therefore, in this genomics and
proteomics age, diversity-oriented synthesis will play an important role in
understanding the function of biological targets.
1.5.
Diversity-oriented approach to solid-phase synthesis of
heterocyclic small molecules
12
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Heterocyclic compounds have received special attention due to their broad range of
biological
activities,
and
many
of pharmaceuticals
and
biological
active
agrochemicals are heterocycles. Therefore, organic chemists have been making
extensive efforts to produce these heterocyclic compounds by developing new and
efficient synthetic methodologies. Substituted heterocyclic compounds can offer a
high degree o f structural diversity and many o f them are useful therapeutic agents.
For this reason, it is not surprising that this structural class has attracted dramatic
interests in medicinal chemistry and combinatorial chemistry.
In addition, many heterocycles are included in the family o f “privileged structures”,
such
as
1,4-benzodiazepines,
quinazolinones,
benzofurans,
indoles
and
benzimidazoles, which represent a class o f molecules capable o f binding to multiple
receptors with high affinity . 2 6 The term of “privileged structures” was first proposed
by Evans et al. in 1988, which was defined as “a single molecular framework able to
provide ligands for diverse receptors”, To medicinal chemists, the true utility of
privileged structures is the ability to synthesize one library based upon one core
scaffold and screen it against a variety o f different receptors, yielding several active
compounds. The exploration of privileged structures is a rapidly emerging theme in
medicinal chemistry. Moreover, the diversity-oriented synthesis of privileged
structures libraries will also play an important role in chemical genetics research.
In recent years, the development o f strategies for generation o f heterocyclic small
molecules on solid-phase has been a hot topic in combinatorial chemistry . 2 6 6
Moreover, the diversity-oriented synthetic strategy for the synthesis of heterocycles
also has been received wide attention due to their important biological activities.
Very recently, several research groups have taken the challenge o f developing solidphase methods for the diversity-oriented synthesis of heterocyclic small molecules.
13
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In 2002, Purandare et al.25b reported a diversity strategy for the synthesis of
heterocycles from o-fluoronitrobenzoic acid. As shown in Scheme 5, in this approach,
six heterocycles were formed from the same intermediate. Displacement of the resinbound 22 with a primary amine gave the intermediate o-nitroaniline 23. Through 3step reactions, quinoxalin-2-one 24 was obtained. To access the remaining five cores,
the nitro group in 23 was reduced to furnish the phenylenediamine 25, which reacted
with different reagents to form the heterocycles 26a-e after cleavage from the resin
(Scheme 6 ). According to this strategy, a large library possessing six different core
heterocyclic derivatives could be synthesized.
21, DIC
NHR1
HOOC.
OMe
N 02
HOAt.DMF
NO.
OMe
OH
X
O
N0 2
3 steps
NH
24
23
Scheme 5. Solid-phase synthesis of quinoxalin-2-ones by Purandare et al.
14
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X
R1HN
X
XX)
26b
26a
OMe
NH2
NH
26c
26d
Scheme 6 . Solid-phase synthesis o f diverse heterocycles by Purandare et al.
Nicolaou et a l}4 reported an example involving reagent-based skeletal diversitygenerating synthesis as shown in Scheme 7. They developed a new solid-phase
selenium-based seamless linker, selenenyl bromide resin 28, which was conveniently
prepared from commercial polystyrene by lithiation followed by selenidation and
oxidation with bromine. Simple loading of various or/ho-prenylated phenols 29
provided functionalized resin-bound benzopyrans 30, which could be strategically
employed for construction of various 2,2-dimethylbenzopyran libraries 31a-e
through the reactions with different regents.
15
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1. n-BuLi
■SeBr
►
2. (M e S e )2
FH-
3. Br2, CHCI3
4 . EtOH
.S e
Me
.OH
Me
R-r
31b
29
-S e
coupling
R‘
•S e
glycosidation
•Me
-Me
Me
Me
31a
addition
sugar-X
Se
Me
X
Me
-S e
-M e
Y
Se
Me
31e
Me
Me
31c
Scheme 7. Strategy for the construction o f resin-bound 2,2-dimethylbenzopyran scaffolds by Nicolaou et al.
For example, the selenide resin-bound benzopyran derivative 32 could react under
either Wittig or Knoevenagel conditions to yield the coumarin derivative 33 after the
oxidative cleavage from the resin. Treatment o f substituted aldehydes with 34 gave
dimethylbenzopyran 35 after cleavage from the resin (Scheme 8 ).
16
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OH
•Se
Me
H
Me
or
O
Me
O
K ^ O M e
[R = Me, Ph]
32
Me
33
or CH2(C 0 2Et)2
NaOMe
Me"
Me
i
Me
CHO
Me
35
34
Scheme 8. Examples for the synthesis of dimethylbenzopyran.
This selenenyl bromide resin also has been used for the synthesis of indoles and
indolines library in solid-phase,25a as illustrated in Scheme 9. Using a resin-bound
selenenyl bromide, o-allyl and o-prenyl anilmes were cycloadded to afford a series of
solid supported indoline scaffolds 37. These scaffolds were then fimctionalized and
cleaved via four distinct methods, namely, traceless reduction, radical cyclization,
radical rearrangement, and oxidative elimination, to afford 2-methyl indoles 38a, 2methyl indolines 38b, 2-propenyl indolines 38c, and polycyclic indolines 38d,
respectively.
17
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oxidative
cleavage
functionalization
radical
cleavage
Se
x -b
functionalization
I
N
H
functionalization
r
1
-----------------------functionalization
37
cyclization
cleavage
SeBr
traceless
, r cleavage
Me
36
38b
38d
Scheme 9. Strategy for the construction o f indole and indoline libraries
by Nicolaou et al.
A strategy o f diversity-oriented synthesis for the synthesis o f pyrrole derivatives was
developed by Jung et al.2$c Rink amide resin was acetoacetylatd with diketene.
Treatment with primary amines resulted in resin-bound enaminones which then
underwent a Hantzsch reaction to form the resin-bound 5-(2’-bromoacetyl) pyrroles
39 (Scheme 10). The latter offers a wide range of possible transformations to afford
different pyrrole derivatives (40a-d).
18
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h 2n
.0
Me'
Me'
MeBr
N'
R3
40a
40d
\
h 2n
Me-
Me-
40c
40b
Scheme 10. Strategy for the synthesis o f pyrroles derivatives
from 5-(2’-bromoacetyl) pyrroles.
Schultz and co-workers25d have developed several strategies for the synthesis of
purine-based compounds with structural diversity at the C2, C 6 , and N9 positions.
Using solid-phase approaches, a few o f libraries containing hundreds to thousands of
purine analogues have been synthesized.
1.6.
Planned studies of this thesis research
This thesis involves the diversity-oriented synthesis o f benzoannelated heterocyclic
compounds. Many benzoannelated heterocyclic compounds such as indoles,
benzimidazoles, and benzofurans, are included in the family o f “privileged
structures” due to their important bioactivities in medicinal chemistry . 2 6 Our efforts
are focused on designing the diversity-oriented synthesis of benzoannelated
h eterocyclic
com p ou n d s
v ia
solution
and
m icro w a v e-a ssisted
solid-ph ase
combinatorial chemistry.
19
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As shown in Figure 4, a new approach was designed for the synthesis o f heterocyclic
compounds
such
as
indoles
43,
benzoxopines
44,
benzofurans
45,
and
benzimidazoles 46. 2-Aminophenols 41 and 2-chloronitrobenzene 42 are two kinds
of inexpensive and commercially available compounds with structural diversity. By
selecting appropriate reaction sequences, a series o f benzoannelated compounds 4346 can be synthesized. This thesis is focused on the synthesis of indole and
benzimidazole libraries.
OH
H2 N -A r
NH2
NO.
42
OEt
/> -*
43
44
45
46
Figure 4. Approaches to diversity-oriented synthesis
of functional heterocyclic compounds.
First, a new protocol for the synthesis o f 2-substituted indoles was proposed starting
from 2-aminophenols 41 for the first time. The key step was to convert 41 to the
corresponding triflates followed by the Sonogashira cross-coupling reactions with
terminal alkynes and the base or metal-mediated cyclization reactions. Since various
nitro-substituted
2
-aminophenols are commercially available, the above coupling-
heteroannulation protocol would be useful for synthesis o f nitrogen-substituted
indoles with high structural diversity. Second, solid-phase combinatorial synthesis of
20
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indole library was planned based on the chemistry of 2-aminophenols. In order to
facilitate solid-phase reactions, microwave irradiation at controlled reaction
temperature would be used. Design and selection o f linkers or spacers are crucial for
converting the solution phase chemistry onto solid supports. Ideally, traceless solidphase synthesis would be advantageous.
Finally, a benzimidazole library was attempted by using the inexpensive 2nitrophenyl chlorides 42 as the starting materials instead of the commonly used 2nitrophenyl fluorides such as 21 used in Scheme 5. Microwave-assisted catalyst-free
amination on solid-support is the key step for the success of the benzimidazole
library synthesis.
21
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Chapter 2
Novel Synthesis o f Indoles via
Sonogashira Cross-Coupling o f
2-Carboxamidoaryl T riflates
2.1.
Introduction
Indoles are probably the most widely distributed heterocyclic compounds in nature.
Synthesis and functionalization o f indoles have been the object of research for over
one hundred years. The first preparation o f indole dates back to 186631e and the
Fischer indole synthesis was first reported in 1883, which remains the m ost versatile
m ethod for preparing indoles.3ld The indole nucleus is a fundamental o f a num ber o f
natural and synthetic products w ith biological activities. For example, one o f a basic
skeleton serotonin (5-hydroxytryptamine, 5-HT) is a very important neurotransmitter,
w hich plays an important role in a num ber o f processes through the activation o f
5-HT receptors . 2 7 A num ber o f natural products containing indole ring have been
identified such as the antitumoral agent Nortopsentins,28athe potent inhibitors o f lipid
peroxidation M artefragin A,28b the peptidal mimetic somatostain agonist,28c selective
doptam ine D 4 receptor agonist cyanoindole derivatives,28d potent and selective factor
X a inhibitors,28e the protein kinase C activator indololactam V 28f as well as
Fum itrem orgin C that has recently been identified as a specific reversal agent for the
breast cancer resistance protein transporter.28®
Indoles possessing a substituent at C2 position are pharm acologically important
s u b sta n c e s and h a v e b e e n rep o rted to e x h ib it a w id e ra n g e o f b io lo g ic a l a c tiv itie s .29
For instance, as illustrated in Figure 5, 2-aryl indoles 47 have been reported as NKi
antagonists,30a and
other
2
-substituted
indoles
have
been
demonstrated
22
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as
nonsteroidal antiflammatory agent 48,30e nonpeptide GnRH receptor antagonists
49,30b analgesic agent 50,30d m elatonin receptor ligands 51,30g h5-HT2A antagonist
52,30f as well as PK C inhibitors 53.30c
MeO.
47:
antagonist
48: indomethacin
nonsteroidal antiflammatory
OMe
Me
X = H, Y = OH
X = H, Y = N H S02Me
X = Me 2 N C(0), Y = OH
r?
50: pravadoline
analgesic agent
49: GnRH receptor antagonists
NHAc
Ph
H
H
51: melatonin receptor ligands
52: h5-HT2A antagonist
53: PKC inhibitors
F ig u re 5. Bioactive compounds containing 2-substituted indole scaffolds.
Due to the rem arkably broad range o f biological activities that have been displayed
by 2 -substituted indoles, the challenges for the synthesis o f indole ring have attracted
the dramatic attention o f organic chemists and m any synthetic m ethodologies have
been developed
for accessing this
scaffold . 3 1
The
classical
Fischer indole
23
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synthesis , 3 ’ 8 and other synthetic methods such as nucleophilic cyclization , 3 ” 1
electrophilic cyclization , 3 ’ 1 reductive cyclization,3lj oxidative cyclization,3lk radical
cyclization,3” cycloaddition and electrocyclization,31™ as well as m etal-catalyzed
indole synthesis 3 ” 3 have been widely used for the construction o f indole ring present
in
drugs
and
other compounds.3la,b Am ong these synthetic
methodologies,
m etal-catalyzed indole synthesis is one o f the most important and effective
approaches to the construction o f substituted indole scaffolds in recent years. Our
interests are focused on developing the synthesis of indole derivatives possessing a
substituent at C2 position starting from commercially available 2-aminophenols. The
key step involves palladium -catalyzed cross-coupling or heteroannulation reaction
sequence.
2.2.
Synthetic m ethodologies toward 2-substituted indoles
Am ong the approaches employing transition metal catalysts, the palladium -catalyzed
cross-coupling/annulation indole ring construction has been extensively investigated.
The previous methods are categorized under the following types: the one-step
interm olecular annulation
cyclization
of
of
2
2-alkynylaniline
-haloanilines and alkynes ; 3 2 the intramolecular
derivatives ; 3 3
and
Heck-type
cyclization
of
2-halo-A-allyl- or vinylanilines , 3 4 and 2-alkynyl-A-alkylideneanilines . 3 5 Here our
interests are focused on the first two types, in which the indole ring is formed
betw een N and C2 bond. In addition, other m etal-catalyzed coupling-annulation (Cu,
Mo) is also covered in this part.
2.2.1.
M etal-catalyzed interm olecular annulation of haloanilides
w ith alkynes
24
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Larock et a/.32a,b developed an excellent m ethod for the synthesis o f 2,3-disubstituted
indoles in 1991, w hich involved the one-pot palladium -catalyzed heteroannulation o f
internal alkynes w ith o-iodoanilines (Scheme 11). The cyclization w as regioselective
w ith unsym m etrical alkynes. This m ethod has been applied to the synthesis of
im portant tryptophan analogs , 3 2 0 the preparation o f psilocin,32d and other bioactive
heterocycles.
Pd(OAc)2, PPh3
(51-98%)
33
R 1 = H, Me, Ts
R 2 ,R 3 = n-Pr, t-Bu, cyclohexyl, TMS, Ph, CH 2 OH, C(Me)=CH2, (CH 2 )2 OH, CMe2OH
Scheme 11. Larock indole synthesis.
V ery recently, Yum et al.32e reported a convenient new route to the synthesis o f
2
-substituted indoles by palladium -catalyzed heteroannulation of o-iodoaniline and
term inal alkynes w ith Pd-zeolite catalyst. Furthermore, it is interesting that the
catalyst could be recycled and recycled w ith good reusability in the heteroannulation
reaction.
In 2001, Kabalka et a l m described a m icrowave-assisted route to 2-substituted
indoles catalyzed by palladium on alum ina from o-iodoanilines w ith 1-alkynes. In
this case, as Y (Scheme 12) was an electron-withdrawing group (amide, sulfonamide),
the reaction occurred in favor o f the indole ring formation. Otherwise, the
coupling-open form o f products existed in various ratios.
25
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Pd-Cul-PPh 3
KF-AI2 0 3
+
Ri ^ - H
—
NHY
7— 7 — 7777^
solventless, MW
f:
t v
r
1
H
56
57
58
Y = H, COCH 3 , COCF 3 , S 0 2 CH 3
R 1 = Ph, p-CH 3 C 6 H4
Scheme 12. Sonogashira coupling and cyclizations on alumina.
Copper combined w ith palladium was also beneficial to the form ation o f indoles via
annulation. Yamanaka et al.32g reported a one-step synthesis o f 2-substituted
1-methylsulfonylindoles
from
A/-(2-halophenyl)
m ethanesulfonam ides
in
the
presence o f Pd(II)-C uI, which tolerated different functional groups such as
hydroxymethyl, diethoxymethyl at the C2 position (Scheme 13). This m ethod has
been successfully used in the solid-phase synthesis o f 2 -substituted indoles.32h
Pd(PPh 3 )2 CI2, Cul
+
r—
—h
------------------------------- ►
N H S 0 2Me
59
r
][
(31E,7^ %)
60
61
S 0 2 Mg
R = TMS, n-Bu, Ph, CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 C 0 2Et
Schem e 13. Pd(II)-Cu(I)-catalyzed cyclization toward indole synthesis.
A
palladium -m ediated,
one-pot,
m ulti-component
coupling
approach
to
2,3-disubstituted indoles was reported by Flynn et al.32lJ It was noted that this
process involved initial deprotonation o f o-iodoacetanilides and
1
-alkynes with
m ethylm agnesium chloride, followed by cross-coupling to afford the intermediate 64
(Scheme 14). Then oxidative addition o f aryl iodide to Pd(0) took place and it was
followed by Pd(II)-induced cyclization and reductive elimination to give the indole
26
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6 6
in 85% yield. If CO (g) was used to exchange the N 2 (g) at the point of
introduction o f aryl iodide, the product obtained was the C3-carbonylated indole. The
desired indole was proved to be a tubulin polymerization inhibitor. Using this m ethod
the benzofuran analogs also can be accessed readily starting from o-iodophenols.
■ O M e-1
OMe
M eM gC I (2 e q )
jfY
NHAc
M eO -
N -M gC I
Ac
62
63
64
Ar-I
.OMe 1
I— P d A r
c y c liz a t io n
OMe
r e d u c tiv e
elim in a tio n
M eO ’
M eO -
N -M gC I
Ac
66
A r = 3 ,4 ,5 -t r im e t h o x y p h e n y l
65
Scheme 14. One-pot multi-component coupling approach to indoles.
M ore recently, Cacchi et al.32k described a copper-catalyzed coupling-cyclization
process for 2 -arylindole synthesis from o-iodotrifluoroacetanilides w ith
1
-alkynes in
a single step (Scheme 15). The reaction proceeded smoothly and appeared to tolerate
a w ide range o f functionalized
1
-alkynes, including those containing ether, amide,
aldehyde, ester, nitro, and heterocyclic groups.
27
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i
a
[Cu(Phen)(PPh 3 ) 2 NO 3
*
C
NHCOCF 3
TV-f
K3 PO4 , tolune, 110 °C
or Cul, PPh3 K3 PO 4 , dioxane
^
67
68
Schem e 15. A domino copper-catalyzed coupling-cyclization process to indoles.
2.2.2.
M etal-catalyzed intram olecular cyclization of
2-alkynylanilines
2-Alkynylaniline derivatives have been reported as the m ost common starting
m aterials tow ard indoles, w hich could be obtained through the Sonogashira
cross-coupling
2
reaction
of
2-haloanilines
w ith
1-alkynes . 3 6
Cyclization
of
-alkynylaniline derivatives provided a versatile synthesis o f indoles and several
variants o f the reaction have been reported.
Early in 1980s, Yamanaka et al. reported an efficient approach using a base to yield
indoles as shown in Scheme 16.33a‘c 2-Bromocarbanilate 69 underwent Sonogashira
cross-coupling
reaction
catalyzed
by
a
palladium -copper
system
to
give
2-alkynylcarbanilate 70, which was subjected to ring closure reaction in the presence
o f sodium ethoxide to afford indoles
6 8
.
R
Br
Pd(PPh 3 )2 Cl2
1. NaOEt
►H i
N H C 0 2Et Cul, Et3 N, heating
69
^ ^ ^ M H C O z E t Z H2°
70
►I
I N
)-R
Ov IQ
»
£j
68
Schem e 16. A base-catalyzed approach to indoles by Yamanaka et al.
Later on, the base-m ediated 5-endo-dig cyclization o f 2-alkynylanilines was proved
to be also effective with other bases such as potassium or cesium alkoxides.33d,e
28
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Palladium -catalyzed cyclization o f 2-alkynylanilines to yield indoles has been
reported as a versatile m ethod . 3 3 1 "1 The prototypical reaction is shown in Scheme 17,
in which Pd(M eCN) 2 Cl2 or PdCl 2 was frequently used as the catalyst.
Pd(ll)
f
V _r2
MeCN
reflux
N
R1
73
*1
R1
74
R 1 = H, Ac, COOMe
Schem e 17. Pd(II)-catalyzed cyclization o f 2-alkynylanilines.
The m echanism for this cyclization undoubtedly requires nucleophilic attack by
nitrogen on the Pd(II)-com plexed alkyne to give 3-indolylpalladium 73 species.
Cleavage o f the palladium -carbon bond gave the indole 74 and regenerated the
palladium (II) catalyst. The cyclization proceeds without the need to reoxidize the
m etal and is m ost efficient w ith aliphatic substituents on the alkynyl terminus.
Recently, Barleuenga et al.33n described a process to synthesize 3-iodo-functionalized
indoles prom oted by iodinating agent IPy 2 BF 4 as shown in Scheme 18, which
required a simple activation o f the iodinating agent by HBF4. A tentative m echanism
assum ed a reaction path that implies an initial interaction o f electrophilic iodine with
2-alkynylanilines 75 to give the intermediate 76. Subsequent nucleophilic attack of
the nitrogen w ould lead to ring-closure. Only one equivalent o f the acid was used to
activate the regent in this reaction, therefore the second pyridine molecule m ight help
to rem ove a proton from the nitrogen atom in 77, giving the indoles 78. The desired
3-iodoindoles could be transform ed into other products through cross-coupling
reaction such as Suzuki cross-coupling, and Sonogashira cross-coupling reactions.
29
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This strategy has also been applied to solid-phase synthesis o f indoles.
R2
NHR 1
BF,
75
+
IPy2BF4/HBF4
H, S 0 2 Me, C 0 2 f-Bu
I
R3
-PyHBF 4
V
N
BF4
R
+V
R 2
A-
R
78
A
r2
^
H
N
Py
77
Schem e 18. IPy 2 BF 4 -promoted intramolecular cyclization to indoles.
M ore recently, Larock et al.33° reported a new approach to 3-iodoindoles involving
the palladium /copper-catalyzed coupling o f N.A-dialkyl-o-iodoanilines and terminal
alkynes, followed by electrophilic cyclization prom oted by h at room tem perature to
give indoles in good yields. This iodocyclization process also readily accom modated
a w ide variety o f functional groups on the alkyne moieties. Knight et al.33f> also
reported an efficient approach to 3-iodoindoles, which involved the sequential
Sonogashira cross-coupling o f 2-haloanilides with terminal alkynes and 5-endo-dig
iodocyclization prom oted by h in the presence o f K 2 C 0 3. Azaindoles also could be
obtained using this method.
C o p p er c a ta ly sts h a v e draw n c o n sid e r a b le a tten tion in o rg a n ic sy n th e s is d u e to th eir
inexpensiveness and readily availability. Lamas et al.33q reported a Cul-m ediated
cyclization o f 2-[(trimethylsilyl)ethynyl]anilines in 1996, in which the substrates
30
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w ere the unm asked anilines. Saulnier et al.33r first reported the Cu(OAc)2-promoted
cyclization of 2-ethynyltrifluoroacetanilide. Later, in 2002, H iroya et o/.33s,t described
an efficient procedure for the indole ring synthesis from 2 -alkynylanilines catalyzed
by Cu(II) salts (Schem e 19). This Cu(II)-catalyzed reaction can be applied to not
only the sulfonamides, but also the unsubstituted primary and secondary aniline
derivatives. It was possible to realize the sequential cyclization reaction o f the
2-alkynylaniline derivatives that have the electrophilic moieties in R2. But the
m ethod was lim ited to the five- and six-membered ring for the second cyclization.
CuX2
►
NHR
R 1 = H, Ms, COOEt
79
'-€ X >
r2
82
X = OAc, OTf
4
Cu
C u -X
NHR
80
Schem e 19. Cu(II) salts-catalyzed cyclization o f 2-alkynylanilines.
Tetrabutylamm onium fluoride was proved to be a convenient catalyst prom oting the
cyclization o f 2 -alkynylanilines to give indoles.33u
M cDonald et al.33v described a group VI m etal-promoted cyclization o f 2-alkynyl
anilines to form the indoles. This high-yielding cycloisomerization could be
accom plished m etal m olybdenum (Mo) carbonyl reagent. This indole synthesis is
31
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favored not only by the therm odynam ic stability o f the aromatic products, but also by
the reduced basicity o f the aniline precursor relative to aliphatic amines.
Cacchi et a/.33w described an approach using the aminodopalladation/reductive
elim ination domino reaction to synthesize 2,3-disubstituted indoles, w hich started
from o-triflluoroacetanilide and aryl halides, triflates, and allyl esters etc. The typical
reaction is shown in Scheme 20. The reaction m ost probably proceeded through the
interm ediacy
of
the
( n 2 -alkyne)organopalladium
complex
84— form ed
by
coordination o f the alkynes to an organopalladium complex generated in situ— that
underw ent an intramolecular nucleophilic attack by the nitrogen atom across the
carbon-carbon
triple
bond.
Subsequently,
the
resultant
o -indolylpalladium
interm ediate 85 afforded the desired indole product by a reductive elimination step
that regenerated the palladium catalyst.
R
Pd(PPh3)4, CsCQ 3
R X
NHCOCF
M e C N ,1 0 0 °C
H
86
83
R = H, alkyl, vinyl, aryl, heteroaryl
X = aryl and vinyl halide or triflate, alkyl halide, allyl ester
-Pd(0)
-CF3COOH
\
,R 1
-HX
NHCOCF
co cf3
84
85
Schem e 20. Cacchi’s approach to indole synthesis.
32
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In the presence o f the third component o f carbon monoxide, indole derivatives
containing an acyl group at C3 were readily yielded under the above reaction
conditions . 3335 This m ethod has been adapted to a solid-phase synthesis for the
preparation o f indole library 3 3 7 and also was successfully applied to the synthesis o f
bioactive m olecules such as arcyriaflavin A and the potent antitumor agent
rebeccam ycin.33z
In conclusion, the m etal-catalyzed coupling-annulation indole synthesis has been
w idely used in the synthesis o f indole scaffolds. It is notable that the approaches
described
above involve the sequential cross-coupling o f
2
-haloanilines
or
2-halonitroanilines w ith terminal alkynes. The corresponding aryl triflates have not
been widely used in indole synthesis. Therefore, as an extension o f the palladium catalyzed synthesis o f indole derivatives, w e designed an efficient strategy toward
the synthesis o f substituted indoles involving Sonogashira cross-coupling o f aryl
triflates obtained from 2 -aminophenols.
2.3.
Results and discussion
To the best o f our knowledge, 2-alkynylanilines are commonly synthesized from
2
-iodoanilines w hich are prepared by iodination o f anilines w ith iodinating agent
(IPy 2 BF 4 ) . 3 7 2-Bromoanilines can be used in the cross-coupling reactions w ith low
yields under harsh reaction
conditions . 3 8 ®’13 The electron-deficient 2-nitroaryl
chlorides and bromides are the alternative substrates which exhibit reasonably good
reactivity
toward
the
comm ercially available
Sonogashira
2
cross-coupling
reaction . 3 9
However,
the
-aminophenols have not been used for the synthesis o f
indoles.
In order to attain structural diversity o f indoles, we designed an approach for the
synthesis of substituted indole libraries using
2
-aminophenols as the starting
33
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materials. The key step involved the cross-coupling reaction o f aryl triflates which
w ere prepared from 2-aminophenols, as illustrated in Scheme 21.
R1
, / V
x-rr
liv^
° H
Tf2 Q, Et3 N ^
s'N H
CH 2 CI2, 0 °C
OTf
xJ t T Y ' U ' T
► *
A
4-6 h
O'
88
NH
Pd(PPh 3 )4 , Cul
► X-Hadditive
Et3 N-MeCN (1:5)
O
89
A
f-BuOK, NMP
selective
acylation
OH
NH 2
60 °C,
6
h ,
OTf
c o 2r
89'
< x H>
91
87
Scheme 21. Synthetic approach to substituted indoles.
A variety o f 2-aminophenols are commercially available and relatively inexpensive.
They are the excellent starting materials for indole library synthesis after
m odification o f the phenolic hydroxyl group, for the cross-coupling reaction w ith
1-alkynes. 2- Am inophenols w ere selectively A-acylated to give the aryl amides
8 8
,
using three acylation methods: (i) heating with 3-butyryl-l,3-thiazolidine-2-thione in
refluxing THF for 50 h ; 4 0 (ii) treating with butyryl chloride in the presence of N aH in
THF at room tem perature; and (iii) treating with butyryl chloride and pyridine at
room tem perature (Table 1). Butyryl chloride was selected for the reason that the
resultant amides exhibited relatively good solubility in common organic solvents.
2-Carboxam idophenyl triflates 89 were obtained in good yields by treating o f amides
8 8
w ith 1.1 equiv. o f Tf20 and 1.3 equiv. o f EftN in dichloromethane at 0 °C for 4 -6
34
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h (Table 1).
Table 1. IV-Acylation o f 2-aminophenols and formation o f triflates
Entry
87: Xa
1
87a: H
8 8
2
: Yield (%)
89: Yield (%)
a: 95b
89a: 94
87b: 5-Me
8 8 b :9 6 b
8 9 b :90
3
87c: 6 -Me
8 8
c: 98 b
89c: 96
4
87d: 5,6-(CH 2 ) 2
8 8
d: 88b
8 9 d : 88
5
87e: 4-C1
8 8
e: 89b
89e: 77
6
87f: 6 -S 0 2Et
8 8
f: 95'
89f: 62
8
87g: 4,6-M e 2
8 8
g: 89b
89g: 93
9
87h: 5-OMe
8 8
h: 96d
8 9 h :96
i: 91c
89i: 82
1 0
8 8
87i: 2-NH 2 ,3-OH (Py)
8 8
aIndole skeleton num bering was used here.
bHeated w ith 3-butyryl-l,3-thiazolidine-2-thione for 50 h in refluxing THF.
cReaeted w ith butyryl chloride in the presence o f sodium hydride at rt.
dReacted w ith butyryl chloride in the presence o f pyridine at rt.
Vinyl and aryl triflates have been widely used in organic synthesis due to their
excellent reactivity . 4 1 Palladium-catalyzed cross-coupling reaction o f vinyl and aryl
triflates w ith alkynes, alkenes, and organometallic regents have been proved to be a
powerful m ethod for the carbon-carbon bond formation in organic synrhesis . 4 1 Aryl
triflates have been reported to undergo the Sonogashira cross-coupling reaction with
1-alkynes under the Pd(0)-C ul catalysis in the presence of base . 4 2 It is known that a
2-alkoxycarbonyl group presented in the aryl and vinyl triflates such as 89’ (Scheme
21) did not show any inhibitory effect on the cross-coupling reaction.42d’h Selective
stepwise cross-coupling o f naphthalene 2,3-bistriflate w ith two different 1-alkynes
w as also achieved without difficulty 42b,c
W e used 2-carboxamidoaryl triflates 89 to react w ith terminal alkynes catalyzed by
35
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Pd(PPh 3 )4 -C u I in M eCN to form 2-alkynylanilides 90. In this reaction, we observed
a rem arkable additive effect as shown in Table 2. In the absence o f an additive, the
reaction o f triflate 89a w ith phenylacetylene initially proceeded in Et3 N -M eC N (1 :5)
at 20 °C to form 90a, but it stopped at about 30% conversion o f 89a. W hen 1.0-1.5
equiv. o f w-Bu4 N B r was added, the isolated yield o f 90a increased from 29% to ca.
60% (entries 2 -3 , Table 2). Improvement o f the product yield w as also observed
w hen «-Bu 4NI was used (entries 4 -7 , Table 2). Conversion o f 89a completed within
24 h in the presence o f over 1.0 equiv. o f 77 -BU4 NI to provide 90a in 84-91% yield
(entries 5-7). A sim ilar result was obtained for « - B u 4N C1 (entry
8
). These data
indicated that iodide is a better additive than bromide. W e also examined other
palladium catalysts such as Pd(PPh 3 ) 2 Cl2 (entry 9), Pd(PhCN) 2 Cl2 (entry 10), and
Pd(OAc ) 2 (entry 11) and found that the cross-coupling reaction almost did not occur
in the presence of iodide or bromide without PPI1 3 . Therefore, Pd(PPh 3 ) 4 was proved
to
2
be
the
m ost
favorable
catalyst
precursor
for
the
cross-coupling
-carboxam idophenyl triflates w ith 1 -alkynes.
36
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of
Table 2. Effects of additives on the cross-coupling o f triflate 89a with
phenylacetylenea________________________
Entry
Additive (mol%)
/(h )
90a: yield (%)
1
None
17
29
2
«-Bu4N B r (100)
24
58
3
«-Bu4N B r (150)
24
62
4
«-Bu4NI (50)
24
56
5
«-B u4NI (100)
24
84
6
n-Bu4NI (150)
24
91
7
«-B u4NI (300)b
15
91
8
m-Bu4 NC1 (150)b
24
90
9
n-Bu4NI (300)°
36
82
1 0
n-Bu4NI (300)d
24
2
11
«-Bu4N B r (100)e
43
5
aCarried out w ith 10 mol% Pd(PPh 3 ) 4 and 30 mol% Cul in EtsN -M cCN (1:5)
at 20 °C under nitrogen.
b20% Cul was used.
cPd(PPh 3 ) 2 Cl2 w as used to replace Pd(PPh 3 ) 4 .
dPd(PhCN) 2 Cl2 and 20% Cul were used.
ePd(OAc ) 2 was used.
As illustrated in Scheme 22, parallel experiments w ith the meta analog 92 o f the
2-carboxam idophenyl triflate 89a (X = H) was carried out. The triflate 92 could not
undergo cross-coupling reaction at 20 °C without or with an additive. However, the
cross-coupling proceeded smoothly w hen refluxing for 6-9 h without an additive.
There was no difference when adding «-Bu4NI to the reaction at refluxing
tem perature. These data confirmed that the 2-carboxamido group in triflates 89 is the
origin o f the halide anion additive effect. Although chloride anion also showed the
same effect on the cross-coupling reaction (entry
8
, Table 2), w e used the iodide as
37
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the additive in our reactions due to lower cost and ease o f handling. n-Bu 4 NCl is
m uch m ore hygroscopic than M-BU4 N I.
Pd(PPh3)4, Cul
Et3N-MeCN (1:5)
(see Table 3)
92
93
Schem e 22. Cross-coupling reaction o f phenylacetylene with 3-carboxamidophenyl
triflate 92.
Table 3. Effects o f additive on the cross-coupling reaction o f triflate 92
Entry
Additive (mol%)
1
None
2
m-B u4NI
3
T(°C),t(h)
93:
Yield (%)
20, 24
(95)a
2 0 ,2 4
(89)a
«-Bu 4 NC1 (150)
20, 24
(90)a
4
None
reflux,
5
None
reflux, 9
95
6
77-B U 4 N I
reflux,
91
(150)
(150)
6
6
90
aRecovered starting materials.
M oreover, w e also investigated the influence o f other A-protected groups on the
cross-coupling reaction (Scheme 23). 2-Aminophenyl iodide readily underw ent the
Sonogashira cross-coupling reaction using 10 mol% Pd(PPh 3 ) 4 and 30 mol% Cul at
20 °C without an additive (entry 2, Table 4). In contrast, unprotected 2-am inophenyl
triflate could not undergo the same Sonogashira cross-coupling reaction under the
same conditions (entry 1, Table 4). W hen the additive «-Bu 4 N I was used, the
38
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cross-coupling reaction also did not occur. 2-Aminophenol was jY-acylated by Boc-,
BnO CH 2 CO-, and PhCO- group, respectively, to give the amide intermediates. The
latter reacted w ith Tf20 in the presence of a base to give triflates 94b-d. W e found
that the cross-coupling reactions o f triflates 94 b -d proceeded successfully w ith 10
m ol% Pd(PPh 3 ) 4 , 30 mol% Cul, and 150 mol% n-Bu 4 N I in good yields (entries 3-5,
Table 4). W hen the additive was not used in the cross-coupling reaction o f the
Boc-protected substrate 94d w ith phenylacetylene, the yield decreased from 65% to
39% (entry 5, Table 4). These data further confirmed that the acyl group in
2
-carboxyamidophenyl triflates 89 and 94b -d is the origin o f the additive effect.
Com plexation o f the amide carbonyl group with Pd(0) m ight help in the oxidative
addition step so that the reaction took place at room temperature.
Pd(PPh3)4 , Cul
Et3N-MeCN (1:5)
R
n-Bu4NI, 20 °C
R
95
94
Schem e 23. Cross-coupling reaction o f 94 possessing different
iY-protecting groups.
39
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T able 4. Influence o f iV-protected group on cross-coupling reaction®
Entry
94: R
/(h )
95: Y ield (%)
1
94a: H
24
2
94a: Hb
2
95a: 98
3
94b: PhC(O)
24
95b: 71
4
94c: B n 0 C H 2 C (0)
24
95c: 90
5
94d: /-BuOC(O)
24
95d: 65°
95a: 0
aCarried out with 10 mol% Pd(PPh 3 )4 , 30 mol% Cul, and 150 mol%
n -B u N Jin Et3 N -M eC N (1:5) at 20 °C under a nitrogen atmosphere.
bThe substrate is 2-aminophenyl iodide. No additive was used.
°When « -B uN4I was not used, the yield w as 39%.
It has been reported that halide could affect the transition m etal-catalyzed
cross-coupling reaction o f aryl halide.43b,c In 1996, Powell et al.42f reported an iodide
acceleration in the Sonogashira cross-coupling reaction o f aromatic 1,2-ditriflates
w ith alkynes. O ur data obtained above also confirmed this point.
It is highly possible that complexation o f the acyl group with the Pd(II) species 94’
possessing a triflate anion ligand, which was formed in the oxidative addition step o f
the catalytic cycle, m odifies the chemical and/or physical properties o f the complex.
Iodide anion m ay act by replacing the triflate anion in the square-planar Pd(II)
complex or to form a new penta-coordinated anionic palladium species , 4 3 1 ’ ’0 which
m akes the following transm etalation or reductive elimination occur easily. It is clear
that the iodide anion does not activate the Pd(0) species for oxidative addition to the
triflates 89 because the cross-coupling reaction proceeds without added iodide anion
in the initial stage. The catalyst becam e poisoned by the triflate anion as the
cross-coupling reaction progressed.
40
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T able 5. Synthesis of 2-alkynylanilides from 2-carboxamidophenyl triflatesa
Entry
89: Xb
R1
1 (h)
1
89a: H
Ph
24
90a: 91
2
89b: 5-Me
Ph
2 2
9 0 b : 96
3
89c: 6 -Me
Ph
2
90c: 97c
4
89d: 5,6-(CH 2 ) 4
Ph
1 0
9 0 d :95
5
89e: 6-C1
Ph
6
90e: 89
6
89f: 6 -S 0 2Et
Ph
3
90f: 87
7
89g: 4, 6 -Me 2
Ph
24
9 0 g :7 1 c
8
89h: 5-OMe
Ph
24
9 0 h : 81
9
891: H(7-aza)
Ph
2
90i: 97
1 0
89a: H
«-Pr
3
90j: 98
11
89a: H
SiMe 3
3
90k: 89
1 2
89f: 6 -S 0 2Et
«-Pr
0.5
901: 90
13
89i: H(7-aza)
n-Pr
2
90m : 98
14
89c: 6 -Me
n-Pr
24
9 0 n : 71
15
89d: 5,6-(CH 2 ) 4
«-Pr
6
9 0 o :97
90: Yield (%)
aCarried out w ith 10 mol% Pd(PPh3)4, 30 mol% Cul, and 150 mol% «-Bu4NI
in Et 3 N -M eC N (1 :5) at 20 °C under a nitrogen atmosphere.
bIndole skeleton numbering was used.
cThe cross-coupling reaction was carried out at refluxing temperature.
In
the
presence
2-alkynylanilides
o f the
from
additive
«-Bu 4 NI,
we
synthesized
2-carboxamidophenyl triflates
89 via
a num ber
of
Pd(PPh 3 )4 -C u I-
catalyzed cross-coupling reaction. The reactions tolerate the electron-rich and
electron-deficient substituents on the benzene ring. The results are shown in Table 5.
The electron-rich substituents deactivated the triflates and the reactions proceeded at
41
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refluxing tem perature (entries 3 and 7, Table 5). In contrast, the electron-deficient
substituents activated the triflates so that the reaction times shortened significantly at
20 °C (entries 5, 6 , and 12, Table 5).
Cyclization reaction o f 2-alkynylanilides 90 to indoles was examined under different
conditions using Pd(OAc ) 2 and Pd(PPh 3 ) 2 Cl2 , unfortunately, the ring closure almost
T able 6 . Synthesis of indole from 2-alkynylanilidesa
Entry
90: Xb
R1
91: Y ield (%)
1
90a: H
Ph
91a: 81
2
90b: 5-Me
Ph
9 1 b : 81
3
90c: 6 -Me
Ph
91c: 84
4
90d: 5,6-(CH 2 ) 4
Ph
91d: 81
5
90e: 6-C1
Ph
91e: 81
6
90f: 6 -S 0 2Et
Ph
91f: 76
7
90g: 4, 6 -Me 2
Ph
91g: 78
8
90h: 5-OMe
Ph
91h: 81
9
90i: H (7-aza)
Ph
91i: 96
1 0
90j: H
n-Pr
91 j:
11
90k: H
MeaSi
91k: 93 (R 1 = H)
1 2
901: 6 -S 0 2Et
n-Pr
911: 91
13
90m: H (7-aza)
n-Pr
91m: 90
14
90n: 6 -Me
n-Pr
91n: 93
15
90o: 5,6-(CH 2 ) 4
n-Pr
91o: 85
8 6
“Cyclization was carried out in the presence o f f-BuOK (1.2 eq) at 60-80 °C
for 6 - 8 h.
bIndole skeleton num bering was used.
42
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did not occur. For this reason, we tried to use the alkoxide as the mediator.
Intramolecular cyclization of 2-alkynyanilides 90 proceeded smoothly upon exposure
to /-BuOK (1.2 equiv.) in l-m ethyl-2-pyrrolidinone (NMP) at 60 °C for 6 h to
provide indoles 91, whose acyl group was rem oved presumably after the indole ring
was formed.336 The results are listed in Table 6. The SiMe 3 group was lost during the
indole cyclization to give indole 91k.
2.4.
Conclusion
In summary, w e have developed a novel and general synthesis o f 2-substituted
indoles from commercially available and inexpensive 2-aminophenols. By taking
advantage o f the structural diversity o f these 2-aminophenols, this approach enables
synthesis o f indole compound library possessing diverse structural variation on the
benzene ring. The key step o f our approach relies on the successful cross-coupling of
2-carboxam idoaryl triflates readily synthesized from 2-aminophenols through IV-acyl
protection followed by treatm ent w ith trifluoromethanesulfonic anhydride. A
rem arkable rate enhancement was observed for the Sonogashira cross-coupling
reactions o f 2-carboxamidophenyl triflates with terminal alkynes in the presence of
iodide anion. This finding is useful for understanding the reaction m echanism o f the
related cross-coupling reactions in the presence o f halide additive. Potassium
feri-butoxide-m ediated cyclization reaction o f 2-alkynylanilides proceeded smoothly
under m ild reaction conditions to give the desired 2-substituted indoles in good to
excellent yields. Therefore, substituted 2-aminophenols have been demonstrated as
the useful building blocks for a diversity-oriented approach to indoles.
43
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Chapter 3
Palladium-Catalyzed Synthesis o f
C4, C5, C6, and C l Nitrogen
Substituted Indoles
3.1.
Introduction
N itrogen-substituted indoles have been proved to exhibit a broad range o f biological
activity.
For
example,
the
indole
sulfonamides
are
a kind
o f important
pharm aceutical tem plate in drug discovery as they incorporate two important
pharm acophores in the structures: the indole nucleus and the sulfonamide moiety. As
illustrated in Figure 6, the C4 nitrogen-substituted indole, SDZ-216525 (96), is a
5
-HT 7 selective agonist.44 Delavirdine (97), is one o f the non-nucleoside reverse
transcriptase inhibitors (NNRTIs) approved for HIV therapy.45 Zafirlukast (98) is an
LTD4
antagonist effective against exercise-induced asthma, in antigen-induced
bronchospasm,
and
for
protection
in
cold-air
challenge
studies.46 The
A-(7-indolyl)benzenesulfonam ide E7070 (99), was reported to be in phase I clinical
trials for anticancer activity and is thought to affect the progression of the cell cycle
in the G1 phase w ith inhibition o f expression o f cyclin E and phosphorylation of
cdk2.47 Some indole compounds possessing sulfamoyl group such as tryptamines,
including sumatriptan, CP-122, 288, avitriptan, and almotriptan have been used in
clinic as the anti-migraine drugs.48 Other indoles containing nitrogen substituents
such as nitroindoles derivatives also exhibit biological activities. It was reported that
indole derivatives 101 containing a nitro group in the C4-, C6-, and C7-position,
respectively, exhibit high affinity and selectivity for melatoninergic binding sites
MTi, MT2, or MT3.49Another C5 nitrogen-substituted indole, LY334370 (100), is a
44
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selective 5-HTiF receptor agonist.50 It was reported to be a potent inhibitor o f
neurogenic dural inflammation and was tested for treatment o f m igraine although it
was suspended from phase III clinical trial due to non-mechanism based liver
toxicity.
)=\
Me
HN— (
Mev
O
H
Me
N
O O
' O HK
H
96: SDZ-216525
97: Delavirdine
MeO
,CL
cri
H
NH
Me
98: Zafirlukast
99: E7070
Me
NHCOMe
MeO„
:w
O N
2
H
Y (H ,M e )
101: MT 1 MT2 ior MT3 affinities
100: LY334370
Figure 6. Selected examples of bioactive nitrogen substituted indoles.
D ue to their im portant biological activities, various methodologies to access these
scaffolds
have
been
investigated.
The
synthesis
of
AL(7-indolyl)
45
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benzenenesulfonam ide library was reported by Owa et al.41c for the discovery of
potent cell cycle inhibitors. Bosch et a/.48 described the synthesis o f tryptam ine-like
indoles possessing a sulfamoyl group, which involved the Grandberg m odification of
the
Fischer
indolization
and
intramolecular
Heck
reaction
of
stable
o-halotrifluoroacetanilides.
Recently,
Preobrazhenskaya et
al.51 reported
the
synthesis
o f (indol-3-yl)-
m ethanesulfonam ide and its 5-methoxy derivative. Two methods w ere elaborated
based on the “switching o f f ’ the reactivity o f the indole nucleus in the intermediates
by using indoline or indoxyl compounds. (2,3-Dihydroindol-3-yl)-m cthanesulfonic
acid
was
the
key
compound
used
in
the
indole-indoline
approach
and
(l-acetyl-3-hydroxy-2,3-dihydroindole-3-yl)-A '-(ter/-butyl)-m ethanesulfonam ide
was the key intermediate w hen 1-acetylindoxyl was used as the starting material.
The nitro group is one o f the most useful and versatile functionality, which can be
converted into m any other derivatives. Therefore, nitroindoles are attractive
precursors in the synthesis o f m ore elaborated molecules such as sulfamoylindole
derivatives, pyrrolo[2,3-6]indole,55a arcyriarubin etc.55b There are a num ber o f
reported methods for the synthesis o f nitroindoles such as direct nitration of indole
derivatives,550 Fischer cyclization of nitro-substituted starting m aterials,55di Bergman
approach,55k n Sundberg m ethod,55a and other cyclization approaches. Am ong these
synthetic methods toward nitroindoles, low yields and form ation o f m ixtures of
nitroindoles w ere frequently observed.
To
the
best
of
nitrogen-substituted
our
knowledge,
group
on
the
the
synthesis
benzenoid
of
ring
indoles
skeleton
possessing
via
the
palladium -catalyzed coupling-heteroannulation reaction has not been reported. In
connection w ith our studies on diversity-oriented synthesis o f bioactive heterocycles
from readily available commercial reagents,52 we extended the study to develop an
46
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efficient methodology for construction o f indole libraries containing nitrogen
substituents on the benzenoid ring skeleton using 2-aminophenols as the staring
materials.
3.2.
Results and discussion
3.2.1.
Synthesis of arenesulfamoylindole derivatives at C4, C5,
C6, and C7 positions
In order to achieve the diversity o f our indole libraries, we designed a novel synthetic
approach to the synthesis o f nitrogen-substituted indoles. According to the
palladium -catalyzed coupling-heteroannulation methodology to the 2-substituted
indoles as described in the previous Chapter,52 three commercially available 2-amino
nitrophenols, i.e. 2-amino-5-nitrophenol 102a, 2-amino-4-nitrophenole 102b, and
2-am ino-3-nitrophenol 102c, were used as the starting materials for the synthesis o f
C5, C6, and C7 nitroindoles and related derivatives (Scheme 24).
Selective iV-acylation o f the amino group in 102 was carried out by treatm ent with
butyryl chloride in the presence o f pyridine in refluxing THF to give 103. In our
initial experiments, N aH was used as the base in acylation o f 2-am ino-3-nitrophenol
102c, but the yield was lower (60%) after refluxing in THF for 24 h. W hen using
pyridine as the base, the acylation yield o f 2-amino-3-nitrophenol 102c increased
from 60% to 80%. The triflates 104 were readily prepared by treating the amides
w ith Tf20 in the presence o f a base (Table 7). Am ong them, 104a and 104b were
prepared in the presence o f NaH as the base in yields o f 87% and 80%, respectively.
But, 103c did not w ork well when using NaH as base; therefore, 104c was prepared
using triethylam ine as the base in acetonitrile in 94% yield.
According to the cross-coupling reaction conditions described in Chapter 2, the
Sonogashira cross-coupling reactions o f nitro 2-carboxamidophenyl triflates 104
47
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with 1-alkynes were carried out. The electron-withdrawing nitro group makes 104
n -P rC O C I, P y
4 1
T f20 . b a s e
( ^
^
--------- ° 22Nf I N H ---------►
022 N-F I
Wu
T H F , r eflu x
M e C N , - 5 - 0 °C
0 2 N -H \ A
OTf
6h
102a-c
103a-c
104a-c
HN-fj
MO
0
P d ( P P h 3)4 C u l, n -B u 4NI
"N
H
— s '*
E t3N -M e C N (1 : 5 )
108
rt, 0 . 5 - 1 h
f-B u O K . N M P
A r S 0 2CI, P y
6 0 - 7 0 °C
6 - 7 h
0 °C - rt, 2 4 h
105a-c
106a-c
E tO H , rt
t .
106a-c: X = N 0 2
107a-c: X = nh 2
*ru\
F
Schem e 24. Synthesis o f C5, C6, and C7-arenesulfamoyl indoles
starting from 2-amino nitrophenols.
Table 7. Some results o f acylation o f aminophenols and their triflates
Entry
Substrate 102a
103: Yield (%)
1
102a: X = 5 -N 0 2
103a: 86
1 0 4 a :87b
2
102b: X = 6 -N 0 2
103 b :97
104b: 80b
3
102c: X = 7 -N 0 2
103c: 80
104c: 94°
104: Yield (%)
aIndole skeleton num bering was used.
bN aH was used as the base.
cTriethylamine was used.
48
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m ore reactive in the cross-coupling reaction. Therefore, the triflates 104 underw ent a
facile Sonogashira cross-coupling reaction w ith 1-alkynes catalyzed by 10 mol%
Pd(PPh 3 ) 4 and 30 mol% Cul in the presence o f the additive m-BuNJ (150 m ol% ) in
EtsN -M eC N (1:5). To evaluate the reactivity o f alkyl and aryl alkynes w ith the
triflates 104, 1-pentyne and 1-phenylacetylene were used in the cross-coupling
reactions, w hich w ere complete w ithin 0.5-1 h (1-pentyne, 0.5 h; 1-phenylacetylene,
1 h) to provide 2-alkynylnitroanilides 105 in excellent yields. Com parison of the
nitrophenol triflates 104a-c w ith other substituted aryl triflates reveals that the
reaction tim e reduced rem arkably for the cross-coupling with 1-alkynes (Chapter 2).
A ccording to the procedure developed before, the intramolecular cyclization o f nitro
2-alkynylanilides 105 w as carried out using 1.2 equiv. o f /-BuOK in NMP at 60-70
°C to provide C5, C6, and C7 nitroindoles 106 in good yields (Table 8). It was found
that the nitro group survived the basic conditions without significant decomposition.
Table 8. Yields of cross-coupling products, nitroindoles and aminoindoles
105: Yield
106: Yield
107: Yield
(%)
(%)
(%)
n-Pr
105a-l: 95
106a-l: 84
104a: 5 -NO 2
Ph
105a-2: 95
106a-2: 85
3
104b: 6 -NO 2
n-Pr
105b-l: 90
106b-l:
4
104b: 6 -NO 2
Ph
105b-2: 96
106b-2: 84
5
104c: 7 -NO 2
n-Pr
105c-l: 91
106c-l. 72
6
104c: 7 -NO 2
Ph
105c-2: 90
106c-2: 76
104: N 0 2a
R
1
104a: 5 -N 0 2
2
Entry
107a: 85
8 6
1 0 7 b :96
107c: 86
aIndole skeleton num bering was used.
The nitro group in nitroindoles 106 w as reduced over Pd/C at 20 °C via
49
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hydrogenation in EtOH and the aminoindoles 107 w ere isolated in 85-96% yields,
w hich w ere converted into the arenesulfamoylindoles 108 smoothly under the
standard reaction conditions. For C5 substituted indoles, the product 108a was
obtained in 84% yield. To demonstrate the generality o f the sulfonamide formation,
for the C6 amino indole, three arenesulfonyl chlorides were used to form 108b -l,
108b-2, and 108b-3, respectively, in 70-80% yields. For C7 substituted indole, 108c
w as obtained in 73% yield.
1 0 8 a (84%)
1 0 8 b - 2 (70%)
1 0 8 c (73%)
Figure 7. Structures o f synthesized C5, C6, and C7 arenesulfamoylindoles.
The C4 nitrogen-substituted indoles were synthesized starting from comm ercially
available 2-chloro-1,3-dinitrobenzene, as illustrated in Scheme 25. The key step is
the cross-coupling reaction o f 109 w ith 1-alkynes, which m ust be conducted using a
suitable palladium catalyst system. Although the nitro groups in the substrate may
50
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activate the C— Cl bond, the steric repulsion m ay make the cross-coupling difficult.
W hen Pd(PPh 3 ) 4 -C u I was used as the catalyst, the cross-coupling reaction failed at
room tem perature or on heating.
Sonogashira cross-coupling reaction o f aryl halides is an important tool for the
carbon-carbon bond formation in organic synthesis. Aryl chlorides are one o f the
m ost attractive starting materials because o f their structural diversity and availability.
However, there is no efficient protocol for the Sonogashira cross-coupling reaction o f
aryl chlorides. Until recent years, there are a few examples o f Sonogashira reactions
o f alkynes w ith aryl chlorides.53 A diminished catalytic activity was observed for the
cross-coupling by using Pd(0) species containing ligands such as dba. It has been
reported that the palladium catalysts that incorporate w ith bulky, electron-rich
phosphine ligands can display unusually high reactivity in a wide range o f coupling
reactions. Buchwald and Fu reported a m odified catalyst system for the Sonogashira
cross-coupling reaction o f aryl bromides at room temperature, where a bulky
phosphine, P(/-Bufi w as used together w ith Pd(PhCN)Cl 2 .54 M ore recently, Plenio
et a/.53j described a versatile catalyst Na 2 PdCU for the Sonogashira cross-coupling
reactions o f aryl halides, where an bulky ligand (l-A d ^ P B n was used.
51
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= —R
N 02
4^01
Pd(PhCN)2CI2
P(f-Bu)3,Cul, n-Bu4NI
2
109
Et3N-MeCN (1:5)
rt, 1 h (for R = n-Pr)
or Et3N-DMF (1:5)
80 °C, 1 h (for R = Ph)
N 02
NH2
R
R
SnCI2*2H20
NQ
DMF-CH2CI2 (1:1)
2
20 °C, 4 h
110a: R = n-Pr (93%)
111a: R = n-Pr (66%)
110b: R = Ph (60%)
111b: R = Ph (80%)
f-BuOK, NMP
80 °C, 5-8 h
F3C
3-CF3C6H4S 0 2CI
NH2
Py, 0 °C - rt
•R
24 h
H
H
113a: R = n-Pr (83%)
112a: R = n-Pr (75%)
113b: R = Ph (75%)
112b: R = Ph (90%)
Schem e 25. Synthetic approach to 4-aminoindoles and C4 arenesulfamoylindoles.
We tried the cross-coupling reaction o f 2-choro-l,3-nitrobenzene w ith 1-pentyne
using 10 mol% Pd(PhCN)2Cl2, 20 mol% P(/-Bu)3, and 20 mol% Cul in Et3N -M eC N
(1:5). The reaction was completed at room tem perature after 1 h and the product
110a w as isolated in 93% yield. However, this catalytic system did not work well for
the coupling reaction with phenylacetylene at room tem perature in MeCN. The
reaction tem perature was increased to 80 °C in Et3N -D M F (1:5) for 1 h to give 110b
in 60% yield. Reduction o f the nitro groups in 110a,b was attempted under different
sets o f conditions. For example, using Fe + HC1 (0.5%) as the reductant in 50%
EtOH, the nitro groups in 110a w ere reduced in 51% yield. W hen using SnCl2*2H20
(10 eq) in hot EtOH (65 °C, 0.5 h), the substrate was consumed but the desired
product was not detected. By changing the solvent to DM F—CH 2 CI2 , the nitro
compound 110a w as reduced to 111a by SnCl2*2H20 (60 eq, rt, 4 h) in 66% yield.
Similarly, 111b w as obtained in 80% yield. Then, we tried the sulfonylation of
52
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compound 111a to obtain 2-alkynyl sulfonamide, but the cyclization reaction to
indole suffered from difficulties. Ring closure o f 2-alkynyl sulfamide could not be
com pleted under the basic conditions o f i-BuOK. Ring closure w ithin 111 was
exam ined under two different conditions. Treatment o f lll a ,b with Cul in DM F (100
°C, 2 h) afforded the product 112a in 42% (R = n-Pr) and 112b in 10% yields (R =
Ph), respectively. Alternatively, high yields were obtained via the f-BuOK-mediated
ring closure w ithin 111a,b in NM P at 80 °C for 5 h (112b: R = Ph, 90%) and 8 h
(112a: R = n-Pr, 75%).
Finally, treatm ent o f the C4 aminoindoles 112a,b w ith 3-(trifluoromethyl)benzenesulfonyl chloride in pyridine furnished the C4 arenesulfamoylindoles 113a,b
in 75% ( R = Ph) and 83% ( R = w-Pr) yields.
A s described above, w e have developed a general synthesis o f indoles possessing a
nitrogen substituent at C4, C5, C6, and C7 positions via palladium -catalyzed
coupling-heteroannulation from the commercially available nitro 2-am inophenols
102 and 2-chloro-l,3-dinitrobenzene 109, including nitroindoles, aminoindoles and
arenesulfamoylindoles. Structural diversity at the C2 position can be achieved by
using comm ercially available 1-alkynes, and the diversity o f six-m em ber benzenoid
ring skeleton can be achieved by reacting w ith different arenesulfonyl chlorides with
the aminoindoles. In combination o f the potential o f introducing diversity at C l
position, an indole library can be generated w ith three points o f diversity.
3.2.2.
One-pot palladium-catalyzed synthesis of nitroindoles
Cacchi et a/.33,11 reported a novel approach to 2,3-disubstituted indoles through the
palladium (0)-catalyzed cyclization o f o-alkynyltriflluoroacetanilides w ith other aryl
triflates and aryl halides in 1994. It was interestingly noted that only the
trifluoroacetam ido group could work well in this reaction. No indole derivatives
53
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w ere obtained using aniline intermediates containing a free amino group or an
acetamido group. The Larock’s group32a described a one-pot approach to the
synthesis o f 2,3-disubstituted indoles by the palladium -catalyzed heteroannulation o f
an aryl iodide w ith internal alkynes in the presence o f halide anion. This approach
could tolerate various /V-protcctcd groups for o-iodoaniline, including /V-methyl,
/V-acctyl, ;V-tosyl and free amino group. To the best o f our knowledge, the
palladium -catalyzed intermolecular coupling-annulation o f 2-trifluoroacetamidoaryl
triflates w ith term inal alkynes to form 2-substituted indoles in one-pot m anner has
not been reported in solution synthesis.
We took the advantage of the Pd-catalyzed cross-coupling-heteroannulation
sequence and established a general stepwise synthesis o f C5, C6, C7 nitroindoles
using 2-amino nitrophenols as the substrates. We explored a one-pot procedure by
using trifluoroacetanilides as the intermediates which w ere prepared to facilitate
heteroannulation catalyzed by palladium.
A s shown in Scheme 26, three commercially available 2-amino nitrophenols 102a-c
were used as the starting m aterials for the synthesis o f nitroindoles 106a-c. Firstly,
the amino groups in 102a-c were selectively protected by treating w ith trifluoroacetic
anhydride in the presence o f pyridine to give 114a (96%), 114b (98%), and 114c
(86%). We tried to prepare the triflates using TfjO (1.1 eq) and Et 3 N (1.25 eq) as the
triflating agent, unfortunately, the conversion o f trifluoroacetanilide 114a w as very
low (20%). Then, w e tried the reaction with A-phenyltrifluoromethanesulfonimide in
the presence of NaH to give the triflate 115a (84%), 115b (93%), and 115c (87%).
The triflate 115a was subjected to the cross-coupling reaction w ith 1-alkynes to
provide 2-alkynyltrifluoroacetanilides, w hich cyclized under the reaction conditions
to furnish nitroindole 106a-l in one-pot fashion. The 2-alkynyltrifluoroacetanilide
interm ediate was not observed.
54
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OTf
OH
0 2N - f
PhNTf2 (1.1 eq), NaH (1.5 eq)
THF, 0 °C - rt, 6 h
115a-c
114a-c
(CF3C 0 )20 (1 .1 eq)
Py (1.5 eq), THF
0 °C - rt
= -R
Pd(PPh3)4 (0.1 eq), Cul (0.3 eq)
Et3N-DMF (1:5), n-Bu4NI, 80 °C
OH
R
0 2N—}r
0 2N
nh2
H
102a-c
106a-c
Schem e 26. One-pot synthetic approach toward nitroindoles.
We examined the influence o f different palladium precursors for the one-pot reaction.
The reaction o f 115a w ith 1-pentyne did not occur at room tem perature w hen using
Pd(PPh3)4 (10 mol%), Cul (30 mol%), and «-BuN4I (150 mol%) in Et3N -D M F (1:5)
for 10 h. W hen the reaction tem perature was raised to 80 °C for 24 h, the yield o f
106a-l increased to 90%. The reaction also occurred using Pd(PPh3)2Cl2 as the
catalyst to give 106a-l in 82% yield at room tem perature for 24 h. The solvent effect
was also observed in the one-pot reactions and three different solvent combinations
were used, i.e. Et3N -D M F (1:5), Et3N -M eC N (1:5), andT M G -D M F (1:5).
We synthesized 5-, and 6-nitroindole derivatives from various 1-alkynes by using
Pd(PPh3)4 (10 mol%), Cul (30 mol%), and «-BuN4I (150 mol% ) in Et3N -D M F (1:5)
and the results are shown in Table 9. U nder the one-pot conditions, some functional
groups such as OH, CN, and Cl rem ained intact and the protection o f OH was not
required.
However, the one-pot procedure to 7-nitroindoles could not proceed smoothly.
55
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Pd(PPh 3 ) 4 did not w ork well in the reaction o f 115c with 1-pentyne. W hen using
Pd(PPh3)2Cl2, and a strong base, TMG, the reaction could occur at high tem perature
(100 °C) to give 106c-l in a moderate yield (entry 11, Table 9).
Table 9. One-pot synthesis of nitroindolesa
Entry
115: N O /
R
1
115a: 5 -N 0 2
n-Pr
24
106a-l: 90
2
115a: 5 -N 0 2
Ph
41
106a-2: 86
3b
115a: 5 -NO 2
(CH2)2OH
42
106a-3: 68
4
115a: 5 -NO 2
(CH2)3CN
25
106a-4: 75
5b
115a:
(CH2)3C1
24
106a-5: 45
6b
115b: 6 -NO 2
n-Pr
2 1
106b-l: 84
7
115b: 6 -NO 2
Ph
17
106b-2:
8
115b: 6 -NO 2
(CH2)2OH
19
106b-3: 69
9
115b: 6 -NO 2
(CH2)3CN
8
106b-4: 73
115b: 6 -N 0 2
(CH 2 )3 C1
2 0
106b-5:
115c: 7 -NO 2
n-Pr
7.5
106c-l: 39
115c: 7 -N 0 2
Ph
3.5
106c-2: 52
115c: 7 -NO 2
(CH2)2OH
12
106c-3: 48
1 0
b
^|C ,d,e
1 2
c,d
13d
5
-NO 2
/(h )
106: Yield (%)
8 8
6 6
“Carried out in Et3N -D M F (1:5) w ith 10 mol% Pd(PPh3)4, 30 m ol% Cul, and
150 m ol% n-Bu4N I at 80 °C.
bCarried out in Et3N -C H 3CN (1:5).
“Carried out in TM G -D M F (1:5).
dPd(PPh3)2Cl2 was used to replace Pd(PPh3)4.
“Carried out at 100 °C.
fIndole skeleton num bering was used.
56
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A ll nitroindoles are crystalline compounds, the C6 nitroindole 106b-l was analyzed
by X-ray crystallography.56b The crystal structure of 106b-l is given in Figure 8,
showing a flat nitroindole skeleton.
X5A
JC10A
C9A
w*.
Figure 8. X-ray crystal structure o f 106b-l (taken from ref.56b).
A s described above, a simple and efficient m ethodology for the synthesis of C5, C6,
and C7 nitroindoles was developed successfully, via the key step o f the
palladium -catalyzed one-pot coupling-heteroannulation o f 2-trifluoroacetamidophenyl triflates w ith terminal alkynes. However, for C7 nitroindoles, the stepwise
procedure seems m ore reliable than the one-pot synthesis.
3.2.3.
Synthesis of 4- and 7-azaindoles
As an analog of indole nucleus, azaindoles have attracted w idespread attention
because o f their unique bioactivities.57 There are only a few azaindoles in nature, so
many azaindole derivatives are synthetically prepared as potential pharm aceutical
agents. The synthesis o f azaindoles has been reported via classical methods such as
Fischer, M adelung and Reissert58a during last decade. Recently, Wang et al.57g
described a simple and efficient example for the synthesis o f 4- and 6-azaindoles via
the
Bartoli
reaction
starting
from
nitropyridines
(Scheme
57
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27).
The
palladium -catalyzed heteroannulation57ae was also applied to the synthesis o f
azaindoles by using amino iodopyridines as the starting materials. The latter are
prepared from lithiation o f fluoropyridines. These synthetic approaches w ere based
on Larock’s indole synthesis, involving the palladium -catalyzed heteroannulation o f
amino iodopyridines with internal alkynes for the synthesis o f 5, 6, and 7-azaindoles,
as shown in Scheme 27. The Stille cross-coupling reaction was also applied to the
synthesis o f azaindoles.
CHP
The synthesis of 4-azaindoles was reported scarcely.
<^M gB r
118
119
120
Schem e 27. Synthesis of azaindoles by palladium -catalyzed heteroannulation
and Bartoli cyclization.
According to the general approach, as described in Chapter 2, to substituted indoles
starting w ith 2-aminophenols, 7-azaindoles were synthesized from 2-am ino-3hydroxylpyridine via the cross-coupling reaction o f 2-carboxamidopyridyl triflate
w ith 1-alkynes.
In order to achieve high structural diversity, we selected other comm ercial reagents
such as halo nitropyridine or halo aminopyridines as the substrates for azaindoles.
Described in the following is the synthesis o f 4- and 7-azaindoles via the
Pd-catalyzed cross-coupling-heteroannulation as the key step.
58
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R—=
(2.0 eq)
Pd(PPh3 ) 4 (0.1 eq), Cul (0.3 eq)
Et3N-MeCN (1:5), rt
f-BuOK (2.0 eq)
NMP, rt
H
124
121
Scheme 28. Synthesis o f 4-azaindoles.
A s illustrated in Scheme 28, 2-chloro-3-nitropyridine 121 was subjected to the
Sonogashira cross-coupling reaction to give 2-alkynyl-3-nitropyridines 122. We
exam ined different reaction conditions and found that the Pd precursor was essential
to the success. Initially, Pd(PPh 3 )2Cl2 -C u I were used as the catalyst system according
to the published m ethod59a,b but the yield o f 122a was very low after heating for 10 h.
When the catalyst system with a bulky phosphine ligand Pd (PhCN) 2 Cl2-P(/-Bu)3 was
used at refluxing tem perature in M eCN for 24 h, the reaction o f 121 w ith 1-pentyne
did not occur. Russel et al.60reported that Pd(PPh 3 ) 4 was superior to Pd(PPh3)2Cl2 for
the cross-coupling reaction o f chloropyridine w ith terminal alkynes. Then, Pd(PPh 3 ) 4
was used in combination w ith Cul for the cross-coupling reaction at room
tem perature for 2 h to afford 122a in 83% (entry 1, Table 10). A num ber of
functionalities in 1-alkynes tolerated the reaction conditions, giving 122b-d in good
to excellent yields (entries 2-4, Table 10). The nitro group in 122a-d was required to
be converted into the amino group before cyclization. Unfortunately, the reduction o f
122a by using SnCl2 • 2 H 2 O in DMF gave only 20% yield o f the amino product
123a. We found that the yield increased to 78% w hen using SnCl2 * 2H20 - N H 4C1 in
59
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EtOH at refluxing tem perature for 12 h. NM P was found to be the best solvent for
the reduction of nitropyridines 122a-d and the aminopyridines 123a-d were
obtained in 60-80% yields (Table 10). Finally, cyclization o f 123 was carried out to
give 2-substituted 4-azaindoles 124a-d in the presence o f f-BuOK at room
tem perature for 24 h in good yields (Table 10). The TMS group in 123c was lost
during the ring closure to give C2 unsubstituted 4-azaindole 124c (entry 3, Table 10).
Table 10. Results for the synthesis of 4-azaindoles
Entry
R
122: Yield (%)
124: Yield (%)
123: Yield (%)
1
n-Pr
1 2 2 a :83b
123a: 78
124a: 85d
2
Ph
122b: 84b
1 2 3 b :80
124b :80d
3
TMS
122c: 50a
123c: 60a
124c: 70 (R = H)C
4
(CH2)3CN
122d: 94b
123d: 65b
124d: 75°
aReaction tim e is 4 h. bReaction tim e is 2h. cReaction time is 5 h.
dReaction tim e is 24 h.
2-Am ino-3-brom o-5-methylpyridine
125
was
selected
as
the
substrate
for
3,5-disubstituted 7-azaindole. The Pd (P P h ^ -C u I catalyst system was also efficient
for the cross-coupling reaction o f the bromopyridine 125 with 1-alkynes at 80 °C for
24 h. 2-Alkynylaminopyridins 126 and 127 were obtained in 81% and 65% yields,
respectively. The t-BuOK-mediated ring closure within 126 and 127 afforded
2-substituted 5-meyhyl-7-azaindoles 128 and 129 in excellent yields (Scheme 29).
60
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R -ss (2.0 eq)
R
Me
Pd (PPh3)4 (0.05 eq)
NH2
125
Cul (0.1 eq)
Et3N-MeCN (1:5)
80 °C, 24 h
N
NH2
n-Pr
126: R =
(81%)
1 2 7 : R = Ph (65%)
t-BuOK (2.0 eq)
NMP, rt, 24 h
Me
R
H
1 2 8 : R = n-Pr (88%)
1 2 9 : R = Ph (95%)
Schem e 29. Synthesis o f 2,5-disubstituted 7-azaindoles.
3.3.
Conclusion
In summary, as the extension of the Pd-catalyzed cross-coupling-heteroannulation
approach tow ard indoles starting from 2-aminophenols as described in Chapter 2, we
have been successful in establishing a general and efficient synthesis o f C4, C5, C6,
and C7 nitrogen-substituted indoles, including nitroindoles, from three comm ercial
2-amino nitrophenols and 2-chloro-l ,3-dinitrobenzene. Both stepwise and one-pot
procedures for the cross-coupling-heteroannulation toward C5, C6, and C7
nitroindoles w ere explored, among these, it seems that the stepwise approach is m uch
m ore
general
and reliable.
M oreover,
ortho-amino hydroxypyridine,
2-halo
aminopyridines, and 2-halo nitropyridines were used for the synthesis o f azaindoles
through sim ilar key steps o f the Pd-catalyzed coupling with 1-alkynes and the
/-BuOK-m ediatcd
heteroannulation
of
ortho-amino
alkynylpyridines.
Our
approaches to the nitrogen-substituted indoles and azaindoles provide reliable access
to these classes o f important bioactive heterocycles.
61
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Chapter 4
A Novel Solid-Phase Synthesis o f Indole
Library under Microwave Irradiation
4.1.
Introduction
Com binatorial chemistry9,13 has emerged as a powerful new technology for the
diversity-oriented synthesis o f small molecules. It is a special type o f synthetic
strategy by w hich a large num ber o f compound libraries can be synthesized in
parallel m anner w ith various variants. Solid-phase organic synthesis9 (SPOS) is the
core technique for generating combinatorial libraries o f compounds due to the
advantages o f this technique over the traditional solution approaches, w hich has been
w idely used in the preparation o f biologically active compound libraries, including
either peptide compounds or non-peptide small organic molecules.61 However, it still
suffers from several disadvantages owing to the nature o f the heterogeneous reaction
conditions. N onlinear kinetic behavior, slow reactions, incom plete conversion o f
starting materials, and degradation o f the polym er support resulting from long
reaction tim es are some o f the problems experienced in solid-phase synthesis.
M icrowave irradiation now has been known to allow striking reduction in reaction
times, good yields, and cleaner reactions over conventional therm al procedures, since
m icrow ave-assisted organic synthesis (MAOS) was first demonstrated by Giguere
and Gedye in 1986.62 Many organic reactions under m icrowave irradiation can be
perform ed at a tem perature and pressure controlled manner, providing reproducible
results.63 The short reaction tim e normally attained at high tem perature under
m icrowave heating is ideally suited for combinatorial chemistry. The use o f
62
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m icrowave irradiation in solid-phase synthesis was first reported by Wang et al.M in
1992 who demonstrated that the rate enhancement in difficult coupling reactions o f
M errifield peptides synthesis. M icrowave-assisted solid-phase organic synthesis
(M ASPOS) has been proved efficient in reducing the reaction tim e from days and
hours to m inutes and seconds and more promisingly to produce im proved yields w ith
high purities. This technique offers an opportunity for the design and synthesis of
biologically active libraries through novel reaction routes, w hich m aybe sometim es
im possible or difficult in conventional solution-phase chemistry. Therefore, it is not
surprising that M ASPOS has attracted dramatic attentions in the area of organic
chemistry and m edicinal chemistry in very recent years.65
Experience has shown that compounds w ith biological activity are often derived
from heterocyclic structures. Substituted heterocyclic compounds have been proven
to be broadly useful as therapeutic agents and can offer a high degree of structural
diversity. For this reason, the synthesis o f heterocyclic compounds is a m ajor subject
o f solid-phase synthesis in recent years, and various synthetic approaches for the
construction o f heterocyclic compounds have been transferred to the solid-phase.66,67
4.2.
Recent advances in palladium-catalyzed indole synthesis on
solid-phase
Indole nucleus probably represents the most important heterocycles in m edicinal
chemistry due to their broad varieties o f biological activity and m any synthetic
m ethodologies have been developed for the construction o f indole nucleus. In 1996,
several groups successfully synthesize indoles on solid-phase almost at the same time.
Till now, a num ber o f efficient synthetic approaches have been transferred to the
63
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synthesis o f indole libraries on solid supports. These approaches m ainly include the
Fisher indole synthesis,68 M adelung synthesis,69 Nenitzescu indole synthesis,70 the
intram olecular
W ittig
reaction,71 palladium -catalyzed
cyclization72 and
other
m iscellaneous cyclization methods leading to indole compounds.73 Am ong these
methods, palladium -catalyzed cyclization is the m ost effective m ethodology for the
construction o f indole nucleus w ith a high degree of structural diversity, and has
gained a high popularity in solid-phase synthesis.
Yun and M ohan72a first described the synthesis of indole derivatives using
solid-phase intram olecular Heck reaction of resin-bound aryl bromids. Starting from
4-brom o-3-nitroanisole, resin-bound bromoaniline 130 was prepared, w hich was
converted to amide 132 through acylation followed by alkylation. Then, an
intram olecular Heck reaction w ithin 132 proceeded to afford indole derivatives 133
after
cleavage
(Scheme
30).
Later,
a
similar
approach
was
reported
by
Balasubram anian el al.12h for the synthesis of 2-oxindoles on solid-phase.
Br
1.20% piperidine, DMF
NHFmoc
2
. R 1 COCI, Py
130
R1
131
r 2 1.Pd(PPh3)4,PPh:
Et3 N, DMA
')
n-BuLi
2.TFA
R2 CH=CHCH?Br
132
133
Schem e 30. Intramolecular Heck reaction for the synthesis o f indoles on solid-phase.
A lm ost at the same tim e, Zhang et a l 12c immobilized the y-bromocrotonic acid to the
64
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solid support, which reacted w ith substituted 2-iodoanilines followed by alkylation to
give resin-bound 136, as shown in Scheme 31. Palladium -mediated intramolecular
H eck annulation of 136 proceeded smoothly and the desired indoles 137 were
obtained after cleavage from the resin.
r i£
'Y
o
^ x
—
^
V
°v
NHz >
DIPEA, DMF
RlJj_
n~
j
T
r
H
134: X = CH2 Br, CHO
135
conh2
ArCH2Br
^
► R1- r
1
I
DIPEA, DMF
r
1. Pd(Pph3)2ci2
^ - b u 4 n c i , E t3N ^
R
i f Y
\
DMF-H20
^
ZTFA
136
Ar
137
Schem e 31. Solid-phase synthesis o f indoles by Zhang et al.
Recently, Kondo et al.12d developed a new route to indole 3-carboxylates by the
palladium -m ediated cyclization o f resin-bound haloarylenaminoester 140, which was
prepared
through
two
approaches,
acid-catalyzed
condensation
of
138
or
palladium (II)-catalyzed oxidative amination o f 139. Palladium -catalyzed cyclization
o f the resin-bound 140 followed by cleavage under basic condition released indole
3-carboxylates 141 in high purity (Scheme 32).
65
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X
T sO H , B e n z e n e
,2
138
O
140
Pd(PPh3 )2 CI2, LiCI
139
COOM e
1.
P d (O A c )2 , E t3N
2.
M e O N a , M eO H , T H F
H (M e )
H
141
Schem e 32. Synthesis of indoles on solid-phase by Kondo et al.
At
the
same
time,
the
Kondo
group72e developed
the
first
solid-phase
Rh(II)-catalyzed N — H insertion reaction o f immobilized a-diazophosphonoacetate
w ith 2-haloanilines, followed by Homer-Emmons reaction to give imm obilized
enam inoesters on resin, which were efficiently cyclized to indoles via an
intram olecular palladium -catalyzed reaction.
Cleavage by
sodium
m ethoxide
released 3-substituted indole-2-carboxylates.
Bedeschi et a/.72freported a one-pot approach to the synthesis o f indoles involved a
palladium -catalyzed
coupling-cyclization
of
iodoanilines
with
alkynes
on
solid-phase, in which the new carbon-carbon bond and carbon-nitrogen bond were
form ed (Scheme 33). Resin-bound 2-iodoanilide 142 was coupled w ith alkynes
catalyzed by palladium in the presence o f TM G to provide resin-bound alkynes,
w hich cyclized in situ to give resin-bound indoles 143. After cleavage from resin
under the basic conditions, indole derivatives 144 were obtained.
66
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O
NHAc
i
Pd(PPh3 )2 Cl2 , Cul
y -K '
143
142
NaOH, /-PrOH
144
Schem e 33. Synthesis o f indoles on solid-phase by Bedeschi et al.
Cacchi indole synthesis was successfully transferred to solid-phase by Ellingboe et
al.12% using Wang resin-attached 3-amino-4-iodobenzoic acid. Similarly, another
exam ple o f palladium -catalyzed indole synthesis on solid-phase was reported by
Zhang et a /.7211’1 in which the Larock indole synthetic strategy was applied to for the
solid-phase synthesis o f trisubstituted indoles or 2-aryl indoles using Rink amide
resin and 3-amino-4-iodobenzoic acid.
A
publication
of
Huang72j
described
a
palladium -catalyzed
annulation
of
functionalized aryl halides w ith 1,3-dienes. Using 4-amino-3-iodobenzoic acid as the
starting m aterial to load onto Rink resin, cyclization o f resin-bound iodoanilincs with
1,3-dienes m ediated by Pd(II) was carried out
in DM F to give the desired
2-substituted indolines after cleavage from the resin. Under the palladium -catalyzed
conditions, the carbon-carbon bond and carbon-nitrogen bond were created during
the intram olecular cyclization o f aryl halides to afford the indole derivatives. This
m ethod has proven to be an efficient m ethod for forming the indole nucleus on
solid-phase.
Palladium -catalyzed solid-phase indole synthesis involved traceless strategy and
67
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m icrowave irradiation w ere not covered in this part, which will be discussed in
Chapter 5.
4.3.
M icrowave-assisted solid-phase synthesis o f heterocycles
M icrowave-assisted organic synthesis (MAOS) is a new and rapidly developing area
in synthetic chemistry.74 Solid-phase organic synthesis provides a powerful means for
the preparation o f compound libraries for high-throughput biological screening in
drug discovery, in addition, this technique also provides a prim ary solution for the
rapid generation o f a large num ber o f new structurally diverse m olecules leading to
the discovery o f new targets in the hum an genomic research.18,21 However,
solid-phase organic reactions are typically characterized by longer reaction times
compared to the solution reactions. M icrowave-assisted solid-phase organic synthesis
(M ASPOS) was recognized as a powerful tool to overcome this limitation.
M ASPOS was m ainly used in the following fields: (i) organic reactions and their
application in rapid synthesis o f small m olecular libraries (primarily focusing on
heterocyclic compounds); and (ii) solid-supported reagents (or catalysts).
U nder m icrowave irradiation, a num ber o f organic reactions have been successfully
perform ed on solid-phase in a short time in high yields, such as the synthesis of
peptides,75 synthesis o f esters,76h,1,q’1 metal-catalyzed cross-coupling reactions77 (such
as
Suzuki
reactions,
Stille
reactions,
and
Sonogashira
reactions),
Claisen
rearrangem ent reactions,76f m ulti-component reactions (M CR),76c and aromatic
n u c le o p h ilic su b stitu tio n 76"’1 etc.
A pplication o f these reactions in the synthesis o f biologically interesting heterocycles
is
found
to
be
m uch
advantageous.
For
example,
microwave-assisted,
68
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copper-mediated vV-arylation of heterocycles on solid support has been described by
Combs et al..llh In this work, benzimidazole, imidazole, pyrazole and benzotriazole
w ere im m obilized on PS-PEG resins, as shown in Scheme 34. Each solid-bound
heterocycle was treated w ith /?-tolylboronic acid in the presence o f Cu(OAc ) 2 and
m olecular sieves in N M P-pyridine m ixed solvent. The mixture w as then heated in a
loosely capped glass vial at 1000 W in a kitchen microwave oven. The heating was
perform ed for 3x10 seconds. A fter cleavage from resin, the A-arylated heterocycles
w ere obtained in high purity. It was noted that the reaction tim e decreased and yield
and purity increased under m icrowave irradiation, in comparison w ith the same
reaction under conventional heating.
o
Me-@-B(OH)2
N
1. C u(OAc)2i MW, 3 x 1 0 sec
O
Other heterocycles used:
147
H
150
Schem e 34. M icrowave-assisted Cu-mediated A-arylation o f heterocycles.
M ulti-component reactions have the advantage o f high efficiency in heterocycle
preparation. Using Biginelli three-com ponent protocol, various bicyclic scaffolds o f
69
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furo[3,4-c/]pyrimidincs
pyrro [3,4-<i]pyrimi din cs
154,
and
155
pyrim ido [4,5 -<7]pyrinii dazines 156 w ere prepared on solid-phase under m icrowave
irradiation by Kappe et al?% The crucial steps were the m icrowave-prom oted
acetoacetylation o f hydroxymethyl resin with 4-chloroacetoacetate and a rapid three
different traceless cyclative cleavage under microwave irradiation (Schem e 35).
o
NH
R1 CHO, urea
►
MW
153
152
MW
MW
NH
,
/
rA^ o
R
N'
NH
HN
NH
A o
H
154
155
Schem e 35. M icrow ave-assisted solid-phase synthesis o f
bicyclic dihydropyrimidones.
The synthesis of indole skeleton o f new melatoninergic analogs on solid-phase
com bined w ith m icrowave irradiation was described by Raboin et al.lle (Scheme 36).
A lso the results w ere compared w ith classical thermal heating methods. It was
notified that reaction time was reduced strikingly and the yields increased for
solid-phase synthesis in association w ith m icrowave irradiation.
70
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-NH,
TBTU, HOBt, MW
NH,
Rink amide resin
157
(M e )3 S i—= — v
'—N H A c
Pd(OAc)2, PPh3
LiCI, NaOAc, MW , ,
NHAc
NHAc
O
1.N IS, MW
H,N
------------------------------
2. TFA
_
C ^ -N
„
H
Si(Me ) 3
l|
159
158
Schem e 36. M icrowave-assisted solid-phase synthesis o f
melatoninergic analogues.
Recently, Porcheddu et al.79a reported a one-pot synthesis o f pyrazoles and isoxazoles
using
cellulose
aniline
support,
as
demonstrated
in
Scheme
37.
The
polym er-supported enaminones 162 were prepared by the one-pot Bredereck-type
condensation under microwave irradiation, which were cyclized under microwave
irradiation in the presence of r'-PrOH to give the desired pyrazoles and isoxazoles 163
in high yields and purities. Significant rate enhancements w ere observed for
reactions
carried
out under
microwave
heating
conditions
compared
with
conventional heating conditions, reducing the reaction times from hours to minutes.
The released aniline cellulose can be recycled.
71
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-NH 2
+
Cellulose
aniline
Q
*
A
^ y
'r’
CH(OMe ) 2
160
r Y ^ Y K r’
O
1 6 1 :Y = 0 ,o r N
O
162
NH
MW
163
Schem e 37. M icrowave-assisted cellulose-supported synthesis of
pyrazoles and isoxazoles.
M ore recently, a similar strategy o f “catch and release” for the parallel synthesis of
2,4,5-trisubstituted pyrimidines was described by the same group.79b By comparison
w ith conventional thermal heating conditions, the remarkable reduction o f reaction
tim e was observed.
The use o f polymer-supported reagents (PSR) has gained increasing attention in
combinatorial chemistry.80 The most important advantage o f these reagents is the
sim plification o f reaction work-up and product isolation, these processes being
reduced to simple filtrations. The use o f solid-supported reagents was thought to
com bine the advantages o f both solid-phase and solution-phase chemistry. M ajor
drawbacks o f this approach are the lim ited loading on the support and long reaction
tim e usually observed. M icrowave-assisted synthesis of solid-supported reagents
could eliminate the drawback of long reaction tim e on solid-phase. Very recently, this
strategy has been reported in the literature such as Burgess reagent,8la thionating
reagent,810 and W ittig reagent etc.81c,d In a protocol described by Brain et al., as
72
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shown in Scheme 38, a solid-supported Burgess reagent 164c was employed for the
synthesis
of
1,3,4-oxadiazile
from
1,2-diacylhydrazines.
Under
m icrowave
irradiation, the desired products were produced in high purity and yield in only 2-8
minutes. Under conventional refluxing conditions, a 40% conversion was obtained
after 3 hours. Solid-bound reagents 164a and 164b were also applied to the same
reactions successfully.
R1^ °
° ^
R2
164a,b or 164c^
H N -N H
MW
O O O
y
\'//
n -N
.Nf-Bu
Et,N
N'
■
R V / V r2
N'
^ 6
O . NM e,
164a
164b
o o
\>'/
N
+
NEt3
164c
Schem e 38. M icrowave-assisted solid-phase synthesis o f 1,3,4-oxadiazoles using
polymer-supported Burgess reagent.
A lthough MASPOS has been used in the synthesis o f heterocycles, the examples
reported are very limited, especially in indole synthesis. It has been reported that
several indole structures featuring a C5-substituent group w ould increase the binding
affinity at various bioreceptors, for instance at the NM DA-receptor,471 and the
rHLGPa-receptor.476 Moreover, the C5-subtituent has been shown to be im portant in
structure-activity relationship studies for improving the affinity and selectivity at the
5 -H T m rcccp tor:47f a C 5 -su b stitu en t ca p a b le o f p a rticip a tin g in h y d r o g e n b o u n d in g
could be critical for the binding affinity.478 In addition, at least one heteroatom
attached to C5 has been reported in several 5 - H T iD receptor agonists.47h Moreover,
73
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some arenesulfamoylindoles at C5 position have exhibited strong antitum or and
antiviral activities.82 However, the synthesis of indoles possessing an arenesulfamoyl
group on the ring skeleton on solid supports has not been reported up to date. For this
reason, w e aimed to establish a solid-phase approach to construct a library of
sulfonamides engineered on the indole scaffold using split-pool combinatorial
synthetic strategy.
4.4.
Results and discussion
M ethods for aromatic substitution based on catalysis by transition metals,
particularly palladium, have proven to be efficient approaches towards the synthesis
o f indoles in solution. These approaches are very attractive for combinatorial
synthesis owing to the mild reaction conditions and high reaction yields. However, in
general the source o f the starting materials used, such as 2-brom oanilines and
2-iodoanilines, is limited. A s presented in Chapters 2 and 3, w e have successfully
developed a novel and general synthesis o f substituted indoles in solution, by using
palladium -catalyzed
cross-coupling
and
base-m ediated
cyclization,
from
comm ercially available 2-aminophenols. Our continuing interest was to transfer this
efficient m ethod from solution to solid support for construction o f novel indole
libraries. We envisaged a solid-phase split-pool strategy by using the directed sorting
m ethod and the IRORI radio frequency (7?/)-encoded M icroKan reactors for
generation o f a 96-mem bered indole library (Figure 9).
74
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
H
p
n-Pr
166
165
A r = 3-ClC6H4, 3,5-Cl2C6H3, 4-FC6H4, 2,3,4-F3C6H2, 4-/-PrCfiH4,
4-M eOC6H4, 4 -N 0 2C6H4, 2-thienyl, 4-CF3OC6H4, 2-CF3C6H4,
3-CF3C6H4, 4-CF3C6H4
n=
2, 3, 4, 8
F igure 9. Structures o f an indole library.
4.4.1
Synthesis of 5-nitroindoles on solid-phase
Our initial efforts focused on determining the appropriate conditions to facilitate the
synthesis o f indole compounds on solid support as illustrated in Scheme 39. Alkynes
were loaded onto the commercially available Rink amide resin (deprotected with
20% piperidine in DM F) in the presence o f DIC and HOBt to give the resin-bound
alkynes 167 in nearly quantitative yields. The 2-alkynylanilides 168 were prepared
via the Pd(PPh3)4-C uI-catalyzed cross-coupling reaction o f the resin-bound alkynes
167 w ith an aryl triflate prepared from 2-amino-5-nitrophenol, in which m-Bu4NI was
used as an additive to facilitate the cross-coupling. The structures o f 168 w ere
confirmed, after cleavage from the resin, by H N M R to be of high purity and high
yield. The cyclization o f 168 was carried out via the base-m ediated reaction, and a
num ber o f experiments were performed to optimize the cyclization conditions. Some
o f the results are sum m arized in Table 11.
75
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Rink amide resin
H
H
NH
■N
y ~ n-pr
o
168
167
■N
170
169
166
oo=s _Ar
H
H,N
V S r
171a (16 units higher in MS)
171b (no C3-H in 1H NMR)
TfO.
R C 02H = HO'
i
NO.
triflate = HN
n = 3,4,8
'n-Pr
Reagents and conditions: (a) 20% piperidine-D M F, rt, 1 h; (b) alkyne (5.0 eq),
DIC (5.0 eq), HOBt (5.5 eq), D M F-C H 2C12 (1:1), rt, 1 h; (c) triflate (5.0 eq),
Pd(PPh3)4 (0.1 eq), Cul (0.2 eq), n-Bu4NI (1.5 eq), D M F-E t3N (5:1), 30 °C, 24
h; (d) f-BuOK (5.0 eq, 0.06 M), NMP, rt, 10 h; (e) SnCl2-2H20 (30 eq, 2.0 M),
DMF, 30 °C, 24 h; (f) 4-CF3C6H4S 0 2Cl (5.0 eq), pyridine-C H 2Cl2 (1 :2), rt, 24 h;
(g) 20% TFA -C H 2C12, rt, 1 h.
Schem e 39. Synthetic approach to nitroindoles on solid-phase.
76
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 11. Some results of cyclization mediated by f-BuOK in NMP
168: n
/-BuOK (eq)
T (°C); t (h)
169: Yield (% )a
1
168c: n =
8
1 0
rt; 24
32
2
168c: n =
8
5
rt; 24
60
3
168c: n =
8
4
rt; 24
70b
4
168c: n =
8
5
rt;
57
5
168c: n =
8
5
rt; 18
55
6
168c: n =
8
5
rt;
1 0
81c
7
168a: n = 3
5
rt;
1 0
00
Entry
8
168b: n = 4
5
rt;
1 0
80c
2 2
iso la te d yield after cleavage from the resin.
bCom bined yield o f cleaved 168 and 169 (3:4 = 70:30).
cSometimes, trace starting compound 168 w as detected by TLC after cleavage.
A s shown in Table 11, for the base-catalyzed cyclization, the best results (ca. 80%
yields, entries
6
- 8 ) w ere obtained by treatment o f 168 with t-BuOK (5 equiv) in
N M P at room tem perature for 10 h. Prolonged reaction tim e (entries 2 and 4-5) or
increasing base loading (entry 1) diminished the yields; however, the purities o f 169,
determ ined by TLC after cleavage, are high, presumably due to cleavage o f the
product from the resin under the cyclization conditions. Reducing loading o f the base
(4 equiv, entry 3), the cyclization only proceeded partially, generating a m ixture of
168 and 169.
Unfortunately, subsequent reduction o f the nitro group in 169 w ith SnCl2 ' 2 H 2
0
, the
m ost comm on reductant used for conversion o f nitro moiety into amine on solid
77
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
support could not completely form the desired aminoindoles 170, giving a m ixture
contam inated w ith the hydroxylam ine intermediates. These w ere further confirm ed
by the followed sulfonylation, in which 171a and 171b (Scheme 39) were isolated
after cleavage from the solid support. The MS m easured for 171a (n = 4,8) is 16 units
higher than the desired sulfonamide 166, however, compound 171b, which has the
correct MS value, does not posses the signal o f C3-H in
NM R, showing the
sulfonyl group attached to C3 position on the indole skeleton.
4.4.2.
M icrow ave-assisted cyclization o f 2-alkynylanilides on
solid-phase
Alternatively, reduction o f nitrobenzimides 168 was successfully achieved w ith a 1
M solution o f SnCl 2 -2 H 2
0
in NM P to furnish amines 172 in excellent yields and high
purities (Schem e 40). Treatment o f 172 w ith excess ArSC^Cl in the pyridine-C H 2 Cl 2
m ixed solvent gave the resin-bound sulfonamides 173. However, attempts to cyclize
173 under a variety of conditions, which w ere m ost used in solution phase, proved to
be problem atic again. These include the followings: (i) f-BuOK (5-10 equiv) in DMF
at 80 °C for 24 h; (ii) /7 -B 114 NF (10 equiv) in THF, 80 °C for 24 h; and (iii) Cu(OAc ) 2
(1 equiv) in CICH 2 CH 2 CI at 85 °C for 24 h (entry 5, Table 12). The m aterials
recovered from the above reactions, after treatm ent w ith 20% TFA in CH 2 CI2 , are
m ainly the uncyclized 2 -alkynylanilides.
Then, w e turned our attention to the m icrowave-assisted solid-phase organic
synthesis (M ASPOS) technique for the cyclization o f 173, which has proven to be
efficient for combinatorial synthesis.
78
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
H
NO,
p
h
P
NH,
1^—0
"
HN
168
HN
}-n-Pr
) ~ n' Pr
O
172
O
HN -S'
n
HN
}-n-Pr
173
174
O
H,N
n = 2, 3, 4, 8 ;
Ar —0 -CF 3 C6 H4
A77-CF3C6H4
P-CF3 C6 H4
165
Reagents and conditions: (a) SnCU^FUO (50.0 eq, 1.0 M), NMP, rt, 24 h; (b)
A rS 0 2Cl (5.0 eq), pyridine-C H 2Cl 2 (1:5), rt, 20 h; (c) Cu(OAc)2, (1.0 eq),
NMP, 200 °C, 10 min, M W or Pd(M eCN)2Cl2 (0.2 eq), THF, 160 °C, 10 min,
MW; (d) 20% TFA in CH2C12, rt, 1 h.
Schem e 40. M icrowave-assisted solid-phase synthesis o f indoles.
Because the M icroKan reactors used are not suited for the reaction tem perature
higher than 85 °C, the resin-bound 173 in each reactor was then transferred to a 5-mL
Emrys process vial together w ith the 7?/tag for preserving the structural information
o f the individual library member. M ASPOS was subsequently perform ed on an
Emrys creator from Personal Chemistry AB. Table 12 summarizes the results o f the
Cu(II)- and Pd(II)-m ediated cyclization o f 173. Under therm al heating below 80 °C
79
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for 240-300 min, partial cyclization took place w ith catalytic Pd(M eCN) 2 Cl 2 to give
indole 165 in <80% purities (entries 1 and 2). In contrast, under m icrowave dielectric
heating, 173 cyclized at 160 °C (THF, 10 min) in the presence o f 0.2 equiv o f
Pd(M eCN) 2 Cl 2 to afford, after cleavage, the indole 165 in 75% overall yield from
Rink amide resin and in 94% purity. However, replacement o f THF w ith NM P (180
°C, 10 min) decreased both the yield (61%) and purity (85%) o f indole 165,
presum ably due to cleavage o f the product from the resin (entry 3 vs. entry 4, Table
12).
T able 12. Cyclization results o f resin-bound 2-alkynylanilides 173 w ith or without
m icrowave irradiation
Entry
165: A r
n
Cat (eq)a
Yield
Purity
(%)b
(%r
T (°C); t (min)
1
P-CF3C6H4
2
Pd(II) (0.1)
75; 300d
65
7 5
2
P-CF3C6H4
8 ' Pd(II) (0.5)
80; 240e
70
80
3
p-C f 3c 6h 4
8
Pd(II) (0.2)
160; 10f’h
75
94
4
W-CF3C6H4
4
Pd(II) (0.2)
180; 10d’h
61
8511
5
P-CF3C6H4
3
Cu(II) (1.0)
8 5 ; 1440s
j
6
o-CF3C6H4
2
Cu(II) (1.0)
160; 15f>h
56
70
7
w -CF3C6H4
3
Cu(II) (1.0)
180; 10s’h
68
70
8
m-C F3C6H4
2
Cu(II) (1.0)
200; 10d’h
82
98
9
0-CF3C6H4
3
Cu(II) (0.2)
200; 15d,h
70
80
aPd(II) = Pd(M eCN) 2 Cl2 ; Cu(II) = Cu(OAc) 2 . bYield was calculated based on
loading o f the commercial resin. cPurity was estimated by *H N M R o f the crude
product m ixture. The m ajor impurity is the unreacted substrate. dIn NMP. Tn DMF.
fIn THF. gIn CICH 2 CH 2 CI. hWith m icrowave irradiation. ‘Unidentified impurity was
detected. JThe substrate was recovered.
80
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
For the m icrowave-assisted Cu(OAc) 2 -promoted cyclization, the best results (82%
yield and 98% purity) were obtained in NM P at 200 °C for 10 min. Low er reaction
tem perature (entries
and 7 vs. entry 8 , Table 12) or less catalyst loading (entry 9 vs.
6
entry 8 , Table 12) reduced the yield and purity.
A s given in Table 13, a small library o f 12 indoles w ith two points of diversity was
T able
13.
Synthesis
o f indoles
165 via microwave-assisted cyclization
of
resin-bound 2-alkynylanilides 173
Entry
165: A r
-CF 3 C 6 H 4
n
MS
Method"
Yield (%)b
Purity (%)c
2
481
A
70
99
1
0
2
o-CF 3 C 6 H 4
3
495
B
72
95
3
0
-CF 3 C 6 H 4
4
509
A
71
99
4
o-CF 3 C 6 H 4
8
565
A
65
99
5
m-CF 3 C 6 H 4
2
481
B
82
98
6
W-CF3 C 6 H 4
3
495
B
75
96
7
W-CF3 C 6 H 4
4
509
A
71
99
8
w -CF 3 CfiH4
8
565
A
6 8
99
9
p -C F 3 C 6 H 4
2
481.13
B
74
95
1 0
p -c f3c 6h 4
3
495
B
71
96
11
^ - c f 3c 6h
4
509
B
70
97
1 2
p-c f3 c 6 h 4
8
565
B
72
95
4
"Method A: 20 mol% Pd(M eCN) 2 Cl2, THF, 160 °C, 10 min, MW; M ethod B: 100
m ol% Cu(OAc)2, NMP, 200 °C, 10 min, MW.
bCalculated based on loading o f the commercial resin.
cD eterm ined by HPLC. The structure was confirmed by *H NM R and MS.
81
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planned, before applying split-pool technology in the synthesis o f a full-scale library,
for the confirmation o f every key reaction including conversions, purities, and
toleration o f substituents on the benzenoid ring. Indoles 165 were synthesized with
M ASPOS
as
the
key
step
(167—>168—>172—>173->165).
via
Table
the
synthetic
13
shows
sequence
two
sets
described
of
results
above
with
Pd(M eCN) 2 Cl 2 and Cu(OAc ) 2 as the catalyst, respectively. In all cases, purities o f
>95% for the crude products 165 were obtained w ith estimated overall yields o f
56-82% calculated from the commercial Rink amide resin. A ll m em bers o f the
library w ere characterized by LC-M S analysis and the m olecular structures o f 165
w ere confirmed by 'H NM R. All LC-MS data o f the indoles 165 are sum m arized in
Table 13.
4.4.3.
C onstruction o f a 96-m em ber indole library
A fter successfully generating a small indole library via the M ASPOS technique, w e
w ere encouraged to construct a large one by the method described above. We
planned to synthesize a new library, which consists o f 96 indole members, using the
M ASPOS as the key step via the multiple-step synthetic sequence. These m ainly
include: (i) palladium -catalyzed coupling o f alkynes with aryl triflate using /7 -BU4 NI
as a prom oting additive; (ii) reduction o f nitrobenzamides into the corresponding
amines by SnC L^PLO in NM P; (iii) sulfonylation w ith excess A rS 0 2Cl in
pyridine-CPLCL m ixed solvent; (iv) Cu(II)-mediated-cyclization under m icrowave
irradiation; and (v) base-m ediated hydrolysis.
In the cyclization step, Cu(OAc ) 2 was preferentially selected as the catalyst since it is
cheaper than Pd(M eCN) 2 Cl2 . We expanded the size o f the indole library by using
82
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
various
ArSCLCI
for the
form ation
of sulfonamides
173
and
found that
m icrowave-assisted Cu(II)-m ediated ring closure o f 173 tolerated a variety o f
functional groups in the sulfonamide subunit, including the F-, C1-, MeO-, CF30 -,
and alkyl-substituted phenyl, and thienyl groups. Structures and purities o f 48 indoles
165 w ere confirmed by MS and HPLC, respectively. The results are illustrated in
Table 14. Figure 10 shows the typical profile for LC-M S data o f 165.
NaOMe, MeOH
165
166
Schem e 41. Base-m ediated cleavage o f A-acylindoles.
A fter deprotection o f the butyryl group in indoles 165, another 48 indoles 166 were
obtained (Scheme 41). Initially, w e tried to carry out the hydrolysis o f the
resin-bound arenesulfamoylindoles 174 (Scheme 40, page 79) using t-BuOK on
solid-phase,
unfortunately,
deacylation
could
not
complete.
However,
the
post-m odification o f indole structures 165 was successfully by using NaO M e (1.0 eq)
in M eOH at room tem perature for 1 h, giving indole structures 166. Finally, the
indole products 166 in the indole library w ere formed by NaO M e-m ediated
deprotection. A ll members were characterized by LC-MS analysis and structures
w ere confirmed by
H NM R and/or MS. The results are illustrated in Table 14.
Figure 11 shows a typical example o f LC-MS data for 166.
83
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
03/24/03 02:03:59 PM
F:\X calibui\da1a\Chem\ch00465
RT: 0 .0 0 -5 1 .3 1
RT: 10.56
MA 113145707
6.57E6
6500000-
C hann el A
6 000000-;
5500000^
5000000-:
H
,^ N
45 0 0 0 0 0 “
NH
O
4000000-:
^3500000:
2
■nPr
3000000^
Purity 94%
2500000^
C 23H 24F3N 3O 4S
2000000-j
Exact Mass 495.14
1500000-;
10 00000-:
50000CF;
2 3 J 3 26.&0 28.53 30.91
F:\X calibur1data\Chem\ch00465
33.76
38.28
4 2 £ B 44.19
4 7 .2 7
50.44
03/24/03 02:03:59 PM
ch 0 0 4 6 5 # 6 3 7 RT: 10.63 AV: 1 NL: 3.89E7
T: + cE S I Full m s [100.00-1200.00]
[M+l]
I 45“
§
42.7.19
389.-38
Figure 10.
L C - M S d a ta o f
165
1012.35
600.12,
1 1030.12 1095.(
( n = 3 , A r = W -C F 3 C 6 H 4 ). H P L C s e t ti n g : 5 0 %
C H 3 C N i n H 20 ( v / v ) w i t h 0 .1 % a c e t i c a c id ; U V d e t e c t i o n a t 2 5 4 n m ; f l o w r a t e
a t 0 .8 m L / m i n .
84
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
F:\X calibur\data\C hem \ch00588
07/25/03 10:37:04 AM
GDS-IL-34B
RT: 0 .0 0 - 4 4 .9 7
RT: 6.29
MA: 4 1 4 2 6 8 2 9
Purity 100%
i
C 19H 18F3N 3O 4S
Exact Mass 441.10
1 4 0 0 00 0 “
T in e (min)
F:\X calibur\data\C hem \ch00588
07/25/03 10:37:04 AM
GDS-IL-34B
[M+l]'
25z
A43(
[2M]
1019,17
F ig u r e 11. L C -M S d a ta o f 1 6 6 (n = 3, A r =
4
1120-20 1 1 5 7 7 2
- F 3 C O C 6 H 4 ). H P L C s e t t i n g : 5 0 %
C H 3 C N i n H 2 O ( v / v ) w i t h 0 .1 % a c e t i c a c id ; U V d e t e c t i o n a t 2 5 4 n m ; f l o w r a t e
a t 0 .8 m L / m i n .
85
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 14. Results of the 96-member indole library (part a)
Indole
Ar
n
Mass
Yield (%)
Purity (%)
165-01
3-ClC6H4
2
447
68
100
165-02
3-ClC6H4
3
461
60
100
165-03
3-ClC6H4
4
475
59
100
165-04
3-ClC6H4
8
531
58
100
165-05
3,5-Cl2C6H 3
2
481
66
93
165-06
3,5-Cl2C6H 3
3
495
47
95
165-07
3,5-Cl2C6H 3
4
509
46
91
165-08
3,5-Cl2C6H 3
8
565
30
98
165-09
4-FC6H4
2
431
91
100
165-10
4-FC6H4
3
445
65
94
165-11
4-FC6H4
4
459
53
97
165-12
4-FC6H4
8
515
49
97
165-13
2,3,4-F3C6H2
2
467
90
91
165-14
2,3,4-F3C6H2
3
481
72
90
165-15
2,3,4-F3C6H2
4
495
70
90
165-16
2,3,4-F3C6H2
8
551
55
88
165-17
4-/-PrCeH4
2
455
87
97
165-18
4-/-PrC6H4
3
469
80
96
165-19
4-/-PrC6H4
4
483
64
94
165-20
4-/-PrC6H4
8
539
64
94
165-21
4-M eOC6H4
2
443
88
96
165-22
4-M eOC6H4
3
457
73
95
165-23
4-M eOC6H4
4
471
75
98
165-24
4-M eO C6H4
8
527
72
96
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 14. Results of the 96-member indole library (part b)
Indole
Ar
n
Mass
Yield (%)
Purity (%)
165-25
4 -N 0 2C6H 4
2
458
61
96
165-26
4 -N 0 2C6H 4
3
472
24
100
165-27
4 -N 0 2C6H4
4
486
20
83
165-28
4 -N 0 2C6H4
8
542
18
82
165-29
2-thiophenyl
2
419
73
99
165-30
2-thiophenyl
3
433
66
95
165-31
2-thiophenyl
4
447
72
97
165-32
2-thiophenyl
8
503
57
97
165-33
4-CF3OC6H4
2
497
82
96
165-34
4-CF3OC6H4
3
511
56
94
165-35
4-CF3OC6H4
4
525
45
96
165-36
4-CF3OC6H4
8
581
38
100
165-37
2-CF3C6H4
2
481
81
97
165-38
2-CF3C6H4
3
495
62
95
165-39
2-CF3C6H4
4
509
56
96
165-40
2-CF3C6H4
8
565
52
96
165-41
3-CF3C6H4
2
481
79
95
165-42
3-CF3C6H4
3
495
81
94
165-43
3-CF3C6H4
4
509
49
98
165-44
3-CF3C6H4
8
565
45
100
165-45
4-CF3C6H4
2
481
75
95
165-46
4-CF3C6H4
3
495
64
96
165-47
4-CF3C6H4
4
509
60
98
165-48
4-CF3C6H4
8
565
57
94
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 14. Results of the 96-member indole library (part c)
Indole
Ar
n
Mass
Yield (%)
Purity (%)
166-01
3-ClC5H4
2
377
56
99
166-02
3-ClC6H4
3
391
49
99
166-03
3-ClC6H4
4
405
38
a
166-04
3-ClC6H4
8
461
34
99
166-05
3,5-Cl2C6H3
2
411
62
92
166-06
3,5-Cl2C6H3
3
425
41
a
166-07
3,5-Cl2C6H3
4
439
41
86
166-08
3,5-Cl2C6H3
8
495
27
93
166-09
4-FC6H4
2
361
66
98
166-10
4-FC6H4
3
375
57
86
166-11
4-FC6H4
4
389
51
87
166-12
4-FC6H4
8
445
44
90
166-13
2,3,4-F3C6H2
2
397
73
85
166-14
2,3,4-F3C6H2
3
411
52
86
166-15
2,3,4-F3C6H2
4
425
49
85
166-16
2,3,4-F3C 6H2
8
481
41
85
166-17
4-/-PrC6H4
2
385
67
88
166-18
4-i-PrCr,H4
3
399
54
88
166-19
4-i-PrC6H4
4
413
55
81
166-20
4-/-PrC6H4
8
469
46
88
166-21
4-M eOC6H4
2
373
71
92
166-22
4-M eOC6H4
3
387
57
94
166-23
4-M eO C6H4
4
401
58
80
166-24
4-M eO C6H4
8
457
50
86
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 14. Results of the 96-member indole library (part d)
Indole
Ar
n
Mass
Yield (%)
Purity (%)
166-25
4 -N 0 2C6H4
2
388
37
95
166-26
4 -N 0 2C 6H4
3
402
13
95
166-27
4 -N 0 2C6H4
4
416
11
95
166-28
4 -N 0 2C6H4
8
472
10
90
166-29
2-thiophenyl
2
349
65
94
166-30
2-thiophenyl
3
363
48
94
166-31
2-thiophenyl
4
377
59
92
166-32
2-thiophenyl
8
433
45
70
166-33
4-CF3OC6H4
2
427
59
95
166-34
4-CF3OC6H4
3
441
36
100
166-35
4-CF3OC6H4
4
455
32
91
166-36
4-CF3OC6H4
8
511
33
93
166-37
2-CF3C6H4
2
411
63
90
166-38
2-CF3C6H4
3
425
45
94
166-39
2-CF3C6H4
4
439
39
96
166-40
2-CF3C6H4
8
495
38
a
166-41
3-CF3C6H4
2
411
61
88
166-42
3-CF3C6H4
3
425
48
94
166-43
3-CF3C6H4
4
439
43
86
166-44
3-CF3C6H4
8
495
39
91
166-45
4-CF3C6H4
2
411
65
92
166-46
4-CF3C6H4
3
425
50
95
166-47
4-CF3C6H4
4
439
39
85
166-48
4-CF3C6H4
8
495
36
95
aSample decomposed during LC-M S analysis.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
4.5.
Conclusion
In summary, w e have successfully developed a new synthetic route by applying
M ASPOS to the solid-phase synthesis o f a C5 arenesulfamoyl-substituted indole
library, w hich features a combination o f m icrowave-assisted fast organic reaction
w ith solid-phase combinatorial chemistry technology for production o f high-quality
single-m olecule libraries. In this synthetic process, the Sonogashira cross-coupling
reaction o f
2
-carboxamidophenyl triflates with terminal alkynes was successfully
transferred to solid-phase; reduction o f nitro group and the following sulfonylation
proceeded smoothly under m ild conditions; and the m icrowave-assisted Cu(II)- or
Pd(II)-catalyzed cyclization o f 2-alkynylsulfonamides on solid-phase gave indole
products as the key step. This microwave-assisted Cu(II)-catalyzed cyclization can
tolerate a variety of functional groups in the sulfonamide subunit, including the F-,
C1-, M eO-, CF 3 O-, CF 3 - N O 2 - , and alkyl-substituted phenyl, and thienyl groups.
Our synthetic m ethod allows facile introduction of three points o f diversity through (i)
functional groups in the sulfonamide subunit; (ii) carbon chain at C2 position of
indole; and (iii) protection or deprotection o f N —H at N1 position o f indole.
Therefore, a 96-member indole library was finally constructed using this M ASPOS
strategy combined w ith split-pool synthetic technology in good overall yields with
high purities.
90
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Chapter 5
M icrowave-Assisted Traceless
Sol id-Phase Synthesis o f Indoles
5.1.
Introduction
The im portant biological activities o f heterocycles have attracted a great deal o f
interests in the development o f synthetic strategies for generating heterocyclic
libraries on solid supports. In general, compound libraries synthesized on solid-phase
leave the polar support attachment functionality, such as, COOH, CO NH2) OH, SH,
and N H 2 incorporated into the product structures. These invariable functional groups
m ay lim it the biological studies. Therefore, to this end, one challenging for
solid-phase synthesis o f heterocyclic compounds has been the developm ent o f
m ethods to synthesize target m olecules w hich lack functional groups after leaving
from the linkers. The term o f traceless solid-phase synthesis refers to such a strategy
that has been widely used in the solid-phase synthesis o f heterocycle libraries.66'1’83
Owing to the biological importance of indole nucleus, several efficient synthetic
approaches for the construction o f indole-based combinatorial libraries have been
devised on solid supports.84’66,67 Also, a num ber o f traceless strategies have been
developed in solid-phase synthesis o f indoles,87 such as THP linker, sulfonyl linker,
DEM linker, and chameleon catch strategy, etc.
In Chapter 4, w e have developed a solid-phase synthetic strategy for the construction
o f the arenesulfamoylindole library, w hose members possess a CONH2 group in the
substituent to the indole ring. As an extension o f our interests in diversity-oriented
synthesis
for
heterocyclic
compounds,
we
planned
to
introduce
a
novel
spacer-m odified linker for the traceless synthesis of indole library on solid-phase.
91
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The key point is to use the indole JV-H as the resin attachment site for constructing
N -free arenesulfamoylindole derivatives after cleavage from the resin.
5.2.
Traceless solid-phase organic synthesis
Solid-phase organic synthesis has exhibited a num ber o f advantages for the
construction o f small molecules over traditional solution synthesis. For a successful
solid-phase synthesis to be practical, several important factors need to be considered,
including the correct choice of solid support and the m ode o f attachm ent and
cleavage o f m aterials from the resin matrix.
Efficiency in anchoring and rem oving a small organic molecule from the polymeric
resin relies on the correct choice o f the linker group. This key fragment is crucial in
planning a synthetic strategy.
Linkers are classified as two types according to the residues cleaved from resin:85 (i)
norm al linkers, leaving a residue attached to the cleaved molecule, which is the
functional group (or a derivative thereof) such as a carboxylic acid, an amide or an
alcohol; and (ii) traceless linkers, that is, the linkers do not leave an obvious residue
on the cleaved product. A traceless linker is defined as one w here a new
carbon-hydrogen (should include heteroatom -hydrogen) or carbon-carbon bond is
form ed at the linkage site o f the cleaved molecule. In solid-phase synthesis of
heterocyclic compounds, N— H linkers result in N— H bond in the seceding
molecule. The advantage of traceless linker is to form the cleaved product m olecules
in high purity because the cleavage reaction can be designed so that only the desired
product can be cleaved selectively from the resin. Due to the influence o f the linker
residue on the potential m edicinal efficacy o f the final drug-like molecules, design o f
traceless linkers has drawn the attentions and played an important role in the
synthesis o f small organic m olecules on solid-phase.
92
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Some know n traceless linkers include86 the followings: (i) silicon linkers; (ii)
germ anium linkers; (iii) sulfur linkers; (iv) selenium linkers; (v) nitrogen linkers; (vi)
phosphorous linkers; (vii) boron linkers; and (viii) chromium linkers, etc.
Traceless solid-phase synthesis861’83 refers to synthetic route yielding the cleaved
products w ithout residues from resin, w hich includes (i) using traceless linkers; (ii)
cyclative
cleavage
m odification.
(cyclization-cleavage)
These three traceless
strategy;
solid-phase
and
synthetic
(iii)
post-cleavage
strategies
will
be
demonstrated in the following examples.
5.2.1.
U sage o f traceless linkers
Traceless linkers have been widely used in the synthesis o f heterocycles on
solid-phase. For example, Ellm an et a/.87a,b first described a silicon-based traceless
linker and used it in the synthesis o f 1,4-benzodiazepine derivatives (Schem e 42).
The building block was first synthesized in solution and was then loaded onto the
NH2
fj
T
Sj^
1. R1COCI, Pd2(dba)3
SnMe3
.0
2. 3% TFA in CH2CI2
R1
175
176
NHFmoc
1. lithiated
oxazolidinone
2. 20% piperidine
3. 5% AcOH
177
1. TFA, H20, Me2S
2. aqueous HF
178
Schem e 4 2 . 1,4-Benzodiazepine synthesis based on silicon traceless linker.
93
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(am inomethyl)polystyrene resin. The resin-bond arylstannane 175 w as coupled with
acid chlorides via the Stille reaction followed by deprotection o f the Boc group to
give the
resin-bound
aniline
176.
This
compound was
acylated
with
an
A-Fmoc-amino acid fluoride, and the protecting group was then removed. The
interm ediate was
cyclized under the m ild
acidic
conditions to
afford the
support-bound benzodiazepine derivatives 177. Deprotonation and alkylation gave
the fully functionalized derivatives with three points o f diversities. A ny amino acid
side chain protecting groups were rem oved by TFA, and the target compounds 178
w ere cleaved from the resin in aqueous HF without leaving any functional group.
A nother silyl lin k e r87c,d used in the synthesis o f pyridine-based tricyclic compound
w as described as given in Scheme 43.
\ /
Fv X I
Si
/ V
3 steps
►
179
^.NHBoc
X ' NX' 'Cl
180
5 or 6 steps
TBAF
THF
182
181
Schem e 43. Synthesis o f pyridine-based tricyclic compound by using a silyl linker.
5.2.2.
Cyclative cleavage
C y c liz a tio n —c le a v a g e , or c y c la tiv e c le a v a g e , is a v e r y o fte n u s e d tr a c e le ss stra teg y in
solid-phase organic synthesis. Cyclative cleavage includes two types, nucleophilic
displacem ent and ring-closing metathesis. Cyclative cleavage by nucleophilic
94
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displacem ent is a frequently used m ethodology whereby a nucleophile of an acyclic
precursor attacks an electrophilic group (e.g. CO) attached to the solid support,
displacing a resin-bound leaving group and forming a ring (generally five-, six, or
seven-membered). A valuable advantage o f this approach is that only cyclic
compounds are released from the resin, and therefore the purity of the target products
is high.
Cyclative cleavage has been developed into a powerful tool for traceless solid-phase
synthesis o f heterocyclic compounds. As shown in Scheme 44, a very simple and
robust route was devised by Smith et a/.87e for the synthesis o f 1,3-disubstituted
quinazoline-2,4-diones. Anthranilic acids 184 were linked to chloroform ate resin 183
through the nitrogen atom, the carboxylic acids 185 were activated and reacted with
amines to form linear precursors 186 o f the target compounds. The cyclization
cleavage was performed upon exposure o f 186 to elevated tem perature to give
quinazolinediones 187 in high purities.
COOH
.COOH
CONH-R'
PyBOP, NMP
Schem e 44.Traceless synthesis o f quinazoline-2,4-diones on solid-phase by
cyclative cleavage.
95
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A nother example is the synthesis o f l,4-benzodiazepine-2,5-diones 191 described by
M ayer et al.m as given in Scheme 45. The Fmoc-protected amino esters were treated
w ith
piperidine,
and
the
liberated
amino
group
was
acylated
either
by
Fm oc-protected anthranilic acids or o-nitrobenzoic acids. After either Fmoc rem oval
or nitro group reduction, the cyclization cleavage was prom oted by NaCfr-Bu in THF
to give the target products in high purities.
u
A
NHFmoc
1.
20% piperidine, DMF
2. /V-Fmoc-anthranilic or
o-nitrobenzoic acids
R1
188
O
NHFmoc
189
20% piperidine
DMF
,
NH
O
- — R 2
NaOf-Bu
THF, 60 °C
191
o VR 1
O
NH2
190
Schem e 45. Traceless synthesis o f l,4-benzodiazepine-2,5-diones
by cyclative cleavage.
5.2.3.
Post-cleavage m odification
It has been reported that post-cleavage modification is also a compelling approach
for traceless solid-phase synthesis. The modification to the target m olecule
proceeded spontaneously during the cleavage step has been the m ost frequently used
m ethod in the synthesis o f heterocyclic compounds, where the cleavage agents result
in not only cleaving from resin but also generating the target structures, including
cyclization reactions, decarboxylation, and oxidation. On the other hand, the cases in
a separate post-cleavage offer the opportunity to evaluate the properties o f both the
prim ary cleavage products as well as the compounds obtained by subsequent
96
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m odification.
A n exam ple involving post-cleavage was described by Krchnak et al.(:bc (Scheme 46).
The precursor 193 was constructed on solid-phase followed by cleavage from the
resin to give 194, which w ere subjected to subsequent cyclization in a separate step
to the target products in solution.
'N
H
R1
3 steps
►
NH
192
193
gaseous HF
\
HN’
R2- iT y
^ ^ N
V
-A
’
,
R3
NH
MeCN
195
-R1
194
Scheme 46. Traceless solid-phase synthesis o f quinazolinones by
post-cleavage modification.
In summary, traceless synthesis is an important and useful strategy in solid-phase
organic synthesis o f compound library. To a successful synthetic approach, several
factors need to be taken into account such as the choice o f the linkage method,
practical usefulness o f linker, and successful cleaving conditions.
5.3.
Traceless solid-phase synthetic m ethodologies toward indoles
A s a useful synthetic strategy on solid-phase, traceless linkers have been used in the
synthesis o f indole libraries. Synthesis o f 2,3-disubstituted indoles using the THP
97
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linker878 provides an example o f traceless heterocycle synthesis in which the nitrogen
atom o f the product is linked to an electron-rich carbon atom. 2-Iodoaniline was
loaded onto THP linker resin 196, followed by Pd(0)-m ediated reaction with
acetylenes according to the Larock reaction in the presence o f a base to form the
indole nucleus 197 (Scheme 47). The free indoles 198 were obtained after cleavage
from the resin by 10% TFA in CH 2 CI2 . Complete regioselectivity was observed for
three out o f four acetylenes.
196: Ellman THP resin
R
Pd(PPh3)2CI2
TMG, DMF
197
198
Schem e 47. Traceless synthesis o f 2,3-disubstituted indoles using a THP linker.
A n activating sulfonyl linker was used by Zhang et a/.87h for the traceless synthesis
o f indole derivatives. A s outlined in Scheme 48, 2-iodoaniline was loaded onto the
PS-TsCl resin 199 followed by the palladium-mediated coupling-annulation with
term inal alkynes to give the resin-bound 2-substituted indoles 200 , w hich w ere
subjected to cleavage by TBAF to release the free 2-substituted indoles 91 in
excellent purities and yields. Alternatively, a direct m ercuration o f the indole at the
C3 position gave 3-indolylmercury, w hich was m ethyl acrylated using a palladium
98
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catalyst. Cleavage w ith TBFA released the 2,3-disubstitutede indole derivative in a
m oderate yield. Later on, this linker was used in the synthesis o f 2,3,5-trisubstituted
indoles by Schultz et al.
87i
pyridine
TBAF
Pd(PPh3)2Cl2, Cul
Et3N, DMF
Schem e 48. Traceless solid-phase synthesis by sulfonyl linker.
A nother example of the traceless synthetic approach o f indoles, was developed by
M acleod et al.,87j w herein a novel titanium(IV) benzylidene regents that allowed the
traceless solid-phase synthesis o f indoles in high purity using a chameleon catch
approach. Titanium benzylidenes were prepared from thioacetals and a lower-valent
titanium , Cp2Ti[P(OEt)3]2 . The Boc group was rem oved by treating w ith 20% TFA in
CH 2 CI2 to give free indoles 202 in high purities.
T iC p 2
,2 _ L
„Ck ^R1
y
SiMe^
_________ : r >
2. 1% TFA, CH2CI2
r 2- e
[ V
ri
^
20% TFA
>
r 2-
£
i v
r
1
Boc
2 0 1
2 0 2
Schem e 49. Traceless solid-phase syntheses by a chameleon catch approach.
99
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1
Recently, Nicolaou et al.25a illustrated an efficient selenium-based linking strategy
for the solid-phase synthesis o f 2-methylindoles and indolines, which could be
elaborated and cleaved in a traceless manner, providing the m edicinally important
products.
On the other hand, the indole-based linkers have been developed for the synthesis of
sm all m olecules on solid-phase. For example, a new versatile indole-based traceless
linker described by Estep et a/.88a,b has been used to access to the ureas, secondary
amides, sulfonamides, carbamates, and guanidines. Another indole-based linkage has
been
reported
for the
synthesis
o f 2-
and
3-piperazinylm ethyl-substituted
OOi
cyanoindoles,
00„
and for M annich and Stille reactions on indole nucleus.
The indole N H as a resin attachment point leads to effective linking o f indoles, which
can be cleaved in a traceless manner. So we decided to design a traceless approach
by attaching the NH o f indole to the solid-support for the indole synthesis via the
Pd-catalyzed
cross-coupling-heteroannulation
approach
described
in
previous
Chapters. The key aspect of our approach is to use a suitable acyl spacer which
attaches
onto
the
nitrogen
atom
and
tolerates
the
m icrowave-assisted
heteroannulation in the presence o f a metal species.
5.4 .
5.4.1.
Results and discussion
Spacer effect on cyclization of 2-alkynylanilides under
microwave irradiation
2-Bromo-4-nitroaniline 203 was selected as the starting material, w hich was prepared
from comm ercially available 4-nitroaniline in high yield (92% ).90b Our initial
strategy was to prepare the resin-bound 2-bromo-4-nitroanilides 206a,b possessing a
spacer betw een the substrate and the linker.
100
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-Br
OMe
0 2N''V^ 5^ ' Br
u c NH?
O (1-1 eq)
X X‘NH
DMAP (1.5 eq), THF
160 °C, 20 min, MW
■-'J ( ' V
2 0 4 a : n = 1 (78%)
20 4 b : n = 2 (85%)
203
aq 1% LiOH, THF
rt, 12 h
-Br
0?N
^^N H
linker
substrate
spacer
OH
PS
c
2 0 5 a : n = 1 (89%)
2 0 5 b : n = 2 (88%)
H?NHOBt, DIC
DMF, rt, 24 h
2 0 6 a : n = 1 (trace)
2 0 6 b : n = 2 (90%)
Schem e 50. Synthesis o f resin-bound 2-bromo-4-nitroanilides.
A s shown in Scheme 50, the microwave-assisted acylation o f 2-brom o-4-nitroaniline
w ith m ethyl succinic chloride was carried out in the presence o f DM AP at 160 °C for
20 m in to provide 204a in 78% yield, which could be obtained only in trace amount
under refluxing in THF for 24 h due to the weak reactivity o f 2-brom o-4-nitroaniline.
Saponification o f 204a in the presence o f 1% lithium hydroxide gave the acid 205a
in high yield. Then, 205a was loaded onto the deprotected Rink amide resin under
the standard coupling conditions, but only a trace product 206a was observed after
cleavage from the resin in 20% TFA. Similarly, w e tried to use m ethyl adipoyl
chloride to react w ith 2-bromo-4-nitroaniline by following the same reaction
sequence to afford 206b in 90% yield after cleavage from the resin, and the structure
101
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w as confirm ed by JH NM R. These results showed that the length of the spacer
betw een the resin linker and the building block m ight play an important role in the
coupling reaction o f the substrate 205a,b on solid-phase.
o 2n
Ph-
(10 eq), Cat.
Cul (30 mol%), Et3N-DMF (1:5)
80 °C
O
206b
Ph
Ph
20% TFA Q2N
o 2n
nh2
c h 2c i 2
o
o
208
207
Cat. = Pd(PhCN)2CI2 (10 mol%), o-PhC6H4P(f-Bu)2 (20 mol%), 48 h (98%)
Pd(PPh3)2CI2 (10 mol%), PPh3 (20 mol%), 8 h (96%)
Schem e 51. Pd-catalyzed cross-coupling o f the resin-bound 2-bromoanilide.
A s shown in Scheme 51, the cross-coupling reaction o f the resin-bound bromoanilide
206b w ith phenylacetylene was examined under different sets o f conditions. The
palladium -catalyzed coupling o f aryl bromides or iodides w ith term inal alkynes, has
been frequently used in the solid-phase organic synthesis.89 Initially w e used 10
m ol% Pd(PPh 3 )2Cl 2 , 20 mol% o-PhCe,H4 P(/-Bu) 2 , and 30 mol% Cul as the catalyst
system. The reaction occurred smoothly in Et3N -D M F at 80 °C for 48 h to give 208
in 98% yield after cleavage from the resin. W hen using 10 mol% Pd(PPh 3 ) 2 Cl 2 with
20% PPh 3 , the coupling reaction tim e decreased to 8 h at the same temperature.
Follow ing the conditions used in Chapter 4, the reduction o f nitro group in 207 and
subsequent sulfonylation were carried out successfully to form 209 in high yield and
purity, as examined by 'H N M R after cleavage from the resin (Schem e 52). However,
102
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the Cu (Il)-catalyzed cyclization failed to provide the product 210 under m icrowave
irradiation at 200 °C in NM P for 10 min. A complex m ixture was obtained after
cleavage from the resin. Also, the attempts to use other catalysts such as
Pd(M eCN) 2 Cl 2 , and Cu(OTf ) 2 were not successful.
1. C u(OAc)2 (2.0 eq), NMP
10 min, 200 °C
2. 20% TFA in CH2CI2
O
H
209: Ar = 4-CF3C6H4
O
210 (trace)
211
O
Schem e 52. Attem pted Cu(II)-catalyzed heteroannulation to indoles via MASPOS.
Com pared w ith the successful results from the microwave-assisted intramolecular
cyclization o f 2-alkynylanilides 173 (page 79) on solid-phase using Cu(OAc ) 2 as the
catalyst, the failure in the substrate 209 seems to be related to the attachment site o f
the spacer on the substrate.
We prepared the resin-bound 211 from m ethyl sebacoyl chloride by following the
same procedures as used for 209. However, the cyclization reaction also encountered
difficulty. The desired indole product could not be detected after cleavage from the
resin.
Therefore, w e turned our attention to modify the spacer betw een the substrate and the
linker by extending the chain length with glycine units (Scheme 53). Fm oc-Gly-OH
103
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w as loaded onto the deprotected Rink amide resin through the C-term inal carboxyl
under the standard conditions91 to produce resin 212a using activating reagent HOBt
(5.0 eq) and DIC (5.0 eq) in DMF at 20 °C for 24 h, the resultant resin w as negative
to the Kaiser ninhydrin test.91 In 1992, Wang et al.15 first reported that microwave
irradiation could enhance coupling efficiency in solid-phase peptide synthesis. Under
m icrowave irradiation conditions, the peptide fragments have higher reactivity and
the reaction tim e (2-3 h at room temperature) decreased to 6 min at 60 °C. We tried
the coupling reaction o f the deprotected Rink amide resin w ith Fm oc-Gly-OH under
m icrow ave irradiation on an Emrys creator from Personal chemistry AB. After 5 min
at 120 °C in DMF, the coupling reaction was completed and the resin was negative to
the K aiser ninhydrin test. After cleaving from the resin, the Fm oc-protected
2-am inoacetam ide was released in 95% yield and the structure was confirm ed by H
NM R. The loading o f the m odified resin was calculated according to the peptide
resin loading protocols.100 It was estimated that the loading o f the resin 212a
increased from 0.56 m m ol/g to 0.65 mmol/g, for the peptide bond form ation under
m icrowave irradiation in comparison w ith the same reactant at room tem perature. It
corresponds to an increase o f yield for 212a from 85% to 95% calculated from the
original loading o f the Rink amide resin (0.70 mmol/g).
A s illustrated in Scheme 53, the second amino acid unit was readily attached to the
resin 212a under microwave irradiation conditions to give the resin-bound dipeptide
212b. Similarly, the third Fm oc-protected glycine was loaded onto the resin at room
tem perature for 2 h to give the resin-bound tripeptide 212c and the resin was
negative to the K aiser test. It indicated that coupling o f the second and third glycine
unit w as relatively easy than the formation o f 212a.
104
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NHFmoc
Rink amide resin
| a .b
O
O
KlX^ ^ N H F m o c
N
H
213a: n = 1
213b: n = 2
213c: n = 3
212a
| a,b (or c)
Reagentsandconditions:
(a) 20% piperidine, rt, 1 h;
NHFmoc
212b
(b) Fmoc-Gly-OH (5.0 eq), HOBt (5.0 eq),
DIC (5.0 eq), DMF, 120 °C, 5 min, MW;
(c) Fmoc-Gly-OH (5.0 eq), HOBt (5.0 eq),
DIC (5.0 eq), DMF, rt, 2 h.
| a,b (or c)
Jv^NHFmoc
212c
Schem e 53. M icrowave-assisted m odification o f Rink amide resin by glycine units.
The building block 205b (Scheme 50, page 101) was then attached to the three resins
212a, 212b, and 212c, respectively, to form the three resin-bound substrates 2 13a-c
possessing the peptide-m odified spacers. Through the similar cross-coupling reaction,
reduction of nitro group, and sulfonylation as described above for the synthesis o f
209 and 211, the resin-bound 2-alkynylsulfonamide 214a-c with three peptide
dom ains w ere obtained (Scheme 54).
The cyclization o f 2 14a-c catalyzed by Cu(OAc ) 2 was conducted under m icrowave
irradiation. The substrate 214a w ith one glycine unit gave only trace amount of
indole product after cleavage from the resin, the substrate 214c w ith a tripeptide
m oiety gave a complex m ixture o f products, while the substrate 214b w ith a
dipeptide subunit gave the indole 215b in high purity after cleavage from the resin.
105
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LC-M S data o f 215b showed a purity o f 90% and the structure was confirmed by H
N M R analysis.
NH
Ar = 4-C H 3OC6H4
214a: n = 1
214b: n = 2
214c: n = 3
1. C u(OA c)2 (2 eq), NMP, 200 °C
10 min, MW
Y
i
VxN
2. 20% TFA, CH2CI2
h
n NH2
2 1 5 a : n = 1 (trace)
2 1 5 b : n = 2 (90%)
2 1 5 c : n = 3 (complex)
216
Schem e 54. Effect o f the peptide-m odified spacers on indole form ation via
MASPOS.
Thus, a rem arkable spacer effect was observed on m icrowave-assisted cyclization o f
2-alkynylanilides 214a-c on solid-phase. One possibility m ay be offered that the
three amide oxygen atoms in 214b helps to bind Cu(II) through three amide oxygen
106
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
atoms as shown in the m odel 216, facilitating the C u(II)-alkyne complex form ation
and the subsequent heteroannulation. In this manner, the glycine-m odified spacer is
considered as a m etal-hunter from the solution and also acts as an essential co-factor
for the m etal-catalyzed reaction on solid-support. In the case o f 214c, the Cu(II)
coordination sites are saturated by the four amide oxygen atoms and it becomes inert
to the heteroannulation.
5.4.2.
Traceless synthesis o f an indole library
A s outlined in Scheme 55, a 16-member 2,5-disubstituted indole library was
synthesized on the m odified Rink amide resin with a dipeptide spacer unit, by using
the split-pool combinatorial chemistry and the IRORI radio frequency (/?/)-encoded
M icroKan reactors. Starting from the resin-bound 2-brormo-4-nitroanilide 213b, the
sulfamides 217 w ere synthesized via the Pd(PPh 3 ) 4 -C uI-catalyzed Sonogashira
cross-coupling reaction with four 1-alkynes followed by reduction of the nitro group
and sulfonylation w ith four aryl sulfonyl chlorides. The resin-bound 217 in each
reactor was then transferred to a 5-mL Emrys process vial together with the R f tag
and was subjected to the m icrowave-assisted Cu(II)-catalyzed cyclization on an
Emrys creator from personal Chemistry AB, to give the resin-bound indole
compounds 218. Initially, w e tried to release the spacer-free indoles 220 directly
from 218 by on-resin hydrolysis using NaO CH3-C H 3OH (1:1) at 60 °C or
pyridine-THF (1 : l) 92 at 60 °C, but unfortunately, only trace indole 220 was observed
after 12 h. Thus, the resin-bound 218 w as treated w ith 20% TFA in CH 2 CI2 to give
the indole 219, w hich was poured into 2 mL o f pyrrolidine-TH F (3:1) solution at 60
°C for 12 h to afford the free indole 220 in high purity (Table 15). A ll members o f the
library w ere characterized by LC-MS analysis and the m olecular structures were
confirm ed by 'H NMR. Indole derivatives were obtained in 89-100% purities and
107
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r = 4-CH3C6H4, 4-CH3OC6H4, Ph, n-Bu
Ar = 4-FC6H4, 4-CH3OC6H4 i 4-/-PrC6H4, 2-thiophene
Reagents and conditions: 1-alkynes, Pd(PPh 3 )2Cl 2 (0.1 eq), PPh3 (0.2 eq), Cul
(0.3 eq), Et3N -D M F (1:5), 80 °C, 8 h; (b) SnCl2*2H20 (1.0 M), NMP, rt, 24 h;
(c) A rS 0 2Cl (5.0 eq), Py-C H 2C12 (1:5), rt, 24 h; (d) Cu(OAc)2 (2.0 eq), 200 °C,
10 min, MW; (e) 20% TFA in CH2C12, 1 h; (1) pyrrolidine-TH F (3:1), 60 °C,
12 h.
Schem e 55. Traceless solid-phase synthesis o f indole library.
108
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m oderate yields, which were calculated from the loading o f the glycine-bound
resin 212a (0.65 mmol/g). Figures 12 and 13 show the typical LC-MS profiles of
the indoles. Interestingly, w e found that the fluorine group in the aryl sulfamide
unit was displaced by pyrrolidine during the post-cleavage operation, (entries 1 ,5 ,
9, and 13, Table 15).
Table 15. A 16-member indole library
Entry
220: R, A r
Yield (%)a
Purity (%)b
1
220a: 4-CH3C6H4,4-F C 6H4
49
98c
2
220b: 4-CH3C6H4,4-C H 30C6H 4
38
97
3
220c: 4-CH3C6H4,4-z-PrC6H4
45
97
4
220d: 4-CH3C6H4,2-thiophene
45
93
5
220e: 4-CH3OC6H4, 4-FC6H4
48
90c
6
22Of: 4-CH3OC6H4, 4-CH3O Q H 4
60
96
7
220g: 4-CH 3OC6H4, 4-i-PrC6H4
53
97
8
220h: 4-CH3OQ,H4, 2-thiophene
43
98
9
220i: Ph,4-F C 6H4
51
95c
10
2 2 0 j:P h ,4 -C H 3OC6H4
44
89
11
220k: Ph, 4-/-PrC6H 4
56
97
12
2201: Ph, 2-thiophene
46
98
13
220m: n-Bu, 4-FCeH4
47
96°
14
220n: «-Bu, 4-CH3OCeH4
51
100
15
220o: m-B u , 4-/-PrCfiH4
43
99
16
220p: n-Bu, 2-thiophene
59
99
aCalculated based on loading o f the glycine-bound resin.
bDeterm ined by HPLC. The structures w ere confirmed by H N M R and MS.
‘T h e fluorine atom in the A r group was displaced by 1-pyrrolidine.
109
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03/17A34 12:09:31 PM
F :\X ca lib u r\d a ta\C h em \ch 0 0 7 4 4
SU N -IV -37-4
RT: 0 . 0 0 - 4 4 . 9 7
RT: 2 0 .2 7
MA: 7 2 3 0 6 3 4 3 8
C hannel A
2600000C H
C h00744
24000000^
2200000CH
20000000-^
18000000”
16000000^
^ 14000000^
Purity 93%
12000000^
10000000^
C 2 5 H 2 5 N 3 O 2 S
Exact Mass: 431.17
800000060000004000000R T : 13.8
MA: 1 6 7 6 5 5 0 8
2000000-
8
-P?.-S--40
1 1 ,5 4
15.02
2 4 .4 3
-nfi s
2 5 .9 5 2 8 .7 4 3 0 .8 2
3 7 .7 8
4 1 .3 3 4 2 .4 1
T im e (m in)
F :\X c a llb u r\d a to \C h e m \c h 0 0 7 4 4
0 3 /1 7 /0 4 12:09:31 PM
c h 0 0 7 4 4 # 1 0 5 1 RT : 2 0 .2 7 AV: 1 NL: 3 .2 5 E 7
T: + c E S I Full m s [ 1 0 0 .0 0 -1 2 0 0 .0 0 }
[M+1]
s
[2M]
431,0.1..
8 5 7 ,9 5
1.87 9 7 4 .9 6
Wrtm ftfrrt
1 0 2 4 .0 6 1 0 9 8 .1 2
Iftv.il
1 1 3 4 .3 4
............
m /z
F ig u re 12. LC-M S data o f 220a. HPLC conditions: 60% acetonitrile with 0.1%
acetic acid; flow rate at 0.8 mL/min; UV detected at 254 nm.
110
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
0 3 /1 7 /0 4 0 3 :3 3 :3 7 PM
F :\X c a lib u rtd a ta \C h e m \c h 0 0 7 4 8
SU N -M -37-12
RT : 0 . 0 0 - 4 4 . 9 7
NL:
5 .2 4 E 7
RT: 8 .3 6
MA; 5 9 3 1 1 6 3 8 6
C hannel A
UV
ch00748
f~ I
H
s A IC O -O
Purity 98%
C-1 8 ^ 1 4 ^ 2 ^ 2 ® 2
Exact Mass: 354.05
RT : 3 .4 4
MA 1 1 0 7 5 5 7 6
1,31
1 4 ,2 2
7 .9 3
1 0 -1 3 1 0 6 7
1 5 ,6 6 . 1 6 .7 2 1 7 ,9 3
2 0 .9 7
2 5 .0 2 2 6 .7 5 2 8 .3 0
T
20
3 2 ,2 0 3 3 ,5 8
3 4 ,7 9 3 8 ,7 3 4 0 .0 0 4.1 ,C
25
T im e (m in)
F:\Xca lib u r \d a ta \C h e m 'c h 0 0 7 4 8
0 3 /1 7 /0 4 0 3 :3 3 :3 7 PM
SU N -IV -37-12
T: + c E S I Full m s (1 0 0 .0 0 -1 2 0 0 .0 0 )
[M+1]
[2M]
40r
3.5 5.95
71.Q.47
.3 5 7 .0 7
73.Q.49
73.1 .t
4 6 4 .7 7 551- 2 0
m /z
F ig u re 13. LC-MS data o f 220c. HPLC conditions: 60% acetonitrile with 0.1%
acetic acid; flow rate at 0.8 mL/min; UY detected at 254 nm.
Ill
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
5.5.
Conclusion
In summary, w e have established a novel traceless approach by m odifying the Rink
amide linker w ith a polyglycine spacer unit and have demonstrated the synthesis o f a
16-member indole library on solid-phase via MASPOS as the key step. The
polyglycine subunit was also synthesized on resin under m icrowave irradiation, so
that the Gly-Gly dipeptide was attached to the Rink amide resin in high yield. U sing
the spacer-m odified linker, the building block 2-bromo-4-nitroaniline, was loaded
onto the resin w ith the nitrogen atom as the site o f attachment. The resin-bound
2-alkynylanilides were prepared via the Sonogashira cross-coupling, reduction o f the
nitro group, and sulfonylation by the split-pool combinatorial synthesis .The
Cu(OAc) 2 -catalyzed heteroannulation toward indoles was successfully achieved on
resin under m icrowave irradiation. A remarkable effect o f the diglycine-containing
spacer unit on the heteroannulation was observed. It might be interpreted by binding
o f the tripeptide m oiety o f the spacer with Cu(II) and transporting Cu(II) from
solution onto the resin.
This finding m ay be useful for prom oting
other
m etal-catalyzed chemical transformations on resin. The resin-bound indoles were
cleaved from the resin and were subjected to post-cleavage m odification by
pyrrolidine to release the traceless indole products. The synthetic strategy enables the
introduction o f two points o f diversity on the indole ring with different arylsulfamoyl
groups at C5 position, and different substituents at C2 position. A library of
16-member indoles
was
efficiently
synthesized using
split-pool
solid-phase
technology in combination w ith M ASPOS in m oderate overall yields and in high
purities.
112
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Chapter 6
M icrowave-Assisted Solid-Phase
Synthesis o f a Benzimidazole Library
6.1.
Introduction
Benzim idazole is a crucial heterocyclic skeleton and represents an important
pharm m acophore in medicinal chemistry. It has received extensive attention in drug
discovery, especially after the comm ercialization of the antihistamine Astemizole
22193a and the antiulcerative Omeprazole 22293b,c (Figure 14). M olecules containing
the benzim idazole scaffold have shown a broad range o f biological activities,
including inhibition o f gelatinase B,93d selective inhibition o f the platelet-derived
grow th factor receptor,936 class III antiarrhythmic activity 223,93f PD GFR inhibitors
224,
angiotensin II receptor antagonism 225,93j
neuropeptide Y1
receptor
antagonism,93® antiproliferative activity,9311’1 inhibition o f phosphodiesterase IV,
inhibition o f proton pumps, antiviral properties 226,93k’' high affinity 5-H TiA receptor
ligands,
serine protease inhibitors, m icrosomal triglyceride transfer protein
inhibitors,93"1activity against hum an cytomegalovirus, and antiparasitic activity etc.
The diversification o f biological activities and close structural relationship to
benzodiazepines suggest that benzimidazoles be in the family o f “privileged
structures”, which represent a class o f m olecules capable o f binding to m ultiple
receptors w ith high affinity. The exploitation o f these molecules allows medicinal
chemists to rapidly discover biologically active compounds across a broad range o f
therapeutic areas. Due to the structural diversity of benzimidazole scaffold placed, it
has been an important tem plate for the diversity-oriented synthesis. For these reasons,
the benzim idazoles have drawn the attention for combinatorial synthesis/’6
113
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W e selected benzim idazole as a target scaffold for construction o f a library on solid
phase by applying M ASPOS. In this library synthesis, w e planned to establish an
efficient strategy for integration o f MASPOS with encoded split-pool combinatorial
synthesis (ESPCS).
MeO.
OMe
f Y V s /0
MeO
222: Antiuclcerative Omperazole
221: Aantihistamine Astemizole
^
^
Ms
Ms
/
^NS02—^
OMe
v
NHSQ2CH3
Me
224: PDGFR inhibitors
223: Class III antiarrhythmic
V
'N
r1
" 't X .
225: Angiotensin II receptor antagonism
226: Antiviral agent
F ig u re 14. Structures o f drugs based on the benzim idazole scaffold.
6.2. R ecent advances in the solid-phase synthesis o f benzim idazoles
Benzimidazoles have been efficiently synthesized for more than 100 years in solution
s in c e the first b e n z im id a z o le w a s prep ared in 1 8 7 2 b y H o e b r e c k e r .95
E ffic ie n t
preparation on solid-phase, however, dates back only about 10 years because
combinatorial chemistry did not begin to be widely adopted for the synthesis o f small
114
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m olecules until 1992. However, because o f their ease o f synthesis and precedence as
bioactive molecules, benzim idazoles have rapidly been an important target for the
developm ent o f solid-phase synthesis. Several synthetic routes have been reported
for the synthesis o f benzimidazoles on solid supports.94
The synthetic routes are categorized as two types, including non-traceless and
traceless strategies. In m ost o f the cases, o-fluoronitrobenzene derivatives (e.g. ofluoronitrobenzoic acid) or o-phenylenediamines have been used as the starting
m aterials and w ere attached to the resin, followed by nucleophilic substitution,
reduction o f the nitro group, and cyclization to afford benzimidazoles w ith functional
groups from the linker, such as COOH, CONH 2 and OH. A nother synthetic route
involved the traceless solid-phase strategy, in which 2-nitroanilines w ere attached to
the solid support, through alkylation, reduction, and cyclization to give traceless
benzim idazole products. As shown in Scheme 56, the key step o f these two routes
was the reduction o f the nitro group to obtain o-phenylenediamine 227 and 228. The
benzim idazole unit was then form ed by a cyclization reaction w ith various reagents
such as aldehydes, carboxylic acids, carboxylic anhydrides, acyl chlorides, XCN, and
triethyl orthoformic ester.
115
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N on-traceless approach
O
,NOz
H,N
NHR'
NHR
227
Tracelss approach:
NV ° '
a
no2°
x
N
228
Schem e 56. Synthetic routes to benzimidazoles.
W ei et al. described a pathway to benzimidazoles in 199 6 94°, as shown in Scheme 57.
3-Fluoro-4-nitrophenol w as attached to the TentaGel S-NH2 resin. A fter nucleophilic
aromatic substitution w ith prim ary aliphatic amines, the nitro group w as reduced to
give o-phenylenediamines. The benzimidazoles were form ed by treatm ent w ith ethyl
benzim idate hydrochloride in n-BuOH -D M F. A fter cleavage from the resin by using
TFA, a small library o f benzim idazoles 229 was prepared in high yields and purities.
NO?
amine
NH
1. NaBH4, Cu(acac)2
2-
TFA
NH HCI
R1
R2-K
OEt
229
Schem e 57. Solid-phase synthesis o f benzimidazoles by W ei et al.
116
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Tum elty et al.94k also described an example o f synthesis o f 2-amino- and 2-thiom ethylbenzim idazoles starting from 4-fluoro-3-nitrobenzoic acid and ArgoGel Rink
resin. A s described in Scheme 58, the resin bound o-phenylenediamines 230 reacted
with bromoacetic acid anhydride, followed by displacement o f the bromide 231 with
amines or thiols. Finally, on cleavage from the resin, the cyclization took place to
afford a library o f benzimidazoles 232 in good yields and high purities.
O
^NH;
A O C
s„
NH
1
Ar
230
(BrCH20 ) 2, DMF
1. R 1CH2, or
O
2. TFA
NH
i
Ar
232: X = NH, NR2, or S
231
Schem e 58. Synthesis o f benzimidazoles by Tum elty et al.
One exam ple o f traceless solid-phase synthesis o f benzimidazoles was dem onstrated
by Huang et a l 94> wherein the five-membered ring compound was constructed on the
side o f the solid support. A s outlined in Scheme 59, the building block 2nitroanilines were attached to p-nitrophenyl carbonate W ang resin 233, after
alkylation o f the carbamate m oiety in the presence o f lithium /-butoxide, the nitro
group in 235 w as reduced by SnCl 2 ■ H 2 O. Finally, the benzim idazoles 237 were
form ed by the cyclative cleavage o f 236. Later on, several other groups reported the
117
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traceless synthesis o f benzimidazoles w ith three points o f diversity .94d,e,1,p All o f these
traceless methods allow the attachment o f the solid support through the anilinic
'€c
nr'°Y °V
O
H
nh
2
n o
2
?144-
NV
n o
o
'
2
B SA , DM AP, DMF
233
234
R2
R2
R 2 Br
L iO f- Bu
S n C I 2* 2 H 2 0
~
r i 4I-
i
^
n
*
DMF
V
R n
no2°
'
NH2 °
235
236
TFA, C H (O C H 3 ) 3
ch
2
c i2
237
Schem e 59. Traceless solid-phase synthesis of benzimidazoles by Huang et al.
nitrogen o f the precursors. M ore recently, W u et a/.94q demonstrated one example o f
synthesis o f benzim idazole A-oxides on SynPhase Lanterns, as shown in Scheme 60.
o
-R in k — N
H
n o
|,
RNH,
2
I
■Ri"k “ a A X
238
X
!
N° H R
239
O O
H3CoY Y C|
o
N02
R in k— N
O
O
JL ^ ^XO C H i
N^
240
O
R
O“
1. S n C I 2 *H20
N+
H ,N
')
2 . 2 0 % T F A in C H 2C U
N
241
\
COOCH3
R
Schem e 60. Synthesis of benzimidazole A-oxides by W u et al.
118
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In addition, m icrowave technology has also been used in the synthesis o f
benzimidazoles. M ore recently Sun et al.941' described a liquid phase combinatorial
synthesis o f 2-(arylamino)benzimidazoles. As outlined in Scheme 61, each reaction
step was carried out under m icrowave heating and the reaction tim es were all shorter.
The building block 4-fluoro-3-nitrobenzoic acid was attached to M eO-PEG-OH,
after the substituted reaction, reduction o f the nitro group, cyclization in the presence
o f R2NCS, the benzimidazaoles 246 w ere formed by m icrowave-assisted cleavage
from PEG in high yields and high purities.
O
NO,
r
1
nh
.N O ;
2
-O '
y.
C H C I 3 i M W , 1 m in
NH
243
242
R1
Z n , N H 4 CI
O H = M eO -PE G -O H
CH3 OH
M W 2 min
O
R NCS, DCC
^ — NHR2
NH,
C H 3 OH
M W , 9 m in
NH
R'
245
244
LiBr, D B U , C H 3O H
M W , 4 min
HoCO
^5,
|T
^ — NHR2
246
Schem e 61. M icrowave-assisted liquid-phase combinatorial synthesis o f 2(arylamino)benzimidazoles.
A lthough the above approach is the first example o f the m icrowave-assisted
com binatorial synthesis o f benzimidazoles, the reactions w ere carried out in liquidphase polym er support. To the best o f our knowledge, microwave-assisted synthesis
119
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o f benzim idazoles on solid-phase support has not been reported in literature. Solid
support synthesis has m ore advantages than liquid-phase support such as simple
purification and work up procedures. W e integrated m icrowave technology with
solid-phase encoded split-pool combinatorial chemistry and developed a simple and
efficient synthesis o f benzimidazole library, for the first time, using Rink amide resin
and inexpensive and commercial building block, 4-chloro-3-nitrobenzoic acid
derivative.
6.3. Results and discussion
To the best o f our knowledge, m ost reported syntheses o f benzim idazole focuse on
using o-fluoro-nitrobenzene derivatives as the starting m aterials to form the
intermediate o-phcnylenediamines. In our work, an inexpensive and comm ercially
available o-chloronitrobenzene derivative (benzoic acid) was used in place o f ofluoronitrobenzene as the starting material, which has not been reported in the
synthesis of benzimidazoles. By combination o f MASPOS technology w ith encoded
split-pool combinatorial synthesis (ESPCS) using radio frequency (Rf)-encoded
M icroKan reactors, a 50-member benzim idazole library was successfully constructed
via a four-step synthetic sequence on solid-phase. A s illustrated in Scheme 62, the
key step was the microwave-assisted catalyst-free amination reaction o f the resinbound 247 w ith five benzylamines.
A num ber o f studies on the amination o f aryl halides in solution have been reported
and the amination reaction has become an important m ethod for C— N bond
form ation in organic synthesis. Buchwald and Hartwig96 reported the efficient
am ination o f aryl halides catalyzed by transitional metals (Pd, or Cu). There are a
few reports on solid-phase amination in the literature. W illoughby97* and W ard971’
120
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described the solid-phase amination o f aryl bromides with aryl amines m ediated by
palladium . Recently, W eigand97c reported the first example o f Pd(0)-catalyzed
Cl
1. 20% piperidine, DMF
rt, 1 h
$ — NHFmoc
Cl
Cl
Rink amide
resin
no2
O
N02
O
247
Py - CH2CI2 (1:5)
rt, 24 h
X—
CH2NH2
Et3N - NMP (1:2)
200 °C, MW
15 min
( X = H, F, Cl, CH3, CH30 j
SnCI2- 2H20 (1.0 M)
NMP, 40 °C, 24 h
NH
NO.
249
248
ArCHO (30 eq)
0 -
Py, 50 °C, 12 h
O '
6
O ' 4
"* -o -
02N - Q - C I-@ — B r - ^ —
jr
N
Ar
Ar
25% TFA, CH2CI2, rt, 1 h
h 2n
O
250
251
Schem e 62. Synthesis o f a 500-member benzim idazole library.
am ination o f aryl halides using Rink-resin as the nitrogen source. Ham ann98
described the m icrowave-assisted amination o f 1-bromonaphthalenes, and 5-, and 8bromoquinolines, by using palladium as the catalyst. Recently, Tu et al.99a and W ang
121
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et al.99b reported microwave-assisted amination reactions o f aryl halides and triflates
without transition-m etal catalyst.
In our work, w e developed a new efficient method for the m icrowave-assisted
transition m etal-free amination o f aryl chlorides 247 on solid-phase for the first time.
The reactions were perform ed in Emrys process vials on an Emrys creator from
Personal Chemistry AB. In the initial experiments, w e examined the influence o f the
reaction tem perature and the ratio o f base and solvent as shown in Table 16. W e
found that there w as no remarkable difference between pyridine and triethylam ine as
the base. However, the reaction tem perature and time were very important for the
successful amination. W hen reacting at 250 °C for 5 min, the starting m aterial
decom posed and the resin w as broken (entry 1, Table 16). W hen lowing the
tem perature to 200 °C, a dramatic change was observed, the yield o f 248a (X = H)
after cleavage from the resin was 68% (entry 2, Table 16). W hen prolonging the
reaction tim e to 15 min, and changing the ratio o f Et3N -N M P to 1:2, the yield o f
248a increased from 68% to 90% (entry 7, Table 16). Dimethylsulfoxide (DM SO)
w as also suitable for this reaction. The structure o f 248a was confirmed by 'H NM R.
122
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Table 16. Optimization o f amination conditions on solid-phase under m icrowave
irradiation
B ase-Solvent (v:v)
Entry
PhCH2N H 2(eq)
1
20
Et3N -N M P (1:5)
250; 5
248a: 0
2
20
Et3N -N M P (1:5)
200; 5
248a: 68
3
20
Et3N -N M P (1:5)
200; 10
248a: 86
4
20
Et3N -D M SO (1:5)
200;10
248a: 88
5
20
Py-N M P (1:5)
2 00;10
248a: 87
6
20
Py-D M SO (1:5)
20 0 ;1 0
248a: 85
7
20
Et3N -N M P (1:2)
200; 15
248a: 90
T (°C); t (min)
Yield (%)
R eduction o f the nitro group94 in 248a was accomplished by treatm ent with
SnCl 2 • 2 H 2 O (1.0 M) in l-m ethyl-2-pyrrolidinone (NMP) at 40 °C for 24 h,
producing the desired o-phenylenediamine 249a in greater than 90% yield after
cleavage.
W e examined the condensation reaction of 249a with aryl aldehydes. Several
studies94g‘1,1,s for the form ation o f benzimidazoles from o-phenylenediam ine and
aldehydes on solid support have been reported. Some representative procedures are
shown below: (i) the resin-bound o-phenylenediamines were treated w ith aldehydes
and
2,3-dichloro-5,6-dicyano-l,4-benzoquinone
(DDQ)
in
DMF
at
room
tem perature;941 (ii) the resin-bound o-phenylenediamines were treated with an
aldehyde in N M P at room temperature, followed by heating at 50 °C;94h (iii) the
resin-bound benzaldehyde was coupled to phenylenediamines in nitrobenzene at 130
°C.94s and (iv) the resin-bound o-phenylenediamines were treated with an aldehyde in
NM P at 50 °C for overnight.940
123
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In our study, benzim adazoles nucleus 250a-G, and 250a-J w ere formed by the
treatm ent
of
249a
w ith
aromatic
aldehydes,
4-nitrobenzaldehyde,
and
4-
m ethylbenzaldehyde in the presence o f pyridine at 50 °C for 12 h. Finally, resinbound 250a-G and 250a-J were cleaved with 25% TFA to give the free
benzim idazoles 250a-G and 250a-J in 80% and 70% yields, respectively (Table 17).
The structures w ere confirmed by 'H N M R and MS data.
Using the optimized reaction conditions, a 50-member benzim idazole library was
constructed. By placing m icrowave-assisted catalyst-free amination reaction on
solid-phase (M ASPOS) at the early stage o f the library construction, only 5
individual m icrowave-assisted amination reactions in Emrys process vials were
carried out for 247 with 5 benzylamines. The resultant o-nitro anilines 248a-e were
then equally split into 50 (5x10) (R/)-encoded M icroKan reactors for encoded splitpool combinatorial synthesis (ESPCS). Reduction o f 248 in the was carried out for
the pooled 50 M icroKan reactors (in one vessel) by SnCl2*2H20 in N M P at 30 °C to
give 249, w hich w ere then split into 10 groups (5 M icroKan reactors each) and
reacted w ith 10 aromatic aldehydes (parallel reactions in 10 vessels) to give 50 o f
2,3-disubstituted benzimidazoles 250. Finally, the resin-bound benzim idazoles w ere
cleaved w ith 25% TFA in CH2C12 to give the desired products 251 in good yields
w ith high purities. The results are shown in Table 17. The purities were determined
by LC-M S and m ost o f the products w ere obtained in high purities (>90%). Selected
structures o f products were confirmed by
N M R spectra. Figure 15 shows the
typical LC-MS data.
124
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Table 17. Purity (%)a and yield (%)b of a library of 50 benzimidazoles
-X
nV*
H?N
O
251
x =
a: 4-H
Ar = ^
B:
°
jQ
D:
E:
X >
F:
XT2
V
V
b: 4-F
c: 4-C1
d: 4-O CH 3
e: 4 -CH 3
91
(65)
95
(88)
71
(86)
96
(71)
84
(75)
100
(65)
93
(77)
96
(71)
91
(70)
93
(81)
91
(51)
100
(63)
100
(60)
100
(75)
98
(52)
97
(51)
100
(70)
95
(78)
94
(70)
100
(80)
90
(52)
90
(81)
89
(60)
96
(71)
88
(82)
86
(70)
92
(81)
72
(61)
95
(80)
94
(75)
81
(50)
96
(72)
84
(60)
84
(82)
93
(62)
90
(62)
94
(75)
100
(50)
92
(70)
85
(91)
94
(51)
93
(67)
95
(50)
87
(87)
91
(68)
85
(51)
87
(65)
94
(52)
92
(92)
85
(71)
\
01
r
a Purity determined by HPLC.
'’Numbers in the parentheses are the yields o f the benzimidazole products,
w hich w ere calculated based on the loading o f the commercial Rink amide resin.
125
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F:\X calibur\date\C hem \ch00639
10/02/03 04:08:09 PM
SU N -A3
RT: 0 .0 0 - 4 4 .9 7
RT:2.91
WA: 4 4 9 8 4 2 8 2 7
5.25E7
C ha nnel A
N
O
Purity 100%
20000000-
C20H15FN4O
Exact Mass: 346.12
15000000-
1 0 00 0 0 0 0 -
50000002 .2 3 ^
■I I ^
F:\X caliburW ata\Chem \ch00639
10/02/03 04:08:09 PM
SUN-A3
c h 0 0 6 3 9 # 1 7 0 RT; 2 .9 8 AV: 1 NL: 1.26E 8
T; + c ESI Full m s [ 100.00-1200.00]
[M+l]
8
I
I
[2M]
72Q.10
5.04 8§5.31
m/z
Figure 15. LC-MS data of the benzim idazole 251b-C. HPLC conditions: 60%
acetonitrile w ith 0.1 % acetic acid; flow rate at 0.8 mL/min; U V detected at 254
nm.
126
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On the basis o f our practice in combinatorial synthesis o f heterocycles on solid
support under m icrowave irradiation, it is interesting for us to make a comparison on
the strategies for integration o f microwave-assisted solid-phase organic synthesis
(M ASPOS) into encoded split-pool combinatorial synthesis (ESPCS). Figure 16
summ arizes the indole and benzim idazole library syntheses. In the 48-m em ber indole
library synthesis, M ASPOS was applied after introduction o f two points o f diversity
(4
x
12)
through
ESPCS,
therefore
48
individual
m icrowave-assisted
heteroannulation reactions were carried out. This is the m ost tim e-consum ing
operation for this indole library synthesis because the resin-bound substrates and
products needed to be transferred out and back to the M icroKan reactors w ith the R/
tags. The total synthetic operations are 65 as shown in Figure 16a. In contrast, for the
benzim idazole
(a)
ESPCS
MASPOS
4 pooled alkyne couplings
1 pooled reduction
12 pooled sulfonylations
48 individual MW cyclizations
library size: 48
total operations: 4 + 1 + 12 + 48 = 65
(b)
MASPOS
ESPCS
5 individual MW aminations
1 pooled reduction
10 pooled cyclizations
library size: 50
total operations: 5 + 1 + 1 0 = 16
F ig u re 16. Comparison o f two strategies for integration o f
M ASPOS into ESPCS.
127
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library synthesis, w e placed M ASPOS in the beginning o f the sequence and only 5
m icrowave-assisted catalyst-free aminations were performed to introduce one point
o f diversity. It was followed by 1 pooled reduction o f the nitro group and 10 parallel
pooled cyclizations. The total synthetic operations are only 16 as given in Figure 16b.
Therefore, it is clear that integration o f M ASPOS at the early stage o f the library
synthesis is m uch m ore efficient and the benefit will be m anifested when the library
size increases.
6.4.
Conclusion
In summary, w e have successfully established a new approach to the solid-phase
synthesis of benzim idazoles from commercially available 4-chloro-3-nitrobenzoic
acid. The m icrowave-assisted transition metal-free amination reaction o f the resinbound o-chloronitrobenzene with benzylamines was first developed. The reaction
can tolerate a variety o f functional groups including electron-withdrawing and
electron-donating groups in the benzylamine building blocks. This microwaveassisted solid-phase organic synthesis (MASPOS) w as successfully integrated into
encoded split-pool combinatorial synthesis (ESPCS). The advantage o f both
techniques can be best achieved by carrying out MASPOS at the early stage o f the
library synthesis, resulting in significantly reduced individual operations (with only
16 synthetic operations). Two points o f diversity (5 x 10) w ere introduced into 4chloro-3-nitrobenzoic acid to furnish w ith a 50-member benzim idazole library in
good yields and high purities.
128
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Summary
Diversity-oriented organic synthesis of small molecules is an emerging subject,
which focuses on developing novel methodologies for generating small molecules
with structural complexity and diversity. It is central to chemical genetics or, in a
broad sense, chemical biology aiming to explore biology with small molecules in a
systematic approach. Heterocyclic compounds are the “privileged structures” known
for structural diversity and versatile biological activity and have been the targets of
diversity-oriented synthesis. As described above, this thesis research has addressed
the diversity-oriented synthesis of indole and benzimidazole scaffolds, covering
development of novel synthetic methodologies, both in solution and on solid support,
by
2
using
readily
available
and
structurally
diverse
2
-aminophenols
and
-chloronitrobenzenes as the starting materials.
In solution synthesis of indoles, a remarkable additive effect was observed for the
Pd-catalyzed
cross-coupling
of 2-carboxamidoaryl
triflates,
prepared
from
2-aminophenols, with 1-alkynes. In the presence of 150 mol% h-Bu4 NI, excellent
yields were obtained for the cross-coupling products,
2
-alkynylanilides, which
underwent the KOi-Bu-mediated heteroannulation to furnish 2-substituted indoles.
This stepwise cross-coupling-heteroannulation approach is general and efficient and
has been extended, for example, to the synthesis of C4, C5, C 6 , and Cl
nitrogen-substituted indoles, and 4- and 7-azaindoles. A one-pot cross-couplingheteroannulation route to C5, C 6 , and C l nitroindoles was established as well.
Solid-phase organic synthesis (SPOS) in combination with split-pool technique is a
powerful strategy for diversity-oriented synthesis of combinatorial libraries of small
molecules. Our solution indole synthesis was then transferred to the solid-phase
129
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combinatorial synthesis by using radio-frequency (i?/)-encoded MicroKan reactors.
We developed, for the first time, a microwave-assisted Cu(II)- or Pd(II)-catalyzed
heteroannulation of the resin-bound 2-alkynylanilides, which afforded a 96-member
indole library in good overall yields and in high purities. We developed a traceless
version of the microwave-assisted solid-phase organic synthesis (MASPOS) of
indoles and discovered a unique role of the glycine-based spacer that bridges the
substrate and the Rink amide resin. The spacer possessing a tripeptide unit was found
essential for giving high yields for the Cu(II)-mediated heteroannulation of the
resin-bound
2
-alkynylanilides, suggesting a possible mechanism for the spacer to
catch Cu(II) from solution onto the resin and to facilitate catalysis in solid-phase
reactions. This finding, if general, seems very useful for designing spacers/linkers
with self-promotion capability for solid-phase organic synthesis.
The last topic of this thesis work aimed to establish an efficient strategy for
integration of MASPOS with encoded split-pool combinatorial synthesis (ESPCS) in
the synthesis of a 50-member benzimidazole library. The early stage of the library
synthesis, MASPOS was used to promote the catalyst-free amination of the
resin-bound 2-nitroaryl chloride. The resultant resin-bound amination products were
then split into MicroKan reactors for diversification via ESPCS. With this order of
sequence for MASPOS-ESPCS, a speedy and efficient protocol for library synthesis
can be achieved.
The results accomplished during the thesis work on diversity-oriented synthesis of
heterocyclic small molecule library via MASPOS-ESPCS should be useful for
combinatorial synthesis in general and further development in this direction is
expected.
130
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Experimental Section
General Techniques
*H and 13C NMR were recorded on either a Bruker RX-300 or a Varian 300
spectrometer. Chemical sifts are reported in ppm related to the residual solvent peak.
Multiplicity is designated as singlet (s), doublet (d), doublet of doublet (dd), triplet
(t), triplet of doublet (td), quartet (q), quintet (qn), sextet, septet (sept), AB quartet
(ABq), multiplet (m), or broad singlet (brs). Infrared (IR) spectra were taken on a
Perkin-Elmer FT-IR spectrophotometer as thin film on NaCl or KBr pellets. Mass
spectra (MS) were measured on a Finnigan TSQ 7000 mass spectrometer. High
resolution mass spectra (HRMS) were performed by Zhejiang University. LC-MS
was performed on Finnigan LCQ classic mass spectrometer using a reverse-phase
Restek Inertsil ODS-2 column (150 x 4.6 mm) coupled with an Agilent ODS-guard
column (12.5 x 4.6 mm). Melting points were determined in capillary tube with a
MEL-TEMP II apparatus and are uncorrected. Elemental analyses are within ± 0.4%
of theoretical values and were done by Zhejiang University and Shanghai Institute of
Organic Chemistry, The Chinese Academic of Sciences.
All reactions in solution were carried out under a nitrogen atmosphere and monitored
by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60 F 2 5 4 ) using
UV light, or 7% ethanolic phosphomolybdic acid and heating as the visualizing
methods. Dichloromethane (DCM) was distilled over calcium hydride prior to use.
Tetrahydrofuran (THF), 1, 4-dioxane were distilled from sodium benzophenone ketyl
immediately prior to use. Acetonitrile (MeCN), N, N- dimethylformamide (DMF), Nmethylpyrrolidinone (NMP), piperidine, pyridine and triethylamine were distilled
over calcium hydride and stored over molecular sieves (4 A). During all palladiumcatalyzed reactions and reductive reactions, the solvent was purged with nitrogen or
131
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degassed prior to use. Potassium ferf-butoxide was transferred inside a Vacuum
Atmospheres glovebox under nitrogen to small vials that were stored in a desiccator.
Unless otherwise noted, all chemicals were obtained commercially and used as
received. E. Merck silica gel (60, particle size 0.040-0.063 mm) was used for flash
column chromatography. Preparative and semi-preparative TLC was performed
using E. Merck 1-mm or 0.5-mm coated silica gel 60 F2 5 4 plates, respectively.
Yields refer to chromatographically and spectroscopically ('H NMR) pure (>95%)
homogeneous materials.
The Rink amide resin (loading 0.70 mmol/g) was used for the solid-phase reactions.
All solid-phase reactions were carried out under a nitrogen atmosphere and
anhydrous
conditions using IRORI MicroKan™ reactors
together with
a
radiofrequency (Rj) tag or custom-made solid-phase vessels except for the
microwave-assisted reactions.
Kaiser reagent: 5% ninhydrin in EtOH, 80% phenol in EtOH, KCN in pyridine (2
mL 0.001 M KCN).91
All microwave reactions in solution and solid-phase were conducted in Emrys
process vials (5 mL) sealed with aluminum crimp caps fitted with a silicon septum
from Personal Chemistry AB (Uppsala, Sweden). The microwave heating was
performed in an Emrys Creator single-mode microwave cavity producing continuous
irradiation at 2450 MHz at pre-set reaction temperature and reaction time.
132
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Representative procedure for the /V-acylation of 2-aminophenols by 3-(butyryl-l,
3-thiazolidine-2-thione
7V-(5’-Methyl-2’-hydroxyphenyI)butyramide 88c
88c
A mixture of the 2-amino-p-phenol 87c (369.0 mg, 3.0 mmol) with 3-(butyryl-l,3thiazolidine-2-thione (586.0 mg, 3.0 mmol) in THF (15 mL) was heated at 80-85 °C
under a nitrogen atmosphere for 50 h. After cooling the mixture to rt, the solvent was
removed under reduced pressure and the residue was purified by flash column
chromatography over silica gel (33% EtOAc in hexane) to give 88c (567.4 mg, 98%)
as a white solid.
mp 80-81 °C; R/ = 0.45 (16% EtOAc in hexane);
IR (film) 3218, 2965, 1670, 1638, 1600, 1524 cm'1;
*H NMR (300 MHz, CDCI3 )
8
7.62 (s, 1 H), 6.87 (d, J = 8 . 6 Hz, 3 H), 2.40 (t, J = 7.3
Hz, 2 H), 1.76 (sextet, J = 7.4 Hz, 2 H), 1.01 (t, J = 7.4 Hz, 3 H);
13C N M R (75 MHz, CDCI3 ) 5 174.5, 147.2, 132.1, 128.4, 126.3, 123.1, 120.1, 39.5,
21.0, 20.0, 14.3;
MS (ESI) m/z 194 (M + H+, 100);
Anal. Calcd. for C 1 1 H 15 NO 2 C, 68.37; H, 7.82; N, 7.25. Found C, 68.38; H, 7.70; N,
7.27.
133
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7V-(2’-Hydroxyphenyl)butyramide 88a
88a
Prepared from 87a in 95% yield as a white solid. 88a: R/ = 0.34 (25% EtOAc in
hexane);
IR (film) 3256, 2959, 1668, 1637, 1537 cm'1;
NMR (300 MHz, CDC13) 6 7.62 (s, 1 H), 7.11 ( td, J = 1.4, 8.5 Hz, 1 H), 7.02 (qd,
y = 1.4, 8.5 Hz, 2 H), 6.85 (td, J = 1.4, 8.5 Hz, 1 H), 2.43 (t, J = 7.3 Hz, 2 H), 1.78
(sextet, J = 7.3 Hz, 2 H), 1.01 (t, J = 7.3 Hz, 3 H);
13C NMR (75 MHz, CDC13) 8 173.5, 148.7, 127.1, 122.1, 120.5, 119.8, 38.8, 19.2,
13.6;
MS (+CI) m/z 180 (M + H+, 100).
./V-(2’-Hydroxy-5’,6’,7’,8’-tetrohydro -naphthalene - 2 ’-yl)butyramide 88d
88d
Prepared from 2-ammo-5,6,7,8-tetrahydro-nathphol 87d in 88% yield as pale yellow
crystal;
88d: mp 103-104 °C (DCM-hexane); R/ —0.57 (50% EtOAc in hexane);
’H N M R (300 M H z, CDCI 3 )
8
8.17 (s, 1 H ), 6 .84 (s, 1 H), 6 .67 (s, 1 H ), 2.61 (br, 2
H), 2.35 (t, J = 7.5 Hz, 2 H), 1.79-1.67 (m, 6 H), 0.97 (t, J = 7.4 Hz, 3 H);
134
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13C NMR (75 MHz, CDCI3 ) 5 173.5, 145.8, 135.8, 129.0, 123.3, 122.2, 118.8, 38.6,
28.8,28.4, 23.2, 23.0, 19.2, 13.5;
MS (+CI) m/z 234 (M + H+, 100);
Anal. Calcd. for C 1 4 H 19 NO 2 C, 72.07; H, 8.21; N, 6.00. Found C, 71.70; H, 8.76; N,
5.89.
./V-(4’-Chloro-2’-hydroxyphenyl)butyramide 88e
88e
Prepared from 2-amino-4-chloro-phenol 87e in 89% yield.
88e: white crystalline solid; Rf = 0.51 (50% EtOAc in hexane);
IR (film) 3407, 2961, 1649, 1534 cm'1;
3H NMR (300 MHz, CDC13) 8 7.97 (s, 1 H), 7.35 (s, 1 H), 7.02 (dd, J = 2.3, 8.7 Hz,
6.89 (d, J = 8.6 HZ, 1 H), 2.42 (t, J = 7.4 Hz, 2 H), 1.75 (sextet, J = 7.4 Hz, 2 H),
1.00 (t, 7 = 7 .4 Hz, 3 H);
13C N M R (75 MHz, CDCh) 5 174.5, 147.2, 127.3, 127.0, 125.7, 122.3, 120.2, 39.7,
19.9, 14.2;
MS (+CI) m/z 199 (M + H+, 100).
Representative procedures for the 7V-acylation of 2-aminophenols in the
presence of NaH and butyryl chloride.
jV-(5’-E th y ls u lfo n y l-2 ’-h y d ro x y -p h en y l) b u ty ra m id c 8 8 f
135
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rr
JOH
Et02S ' ^ ^ v‘NH
O'
88f
To a suspension of NaH (60%, 0.2 g, 5.0 mmol) in dry THF (10 mL) cooled in an
ice-water bath was added a solution of 2-amino-4-(ethanesulfonyl) phenol 87f (805.0
mg, 4.0 mmol) in dry THF followed by stirring for 15min at the same temperature.
To the resultant mixture was added butyryl chloride (0.42 mL, 4.0 mmol). After
stirring for 12h at rt , the reaction mixture was treated with saturated NH 4 C1 and
extracted with ethyl acetate(3 x 20 mL).The organic layer was then washed with
brine, dried over anhydrous MgSCfi, and evaporated reduced pressure. The crude
product was purified by flash column chromatography (silica gel, 80% EtOAc in
hexane) to give the product 88f (1.02g) in 95% yield as a white solid.
Rf = 0.25 (25% EtOAc in hexane);
IR (film) 3401, 1635, 1581 cm’1;
‘H NMR (300 MHz, CDCI3 ) 5
2.3,
8 .6
8 .6 8
(s, 1 H), 7.65 (d, 7 = 2.2 Hz, 1 H), 7.59 (dd, J =
Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 3.10 (t, J = 7.5 Hz, 2 H), 2.50 (t, J = 7.4
Hz, 2 H), 1.76 (sextet, J = 7.4 Hz, 2 H), 1.28 (t, J = 1.4 Hz, 3 HO, 1.04 (t, J = 7.4 Hz,
3 H);
,3C NMR (75 MHz, CDCI3 ) 5 175.8, 155.1, 129.1, 127.6, 123.5, 121.6, 51.8, 39.2,
19.9, 14.3,8.3;
MS (+CI) m/z 272 (M + H+, 100).
Representative procedure for the /V-acylation of 2-aminophenols in the presence
of pyridine and butyryl chloride.
136
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AL(2’-Hydroxy-4’-methoxy-phcnyl)butyramide 88h
88h
To a solution of 2-hydroxy-4-methoxyaniline hydrochloride 87h (351.0 mg, 2.0
mmol) in dry THF (25 mL) cooled in an ice-water bath was added pyridine (0.4 mL,
5.0 mmol). Butyryl chloride (0.23 mL, 2.2 mmol) was added through syringe. After
stirring for 6h at 0 °C and then at room temperature for 1 h under nitrogen
atmosphere, water was added to reaction mixture. The resultant mixture was
extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed
with brine, dried over anhydrous MgSCL, and evaporated under reduced pressure.
The crude was purified by flash column chromatography (silica gel, 33% EtOAc in
hexane) to give 88h (401.2 mg) in the yield of 96% as a white solid, mp 99-100 °C
(DCM-hexane); R f = 0.38 (33% EtOAc in hexane);
IR (film) 3296, 3082, 2965, 2875, 1631, 1527 cm'1;
*H NMR (300 MHz , CDCT) 5 7.66 (s, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.55 (d, J =
2.8 Hz, 1 H), 6.40 ( d d ,/= 2.7, 8.8 Hz, 1 H), 3.75 (s, 3 H), 2.39 ( t , / = 7.3 Hz, 2 H),
1.75 (sextet, J = 7.5 Hz, 2 H), 0.99 (t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 5 173.4, 159.0, 150.2, 122.9, 118.9, 106.7, 104.4, 55.4,
38.6, 19.2,13.6;
MS (ESI) m/z 210 (M + H+, 100);
Anal. Calcd. for C1 1 H 15 NO 3 C, 63.14; H, 7.23; N, 6.69. Found C, 63.19; H, 7.04; N,
6 .6 8 .
137
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./V-(3’-Hydroxy-pyridm-2’-yl)-butyrainide 88i
88i
Prepared from 2-amino-3-hydroxypyridine 87i in 91% yield. 88i: white crystalline
sold; mp 48-49 °C (DCM-hexane); R/= 0.43 (33% EtOAc in hexane);
IR (KBr) 3100 (NH, OH), 1659 (CO) cm'1;
3H NMR (300 MHZ,
C D 3 C O C D 3 )
5 10.76 (NH), 10.03 (OH), 7.99 (d, J = 4.5 Hz,
1H), 7.41 (d, J = 8.1 Hz, 1H), 7.26 (t, J = 4.5 Hz, 1H), 2.77 (t, J = 7.2 Hz, 2H), 1.99
(m, 2H), 1.14 (t, J - 7.2 Hz, 3H);
13C NMR (75 MHz, CD 3 COCD3 ) 5 175.0, 144.4, 140.4, 138.5, 126.8, 122.2, 37.5,
18.9, 13.0;
MS (+CI) m/z 181 (M + H+, 100), 182(11);
Anal. Calcd. for C9H12N20 2 C, 59.99; H, 6.71; N, 15.55. Found C, 60.03; H, 6.72; N,
15.61.
N-(3’,5’-Dimcthyl-2’-hydroxyphenyl)butyramide 88g
CH3
,OH
H3( T ^
'N H
88g
Prepared from 2-amino-4,6-dimethylpheniol 87g in 89% yield. 88g: white solid;
138
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Rf = 0.50 (16% EtOAc in hexane );
IR (film) 3292, 2964, 2874, 1636, 1542 cm'1;
!H NMR (300 MHz, CDCI3 ) 8 7.36 (s, 1 H), 6.84 (s, 1 H), 6.60 (s, 1 H), 2.42 (t, J =
7.3 Hz, 2 H), 2.26 (s, 3 H), 2.21 (s, 3 H), 1.78 (sextet, J = 7.4 Hz, 2 H), 1.02 (t, J =
7.4 Hz, 3 H);
MS (ESI) m/z 208 (M + H+, 100).
Representative procedure for the synthesis of 2-carboxamidoaryl triflates.
A-[4’-Methyl-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]butyramide 89b
89b
To a solution of 88b (773.3 mg, 4.0 mmol) and Et3 N (0.7 mL, 5.0 mmol) in dry
CH 2 CI2 10 mL, was added trifluoromethanesulfonic anhydride (0.56 mL, 3.3 mmol)
under nitrogen atmosphere at 0 °C. And the reaction mixture was stirred for 6 h at
the same temperature. After removal of EtOAc and then washed with 5% HC1,
saturated NaHC 0 3 and brine. The organic layer was dried over anhydrous MgS0 4 ,
and evaporated under reduced pressure. The residue was purified by flash column
chromatography over silica gel (25% EtOAc in hexane) to give the products 89b
(1.46g) in the yield of 90% as a white sold.
89b: white crystalline solid (DCM-hexane); mp 66-67 °C (DCM-hexane); Rf = 0.41
(16% EtOAc in hexane);
IR (film) 3246, 2972, 2876, 1663, 1531 cm'1;
139
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
!H NMR (300 MHz, CDC13) 5 8.04 (d, J = 8.2 Hz, 1 H), 7.28 (s, 1 H), 7.16 (d, J =
8.3 Hz, 1 H), 7.08 (s, 1 H), 2.39-2.30 (m, 5 H), 1.76 (sextet, J = 7.4 Hz, 2 H), 1.01 (t,
J = 7.4 Hz, 3H);
13C NMR (75 MHz, CDC13) 5 172.0, 140.1, 136.6, 130.3, 128.3, 124.9, 122.5, 121.3,
117.1,40.0,21.5,19.4, 14.3;
MS (ESI) m/z 326 (M + H+, 100);
Anal. Calcd. for C 1 2 H 1 4 F 3 NO4 S C, 44.31; H, 4.34; N, 4.31. Found C, 45.01; H, 4.13;
N, 4.41.
7V-[2’-(((Trifluoroincthane)sulfonyl)oxy)phenyl]butyrainide 89a
89a
Prepared from 88a in 94% yield as white solid. 89a: Rf = 0.54 (25% EtOAc in
hexane);
IR (film) 3012, 2968, 2878, 1673, 1611, 1524 cm'1;
3H NMR (300 MHz, CDC13)
8
8.44 (s, 1 H), 7.59-7.54 (m, 2 H), 7.4 (td, 7 = 1.3, 8.5
Hz, 1 H), 7.37 (td, 7 = 1.3, 8.5 Hz, 1 H), 2.59 (t, J = 7.4 Hz, 2 H), 1.95 (sextet, J
7.4 Hz, 2 H), 1.22 (t,7 = 7.4 Hz, 3 H);
13C NMR (75 MHz,
C D C I3 )
5 171.0, 132.5, 130.4, 129.1, 125.1, 123.9, 121.5, 118.3
(q, J = 318.2 Hz), 39.5, 18.7, 13.6;
MS (ESI) m/z 312 (M + H+, 100);
140
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AL[5,-Methyl-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]butyramide 89c
O'
89c
Prepared from 88c in 90% yield. 89c: white crystalline solid (DCM-hexane); mp 8182 °C (DCM-hexane); Rj = 0.54 (16% EtOAc in hexane);
IR (film) 2979, 1656, 1534 cm’1;
XH NMR (300 MHz, CDC13) 5 8.05 (s, 1 H), 7.32 (s, 1 H), 7.15 (d, J= 8.5 Hz, 1 H),
6.96 (dd, J = 1.4, 8.5 Hz, 1 H), 2.38 (t, J = 7.3 Hz, 5 H), 1.76 (sextet, J= 1 A Hz, 2 H),
1.01 (t, J = 7.4 Hz, 3H);
13CN M R (75 MHz, CDCI3 ) 5 172.1, 140.2, 137.5, 130.6, 126.5, 125.6, 125.1, 121.7,
121.3, 117.1,40.1,21.9, 19.4, 14.3;
MS (ESI) m/z 326 (M + H+, 100);
Anal. Calcd. for
C I2 H 1 4 F 3 N O 4 S
C, 44.31; H, 4.34; N, 4.31. Found C, 44.28; H, 4.54;
N, 4.22.
A-[5’, 6,,7’,8’-Ttetrohydro-2’-(((trifluoromethane)sulfonyl)oxy) naphthalene-2’yl] butyramide 89d
O
89d
Prepared from 88d in 90% yield. 89d: white crystalline solid; mp 90-91 °C (DCMhexane); R f - 0.53 (16% EtOAc in hexane );
141
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IR (film) 3246, 2968, 2878, 1670, 1592, 1532 cm'1;
NMR (300 MHz, CDCI3 ) 5 7.82 (s, 1 H), 7.27 (s, 1 H), 6.94 (s, 1 H), 2.73 (d, J =
6.3 Hz, 4 H), 2.35 (t, / = 7.4 Hz, 2 H), 1.81-1.69 (m, 6 H), 1.00 ( t J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 171.4, 138.3, 137.6, 135.0, 127.1, 124.8, 121.3, 118.5
(q, J = 318.4 Hz), 39.3, 29.1, 28.9, 22.6, 22.5, 18.7, 13.6;
MS (+CI) m/z 365 (M + H+, 100).
Anal Calcd. for C 1 5 H 1 8 F3 NO 4 S C, 49.31; H, 4.97; N, 3.83. Found C, 49.71; H, 4.90;
N, 3.96.
A-[5’-Chloro-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]butyramide 89e
89e
Prepared from 88e in 77% yield. 89e: white solid; mp 61-62 °C (DCM-hexane); Rf
= 0.45 (16% EtOAc in hexane);
IR (film) 3243, 2964, 1666, 1601 cm'1;
!H NMR (300 MHz , C
D C I3 )
5 8.43 (d, J = 2.2 Hz, 1 H), 7.32 (s, 1 H), 7.22 (d, J = 8.
9Hz, 1 H), 7.13 (dd, J = 2.5 Hz, 8.8Hz, 1 H), 2.39 (t, J = 7.5 Hz, 2 H), 7.77 (sextet, J
= 7.4 Hz, 2 H), 1.02 9t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz,
C D C I3 )
5 134.7, 131.4, 124.8, 123.6, 122.3, 120.6, 118.4
(q ,
JC-
F= 318.5 Hz);
MS (+CI) m/z 346 (M + H+, 100);
Anal. Calcd. for
C 1 1 H 1 1 C IF 3 N O 4 S ,
C, 38.21; H, 3.21; N, 4.05. Found C, 38.25; H,
3.27; N, 3.95.
142
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Ar-[5’-Ethanesulfonyl-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]butyramide
89f
89f
Prepared from 88f in 62% yield. 89f: white crystalline solid; mp 81-82 °C (DCMhexane); R f = 0.32 (25% EtOAc in hexane);
IR (film) 3307, 2970, 2941, 1682, 1531 c m 1;
*H NMR (300 MHz, CDC13) 5 8.84 (d, J = 2.2 Hz, 1 H), 7.72 (dd, J = 2.3, 8.6 HZ, 1
H), 7.56 (s, 1 H), 7.48 (d, J = 8.6 Hz, 1 H), 3.16 (q, J = 7.5 Hz, 2 H), 2.42 (t, J = 7.5
Hz, 2 H), 1.74 (sextet, 7 = 7 .5 Hz, 2 H), 1.32 (t, / = 7.4 Hz, 3 H), 1.01 (t, J = 7.4 Hz,
3 H);
13CN M R (75 MHz, CDC13) 5 172.1, 142.7, 140.0, 132.2, 125.4, 124.3, 123.0, 119.1
(q, J c-f —318.6 Hz), 51.2, 39.9, 19.2, 14.2, 7.97;
MS (+CI) m/z 404 (M + H+, 100);
Anal calcd for CnHieFaNOeSa C, 38.71; H, 4.00; N, 3.47. Found C, 38.92; H, 4.12;
N, 3.52.
7V-[3’, 5’-Dimethyl-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]butyramide 89g
c h
3
A"
89g
143
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Prepared from 88g in 93% yield. 89g: white solid; mp 75-76 °C (DCM-hexane);
Rf = 0.54 (16% EtOAc in hexane );
IR (film) 3241, 2966, 2879, 1668, 1604, 1526 cm'1;
!H NMR (300 MHz, CDC13) 5 7.82 (s, 1 H), 7.44 (s, 1 H), 6.86 (s,1H), 2.38-2.27 (m,
8 H), 1.75 (sextet, 7 = 7.4 Hz, 2 H), 1.00 (t, 7 = 7.7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 8 172.2, 139.6, 132.0, 131.1, 129.1,123.8, 121.3,119.2
(q, J c - f = 317.9 Hz), 40.1,21.8, 19.4, 17.3, 14.3;
MS (ESI) m/z 340 (M + H+, 100);
Anal. Calcd. for C ^H ^F sNO aS C, 46.01; H, 4.75; N, 4.13. Found C, 46.01; H, 4.75;
N, 4.13.
7V-[4’-Methoxy-2’-(((trifluoromethane)sulfonyl)oxy)phcnyl|butyramidc 89h
89h
Prepared from 88h in 96% yield. 89h: white solid;
R f —0.40 (33% EtOAc in hexane);
IR (film) 3285, 3080, 2696, 2879, 1659, 1530 cm'1;
•H NMR (300 MHz, CDC13) 5 7.84 (d, 7 = 9.03 Hz, 1 H), 7.32 (s, 1 H), 6.87 (dd, 7 =
2.8, 9.0 Hz, 1 H), 6.79 (d, 7 = 2.7 Hz, 1 H), 2.34 (t, 7 = 7.3 Hz, 2 H), 1.73 (sextet, 7 =
7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 5 171.6, 157.3, 141.2, 126.5, 123.0, 118.5 (q, J C.F =
318.5 Hz), 114.0, 107.6, 55.8, 39.0 18.7, 13.6;
MS (ESI) m/z 342 (M + H+, 100).
144
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7V-[3’-(((Trifluoromcthaiic)sulfonyl)oxy)ptridin- 2’-yl]butyramide 89i
89 i
Prepared from 88i in 82% yield. 89i: white crystalline solid; mp 77-78 °C (DCMhexane); R f = 0.55 (50% EtOAc in hexane);
IR (film) 3278, 2971, 1672, 1513 cm'1;
*H NMR (300 MHz, CDC13) 6 8.42 (s, 1H), 7.93 (s, 1 H), 7.69 (dd, J = 0.8, 0.9 Hz,
7.26 (s, 1 H), 2.50 (t, J= 7.4 Hz, 2 H), 1.77 (sextet, J = 1 A Hz, 2 H), 1.02 (t, J = 7.3
Hz, 3 H);
13C NMR (75 MHz, CDC13) 6 173.2, 140.1, 138.8, 131.1, 124.1, 38.6, 18.4, 13.7;
MS (+CI) m/z 313 (M + H+, 100);
Anal. Calcd. for C ioH ii F3N20 4S C, 38.46; H, 6.47; N, 8.97. Found C, 38.56; H, 3.53;
N, 8.73.
Representative procedure for the synthesis of 2-alkynylanilides.
Ar-(2’-Phenylethynyl-phenyl)-butyramide 90a
90a
To a su spension o f com pound 8 9 a (1 2 4 .0 m g, 0 .4 m m ol), Pd(PPh 3 ) 4 (46.0 m g, 0 .0 4
m m ol), Cul (23.1 m g, 0.12 m m ol) and «-Bu4N1 (222.0 m g, 0.6 m m ol) in dry MeCN
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(5 mL), was added Et3 N (1.0 mL) and phenylacetylene (0.09 mL, 0.8 mmol) under
nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature
for 24h under nitrogen atmosphere. The saturated NH 4 CI solution and ethyl acetate
was added. The organic layer was washed with brine and then dried over anhydrous
MgSCL, concentrated under reduced pressure and purified by flash column
chromatography (silica gel, 25% EtOAc in hexane) to give 90a (94.0 mg) in the
90% yield as a white solid.
90a: white crystalline solid; mp 102-103 °C (DCM-hexane); Rj = 0.48 (16% EtOAc
in hexane );
IR (film) 3301 (NH), 1659,1577, 1529 cm’1;
'H NMR (300 MHz, CDC13) 8 8.44 (d,J= 8.3 Hz, 1 H), 8.02 (s, 1 H), 7.56- 7.51 (m,
3 H), 7.49-7.45 (m, 4H), 2.42 (t, J = 7.4 Hz, 2 H), 1.78 (sextet, J = 7.4 Hz, 2 H), 1.04
(t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 8171.1, 138.9, 131.6, 131.4, 129.8, 128.9, 128.6, 123.3,
122.3, 119.3, 96.4, 84.3, 40.0, 19.0, 13.7;
MS (+CI) m/z 263 (M + H+, 100);
Anal. Calcd. for CigHnNO C, 82.10; H, 6.51; N, 5.32. Found C, 82.34; H, 6.69; N,
5.16.
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jV-(4’-Methyl-2’-Phenylethynyl-phenyl)-b\ityramide 90b
90b
Prepared from 89b in 96% yield. 90b: white crystalline solid; mp 90-91 °C (DCMhexane); R f = 0.59 (16% EtOAc in hexane);
IR (film) 3292, 2920, 2847, 2210, 1654, 1526 cm'1;
’H NMR (300 MHz, CDC13) 5 8.31 (d, J = 8.4, 1H), 7.94 (td, 1H), 7.50-7.56 (m,
2H), 7.41-7.35 (m, 2H), 7.31 (d, J = 1.6Hz, 1H), 7.16 (dd, J = 8.6 and 1.8Hz, 1H),
2.41 (t, J = 1 A Hz, 2H), 2.31 (s, 3H), 1.76-1.84 (m, 2H), 1.04 (t, J = 1 A Hz, 3H);
13C NMR (75 MHz, CDC13) 5 170.9, 136.5, 132.8, 131.8,131.4,130.5, 128.8, 128.5,
122.5, 119.3, 111.7, 95.9, 84.5, 39.9, 20.6, 19.0, 13.7;
MS (+CI) m/z 277 (M + H+, 100).
/V-(5’-Methyl-2’-Phcnylethynyl-phenyl)-butyramide 90c
Ph
Me'
NH
90c
Prepared from 89c in 97% yield. 90c: white crystalline solid; mp 117-118 °C
(DCM-hexane); R f = 0.56 (16% EtOAc in hexane );
IR (film) 3290, and 1660 cm'1;
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3H NMR (300 MHz, CDCI3 ) 5 8.30 (s, 1H), 7.99 (td, 1H), 7.50-7.54 (m, 2H), 7.337.44 (m, 4H), 6.89 (d, J = 8.0Hz, 1H), 2.42 (dt, J = 7.4, 2.3 Hz, 2H), 2.38 (s, 3H),
1.74-1.87 (m, 2H), 1.04 (dt, J = 1 A and 2.3 Hz, 3H);
13CN M R (75 MHz, CDC13) 5 171.1, 140.3, 138.7, 131.3, 128.7, 128.5, 124.2, 122.6,
119.9, 108.9, 95.73, 84.5, 39.9, 21.9, 19.0, 13.7;
MS (+CI) m/z 277 (M + H+, 100);
Anal. Calcd. for C 1 9 H 19 NO C, 82.28; H, 6.90; N, 5.05. Found C, 82.56; H, 4.38; N,
5.84.
/V-(5’,6’,7’,8’ -Tetrahydro-naphthalene- 2’-Phenylethynyl-phenyl)-butyramide
90d
Ph
90d
Prepared from 89d in 95% yield. 90d: white crystalline solid; m p 102-103°C
(DCM-hexane); R f = 0.44 (16% EtOAc in hexane);
IR (film) 3295, 2929, 2661, 1571, 1519 cm "1;
*H NMR (300 MHz, CDCI3 )
6
8.15 (s, 1 H), 7.90 (s, 1H),7.52-7.50 (m, 2 H), 7.38
(t, 3 H), 7.20 (s, 1 H), 2.79 (s, 2 H), 2.70 (s, 2 H),2.40(s, J =
U S (m,
6
7.4 Hz, 2H),1.SO­
H), 1.04 (t, J = 1 A Hz, 3 H);
13C NMR (75 MHz, CDC13) 5 170.9, 139.4, 136.1, 132.3,131.8, 131.3, 128.6, 128.5,
122.6, 119.7, 109.2, 95.2, 84.8, 39.9, 29.8, 28.6, 23.0, 22.9, 19.0, 13.7;
MS (+CI) m/z 318 (M + H+, 100);
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Anal. Calcd. for C22H23NO C, 83.24; H, 7.30; N, 4.41. Found C, 83.11; H, 7.32; N,
4.47.
TV-lS’-Chloro-l’-Phenylethynyl-phenyll-butyramide 90e
90e
Prepared from 89e in 89% yield. 90e: white crystalline solid; mp 148-149 °C (DCM-hexane); R f = 0.53 (16% EtOAc in hexane);
IR (film) 3267, 2917, 2849, 1659, 1564 cm'1;
*H NMR (300 MHz, CDCI3 ) 5 8.55 (s, 1 H), 8.00 (sb, 1 H), 7.51-7.54 (m, 2 H),
7.38-7.41 (m, 4 H), 7.04 (dd, J = 8.3, 2.6 Hz, 1 H), 2.42 (t, J = 7.4 Hz, 2 H), 1.761.83 (m, 2 H), 1.03 (t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 171.1, 139.7, 135.6, 132.3, 131.4, 129.1, 128.6, 123.1,
122.0, 119.4, 110.1, 97.2, 83.4, 39.98, 18.9, 13.7;
MS (+CI) m/z 297 (M + H+, 100);
Anal. Calcd. for C i 8H i 6C1NO C, 72.60; H, 5.42: N, 4.70. Found C, 72.76; H, 5.29; N,
4.46.
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7V-(5’-Ethanesulfonyl-2-phenylethynyl-phenyl)-butyramide 90f
Et02S
90f
jf'
Prepared from 89f in 90% yield. 90f: white crystalline solid; mp 130-131 "C ( DCM-hexane); Rj = 0.44 (33% EtOAc in hexane );
IR (film) 3299, 2959, 2215, 1563, 1410 cm'1;
*H NMR (300 MHz , CDC13>) 5 8.30 (s, 1 H), 7.99 (td, 1H), 7.50-7.54 (m, 2 H),
7.33-7.44 (m, 4 H), 6.89 (d, J = 8.0 Hz, 1 H), 2.45 (t, J = 7.3 Hz, 2 H), 1.73-1.85 (m,
2 H), 1.29 (t, / = 7.4 Hz, 3 H), 1.03 (t, J = 7.3 Hz, 3 H);
13C NMR (75 MHz, CDC13;) 5 171.1, 140.3, 138.7, 131.3, 128.7, 128.5, 124.2, 122.6,
119.9, 108.9, 95.7, 84.5, 13.7, 39.9, 21.9, 18.9;
■
MS (+CI) m/z 356 (M + H+, 100);
Anal. Calcd. For C20H2iNO3S C, 67.58; H, 5.95; N, 3.94. Found C, 67.61; H, 6.00; N,
3.89.
A-(3’,5’-Dimethyl-2’-Phenylethynyl-phenyl)-butyramide 90g
M e^^Ph
f
90g
Prepared from 89g in 71% yield. 90g: white solid; R/= 0.64 (16% EtOAc in hexane );
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IR (film) 3418, 2963, 2095, 1531cm'1;
!H NMR (300 MHz, CDC13) 5 8.14 (s, 1 H), 8.04 (s, 1H), 7.51-7.56 (m, 2 H), 7.377.44
(m, 3 H), 6.80 (s, 1 H), 2.46 (s, 3 H), 2.42 (t, J = 7.4 Hz, 2 H), 2.34 (s, 3 H),
1.77-1.84 (m, 2 H), 1.04 ( t,/ = 7 .4 Hz, 3 H);
13C N M R (75 MHz, CDC13) 5 171.0, 140.2, 139.6, 138.8, 131.2, 128.6, 128.6, 125.4,
122.82, 117.2, 99.8, 83.6, 40.1, 21.8, 20.9,19.1, 13.7;
MS (+CI) m/z 292 (M + H+, 100).
/V-(4’-MethoxyI-2’-Phenylethynyl-phenyl)-butyramide 90h
90h
Prepared from 89h in 81% yield. 90h: white solid; mp 114-115 “C; Rf = 0.30 (33%
EtOAc in hexane);
IR (film) 2984, 2876, 2086, 1743, 1465 cm'1;
!H NMR (300 MHz, CDC13j)
6
8.29 (d, J = 9.09 Hz, 1 H), 7.85( s, 1 H), 7.56-7.50
(m, 2 H), 7.41-7.37(m, 3H), 7.01(d, J = 3.0 Hz, 1 H), 8.91 (dd, J = 3.0, 9.1 Hz, 1 H),
2.39 (t, J = 7.4 Hz, 2 H), 1.84- 1.73 (sextet, 2 H), 1.02 (t, J= 7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13;) 5 170.7, 155.1, 132.6, 131.4, 128.9, 128.5, 122.2,
121.1, 115.9, 115.8, 113.1, 96.0, 84.4, 55.5, 39.8, 19.1, 13.7;
MS (+CI) m/z 294 (M + H+, 100).
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7V-(3,-Phcnylethynyl-pyridin-2-yl)-butyramide 90i
N
N
H
90i
Prepared from 89i in 97% yield. 90i: white solid; R/ = 0.48 (50% EtOAc in hexane);
IR(KBr) 3256(NH), 1669(CO) cm'1;
*H NMR (300 MHz, CDC13) 5 8.33 (dd, J = 6.7, 4.9 Hz, 1 H), 8.27 (s, 1 H), 7.77 (dd,
/ = 7.7, 1.9 Hz, 1 H), 7.48-7.54 (m, 2 H), 7.34-7.40 (m, 3 H), 7.33-7.44 (m, 4 H),
7.00
(dd, J = 7.7, 4.9Hz, 1 H), 2.70 (t, J = 1A Hz, 2 H), 1.71-1.83 (m, 2 H), 1.01 (t, J
= 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 172.5, 151.3, 147.4, 140.3, 131.5, 129.1, 128.4, 121.7,
118.6, 109.1, 97.5, 82.9, 39.1, 18.5, 13.7;
MS (+CI) m/z 265 (M + H+, 100).
/V-(2’-Pentynyl-phenyl)-butyramide 90j
90j
*
Prepared from 89a in 91% yield. 90j: white solid; Rj = 0.61 (16% EtOAc in hexane );
IR (film) 3392, 2152, and 1698 cm'1;
!H NMR (300 MHz, CDC13) 5 8.40 (d, / = 8.3 Hz, 1 H), 7.99 (s, 1 H), 7.36 (dd, J =
1.5,
7.7 Hz, 1 H), 7.31-7.24 (m, 1 H), 7.02-6.97 (m, 1 H), 2.49 (t, / = 6.96 Hz, 2 H),
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2.38 (t, 7 = 7.6 Hz, 2 H), 1.78 (qn, 7 = 1A Hz, 2 H), 1.68 (qn, 7 = 7.2 Hz, 2 H), 1.09
(t, 7 = 7.3 Hz, 3 H), 1.03 (t, 7 = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 171.7, 139.6, 132.1, 129.6, 123.8, 119.7, 98.3, 78.8,
40.7, 22.9, 22.2, 19.7, 14.4, 14.3;
MS (+CI) m/z 229.9 (M + H+, 100).
N-(2’-trimethylsilicon-phenyl)-butyramide 90k
Si(CH3)3
90k
Prepared from 89a in 89% yield. 90k: white solid; Rj = 0.65 (16% EtOAc in hexane);
IR (film) 3392, 2152, and 1699 cm'1;
]H NMR (300 MHz, CDCI3 ) 5 8.34-8.47 (m, 1 H), 8.04 (td, 1 H), 7.26-7.46 (m, 2 H),
6.94-7.07 (m, 1 H), 2.38 (t, 7 = 7.5 Hz, 2 H), 1.72-1.85 (m, 2 H), 1.03 (t, 7 = 7.5 Hz,
3 H), 0.29 (s, 9 H);
13C NMR (75 MHz, CDCI3 ,) 5 170.9, 139.4, 131.4, 129.9, 122.9, 118.9, 111.5, 102.1,
100.3,40.0, 19.0, 13.7;
MS (+CI) m/z 260 (M + H+, 100).
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N-(5,-Ethanesulfonyl-2’-pentynyl-phenyl)-butyramide 901
901
Prepared from 89f in 90% yield. 901: white solid; mp 83-84 °C (DCM-hexane); Rj =
0.28 (33% EtOAc in hexane);
*H NMR (300 MHz, CDC13) 5 8 . 8 8 (d, J = 1.4 Hz, 1 H), 8.01 (s, 1 H), 7.52-7.45(m, 2
H), 3.10 ( d ,J = 7.4 Hz, 2 H), 2.49 (t, J = 7.0 Hz, 2 H), 2.38 (t, J = 7.5 Hz, 2 H), 1.18
-1.63(m, 4 H), 1.24 (t, J = 7.4 Hz, 3 H), 1.02 (dt, J = 7.4 Hz,
6
H);
13CN M R (75 MHz, CDC13) 5171.1, 139.4, 138.1, 131.9, 122.3, 118.3, 117.8, 101.7,
75.0, 50.2, 39.6, 21.8, 21.5, 18.7,13.4, 13.5, 7.3;
MS (+CI) m/z 322 (M + H+, 100).
N-(3’-Peiitynyl-pyridin-2’-yl)-butyramide 90m
H
90m
Prepared from 89i in yield. 90m: white solid; Rj = 0.45 (50% EtOAc in hexane);
IR (KBr) 3256 (NH), 1669 (CO) cm'1;
*H NMR (300 MHz, CDCI3 ) 5: 8.28 (d, J = 2.1 Hz, 1 H), 8.14(s, 1 H), 7.65(d, J =
7.8 Hz, 1 H), 6.95 (t, J = 6.0 Hz, 1 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.47 (t, J = 6.9 Hz, 2
H), 1.78 (m, 2 H), 1.67 (m, 2 H), 1.05 (m,
6
H);
154
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13C NMR (75 MHz, CDC13) 5: 155.4, 152.2, 147.9, 119.0, 110.1, 100.2, 75.4, 40.0,
22.8, 22.4, 19.4, 14.6, 14.4;
MS (+CI) m/z 231 (M + H+, 100), 232 (32).
yV-(5’-Methyl-2-pentynyl-phenyl)-butyramicle 90n
90n
Prepared from 89c in 71% yield. 90n: white solid; R/ = 0.58 (33% EtOAc in hexane);
IR (film) 3400, 2092, 1644 cm'1;
*H NMR (300 MHz ,CDC13)
6
8.25 (s, 1 H), 7.95 (s, 1 H), 7.24 (dd, J = 2.79, 7.38
Hz, 1 H), 6.81 (dd, J = 0.99, 7.9 Hz, 1 H), 2.47 (t, J = 6.9 Hz, 2 H), 2.37 (t, J = 7.5
Hz, 4 H), 2.33 (s, 1 H), 1.77 (sextet, J = 7.5 Hz, 2 H), 1.67 (sextet, J = 7.2 Hz, 2 H),
1.08 (t, J = 7.4 Hz, 3 H), 1.02 (t, J = 7.4 Hz, 3 H).
,3C NMR (75 MHz, CDCI3 ) 8171.0, 139.3, 138.7, 131.1, 123.9, 19.5, 09.6, 96.8,
76.1, 40.0, 22.2, 21.8, 21.5, 19.0, 13.7, 13.6;
MS (Cl) m/z 244 (M + H+, 100).
155
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iV-(5’,6’,7’,8’ -Tetrohydro-naphthalene- 2’-pentynyl-phenyl)-butyramide 90o
90o
>
■
Prepared from 89d in 97% yield. 90o: white crystalline solid; mp 55-56 °C; R/ =
0.55 (33% EtOAc in hexane);
IR (film) 3298, 2929, 2872, 1695, 1524cm'1;
•H NMR (300 MHz, CDCI3 )
8
8.10 (s, 1 H), 7.86 (s, 1 H), 7.05(s, 1 H), 2.74 (s, 2 H),
2.64 (s, 2 H), 2.45 (t, J = 7.0 Hz, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 1.80- 1.62 (m,
8
H),
1.07 (t, J = 7.3 Hz, 3 H), 1.01 ( t , / = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 )
8
170.7, 138.2, 136.0, 131.9, 131.6, 119.2, 109.8, 96.2,
76.2, 39.8, 29.6, 28.6, 23.0, 22.9, 22.2, 21.4, 19.0, 13.6, 13.5;
MS (+CI) m/z 284 (M + H+, 100);
Anal Calcd. for C 1 9 H25NO C, 80.52; H, 8.89; N, 4.94. Found C, 80.21; H, 9.13; N,
4.80.
Representative procedure for the synthesis of iondoles from 2-alkynylanilides.
2-phenyl- lEf-indole 91a
H
91a
A mixture of 90a (47.6 mg, 0.185 mmol), potassium tenr-butoxide (25.0 mg, 0.22
mmol), NMP 2 mL was heated at 60-70 °C for 7 h under nitrogen atmosphere ,then
156
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cooled to room temperature. The reaction solution was added 2 mL water and 50 mL
ethyl acetate ,then extracted with ethyl acetate 3 times (3x20 mL).The organic layer
was washed with brine, dried over anhydrous MgSC>4 ,concentrated under reduced
pressure and purified by flash column chromatography (silica gel, 33% EtOAc in
hexane) to give 91a (28.7 mg, 81%) as a white solid.
91a: white crystalline solid; mp 188-189 °C; R/ = 0.58 (33% EtOAc in hexane);
IR (film) 3432, 1644 cm'1;
!H NMR (300 MHz, CDC13) 5 8.28 (s, 1H), 7.61-7.65 (m, 3 H), 7.36-7.45 (m, 3 H),
7.31-7.33 (m, 1 H), 7.09-7.22 (m, 2 H), 6.82 (s, 1 H);
13CN M R (75 MHz, CDCU) 5137.9, 136.8, 132.3, 129.2, 129.0, 127.7, 125.1, 122.3,
120.7,120.3,110.9, 99.9;
MS (+CI) m/z 193 (M + H+, 100);
Anal. Calcd. for Ci4Hn N: C, 87.01; H, 5.74; N, 7.25; Found: C, 87.06; H, 5.96; N,
7.11.
5-Methyl-2-phenyl-l/f-indole 91b
H
91b
Prepared from 90b in 81% yield. 91b: white crystalline solid; mp 215-216 °C; R/ =
0.70 (33% EtOAc in hexane);
IR (film) 3433, 2917, 1449 cm'1;
•H NMR (300 MHz, CDC13) 5 8.21 (s, 1 H), 7.65-7.62(m, 2 H), 7.45-7.40 (m, 3 H),
7.73-7.27 (m, 2 H), 7.01 (dd, J = 1.4, 8.10 Hz, 1 H), 6.74 9(quartet, J = 0.9, 2.2 Hz,
1 H), 2.44 (s, 3 H);
157
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,3C NMR (75 MHz, CDCI3 )
137.9, 132.5, 129.5, 129.4, 128.9, 127.6, 125.0, 124.0,
6
120.3, 110.5, 99.5,21.4,0.02;
MS (+CI) m/z 207 (M + H+, 100);
Anal. Calcd. for C 1 5 H 13 N C, 86.92; H, 6.32; N, 6.76. Found C, 7.05; H, 6.15; N, 6.81.
6-Methyl-2-phenyl-l//-indole 91c
91c
Prepared from 90c in 84% yield. 91c: white crystalline solid; mp 185-186 °C; Rf =
0.65 (33%EtOAc in hexane);
IR (film) 3431, 2917, 1618, 1453 cm'1;
!H NMR (300 MHz, CDCI3 )
8
8.16 (s, 1H), 7.60-7.64 (m, 2 H), 7.50 (d, / = 8.0, 1
H), 7.38-7.44 (m, 2 H), 7.27-7.32 (m, 1 H), 7.16 (s, 1 H), 6.95 (dd, J = 8.0, J = 0.90,
1 H), 6.77 (s, 1 H), 2.46 (s, 3 H);
13C NMR (75 MHz, CDCI3 ) 8137.30, 137.20, 132.53, 132.24, 128.97, 127.44, 127.06,
124.95, 122.05, 120.28, 110.84, 99.82, 21.80;
MS (+CI) m/z 207 (M + H+, 100).
Anal. Calcd. for C 1 5 H 1 3 N C, 86.92; H, 6.32; N, 6.76; Found C, 86.46; H, 6.48; N,
6.56.
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2-Phcnyl-5,,6,,7’,8’-tctrahydro-l/7-bcnzo[f|indoIe 91d
H
91 d
Prepared from 90d in 81% yield. 91d: white solid; Rj = 0.73 (33% EtOAc in hexane);
IR (film) 3427, 2916, 2848, 1460 cm'1;
*H NMR (300 MHz, CDCfi) 5 8.10 (s, 1 H), 7.65 (d, J = 7.6 Hz, 2 H), 7.49 -7.40 (m,
2 H), 7.33 - 7.29 (m, 2 H), 7.10 (s, 1 H), 6.73 (s, 1 H), 2.92 (s, 4 H), 1.88-1.83 (m, 4
H);
13CN M R (75 MHz, CDCI3 ) 8 137.5, 135.7, 132.6, 132.2, 129.6, 128.9, 127.8, 127.4,
124.9,119.9,110.2,
99.3, 30.2, 29.8, 23.8,23.6;
MS (+CI) m/z 247 (M + H+, 100).
6-Chloro-2-phenyl-l//-indole 91 e
91e
Prepared from 90e in 81% yield. 91e: white crystalline solid; mp 179-180 °C; Rf =
0.47 (13% EtOAc in hexane);
IR (film) 3432, 1485, 1450 cm'1;
!H NMR (300 MHz, CDCI3 ) 5 8.33 (s, 1 H), 7.66-7.63 (m, 2 H), 7.54-7.32(m, 5 H),
7.09 (dd, J = 1.8, 8.4 Hz, 1 H), 6.79 (d, J = 1.8 Hz, 1 H);
13C NMR (75 MHz, CDC13) 5 129.1, 128.0, 125.1, 121.4, 121.0, 110.8, 99.9;
MS (+CI) m/z 227 (M + H+, 100);
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.1
Anal. Calcd. For C14 H 1 0 CIN C, 73.85; H, 4.43; N, 6.15. Found C, 73.71; H, 3.99; N,
5.94.
6-Ethanesulfonyl-2-phenyl-l/7-indole 91f
91 f
Prepared from 90f in 86% yield. 91f: pale brow crystal; mp 150-151 °C; Rf = 0.32
(33% EtOAc in hexane);
IR (film) 3339, 2940, 2879, 1611, 1486 cm'1;
*H NMR (300 MHz, CDCI3 ) 6 9.74 (s, 1 H), 8.20 (s, 1 H), 7.79-7.72 (m, 3 H), 7.59
(dd, J = 1.6, 8.4 Hz, 1 H), 7.50-7.44 (m, 2 H), 7.40-7.34 (m, 1 H), 6.90 ( t , / = 1.3 Hz,
1 H), 3.19 (q, J —7.5 Hz, 2 H, 1.27 9 (t, J = 7.4 Hz, 3 H);
13CN M R (75 MHz, CDCI3 ) 8 142.6, 135.7, 133.2, 131.2, 130.4, 129.2, 128.7, 125.6,
121.0, 118.9, 112.3, 99.7,51.2,7.6;
MS (+CI) m/z 285 (M + H+, 100);
Anal. Calcd. For Ci6 Hi 5 N 0 2S C, 67.34; H, 5.30; N, 4.91. Found C, 67.18; H, 5.32;
N, 4.87.
*
160
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3,5-Dimethyl- 2-phenyl-lET-indole 91 g
Me
-Ph
9lg
Prepared from 90g in 81% yield. 91g: white crystalline solid; mp 95-96 "C; R/ =
0.52 (13% EtOAc in hexane);
IR (film) 3427, 2916, 2856, 1603, 1487, 1449 cm'1;
!H NMR (300 MHz, CDCI3 ) 5 8.20 (s, 1 H), 7.68-7.65 (m, 2 H), 7.47-7.41 (m, 2 H),
7.35-7.28 (m, 1 H), 7.04 (s, 1 H), 6.82 (d, J = 1.3 Hz, 1 H), 6.80 (s, 1 H), 2.57 (s, 3
H), 2.50 (s, 3 H);
13C NMR (75 MHz, CDCfi) 5 137.0, 136.6, 132.6, 132.4, 129.8, 129.0, 127.3, 127.0,
124.9, 122.3, 108.4, 98.4, 21.7, 18.7;
MS (+CI) m/z 221 (M + H+, 100).
5-Methoxyl-2-pentyl-l//-indole 91 h
M eC X
T r" \ \
-Ph
91h
Prepared from 90h in 81% yield. 91h: white solid; mp 167-168 °C; Rf = 0.4 ( 20%
EtOAc in hexane);
IR (film) 3427, 2918, 2849, 1620, 1476, 1217 cm'1;
!H NMR (300 MHz, CDCI3 ) 6 8.29 (s, 1 H), 7.66-7.62 (m, 2 H), 7.34 (d, / = 7.4 Hz,
1 H), 7.28 (dd, J = 2.6, 8.76 Hz, 1 H),), 7.11 (d, J = 2.4 Hz, 1 H), 8.87 (dd, J = 2.5,
8 .8
Hz, 1 H), 6.77 (d, J = 1.6 Hz, 1 H);
161
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13C NMR (75 MHz, CDC13) 5 154.4, 138.6, 2132.4, 132.0, 129.7, 129.0, 127.6, 125.0,
112.6, 111.6, 102.2, 99.7, 55.8;
MS (+CI) m/z 224 (M + H+, 100).
Anal. Calcd. for C 1 5 H 1 3 NO C, 80.69; H, 5.87; N, 6.27. Found C, 80.32; H, 3.77; N,
5.67.
i
2-Phenyl-l/f-azaindole 91i
91 i
Prepared from 90i in 96% yield. 911: Rj = 0.74 (6 6 % EtOAc in hexane);
IR (KBr) 3065 (NH) cm'1;
!H NMR (300 MHz, CD3 COCD3 ) 6 11.62 (s, 1 H), 8.39 (dd, J = 1.1, 4.56 Hz, 1 H),
8.15- 8.09 (m, 3 H), 7.69-7.62 (m, 2 H), 7.56-7.50 (m, 1 H), 7.23 (dd, J = 4.4, 7.8
Hz, 1 H), 7.07 (s, 1 H);
13C NMR (75 MHz, CD3 COCD 3 ) 5 142.8, 128.8, 127.9, 127.7, 125.3, 116.0, 97.2;
MS (+CI) m/z 195 (M + H+, 100).
2-propyl-l/?-indoe 91j
91 j
Prepared from 90j in
8 6
% yield. 91j: white solid; Rj = 0.67 (33% EtOAc in hexane);
IR (film) 3402, 2959, 2871, 1618, 1457 cm'1;
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'H NMR (300MHz, CDC13) 8 7.74 (s, 1 H), 7.58-7.63 (m, 1 H), 7.30-7.33 (m, 1 H),
7.13-7.23 (m, 2 H), 6.31 (s, 1 H), 2.74 (t, J = 7.3 Hz, 2 H), 1.73-1.85 (m, 2 H), 1.07
(t, J = 7.3Hz, 3 H);
13C NMR (75MHz, CDC13) 5 139.8, 135.7, 128.8, 120.8, 119.7, 119.5, 110.3, 99.4,
30.2, 22.4,13.8;
MS (+CI) m/z 160 (M + H+, 100).
l//-indole 91k
H
91k
Prepared from 90k in 84% yield. 91k: white solid; R/ = 0.55 (33% EtOAc in hexane);
IR (film) 3404, 1455, 1414 cm'1;
!H NMR (300 MHz, CDC13) 8 8.00 (s, 1 H), 7.73-7.77 (m, 1 H), 7.39-7.42 (m, 1 H),
7.18-7.32 (m, 3 H), 6.62-6.64 (m, 1 H);
13C NMR (75 MHz, CDC13) 8 135.6, 127.7, 124.1, 121.9, 120.6, 119.7, 111.0, 102.4;
MS (+CI) m/z 117 (M + H+, 1);
6-Ethanesulfonyl-2-pentyl-l//-indole 911
911
Prepared from 901 in 86% yield. 911: pale brow crystal; mp 73-74 °C;
Rf = 0.46 (33% EtOAc in hexane)
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IR (film) 3583, 3053, 2925, 2853, 1459 cm'1;
!H NMR (300 MHz, CD3 COCD3 ) 5 10.78 (s, 1 H), 8.05- 8.04 (m, 1 H), 7.81 (d, J =
8.2 Hz, 1 H), 7.63 (dd, J = 1.6, 8.4 Hz, 1 H), 6.53 (q, J = 0.7, 1.9 Hz, 1 H), 3.28 (q, J
= 7.3 Hz, 2 H), 2.97 (t, J = 7.3 Hz, 2 H), 1.94 (sextet, / = 7.5 Hz, 2 H), 1.32 (t, J =
7.5 Hz, 3 H), 1.13 (t, .7 = 7.3 Hz, 3 H);
13C NMR (75 MHz, CD 3 COCD3 X5 144.9, 134.8, 132.5, 130.1, 119.2, 117.8, 111.2,
99.4, 50.2,29.7,21.9, 12.9, 6 .8 ;
MS (+CI) m/z 252 (M + H+, 100).
2-Propyl-7/7-azaindole 91m
91m
Prepared from 90m in 90% yield. 91m: Rf = 0.42 (33% EtOAc in hexane);
IR (KBr) 3217 (NH) cm'1;
■H NMR (300 MHz, CDCI3 ) 5 11.88 (NH), 8.21 ( d ,/= 4 .2 H z , 1 H), 7.8 5 (d ,J= 8 .1
Hz, 1 H), 7.05(t, J = 6.5 Hz, 1 H), 6.21(s, 1 H), 2.87(t, J = 7 .5 Hz, 2 H), 1.88(m, 2 H),
1.07(t, J = 7.2 Hz, 3 H);
13CNMR (75 MHz, CDCI3 ) § 149.7, 142.2, 140.0, 128.2, 122.6, 116.4, 97.4,31.9,
23.5, 14.3;
MS (+CI) m/z 161 (M + H+, 100).
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6-Methyl-2-pentyl-l//-indole 91n
91 n
Prepared from 90n in 90% yield. 91n: white solid; Rj = 0.4 (20% EtOAc in hexane);
IR (film) 2923, 2852, 1619 cm'1;
!H NMR (300 MHz, CD3COCD3) 8 10.01 (s, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.24
(dd, J = 0.7, 1.4 Hz, 1 H), 6.94 (dd, J = 1.5, 8.0 Hz, 1 H), 6.26 (dd, 7 = 0.9, 2.2 Hz, 1
H), 2.87 (t, J = 7.7 Hz, 2 H), 2.52 (s, 3 H), 1.88 9 (sextet, / = 7.4 Hz, 2 H), 1.11 (t, J
= 7.4 Hz, 3 H);
13C NMR (75 MHz, CD3COCD3) 5 139.1, 136.7, 129.2, 126.7, 120.2, 118.7, 110.2,
98.3,29.8,22.2, 20.7, 13.0;
MS (+CI) m/z 174 (M + H+, 100).
2-Pentyl-5’,6’,7’,8’-tetrahydro-l//-benzo[/]indole 91o
H
91o
Prepared from 90o in 85% yield. 91o: yellow needle; mp 193-194 °C; Rj = 0.73
(13% EtOAc in hexane);
IR (film) 3382, 2919, 2849, 1464 cm'1;
JH NMR (300 MHz, CD3COCD3) 5 9.80 (s, 1 H), 7.23 (s, 1 H), 7.10 (s, 1 H), 6.17 (t,
J = 0.8 Hz, 1 H), 2.96 (br, 4 H), 2.85 9 (t, J = 7.6 Hz, 2 H), 1.95-1.91 (m, 4 H), 1.901.84 (m, 2 H), l . l l ( t , / = 7.3 Hz, 3 H);
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13C N M R (75 MHz, CD3 COCD 3 ) 5 139.4, 135.4, 129.1, 127.5, 127.2, 118.4, 109.5,
97.7, 23.7, 23.6, 22.2, 13.0.
Representative procedure for the acylation of nitro 2-aminophenols 102a-c.
Af-(2’-Hydroxy-5,-nitrophenyl)butyramide 103b
cr
103b
To a solution of 2-amino-4-nitrophenol 102b (462.0 mg, 3.00 mmol) in dry THF (25
mL) cooled in an ice-water bath was added pyridine (0.30 mL, 3.80 mmol) and
butyryl chloride (0.34 mL, 3.30 mmol) through a syringe, respectively. The resultant
mixture was stirred for 60 h at refluxing temperature under a nitrogen atmosphere.
The reaction was quenched by water and the resultant mixture was extracted with
EtOAc (3 0 x 3 mL). The combined organic layer was washed with brine, dried over
anhydrous M gS04, and evaporated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 25% EtOAc in hexane) to give 103b
(650.0 mg, 97%) as a pale yellow crystalline solid; mp 191-192 °C (DCM-hexane);
R/= 0.53 (33% EtOAc in hexane);
IR (film) 3406, 1646, 1529, 1498, 1343, 1289 cm’1;
*H NMR (300 MHz, CD 3 COCD3) 5 10.85 (br s, 1 H), 9.24 (br s, 1 H), 8.99 (d, J =
2.8 Hz, 1 H), 8.06 (dd, J = 8.9, 2.8 Hz, 1 H), 7.2 (d, J = 9.0 Hz, 1 H), 2.68 (t, J = 7.4
Hz, 2 H), 1.88 (sextet, / = 7.4 Hz, 2 H), 1.13 (t, J= 1A Hz, 3 H);
13C N M R (75 MHz, CD3 COCD3) 5 172.8, 152.8, 140.2, 126.9, 120.2, 116.3, 115.8,
37.9, 18.4, 12.7;
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MS (+CI) m/z 225 (M + H+, 100);
Anal. Calcd. for Ci0 H 12 N 2 O4 C, 53.57; H, 5.39; N, 12.49. Found C, 53.81; H, 5.40; N,
12.31.
Ar-(2,-Hydroxy-4,-nitrophenyl)butyramide 103a
XX„
103a
Prepared from 2-amino-5-nitrophenol 102a in
8 6
% yield. 103a: a colorless
crystalline solid; mp 175-176 °C (DCM-hexane); R/= 0.51 (50% EtOAc in hexane);
IR (film) 3409, 1664, 1504, 1421, 1341 cm'1;
!H NMR (300 MHz, CD3 COCD3 ) 5 9.22 (br s, 1 H), 8.36 (d, J = 8 . 8 Hz, 1 H), 7.947.87 (m, 2 H), 2.69 (t, / = 7.4 Hz, 2 H), 1.87 (sextet, J = 7.4 Hz, 2 H), 1.12 (t, J = 7.4
Hz, 3 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5172.5, 146.3, 143.2, 133.2, 119.6, 115.4, 110.1,
38.1, 18.3, 12.7;
MS (+CI) m/z 225 (M + H+, 100);
Anal. Calcd for Ci0 Hi 2 N 2 O4 C, 53.57; H, 5.39; N, 12.49. Found C, 53.62; H, 5.48; N,
12.38.
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7V-(2’-Hydroxy-6’-nitrophenyl)butyramide 103c
OH
NH
°2N
O'
103c
Prepared from 2-amino-3-nitrophenol 102c in 60% yield using NaH to replace
pyridine as the base (rt, 24 h). 102c: a yellow crystalline solid; mp 119-120 °C
(DCM-hexane); Rf = 0.34 (25% EtOAc in hexane);
IR (film) 3395, 3141 (br), 1663, 1540, 1511, 1367 cm’1;
*H NMR (300 MHz, CDCI3 ) § 10.09 (br s, 1 H), 9.32 (s, 1 H), 7.71 (dd, J = 8.4, 1.5
Hz, 1 H), 7.36 (dd, / = 8.2, 1.5 Hz, 1 H), 7.24 (t, J = 8.3 Hz, 1 H), 2.56 (t, J = 7.4 Hz,
2 H), 1.82 (sextet, J = 1A Hz, 2 H), 1.04 (t, J = 7.4 Hz, 3 H);
13CNMR (75 MHz, CDCI3 ) 5 175.0, 151.2, 141.2, 127.1, 126.1, 122.2, 117.9, 39.4,
19.0, 13.5;
MS (+CI) m/z 225 (M + H+, 100);
Anal. Calcd. for C 1 0 H 12 N 2 O4 C, 53.57; H, 5.39; N, 12.49. Found C, 53.72; H, 5.45; N,
12.42.
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Representative procedure for the synthesis of nitroaryltriflates using NaH as the
base.
7V-[5,-Nitro-2,-(((trifluoromethanc)sulfonyl)oxy)phcnyl|butyramidc 104b
^
o 2n x ^
5j
. 0 S 0 2C F 3
>^ n h
O'
104b
To a suspension of NaH (60%, 80.0 mg, 2.03 mmol) in dry MeCN (15 mL) cooled in
an ice-water bath under a nitrogen atmosphere was added a solution of 103b (363.0
mg, 1.62 mmol) in dry MeCN (5 mL) followed by stirring at the same temperature
for 20 min. Tf20 (0.30 mL, 1.78 mmol) was then added dropwise, and the resultant
mixture was stirred for
6
h at -5 -0 °C. The reaction was quenched by water and the
resultant mixture was extracted with EtOAc (30 x 2 mL). The combined organic
layer was washed with saturated aqueous NaH C0 3 and brine, dried over anhydrous
MgS 0 4 , and evaporated under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 25% EtOAc in hexane) to give 104b (461.0 mg,
80%) as a white crystalline solid; mp 73-74 °C (CH 2 Cl2 -hexane); Rj = 0.51 (25%
EtOAc in hexane);
IR (film) 3271 (br), 2969, 1681, 1542, 1430,1217 cm'1;
!H NMR (300 MHz, CDC13) 5 9.30 (d, J = 2.7 Hz, 1 H), 8.04 (dd, J = 9.0, 2.7 Hz, 1
H), 7.55-7.47 (br s, 1 H),,7.48 (d, J = 9.0 Hz, 1 H), 2.45 (t, J = 1A Hz, 2 H), 1.79
(sextet, J = 7.4 Hz, 2 H), 1.03 (t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 5 171.3, 148.6, 141.9, 131.6, 122.1, 119.6, 118.5, 118.3
(q,yC-F= 3 18.4 H z), 39.4, 18.5, 13.6;
MS (+CI) m/z 357 (M + H+, 100);
169
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Anal. Calcd. for C1 1 H 11 F3 N 2 O6 S C, 37.08; H, 3.11; N, 7.86. Found C, 37.45; H, 3.13;
N, 7.77.
Ar-[4,-Nitro-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]butyramide 104a
104a
Prepared from 103a in 87% yield. 104a: a colorless crystalline solid; mp 88-89 °C
(EtOAc); R/ = 0.45 (25% EtOAc in hexane);
IR (film) 3274 (br), 2972, 1690, 1516, 1435, 1350, 1217 cm'1;
*H NMR (300 MHz, CD3 COCD3) 5 9.68 (br s, 1 H), 8.68-8.48 (m, 3 H), 2.70 (t, J =
1A Hz, 2 H), 1.88 (sextet, J = 1A Hz, 2 H), 1.12 (t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 5 171.5, 142.7, 138.8, 136.8, 123.9, 123.6, 118.3 (q, JCF = 318.4 Hz), 117.4,38.0, 17.9, 12.7;
MS (+CI) m/z 357 (M + H+, 100);
Anal. Calcd. for CnH iiF 3 N 2 0 6S C, 37.08; H, 3.11; N, 7.86. Found C, 37.45; H, 3.13;
N, 7.77.
170
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Representative procedure for the synthesis of nitroaryltriflate using Et3N as the
Base.
AL[6’-Nitro-2’-(((trifIuoromethane)sulfonyl)oxy)phenyl]butyramide 104c
°2N
104c
To a solution of 103c (395.0 mg, 1.76 mmol) and Et3N (0.35 mL, 2.20 mmol) in dry
CH2 CI2 (20 mL) cooled in an ice-water bath under a nitrogen atmosphere was added
Tf2
0
(0.33 mL, 1.03 mmol) dropwise. The resultant mixture was stirred at the same
temperature for 7 h. After removal of CH2 CI2 under reduced pressure, the residue
was dissolved in 25 mL EtOAc and then washed with 5% aqueous HC1, saturated
aqueous NaHC 0 3 , and brine. The organic layer was dried over anhydrous MgS 0 4
and evaporated under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 25% EtOAc in hexane) to give 104c (590.0 mg, 94%) as
a white crystalline sold; mp 119-119.5 °C (DCM-hexane); R/= 0.40 (25% EtOAc in
hexane);
IR (film) 3248 (br), 2973, 1676, 1541, 1518, 1425, 1209 cm'1;
NMR (300 MHz, CDCI3 ) 5 8.18 (br s, 1 H), 8.10 (dd,J= 8.4, 1.4 Hz, 1 H), 7.62
(dd, J = 8.4, 1.4 Hz, 1 H), 7.48 (t, J = 8.4, 1 H), 2.46 (t, J = 7.4 Hz, 2 H), 1.77 (sextet,
J = 1A Hz, 2 H), 1.02 (t, J = 1A Hz, 3 H);
13CNMR (75 MHz, CDCI3 ) 5 171.2, 145.1, 145.0, 127.5, 126.9, 126.1, 124.9, 118.4
(q,JC-F= 318.5 Hz), 38.5, 18.4, 13.6;
M S ( I C l) m /z 3 57 (M t H +, 100);
171
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Anal. Calcd for C nH nF^O eSC , 37.08; H, 3.11; N, 7.86. Found C, 37.16; H, 3.15;
N, 8.06.
Representative procedure for the cross-coupling of triflates with l-alkynes.
7V-[(5’-Nitro-2’-phenylethynyl)phenyl]butyramide 105b-2
Ph
0 2N
NH
105b-2
To a suspension of triflate 104b (142.0 mg, 0.40 mmol), Pd(PPh3 ) 4 (46.0 mg, 4.0 x
10' 2
mmol), Cul (23.0 mg, 0.12 mmol), and «Bu4NI (222.0 mg, 0.60 mmol) in
degassed dry MeCN (5.0 mL) was added Et3N (1.0 mL) and phenylacetylene (90.0
pL, 0.80 mmol), respectively, through a syringe under a nitrogen atmosphere. The
resultant mixture was stirred at room temperature for 1 h. The reaction was quenched
by saturated aqueous NH 4 CI and the resultant mixture was extracted by EtOAc (20 x
2 mL). The combined organic layer was washed with brine, dried over anhydrous
M gS04, and concentrated under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 30% EtOAc in hexane) to give 105b-2 (126.0
mg, 96%) as a yellow crystalline solid; mp 168-169 °C (DCM-hexane); R/ = 0.44
(25% EtOAc in hexane);
IR (film) 3290, 2960, 2214, 1665, 1534, 1341 cm’1;
*H NMR (300 MHz, CDC13) 5 9.36 (d, J = 2.2 Hz, 1 H), 8.09 (br s, 1 H), 7.92 (dd, J
= 8.5, 2.2 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 7.58-7.55 (m, 2 H), 7.47-7.40 (m, 3 H),
2.47 (t, J = 7.4 Hz, 2H ), 1.82 (sextet, J = 7.4 Hz, 2 H), 1.05(t, J = 7.4 Hz, 3 H);
172
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13C NMR (75 MHz, CDC13) § 171.3, 147.9, 139.5, 132.0, 131.7 (x 2), 129.9, 128.8 (x
2), 121.2, 118.0, 117.8, 114.3, 100.8, 82.8, 39.8, 18.8, 13.7;
MS (+CI) m/z 309 (M + H+, 100);
Anal. Calcd for Ci 8 Hi 6 N 2 0 3 C, 70.12; H, 5.23; N, 9.09. Found C, 69.75; H, 6.00; N,
9.20.
/V-[(5’-Nitro-2’-(pentyn-l ” -yl))phenyl|butyramide 105b-l
105b-1
Prepared from the triflate 104b and 1-pentyne in 90% yield. 105b-l: a white
crystalline solid; mp 91-92 °C (DCM-hexane); R/= 0.38 (25% EtOAc in hexane);
IR (film) 3290, 2962, 2223, 1668, 1529, 1344 cm'1;
!H NMR (300 MHz, CDCI3 ) 5 9.31 (d, J = 2.2 Hz, 1 H), 8.04 (br s, 1 H), 7.85 (dd, J
= 8.5, 2.2 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 1 H), 2.55 (t, / = 7.0 Hz, 2 H), 2.42 (t, J =
1A Hz, 2 H), 1.82-1.67 (m, 4 H), 1.11 (t, J= 7.4 Hz, 3 H), 1.04 (t, J = 1A Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 171.2, 147.4, 139.5, 131.9, 118.5, 117.8, 113.9, 102.9,
75.0, 39.8, 21.9, 21.6, 18.8, 13.7,13.6;
MS (+CI) m/z 275 (M + H+, 100);
173
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Ar-[(4’-Nitro-2’-phenylcthynyl)phenyl|butyrainide 105a-2
Ph
OoN
NH
O
105a-2
Prepared from the triflate 104a and 1-phenylacetylene in 95% yield. 105a-2: a
colorless crystalline solid; mp 149-150 °C (DCM-hexane); R/= 0.54 (25% EtOAc in
hexane);
IR (film) 3306, 2959, 2212, 1677, 1574, 1506 cm'1;
XH NMR (300 MHz, CDCI3 ) 6 8.68 (d, J = 9.2 Hz, 1 H), 8.38 (d, J = 2.6 Hz, 1 H),
8.25 (br s, 1 H), 8.20 (dd, J = 8.6, 2.6 Hz, 1 H), 7.58-7.55 (m, 2 H), 7.47-7.40 (m, 3
H), 2.49 (t, J = 7.4 Hz, 2 H), 1.82 (sextet, J = 1A Hz, 2 H), 1.05 (t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 171.4, 143.9, 142.6, 131.6 (x 2), 129.7, 128.8 (x 2),
127.1, 125.2, 121.2, 118.7, 112.3, 98.5, 82.02, 40.0, 18.8, 13.7;
MS (+CI) m/z 309 (M + H+, 100);
Anal. Calcd for C18H16N20 3 C, 70.12; H, 5.23; N, 9.09. Found C, 70.34; H, 5.63; N,
8.87.
174
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Ar-[(4’-Nitro-2’-(pentyn-l” -yL))phenyl]butyramide 105a-l
o 2n
105a-1
Prepared from the triflate 104a and 1-pentyne in 95% yield. 105a-l: a white
crystalline solid; mp 87-88 °C (DCM-hexane); R/= 0.59 (25% EtOAc in hexane);
IR (film) 3335, 2965, 2228, 1678, 1503, 1345 cm'1;
NMR (300 MHz, CDC13) 5 8.59 (d, J = 9.2 Hz, 1 H), 8.23-8.15 (br s, 1 H), 8.19
(d, J = 2.6 Hz, 1 H), 8.09 (dd, J = 9.2, 2.6 Hz, 1 H), 2.51 (t, J = 7.0 Hz, 2 H), 2.42 (t,
J = 7.4 Hz, 2 H), 1.81-1.65 (m, 4 H), 1.08 ( t,7 = 7.4 Hz, 3 H), 1.02 (t, J = 7.4 Hz, 3
H);
13CN M R (75 MHz, CDC13) 5 171.4, 144.0, 142.3, 126.9, 124.4, 118.2, 112.9, 100.3,
74.2, 39.9, 21.9, 21.4, 18.7, 13.6,13.5;
MS (+CI) m/z 275 (M + H+, 100);
Anal. Calcd. for C is H ^ O a C, 65.68; H, 6.61; N, 10.21. Found C, 66.03; H, 6.73; N,
10.05.
175
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N- [(6’-Nitro-2’-phenyLethynyl)phenyl]butyramide 105c-2
NH
°2N
Prepared from the triflate 104c and 1-phenylacetylene in 90% yield. 105c-2: a white
crystalline solid; mp 167-168 °C (DCM-hexane); Rj = 0.31 (25% EtOAc in hexane);
IR (film) 3275, 2923, 2215, 1668, 1509 cm'1;
*H NMR (300 MHz, CDCI3 ) 5 8.13 (br s, 1 H), 7.89 (dd, 7 = 8.3, 1.4 Hz, 1 H), 7.76
(dd, J = 8.3, 1.4 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.42-7.35 (m, 3 H), 7.29 (d, J = 8.1
Hz, 1 H), 2.44 (t, J = 7.4 Hz, 2 H), 1.78 (sextet, J = 7.4 Hz, 2 H), 1.01 (t, .7=7.4 Hz,
3 H);
13C NMR (75 MHz, CDC13) 5 170.9, 144.3, 136.7, 131.6 (x 2), 131.4, 129.3, 128.6
(x 2), 125.3, 124.9, 121.8, 120.9, 97.2, 83.7, 38.9, 18.8, 13.7;
MS (+CI) m/z 309 (M + H+, 100);
Anal. Calcd for Ci 8 Hi 6 N 2 0 3 C, 70.12; H, 5.23; N, 9.09. Found C, 70.31; H, 5.91; N,
8.82.
176
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/V-[(6,-Nitro-2,-(pentyn-l” -yl))phenyl|butyramide 105c-l
NH
105C-1
Prepared from the triflate 104c and 1-pentyne in 91% yield. 105c-l: a white
crystalline solid; mp 144-145 °C (DCM-hexane); R/= 0.36 (25% EtOAc in hexane);
IR (film) 3272, 2961, 2225, 1670, 1511, 1536 cm'1;
*H NMR (300 MHz,
C D C I3 )
5 7.95 (br s, 1 H), 7.79 (dd, J = 8.0, 1.4 Hz, 1 H), 7.60
(dd, J = 8.0, 1.4 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H), 2.44 (t, J = 7.0 Hz, 2 H), 2.39 (t,
J = 1A Hz, 2 H), 1.83-1.56 (m, 4 H), 1.05 ( t ,J = 7.3 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3
H);
b CN M R (75 MHz, CDCI3 ) 5 170.8, 144.3, 136.4, 131.0, 124.9, 124.2, 121.0, 99.2,
75.3, 38.7, 21.9, 21.4, 18.7, 13.6,13.5;
MS (+CI) m/z 275 (M + H+, 100);
Anal. Calcd for C 1 5 H 18 N 2 O3 C, 65.68; H, 6.61; N, 10.21. Found C, 64.19; H, 6.05; N,
10.50.
Representative procedure for the f-BuOK-promoted ring closure of 106.
6-Nitro-2-phenylindole 106b-2
106b-2
177
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A mixture of 105b (60.0 mg, 0.19 mmol), t-BuOK (25.0 mg, 0.22 mmol) in dry
NMP (2.0 mL) was heated at 60-70 °C for 7 h under a nitrogen atmosphere. After
cooling to room temperature, water (2 mL) and EtOAc (50 mL) were added to the
reaction mixture, respectively. The separated aqueous layer was extracted with
EtOAc (20 x 3 mL). The combined organic layer was washed with brine, dried over
anhydrous MgS0 4 , concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 30% EtOAc in hexane) to give 160b-2
(30.7 mg, 84%) as a yellow crystalline solid; mp 211-212 °C (DCM-hexane); Rj =
0.61 (33% EtOAc in hexane);
IR (KBr) 3322, 2923, 1298 cm'1;
!H NMR (300 MHz, CD3 COCD3) 5 11.61 (br s, 1 H), 8.51 (d, 7 = 2.0 Hz, 1 H),
8.12-8.06 (m, 3 H), 7.88 (d, J =
8 .8
Hz, 1 H), 7.70-7.63 (m, 2 H), 7.61-7.54 (m, 1
H), 7.25 (dd, J = 2.0, 0.8 Hz, 1 H);
,3C NMR (75 MHz, CD3 COCD3 )
8
144.0, 142.5, 135.5, 133.9, 131.0, 128.9 (x 2),
128.6, 125.5 (x 2), 119.9, 114.7, 107.5,99.7;
MS (+CI) m/z 239 (M + H+, 100);
Anal. Calcd for C 1 4 HioN2 0 2 C, 70.58; H, 4.23; N, 11.76. Found C, 70.40; H, 4.11; N,
11.64.
6-Nitro-2-propylindole 106b-l
106b-1
Prepared from 105b-l in
8 6
% yield. 106b-l: a yellow crystalline solid; mp 94-95 °C
(DCM-hexane); Rf = 0.54 (33% EtOAc in hexane); IR (film) 3367, 2962, 1302 cm4;
178
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3H NMR (300 MHz,
(dd, 7 =
8
C D 3 C O C D 3 )
5 10.98 (br s, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 8.04
.8 , 2.2 Hz, 1 H), 7.73 (d, / =
8 .8
Hz, 1 H), 6.55 (d, J = 0.5 Hz, 1 H), 2.98 (t,
J = 7.5 Hz, 2 H), 1.94 (sextet, J = 7.5 Hz, 2 H), 1.13 (t, J = 7.5 Hz, 3 H);
13C NMR (75 MHz, CD 3 COCD3 ) 5 141.5, 119.3, 118.6, 114.8, 114.0, 107.3, 106.7,
99.8, 29.9,21.7, 12.8;
MS (+CI) m/z 205 (M + H+, 100);
Anal. Calcd. for C 1 1 H 12 N 2 O2 C, 64.69; H, 5.92; N, 13.72. Found C, 64.74; H, 6.08; N,
14.13.
5-Nitro-2-phenylindole 106a-2
H
106a-2
Prepared from 105a-2 in 85% yield. 106a-2: a yellow crystalline solid; mp 190-191
°C (DCM-hexane); R/= 0.37 (25% EtOAc in hexane);
IR (film) 3344, 1329 cm'1;
XH NMR (300 MHz,
C D 3 C O C D 3 )
5 11.52 (br s, 1 H), 8.69 (d, J = 2.2 Hz, 1 H), 8.26
(dd, J = 8.9, 2.2 Hz, 1 H), 8.05-8.00 (m, 2 H), 7.76-7.60 (m, 3 H), 7.56-7.50 (m, 1
H), 7.28 (s, 1 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5 141.3, 139.8, 130.9, 128.6 (x 2), 128.2, 128.1,
128.0, 125.0 (x 2), 116.6, 116.5, 110.8, 100.4;
MS (+CI) m/z 239 (M + H+, 100);
Anal. Calcd for C 1 1 H 12 N 2 O2 C, 64.69; H, 5.92; N, 13.72. Found C, 64.74; H, 6.08; N,
14.13.
179
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5-Nitro-2-propylindole 106a-l
H
106a-1
Prepared from 105a-l in 84% yield. 106a-l: a yellow crystalline solid; mp 125-126
°C (DCM-hexane); R/= 0.34 (50% EtOAc in hexane);
IR (KBr) 3325, 1314 cm’1;
!H NMR (300 MHz,
C D 3 C O C D 3 )
5 10.86 (br s, 1 H), 8.57 (d, J = 2.1 Hz, 1 H), 8.11
(dd, J = 9.0, 2.1 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 1 H), 6.56 (d, J = 0.7 Hz, 1 H), 2.92 (t,
/ = 7.4 Hz, 2 H), 1.90 (sextet, J = 7.5 Hz, 2 H), 1.12 (t, / = 7.5 Hz, 3 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5 143.6, 140.6, 138.9, 127.6, 115.4, 115.2, 109.8,
100.4,28.1,21.4,12.5;
MS (+CI) m/z 205 (M + H+, 100);
Anal. Calcd. for C nH 12 N20 C, 64.69; H, 5.92; N, 13.72. Found C, 64.74; H, 5.85; N,
13.46.
7-Nitro-2-phenylindole 106c-2
106c-2
Prepared from 105c-2 in 76% yield. 106c-2: a white crystalline solid; mp 142-143
°C (DCM-hexane); Rf = 0.74 (25% EtOAc in hexane);
IR (film) 3149, 2921, 1338, 1292 c m 1;
180
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!H NMR (300 MHz,
C D 3 C O C D 3 )
5 11.09 (br s, 1 H), 8.25 ( d d ,/ = 8.1, 0.9 Hz, 1 H),
8.18 (dd, J = 8.1, 0.9 Hz, 1 H), 8.13-8.09 (m, 2 H), 7.67-7.55 (m, 3 H), 7.40 (t, / =
7.9
Hz, 1 H), 7.25 (d, / = 1.6 Hz, 1 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5 140.8, 132.9, 130.8, 129.8, 128.9, 128.6 (x 2),
128.2, 128.0, 125.8 (x2), 119.1, 118.3, 100.4;
MS (+CI) m/z 239 (M + H+, 44), 153 (100);
Anal. Calcd. for C 1 4 H 10 N 2 O2 C, 70.58; H, 4.23; N, 11.76. Found C, 70.36; H, 4.25; N,
12. 00 .
7-Nitro-2-propylindole 106c-l
I
H
N 02
106c-1
Prepared from 105c-l in 72% yield. 106c-l: a yellow crystalline solid; mp 79-80 °C
(DCM-hexane); R/ = 0.71 (25% EtOAc in hexane);
IR (KBr) 3409, 2956, 1512, 1339 cm4 ;
*H NMR (300 MHz, CDC13) 5 9.69 (br s, 1 H), 8.05 (d, J= 8.1 Hz, 1 H), 7.80 (d, J =
7.6
Hz, 1 H), 7.13 (t, J = 7.9 Hz, 1 H), 6.38 (s, 1 H), 2.81 (t, J = 7.4 Hz, 2 H), 1.80
(sextet, / = 7.4 2 H), 1.04 (t, J = 1A Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 142.7, 132.6, 129.4, 128.4, 127.6, 118.9, 117.9, 100.7,
30.0,
22.2, 13.8;
MS (+CI) m/z 205 (M + H+, 100);
A nal. C alcd for C iiH 12N 20 2 C, 64.69; H, 5.92; N , 13.72. Found C, 64.92; H, 6.12; N ,
14.43.
181
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Representative procedure for the reduction of nitroindoles
6-Amino-2-phenylindole 107b
107b
To a solution of 106b-2 (R = Ph, 101.0 mg, 0.42 mmol) in EtOH was added Pd/C
( 1 0 %,
6 8 .0
mg) followed by stirring at room temperature for
1
h under a hydrogen
atmosphere. The suspension was filtered off through Celite and the filtrate was
condensed under reduced pressure to give 107b (80.0 mg, 90%) as a solid; /?/ = 0.88
(33% EtOAc in hexane);
IR (KBr) 3369 (br), 2925, 1601,1449 cm'1;
NMR (300 MHz, CD 3 COCD3) 5 10.30 (br s, 1 H), 7.91-7.87 (m, 2 H), 7.56-7.49
(m, 2 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.36 ( tt,J = 7.3, 1.2 Hz, 1 H), 6.87-6.83 (m, 2 H),
6 .6 6
(dd, J = 8.4, 2.9 Hz, 1 H);
13C N M R (75 MHz, CD3 COCD3 ) 5 144.1, 139.0, 134.8, 133.1, 128.6, 128.4, 126.0,
123.9,120.3,110.3,98.9, 95.1;
MS (+CI) m/z 209 (M + H+, 6 6 ), 153 (100).
5-Amino-2-phenylindole 107a
H
107a
Prepared from 106a-2 in 85% yield. 107a: a solid; Rf = 0.24 (25% EtOAc in hexane);
IR (film) 3422, 2923, 1461 cm'1;
182
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*H NMR (300 MHz, CD3 COCD3 ) 5 10.42 (br s, 1 H), 7.96-7.91 (m, 2 H), 7.55 (br t,
J = 7.6 Hz, 2 H), 7.41 (br t, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 6.97 (d, J =
2.0 Hz, 1 H), 6.80 (s, 1 H), 6.75 (dd, / = 8.5, 2.0 Hz, 1 H);
13C NMR (75 MHz, CD3 COCD 3 ) 5 141.0, 137.2, 132.7, 131.0, 129.8, 128.4 (x 2),
126.5, 124.3 (x 2), 112.4, 111.0, 103.5, 97.6;
MS (+CI) m/z 209 (M + H+, 6 6 ), 153 (100).
7-Amino-2-phenylindole 107c
Ph
NH2
107c
Prepared from 106c-2 in
8 6
% yield. 107c: a solid; R/ = 0.29 (33% EtOAc in hexane);
IR (KBr) 3410 (br), 3369, 3291,1456, 1276 cm'1;
3H NMR (300 MHz, CD 3 COCD 3 ) 5 11.01 (s, 1 H), 7.92 (d, J = 9.0 Hz, 2 H), 7.56 (t,
J = 7.5 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 1 H), 6.90-6.81 (m, 3 H), 6.43 (d, J = 7.2 Hz, 1
H), 5.25 (s, 2 H);
13C NMR (75 MHz, CD3 COCD3 ) 5 136.3, 133.7, 132.6, 129.3, 129.0 (x 2), 127.2,
126.5, 124.7 (x 2), 120.6, 108.6, 105.3, 99.3;
MS (+CI) m/z 209 (M + H+, 50), 82 (100).
183
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Representative procedure for the sulfonyiation of aminoindoles 108.
2-Phenyl-7-[((3’-trifluoromethyl)benzene)sulfamoyl]indole 108c
108c
To a solution of 107c (87.0 mg, 0.42 mmol) in dry THF (20.0 mL) and pyridine (40.0
pL, 0.53 mmol) cooled to 0 °C was added 3-[(trifluoromethyl)benzene]sulfonyl
chloride (74 pL, 0.46 mmol) through a syringe. The resultant mixture was stirred at
the same temperature for 5 h under a nitrogen atmosphere. After removal of the
solvent under reduced pressure, the residue was dissolved in EtOAc (30.0 mL), and
then washed with 5% HC1, saturated aqueous NaHC 0 3 and brine. The organic layer
was dried over anhydrous MgS0 4 , and evaporated under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 30% EtOAc in
hexane) to give 108c (127.0 mg, 73%) as a solid; Rf= 0.43 (25% EtOAc in hexane);
IR (film) 1326, 1159 cm'1;
!H NMR (300 MHz, CDC13) 5 9.44 (s, 1 H), 8.06 (s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H),
7.77 (d, J = 7.9 Hz, 1 H), 7.72-7.69 (m, 2 H), 7.53-7.31 (m, 5 H), 7.19 (s, 1 H), 6.87
(t, J = 7.7 Hz, 1 H), 6.82 (d, J = 2.1 Hz, 1 H), 6.46 (d, J = 7.5 Hz, 1 H);
MS (+CI) m/z 417 (M + H+, 100), 209 (68).
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2-Phenyl-5-[((3’-trifluoromethyl)benzene)sulfamoyl]indole 108a
108a
Prepared from 107a in 84% yield. 108a: a solid; R/ = 0.71 (50% EtOAc in hexane);
IR (film) 1326, 1164 cm'1;
‘H NMR (300 MHz,
C D 3 C O C D 3 )
5 10.90 (s,
1 H), 9.03 (s, 1 H), 8.18(s, 1 H),8.09
(d, J = 8.0 Hz, 2 H), 8.02-7.84 (m, 3 H), 7.63-7.42 (m, 5
H),7.53(dd,J = 8.6,2.1
Hz, 1 H), 6.99 (d, J = 2.0 Hz, 1 H);
MS (+CI) m/z 417 (M + H+, 98), 209 (100).
2-Phenyl-6-[((3’-trifhioromethyl)benzene)sulfamoyl]indole 108b-l
108b-1
Prepared from 107b in 80% yield. 108b-l: a solid; R/= 0.38 (33% EtOAc in hexane);
IR (film) 1327, 1168,1154 cm'1;
!H NMR (300 MHz,
C D 3 C O C D 3 )
5 10.84 (s, 1 H), 8.20 (s, 1 H), 8.09 (t, J = 8.4 Hz,
2 H), 8.02-7.82 (m, 3 H), 7.64-7.41 (m, 5 H), 7.20-6.95 (m, 2 H);
MS (+CI) m/z 417 (M + H+, 100), 209 (70).
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6-[(4’-Fluorobenzene)s\dfamoyl]-2-phenylindole 108b-2
108b-2
Prepared from 107b in 70% yield. 108b-2: a pale yellow oil; /?/= 0.36 (25% EtOAc
in hexane);
IR (film) 1154 cm'1;
XH NMR (300 MHz, CD3COCD3) 5 10.85 (s, 1 H), 8.99 (s, 1 H), 7.99-7.92 (m, 4 H),
7.6-7.36 (m, 7 H), 7.00-6.97 (m, 2 H);
MS (+CI) m/z 367 (M + H+, 74), 209 (100).
2-Phenyl-6- [(thiop hen-2’-yl)sulfamoyl] indole 108b-3
108b-3
Prepared from 107b in 80% yield. 108b-3: a pale yellow oil; Rj = 0.38 (33% EtOAc
in hexane);
IR (film) 1150 cm'1;
•H NMR (300 MHz, CD3 COCD3 ) 5 10.85 (s, 1 H), 9.12 (s, 1 H), 8.00-7.96 (m, 2 H),
7.87 (dd, J = 5.0, 1.3 Hz, 1H), 7.69-7.55 (m, 5 H), 7.45 (tt, J = 7.4, 1.1 Hz, 1 H),
7.19 (dd, J = 5.0, 3.8 Hz, 1 H), 7.07 (dd, J = 8.4, 1.9 Hz, 1 H), 7.01 (dd, J = 2.2, 0.7
Hz, 1 H);
13C N M R (75 MHz,
C D 3 C O C D 3 )
5 140.1, 138.1, 137.0, 131.9, 131.7, 131.6, 131.4,
128.4 (x 2), 128.2, 127.0, 126.7, 124.4 (x 2), 120.1, 115.1, 104.7, 98.5;
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MS (+CI) m/z 355 (M + H+, 42), 209 (100).
2-Propyl-4-[((3’-trifluoromethyl)benzene)sulfamoyl]indole 113a
S—NH
113a
Prepared from 112a in 83% yield. 113a: a yellow oil; Rj = 0.40 (25% EtOAc in
hexane);
IR (film) 2958, 1611, 1465 cm'1;
*H NMR (300 MHz, CDCI3 ) § 8.00 (br s, 2 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.68 (d, J =
7.6 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.13-7.10 (m, 1 H), 7.02 (s, 1 H), 7.00 (d, J =
2.0 Hz, 1 H), 6.91 (br s, 1 H), 5.92 ( d ,J = 1.1 Hz, 1 H), 2.61 (t, J = 7.5 Hz, 2 H), 1.63
(sextet, J = 7.4 Hz, 2 H), 0.92 (t, J = 1A Hz, 3 H);
MS (+CI) m/z 383 (M + H+, 100).
2-Phenyl-4-[((3’-trifluoromethyl)benzene)sulfamoyl]indole 113b
S—NH
■Ph
113b
Prepared from 112b in 75% yield. 113b: a solid; R f = 0.31 (25% E tO A c in hexane);
IR (film ) 3404, 3246, 1325, 1166, 1127 cm '1;
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NMR (300 MHz, CDCI3 ) 5 10.97 (br s, 1 H), 9.23 (br s, 1 H), 8.24 (s, 1 H), 8.17
(dd, J = 8.0, 0.6 Hz, 1 H), 8.01 (dd, J = 8.0, 0.6 Hz, 1 H), 7.89-7.84 (m, 3 H), 7.607.55 (m, 2 H), 7.49-7.37 (m, 2 H), 7.19 (dd, J = 10.0, 7.6 Hz, 1 H), 7.18 (s, 1 H),
7.03 (dd, J = 2 3 , 1.1 Hz, 1 H);
MS (+CI) m/z 417 (M + H+, 100).
Representative Procedure for the Cross-Coupling of 109.
1,3-Dinitr o-2-(p enty n-1 ’-yl)-b enzene 110a
To
a suspension
of 2-chloro-1,3-dinitrobenzene
(101.0
mg,
0.50
mmol),
Pd(PhCN)2 Cl2 (17.2 mg, 5.0 x 10' 2 mmol), Cul (28.6 mg, 0.15 mmol) and /1 -B 1 1 4 NI
(277.0 mg, 0.75 mmol) in dry MeCN (5 mL), was added Et3 N (1.0 mL) and P(i-Bu) 3
(0.30 mL) under a nitrogen atmosphere. Then, 1-pentyne (0.10 mL, 1.00 mmol) was
added through a syringe. The resultant mixture was stirred at room temperature for 1
h. The reaction was quenched by saturated aqueous NH 4 CI and extracted with EtOAc
(20 x 3 mL). The combined organic layer was washed with brine, dried over
anhydrous MgS0 4 , and evaporated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 17% EtOAc in hexane) to give 110a
(109.0 mg, 93%) as a brown oil; Rf = 0.60 (25% EtOAc in hexane);
IR (KBr) 2970, 2237, 1538, 1354 cm'1;
JH NMR (300 MHz, CDCI3 ) 5 8.06 (d, J = 8.2 Hz, 2 H), 7.53 (t, J = 8.2 Hz, 1 H),
2.49 (t, J = 6.9 Hz, 2 H), 1.67 (sextet, J = 7.2 Hz, 2 H), 1.06 (t, J = 7.4 Hz, 2 H);
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13C NMR (75 MHz, CDCI3 ) 5 152.3 (x 2), 127.7, 127.3 (x 2), 113.7, 109.0, 69.7,
22.1,21.4,
13.4;
MS (+CI) m/z 235 (M + H+, 3), 89 (100).
l,3-Dinitro-2-(phenylethynyl)benzene 110b
110b
Prepared from 109 and phenylacetylene in 60% yield (80 °C, 1 h) by using DMF to
replace CH3 CN. 110b : a solid; R/ ~ 0.42 (25% EtOAc in hexane);
IR (KBr) 2216, 1531, 1340 cm'1;
NMR (300 MHz, CDCI3 ) 6 8.19 (d, J = 8.3 Hz, 2 H), 7.65-7.61 (m, 2 H), 7.59 (t,
J = 8.3 Hz, 1 H), 7.48-7.37 (m, 3 H);
13C NMR (75 MHz, CDC13) 5 151.6 (x 2), 132.5, 130.4, 128.6 (x 2), 128.1 (x 2),
128.0 (x 2), 121.3, 113.6, 106.0, 78.6;
MS (+CI) m/z 268 (M + H+, 9), 104 (100).
Representative procedure for the reduction of 110.
l,3-Diamino-2-(p enty n-1’-yl)b enzene 111a
111a
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A mixture of 110a (69.6 mg, 0.30 mmol) and tin(II) chloride dihydrate (4.02 g, 17.80
mmol) in CH 2 CI2 DMF (1:1, 9.0 mL) was stirred for 4 h at room temperature under
a nitrogen atmosphere. The resultant mixture was adjusted to pH 11 with saturated
aqueous NaHCC>3 . The slurry was filtered off through Celite with washing by EtOAc.
The aqueous layer was separated and extracted by EtOAc (50 x 3 mL). The
combined organic layer was washed with brine, dried over anhydrous MgS 0 4 , and
evaporated under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 25% EtOAc in hexane) to provide 111a (34.0 mg, 65%)
as a yellow oil; Rf= 0.48 (25% EtOAc in hexane);
IR (film) 3402, 3272, 2963, 1327, 1163 cm'1;
‘H NMR (300 MHz, CDCI3 ) 5 6.86 (t, J = 8.0 Hz, 1 H), 6.12 (d, J = 8.0 Hz, 2 H),
4.10 (br s, 4 H), 2.51 (t, J = 7.1 Hz, 2 H), 1.67 (sextet, / = 7.3 Hz, 2 H), 1.07 (t, J =
7.3 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 5 148.3 (x 2), 129.1, 104.0 (x 2), 101.0, 95.4, 73.7, 22.5,
21.8, 13.6;
MS (+CI) m/z 175 (M + H+, 100).
l,3-Diamiiio-2-(phenylethynyl)benzene 111b
NH,
Ph
111b
Prepared from 110b in 80% yield. 111b: a solid; Rj = 0.45 (25% EtOAc in hexane);
IR (KBr) 3432, 3353, 3314, 2200, 1610, 1467 cm'1;
'H NMR (300 MHz, CDCI3 ) 6 7.55-7.51 (m, 2 H), 7.39-7.33 (m, 3 H), 6.94 (t, J =
8.0 Hz, 1 H), 6.15 (d, / = 8.0 Hz, 2 H), 4.22 (br s, 4 H);
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13C NMR (75 MHz, CDCI3 ) 5. 148.5 (x 2), 131.3 (x 2), 130.2, 128.4 (x 2), 128.1,
123.3, 104.0 (x 2), 100.1, 94.4, 82.5;
MS (+CI) m/z 209 (M + H+, 100).
Representative procedure for the /-BuOK-promoted ring closure of 112.
4-Amino-2-propylindole 112a
112a
A mixture of 111a (20.0 mg, 0.1 lmmol), f-BuOK (25.0 mg, 0.22 mmol) in dry NMP
(2.0 mL) was heated at 80 °C for 8 h under a nitrogen atmosphere. The reaction
mixture was allowed to cool to room temperature and diluted with water (2 mL). The
resultant mixture was extracted with EtOAc (20 x 3 mL). The combined organic
layer was washed with brine, dried over anhydrous MgSO-t, and concentrated under
reduced pressure. The residue was purified by flash column chromatography (silica
gel, 25% EtOAc in hexane) to give 112a (15.0 mg, 75%) as a yellow oil; R/ = 0.38
(25% EtOAc in hexane);
IR (film) 3393 (br), 2955, 1618 cm'1;
•H NMR (300 MHz, CDC13) § 7.84 (br s, 1 H), 6.94 (t, J = 7.7 Hz, 1 H), 6.79 (d, J =
8.1 Hz, 1 H), 6.38 (dd, J = 7.6, 0.6 Hz, 1 H), 6.15 (dd, / = 2.1, 0.9 Hz, 1 H), 3.85 (br
s, 2 H), 2.71 (t, J = 7.4 Hz, 2 H), 1.74 (sextet, J = 7.4 Hz, 2 H), 1.00 (t, J = 13 Hz, 3
H);
13C NMR (75 MHz, CDCI3) 5 138.6, 137.9, 136.7, 122.1, 118.0, 104.3, 101.7, 95.8,
30.3,22.5,
13.9;
MS (+CI) m/z 175 (M + H+, 100).
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4-Amino-2-phenylindole 112b
H
112b
Prepared from 111b in 90% yield. 112b: a solid; Rf —0.31 (25% EtOAc in hexane);
IR (KBr) 3373, 3305, 3176 (br), 1604 cm'1;
JH NMR (300 MHz, CDC13) 5 10.69 (br s, 1 H), 7.97-7.94 (m, 2 H), 7.59-7.53 (m, 2
H), 7.40 (tt, J = 7 A , 1.1 Hz, 1 H), 7.14 (br s, 1 H), 7.01 (t, J= 7.8 Hz, 1 H),
6 .8 8
(d, J
= 8.1 Hz, 1 H), 6.43 (dd, J = 7.4, 0.7 Hz, 1 H), 4.92 (br s, 2 H);
13C NMR (75 MHz, CDCI3 ) 5 140.8, 138.3, 135.0, 132.8, 128.5, 126.4, 124.6, 124.2,
122.9, 102.6, 100.3,96.2;
MS (+CI) m/z 209 (M + H+, 100).
Representative procedure for the synthesis of trifluoroacetanilides
Ar-(2’-Hydroxy-5’-nitrophenyl)trifluoroacetamide 114b
114b
To a solution of 2-amino-4-nitrophenol 102b (3.1g, 20 mmol) in dry THF (83.0 mL)
and pyridine (2.4 mL, 29.9 mmol) cooled in an ice-water bath was added dropwise a
solution of trifluoroacetic anhydride (3.1 mL, 22.0 mmol) in dry THF (7.0 mL). The
resultant mixture was stirred for 16 h at room temperature under a nitrogen
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atmosphere. The reaction was quenched by adding water (10.0 mL) and brine (10.0
mL). The organic layer was separated and the aqueous layer was extracted with
EtOAc (20 x 2 mL). The combined organic layer was washed with 5% HC1 (15.0
mL), saturated aqueous NaHCOs (20.0 mL), and brine (20.0 mL), dried over
anhydrous Na 2 S0 4 , and evaporated under reduced pressure. The crude product was
purified by flash column chromatography (silica gel, 50% EtOAc in hexane) to give
114b (5.0 g, 99%) as a yellow crystalline solid; mp 188-189 °C (EtOAc-hexane); Rf
= 0.30 (50% EtOAc in hexane);
IR (KBr): 3386, 3188 (br), 1696 cm'1;
XH NMR (300 MHz,
9.02
5 11.20-10.30 (br s, 1 H), 9.90-9.55 (br s, 1 H),
(d, J = 2.7 Hz, 1 H), 8.22 (dd, J = 9.1, 2.8 Hz, 1 H), 7.34 (d, J = 9.0 Hz, 1 H);
13C NMR (75 MHz,
Jc-f
C D 3 C O C D 3 )
5 153.7, 146.6, 140.0, 123.4, 122.4, 118.0, 115.4 (q,
C D 3 C O C D 3 )
= 287.1 Hz), 114.9;
MS (+CI) m/z 251 (M + H+, 100);
Anal. Calcd. for C8 H5 F 3 N 2 O4 C, 38.41; H, 2.01; N, 11.20. Found C, 38.32; H, 1.88;
N, 11.00.
A/-(2,-Hydroxy-4’-nitrophenyl)trifluoroacetamide 114a
^ N ^ O H
XX
o^
" cf3
114a
Prepared in 99% yield from 2-amino-5-nitrophenol 102a after reaction at room
temperature for 4 h. 114a: as a yellow crystalline solid: mp 164-165 °C (EtOAchexane); R f = 0.32 (25% EtOAc in hexane);
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IR (KBr) 3374, 3222 (br), 1697 cm'1;
!H NMR (300 MHz, CD3 COCD3 ) 6 10.60-9.35 (br s, 2 H), 8.40 (d, J = 8.7 Hz, 1 H),
8.02-7.90 (m, 2 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5 154.7 (q,
J C- f
= 45.3 Hz), 147.7, 145.1, 129.7,
121.5, 115.6 (q, J c - f ~ 271.7 Hz), 115.2, 109.7;
MS (+CI) m/z 251 (M + H+, 100);
Anal. Calcd for C 8 H 5 F 3 N 2 O4 C, 38.41; H, 2.01; N, 11.20. FoundC, 38.15; H, 1.94; N,
11.39.
A'-(2,-Hydroxy-6,-nitrophenyl)trifluoroacetamide 114c
114c
Prepared in 86% yield from 2-amino-3-nitrophenol 102c after reaction at room
temperature for 9 h. 114c: as a yellow crystalline solid; mp 136-137 °C (EtOAchexane); Rf= 0.41 (50% EtOAc in hexane);
IR (KBr) 3310 (br), 1729 cm'1;
!H NMR (300 MHz, CDC13) 8 11.04 (br s, 1 H), 8.05-7.75 (br s, 1 H), 7.85 (dd, J =
7.8, 2.1 Hz, 1 H), 7.47-7.38 (m, 2 H);
13C NMR
(C D C I3 )
8 153.4 (q,
J C- f
= 43.5 Hz), 146.4, 146.0, 128.5, 120.7, 115.3,
115.5 (q, J c-f = 286.8 Hz), 115.0;
MS (+CI) m/z 251 (M + H+, 100);
A nal. C alcd for CgH 5F3N 20 4C, 38.41; H, 2.01; N , 11.20. Found C, 38.41; H, 1.85; N ,
10.80.
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Representative procedure for the synthesis of nitroaryl triflates
7V-[5’-Nitro-2’-(((trifluoromethane)sulfonyl)oxy)phenyl]trifluoroacetamide 115b
0^
'
cf3
115b
To a suspension of NaH (0.5 g, 13.5 mmol) in dry THF (80.0 mL) cooled in an icewater bath was added dropwise a solution of 114b (2.2 g, 9.0 mmol) and PhNTf2 (4.8
g, 13.5 mmol) in dry THF (20.0 mL). The resultant mixture was stirred for 19 h at
room temperature under a nitrogen atmosphere. The reaction was quenched by water
(25.0 mL) and brine (25.0 mL). The organic layer was washed with saturated
aqueous NaHCCL (45.0 mL x 5) and brine (35 mL), dried over anhydrous Na2 SC>4 ,
evaporated under reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 25% EtOAc in hexane) to give 115b (3.2 g, 93%) as a
yellow crystalline solid; mp 88-89 °C (EtOAc-hexane); Rf = 0.54 (25% EtOAc in
hexane);
IR (KBr) 3292 (br), 1717 cm'1;
'H NMR (300 MHz, CDCL) 5 9.17 ( d , J = 2.7 Hz, 1 H), 8.28 (br s, 1 H), 8.24 (dd, J
= 9.3, 3.0 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H);
13C NMR (75 MHz, CDCI3 ) 5 155.9 (q, J C-f = 39.4 Hz), 148.0, 143.8, 129.4, 123.7,
123.2, 120.1, 119.2 ( q , J C- F = 320.9 Hz), 115.8 (q, J C-^ = 288.4 Hz);
MS (+CI) m/z 383 (M + H+, 100);
Anal. Calcd. for C9 H4 F6 N 2 O6 S C, 28.28; H, 1.05; N, 7.33. Found C, 28.39; H, 0.89;
N , 6.65.
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N- [4,-Nitro-2,-(((trifluoromethane)sulfonyl)oxy)phenyl]trifluoroacetamide 115a
115a
Prepared from 114a in 84% yield after reaction at room temperature for 4 h. 115a: as
a yellow crystalline solid; mp 66-67 °C (EtOAc-hexane); R/= 0.38 (25% EtOAc in
hexane);
IR (KBr) 3284, 1725 cm’1;
!H NMR (300 MHz, CDC13)
8
8.62 (d, J = 9.3 Hz, 1 H), 8.46-8.32 (br s,1H), 8.38
(dd, J = 9.0, 2.7 Hz, 1 H), 8.31 (d, J = 2.4 Hz, 1 H);
13C NMR (75 MHz, CDC13)
8
155.8 (q, J C-f = 45.1 Hz), 145.4, 138.3,134.1,125.4,
123.5, 119.1 ( q ,/ = 320.2 Hz), 118.8, 117.2 (q, J = 288.1 Hz);
MS (+CI) m/z 383 (M + H+, 100);
Anal. Calcd. for C^FeN zO gS C, 28.28; H, 1.05; N, 7.33. Found C, 28.53; H, 0.98;
N, 6 .8 6 .
iV-[6,-Nitro-2’-(((trifluoromethane)sulfonyl)oxy)phenyI]trifluoroacetamide 115c
115c
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Prepared from 114c in
8 8
% yield after reaction at room temperature for 24 h. 115c:
as a yellow crystalline solid; mp 108.5-109.5 °C; Rj = 0.37 (25% EtOAc in hexane);
IR (KBr) 3255, 1732 cm'1;
lH NMR (300 MHz, CDC13) 5 9.10 (br s, 1 H), 8.22 (dd, J = 8.2, 1.3 Hz, 1 H), 7.75
(dd, J = 8.4, 1.5 Hz, 1 H), 7.66 (t, J = 8.4 Hz, 1 H);
13C NMR (75 MHz, CDC13) 5 156.1 (q, JC-f = 43.2 Hz), 145.6, 145.3, 129.8, 129.1,
126.1, 123.6, 119.1 (q, J c-f ~ 320.6 Hz), 115.9 (q, JC-f = 288.2 Hz);
MS (+CI) m/z 383 (M + H+, 100);
Anal. Calcd. for C sd W ^ O g S C, 28.28; H, 1.05; N, 7.33. Found C, 28.34; H, 0.96;
N, 7.25.
Representative procedure for the Pd-Catalyzed one-pot cross-coupling and
heteroannulation toward nitroindoles. 6-Nitro-2-propylindole (106b-l).
A mixture of 115b (115.0 mg, 0.3 mmol), w-BruNI (169.6 mg, 0.45 mmol),
Pd(PPh3 ) 4 (11.1 mg, 0.03 mmol), Cul (17.14 mg, 0.09 mmol), and 1-pentyne (40.8
mg, 60 pL, 0.6 mmol) in degassed DMF (5 mL) containing Et3N (1 mL) was heated
at ca. 80 °C for 21 h. After cooling to room temperature, the reaction mixture was
diluted with EtOAc (20 mL) and washed with saturated aqueous
N H 4 C I
(10 mL) and
brine (15 mL). The organic layer was dried over anhydrous MgS 0 4 , and evaporated
under reduced pressure. The crude product was puried by flash column
chromatography (silica gel, MeOH-CH 2 Cl2 -hexane = 1:40:30) to give 106b-l (51.7
mg, 84%) as a yellow crystalline solid.
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5-Nitro-2-(2’-hydroxyethyl)indole 106a-3
OH
H
106a-3
Prepared from 115a in
6 8
% yield. 106a-3: a crystalline solid; mp 114-115 °C
(EtOAc-hexane); Rj = 0.29 (67% EtOAc in hexane);
IR (KBr) 3469, 3185 (br), 1512, 1471, 1337 cm'1;
*H NMR (300 MHz, CD3 COCD3) 5 10.85 (br s, 1 H), 8.60 (d, J = 2.2 Hz, 1 H), 8.11
(dd, J = 9.0, 2.3 Hz, 1 H), 7.75 (d, J = 8.9 Hz, 1 H), 6.67 (d, J = 0.9 Hz, 1 H), 4.22 (t,
J = 5.3 Hz, 1 H), 4.07 (q, J = 6.3 Hz, 2 H), 3.18 (t, J = 6.2 Hz, 2 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5 142.0, 141.1, 139.3, 127.9, 115.8, 115.6, 110.5,
101.5, 60.8,31.4;
MS (+CI) m/z 207 (M + H+, 100);
Anal. Calcd. for
N ,
C , 0H io N 2
0 3 C, 58.25; H, 4.89; N, 13.59. Found
C ,
58.25; H, 5.00;
13.75.
5-Nitro-2-(3’-cyanopropyl)indole 106a-4
CN
H
106a-4
prepared from 115a in 75% yield. 106a-4: a crystalline solid; mp 125.5-126 °C
(EtOAc-hexane); Rj = 0.41 (50% EtOAc in hexane);
IR (KBr) 3321, 2250, 1471, 1334 cm'1;
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'H MNR (300 MHz,
C D 3 C O C D 3 ):
5 10.9 (br s, 1 H), 8.59 (d, J = 2.1 Hz, 1 H), 8.11
(dd, / = 8.7, 2.4 Hz, 1 H), 8.60 (d, J = 8.7 Hz, 1 H), 6.70 (s, 1 H), 3.16 (t, J = 7.5 Hz,
2 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.33-2.22 (m, 2 H);
13C NMR (75 MHz,
C D 3 C O C D 3 ) 8
142.0, 141.5, 138.5, 128.1, 119.2, 116.1, 116.0,
110.6, 101.5,26.7, 24.7,15.8;
MS (+CI) m/z 230 (M + H+, 100);
Anal. Calcd for C 1 2 H 11 N 3 O2 C, 62.87; H, 4.84; N, 18.33. Found C, 62.75; H, 4.89; N,
18.67.
5-Nitro-2-(3’-chloropropyl)indole 106a-5
H
106a-5
Prepared from 115a in 45% yield. 106a-5: a crystalline solid; mp 107-107.5 °C
(EtOAc-hexane); R f = 0.34 (25% EtOAc in hexane);
IR (KBr): 3336, 1323 cm'1;
*H NMR (300 MHz,
C D 3 C O C D 3 )
5 10.86 (br s, 1 H), 8.59 (d, J = 1.8 Hz, 1H), 8.11
(dd, J = 8.7, 2.1 Hz, 1 H), 7.61 ( d ,/= 8 .7 H z , 1 H),
6 .6 8
(s, 1 H), 3.84 (t,/ = 6.3 Hz,
2 H), 3.17 (t, J = 7.8 Hz, 2 H), 2.44-2.35 (m, 2 H);
I3C NMR (75 MHz,
C D 3 C O C D 3 ) 8
142.2, 140.8, 139.2, 127.7, 115.7, 115.6, 110.2,
101.0, 43.2,30.8,24.2;
MS (+CI) m/z 239 (M + H+, 100);
A nal. Calcd. for C 1 1 H 1 1 CIN 2 O 2 C, 55.36; H, 4.654; N , 11.74. Found C, 55.28; H,
4.71; N, 11.16.
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6-Nitro-2-(2’-hydroxyethyl)indole 106b-3
106b-3
Prepared from 115b in 69% yield. 106b-3: a crystalline solid; mp 141-142 °C
(EtOAc-hexane); Rj = 0.28 (50% EtOAc in hexane);
IR (KBr) 3490, 3275 (br), 1501, 1316, 1051 cm’1;
NMR (300 MHz,
C D 3 C O C D 3 )
5 10.90 (br s, 1 H), 8.47 (d, J = 2.1 Hz, 1 H), 8.03
(dd, J = 8.4, 2.1 Hz, 1 H), 7.73 (d, J = 9.0 Hz, 1 H), 6.60 (d, J = 2.4 Hz, 1 H), 4.25
(br s, 1 H), 4.08 ( b r t , / = 6.0 Hz, 2 H), 3.21 (t, J = 6.3 Hz, 2 H);
13C NMR (75 MHz, CD3 COCD3 ) 5 145.3, 142.1, 134.2, 133.7, 118.8, 114.1, 107.2,
100.7, 60.7,31.6;
MS (+CI) m/z 207 (M + H+, 100);
Anal. Calcd. for Ci0 H 10 N 2 O3 C, 58.25; H, 4.89; N, 13.59. Found C, 58.29; H, 4.77;
N, 13.37.
6-Nitro-2-(3’-cyanopropyl)indole 106b-4
106b-4
Prepared from 115b in 73 yield. 106b-4: a crystalline solid; mp 117-118 °C
(E tO A c—h ex a n e); Rj = 0.47 (5 0 % E tO A c in h ex an e);
IR (KBr) 3326, 2254, 1499, 1308 cm’1;
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'H NMR (300 MHz, CD 3 COCD 3 ) 5 10.99 (br s, 1 H), 8.41 (d, J = 1.8 Hz, 1 H), 8.18
(dd, J = 8.7, 2.4 Hz, 1 H), 7.75 (d ,7 = 8.7 Hz, 1 H), 6.63 (d, J = 3.0 Hz, 1 H), 3.19 (t,
J = 7.8 Hz, 2 H), 2.72 (t, J = 8.4 Hz, 2 H), 2.35-2.27 (m, 2 H);
13C NMR (75 MHz, acetone-d6) 5 145.9, 142.8, 134.6, 133.6, 131.6, 119.1, 114.3,
107.1, 100.6, 26.9, 24.7, 15.9;
MS (+CI) m/z 230 (M + H+, 100);
Anal. Calcd. for C 1 2 H 11 N 3 O2 C, 62.87; H, 4.84; N, 18.33. Found C, 62.72; H, 4.85;
N, 18.46.
6-Nitro-2-(3’-chloropropyl)indole 106b-5
106b-5
Prepared from 115b in
6 6
% yield. 106b-5: a white crystalline solid; mp 98-99 °C
(EtOAc-hexane); Rf = 0.49 (25% EtOAc in hexane);
IR (KBr) 3329, 1505, 1337, 1298 cm'1;
!H NMR (300 MHz,
C D 3 C O C D 3 ) 8
10.95 (br s, 1 H), 8.42 (d, J = 1.2 Hz, 1 H), 8.04
(dd, J = 8.7, 2.1 Hz, 1 H), 7.74 (d, / = 8.7 Hz,l H), 6.60 (d, J = 3.0 Hz, 1 H), 3.83 (t,
J = 6 . 6 Hz, 2 H), 3.19 ( t,J = 7.8 Hz, 2 H), 2.45-2.35 (m, 2 H);
13C NMR (75 MHz,
C D 3 C O C D 3 )
5 145.7, 142.0, 134.6, 133.7, 118.1, 114.3, 107.1,
100.4, 44.0,31.6, 25.2;
MS (+CI) m/z 239 (M + H+, 100);
A nal. Calcd. for C 1 1 H 1 1 CIN 2 O 2 C, 55.36; H, 4.654; N , 11.74. Found C, 55.28; H,
4.51; N , 11.72.
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7-Nitro-2-(2’-hydroxyethyl)indole 106c-3
OH
N02
106C-3
Prepared from 115c in 48% yield. 106c-3: a yellow crystalline solid; mp 117-118 °C
(EtOAc-hexane); Rf = 0.47 (50% EtOAc in hexane);
IR (KBr): 3394, 3291 (br), 2923, 1514, 1338 cm'1;
‘H N M R (300 MHz, CD3COCD3) 8 11.11 (br s, 1 H), 8.19 (d, J = 7.8, 1H), 8.09 (d,J
= 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 6.67 (d, J = 0.9 Hz, 1 H), 4.29 (br s, 1 H),
4.11 (t, J = 6.2 Hz, 2 H), 3.26 (t, J = 6.4 Hz, 2 H);
,3C NMR (75 MHz, CD3 COCD3 ) 5 141.7, 132.8, 132.2, 129.1, 127.4, 118.5, 117.2,
101.0,61.0,31.0;
MS (+CI) m/z 207 (M + H+, 100);
Anal. Calcd. for Q 0 H 10 N 2 O3 : C, 58.25; H, 4.89; N, 13.59. Found: C, 58.39; H, 4.89;
N, 13.70%.
Representative procedure for the synthesis of 122 from 121.
3-Nitro-2-pent-l-ynyl-pyridine 122a
122a
A mixture of 2-chloro-3-nitropyridine 121 (20.0 mg, 0.13 mmol), Pd(PPh3 ) 4 (15.0
mg, 0.01 3mmol), Cul (5.0 mg, 0.026 mmol), pentyne (0.025 mL, 0.26mmol), and
Et3N (1.0 mL), MeCN 5.0 mL was stirred at room temperature for 2 h, After removal
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of the solvent, the residue is purified by flash silica gel column chromatography
(33% EtOAc in hexane) to give 122a (20.5 mg, 83%) as a brown oil;
Rf - 0.50 (50% EtOAc in hexane);
IR (film) 3071, 2966, 2874, 2229, 1593,1560, 1526 cm’1;
•H NMR (300 MHz, CDCfi) S 8.74 (dd, J =4.7, 1.5Hz, 1 H), 8.27 (dd, J = 1.5, 8.3
Hz, 1 H), 7.37 (dd, J = 4.7, 8.3 Hz, 1 H), 2.50 (t, J = 7.0 Hz, 2 H), 1.72-1.65 (m, 2
H), 1.07 (t, J = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDC13) 3 153.3, 137.62, 132.1, 130.9, 122.2, 100.7, 76.7, 21.7,
21.5, 13.5;
MS (+CI) m/z 191 (M + H+, 100).
3-Nitr o-2-p hene-1-y nyl-py ridine 122b
122b
Prepared from 121 in 84% yield. 122b: Brown crystal; mp 109-110 °C; Rf = 0.45
(50% EtOAc in hexane);
IR (film) 3003, 2223, 1560 cm’1;
]H NMR (300 MHz, CDCI3 ) 3 8.81 (dd, J =1.3, 4.7 Hz, 1 H), 8.36(dd, J =1.3, 8.3
Hz, 1 H), 7.66 (dd, J = 2.0, 8.0 Hz, 2 H), 7.44-7.34 (m, 4 H);
13C NMR (75 MHz, CDCI3 ) 3 153.4, 146.7, 137.3, 132.5, 132.4, 129.9,128.5,122.6,
121.3,97.7, 84.9;
MS(+CI) m/z 225 (M + H+, 100).
Anal Calcd. for Ci3H8N20 2C, 69.64; H, 3.60; N, 12.49; Found: C, 69.40; H, 3.46; N,
12.59.
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3-Nitro-2-trimethylsilylethynyl-pyridine 122c
TMS
Prepared from 121 in 50% yield. 122c: brown oil; Rf = 0.66 (50%EtOAc in hexane);
IR (film) 3074, 2962,2864, 2297,1591,1562cm'1;
3H NMR (300MHz, CDCU) S 8.75 (dd, J = 1.5, 4.8 Hz, 1 H), 8.28 (dd, / = 1.8, 8.7
Hz, 1 H), 7.42 (dd, J = 4.8, 8.7 Hz, 1 H);
13C NMR (75 MHz, CDCI3 ) 5 153.1, 147.1,136.5, 132.1, 122.9, 105.2, 98.7;
MS (+CI) m/z 221 (M + H+, 40).
6-(3-Nitro-pyridin-2-yl)-hex-5-ynenitrile 122d
122d
Prepared from 121 in 94% yield. Rf = 0.3 (50% EtOAc in hexane);
IR (film) 2945, 2238, 1593, 1525 cm'1;
3H NMR (300 MHz, CDCI3 ) S 8.74 (d, J = 3.7 Hz, 1 H), 8.29 (dd, J = 1.5, 11.4Hz, 1
H), 7.42 (dd, / = 6.5, 8.3 Hz, 1 H), 2.69 (t, J = 6.7 Hz, 2 H), 2.60 (t, J = 7.1Hz, 2 H),
1.94-2.04 (m, 2H);
13C NMR (75 MHz, CDC13) <5 153.2, 146.9, 136.8, 132.2, 122.7, 118.8, 96.8, 78.1,
23.8, 18.7, 15.9;
MS (+CI) m/z 216 (M + H+, 100).
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Representative procedure for the synthesis of 123.
2-Pent-l-ynyl-pyridin-3-ylamine 123a
123a
A mixture of 122a (102.0 mg, 0.54 mmol) and tin(II) chloride dihydrate (1.8g, 8.1
mmol) in NMP (16.2 mL) was stirred for 24 h at room temperature under a nitrogen
atmosphere. The resultant mixture was adjusted to pH 11 with saturated aqueous
NaHCCL. The slurry was filtered off through Celite with washing by EtOAc. The
aqueous layer was separated and extracted by EtOAc (50 x 3 mL). The combined
organic layer was washed with brine, dried over anhydrous M gS04, and evaporated
under reduced pressure. The residue was purified by flash column chromatography
(silica gel, 33% EtOAc in hexane) to provide 123a (67.0 mg, 78%).
123a: brown oil; Rf = 0.35 (50%EtOAc in hexane);
IR (film) 3058, 2963, 2871, 2217, 1615, 1578, 1460cm'1;
•H NMR (300 MHz, CDC13) 8 7.88 (t, J = 3.0 Hz, 1 H), 6.94 (dd, J =5.4, 8.1Hz, 2
H), 4.21 (s, 2 H), 2.42 (t, J = 6.9 Hz, 2 H), 1.68-1.55 (sextet, J = 7.2 Hz, 2 H), 1.01
(t, J = 7.2 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 8 1460.3, 138.1, 128.1, 124.0, 120.6, 95.8, 78.5, 22.5,
21.7, 14.39;
MS(+CI) m/z 161 (M + H+, 100).
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2-Phenylethynyl-pyridin-3-ylamine 123b
Ph
123b
Prepared from 122b in 80% yield. 123b: white crystal; Rf = 0.41 (50% EtOAc in
hexane); mp 129-130 °C;
IR (film) 3063, 2214, 1616, 1579 1461cm'1;
•H NMR (300 MHz, DMSO-J6) S 8.88 (s, 1 H), 8.82 (s, 1 H), 8.10 (t, J =3.3 Hz, 1
H), 7.78 (dd, J = 3.5, 7.2 Hz, 2 H), 7.55-7.50 (m, 4 H), 7.39(dd, J = 4.6, 8.3 Hz, 1
H);
13C NMR (75 MHz, DMSO-J6) S 149.4, 140.3, 131.7, 129.1, 128.6, 126.2, 124.1,
122.0, 119.3, 119.2, 94.5, 85.5;
MS (+CI) m/z 195 (M + H+, 52);
Anal. Calcd. for C i 3H i 0N2C, 80.39; H, 5.19; N, 14.42; Found: C, 80.05; H, 5.25; N,
14.43.
2-Trimethylsilanylethynyl-pyridin-3-ylamine 123c
TMS
123c
Prepared from 122c in 60% yield. 123c: brown oil; Rf = 0.3 (50% EtOAc in hexane);
IR (film) 3418, 2156, 1643, 1265 cm'1;
!H N M R (300 MHz, DMSO-rf6) S 7.92 (br, 1 H), 7 .00 (dd, J = 5.6, 8.4 Hz, 2 H), 4 .4 2
(s, 2 H), 0.23 (s, TMS);
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13C NMR (75 MHz, CDC13) 8 144.8,139.3,127.7, 123.9, 121.1, 100.8, 100.1;
MS (+CI) m/z 191 (M + H+, 100).
6-(3-Amino-pyridin-2-yl)-hex-5-yneiiitrile 123d
CN
123d
Prepared from 122din 65% yield. 123d: yellow oil; R/= 0.5 (80% EtOAc in hexane);
IR (film) 3362, 2942, 2248, 1618 cm'1;
*H NMR (300 MHz, CDCI3 ) 5 8.73 (d, J =3.7 Hz, 1H), 8.29 (dd, J =1.5, 11.4 Hz, 1
H), 7.40 (q, J =6.5, 8.3 Hz, 1 H), 2.69 (t, J =6.7 Hz, 2 H), 2.60 (t, y = 7.1 Hz, 2 H),
1.94-2.04 (m, 2 H);
13C NMR (75 MHz, CDCI3 ) S 153.2, 146.8, 136.6, 132.2, 122.7, 118.8, 96.7, 78.1,
23.8, 18.7, 15.9;
MS (ESI) m/z 186 (M + H+, 100).
Representative procedure for the synthesis of azaindoles
2-Phenyl- 1/Z-pyrrolo [3,2-A| pyridine 124b
H
124b
A mixture of 123b (46.0 mg, 0.24 mmol), potassium tert-butoxide (53.0 mg, 0.47
mmol), NMP 2 mL was heated at room temperature for 24 h under nitrogen
atmosphere, then cooled to room temperature. The reaction solution was added 2 mL
water and 50 mL ethyl acetate, then extracted with ethyl acetate 3 times (3 x 20
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mL).The organic layer was washed with brine, dried over anhydrous M gS04,
concentrated under reduced pressure and purified by flash column chromatography
(silica gel, 50% EtOAc in hexane) to give 124b (36,0 mg, 80%).124b: yellow solid;
Rf= 0.43 (50% EtOAc in hexane);
IR (film) 3418, 1644cm'1;
!H NMR (300 MHz, DMSO-J6) S 11.7 (s, 1 H), 8.29 (d, J = 3.0 Hz, 1 H), 7.90 (d, J
=7 .5 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.48 (t, J = 7.2, 8.1 Hz, 2 H), 7.35 (t, J
= 1 2 , 7.5 Hz, 1 H), 7.07 (dd, J = 4.8, 3.6 Hz, 2 H);
13C NMR (300 MHz, DMSO-<76) <5 146.7, 142.7, 140.6, 131.4, 129.7, 128.8, 128.1,
125.2, 117.9, 116.5, 99.0;
MS (ESI) m/z 195 (M + H+, 100).
4-(l//-Pyrrolo [3,2-6]pyridin-2-yl)-butyronitrile 124d
(CH2)3CN
N
H
124d
Prepared from 124d in 75% yield. 124d: R f = 0.43 (33% EtOAc in hexane);
IR (film) 3418, 2248, 1644 cm'1;
1 H NMR (300 MHz, CDCfi) 5 11.3 (s, 1 H), 8.40 (d, J = 4.8 Hz, 1 H), 7.64 (d, J =
8.1 Hz, 1 H), 7.04 (dd, J = 4.8, 8.1 Hz, 1 H), 6.45 (s, 1H), 2.99 (t, J = 7.5 Hz, 2 H),
2.37 (t, J = 6.9 Hz, 2 H), 2.09 (quintet, J = 6.9 Hz, 2 H);
13C NMR (75 MHz, CDCfi) 5 146.5, 142.0, 141.8, 129.6, 119.1, 118.2, 115.9, 99.8,
27.3,24.8,16.5;
MS (ESI) m/z 186 (M + H+, 100).
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l//-Pyrrolo[3,2-Z>|pyridine 124c
H
124c
Prepared from 123c in 93% yield. 124c: pale yellow solid, mp 119-120 °C (DCMhexane). R f = 0.40 (50% EtOAc in hexane);
IR (film) 2917, 1563,1243 cm'1;
:H NMR (300 MHz, DMSO-c/6) S 10.91 (s, 1H), 8.46 (d, J = 4.8 Hz, 1 H), 7.79 (d, J
= 8.2 Hz, 1 H), 7.54 (d, J = 3.3 Hz, 1 H), 7.12 (dd, 7 = 4.8, 8.2 Hz, 1 H), 6.71 (d, J =
3.3 Hz, 1 H);
,3C NMR (75 MHz, DMSO-r/g) <5 145.5, 141.9, 129.4, 129.2, 119.6, 116.5, 101.9;
MS (ESI) m/z 119 (M + H+, 100);
Anal Calcd. For C7 H6 N 2 C, 71.17; H, 5.12; N, 23.71. Found C, 0.74; H, 5.28; N,
23.71.
5-Methyl-3-pent-l-ynyl-pyridin-2-ylamine 126
N
NH2
126
A mixture of 2-amido-3-bromo-5-methylpyridine 125 (18.7 mg, 0.10 mmol),
Pd(PPh 3) 4 (5.8 mg, 0.005 mmol), Cul (1.9 mg, 0.01 mmol), pentyne (0.01 mL, 0.2
mmol), and EfiN (1.0 mL), MeCN (5.0 mL) was stirred at 80°C for 24h, After
removal of the solvent, the residue is purified by flash silica gel column
chromatography (33% EtOAc in hexane) to give 126 ( 14.0 mg, 81%) as a brown oil;
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R f = 0.48 (50% EtOAc in hexane);
IR (film) 2962, 2871, 2223, 1614 cm'1;
!H NMR (300 MHz, CDCI3 ) 3 7.75 (s, 1 H), 7.26 (d, 7 = 1.3 Hz, 1 H), 4.85 (s, 2 H),
2.38
(t, J = 7.0 Hz, 2 H), 2.09 (s, 3 H), 1.62-1.54 (m, 2 H), 0.99 (t, / = 7.4 Hz, 3 H);
13C NMR (75 MHz, CDCI3 ) 3 157.0, 146.5, 140.3, 122.0, 103.6, 96.2, 76.0, 22.1,
21.4, 17.0,13.4;
MS (+CI) m/z 175.0 (M + H+, 100).
5-Methyl-3-phenylethynyl-pyridin-2-ylamine 127
127
Prepared from 125 in 65% yield. 127: yellow solid; mp 155-160 °C (DCM-hexane);
Rf=0.31 ( 6 6 % EtOAc in hexane);
IR (film) 3077, 2950, 2873, 2230, 1594, 1560, 1438 cm'1;
lH NMR (300 MHz, CDCI3 ) 3 7.85 (d, J = 2.2 Hz, 1 H), 7.51-7.47 (m, 2 H), 7.41 (d,
J = 2.2 Hz, 1 H), 7.35-7.30 (m, 3 H), 2.15 (s, 3 H);
13C NMR (75 MHz, CDC13) S 156.9, 147.5, 140.5, 131.3, 129.4, 128.3, 122.6, 122.2,
102.7,95.2, 84.5, 17.1;
MS (ESI) m/z 209 (M + H+, 100);
Anal Calcd. for Ci4 Hi 2 N 2 C, 80.74; H, 5.81; N, 13.45. Found C, 80.31; H, 5.95; N,
13.55.
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5-Methyl-2-propyl-l//-pyrrolo[2,3-A|pyridinc 128
128
Prepared from 126 in
8 8
% yield. 128: white crystal; m pl27-128 °C; Rf = 0.50 (33%
EtOAc in hexane);
IR (film) 3418, 2960,1645 cm'1;
*H NMR (300 MHz. DMSO-J6) 8 11.26 (s, 1 H), 2.65 (t, J = 7.2 Hz, 2 H), 2.31 (s, 3
H), 1.75-1.62 (m, J = 7.2 Hz, 2 H), 0.91ft J = 7.2 Hz, 3 H);
13C NMR (75 MHz, DMSO-J6) S 147.2, 141.5, 141.0, 126.4, 123.2, 120.3, 99.0,
29.9,21.8,18.1,13.7;
MS (ESI) m/z 175 (M + H+, 100);
Anal. Calcd. For C nH 14 N 2 =C, 75.82; H, 8.10; N, 16.08. Found C, 75.53; H, 8.51; N,
16.07.
5-MethyI-2-phenyl-l//-pyrrolo[2,3-Z>]pyridine 129
129
Prepared from 127 in 95% yield, 129: white solid, mp > 250°C; Rf = 0.50 (33%
EtOAc in hexane);
1H NMR (300 MHz. DMSO-c/6) 8 12.09 (s, 1 H), 8.16 (d, J = 1.6 Hz, 1 H), 8.048.00
(m , 2 H ), 7.81 (d, J = 1.5 H z, 1 H ), 7 .5 7 -7 .3 9 (m , 3 H ), 6.9 2 (d,J= 2.1 H z, 1 H);
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13C NMR (75 MHz, DMSO-t/6) <5 148.3, 143.62, 138.2, 131.7, 128.8, 127.8, 127.6,
125.2, 124.4, 120.7, 96.5, 18.1;
MS (ESI) m/z 209 (M + H+, 100);
Anal Calcd. For Ci4 Hi 2 N 2 C, 80.74; H, 5.81; N, 13.45 Found C, 80.50; H, 6.09; N,
12.76.
Preparation of the resin-bound alkynes 167
1 6 7 (n = 2 , 3 , 4 , 8 )
The MicroKan™ reactors, preloaded with the Rink amide resin and an encoded Rf
tag, were treated with a solution of 20% piperidine in DMF for 1 h at room
temperature and then washed with DMF and DCM. The washing procedure was
repeated five times and the resin was dried overnight in vacuo. Alkynoic acid (5.0 eq)
was coupled to the resin using DIC (5.0eq) and HOBt (5.5 eq each) in DMF-DCM
(1:1) at room temperature for 1 h followed by washing with DMF and DCM (x 5
each). The resin-bound 167 was dried overnight in vacuo. A resin-free sample of the
attached alkyne 2 (n = 8 ) was obtained in quantitative yield after cleavage from the
resin. Resin-free 2 (n = 8 ): ’H NMR (300 MHz, CDC13) 5 5.70-5.25 (br, 2 H), 2.242.08 (m, 4 H), 1.93 (t, J = 2 .5 Hz, 1 H), 1.69-1.56 (m, 2 H), 1.56-1.43 (m, 2 H), 1.431.19 (m,
8
H).
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Preparation of the Resin-Bound 2-Alkynylanilides 168
no2
HN
}-n-Pr
168
O
The resin-bound alkynes 167 (20 reactors, 0.42 mmol) were charged in a Schlenk
flask along with the aryl triflate (748.2 mg, 2.10 mmol), Pd(PPh ? ) 4 (48.5 mg, 4.20 x
10' 2 mmol), Cul (16.0 mg, 8.40 x 10-2 mmol) and «-Bu4NI (232.7 mg, 0.63 mmol).
The flask was evacuated and backfilled with N 2 gas. DMF- Et3N (5:1 v/v, 30.0 mL)
was added via a syringe. After shaking at room temperature for 24 h the reactors
were then washed with DMF, MeOH and DCM. The washing procedure was
repeated five times and the resin-bound 2 -alkynylanilides 168 were dried overnight
in vacuo. Resin-free samples of the 2-alkynylanilides 168 were obtained in
quantitative yield after cleavage from the resin.
Resin-free 168 (n = 2): *H NMR (300 MHz, DMSO-dfi) 5 9.46 (s, 1 H), 8.51 (dd, J =
9.1, 3.00 Hz, 1 H), 8.28 (dd, / = 9.1, 2.70 Hz, 1 H), 8.23 (d, / = 2.6 Hz, 1 H), 7.62
(br s, 1 H), 7.09 (br s, 1 H), 2.82 (t, / =
J=
6 .8
6 .8
Hz, 2 H), 2.66 (t, J = 7.2 Hz, 2 H), 2.53 (t,
Hz, 2 H), 1.74 (sextet, J = 7.3 Hz, 2 H), 1.04 (t, J = 7.3 Hz, 3 H).
Resin-free 168 (n = 8 ): lU NMR (300 MHz, CDC13) 5 9.30 (d, J = 2.0 Hz, 1 H), 8.03
(br s, 1 H), 7.86 (dd, 7 = 8.4, 2.31 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 1 H), 5.69 (br s, 1 H),
5.52 (br s, 1 H), 2.55 (t, J = 7.0 Hz, 2 H), 2.43 (t, J = 13 Hz, 2 H), 2.22 (t, J = 7.3 Hz,
2 H), 1.79 (sextet, J = 7.4 Hz, 2 H), 1.72-1.56 (m, 2 H), 1.54-1.42 (m, 2 H), 1.421.29 (m,
6
H), 1.04 (t, J = 7.3 Hz, 3 H).
213
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Synthesis of 5-Nitroindoles 169
169 ( n = 3, 4, 8)
To the resin-bound 168 (3 reactors, 6.30 x 10-2 mmol) was added a solution of tBuOK in NMP (5.0 eq, 6.0 mL), and the mixture was shaken for 10 h at room
temperature. The reactors were rinsed with DMF (x 5) and DCM (x 5) and dried in
vacuo. Resin-free samples of the nitroindoles 169 (n = 3, 4, 8 ) were obtained in ca.
80% yield each after cleavage from the resin. The purities are higher than 98% as
estimated according the 'H NMR spectra.
Resin-free 169 (n = 3): *H NMR (300 MHz, CD3 OD) 5 8.62 (d, / = 2.2 Hz, 1 H),
8.16 (dd, J =
8
.8 , 2.2 Hz, 1 H), 7.56 (d, J = 9.0 Hz, 1 H), 6.62 (d, J = 0.5 Hz, 1 H),
3.06 (t, J = 7.6 Hz, 2 H), 2.48 (t, J = 7.5 Hz, 2 H), 2.24 (quintet, J = 1A Hz, 2 H).
Resin-free 169 (n = 4): 'H NMR (300 MHz, CD 3 OD) 5 8.61 (d, J = 2.1 Hz, 1 H),
8.15 (dd, J =
8
.8 , 2.16 Hz, 1 H), 7.55 (d, J = 8.9 Hz, 1 H), 6.60 (s, 1 H), 3.02 ( t,/ =
7.4 Hz, 2 H), 2.45 (t, J = 7.3 Hz, 2 H), 2.17-1.82 (m, 4 H).
Resin-free 169 (n = 8 ): *H NMR (300 MHz,
C D 3 O D )
8
8.61 (d, J = 2.2 Hz, 1 H),
8.15 (dd, J = 9.0, 2.28 Hz, 1 H), 7.55 (d, J = 8.9 Hz, 1 H), 6.57 ( d , / = 0.6 Hz, 1 H),
2.98 (t, J = 7.6 Hz, 2 H), 2.37 (t, J = 7.5 Hz, 2 H), 2.02-1.88 (m, 2 H), 1.85-1.74 (m,
2 H), 1.65-1.47 (m,
8
H).
214
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*
Representative procedure for the synthesis of 173 (Ar =/)-CF3CsH4)
HN-S'
HN
173
To the resin-bound 4-nitrobenzamides 168 (10 reactors, 0.21 mmol) were added a
solution of SnCl2’2H20 in NMP (1.0 M, 12.0 mL), and the mixture was shaken for
24 h at room temperature. The reactors were rinsed with DMF (x 5) and DCM (x 5).
After drying the resin-bound 4- aminobenzamides 172 in DCM-pyridine (5:1, v/v)
were treated with 4-(trifluoromethyl)-benzenesulfonyl chloride (0.16 mL, 1.05
mmol). The reaction was shaken at room temperature for 24 h, and the formed resinbound sulfonamides 173 were washed with DMF and DCM (x 5 each) and dried
overnight in vacuo. Resin-free samples of the sulfonamides 173 were obtained in
quantitative yield after cleavage from the resin.
Resin-free 173 (Ar = />CF3C6H4, n = 3): 'H NMR (300 MHz, CDC13) 5 7.93 (d, J =
8.1 Hz, 2 H), 7.80 (d, J = 7.5 Hz, 2 H), 7.58 (d, J = 8.1 Hz, 1 H), 7.14 (d, J = 2.4 Hz,
1 H), 6.99 (dd, J = 8.7, 2.4 Hz, 1 H), 2.53 (t, J = 6.9 Hz, 2 H), 2.39 (t, J = 7.5 Hz, 4
H), 1.92 (quintet, J = 6.9 Hz, 2 H), 1.73 (sextet, J = 7.2 Hz, 2 H), 1.02 (t, / = 6.9 Hz,
3 H).
Resin-free 173 (Ar = /?-CF3C6H4 , n = 8): *H NMR (300 MHz, CDCL) 5 7.91 (d, J =
8.1 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.08 (d, J = 2.7 Hz,
1 H ), 6.9 7 (dd, J = 8.7, 2 .7 Hz, 1 H ), 2.45 (t,
6.9 Hz, 2 H ), 2.35 (t, J = 7.5 Hz, 2
H), 2.19 (t, J= 7.2 Hz, 2 H), 1.68-1.26 (m, 14 H), 1.00 (t, J = 7.5 Hz, 3 H).
215
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&'
Representative procedure for synthesis of indole 165 (Ar = wj-CF^QFf), n = 2).
To an Emrys™ process 5- mL vial was added the resin-bound sulfonamide 173 (Ar =
m- CF3 C6 H4 , n = 2; 2.1 x 10' 2 mmol) transferred from the MicroKan™ reactor
together with the R f tag (Caution: The encoded R f tag cannot be archived after
microwave irradiation if a 2- mL process vial is used. Photos of the reaction vials are
given in Figure 1.). To the above vial were added Cu(OAc) 2 (3.8 mg, 2.1 x 10' 2
mmol) and dry NMP (1.5 mL). The vial was then put into the microwave cavity on
the Emrys™ creator from Personal chemistry AB (Uppsala, Sweden) and heated at
200 °C for 10 min. The reaction mixture was transferred back to an empty
microKan™ reactor and the solvent was drained. The resin-bound indole 174 was
washed with DMF, MeOH and DCM, and dried in vacuo. After cleavage from the
resin, the indole 165 (Ar = m-CF 3 C6 FI4 , n = 2) (8.3 mg, 82% from Rink amide resin)
was obtained in 98% purity as determined by LC-MS analysis.
216
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165-37 (Ar = o-CF3 C6 H4 , n = 2 ):
H2N
s=o
n-Pr
*H NMR (300 MHz, CD3 OD) 5 8.19 (d, J = 7.6 Hz, 1 H), 8.10 (d, J = 7.2 Hz, 1 H),
7.90 (d, J = 8.7 Hz, 1 H), 7.89 (t, J =
6 .8
Hz, 1 H), 7.81 (td, J = 7.7, 0.9 Hz, 1 H),
7.42 (d, J = 2.1 Hz, 1 H), 7.18 (dd, J = 8.9, 2.2 Hz, 1 H), 6.58 (s, 1 H), 3.47 (t, J =
7.3 Hz, 2 H), 3.21 (t, / = 7.1 Hz, 2 H), 2.81 (t, J = 7.3 Hz, 2 H), 2.01 (sextet, J = 7.2
Hz, 2 H), 1.23 (t, J = 7.3 Hz, 3 H).
165-38 (Ar = o-CF 3 C6 H4, n = 3):
*H NMR (300 MHz, CD 3 OD) 5 8.20 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 7.6 Hz, 1 H),
7.90 (d, / =
8 .8
Hz, 1 H), 7.89 (t, J = 5.9 Hz, 1 H), 7.82 (td, J= 6.3, 0.9 Hz, 1 H),
7.43 (d, J = 2.1 Hz, 1 H), 7.17 (dd,/ = 8.9, 2.2 Hz, 1 H), 6.59 (s, 1 H), 3.23-3.16 (m,
4 H), 2.48 (t, J - 7.5 Hz, 2 H), 2.17 (quintet, J = 7.4 Hz, 2 H), 2.00 (sextet, J = 7.2
Hz, 2 H), 1.22 (t, J = 7.3 Hz, 3 H).
Ill
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
165-39 (Ar = o-CF3 C6 H4 , n = 4):
’h NMR (300 MHz, CD3 OD) 5 8.19 (d, 7 = 7.7 Hz, 1 H), 8.10 (d, 7 = 7.5 Hz, 1 H),
7.90 (d, 7 =
8 .8
Hz, 1 H), 7.89 (t, 7 = 6.7 Hz, 1 H), 7.81 (td, 7 = 7.6, 1.11 Hz, 1 H),
7.42 (d, 7 = 2 .1 Hz, 1 H), 7.16 (dd,7 = 8.9, 2.2 Hz, 1 H), 6.56 (s, 1 H), 3.24-3.15 (m,
4 H), 2.44 (t, 7 = 6.9 Hz, 2 H), 2.00 (sextet, 7 = 7.2 Hz, 2 H), 1.94-1.84 (m, 4 H),
1.22 (t, 7 = 7.3 Hz, 3H).
165-40 (Ar = o-CF3C6H4, n = 8):
S=0
•CF-
n-Pr
*H NMR (300 MHz, CD3 OD)
6
8.19 (d, 7 = 7.6 Hz, 1 H), 8.10 (d, 7 = 8.9 Hz, 1 H),
7.91 (d, 7 = 7.9 Hz, 1 H), 7.89 (t, 7 = 7.9 Hz, 1 H), 7.82 (td, 7 = 7.59, 1.1 Hz, 1 H),
7.42 (d, 7 = 2.1 Hz, 1 H), 7.15 (dd, 7 =
8
.8 , 2.25 Hz, 1 H), 6.53 (s, 1 H), 3.18 (t, 7 =
7.1 Hz, 2 H), 3.15 (t, 7 = 8.0 Hz, 2 H), 2.38 (t,7 = 7.2 Hz, 2 H), 2.00 (sextet, 7 = 7.2
Hz, 2 H), 1.93-1.72 (m, 4 H), 1.66-1.43 (m,
8
H), 1.21 (t, 7 = 7.3 Hz, 3 H).
218
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165-41 (Ar = OT-CF3 C6 H4 , n = 2):
H2N
S=0
n-Pr
'CF-
'H NMR (300 MHz, CD3 OD) 5 8.14 (s, 1 H), 8.10 (d, J = 7.8 Hz, 1 H), 8.04 (d, J =
7.9 Hz, 1 H), 7.91 (d, J= 8.9 Hz, 1 H), 7.83 (t, J= 7.8 Hz, 1 H), 7.39 (d, J = 2.0 Hz,
1 H), 7.12 (dd, J = 8.9, 2.13 Hz, 1 H), 6.59 (s, 1 H), 3.47 (t, J = 7.32 Hz, 2 H), 3.21 (t,
J = 7.11 Hz, 2 H), 2.83 (t, J = 7.10 Hz, 2 H), 2.01 (sextet, J= 7.26 Hz, 2 H), 1.23 (t,
J = 7.35 Hz, 3 H).
165-42 (Ar = w-CF3C6H4, n = 3):
H2 N-
s=o
n-Pr
'CF-
*H NMR (300 MHz, CD3 OD) 5 8.15 (s, 1 H), 8.10 (d, 7 = 7 .8 Hz, 1 H), 8.05 (d ,7 =
7.9 Hz, 1 H), 7.92 (d, J =
8 .8
Hz, 1 H), 7.81 (t, J = 7.8 Hz, 1 H), 7.40 (d, J = 2.1 Hz,
1 H), 7.11 (dd, / = 8.9, 2.1 Hz, 1 H), 6.60 (s, 1 H), 3.26-3.15 (m, 4 H), 2.49 (t, J =
1 2 Hz, 2 H), 2.18 (quintet, J = 1 2 Hz, 2 H), 2.01 (sextet, J= 1 2 Hz, 2 H), 1.22 (t, J
= 1 3 Hz, 3 H).
219
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165-43 (Ar = m -C F3 C6 H4, n = 4):
CFg
'O
*H NMR (300 MHz, CD3 OD) 5 8.14 (s, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), 8.04 (d, J =
7.9 Hz, 1 H), 7.92 (d ,/= 8 .9 H z , 1 H), 7.84 (t,J = 7.8 Hz, 1 H), 7.39 (d, J = 2.1 Hz,
1 H), 7.10 (dd, / = 8.9, 2.2 Hz, 1 H), 6.58 (s, 1 H), 3.25-3.14 (m, 4 H), 2.45 (t, J =
6 .8
Hz, 2 H), 2.00 (sextet, J = 7.2 Hz, 2 H), 1.94-1.84 (m, 4 H), 1.22 (t, J = 7.3 Hz, 3
H).
165-44 (Ar = ot-CF3 C6 H4 , n = 8 ):
‘H NMR (300 MHz, CD 3 OD) 5 8.13 (s, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), 8.04 (d, J =
7.9 Hz, 1 H), 7.92 (d, J = 8.9 Hz, 1 H), 7.84 (t, J = 7.8 Hz, 1 H), 7.38 (d, J = 2.1 Hz,
1 H), 7.09 (d d ,J = 8 . 8 , 2.2 Hz, 1 H), 6.55 (s, 1 H), 3.19 (t, J = l . l Hz, 2 H), 3.16 (t, J
= 7.7 Hz, 2 H), 2.38 (t, J = 7.2 Hz, 2 H), 2.01 (sextet, J = 7.2 Hz, 2 H), 1.93-1.72 (m,
4 H), 1.66-1.43 (m,
8
H), 1.22 (t, J = 7.3 Hz, 3 H).
220
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165-45 (Ar = p - CF3 C6 H4, n = 2):
H2N
[\L />
S=0
n-Pr
CF3
*H NMR (300 MHz, CD3 OD) 5 8.16-7.93 (A2 ’B2’, 4 H), 7.92 (d, J = 9.0 Hz, 1 H),
7.42 (d, J = 2.0 Hz, 1 H), 7.14 (dd, / = 8.9, 2.19 Hz, 1 H), 6.60 (s, 1 H), 3.48 (t, J =
7.4 Hz, 2 H), 3.22 (t, J = 7.1 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2 H), 2.02 (sextet, J = 7.2
Hz, 2 H), 1.23 (t, / = 7.3 Hz, 3 H).
165-46 (Ar = /?-CF3 C6 H4, n = 3):
S=0
n-Pr
CF3
*H NMR (300 MHz, CD3 OD) 5 8.15-7.93 (A2 ’B2’, 4 H), 7.92 (d, J = 8.9 Hz, 1 H),
7.43
(d, / = 2.1 Hz, 1 H), 7.13 (dd, J = 8.9, 2.2 Hz, 1 H), 6.60 (s, 1 H), 3.26-3.16 (m,
4 H), 2.49 (t, J = 7.4 Hz, 2 H), 2.17 (quintet, J = 7.4 Hz, 2 H), 2.01 (sextet, J = 13
Hz, 2 H), 1.22 (t, J = 7.3 Hz, 3 H).
221
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165-47 (Ar = Jp-CF3 C6 H4, n = 4):
H2N
S -0
n-Pr
CF3
*H NMR (300 MHz, CD3 OD) 5 8.11-7.93 (A2 ’B2\ 4 H), 7.92 (d, 7 = 9.0 Hz, 1 H),
7.41 (d, 7 = 2.1 Hz, 1 H), 7.12 (dd, 7 = 8 .8 , 2.2 Hz, 1 H), 6.58 (s, 1 H), 3.19 (t, 7 =
7.1 Hz, 4 H), 2.45 (t, 7 = 6.7 Hz, 2 H), 2.00 (sextet, 7 = 12 Hz, 2 H), 1.96-1.84 (m, 4
H), 1.22 (t, 7 = 7.3 Hz, 3 H).
165-48 (Ar = p-CF 3 C6 H4, n = 8 ):
S=0
n-Pr
CF3
*H NMR (300 MHz, CD3 OD) 5 8.11-7.94
4 H), 7.93 (d, 7 = 9 .1 Hz, 1 H),
7.41 (d, 7 = 2.1 Hz, 1 H), 7.11 (d d ,7 = 8.9, 2.25 Hz, 1 H), 6.55 (s, 1 H), 3.19 (t, 7 =
7.2 Hz, 2 H), 3.16 (t, 7 =
8 .6
Hz, 2 H), 2.38 (t, 7 = 7.2 Hz, 2 H), 2.00 (sextet, 7 = 7.2
Hz, 2 H), 1.93-1.72 (m, 4 H), 1.67-1.43 (m,
8
H), 1.22 (t,7 = 7.3 Hz, 3 H).
Representative procedure for the synthesis of indoles 166
To a solution of 165 in MeOH (2.0 mL) was added NaOMe (1.0 eq). After shaking
for 1 h at rt, the solvent was removed under reduced pressure. The residue was
dissolved in acetonitrile (1.0 mL) and filtered through a short silica gel plug to give
222
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the product 166.
LC-MS data of indole library (165 and 166) are shown in Appendix.
HPLC setting: 50% CH3 CN in H2 O (v/v) with 0.1% acetic acid; UV detection at 254
nm; flow rate at 0.8 mL/min.
2-Bromo-4-nitroaniIine 203
203
Into a flask were placed 4-nitroaniline (1.4 g, 10 mmol) DCM 30 mL and MeOH 20
mL. «-Bu4 NBr3 (5.3 g, 11 mmol) was as a solid and in one portion at room
temperature. After 5 min at rt, the mixture was poured into a separatory funnel
containing DCM (50 mL) and aqueous Na 2 SC>3 solution (150 mL). The organic layer
was collected, washed with water (2 x 100 mL) and brine (100 mL), dried over
MgSC>4 , and filtered through a short plug of silica gel, and the solvents were removed
to leave 203 (1.99g, 92%) as a yellow solid, mp 102-104 °C. R/ = 0.48 (33% EtOAc
in hexane).The spectral data were consistent with literature values.
'H N M R (300 MHz, CDCI3 ) 5 8.35 (d, J = 2.5 Hz, 1 H), 8.01(dd, J = 9.0, 2.5 Hz, 1
H), 6.74 (d, J = 9.0 Hz 1 H), 4.50 (s, 2 H);
I3CNM R (75 MHz, CDCI3 ) 5 149.9, 138.9, 129.1,
124.9,113.4,106.9;
MS (+CI) m/z 217 (M + H+, 100), 219 (92).
223
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5-(2-Bromo-4-nitro-phenylcarbamoyl)-pentanoic acid
205b
Into a 5.0 mL Emrys vial was placed 203 (434.0 mg, 2.0 mmol), DMAP (366.5 mg,
3.0 mmol), methyl adipoyl chloride (0.37 mL, 2.2 mmol), and 5.0 mL THF. After
heating at 160 °C for 20 mins on Microwave reactor from Personal Chemistry AB,
the mixture was added water and extracted with ethyl acetate. The combined organic
layer was washed by water and brine, dried over anhydrous MgSCL. The crude
product was added in 20 mL 1% LiOH-THF (1:1), the mixture was stirred at rt for
12 h. After basified using 5% HC1, extracted with EtOAc, the organic layer was
washed with water and brine, dried over anhydrous MgS0 4 . The crude product was
purified by flash column chromatography to give 205b (631.8 mg,
8 8
%) as white
solid.
'H N M R (300 MHz, CD3 COCD3) 5 8.95 (s, 1 H), 8.70 (d, J = 9.2 Hz, 1 H), 8.61 (d, J
= 2.6 Hz, 1 H), 8.41 (dd, J = 9.2, 2.6 Hz, 1 H), 2.80 (t, J = 7.0 Hz, 2 H), 2.51 (t, J =
7.3 Hz, 2 H), 1.95-1.81 (m, 4 H);
13CNM R (75 MHz, CD3 COCD3) 5 173.5, 171.7, 143.1, 142.4, 127.8, 123.5, 121.7,
112.6,41.5,36.4,32.9, 24.1;
MS (+CI) m/z 345 (M + H+, 60), 346 (60), 326 (100), 329 (100).
224
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Preparation of resin-bound 206b
0 2N
o
206b
The MicroKan™ reactors, preloaded with the Rink amide resin, were treated with a
solution of 20% piperidine in DMF for 1 h at room temperature and then washed
with DMF and DCM. The washing procedure was repeated five times and the resin
was dried overnight in vacuo. 205b (5.0 eq) was coupled to the resin using DIC (5.0
eq) and HOBt (5.0 eq each) in DMF at room temperature for 24 h followed by
washing with DMF and DCM (x 5 each). The resin-bound 206b was dried overnight
in vacuo.
Preparation of resin-bound 207
207
The resin-bound 206b (10 reactors, 0.21 mmol) was charged in a Schlenk flask along
with the phenylacetylene (0.23 mL, 2.10 mmol), Pd(PPh3 )2 Cl2 (14.7 mg, 2.10 x 10"2
mmol), PPh 3 (11.0 mg, 4.20 x 10' 2 mmol), and Cul (11.9 mg, 6.30 x 10' 2 mmol). The
flask was evacuated and backfilled with N 2 gas. DMF-Et3N (5:1 v/v, 12.0 mL) was
added via a syringe. After stirring at 80 °C for
8
h, the reactors were then washed
with DMF, MeOH and DCM. The washing procedure was repeated five times and
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the resin-bound 207 was dried overnight in vacuo. Resin-free sample of the 207 was
obtained in ca. 90% yield after cleavage from the resin.
Preparation of resin-bound 209
O
209 (Ar = 4-CF3 C6 H4)
To the resin-bound 207 (10 reactors, 0.21 mmol) was added a solution of
SnCl2-2H20 in NMP (1.0 M, 12.0 mL), and the mixture was shaken for 24 h at room
temperature. The reactors were rinsed with DMF (x 5) and DCM (x 5). After drying,
the resin-bound resulted product in DCM pyridine (5:1, v/v) was treated with 4(trifluoromethyl)-benzenesulfonyl chloride (0.16 mL, 1.05 mmol). The reaction was
shaken at room temperature for 24 h, and the formed resin-bound sulfonamide 209
was washed with DMF and DCM (x 5 each) and dried overnight in vacuo. Resin-free
sample of the sulfonamide 209 was obtained in ca 90% yield after cleavage from the
resin.
226
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Preparation of 212a
'Fmoc
or
212
a
To a 5 mL Emrys vial was placed pre-deprotected Rink amide resin 200 mg (0.14
mmol), HOBt (89.0 mg, 1.4 mmol), DIC (0.2 mL, 1.4 mmol), Fmoc-Gly-OH (416.2
mg, 1.4 mmol) and DMF 4.0 mL. After heating at 120 °C on microwave creator from
Personal Chemistry AB, the resin-bound 212a was transfer to a custom-made solidphase reaction vessel and washed with DMF and DCM (x 3) and dried in vacuo.
Resin-free sample was obtained in 98% yield after cleavage from the resin.
'H N M R (300 MHz, CD3OD) 5 7.98 (d, J = 7.4 Hz, 2 H), 7.86 (d, J = 7.4 Hz, 2 H),
7.58 (t, / = 7.3 Hz, 2 H), 7.50 (td, J = 7.5, 1.1 Hz, 2 H), 4.57 (d, J = 6.8 Hz, 2 H),
4.42 (t, J= 6.7 Hz, 1 H), 3.95 (s, 2 H).
Preparation of resin-bound 212b
°
H
N
H
NH Fmoc
s
212b
The resin-bound 212a (100.0 mg) was treated with a solution of 20% piperidine in
DMF for 1 h at room temperature and then washed with DMF and DCM. The
washing procedure was repeated five times and the resin was dried overnight in
vacuo. Fmoc-Gly-OH (5.0 eq) was coupled to the resin using DIC (5.0 eq) and HOBt
227
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(5.0 eq each) in DMF at room temperature for 2 h followed by washing with DMF
and DCM (x 5 each). The resin-bound 212b was dried overnight in vacuo.
Preparation of resin-bound 213b
o 2n
o
o
213b
The resin-bound 212b (100.0 mg) was treated with a solution of 20% piperidine in
DMF for 1 h at room temperature and then washed with DMF and DCM. The
washing procedure was repeated five times and the resin was dried overnight in
vacuo. 205b (5.0 eq) was coupled to the resin using DIC (5.0 eq) and HOBt (5.0 eq
each) in DMF at room temperature for 24 h followed by washing with DMF and
DCM (x 5 each). The resin-bound 213b was dried overnight in vacuo. The resin-free
product was obtained in 96% yield.
Representative procedure for the synthesis of resin-bound 217
R
O
o
o
217
The MicroKan™ reactors (16 reactors), preloaded with the 213b and an encoded Rf
tag, were charged in a Schlenk flask along with the terminal alkynes (10.0 eq),
Pd(PPh3)2Cl2 (0.1 eq), PPI 13 (0.2 eq)), and Cul (0.3 eq). The flask was evacuated and
228
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backfilled with N 2 gas. DMF-Et 3 N (5:1 v/v, 18.0 mL) was added via a syringe. After
stirring at 80 °C for 8 h, the reactors were then washed with DMF, MeOH and DCM.
After drying overnight in vacuo, to the resin-bound alkynylanilides (10 reactors, 0.21
mmol) were added a solution of SnCl2-2H20 in NMP (1.0 M, 12.0 mL), and the
mixture was shaken for 24 h at room temperature. The reactors were rinsed with
DMF (x 5) and DCM (x 5). After drying, the resin-bound resulted product in DCM pyridine (5:1, v/v) was treated with aryl sulfonyl chloride (5.0 eq). The vessel was
shaken at room temperature for 24 h, and the formed resin-bound sulfonamides 217
were washed with DMF and DCM (x 5 each) and dried overnight in vacuo. Resinfree sample of the sulfonamides 217 were obtained after cleavage from the resin.
Resin-free 217 (Ar = 4 -FC6 H4 , R = 4-CH3C6H4)
'H N M R (300 MHz, CD3OD) § 8.03 (dd, J = 8.8, 5.2 Hz, 2 H), 7.69 (d, J = 8.8 Hz, 1
H), 7.60 (d, J = 8.0 Hz, 2 H), 7.43-7.37 (m, 5 H), 7.22 (dd,T= 8.7, 2.5 Hz, 1 H),
4.01 (s, 4 H), 2.63 (s, 2 H), 2.56 (s, 3 H), 2.50 (s, 2 H), 1.92 (br, 4 H).
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Resin-free 217 (Ar = 4 -FC6 H4 , R —w-Bu)
'H N M R (300 MHz,
C D 3 O D )
5 7.99
H), 7.34 (t, J = 8.7 Hz, 2 H), 7.25
(d ,
(d d ,
J = 8.7, 5.2 Hz, 2 H), 7.73
(d ,
J = 8.7 Hz, 1
J= 2.4 Hz, 1 H), 7.16 ( d d , J = 8.7, 2.5Hz, 1 H),
4.05 (s, 2 H), 4.04 (s, 2 H), 1.16 (t, J = 1 2 Hz, 3 H).
Representative procedure for the synthesis of resin-bound indoles 218
H
218
To an Emrys™ process 5- mL vial was added the resin-bound sulfonamide 217 (Ar =
4- FC6 H4 , R =
4
-CH3 OC6 H4 , 2.1 x 10' 2 mmol) transferred from the MicroKan™
reactor together with the Rf tag. To the above vial was added Cu(OAc) 2 (3.8 mg, 2.1
x 10"2 mmol) and dry NMP (1.5 mL). The vial was then put into the microwave
cavity on the Emrys™ creator from Personal chemistry AB (Uppsala, Sweden) and
heated at 200 °C for 10 min. The reaction mixture was transferred back to an empty
micro Kan™ reactor and the solvent was drained. The resin-bound indole 218 was
washed with DMF, MeOH and DCM, and dried in vacuo. After cleavage from the
resin, the indole 219 (Ar = 4- FCgFLt, R = 4 -CH 3 OC6 H4 ) was obtained.
230
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
219g (Ar = 4-/'-PrCfiH4, R = 4-CH3OC6H4)
’HNM R (300 MHz, CD3 OD) 5 8.22 (d, 7 = 8.9 Hz, 1 H), 7.86 (d, 7 = 10.1 Hz, 1 H),
7.58 (d, 7 = 8.7 Hz, 2 H), 7.49 (dd,7 = 8.3, 2.1 Hz, 3 H), 7.23 (d ,7 = 8.7 Hz, 2 H),
7.15 (dd, 7 = 9.0, 2.2 Hz, 1 H), 6.69 (s, 1 H), 4.05 (s, 3 H), 4.02 (s, 2 H), 3.99 (s, 2 H),
3.14-3.07 (m, 1 H), 2.50 (t,7 = 6.9 Hz, 2 H), 2.31 (t, 7 = 7.3 Hz, 2 H), 1.78-1.67 (m,
2 H), 1.59-1.53 (m, 2 H), 1.41 (d, 7 = 6.9 Hz,
6
H).
219e (Ar = 4-FC 6 H4, R = 4-CH3 OC6 H4)
XX
OCH-
h 2n
*HNMR (300 MHz,
H), 7.58 (d ,7 =
8 .6
C D 3 O D )
5 8.10 (d, 7 = 9.1 Hz, 1H), 7.97 (dd,7=8.8, 5.2 Hz, 2
Hz, 2 H), 7.43 (s, 1 H), 7.35 (t,7 =
8 .8
Hz, 2 H), 7.23 (d, 7 = 8.7
Hz, 2 H), 7.14 (d, 7 = 8.9, 2.2Hz, 1 H), 6.67 (s, 1 H), 4.04 (s, 3 H), 4.02 (s, 2 H), 3.99
(s, 2 H), 2.50 (t, 7 = 7.0 Hz, 2 H), 2.31 (t,7 = 8.0 Hz, 2 H), 1.75-1.69 (m, 2 H), 1.581.48 (m, 2 H).
231
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
219i (Ar = 4-FC6H4, R = Ph)
‘HNM R (300 MHz, CD3 OD) § 8.03 ( dd, J = 8.7, 5.2 Hz, 2 H), 7.72-7.69 (m, 3 H),
7.62 (s, 1 H), 7.57 (t, J = 2.4 Hz, 3 H), 7.42-7.37 (m, 3 H), 7.23 (dd, J = 8 .8 , 2.6 Hz,
1 H), 4.0 (s, 4 H), 2.62 (t, J = 6.3 Hz, 2 H), 2.47 (s, 2 H), 1.92-1.77 (m, 4 H).
219m (Ar = 4-FC6H4, R = h-Bu)
'H N M R (300 MHz, CD3 OD) 5 7.96 (m, 3 H), 7.39 -7.33 (m, 3 H), 7.11 (dd, J = 8.9,
2.2 Hz, 1 H), 6.54 (s, 1 H), 4.05 (s, 2 H), 4.04 (s, 2 H), 3.25 (t, / = 7.0 Hz, 2 H), 3.17
(t, J = 7.4 Hz, 2 H), 2.54 (t, J = 7.3 Hz, 2 H), 2.08-1.90 (m, 4 H), 1.83 (t, J = 7.4 Hz,
2 H), 1.62 (septet, 7.4 Hz, 2 H), 1.16 (t, J = 7.3 Hz, 3 H).
Representative procedure for the synthesis of indoles 220
To a solution of 219 in THF (0.5 mL) was added pyrrolidine (1.5 mL). After shaking
at 60 °C for 12 h, the solvent was removed under reduced pressure. The residue was
dissolved in acetonitrile (1.0 mL) and filtered through a short silica gel plug to give
the product 220. LC-MS-data of 16 indoles are shown in Appendix.
232
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
HPLC conditions: 60% acetonitrile with 0.1 % acetic acid; flow rate at 0.8 mL/min;
UV detected at 254 nm.
2-[4’’-Tolyl-5-[((4’-pyrrolidinyl)benzene)sulfamoyl]]mdole 220a
H
220a
*HNMR (300 MHz, CD 3 OD) 5 7.69 (d, J = 8.1 Hz, 2 H), 7.50 (d, J = 8.9 Hz, 2 H),
7.28 (s, 1 H), 7.25-7.22 (m, 3 H), 6.87 (dd, J = 1.9, 8.7 Hz, 1 H), 6.71 (s, 1 H), 5.52
(d, / = 8.9 Hz, 2 H), 3.32-3.37 (m, 4 H), 2.37 (s, 3 H), 2.05-2.09 (m, 4 H).
2-[p-Tolyl-5-[((4’-methoxyl)benzene)sulfamoyl]]indole 220b
220b
*HNMR (300 MHz, CD 3 OD) 5 7.80 (q, J = 8.13, 8.9 Hz, 4 H), 7.43-7.36 (m, 4 H),
7.12 (d, J = 8.9 Hz, 2 H), 6.97 (dd, J = 2.0,
8 .6
Hz, 1 H), 6.82 (s, 1 H),3.99 (s, 3 H),
2.55 (s, 3 H).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
2-[/>-Tolyl-5-[((4’-isoproyl)benzene)sulfamoyl| ]indole 220c
CH-
220c
'H N M R (300 MHz, CD3 OD) 5 7.80 (q, J = 8.1, 8.3 Hz, 4 H), 7.49 (d, J = 8.3 Hz, 2
H), 7.40 (m, J = 7.8 Hz, 4 H), 6.97 (dd, J = 1.9, 8.5 Hz, 1 H), 6.82 (s, 1 H), 3.17-3.07
(m, 1 H), 2.55 (s, 3 H), 1.41 (d, J = 6.9 HZ,
6
H).
2-[4-Tolyl-5-[(thiophen-2’-yl)sulfamoyl]]mdole 220d
H
2 20
d
‘HNM R (300 MHz, CD3 OD) 5 7.83 (t, J = 2.7, 7.8 Hz, 3 H), 7.54 (dd, J= 8.0, 2.6 Hz,
1 H), 7.43-7.40 (m, 4 H), 7.19 (t, / = 3.9, 4.8 Hz, 1 H), 7.02 (dd, J = 1.8, 8.7 Hz, 1
H), 6.84 (s, 1 H), 2.54 (s, 3 H).
234
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2-[4” -Methoxy-phenyl-5-[((4’-pyrrolidinyl)benzeiie)sulfamoyl]iiidole 220e
H
22 Oe
'H N M R (300 MHz, CD 3 OD) 5 7.86 (d, J =
8 .8
Hz, 2 H), 7.63 (d, J = 8.9 Hz, 2 H),
7.37 (d, J = 8.5 Hz, 2 H), 7.16 (d, J = 8.7 Hz, 2 H), 6.83 (dd, J= 2.0, 8.5 Hz, 1H),
6.76 (s, 1 H), 6.67 (d, J = 8.9 Hz, 2 H), 4.02 (s, 3 H), 2.22-2.27 (m, 4 H), 1.54-1.59
(m, 4 H).
2-[4-methoxy-phenyl-5-[((4,-methoxyl)benzene)sulfamoyl]]iiidole 220f
22 Of
'H N M R (300 MHz, CD 3 OD)
6
7.87 (d, J = 8 . 8 Hz, 2 H), 7.78 (d, / = 8.9 Hz, 2 H),
7.37 (q, J= 8.5, 2.0 Hz, 2 H), 7.15 (dd, / =
8
.8 , 8.9 Hz, 4 H), 6.96 (dd, 7 = 2.0, 8.5
Hz, 1 H), 6.76 (s, 1 H), 4.02 (s, 3 H), 3.99 (s, 1 H).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
2-[4-Methoxy-phenyl-5-[((4’-isopropyl)benzene)sulfamoyl]]indole 220g
och3
220g
‘HN M R (300 MHz, CD3 OD) 5 7.86 (d, J =
8 .8
Hz, 2 H), 7.78 (d, J = 8.4 Hz, 2 H),
7.50 (d, J= 8.4 Hz, 2 H), 7.35 (t, J = 9.8 Hz, 2.3 Hz, 2 H), 7.17 (d, J =
8 .8
Hz, 2 H),
6.96 (dd, J = 2.1, 8.5 Hz, 1 H), 6.75 (s, 1 H), 4.02 (s, 3 H), 3.17-3.08 (m, 1 H), 1.41
(d, J = 6.9 Hz,
6
H).
2-[4-Methoxy-phenyl-5-[(thiophen-2’-yl)sulfamoyl]]iiidole 220h
H
220h
‘HNM R (300 MHz, CD3 OD) 5 7.84 (q, J = 8.9, 1.2 Hz, 3 H), 7.55 (dd, J = 1.3, 2.5
Hz, 1 H), 7.41 (q, J = 3.5Hz, 2 H), 7.22-7.16 (m, 3 H), 7.01 (dd, J = 8.7, 1,9Hz, 1 H),
6.78 (s, 1 H), 4.02 (s, 3 H).
236
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
2-Phenyl-5-[((4’-pyrrolidinyl)benzene)sulfamoyl]indole 220i
XX.S
O O
H
220i
'H N M R (300 MHz, CD3 OD) 5 7.93 (d, J = 7.4 Hz, 2 H), 7.61 (q, J = 9.0,7.8 Hz, 4
H), 7.49-7.38 (m, 3 H), 7.00 (dd, J = 7.7, 1.2 Hz, 1 H),
6 .8 8
(s, 1 H), 6.67 (d, J = 9.0
Hz, 2 H), 3.45-3.49 (m, 4 H), 2.23-2.30 (m, 4 H).
2-Phenyl-5-[((4’-methoxyl)benzene)sulfamoyl]indole 220j
H3 CO
H
22 Oj
'H N M R (300 MHz, CD3 0D ) 5 7.94 (d, J = 7.4 Hz, 2 H), 7.78 (d, J = 8.9 Hz, 2 H),
7.60 (t, J = 7.8 Hz, 2 H), 7.49-7.39 (m, 3 H), 7.63 (d, / = 8.9 Hz, 2 H), 6.99 (dd, J =
8
.6 , 2.0 Hz, 1 H), 6.89 (s, 1 H), 3.99 (s, 3 H).
237
Reproduced with permission o f the copyright owner. Further reproduction prohibited without permission.
2-Phenyl-5-[((4’-isopropyl)benzene)sulfamoyl]iiidole 220k
H
220k
'H N M R (300 MHz, CD 3 OD) 5 7.94 (d, / = 7.4 Hz, 2 H), 7.78 (d, J = 8.3 Hz, 2 H),
7.50 (t, J = 7.4 Hz, 2 H), 7.51-7.42 (m, 3 H), 7.41 (d, J = 8.9 Hz, 2 H), 7.00 (dd, J =
8.5, 2.0 Hz, 1 H),
6 .8 8
(s, 1 H), 3.17-3.08 (m, 1 H), 1.41 ( d ,/= 6.9 Hz,
6
H).
2-Phenyl-5-[(thiophen-2’-yl)sulfamoyl]indole 2201
H
2201
'H N M R (300 MHz, CD3 OD) 5 7.95 (d, J = 7.3 Hz, 2 H), 7.85 (dd, 7 = 5.0, 1.2 Hz, 1
H), 7.63-7.55 (m, 3 H), 7.50-7.43 (m, 3 H), 7.21 (dd, J = 3.8, 4.9 Hz, 1 H), 7.05 (dd,
J = 8.7, 2.0 Hz, 1 H), 6.91 (s, 1 H).
238
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
2-Butyl-5-[((4,-pyrrolidinyl)benzene)sulfamoyl]indole 220m
H
220m
‘HN M R (300 MHz, CD3 OD)
8
6.89 (dd ,7 = 8.5, 2.0 Hz, 1 H),
7.61 ( d , J = 8.9 Hz, 2 H), 7.26 (d, J =
6 .6 6
8 .6
Hz, 2 H),
(d, J = 9.0 Hz, 2 H), 6.20 (s 1 H), 3.42-3.51 (m,
4 H), 2.89 (t, J = 6.4 Hz, 2 H), 2.25-2.27 (m, 4 H), 1.88 (qn, J = 7.6 Hz, 2 H), 1.58
(septet, J = 7.6 Hz, 2 H), 1.14 (t, J = 7.3 Hz, 3 H).
2-Butyl-5-[((4’-methoxyl)benzene)sulfamoyl]]indole 220n
H3C (X
Y
l
h
220n
‘HNM R (300 MHz, CD3 OD) 5 7.76 (d, J = 8.9 Hz, 2 H), 7.26 (dd, J = 3.8, 5.8 Hz, 2
H),
6 .8 8
(dd, J = 8 .6 , 1.9 Hz, 1 H), 6.21 (s, 1 H), 3.99 (s, 3 H), 2.90 (t, J = 7.5 Hz,
H), 1.85 (qn, J = 7.4 Hz, 2 H), 1.59 (septet, J = 7.5 Hz, 2 H), 1.14 (t, J = 7.4 Hz, 3 H).
239
Reproduced with permission o f the copyright owner. Further reproduction prohibited without permission.
2-Butyl-5-[((4’-isopropyl)benzene)sulfamoyl]]indole 220o
H
220o
'H N M R (300 MHz, CD3 OD) 5 7.75 (d, 7 = 8.4 Hz, 2 H), 7.48 (d, 7 =
7.26 (d, 7 = 8.2 Hz,
6 .8 8
(dd, 7 =
8
8 .8
Hz, 2 H),
.6 , 1.8 Hz, 1 H), 6.20 (s, 1 H), 3.11 (septet, 7 =
6 .8
Hz, 1 H), 2.90 (t, 7 = 7.6Hz, 2 H), 1.88 (qn, 7 = 7.5 Hz, 2 H), 1.57 (sextet, 7 = 7.5 Hz,
3 H), 1.41 (d, 7 = 6.9 Hz,
6
H), 1.14 (t, 7 = 7.4 Hz, 3 H).
2-butyl -5-[(thiophen-2’-yl)sulfamoyl]]indole 220p
H
220p
*HNMR (300 MHz,
C D 3 O D ) 8
Hz, 1 H), 7.32 (d, 7 =
8 .6
7.84 (dd, 7 = 5.0, 1.1 Hz, 1 H), 7.52 (dd,7 = 3.7, 1.1
Hz, 2 H), 7.19 (dd, 7 = 4.8, 3.9 Hz, 1 H), 6.94 (dd, 7 = 8.5,
2.0 Hz, 1 H), 6.23 (s, 1 H), 2.91 (t, 7 = 7 .5 Hz, 2 H), 1.89 (p, 7 = 7 .5 Hz, 2 H), 1.59
(sextet, 7 = 7.5 Hz, 2 H), 1.15 (t, 7 = 7.3 Hz, 3 H).
240
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Preparation of resin-bound 247
O
247
To a 250 mL flask was added l.Og (0.7 mmol) Rink amide resin, and 20% piperidine
in DMF. The mixture was shaken for lh at room temperature and then the resin was
washed with DMF and DCM (x 3). After drying in vacuo, the deprotected resin was
treated with 4-chloro-3-nitrobenzoic acid (0.77 g, 0.7 mmol), and pyridine-DCM
(1:5) 50 mL for 24 h at room temperature and then washed with DMF (x 3) and
DCM (x 3). The formed resin-bound 247 was dried overnight in vacuo.
Resin-free 247.
Representative procedure for the microwave-assisted animation reaction of
resin-bound 247.
To an Emrys™ process 5- mL vial was added the resin-bound 4-chloro-3nitrobenzamide 247 (300.0 mg, 0.21 mmol), benzylamine (0.70 mL, 30 eq), Et3 N
(1.0 mL) and dry NMP (2.0 mL). The vial was heated at 200 °C for 15 min. The
reaction mixture was transferred to 10 empty MicroKan™ reactors equally and the
solvent was drained. The formed resin-bound 248 was washed with DMF (x 3),
MeOH (x 1 ) and DCM (x 3), and then dried overnight in vacuo.
241
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Resin-free 248 (X - F)
4-(4’-Fluoro-benzylamino)-3-nitro-benzamide
NO.
lH NMR (300 MHz,
C D 3 O D ) 8
8.96
(d
, 7 = 2.2 Hz, 1 H), 8.09
1H), 7.62-7.58 (m, 2 H), 732-7.24 (m, 2 H), 7.15
(d ,
(d d ,
7 = 2.2, 9.1 Hz,
7 = 9.1 Hz, 1 H), 4.85
(d
,7 =
3.9 Hz, 2 H);
MS (+CI) m/z 290 (M + H+, 100).
Resin-free 248 (X = Cl)
4-(4,-Chloro-benzylammo)-3-nitro-benzamide
h
rra
o
'H NMR (300 MHz, CD 3 COCD3 ) 5 9.01 (s, 1 H), 8.90
7 = 2.1, 9.0 Hz, 1 H), 7.59
H), 4.95
(d ,
(d d ,
7 = 8.5 Hz, 5 H), 7.16
(d ,
(d ,
7 = 2.1 Hz, 1 H), 8.14
(d d ,
7 = 9.1 Hz, 1 H), 6.73 (s, 1
7 = 6 .1 Hz, 2 H).
242
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Resin-free 248 (X = CH3)
4-(4’-Methyl-benzylamino)-3-nitro-benzamide
O
'H NMR (300 MHz, CD3 OD) 5 8.96 (d, J = 1.7 Hz, 1 H), 8.09 (dd, J = 1.7, 9.0 Hz, 1
H), 7.45 (dd, J = 7.9 Hz, 2 H), 7.36 (d J = 7.9 Hz, 2 H), 7.17 (d, J = 9.0 Hz, 1 H),
4.80 (s, 2 H), 2.51 (s, 3 H).
Resin-free 248 (X = H)
4-Benzylamino-3-nitro-benzamide
O
*H NMR (300 MHz, CD3 COCD3 ) 5 8.90 (d, .7=2.1 Hz, 1 H), 8.15 (dd, 7 = 2 .1 , 9.0
Hz, 1 H), 7.61-7.35 (m,
6
H), 7.20 (d, / = 9.1 Hz, 1 H), 6.73 (s, 1 H), 4.93 (d, J = 5.9
Hz, 2 H);
MS (+CI) m /z 272 (M + H+, 100).
Representative procedure for the reductive reaction of 248 on solid support
To the resin-bound nitroamines 248 (50 reactors) were added a solution of
SnCl2 -2 H 2 0 in NMP (1.0 M, 110.0 mL) and EtOH (12.0 mL). The mixture was
shaken at 40 °C for 24 h under nitrogen, and then the formed resin-bound o-
243
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
phenylenediamines 249 were washed with DMF (x 3), MeOH (x 1) and DCM (x 3),
and dried overnight in vacuo.
Representative procedure for the synthesis of benzimidazoles 251
To the resin-bound o-phenylenediamines 249 (5 reactors, 0.105 mmol) were added a
solution of 2-pyridinecarboxaldehyde (0.3 mL, 3.15 mmol) in 10 mL pyridine. After
the mixture was shaken at 50 °C for 12 h, the resin-bound benzimidazoles 250 were
washed with DMF (x 3), MeOH (x 1) and DCM (x 3), then dried overnight in vacuo.
The resin-bound benzimidazoles 250 were treated with TFA (25% in DCM), and the
mixture was shaken at room temperature for 1 h. After filtering through a short silica
gel plug, the filtrate was concentrated in vacuo to give benzimidazoles 251.
LC-MS data of 50 benzimidazole library are shown in Appendix.
HPLC conditions: 60% acetonitrile with 0.1% acetic acid; flow rate at 0.8 mL/min;
UV detected at 254 nm.
l-(4’-Methyl-benzyl)-2-(4” -nitro-phenyI)-l//-benzoimidazole-5-carboxylic acid
amide 251e-G
O
251e-G
'H NMR (300 MHz, CD3 COCD3) 5 8.56-8.52 (m, 3 H), 8.27-8.22 (m, 2 H), 8.08
(dd, y = 1.6,
8 .6
Hz, 1H), 7.69 (d, J=
8 .6
Hz, 1 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.15 (d,
J = 8.0 Hz, 2 H), 6.75 (s, 1 H), 5.85 (s, 2 H), 2.40 (s, 3 H).
244
Reproduced with permission o f the copyright owner. Further reproduction prohibited without permission.
l-(4 ,-Chloro-benzyl)-2-(4’’-nitro-phenyl)-l//-benzoimidazole-5-carboxylic
acid amide 251c-G
2 5 1 c-G
!H NMR (300 MHz,
5 8.56-8.53 (m, 3 H), 8.25-8.22 ( m, 2 H), 8.10
C D 3 C O C D 3 )
(dd, 7 = 1 .6 , 8.6 Hz, 1 H), 7.70 ( d, 7 = 8.5 Hz, 1 H), 7.51 (d, 7 = 8.5 Hz, 2 H), 7.3 (d,
7 = 8.5 Hz, 2 H), 6.81 (s, 1 H), 5.91 (s, 2 H).
l-(4,-Methoxy-benzyl)-2-thiophen-2” -yI-l//-benzoimidazole-5-carboxylic acid
amide 251 d-D
MeO
h2n^jCX}~i!>
0
2 5 1 d-D
*H NMR (300 MHz, CD3 COCD 3 ) 5 8.46 (d, 7 = 1.3 Hz, 1 H), 8.05 (dd, 7 = 1.6, 8.5
Hz, 1 H), 7.87 (dd, 7 = 1.0, 5.2 Hz, 1 H), 7.69-7.66 (m, 2 H), 7.33 (dd, 7 = 3.7, 5.2
Hz, 1 H), 7.23 (d, 7 = 8.7 Hz, 2 H), 7.10-7.04 9 (m, 3 H), 6.75 (s, 1 H), 5.91 (d, 7 =
5.7 Hz, 2 H), 3.90 (s, 3 H).
245
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
l-Benzyl-2-(4’-nitro-phenyl)-l//-benzoimidazole-5-carboxylic acid amide 251aG
251 a-G
*H NMR (300 MHz, CD3 OD) 5 8.58-8.54 (m, 3 H), 8.14 (dd, J= 1.8, 6.9 Hz, 2 H),
8.09
(dd, / = 1.6,
8 .6
Hz, 1 H), 7.73 (d, J=
8 .6
Hz, 1 H), 7.52-7.42 (m, 3 H), 7.23-
7.21 (m, 2 H), 5.83 (s, 2 H).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
References and Notes
1.
Schreiber, S. L. Angew Chem. Int. Ed. 2004, 43, 46-58.
2.
Arya, P.; Joseph, R.; Chou, D. T. H. Chem. Biol. 2002, 9, 145-156.
3.
(a) Corey, E. J.; Cheng, X.-M. The Logical o f Chemical Synthesis; John Wiley
& Sons: New York, 1995. (b) Corey, E. J.; Angew. Chem. Int. Ed. Engl. 1991,
30, 455-458. (c) Corey, E. J.; Wipke, W. T. Science 1969,166, 178-179.
4.
Nicolaou, K. C.; Vourloumis, S.D.; Winssinger, N.; Baran, P. S. Angew. Chem.
Int. Ed. 2001, 39, 44-122.
5.
(a) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.
Nature 1994, 367, 630-634. (b) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.;
Guy, R. K.; ouladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1995, 117,
624-633. (c) Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.;
Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J.
Am. Chem. Soc. 1995, 117, 634-644. (d) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.;
Nantermet, P. G.; Claiborne, C. F.; Renaud, J.; Guy, R. K; Shibayama, K. J. Am.
Chem. Soc. 1995, 117, 645-652. (e) Nicolaou, K.C.; Ueno, H.; Liu, J.-J.;
Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K., Chadha, R. J. Am.
Chem. Soc. 1995,117, 653-659.
6
.
(a) Nakatsuka, M.; Ragan, J. A.; Sammakia, D. B.; Smith, D. B.; Uehling, D. E.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583-5601. (b) Williams, D. R.;
Benbow, J. W.; J. Org. Chem. 1988, 53, 4643-4644.
7.
8
.
Li, W. D. Z.; Wang, Y. Q. Org. Lett. 2003, 5, 2931-2934.
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2002,124, 2137-2139.
247
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
9.
(a) Obrecht, D.; Villalgordo, J. M. Solid-Supported Combinatorial and Parallel
Synthesis o f Small-Molecular-Weight Compound Libraries', Pergamon: Oxford,
UK, 1998. (b) Jung, G Combinatorial Chemistry: Synthesis, Analysis,
Screening', Wiley-VCH: Weiheim, Germany, 1999. (c) Bannwarth, W., Felder,
E. Combinatorial Chemistry: A Practical Approach', Wiley-VCH: Weiheim,
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B. J. Med. Chem. 2000, 43 , 2464-2472. (m) Robl, J. A.; Sulsky, R.; Sun, C.-Q.;
Simpkins, L. M.; Wang, T.; Dickson, J. K.; Chen, J. Y.; Magnin, D.R. ; Taunk,
P.; Slusarchyk, W. A.; Biller, S. A.; Lan, S.-J.; Connolly, F.; Kunselman, L.K.;
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94.
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Vourloumis, D.; Takahashi, M.; Simonsen, K. B.; Ayida, B. K.; Berluenga, S.;
W inters, G. C.; Hermann, T. Tetrahedron Lett. 2003, 44, 2807-2811. (b) Wang,
X.; Choe, Y.; Craik, C. S.; Ellman, J. A. Bioorg. Med. Chem. Lett. 2002, 12,
2201-2204. (c) Akamatsu, H.; Fukase, K.; Kusumuto, S. J. Comb. Chem. 2002,
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(e) Mazurov, A. Bioorg. Med. Chem. Lett. 2000, 10, 67-70. (f) Kilbum , J. P.; lau,
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J.; Jones, R. C. F. Tetrahedron Lett. 2000, 41, 5419-5421. (g) Wu, Z.; Rea, R;
Wichkham,
G. Tetrahedron Lett. 2000, 41, 9871-9874. (h) Tumelty, D.;
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6185-6188.
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4887-4890. (p) Krchnak, V.; Smith, J. M.; Vagner, J. Tetrahedron Lett. 2001, 42,
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Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146. (b) Hartwig, J. F.
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Tetrahedron Lett. 1996, 37, 6993-6996. (c) Brill, W. K.-D.; Riva-Toniolo, C.;
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99.
(a) Shi, L.; W ang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5,
3515-3517. (b) Xu, G.; W ang, Y.-G. Org. Lett. 2004, 6, 985-987.
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267
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List o f Publications
5.
Chapter 6
Dai, W.-M.; Sun, L.-P. “Remarkable linker effect on m icrowave-assisted solid
phase combinatorial synthesis. Traceless synthesis o f 2-substituted indole
library” m anuscript in preparation.
4.
Chapter 5
Dai, W.-M.; Sun, L.-P.; Guo, D.-S. “A strategy for integration o f
microwave-
assisted solid phase organic synthesis (MASPOS) into encoded split-pool
combinatorial synthesis (ESPCS). Synthesis o f a 50-benzimidazole library”
m anuscript in preparation.
3.
Chapter 4
Dai, W.-M.; Guo, D.-S.; Sun, L.-P.; Huang, X.-H. “M icrowave-assisted
solid-
phase organic synthesis (MASPOS) as a key step for an indole library
construction” Org. Lett. 2003, 5, 2919-2922.
2.
Chapter 3
Dai, W.-M.; Sun, L.-P.; Guo, D.-S. “Chemistry o f aminophenols. Part 2: A
general and efficient synthesis of indoles possessing a nitrogen substituent at
C4, C5, C6, and C7 positions” Tetrahedron Lett. 2002, 43, 7699-7702.
1.
Chapter 2
Dai, W.-M., Guo, D.-S, Sun, L.-P. “Chemistry o f aminophenols. Part 1:
Rem arkable additive effect on Sonogashira cross-coupling o f 2carboxamidoaryl triflates and application to novel synthesis o f indoles”
Tetrahedron Let. 2001, 42, 5275-5278.
268
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Appendix
1.
LC-M S data o f 96-member indole library..........................................................270
2.
LC-M S data o f 16-member indole library..........................................................318
3.
LC-M S data o f benzimidazole library.................................................................326
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