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Microwave-assisted solid-phase reactions of Dötz benzannulationof naphthoquinones and “click chemistry” of azide-acetylene cycloaddition-efficientformation of water disperse micelles

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MICROWAVE-ASSISTED SOLID-PHASE REACTIONS OF DÖTZ
BENZANNULATION OF NAPHTHOQUINONES AND “CLICK
CHEMISTRY” OF AZIDE-ACETYLENE CYCLOADDITION EFFICIENT FORMATION OF WATER DISPERSE MICELLES
ALEJANDRO BUGARIN CERVANTES
DEPARTMENT OF CHEMISTRY
APPROVED:
________________________
Luis E. Martinez, Ph.D. Chair
________________________
Juan C. Noveron, Ph.D.
________________________
Kristine M. Garza, Ph.D.
________________________
Pablo Arenaz, Ph.D.
Dean of the Graduate School
DEDICATORY
Teniendo siempre en la memoria la imagen de mí
mejor amiga y estrella de la suerte, Marilu Miramontes B.,
deseo dedicar esta obra a:
Noé Alfredo Bugarin
Clementina Cervantes
mis padres
por un sin fin de razones
Alfredo Bugarin
Marlen bugarin
Noé Bugarin
mis hermanos
motivo de orgullo y amor
Nancy Ortiz
a mi gran amor
por todo lo que he pasado con ella...
Alejandro Bugarin Cervantes
MICROWAVE-ASSISTED SOLID-PHASE REACTIONS OF DÖTZ
BENZANNULATION OF NAPHTHOQUINONES AND “CLICK
CHEMISTRY” OF AZIDE-ACETYLENE CYCLOADDITION EFFICIENT FORMATION OF WATER DISPERSE MICELLES
ALEJANDRO BUGARIN CERVANTES
THESIS
Presented to the Faculty of the Graduate School of
The University of Texas at El Paso
in Partial Fulfillment
of the requirements
for the Degree of
MASTER OF SCIENCE
THE UNIVERSITY OF TEXAS AT EL PASO
JULY 2006
UMI Number: 1436395
UMI Microform 1436395
Copyright 2006 by ProQuest Information and Learning Company.
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
ProQuest Information and Learning Company
300 North Zeeb Road
P.O. Box 1346
Ann Arbor, MI 48106-1346
ACKNOWLEDGEMENTS
I wish to express my sincere gratitude and thanks to my research director, Dr. Luis E. Martinez,
for his encouragement, advice, and patience during the course of this work. I’m also extremely indebted
to Dr. Juan C. Noveron, for his advice, help and encouragement during this work. I would like to
expresses a special thanks to Dr. Shan Muthian for his advice, counseling, and technical assistance. I am
also grateful to Israel Garcia and Sandeep Kongara for their kind help during the preparation of this
thesis and Martinez group as well. I wish to express me thanks to my family, for their moral help during
my studies. The financial support provided by the Welch foundation and Biodefense is greatly
appreciated.
Special thanks to my committee members: Dr. Luis E. Martinez, Dr. Juan C. Noveron, and Dr.
Kristine M. Garza for their suggestions on my project of thesis.
My appreciation also goes out to the Department of Chemistry of the UTEP for giving me the
opportunity to develop and prove myself. Thank you for believing in me. Special thanks go to Mrs.
Lucema Armenta for all her assistance.
I wish to thanks my friends for uncounted number of suggestions and for the trust and friendship
given to me without expecting anything in return.
Finally, I would like to thank my Schnecke for being with me all the time I needed her, and for
her unselfish help and support during the process through getting this degree.
Date submitted to the committee: August 15, 2006
iv
ABSTRACT
Solid-phase organic chemistry offers an efficient route to construct large libraries of lead
compounds for combinatorial chemistry. 2,3-disubstituted naphthoquinone derivatives exhibit a broad
spectrum of biological activities that may be attenuated by the incorporation of: protein recognition
elements, amphiphilic properties and active groups for future incorporation of bioactive compounds. The
Dötz Benzannulation is a powerful method to construct naphthoquinones that could easily incorporate of
the properties mentioned above.
The required disubstituted alkynes precursors have been prepared by the palladium-catalyzed
Sonogashira coupling of mono or di-protected propargylamine with iodo alkyl benzoates in good to
excellent yields. The microwave-assisted Dötz benzannulation of the resultant alkynes with solid
supported phenyl Fischer chromium carbene complex and subsequent cleavage of the beads afforded (3aminomethyl-2-benzoyl alkyl ester)-1,4-naphthoquinones in moderate to good yields. The presence of
an amino group and a carboxyl group in the 1,4-naphthoquinone moiety could be an ideal candidate for
the incorporation of polypeptides.
Click Chemistry ([3+2] cycloaddition) of azides and acetylenes has been extremely used in
organic chemistry due to its practical and reliability. Click chemistry reliability gives high yields with
few byproducts and its applications are increasingly found in drug discovery, ranging from lead finding
through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA
research, using bioconjugation reactions. Click Chemistry was the tool to build up a variety of novel
compounds having 1,4-naphthoquinone as core.
The development of liposome technology offers the potential for many beneficial medical
products for the ability of act as carriers for delivering active ingredients directly to the cell level due
their amphiphilic properties. The formation and collapse of micelles is controlled by the existing balance
between polar headgroup and hydrophobic tail. Alteration of the headgroup’s charge state can be
v
controlled, for example by redox switching, which in turn permits regulation of aggregate formation 1 .
The Dötz benzannulation reaction can be used for incorporate amphiphilic properties to 1,4naphthoquinone by adding a long chain to the core.
A. BUGARIN.
August, 2006
vi
TABLE OF CONTENTS
ABSTRACT .............................................................................................................................................v
TABLE OF CONTENTS ...................................................................................................................... vii
LIST OF TABLES...................................................................................................................................xi
LIST OF FIGURES ............................................................................................................................... xii
LIST OF SCHEMES ............................................................................................................................ xiii
CHAPTER 1 INTRODUCTION..............................................................................................................1
1.1 Combinatory Chemistry......................................................................................................................1
1.2 Solid-Phase Organic Synthesis (SPOS)..............................................................................................2
1.2.1 Diversity Oriented Synthesis (DOS) ...............................................................................................5
1.3 Microwave-Assisted Synthesis...........................................................................................................7
1.4 Naphthoquinones ................................................................................................................................8
1.5 Fischer Carbene Complex (FCC) and Dötz Benzannulation..............................................................9
1.6 Sonogashira Coupling.......................................................................................................................10
1.7 Incorporation of all Topics Touched Above (Strategy of Project) ...................................................12
1.8 Click Chemistry ................................................................................................................................13
CHAPTER 2 RESULTS AND DISCUSSIONS ....................................................................................15
2.1 Synthesis of Phenyl Fischer Carbene Complex [1] ..........................................................................15
2.2 Synthesis of Tert-Butyl Ester NH-Propargylcarbamate [4a] and Bis-tert-Butyl Ester NPropargylcarbamate [4b]. .................................................................................................................18
2.3 Synthesis of Alkynes [6]...................................................................................................................20
2.4 Synthesis of 2,3-Disubstituted-1,4-Naphthoquinone [8a-h].............................................................23
vii
2.5 Optimization of the Dötz Benzannulation with Diynes and Phenyl Fischer Carbene Complexes in
Solid-Phase Organic Synthesis .........................................................................................................26
2.6 Dötz Benzannulation with Different Diynes and Phenyl FCC.........................................................29
2.7 CLICK CHEMISTRY ......................................................................................................................30
2.7.1 For Phenyl Fischer Carbene Complex...........................................................................................31
2.7.2 For Phenyl Fischer Carbene Complex but In Situ Formation of Catalyst.....................................33
2.7.3 In Situ Click Chemistry Using Halides .........................................................................................34
2.7.4 Click Chemistry Using Benzyl Azide, and CuI.............................................................................36
2.7.5 Click Chemistry Using Halides and CuI .......................................................................................36
2.8 Synthesis of 2-Methoxyphenyl Fischer Carbene Complex ..............................................................37
2.9 Optimization of the Dötz Benzannulation with different Diynes and 2-Methoxyphenyl Fischer
Carbene Complexes in Solid-Phase Organic Synthesis....................................................................39
2.10 Dötz Benzannulation of Diynes [6a-i] and 2-Methoxyphenyl FCC [B].........................................41
2.11 CLICK CHEMISTRY ....................................................................................................................43
2.11.1 For 2-Methoxyphenyl Fischer Carbene Complex .......................................................................43
2.11.2 In Situ Click Chemistry Using Halides .......................................................................................44
2.11.3 Click Chemistry Using Halides and CuI .....................................................................................45
2.12 Synthesis of Furan Fischer Carbene Complex................................................................................45
2.13 Optimization of the Dötz Benzannulation with Different Diynes and Furan Fischer Carbene
Complexes in Solid-Phase Organic Synthesis..................................................................................47
2.14 CLICK CHEMISTRY ....................................................................................................................48
viii
2.14.1 For Furan Fischer Carbene Complex...........................................................................................48
2.14.2 For Furan Fischer Carbene Complex but In Situ Formation of Catalyst on Different Solvents .49
CHAPTER 3 CONCLUSIONS ..............................................................................................................51
CHAPTER 4 EXPERIMENTAL ...........................................................................................................53
4.1 Materials ...........................................................................................................................................53
4.2 Instrumental ......................................................................................................................................55
4.3 SYNTHESES....................................................................................................................................56
4.3.1 Synthesis of different Fischer Carbenes complexes ......................................................................56
4.3.1.1 Synthesis of Phenyl Fischer Carbene Complex..........................................................................56
4.3.1.2 Synthesis of 2-Methoxyphenyl Fischer Carbene Complex ........................................................57
4.3.1.3 Synthesis of Furan Fischer Carbene Complex............................................................................59
4.3.2 Synthesis of 2,3-Disubstitured-1,4-Naphthoquinones Incorporating Amino and Carboxyl
Groups...............................................................................................................................................60
4.3.2.1 Synthesis of Tert-Butyl Ester NH-Propargylcarbamate [1] and Bis-tert-Butyl Ester NPropargylcarbamate [2] .......................................................................................................................60
4.3.2.2 Synthesis of Different Alkynes [3a-h] by Sonogashira Coupling ..............................................61
4.3.2.3 Synthesis of 2,3-Disubstitured-1,4-Naphthoquinones[4a-h] ......................................................63
4.3.3 Optimization of Dötz Benzannulation with Diynes and Different Fischer Carbene Complexes in
Solid-Phase Organic Synthesis .........................................................................................................64
4.3.3.1 Dötz Benzannulation with Phenyl Fischer Carbene Complex ...................................................64
4.3.3.2 Dötz Benzannulation with 2-Methoxyphenyl Fischer Carbene Complex..................................64
4.3.3.3 Dötz Benzannulation of Diynes [6a-i]........................................................................................65
4.3.4 CLICK CHEMISTRY ...................................................................................................................67
4.3.4.1 Click Chemistry in solid Phase Organic Synthesis.....................................................................67
ix
4.3.4.2 Click chemistry but In Situ Formation of Catalyst.....................................................................69
4.3.4.3 Click chemistry but In Situ Formation of Catalyst and Polar Solvents......................................70
4.3.4.4 In Situ Click chemistry Using different Halides and NaN3 to form different Azides and In Situ
Formation of Catalyst and Polar Solvents ...........................................................................................71
4.3.4.5 Click chemistry Using different Halides, NaN3, and CuI...........................................................72
4.3.4.6 Cleavage of the Click Chemistry Product ..................................................................................73
REFERENCES .......................................................................................................................................74
CURRICULUM VITAE.........................................................................................................................80
ANEXOS : Solid-phase Organic Synthesis of 2-tridecanyl 1,4-naphthoquinone and 2-tridecanyl 1,4naphtadiol that form Redox-Active Micelles .........................................................................................82
x
LIST OF TABLES
Table 1 Conditions for Synthesis of Protected Propargylamine................................................................18
Table 2 Conditions for Sonogashira Coupling Reactions..........................................................................20
Table 3 Dötz Benzannulation ....................................................................................................................22
Table 4 Dötz Benzannulation Optimization for Phenyl Fischer Carbene Complex..................................26
Table 5 Conditions Dötz Benzannulation with Phenyl FCC .....................................................................28
Table 6 Conditions for Click Chemistry of Compound [D] ......................................................................32
Table 7 Conditions for In Situ Click Chemistry of Compound [D] ..........................................................33
Table 8 Conditions for In Situ Click Chemistry of Compound [D] Using Halides ..................................35
Table 9 Conditions for Click Chemistry of Compound [D] Using Halides and CuI ................................36
Table 10 Conditions for Click Chemistry of Compound [D] Using Halides and CuI ..............................37
Table 11 Dötz Benzannulation optimization for 2-Methoxyphenyl Fischer Carbene Complex ...............40
Table 12 Conditions Dötz Benzannulation with 2-Methoxyphenyl FCC .................................................42
Table 13 Conditions for Click Chemistry of Compound [E] ....................................................................43
Table 14 Conditions for In Situ Click Chemistry of Compound [E] Using Halides.................................44
Table 15 Conditions for Click Chemistry of Compound [E] Using Halides and CuI...............................45
Table 16 Conditions Dötz Benzannulation with Furan FCC.....................................................................47
Table 17 Conditions for Click Chemistry of Compound [F].....................................................................49
Table 18 Conditions for In Situ Click Chemistry of Compound [F].........................................................50
xi
LIST OF FIGURES
Figure 1 Approach for planning synthesis pathways that generate skeletal diversity based on reagent. ....2
Figure 2. General structure of a polymeric support.....................................................................................2
Figure 3. Solid-phase chemistry. After reaction the product is liberated and filtered off ...........................3
Figure 4. The split-and-combine protocol. ..................................................................................................4
Figure 5 An example of retrosynthetic analysis used to plan a target-oriented synthesis (TOS)................5
Figure 6 An example of a forward analysis used to plan a diversity-oriented synthesis (DOS).................6
Figure 7 Different Natural and Biological Compounds with Naphthoquinone moiety...............................9
Figure 8 GC of Phenyl Fischer Carbene Complex ....................................................................................17
Figure 9 Structures of Products of the Optimization of Dötz Benzannulation in Phenyl FCC ................27
Figure 10 Structure of Products after Dötz Benzannulation with Phenyl FCC. ........................................29
Figure 11 GC of 2-Methoxyphenyl Fischer Carbene Complex.................................................................39
Figure 12 Structure of Products of the optimization of Dötz Benzannulation in 2-Methoxyphenyl FCC
[15].......................................................................................................................................................41
Figure 13 Structure of Products after Dötz Benzannulation with 2-Methoxyphenyl FCC. ......................42
Figure 14 GC of Furan Fischer Carbene Complex....................................................................................46
Figure 15 Structure of Products after Dötz Benzannulation with Furan FCC...........................................48
xii
LIST OF SCHEMES
Scheme 1 General mechanism of Fischer Carbene complexes in SPOS...................................................10
Scheme 2 General mechanism of Sonogashira Coupling Reaction...........................................................11
Scheme 3 General Mechanism of Click Chemistry Reaction ([3+2] Cycloaddition) ...............................13
Scheme 4 Synthesis of Phenyl Fischer Carbene Complex ........................................................................16
Scheme 5 Protection of Propargylamine ...................................................................................................18
Scheme 6 Sonogashira Coupling Reactions ..............................................................................................20
Scheme 7 Dötz Benzannulation of Phenyl Fischer Carbene Complex 1 and alkynes [6a-h]....................22
Scheme 8 Cleavage of Dötz Benzannulation with Diynes for Phenyl FCC..............................................25
Scheme 9 Dötz Benzannulation and Cleavage of Diynes [9a-h] and Phenyl FCC [1].............................28
Scheme 10 Click Chemistry of Compounds [10a-f]..................................................................................31
Scheme 11 In Situ Click Chemistry of Compound [D].............................................................................33
Scheme 12 In Situ Click Chemistry of Compound [10a] Using Benzyl Bromide and Sodium Azide .....35
Scheme 13 Click Chemistry of Compounds [D] Using Benzyl Bromide .................................................36
Scheme 14 Click Chemistry of Compounds [D] Using Halides ...............................................................36
Scheme 15 Synthesis of 2-Methoxyphenyl Fischer Carbene Complex.....................................................38
Scheme 16 Dötz Benzannulation optimization for 2-Methoxyphenyl Fischer Carbene Complex ...........39
Scheme 17 Dötz Benzannulation and Cleavage of Diynes [6a-h] and FCC [B] .......................................41
Scheme 18 Click Chemistry of Compound [E] .........................................................................................43
Scheme 19 In Situ Click Chemistry of Compound [E] Using Halides......................................................44
Scheme 20 Click Chemistry of Compounds [E] Using Benzyl Bromide..................................................45
xiii
Scheme 21 Synthesis of Furan Fischer Carbene Complex........................................................................45
Scheme 22 Dötz Benzannulation and Cleavage of Diynes [6a-h] and FCC [C] .......................................47
Scheme 23 Click Chemistry of Compound [F] .........................................................................................48
Scheme 24 In Situ Click Chemistry of Compound [F]..............................................................................49
xiv
CHAPTER 1 INTRODUCTION
1.1 Combinatory Chemistry
One of the underlying principles in organic chemistry is the ability to form new carboncontaining substances via a process known as organic synthesis 2 . Such synthesis has allowed
researchers to create synthetic products in bulk quantities that mimic natural products 3 that are only
available in limited amounts. Initially organic synthesis and related fields, such as medicinal
chemistry 4 , focused on creating only the molecule that was structurally identical to the natural product
via a rationally designed synthetic method 5 . However in the last decade a new trend has emerged which
attempts to create a collection of molecules that may not be structurally identical to the natural product
but may have at least equal effectiveness as the natural product. Thus current organic synthesis methods
create a library of compounds instead of only a single product via a more systematic explorations
approach 6 by the use of solid-state synthesis and testing. This technique of concurrently synthesizing a
large number of similar products using a few synthetic paths is known as combinatorial chemistry or
combinatorial synthesis 7 . The distinguishing feature of combinatory chemistry is that it produces a
unique mixture of potentially active compounds and, thus, works as a source of potent new medicines 8 .
One of the most general approaches to fabricate such library is center on structural diversity
(Figure 1). This is to synthesize as many diverse structures as possible by methods such as solid phase
organic synthesis (SPOS) which has techniques like, split-pool 9 , parallel 10 and diversity oriented
synthesis (DOS) 11 . Combinatorial Chemistry core value lies in its ability to accelerate the drug
discovery process and allow for high-throughput screening.
1
reagent X
reagent Y
reagent Z
Figure 1 Approach for planning synthesis pathways that generate skeletal diversity based on reagent.
Combinatorial chemistry can be divided into two categories: solution- or solid-phase synthesis.
Currently solution-phase synthesis is utilized more often than solid-phase, but the latter has distinct
advantages over the former. For example, in solid-phase synthesis the reaction can be driven to
completion through the use of excess reagent, which can then be easily removed at the end of the
reaction via filtration and washing. Even more importantly, solid-phase synthesis is more advantageous
than solution-phase because it allows for the use of the “split-and-pool” synthesis strategy.
1.2 Solid-Phase Organic Synthesis (SPOS)
Spacer
Linker
Polymer
Substrate
Figure 2. General structure of a polymeric support
Solid-phase chemistry was first utilized by Merrifield 12 in peptide and oligonucleotide synthesis.
This synthetic method involves linking the molecule being constructed to a polymeric carrier (bead)
(Figure 2). This process immobilizes the molecule being synthesized, thus allowing for simple
separation of both the intermediates and final product from soluble byproducts and reagents via
filtration. However, this process is only effective if both the bead and linker remain unreactive
throughout all steps of the synthetic process. In additional, there must be some way to cleave the
linkage between the final product and the linker under relatively mild conditions (Figure 3). This often
requires that a specific functional group such as, an amine, phenol, or an acid, are a necessary element of
2
every product. Because this is not always desirable, “traceless” linkers and intramolecular displacement
cleavage strategies are being developed.
A
Inmobilization
A
Transformation
AB
Cleavage
AB
Figure 3. Solid-phase chemistry. After reaction the product is liberated and filtered off
One of the main advantages of solid-phase synthesis is the ability to push the reaction
equilibrium to the right by adding excess reagent. This strategy is not feasible in solution-phase
chemistry because it negatively affects product purity, but in solid-phase synthesis, any additional
reagent leftover at the end of a reaction can be removed via filtration. This advantage, however, is offset
by a variety of negative features. The primary drawback is the difficulty that researchers face when
attempting to find a suitable linker for the substrate. In addition, the type of polymeric bead chosen for
the reaction limits the number of potential solvents. While certain polymers are insoluble in a wide
variety of solvents, others may dissolve or experience swelling or shrinking as a result of the solvent
chosen. While using tentagel resins can alleviate solvent problem, this choice of polymer limits the
temperature range that can be used to run the reaction. Finally solid-phase organic synthesis is also not
viable with chemistry that uses heterogeneous catalysts and there is limited literature that converts
solution-phase synthetic methods to solid-phase techniques.
Because of the ease with which solid-phase synthesized products can be isolated from starting
material, the chemical procedures can be automated. Automatic dispensing systems allow for multiple
syntheses to be run concurrently followed by simple purification procedures. However, if the number of
compounds being produced exceeds 1000, then this automated method is not sufficient. The “split-andpool” method becomes more useful (Figure 4).
3
inmobilization
A
B
A
1. combine
2. split
3. reaction D, E, F
B
C
three reactions
C
three reactions
AD
BD
CD
AE
BE
CE
AF
BF
CF
1. combine in one pot.
2. split in three separate vessels
ADG
BDG
AEG
AD
BD
CD
BEG
CDG reaction
CEG with G
AE
BE
CE
AFG
BFG
CFG
AF
BF
CF
ADH
BDH
CDH reaction
AD
BD
CD
AE
BE
CE
AF
BF
CF
AD
BD
CD
AE
BE
CE
AF
BF
CF
AEH
BEH
CEH
AFH
BFH
CFH
ADI
BDI
CDI
AEI
BEI
CEI
AFI
BFI
CFI
with H
reaction
with I
three reactions
9 reactions, 27 products
Figure 4. The split-and-combine protocol.
Furka and coworkers first introduced this “split-and-pool” synthesis strategy at two European
symposia in 1988. The group’s strategy was later published in 1991. This method involves, reacting a
polymer bead with three different substrates separately. These three reactions are purified separately,
recombined, and then split into three separate sections, which are reacted with three new substrates. As
this process is repeated the number of compounds produced increases by a factor of three. Also, as each
step progresses a small amount of a chemical tag specific for that step is reacted with the polymeric
bead. This allows researchers to track the history of the bead and makes identifying the final product
easier without significantly diminishing the capability of the bead.
Much of the cost of solid-phase synthesis resembles that of solution-phase synthesis; both
methods require instrumentation for identifying the product and determining product purity. However,
the budgeting for solid-phase synthesis must also take into account a higher than usual spending on
reagents, which are always used in excess. Also, the material cost for solid-phase synthesis is increased
by the cost of linkers and resins.
4
1.2.1 Diversity Oriented Synthesis (DOS)
Efforts to produce libraries of compounds via solid-phase synthetic strategies fall into two
categories: target-oriented synthesis (TOS) or diversity-oriented synthesis (DOS). Target-oriented
synthesis involves first identifying the structure of small-molecule natural compounds that have useful
biological aspects and then targeting this structure for chemical synthesis. 13 It is useful for drug
discovery when the goal of a synthesis is to create a library of compounds with common structural
features that facilitate binding to a target protein. 14 This method of synthesis became especially useful
in the mid-1960’s with the development of retrosynthetic analysis (Figure 5), in which complex
molecules are broken down into smaller, less intricate components.1
Target
Starting material
H
OH
O
H
complex
O
simple
Figure 5 An example of retrosynthetic analysis used to plan a target-oriented synthesis (TOS)
Unlike TOS, diversity-oriented synthesis does not aim at synthesizing small molecules for a
particular target protein. Instead the goal of DOS is to create a structurally complex and diverse
collection of compounds. DOS is used with both the protein target and small molecule regulators need
to be identified simultaneously. Diversity is essential to such a collection of small molecules when these
compounds are used in phenotypic screens in which no one particular target is known; rather any
macromolecule of a cell or an organism could be the eventual target. In such a situation, a collection of
diverse compounds is more likely to be successful in such screenings. Creating complexity in a
collection of molecules is critical because small molecule natural products that disrupt protein-protein
interactions are often structurally complex. This complexity is believed to be a necessity of synthetic
molecules if they are expected to have the same biological activity.2
5
Starting Material
O
CO2H
HO
O
HO
N
H
attach to
solid support
simple
O
Complexity, Diversity
O H diversity element
N
O H
N
split-pool O
synthesis
H
O
O complex
Figure 6 An example of a forward analysis used to plan a diversity-oriented synthesis (DOS)
Creating complexity via diversity-oriented synthetic strategies involves the use certain organic
reactions known for the complexity they generate. Such synthetic pathways should allow for the
formation of complex structures in approximately three to five steps. For this reason, pairs of synthetic
pathways in which the product of one synthesis is the substrate for the second are particularly important
for DOS. One such example is the Ugi four-component reaction, which converts four simple
components into a tricyclic ring structure in tandem.
DOS generates diversity in a collection of compounds via the variation of three characteristics:
appendages, stereochemistry, and skeletons. The simplest of these strategies is appendage diversity,
which involves using coupling reactions to apply various ligands to a common molecular skeleton. This
one synthesis-one skeleton method is limited, however, because compounds with identical molecular
skeletons interact with macromolecules similarly in three-dimensional space. 15 Stereochemical diversity
is produced using stereospecific reactions that proceed with enantio- or diastereoselectivity. Through
this type of diversity the number of potential orientations a collection of compounds has to interaction
with macromolecules increases. Finally, creating skeletal diversity is possible through two pathways.
The first strategy involves using different reagents on a common substrate to create products with
different atomic skeletons. This strategy, however, has not been used to generate diversity combinatorial
chemistry. The second method of creating skeletal diversity, which has been used via combinatorial
syntheses, involves using common reactions conditions and varying the substrates used by adding
different appendages (Figure 6).
6
1.3 Microwave-Assisted Synthesis
Typically SPOS reactions must be run at elevated temperatures. Initially this elevated
temperature was induced via thermal energy. However in the eighties, the potential of microwaveassisted in organic synthesis for speeding chemical synthesis was first reported. Such microwaveassisted reaction has led to increased rate-enhancement as well as higher product yields. The first report
on the use of microwave heating in solid-phase synthesis was by Wang et al 16 who demonstrated rate
improvement in complicated coupling reactions observed in the Merrifield peptide synthesis,5 and the
same method was later used for combinatorial synthesis by Khmelnitsky and co-worker in 1998 to
produce libraries of functionalized pyridines via parallel synthesis. 17 These and other initial microwaveassisted syntheses used domestic microwave ovens, but today commercial ovens are available with
features such as built-in magnetic stirrers, fiber-optic probes that control temperature, IR sensors, and
software to control temperature and pressure via regulation of microwave power output 18 . The reason
for the increased rate of reaction time due to microwave irradiation is not completely understood.
Originally the effect was believed to be the result of “nonthermal microwave effects”. However, later
studies proposed that the rate enhancement of microwave-assisted syntheses resulted from “in core”
heating of the solvent.8
Microwave-assisted solid phase synthesis has received attention over the past decade and has
been shown to be more beneficial than traditional thermally-induced temperature changes. In a study by
Stadler and Kappe 19 microwave irradiation was used to attach carboxylic acids to chloromethylated
polystyrene resins. The study showed increased rates and higher loading than when the same reaction
was performed with the conventional thermal methods. Time for reaction was reduced from 12-48 h at
80°C to 5-15 minutes at 200°C with no degradation of the resin.
7
In 2002 Strohmeier and Kappe 20 performed the first SPOS using dedicated parallel microwave
reactors. In this study various β-ketoesters were acetoacetylated with PS Wang resin to product resinbound 1,3-dicarbonyl compounds. The conversions were achieved after 1-10 minutes at 170°C, an
improvement over the several hours needed to complete the reaction via thermal heating. However, in
this parallel synthetic method all vessels are exposed to the same amount of irradiation, thus making it
necessary for identical solvents to be used to insure identical temperatures. Therefore, automated
sequential synthesis, in which each vessel is irradiated separately, allows for better control of reaction
conditions and thus is more optimal.7
1.4 Naphthoquinones
The proliferation of naphthoquinones literature which has been so marked for several years has
continued. The discovery of new routes of unknown naphthoquinones sources together with new
structural and synthetic studies has been challenged in this project. This thesis is an attempt to bring
some of the naphthoquinone chemistry up to date.
Naphthoquinones are naturally occurring quinones that possess a variety of pharmacologic
actions, such as antibacterial, antifungal, and cytostatic effects 21 . Some quinones exert cytotoxic activity
against many cancer cells and tumors 22 . Moreover, these quinones may produce apoptosis or necrosis by
complex mechanisms, not yet completely clarified 23 , as well as, antiviral activities and oxidative
damage catalyzed reactions 24 .
8
O
O
1,4-Naphtoquinone
O
OH
O
OH
*
n
O
O
Nanomycin
OH
OH
CO2H
H
Vitamin K
O
O
O
OH
OHO
O
OH
OH
OMe O
OH
OMe O
O
O
Doxorubicin
H2N
OH
O
O
Epirubicin
H2N
OH
OH
Figure 7 Different Natural and Biological Compounds with Naphthoquinone Moiety
In order to discover a drug, many steps and factors have to be taken in count, some of them are:
identify the specific biological target, screen it with a large variety of compounds, figure out which core
are active and optimize the core by varying the functional groups to improve selectivity, oral
bioavailability, potency, and lower toxicity.
Natural products have always played, and continue to play, important roles in both drug
discovery and chemical biology. In fact, from 1989 to 1995, 60% of all approved drugs and new drug
application (NDA) candidates were derived from natural sources 25 . Yet, in spite of their importance to
both biology and medicine, it was only recently that solid-phase chemistry has been applied to the
synthesis of natural products and their analogs.
1.5 Fischer Carbene Complex (FCC) and Dötz Benzannulation
The actual development of applications in organic synthesis of the Fischer transition metal
carbene complex with the major contributions coming from the groups of Charles P. Casey and Karl
9
Heinz Dötz 26 has been applied in Solid-Phase Organic Synthesis (SPOS) to develop a huge variety of
novels compounds who seem to have a biological activity due the backbone (quinone 27 ) which has been
reported as a bioactive aromatic organic molecule, as well as, the new branches incorporated to the
backbone.
OH
Link
O
CAN
RL
RS
Cr (CO)5
2
R1
1
O
RL
R2
R2
R1
(CO)3Cr O
3
RS
Link
RL
R2
R1
RS
4 O
Scheme 1 General mechanism of Fischer Carbene complexes in SPOS
Fischer carbene complexes offer and the great diversity of the different types of reactions that
they undergo, one of them is the benzannulation of unsaturated complexes with alkynes or diynes 28 . The
general mechanism 29 of Fischer carbene complex is showed in Scheme 1 which involves the ligand
dissociation (CO) followed by [2+2] cycloaddition and subsequent ring opening, CO insertion, reductive
elimination 3, and finally cleavage of the bead 4 (Scheme 1). Fischer carbene complexes are the most
versatile class of organometallics reagents for applications in synthetic organic chemistry 30 . Although a
number of methods have been developed for their synthesis, the most widely used method is still that
originally reported by Fischer which involves the addition of an organo-lithium to chromium carbonyl
followed by alkylation on oxygen 31 . This preparation is simple and rapid and can be performed on
opened ended scale since most complexes are solids and can thus be purified by crystallization. The
complexes are stable to air and water and to dilute acids and bases. The work-up typically involves
washing the organic solution of the carbene complex in a separatory funnel with dilute aqueous base 32 .
1.6 Sonogashira Coupling
The Sonogashira reaction, which involves either a Pd (0) or a Pd II-catalyzed cross-coupling
reaction between an alkyne and a halogen-bearing sp2-carbon, has attracted great interest. Usually, the
10
palladium-catalyzed Sonogashira reaction is carried out in the presence of copper iodide and an amine as
the solvent. The proposal mechanism of reaction 33 is showed on Scheme 2. This reaction has proven to
be extremely useful for the synthesis of key intermediates in a large variety of naturally occurring
substances. However, this useful reaction has not been used in Dötz Benzannulation chemistry. The
application illustrates the synthesis of host molecules prepared by coupling mono or bis-tert-butyl ester
N-propargylcarbamate [1a-b] with alkyls-iodobenzoate [2a-d] as building blocks by the use of
[PdCl2(PPh3)2], CuI, PPh3 , and Et3N. For further Dötz benzannulation [3a-h] in a solid supported phenyl
Fischer carbene complex [A], to obtain 2,3-disubstituted-1,4- naphthoquinones [4a-h].
(PPh 3)2PdCl2
R
[NEt 2H2]Cl
(PPh 3)2Pd
R
2
R
R
(PPh 3)2Pd o
R 1X
R1
R
R1
(PPh 3)2Pd
EXAMPLE:
X
X= I
R= propargylamine
R1= alkyl benzoates
(PPh 3)2Pd
CuI/Et 2NH
R1
[NEt 2H2]X
R
Tetrahedron letters No. 50, pp 4467-4470, 1995
Scheme 2 General mechanism of Sonogashira Coupling Reaction
11
1.7 Incorporation of all Topics Touched Above (Strategy of Project)
In view of the important role of 1,4-naphthoquinone derivatives in pharmacology, has been
initiated a program towards the synthesis of 2,3-disubstituted-1,4- naphthoquinones with amino and
carboxyl groups which can be ideal point of attachment for the incorporation of functionalities like
amino acids. Is required a convenient route to prepare an exciting new class of 2,3-disubstituted-1,4naphthoquinones. The Sonogashira coupling seems to be an ideal tool to introduce such amino and
carboxyl substituents in the related naphthoquinone. Herein, we report the application of the
Sonogashira reaction, to the synthesis of new alkyne with excellent yields (see Table 2). The procedure
will be explained in the respective section.
During the past few years, research on the preparation and use of polymer-supported reagents
has received renewed interest. The properties of these reagents (facilitated work-up, reduced use of
conventional purification techniques, and ease of application to equipment) make them ideal for the
preparation of solid-phase libraries. Additionally, Ley and co-workers have demonstrated that polymersupported reagents and scavengers can also be successfully employed for the total synthesis of complex
products 34 .
The Fisher carbene complex synthesis in solid-phase organic chemistry (SPOS) support was the
tool for achieve the correspondent naphthoquinone using the Wang resin as the solid support and Dötz
benzannulation as the cyclization technique. Fischer carbene complexes are ligands that possess a metalcarbon double bond and are closely related to alkylidenes. Carbene ligands have a heteroatom
substituent unlike alkylidenes which usually have alkyl substituents on the alpha carbon atom. Fischer
carbenes are typically found on electron-rich, low oxidation state metal complexes (mid to late transition
metals) containing π-acceptor ligands. The presence of the heteroatom on the alpha carbon allows to
draw a resonance structure that is not possible for an unsubstituted (Schrock-type) alkylidene Therefore,
12
carbene ligands are usually thought of as neutral species, unlike dianionic Schrock alkylidenes (which
usually lack electrons for back-donation) 35 .
1.8 Click Chemistry
Click Chemistry (azide-acetylene ligation or [3+2] cycloaddition) is what every chemist dreams
of: reactions that always work, give high yields of product and few if any byproducts, proceed best in
water or other benign solvent and use readily available starting materials. Not surprisingly, such
reactions are rare, and most of the best examples involve carbon-heteroatom bond formation 36 .
R1
R1
CuLn-1
6
CuLn-2
N R2
N N 4
R1
N
N 2
R
N
5
D
N
E
3
CuLn-2
N R2
N
N
R2
[LnCu]
C
R1
N
N
A
R1
H
1
R1
B
N
N R2
CuLn-1
2
N
Scheme 3 General Mechanism of Click Chemistry Reaction ([3+2] Cycloaddition)
Click chemistry is a modular approach that uses only the most practical and reliable chemical
transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from
lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and
DNA research, using bioconjugation reactions. The copper-(I)-catalyzed 1,2,3-triazole formation from
azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of
dependability, complete specificity, and the bio-compatibility of the reactants. The scheme 3 shows the
mechanism of reaction of [3+2] cycloaddition 37 . The triazole products are more than just passive
13
linkers; they readily associate with biological targets, through hydrogen bonding and dipole
interactions 38 .
All these tools and science were used to accomplish the synthesis of naphthoquinones
derivatives, which gave a large variety of novels compounds having as a core, the 1,4-naphthoquinone.
Substitutions were presented on positions 2 and 3 followed by cycloadditions on the alkyne previous
synthesized via the Sonogashira coupling by Dötz benzannulation, all the steps were performed in solidphase organic synthesis, followed by oxidative cleavage. Base extraction to eliminate side products was
performed. In the presence of side product column chromatography was utilized.
In order to discover a drug, many steps and factors have to be taken in count, some of them are:
identify the specific biological target, screen it with a large variety of compounds, figure out which core
are active and optimize the core by varying the functional groups to improve selectivity, oral
bioavailability, potency, and lower toxicity.
Natural products have always played, and continue to play, important roles in both drug
discovery and chemical biology. In fact, from 1989 to 1995, 60% of all approved drugs and new drug
application (NDA) candidates were derived from natural sources 39 . Yet, in spite of their importance to
both biology and medicine, it was only recently that solid-phase chemistry has been applied to the
synthesis of natural products and their analogs.
14
CHAPTER 2
RESULTS AND DISCUSSIONS
For solid-phase organic synthesis (SPOS) transition metal-mediated reactions are extremely
interesting because their adaptability, usefulness, compatibility, and potential for synthesize biologically
active compounds. Prominent transition metal carbene chemistry is the Dötz benzannulation of Fischer
carbene complexes with alkynes to form substituted phenols. 40 Dötz benzannulation has been widely
applied to synthesize a diverse array of natural products 41 , but combinatorial library synthesis has not so
far been reported.
The mechanistic complexity of Dötz benzannulation reaction gives distribution of the product
between naphthol, indene, furan and cyclobutanone products by modifying conditions of the reaction
such the solvent, Fischer carbene, alkyne concentrations, and the nature of the alkyne to call some. 42
The formation of the side-products has to be taken in count, to eliminate them, the immobilization of the
Fischer carbene complex has been considered. It could potentially lead to single benzannulation product
due to the partial site isolation imposed by covalent attachment to the polymer support 43 . Herein, is
reported the first example of the solid-supported Dötz benzannulation reaction and subsequent oxidative
cleavage leading to biologically active 2,3-disubstituted-1,4-naphthoquinone derivatives in good to
moderate yields with different functional groups such; amino, carboxyl, and alkynes which can be useful
for further reactions in a combinatory chemistry like incorporation of amino acids or small peptides and
click chemistry.
2.1 Synthesis of Phenyl Fischer Carbene Complex [1]
Modifying the method originally developed by Connor 44 , the synthesis of polymer-supported
Fischer carbene complex [1] was obtained in four steps reaction (Scheme 4) from commercially
15
available chromium hexacarbonyl and phenyllithium by O-acylation of [tetramethylammonium][(2phenyl)oxidocarbene]pentacarbonylchromium with acetyl chloride followed by reaction with PL-Wang
resin (Polymer Laboratories, 1% crosslinked 1.7 mmol/g) to produce resin-bound Fischer carbene
complex [1] ( MW= 297g/mol)with 100% loading. Resin loading of the carbene complex can be easily
monitored qualitatively by colorimetric analysis; the beads turn a dark red color. The appearance of
characteristic Cr-CO stretches at 2060 and 1933 cm-1 in the IR spectrum of [1] correspond to CO
stretches found in analogous aryl carbene complexes 45 .
Li
_
+
OLi
Cr(CO)6 , THF
Cr(CO)5
0 0C, 2 h
0 0 C, 2 h
O
_
+
OMe 4N
Cr(CO) 5
Me4NBr, water,
PL-Wang
O
CH 3COCl,
Cr(CO) 5
DCM, 0 0C, 1 h
DCM, rt, 3 h
O
=
Cr(CO) 5
1
O
HO
(95 % loading)
IR: 2061, 1943 cm-1
Elemental: Cr content Calcd. 5.99%, Obs. 5.67%
Scheme 3 Synthesis of Phenyl Fischer Carbene Complex
16
25
20
Transmittance [%]
10
15
5
D:\alex data\Phenyl FCC april 30.1
3000
Phenyl FCC april 30
2500
2000
Wavenumber cm-1
solid KBr
Figure 8GC of Phenyl Fischer Carbene Complex
17
1450.36
1703.10
1933.20
2060.85
2922.29
0
3500
1500
1000
500
30/04/2005
2.2 Synthesis of Tert-Butyl Ester NH-Propargylcarbamate [4a] and Bis-tert-Butyl
Ester N-Propargylcarbamate [4b].
In order to have a Dötz benzannulation product, first is necessary have alkynes. The alkynes used
were synthesized as scheme 5 and scheme 6 in excellent yields. The idea was to have alkynes with
amino and carboxyl groups for future incorporation of peptides. The table 1 shows the conditions used
to protect the amino group, the protection of the amino group is necessary to avoid reaction in the
further steps. Protecting a group is a common task in chemistry, widely utilized, and simple. Herein, is
reported the protection of propargylamine [2] with BOC2O [3], and was found di-protection instead
mono-protection which was unexpected due the properties of amines.
O
NH2
O
2
O
O
DMAP / Et3N
DCM / RT
O
3
4a. R1 = COOC(CH3)3
R1
N
O
O
4a-b
4b. R1 = H
Scheme 4 Protection of Propargylamine
Table 1 Conditions for Synthesis of Protected Propargylaminea.
a
Entry
BOC2O ( equiv)
1
2
2
3
Time (h)
Total Yieldb
Yield 4a %
Yield 4b %
6
63%
34%
97%
1.5
6
53%
45%
98%
1.1
6
57%
41%
98%
99%
4
1.1
0.5
51%
48%
Reactions of propargylamine 2 (2.482 mmol, 1 equiv) with di-tert-butyl dicarbonate 3 were carried out at room temperature
for different times using DMAP (0.745 mmol, 0.333 equiv) as catalyst and Et3N (1 equiv) in 50 mL of CH2Cl2, followed by
column chromatography.
b
Isolated overall yields were calculated based on compounds 4a and 4b.
The synthesis of NH(BOC) mono-protected amine [4a] and N(BOC)2 diprotected amine [4b]
reagents were achieved and monitored by TLC each 30 minutes, given 6 h as the optimum time. Two
18
spots were found in the TLC plaque, one spot correspond to the product with a Rf = 0.4 for [4a] and the
other correspond to [4b] with a Rf = 0.25, The solvent used for TLC was hexanes/ethyl acetate (9:1).
Extraction was performed with 10 mL of the (9:1) solution for three times each. Subsequently, column
purification was performed, using 60 g of silica gel in 3 cm diameter column. The amount of solvent
was 700 mL, which was collected in two fractions because of TLC Rf. These collection were evaporated
under vacuum pressure to obtain the related products; NH(BOC) [4a] in the first collection and
N(BOC)2 [4b] in the second collection. To collaborate it, different techniques were done, as: 1H NMR,
13
C NMR, IR, and HPLC. These spectrums will be showed in the analysis section. The purpose of this
technique was to protect the alkyne for future reaction (Sonogashira Coupling), which was achieved.
However, as it was suspected that this particular method was associated with the generation of
N(BOC)2, as well as, NH(BOC). Table 1 shows lower yields due to formation of the N(BOC)2
diprotected amine, the remaining yield to get approximately 100% is due to NH(BOC).
19
2.3 Synthesis of Alkynes [6]
After the protection of propargylamine [4a-b], Sonogashira coupling reaction was performed
with different alkyls iodobenzoates [5a-d] to obtain alkynes with amino and carboxyl groups attached to
them [6]. Sonogashira coupling is a useful reaction for the synthesis of alkynes. Herein, is reported a
synthesis of novels alkynes in the presence of catalytic amount of bis(triphenylphosphine)palladium
dichloride- cuprous iodide in diethylamine under moderate conditions, the reaction gives satisfactory
results for the direct synthesis of alkynes.
I
R1
R2
O
N
CuI / (Ph3P)2PdCl2
O
Et2NH / N2 / RT 6 h
O
O
4a,b
R1 = COOC(CH3)3
R1 = H
O
C
O
R2
O
4a:
4b:
O
R1
N
5a-d
6
5a-c: R2 = Et, I = ρ, μ, ο
5d: R2 = Me, I = ο
Scheme 5 Sonogashira Coupling Reactions
Table 2 Conditions for Sonogashira Coupling Reactionsa.
Entry
Protected
propargylamine
Iodobenzoates
Product
Yieldb %
1
4a
5a
6aa
98
2
4a
5b
6ab
93
3
4a
5c
6ac
95
4
4a
5d
6ad
93
5
4b
5a
6ba
97
6
4b
5b
6bb
95
7
4b
5c
6bc
98
8
4b
5d
6bd
96
20
a
Reactions of protected propargylamine 4a-b (10 mmol, 1 equiv) with iodobenzoates 5a-d(11 mmol, 1.1 equiv) were carried
out at room temperature for 6 h using CuI (0.05 mmol) and (Ph3P)2PdCl2 (0.1 mmol) as catalyst in Et2NH in 60 mL, followed
by column chromatography.
b
Isolated overall yields were calculated based on purity by HPLC.
The reaction was monitored by TLC each 1 h, for 6 h. was found that the TLC plaque shows
three spots with Rf = 0.6, 0.4, and 0.2 respectively. After the 6 h stirring, the solvent was removed under
vacuum pressure, followed by an addition of water to extract the product with DCM (10 mL, three
times), to assure a complete elimination of any present aqueous compound. Subsequently, a silica
column was performed. The solvents used were hexanes/ ethyl acetate (8:2) for the column. In this case,
25 g of silica gel were used, in 3 cm diameter column, and 500 mL of the solvents mixture. The first
collection showed a green color, the second an orange color, and the last one a light red color. By using
1
H NMR was demonstrated that the second collection for each one of the reactions (entries 1-8),
contains the expected products [6].
21
2.4 Synthesis Of 2,3-Disubstituted-1,4-Naphthoquinone [8a-h]
For now the reagents for Dötz benzannulation have been synthesized. For Dötz benzannulation
(Scheme 7) the phenyl Fischer carbene complex [1] was reacted under microwave irradiation with
alkynes [6a-h] and Bu2O as a solvent, followed by the oxidative cleavage of the resulting resin-bound
phenol [7a-h] using cerium (IV) ammonium nitrate (CAN) provides a useful model system for reaction
of the solid-supported Dötz benzannulation reaction. The conditions of Dötz benzannulation in solid –
phase organic synthesis are showed on table 3.
R1
N
O
(CO)5Cr
O
Dötz Benzan. / DCM
+
R
O
6a-h
(OC)3Cr
OH
R1
N
O
R2
O
O
8a-h
6a. 4-(3-bis-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid ethyl ester; R1 = COOC(CH3)3, R2 = Et
6b. 3-(3-bis-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid ethyl ester; R1 = COOC(CH3)3, R2 = Et
6c. 2-(3-bis-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid ethyl ester; R1 = COOC(CH3)3, R2 = Et
6d. 2-(3-bis-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid methyl ester; R1 = COOC(CH3)3, R2 = Me
6e. 4-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid ethyl ester; R1 = H, R2 = Et
6f. 3-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid ethyl ester; R1 = H, R2 = Et
6g. 2-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid ethyl ester; R1 = H, R2 = Et
6h. 2-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid methyl ester; R1 = H, R2 = Me
Scheme 6 Dötz Benzannulation of Phenyl Fischer Carbene Complex 1 and alkynes [6a-h]
22
O
CAN
H2O / DCM
R2 Shaking 12 h
O
2
7a-h
O
O
O
MW 90 C / 20 min
O
1
R1
N
O
Link
O
Link
O
O
Table 3 Results of the Microwave-assisted Solid-Phase Dötz Benzannulation of Resin-Bound Phenyl Fischer Carbene
Complex 1 with alkynes 6a-h, Followed by the Oxidative Cleavage Using CANa
a
Entry
Alkyne
Product
% Yieldb
1
6a
8a
46
2
6b
8b
36
3
6c
8c
63
4
6d
8d
56
5
6e
8e
46
6
6f
8f
41
7
6g
8g
61
8
6h
8h
44
Reactions of 1 (0.115 mmol) with different alkynes 6a-h (0.575 mmol) were carried out in the microwave at the specified
temperature for the specified time using 2.00 mL of Bu2O, followed by the oxidative cleavage of the resin using CAN (0.575
mmol).
b
Isolated overall yields were calculated based on the loading of PL- Wang (1.7 mmol/g) by the supplier.
Phenyl Fischer Carbene Complex [1] was taken from previous experiments, 100 mg of beads and
0.25 mL of alkyne [6a-h] from the Sonogashira coupling (Table 2) were taken in microwave vial under
nitrogen atmosphere; 2 mL of Bu2O were added. This mixture was set up in the microwave apparatus at
90 ºC for 20 minutes (Dötz Benzannulation). Then the beads were cleaned with dichloromethane (DCM)
in a filtration process. The cleavage was achieved by adding CAN (0.575 mmol, 0.932 g), 2 mL of
water, and 5 mL of DCM as solvent, the mixture was set up in shaking for 6 h. Consequently, the
solution was filtered and extracted with DCM (5 mL each extraction, five times). The solvent was
removed under reduced pressure. TLCs were taken to check the spots and calculated the possible
product spot, as well as, its Rf. Followed by Pre TLC, to purify the expected products [8a-h] (Table 3).
23
The solvent used was hexanes/ethyl acetate (8:2). The size of the PRE TLC plate was 10 cm * 10 cm *2
mm. This technique showed five spots that were characterized, taken, triturated, dissolved with DCM,
and concentrated under reduced pressure. Was found that the expected product didn’t run in the PRE
TLC because the 1H NMR shows it in the line where the mixture was added. However, it is suspected
that is necessary a new purification with a different mixture of solvents, although it seem that is only the
product and the CAN.
The NMR spectra shows the expected products but there are some impurities on the products that
are prove by some extra peaks that appear on the spectra due the beads decomposition 46 .
To further explore the synthetic scope of the reaction, the reaction was extended to conjugated
diynes. In contrast to the solution phase Dötz benzannulation with conjugated diynes, the reaction of
diynes with [1] under our standard conditions cleanly afforded the mono benzannulation without any
intermolecular double benzannulation or cyclobutenone product formed.
24
2.5 Optimization of the Dötz Benzannulation with Diynes and Phenyl Fischer
Carbene Complexes in Solid-Phase Organic Synthesis
The Dötz benzannulation of 1 with three different diynes (1,4-Diphenyl butadiyne, 10,12Pentacosadiynoic acid, and 2,4-Hexadiyne-1,6-diol) 9a-c was performed under different conditions,
followed by the oxidative cleavage of the resulting resin-bound naphthols 10a-c (Scheme 8). Table 4
illustrates that various diynes that produce 2,3-disubstitured-1,4-naphthoquinones in wide-ranging yields
(entries 1-25) due the changes on temperature and time under microwave irradiation. The results show
that the optima temperature was 85 ºC and the optimum time was 25 min, for temperature above of 85
ºC and irradiation time upper 25 min the table 4 shows a decrease on products yields due the resin
decomposition, for this reason the Dötz product was cleavage from the resin at the same time of the
benzannulation decreasing the yields. In contrast to solution-phase benzannulation, the solid-supported
Dötz benzannulation reaction cleanly produces the quinone product without the indene, indenone, or
cyclobutenone side products typically seen in these reactions. An oxidized product of unreacted resinbound Fischer carbene complex 1, benzoic acid, was the only side product.
R1
Link
(CO)5Cr
O
Link
+
R1=
R
(CO)3Cr
OH
9a-c
10a-c
R1
CAN
1
MW irradiation
R2
1
O
O
Dötz Benzan. / DCM
H2O / DCM
Shaking 12 h
O
R2
2
R
11a-c
R2=
9a =
Phenyl
9b= R1= CH2(CH2)7COOH, R2= CH2(CH2)10CH3
9c = R1= R2= CH2OH
Scheme 7 Cleavage of Dötz Benzannulation with Diynes for Phenyl FCC
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product.
25
Table 4 Optimization of the Microwave-assisted Solid-Phase Dötz Benzannulation of Resin-Bound Phenyl Fischer
Carbene Complex 1 with diynes 9a-c, Followed by the Oxidative Cleavage Using CANa
Entry
DIYNE (R1, R2)
Temperature
Time (min)
Product
Yieldb %
1
1,4-Diphenyl butadiyne
60 ºC
25
11a
20
2
1,4-Diphenyl butadiyne
70 ºC
25
11a
45
3
1,4-Diphenyl butadiyne
85 ºC
25
11a
68
4
1,4-Diphenyl butadiyne
100 ºC
25
11a
60
5
1,4-Diphenyl butadiyne
120 ºC
25
11a
58
6
1,4-Diphenyl butadiyne
130 ºC
25
11a
55
7
1,4-Diphenyl butadiyne
85 ºC
5
11a
15
8
1,4-Diphenyl butadiyne
85 ºC
15
11a
38
9
1,4-Diphenyl butadiyne
85 ºC
35
11a
66
10
1,4-Diphenyl butadiyne
85 ºC
45
11b
64
11
10,12-Pentacosadiynoic acid
60 ºC
25
11b
13
12
10,12-Pentacosadiynoic acid
70 ºC
25
11b
45
13
10,12-Pentacosadiynoic acid
85 ºC
25
11b
65
14
10,12-Pentacosadiynoic acid
100 ºC
25
11b
65
15
10,12-Pentacosadiynoic acid
120 ºC
25
11b
60
16
10,12-Pentacosadiynoic acid
130 ºC
25
11b
58
17
10,12-Pentacosadiynoic acid
85 ºC
5
11b
23
18
10,12-Pentacosadiynoic acid
85 ºC
15
11b
34
19
10,12-Pentacosadiynoic acid
85 ºC
35
11b
56
20
10,12-Pentacosadiynoic acid
85 ºC
45
11b
58
21
2,4-Hexadiyne-1,6-diol
60 ºC
25
11c
25
22
2,4-Hexadiyne-1,6-diol
85 ºC
15
11c
45
23
2,4-Hexadiyne-1,6-diol
85 ºC
25
11c
53
26
24
85 ºC
35
51
11c
130 ºC
25
48
11c
Reactions of 1 (0.115 mmol) with different diynes 9a-c (0.575 mmol) were carried out in the microwave at different
25
a
2,4-Hexadiyne-1,6-diol
2,4-Hexadiyne-1,6-diol
temperature for the specified time using 2.00 mL of CH2Cl2, followed by the oxidative cleavage of the resin using CAN
(0.575 mmol).
b
Isolated overall yields were calculated based on the loading of PL- Wang (1.7 mmol/g) by the supplier.
O
O
O
O
OH
O
Entry 1-10
O
OH
O
Entry 11-20
OH
Entry 21-25
Figure 9 Structures of Products of the Optimization of Dötz Benzannulation in Phenyl FCC
The 1HNMR spectra shows the expected products but there are some impurities on the products.
These extra peaks that appear on the spectra are confirmed that belongs to the resin due the beads
decomposition29.
The 1H NMR spectra shows no regioselectivity for this reaction for the presence of only one
isomer.
2.6 Dötz Benzannulation with Different Diynes and Phenyl FCC
The Dötz benzannulation of 1 was performed under optimized conditions (MW, 85 ºC, 25 min),
with different diynes (9a-i) followed by the oxidative cleavage of the resulting resin-bound naphthols
10a-i (Scheme 9). Table 5 illustrates that various diynes that produce 2,3-disubstitured -1,4naphthoquinones 11a-i in moderate to good yields (entries 1-9). An oxidized product of unreacted resinbound Fischer carbene complex 1, benzoic acid, was the only side product.
27
R1
Link
(CO)5Cr
O
Link
+
R
(CO)3Cr
OH
9a-i
10a-i
9a. R1= R2= Phenyl
9b. R1= R2= CH2OC6H6
9c. R1= R2= CH2(CH2)2CH3
9d. R1= R2= CH2OH
R1
CAN
1
MW 85 C / 25 min
R2
1
O
O
Dötz Benzan. / DCM
H2O / DCM
Shaking 12 h
O
R2
2
R
11a-i
9g. R1= R2= C(CH3)3
9h. R1= R2= C(CH3)2OH
9i. R1= R2= Si(CH3)3
9e. R1= CH2(CH2)7COOH,
R2= CH2(CH2)8CH3
6f . R1= CH2(CH2)7COOH,
R2= -CH2(CH2)10CH3
Scheme 8 Dötz Benzannulation and Cleavage of Diynes [9a-h] and Phenyl FCC [1]
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product.
Table 5 Results of the Microwave-assisted Solid-Phase Dötz Benzannulation of Resin-Bound Phenyl Fischer Carbene
Complex 1 with diynes 9a-i, Followed by the Oxidative Cleavage Using CANa
Entry
DIYNE (9a-i)
Temperature
Time (min)
Product
% Yieldb
1
1,4-diphenyl butadiyne
85 ºC
25
11a
64
2
1,6-diphenoxy-2,4-hexadiyne
85 ºC
25
11b
55
3
5,7-dodecadiyne
85 ºC
25
11c
56
4
2,4-hexadiyne-1,6-diol
85 ºC
25
11d
31
5
10,12-tricosadiynoic acid
85 ºC
25
11e
44
6
10,12-pentacosadiynoic acid
85 ºC
25
11f
45
7
22,77-tetramethyl-3,5ctadiyne
85 ºC
25
11g
none
8
2,7-dimethyl-3,5-octadiyne2,7-diol
85 ºC
25
11h
none
1,4-bis(trimethyl silyl)
9
85 ºC
25
none
11i
butadiyne
a
Reactions of 1 (0.115 mmol) with different diynes 9a-i (0.575 mmol) were carried out in the microwave at different
temperature for the specified time using 2.00 mL of CH2Cl2, followed by the oxidative cleavage of the resin using CAN
(0.575 mmol).
b
Isolated overall yields were calculated based on the loading of PL- Wang (1.7 mmol/g) by the supplier.
28
O
O
O
O
O
O
O
O
11a
O
11c
O
O
O
OH
OH
OH
O
O
11b
O
11d
O
O
11g
O
11f
11e
O
O
OH
O
OH
Si
O
OH
Si
11i
11h
Figure 10 Structures of Products after Dötz Benzannulation with Phenyl FCC.
The 1HNMR spectra shows the expected products but there are some impurities on the products.
These extra peaks that appear on the spectra is confirmed that belongs to the resin due the beads
decomposition29.
The 1H NMR spectra shows regioselectivity for this reaction for the presence of only one isomer.
29
2.7 CLICK CHEMISTRY
The combinatorial chemistry has played an immense role for the generation of a large library of
compounds for screeeing in the drug discovery programme. This novel approach was initially used to
prepare peptide libraries and was later applicable to a large library of small organic molecules
containing heterocyclic moiety. The interesting pharmacokinetic properties of those small molecules
make them as an attractive potential therapeutic agents. In recent years, click chemistry has been a
subject of great interest due to the formation of stable and novel heterocyles that are useful in the
pharmaceutical industry. The Huisgen 1,3-dipolar cycloaddition of alkynes with azides to form the
stable 1,2,3-triazole derivatives forms one of the powerful click reactions. It is noteworthy that the 1,2,3triazole derivatives shows a broad spectrum of biological activities such as anti-allergic, anti-bacterial,
anti-fungal, and anti-HIV activities. In addition, these compounds are found in herbicides, fungicides
and dyes.
During the course of our solid-phase Dötz benzannulation reaction with 1,3-diynes, we resulted
in a single resin-bound 3-alkyne substituted naphthol derivatives. We envisaged that this alkyne can be
used as a potential substrate for click chemistry. It is believed that the resulting triazole moiety with 1,4napthoquinone would exhibit an important biological properties.
The reaction of resin-bound naphthol 1a with 4-methoxybenzyloxycarbonyl azide (2a) was
initially examined. This reaction was performed under microwave irradiations using CuI as the catalyst,
Et3N as the base and CH3CN as the solvent. The oxidative cleavage of the resulting resin-bound product
3a using CAN gives the corresponding 1,4-napthoquinone containing triazole moiety 4a in 47% yield
(Table 1, entry 1). The structure of 4a was characterized by IR and 1H NMR spectral data. In the 1H
NMR spectrum, in addition to the expected signals for 4a there appeared additional signals due to the
bead leachable product. Similarly, the reaction was successfully extended to 4-azido aniline
30
hydrochloride (2b) in 14% yield (entry 2). However, no reaction was observed with other azides 2c-e
(entries 3-5).
Similar to the results with 1a, reactions of 1b-e with azides 2a,b, followed by the CAN cleavage
afforded the corresponding 1,4-napthoquinones in moderate yields (entry 6,7,9, 12, and 15). Reactions
with other azides 1b-d afforded no product (entries 10, 12).
Continuing with the diversity and having an alkyne in the naphthoquinone core, a further
reaction was performed ([3+2] cycloaddition) with different azides and different conditions in order to
optimize click chemistry on solid-phase.
2.7.1 For Phenyl Fischer Carbene Complex
Link
Link
O
O
O
R1
(CO)3Cr OH
R3
2
R
10a-f
N3 Cu I / MW irradiation
Et3N / CH3CN
(CO)3Cr OH
R2
12a-i
R1
N
N
N
R3
13
CAN
H2O / DCM
Shaking 12 h
R1
N
O
R2
14
N
N
R3
Scheme 9 Click Chemistry of Compounds [10a-f]
Caution! Azides compounds are presumed to be toxic and potentially explosive and therefore
should be handled with caution in a fume hood. A small explosion was observed, so is recommend that
these reactions be conducted behind a safety shield.
The procedure described herein illustrate the preparation of 2,3-disubstitured-1,4naphthoquiones. The latter compounds have been used to generate species that undergoes [3+2]
cycloadditions.
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product. For those that 1HNMR proves that the expected
product is present.
31
Table 6 Results of the Microwave-assisted Solid-Phase Click Chemistry of Resin-Bound Naphthols 10a-f with azides
12a-i, Followed by the Oxidative Cleavage Using CANa
AZIDE (R3)
Temp.
Time
(min)
Product
% Yieldb
Entry
DIYNE (R1, R2)
1
1,4-diphenyl butadiyne
4-methoxybenzyloxycarbonyl azide
90 ºC
30
14aa
50.2
2
1,4-diphenyl butadiyne
4-Azido aniline hydrocloride
90 ºC
30
14ab
14
3
1,4-diphenyl butadiyne
Trimethyl silyl azide
90 ºC
30
14ac
0
4
1,4-diphenyl butadiyne
4-methoxybenzyloxycarbonyl azide
85 ºC
25
14aa
47
5
1,4-diphenyl butadiyne
Diphenyl phosphoryl azide
85 ºC
25
14ad
0
6
1,4-diphenyl butadiyne
Azidomethyl phenyl sulfide
85 ºC
25
14ae
0
7
1,4-diphenyl butadiyne
1-azido adamanatane
85 ºC
25
14af
0
8
5,7-Dodecadiyne
4-methoxybenzyloxycarbonyl azide
90 ºC
30
14aa
44
9
5,7-Dodecadiyne
4-Azido aniline hydrocloride
90 ºC
30
14ab
39
10
5,7-Dodecadiyne
Trimethyl silyl azide
90 ºC
30
14ac
0
11
5,7-Dodecadiyne
4-methoxybenzyloxycarbonyl azide
85 ºC
25
14ba
41
12
5,7-Dodecadiyne
4-Azido aniline hydrocloride
85 ºC
25
14bb
36
13
5,7-Dodecadiyne
Trimethyl silyl azide
85 ºC
25
14bc
0
14
5,7-Dodecadiyne
Diphenyl phosphoryl azide
85 ºC
25
14bd
0
15
5,7-Dodecadiyne
Azidomethyl phenyl sulfide
85 ºC
25
14be
0
16
5,7-Dodecadiyne
1-azido adamanatane
85 ºC
25
14bf
0
17
5,7-Dodecadiyne
Sodium Azide
85 ºC
25
14bg
0
18
5,7-Dodecadiyne
Azido-deoxy-B-D-glucopyranoside
85 ºC
25
14bh
0
19
5,7-Dodecadiyne
4-azido phenyl isothiocyanate
85 ºC
25
14bi
0
20
2,4-hexadiyne,1-6-diol
4-methoxybenzyloxycarbonyl azide
90 ºC
30
14ca
18
21
2,4-hexadiyne,1-6-diol
Trimethyl silyl azide
90 ºC
30
14cc
22
2,4-hexadiyne,1-6-diol
4-methoxybenzyloxycarbonyl azide
85 ºC
25
14ca
26
23
2,4-hexadiyne,1-6-diol
Diphenyl phosphoryl azide
85 ºC
25
14cd
0
24
2,4-hexadiyne,1-6-diol
Azidomethyl phenyl sulfide
85 ºC
25
14ce
0
0
32
25
2,4-hexadiyne,1-6-diol
26
1-azido adamanatane
85 ºC
25
14cf
0
10,12-pentacosadiynoic acid
4-methoxybenzyloxycarbonyl azide
90 ºC
30
14da
41
27
10,12-pentacosadiynoic acid
4-Azido aniline hydrocloride
90 ºC
30
14db
15
28
10,12-pentacosadiynoic acid
4-methoxybenzyloxycarbonyl azide
85 ºC
25
14da
38
29
10,12-pentacosadiynoic acid
Diphenyl phosphoryl azide
85 ºC
25
14dd
0
30
10,12-pentacosadiynoic acid
Azidomethyl phenyl sulfide
85 ºC
25
14de
0
31
10,12-pentacosadiynoic acid
1-azido adamanatane
85 ºC
25
14df
0
32
22,77-tetramethyl-3,5octadiyne
4-Azido aniline hydrocloride
90 ºC
30
14eb
0
2,7-dimethyl-3,5-octadiyne2,7-diol
4-methoxybenzyloxycarbonyl azide
90 ºC
30
14fa
0
33
34
a
2,7-dimethyl-3,5-octadiyne2,7-diol
14fb
0
4-Azido aniline hydrocloride
90 ºC
30
Reactions of 10a-f (0.093 mmol) with different azides 12a-i (0.465 mmol) were carried out in the microwave at different
temperature for the specified time using 1.00 mL of Et3N in 2.00 mL of CH3CN, followed by the oxidative cleavage of the
resin using CAN (0.465 mmol).
b
Isolated overall yields were calculated based on the loading of PL- Wang (1.7 mmol/g) by the supplier.
2.7.2 For Phenyl Fischer Carbene Complex but In Situ Formation of Catalyst
O
Link
N3
O
(CO)3Cr OH
10a-f
O
O
O
R1
R1
Cu / CuSO4 / MW 85 C 25 min
Et3N / CH3CN
R2
12a
10a. R1= R2= Phenyl
10b. R1= R2= C(CH3)3
10c. R1= R2= CH2OH
R1
Link
O
(CO)3Cr
HO
R2
O
N
CAN
H2O / DCM
Shaking 12 h
N
N
N
13 O
10d. R1= R2= C(CH3)2OH
10e. R1= R2= CH2(CH2)2CH3
10f. R1= R2= Si(CH3)3
O
O
R2
14a-f
N
N
O
O
O
Scheme 10 In Situ Click Chemistry of Compound [D]
In order to achieve higher yields of click chemistry products, the reaction was performed using
Cu and CuSO4 as the catalyst to generate in situ Cu(1) catalyst (Table 2). Thus, the reaction of 1a with
2a, followed by the CAN cleavage afforded 4aa in 60% yield (entry 1). There is no substantial increase
33
in the yield over to the CuI catalyst. Under these conditions, the reaction was successfully extended to
other alkynes 1b,c (entries 2 and 3). However, no product was obtained with alkynes 1d-f (entries 4-6).
Table 7 Results of the Microwave-assisted Solid-Phase Click Chemistry In Situ Formation of Catalyst of Resin-Bound
Naphthols 10a-f with azide 12a, Followed by the Oxidative Cleavage Using CANa.
ENTRY
DIYNE (R1, R2)
PRODUCT
% Yieldb
1
1,4-diphenyl butadiyne
14a
60
2
22,77-tetramethyl-3,5-octadiyne
14b
55
3
2,4-hexadiyne,1-6-diol
14c
44
4
2,7-dimethyl-3,5-octadiyne-2,7-diol
14d
0
5
5,7-Dodecadiyne
14e
0
6
1,4-bis-(trimethyl silyl) butadiyne
14f
0
a
Reactions of 10a-f (0.093 mmol) with 4-methoxybenzyloxycarbonyl azide 12a (0.465 mmol) were carried out in the
microwave at 85 ºC for 25 minutes using Cuº and CuSO4 as the catalyst in a mixture of solvents (1.00 mL of Et3N in 2.00
mL of CH3CN), followed by the oxidative cleavage of the resin using CAN (0.465 mmol).
b
Isolated overall yields were calculated based on the loading of PL- Wang (1.7 mmol/g) by the supplier.
2.7.3 In Situ Click Chemistry Using Halides
Due the poor yields on the reactions and believing that those yields are due to the azides.
Herein,is tested a different synthesis were the azides are synthesized from different halides and sodium
azide in situ.
Next strategy involves the use of in situ azides rather than using commercially available azide.
The reaction of 1a with benzyl bromide 5 and sodium azide at 85 0C, followed by CAN cleavage
afforded no product (Table 8, entry 1). No product was observed using 130 0C for 10 min. (Table 8,
entry 20). However, with the increase in time furnished poor yield of 4aa (entries 3 and 4).
34
First is demonstrated that the reaction of halides and sodium azide take place by an experiment
were benzyl bromide (0.1 mol, 171 mg) is reacted with sodium azide (0.11 mol, 65 mg) under
microwave irradiation at 125 ºC for 10 min and under nitrogen atmosphere, the solvents used were
triethyl amine (1 mL) and acetonitrilo (3 mL). To obtain the benzyl azide which 1HNMR (300MHz,
CDCl3) δ = 7.523 (d, 2H), 7.395 (d, 3H), 4.710 (s, 2H).
Link
O
O
CAN
Cu / CuSO4 / MW
(CO)3Cr
NaN3
OH
O
Link
Br
H2O / t-BuOH
(CO)3Cr
N
OH
10a
N
N
H2O / DCM
Shaking 12 h
N
N
N
O
16a
15a
Scheme 11 In Situ Click Chemistry of Compound [10a] Using Benzyl Bromide and Sodium Azide
Table 8 Results of the Microwave-assisted Solid-Phase In Situ Click Chemistry of Resin-Bound Naphthols 10a with
Benzyl Bromide and Sodium Azide, Followed by the Oxidative Cleavage Using CANa
ENTRY
DIYNE
HALIDE (R3)
AZIDE
Temp.
Time
(min)
PRODUCT
% Yieldb
1
1,4-diphenyl butadiyne
Benzyl bromide
NaN3
85 ºC
25
16a
0
2
1,4-diphenyl butadiyne
Benzyl bromide
NaN3
130 ºC
30
16a
15
3
1,4-diphenyl butadiyne
Benzyl bromide
NaN3
130 ºC
25
16a
15
a
16a
130 ºC
10
0
4
1,4-diphenyl butadiyne
Benzyl bromide
NaN3
Reactions of 10a (0.093 mmol) with Benzyl Bromide (0.465 mmol) and Sodium Azide (0.465 mmol) were carried out in the
microwave at specified temperatures for specified time, using Cuº and CuSO4 as the catalyst in a mixture of solvents (1.00
mL of t-BuOH in 2.00 mL of H2O), followed by the oxidative cleavage of the resin using CAN (0.465 mmol).
b
Isolated overall yields were calculated based on the loading of PL-Wang (1.7 mmol/g) by the supplier.
35
2.7.4 Click Chemistry Using Benzyl Azide, and CuI
Link
O
OH
O
N3
R1
(CO)3Cr
O
Link
1
R
Cu I / MW 130 C, 25 min
Et3N / CH3CN
R2
(CO)3Cr
10a-b
CAN
N
N
N
OH
R2
N
H2O / DCM
Shaking 12 h
O
R2
N
N
16a-b
15a-b
10a. R1= R2= Phenyl,
R1
10b = R1= -CH2(CH2)7COOH, R2= -CH2(CH2)10CH3
Scheme 12 Click Chemistry of Compounds [D] Using Benzyl Bromide
Table 9 Results of the Microwave-assisted Solid-Phase Click Chemistry of Resin-Bound Naphthols 10a-b with Benzyl
Azide, Followed by the Oxidative Cleavage Using CANa
ENTRY
DIYNE
AZIDE
Temp.
Time (min)
PRODUCT
% Yield b
1
1,4-diphenyl butadiyne
Benzyl azide
130 ºC
25
16a
55.3
2
10,12-tricosadiynoic acid
Benzyl azide
130 ºC
25
16b
0
a
Reactions of 10a (0.093 mmol) with Benzyl Azide (0.465 mmol) were carried out in the microwave at 130 ºC for 25 minutes,
using CuI as the catalyst in a mixture of solvents (1.00 mL of Et3N in 2.00 mL of CH3CN), followed by the oxidative
cleavage of the resin using CAN (0.465 mmol).
b
Isolated overall yields were calculated based on the loading of PL-Wang (1.7 mmol/g) by the supplier.
2.7.5 Click Chemistry Using Halides and CuI
Link
Link
O
(CO)3Cr
O
NaN3
R1
R3
OH
10a-b
R2
Cu I / MW 130 C, 25 min
Et3N / CH3CN
(CO)3Cr
Br
17a-c
19a. R1= R2= Phenyl, R3= CH2C6H6
19b. R1= R2= Phenyl, R3= CHCH3C6H6
19c. R1= R2= Phenyl, R3= CH2(CH2)9CH3
O
R1
N
CAN
H2O / DCM
Shake 12 h
N
OH
N
R2
R3
18a-f
R1
N
O
R2
N
N
19a-f
R3
19d. R1= CH2(CH2)7COOH, R2= CH2(CH2)10CH3, R3= CH2C6H6
19e. R1= CH2(CH2)7COOH, R2= CH2(CH2)10CH3, R3= CHCH3C6H6
19f. R1= CH2(CH2)7COOH, R2= CH2(CH2)10CH3, R3= CH2(CH2)9CH3
Scheme 13 Click Chemistry of Compounds [D] Using Halides
To our delight, the best result was obtained when the reaction was performed using CuI as the
catalyst and the in situ generation of azides (Table 10). The reactions of 1a with benzyl bromide and
36
NaN3 afforded the corresponding 1,4-napthoquinones 4aa in 88% yield (entry 1). In addition to aromatic
azide, the reaction was successfully extended to aliphatic azides (entries 2 and 3). Under these
conditions, reactions of 1b-c with various halides 6a-c and sodium azide afforded the corresponding
product 6a-h in moderate yields (entries 4-10).
Table 10 Results of the Microwave-assisted Solid-Phase Click Chemistry of Resin-Bound Naphthols 10a-b with Benzyl
Bromide and Sodium Azide, Followed by the Oxidative Cleavage Using CANa
DIYNE(R1,R2)
HALIDE (R3)
AZIDE
Temp.
Time
(min)
PRODUCT
% Yieldb
1
1,4-diphenyl butadiyne
Benzyl bromide
NaN3
130 ºC
25
19a
87.5
2
1,4-diphenyl butadiyne
1-bromoethyl benzene
NaN3
130 ºC
25
19b
60.4
3
1,4-diphenyl butadiyne
1-bromoundecane
NaN3
130 ºC
25
19c
40.8
4
10,12-tricosadiynoic acid
Benzyl bromide
NaN3
130 ºC
25
19d
72.6
5
10,12-tricosadiynoic acid
1-bromoethyl benzene
NaN3
130 ºC
25
19e
39.4
ENTRY
a
1-bromoundecane
19f
130 ºC
25
0
6
10,12-tricosadiynoic acid
NaN3
Reactions of 10a-b (0.093 mmol) with benzyl bromide (0.465 mmol) and sodium azide (0.465 mmol) were carried out in
the microwave at
130 ºC
for 25 minutes, using CuI as the catalyst in a mixture of solvents (1.00 mL of Et3N in 2.00 mL of
CH3CN), followed by the oxidative cleavage of the resin using CAN (0.465 mmol).
b
Isolated overall yields were calculated based on the loading of PL-Wang (1.7 mmol/g) by the supplier.
.
37
2.8 Synthesis of 2-Methoxyphenyl Fischer Carbene Complex
To understand the regioselectivity of the solid-supported Dötz benzannulation, the reaction with
o-methoxyphenyl Fischer carbene complex [B], was synthesized as described in Scheme 12, was
investigated. Under our standard conditions.
OMe
Br
OMe
Li
n-ButylLi, THF
-40 0C, 2 h
Cr(CO) 6, THF
0 0 C, 2 h
_
+
OMe OMe4 N
_
+
OMe OLi
Cr(CO)5
Me 4NBr, water,
Cr(CO) 5
CH3COCl,
DCM, 0 0C, 1 h
0 0C, 2 h
O
PL-Wang
OMe O
Cr(CO)5
OMe O
DCM, rt, 3 h
Cr(CO)5
B
(97 % loading)
FT-IR (KBr-Pallet): 2061,1923, Cr-CO
Scheme 14 Synthesis of 2-Methoxyphenyl Fischer Carbene Complex
The capacity of loading for the PL-Wang Resin is 1.7 mmol / g.
This product has to be stored under N2 atmosphere and low temperature to avoid decomposition.
Loading by weight: 100% (2.3112 mmol, MW= 327, grams loaded = 755 g) FT-IR (KBr thin
film): 1922, 2061 (Cr-CO).
38
25
20
Transmittance [%]
10
15
5
D:\alex data\Anisol FCC april 30.1
3000
2500
2000
Wavenumber cm-1
Anisol FCC april 30
1509.92
1737.85
1922.54
2061.37
2924.13
0
3500
1500
1000
500
solid KBr
30/04/2005
Figure 11 GC of 2-Methoxyphenyl Fischer Carbene Complex
2.9 Optimization of the Dötz Benzannulation with different Diynes and 2Methoxyphenyl Fischer Carbene Complexes in Solid-Phase Organic Synthesis
Link
(CO)5Cr
Link
R1
O
+
O
B
Dötz Benzannulation
O
(CO)3Cr
OH
H2O / DCM
Shaking 12 h
R2
Scheme 15 Dötz Benzannulation optimization for 2-Methoxyphenyl Fischer Carbene Complex
39
O
R1
CAN
R1
MW irradiation
R2
O
O
O
15
R2
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product.
Table 11 Dötz Benzannulation optimization for 2-Methoxyphenyl Fischer Carbene Complex
Entry
DIYNE (R1, R2)
Solvent
Condition
Temperature
Time (min)
% Yield (by
weight)
1
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
60 ºC
25
10
2
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
70 ºC
25
34
3
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
85 ºC
25
65
4
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
100 ºC
25
60
5
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
120 ºC
25
58
6
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
130 ºC
25
57
7
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
85 ºC
5
5
8
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
85 ºC
15
18
9
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
85 ºC
35
58
10
1,4-Diphenyl butadiyne
DCM / 2mL
Microwave
85 ºC
45
59
11
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
60 ºC
25
23
12
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
70 ºC
25
43
13
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
85 ºC
25
67
14
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
100 ºC
25
62
15
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
120 ºC
25
60
16
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
130 ºC
25
58
17
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
85 ºC
5
13
18
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
85 ºC
15
24
19
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
85 ºC
35
56
20
10,12-Pentacosadiynoic acid
DCM / 2mL
Microwave
85 ºC
45
58
21
2,4-Hexadiyne-1,6-diol
DCM / 2mL
Microwave
60 ºC
25
15
40
22
2,4-Hexadiyne-1,6-diol
DCM / 2mL
Microwave
85 ºC
15
34
23
2,4-Hexadiyne-1,6-diol
DCM / 2mL
Microwave
85 ºC
25
51
24
2,4-Hexadiyne-1,6-diol
DCM / 2mL
Microwave
85 ºC
35
50
25
2,4-Hexadiyne-1,6-diol
DCM / 2mL
Microwave
130 ºC
25
49
OMeO
O
OMeO
OMeO
OH
O
OH
O
Entry 1-10
OH
O
Entry 11-20
Entry 21-25
Figure 12 Structure of Products of the optimization of Dötz Benzannulation in 2-Methoxyphenyl FCC [15]
The NMR spectra shows the expected products but there are some impurities on the products that
are prove by some extra peaks that appear on the spectra due the beads decomposition.
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product.
2.10 Dötz Benzannulation of Diynes [6a-i] and 2-Methoxyphenyl FCC [B]
Link
(CO)5Cr
Link
R1
O
+
O
B
Dötz Benzannulation
O
6a-i
6a = R1= R2= Phenyl
6b = R1= R2= -CH2OC6H63
6c = R1= R2= -CH2(CH2)2CH3
6d =R1= R2= -CH2OH
(CO)3Cr
OH
6e = R1= -CH2(CH2)7COOH,
R2= -CH2(CH2)8CH3
6f = R1= -CH2(CH2)7COOH,
R2= -CH2(CH2)10CH3
E
H2O / DCM
Shaking 12 h
R2
6g = R1= R2= -C(CH3)3
6h = R1= R2= -C(CH3)2OH
6i = R1= R2= -Si(CH3)3
Scheme 16 Dötz Benzannulation and Cleavage of Diynes [6a-h] and FCC [B]
41
O
R1
CAN
R1
MW irradiation
R2
O
O
O
7a-i
R2
Table 12 Conditions Dötz Benzannulation with 2-Methoxyphenyl FCC
Entry
DIYNE(R1, R2)
Solvent
Condition
Temperature
Time (min)
% Yield (by
weight)
1
1,4-diphenyl butadiyne
DCM / 2mL
Microwave
85 ºC
25
76%
2
1,6-diphenoxy-2,4-hexadiyne
DCM / 2mL
Microwave
85 ºC
25
58%
3
5,7-dodecadiyne
DCM / 2mL
Microwave
85 ºC
25
63%
4
2,4-hexadiyne-1,6-diol
DCM / 2mL
Microwave
85 ºC
25
48%
5
10,12-tricosadiynoic acid
DCM / 2mL
Microwave
85 ºC
25
33%
6
10,12-pentacosadiynoic acid
DCM / 2mL
Microwave
85 ºC
25
64%
7
22,77-tetramethyl-3,5-ctadiyne
DCM / 2mL
Microwave
85 ºC
25
none
8
2,7-dimethyl-3,5-octadiyne-2,7diol
DCM / 2mL
Microwave
85 ºC
25
none
9
1,4-bis(trimethyl silyl) butadiyne
DCM / 2mL
Microwave
85 ºC
25
none
OMeO
OMeO
OMeO
O
O
O
O
7a
OMeO
7c
O
OMeO
OH
O
OMeO
O
O
OMeO
7g
O
OMeO
OH
OH
OH
7d
O
7b
O
O
7e
OH
7h
7f
OMeO
Si
O
OH
7i
Si
Figure 13 Structures of Products after Dötz Benzannulation with 2-Methoxyphenyl FCC.
42
The NMR spectra shows the expected products but there are some impurities on the products that
are prove by some extra peaks that appear on the spectra due the beads decomposition.
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product.
2.11 CLICK CHEMISTRY
2.11.1 For 2-Methoxyphenyl Fischer Carbene Complex
Link
Link
O
O O
O O
R1
R 3 N3
(CO)3Cr OH
R2
E
Et3N / CH3CN
S
(CO)3Cr OH
R2
R1
CAN
R1
Cu I / MW irradiation
O
N
H2O / DCM
Shaking 12 h
N
N
N
O
R2
R3
N
N
16
R3
Scheme 17 Click Chemistry of Compound [E]
The procedure described herein illustrate the preparation of 2,3-disubstitured-1,4naphthoquiones. The latter compounds have been used to generate species that undergoes [3+2]
cycloadditions.
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product. For those that 1HNMR proves that the expected
product is present.
Table 13 Conditions for Click Chemistry of Compound [E]
ENTRY
1
2
3
4
5
DIYNE (R1, R2)
Solvents
AZIDE (R3)
Sodium Azide
Temp.
Time
(min)
% Yield (by
weight)
85 ºC
25
0
5,7-Dodecadiyne
CH3CN/Et3N
5,7-Dodecadiyne
CH3CN/Et3N
4-Azido aniline hydrocloride
85 ºC
25
0
5,7-Dodecadiyne
CH3CN/Et3N
1-azido adamanatane
85 ºC
25
0
5,7-Dodecadiyne
CH3CN/Et3N
Diphenyl phosphoryl azide
85 ºC
25
0
5,7-Dodecadiyne
CH3CN/Et3N
1-azido-1-deoxy-B-D-glucopyranoside
85 ºC
25
0
43
6
7
8
9
10
11
12
13
14
15
16
5,7-Dodecadiyne
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
0
5,7-Dodecadiyne
CH3CN/Et3N
Trimethyl silyl azide
85 ºC
25
0
2,4-hexadiyne,1-6-diol
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
0
2,4-hexadiyne,1-6-diol
CH3CN/Et3N
1-azido adamanatane
85 ºC
25
0
2,4-hexadiyne,1-6-diol
CH3CN/Et3N
1-azido-1-deoxy-B-D-glucopyranoside
85 ºC
25
0
10,12-pentacosadiynoic acid
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
20
10,12-pentacosadiynoic acid
CH3CN/Et3N
1-azido adamanatane
85 ºC
25
18
10,12-pentacosadiynoic acid
CH3CN/Et3N
4-azido phenyl isothiocyanate
85 ºC
25
25
1,4-diphenyl butadiyne
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
22.6
1,4-diphenyl butadiyne
CH3CN/Et3N
1-azido adamanatane
85 ºC
25
26.7
1,4-diphenyl butadiyne
CH3CN/Et3N
4-Azido aniline hydrocloride
85 ºC
25
32.6
2.11.2 In Situ Click Chemistry Using Halides
OMeO
Link
Br
e
OM O
Cu / CuSO4 / MW
(CO)3Cr
NaN3
OH
H2O / t-BuOH
(CO)3Cr
MeO
Link
CAN
N
OH
O
N
N
N
H2O / DCM
Shaking 12 h
N
N
O
E
17
Scheme 18 In Situ Click Chemistry of Compound [E] Using Halides
Table 14 Conditions for In Situ Click Chemistry of Compound [D and E] Using Halides
ENTRY
DIYNE
Solvents
HALIDE (R3)
AZIDE
Temp.
Time
(min)
% Yield (by
weight)
1
1,4-diphenyl butadiyne
H2O/t-BuOH
Benzyl bromide
NaN3
85 ºC
25
0
2
1,4-diphenyl butadiyne
H2O/t-BuOH
Benzyl bromide
NaN3
130 ºC
30
0
3
1,4-diphenyl butadiyne
H2O/t-BuOH
Benzyl bromide
NaN3
130 ºC
25
0
4
1,4-diphenyl butadiyne
H2O/t-BuOH
Benzyl bromide
NaN3
130 ºC
10
0
44
2.11.3 Click Chemistry Using Halides and CuI
OMeO
Link
Br
R1
(CO)3Cr
OH
e
OM O
Et3N / CH3CN
NaN3
R2
(CO)3Cr
E
18a = R1= R2= Phenyl,
R1
R1
Cu I / MW 130 C, 25 min
CAN
N
OH
R2
O
MeO
Link
N
N
N
H2O / DCM
Shaking 12 h
O
R2
N
N
18a-b
18b = R1= -CH2(CH2)7COOH, R2= -CH2(CH2)10CH3
Scheme 19 Click Chemistry of Compounds [E] Using Benzyl Bromide
Table 15 Conditions for Click Chemistry of Compound [ E] Using Halides and CuI
ENTRY
DIYNE
Solvents
HALIDE (R3)
AZIDE
Temp.
Time
(min)
Yield %
(by weight)
1
1,4-diphenyl butadiyne
CH3CN/Et3N
Benzyl bromide
NaN3
130 ºC
25
66
2
10,12-tricosadiynoic acid
CH3CN/Et3N
Benzyl bromide
NaN3
130 ºC
25
58
2.12 Synthesis of Furan Fischer Carbene Complex
n-ButylLi, Ether
O
0
TMEDA 0 C, 2 h
Cr(CO) 6, THF
O
Li
0 0 C, 2 h
_
+
OMe4 N
OLi
Me 4NBr, water,
O
Cr(CO)5
Cr(CO) 5
DCM, 0 0 C, 1 h
O
0 0C, 2 h
O
O
O
Cr(CO) 5
CH3COCl,
O
PL-Wang
DCM, rt, 3 h
O
Cr(CO)5
C
(95 % loading)
FT-IR (KBr-Pallet): 2059,1941, Cr-CO
Scheme 20 Synthesis of Furan Fischer Carbene Complex
45
The capacity of loading for the PL-Wang Resin is 1.7 mmol / g.
This product has to be stored under N2 atmosphere and low temperature to avoid decomposition.
Loading by weight: 100% (4.279 mmol, MW= 287, grams loaded = 1228 g) FT-IR (KBr thin
100
80
60
4000
3500
D:\alex data\FURAN FCC2.0
3000
FURAN FCC2
2500
2000
Wavenumber cm-1
KBr
1500
1000
540.08
695.43
1020.42
1510.24
1610.99
1737.56
1941.12
2058.75
2918.89
3404.92
0
20
40
Transmittance [%]
120
140
film): 1941, 2068 (Cr-CO).
500
30/03/2005
Figure 14 GC of Furan Fischer Carbene Complex
46
2.13 Optimization of the Dötz Benzannulation with Different Diynes and Furan
Fischer Carbene Complexes in Solid-Phase Organic Synthesis
Link
(CO)5Cr
R1
Link
O
O
C
Dötz Benzannulation
+
O
(CO)3Cr
6a-i
R1
CAN
R1
Mw 85 C / 25 min
R2
O
O
H2O / DCM
Shaking 12 h
OH
F
O
R2
O
R2
9a-i
6a = R1= R2= Phenyl
6f = R1= -CH2(CH2)7COOH,
6b = R1= R2= -CH2OC6H6
R2= -CH2(CH2)10CH3
6c = R1= R2= -CH2(CH2)2CH3
6g = R1= R2= -C(CH3)3
6d= R1= R2= -CH2OH
6h = R1= R2= -C(CH3)2OH
6e = none
6i = R1= R2= -Si(CH3)3
Scheme 21 Dötz Benzannulation and Cleavage of Diynes [6a-h] and FCC [C]
Table 16 Conditions Dötz Benzannulation with Furan FCC
Entry
DIYNE
Solvent
Condition
Temperature
Time (min)
% Yield (by
weight)
Microwave
85 ºC
25
65%
Microwave
85 ºC
25
52%
1
1,4-diphenyl butadiyne
DCM / 2mL
1,6-diphenoxy-2,4hexadiyne
DCM / 2mL
2
3
2,4-hexadiyne-1,6-diol
DCM / 2mL
Microwave
85 ºC
25
34%
4
5,7 dodecadiyne
DCM / 2mL
Microwave
85 ºC
25
20%
5
-------------------------
----------
-----------
------------
--------
----------
10,12-pentacosadiynoic
acid
DCM / 2mL
6
Microwave
85 ºC
25
none
22,77-Tetramethyl-3,5octadiyne
DCM / 2mL
7
Microwave
85 ºC
25
none
2,7-dimethyl-3,5octadiyne-2,7-diol
DCM / 2mL
8
Microwave
85 ºC
25
none
1,4-bis(trimethyl silyl)
butadiyne
DCM / 2mL
9
Microwave
85 ºC
25
none
47
O
O
O
O
O
O
O
9a
O
O
O
O
9b
O
9c
O
OH
O
OH
O
OH
O
O
O
9e
9d
O
O
O
OH
Si
O
O
O
O
O
9g
9f
O
OH
9h
9i
Si
Figure 15 Structures of Products after Dötz Benzannulation with Furan FCC
The NMR spectra shows the expected products but there are some impurities on the products that
are prove by some extra peaks that appear on the spectra due the beads decomposition.
2.14 CLICK CHEMISTRY
2.14.1 For Furan Fischer Carbene Complex
Link
O
O
O
R1
O
(CO)3Cr
R2
OH
F
O
R1
O
Cu I / MW 85 C, 25 min
Et3N / CH3CN
O
(CO)3Cr
R1
N
OH
R2
O
9a = R1= R2= Phenyl
9b = R1= R2= -CH2OC6H6
9c = R1= R2= -CH2(CH2)2CH3
9d= R1= R2= -CH2OH
9e = none
O
Link
N3
9f = R1= -CH2(CH2)7COOH,
R2= -CH2(CH2)10CH3
9g= R1= R2= -C(CH3)3
9h = R1= R2= -C(CH3)2OH
9i = R1= R2= -Si(CH3)3
Scheme 22 Click Chemistry of Compound [F]
48
N
N
CAN
H2O / DCM
Shaking 12 h
R3
N
O
O
R2
N
N
O
O
9a-i
Table 17 Conditions for Click Chemistry of Compound [F]
ENTRY
DIYNE (R1, R2)
1
2,4-hexadiyne,1-6-diol
Solvents
AZIDE (R3)
Temp.
Time
(min)
% Yield (by
weight)
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
2
1,4-diphenyl butadiyne
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
3
2,7-dimethyl-3,5-octadiyne2,7-diol
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
4
22,77-tetramethyl-3,5octadiyne
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
5
5,7-Dodecadiyne
6
10,12-pentacosadiynoic acid
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
7
1,6-di-phenoxy-2,4-hexadiyne
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
8
1,4-bis-(trimethyl silyl)
butadiyne
CH3CN/Et3N
4-methoxybenzyloxycarbonyl azide
85 ºC
25
none
2.14.2 For Furan Fischer Carbene Complex but In Situ Formation of Catalyst and
Different Solvents
R1
R1
4 / MW 85 C 25 min
R3 N3Cu / CuSO
Et N / CH CN
3
OH
R1
O
O
O
(CO)3Cr
O
Link
Link
R2
3
O
(CO)3Cr
CAN
N
OH
R2
Scheme 23 In Situ Click Chemistry of Compound [F]
49
H2O / DCM
N Shaking 12 h
N
R3
N
O
O
R2
N
N
R3
Table 18 Conditions for In Situ Click Chemistry of Compound [F]
ENTRY
1
DIYNE (R1, R2)
1,4-diphenyl butadiyne
Solvents
AZIDE (R3)
Temp.
Time
(min)
% Yield (by
weight)
H2O/t-BuOH
Diphenyl phosphoryl azide
85 ºC
25
13
2
10,12-pentacosadiynoic
acid
H2O/t-BuOH
Diphenyl phosphoryl azide
85 ºC
25
none
3
1,6-di-phenoxy-2,4hexadiyne
H2O/t-BuOH
Diphenyl phosphoryl azide
85 ºC
25
none
The procedure described herein illustrate the preparation of 2,3-disubstitured-1,4naphthoquiones. The latter compounds have been used to generate species that undergoes [3+2]
cycloadditions.
TLCs were taken to check the spots and calculated the possible product spot, followed by
column chromatography to purify the expected product. For those that crude 1HNMR proves that the
expected product is present.
50
CHAPTER 3
CONCLUSIONS
It has been demonstrated that it is possible to prepare a 2,3 disubstituted 1-4 naphthoquinone in a
solid phase organic synthesis using the Fisher carbene complex synthesis, as the tool to obtain the
aromatic ring, in an easy, scalable manner from commercially available resins ( Wang resin).
Products with high purities are obtained using columns purification systems (silica gel) and when
less reactive substrates are employed. The potential of microwave- assisted chemistry for the use of the
polymer supported has also been demonstrated, leading to drastically reduced reaction times. The
combination of the short reaction times achievable under microwave irradiation with the workup
procedure granted by the polymer-supported reagents is particularly advantageous, with the total time
required to obtain the final product. Hence, the reported method should be attractive for both synthetic
organic as well as for combinatorial synthesis applications.
In summary, we have developed news resin-bound Fischer carbene of chromium complexes. The
solid-supported Dötz benzannulation reaction followed by CAN cleavage allows an efficient synthesis
of various 1,4-naphthoquinone derivatives in good to moderate yields. Further work in our laboratories
is to utilize this methodology for the preparation of libraries of structurally diverse compounds including
natural products and the screening of these compounds against a variety of biological targets are
currently underway.
Cycloaddition reactions provide access to a variety of substitution patterns around the azole
moiety and allow for further derivatization.
51
Click chemistry (a reinvigoration of an old style of organic synthesis) provides easy access to libraries
of structurally diverse compounds. Where the biological activity and oral bioavailability of Click
chemistry reaction products yet to be determined.
A new amphiphilic compound is reported. It is based on a newly designed 1,4-naphtoquinone
derivatives that contains polar and no polar properties that self-assembles by the solid-support synthesis
and characterization of 2-tridecanyl-1,4-naphthoquinone and 2-tridecanyl-1,4-naphthadiol. These
molecules, depending on the concentration, self-assemble into micelles and liposomes in water and
exhibit redox-active properties. The method used for the synthesis of these amphiphilic molecules can
be employed to form further derivatives that present new functional groups on the surface of liposomes
or micelles.
There are many new challenges, both intellectual and technical, for synthetic organic chemists
engaged in combinatorial chemistry. It is a fertile ground for chemists, one that is beginning to facilitate
the discovery of new drugs today and that promises to make many new connections to biology and
medicine in the future.
52
CHAPTER 4 EXPERIMENTAL
4.1 Materials
The following are the stating materials and source companies.
Isopropanol, ether anhydrous, and dichloromethane (DCM) both HPLC grade were purchased
from J.T. Baker, tetrahydrofuran (THF) GR grade and ethyl acetate HPLC grade were purchased from
EMD, phenyl lithium, ca,1.8M solution in di-n-butylether, acethyl chloride 98% (AcCl), tetramethyl
ammonium bromide 98% (TMABr), tetramethyl ethylenediamine (TMEDA), H2O (O2 free), 2-bromo
anisol, furan, 991%,and
ammonium cerium(IV) nitrate 99.99% (CAN) propargylamine 98%,
magnesium sulfate anhydrous (MgSO4), HCl 1%, NaHCO3 10%, NaCl 10%. 4-(dimethylamino)pyridine
(DMAP), copper (I) iodide 99.9999% CuI, copper sulfate hydrate 98% CuSO4, butyl ether anhydrous
99.3% (Bu2O) , ethyl-4-iodobenzoate, ethyl-3-iodobenzoate, ethyl-2-iodobenzoate, and methyl-2iodobenzoatewere
purchased
from
Sigma
Aldrich,
chromium
hexacarbonyl
and
bis(triphenylphosphine)palladium dichloride were purchased from Steam Chemicals, hexanes HPLC
grade was purchased from Allied Signal,
di-tert-butyl dicarbonate
99.5% (GC) [(BOC)2] was
purchased from Fluka, silica gel 60 (SiO2) 230-400 mesh, particle size 0.04-0.063 was purchased from
EM Science, acetonitrile (CH3CN) HPLC grade, triethyl amine (Et3N) reagent grade, and diethyl amine
(Et2NH) reagent grade were purchased from Fischer Chem. Alert, chloroform-D 99.8% and acetone-D6
99.9% were purchased from Cambridge Isotope Laboratories, methanol anhydrous (MeOH) reagent
grade was purchased from VWR, and PL-WANG resin was purchased from Polymer lab.
The following diynes:1,4-diphenyl butadiyne, 10,12-pentacosadiynoic acid, 2,4-hexadiyne-1,6diol, 5,7-dodecadiyne, 1,6-diphenoxy-2,4-hexadiyne, 22,77-tetramethyl-3,5-ctadiyne, 2,7-dimethyl-3,5octadiyne-2,7-diol, 10,12-tricosadiynoic acid, and 1,4-bis(trimethyl silyl) butadiyne, the next azides:
sodium azide, trimethyl silyl azide, 4-azido aniline hydrochloride, 4-methoxybenzyloxycarbonyl azide,
53
diphenyl phosphoryl azide, azidomethyl phenyl sulfide, azido-deoxy-B-D-glucopyranoside, 4-azido
phenyl isothiocyanate, and 1-azido adamantine, as well as, the next halides: benzyl bromide,
bromomethyl cyclohexane, bromoundecane, 2-bromo-2-methyl propane, bromomethyl cyclobutane,
bromoethyl metyl ether, bromoethyl benzene, tert-butyl benzyl bromide, tetra methyl-bromomethyl
benzoate, and di-methoxy benzyl bromide. All them were purchased from Sigma- Aldrich and used as
received.
All reagents were used without further purification but water was treated with N2 gas for 30
minutes to release all the O2 present, and but propargylamine was fleshly distilled before use it. The
main solvents were purchased dry and obtained from de mBraun solvent-purification system.
54
4.2 Instrumental
The equipment used for analysis of compounds and work-up was:
Brucker AM-300 (300 MHz)
1
Hewlett Packard 1100 series GC*
Gas chromatography (GC) analysis
Biotage
Microwave irradiator
Perkin Elmer 1600 series
Infrared (IR) spectra
Hewlett Packard 1100 series HPLC
High performance liquid chromatography (HPLC) analysis
Merck glass plates
Think layer chromatography
mBRAUN
Solvent-purification system
Hoods
Work safety
Dry Box
Materials air sensitive store and work out
Schlenk line technique
Inert atmosphere manipulations
Bench
Work place
Glassware
Work out
TLC plates
Analysis of purity of samples
UV Lamp
Observe TLC spots
Computer
Information Software
*
H NMR spectra and 13 C NMR spectra
The ramp employed in the GC for all experiments was: Carrier – 35 psi, oven 40 ºC for 1 min., 40 ºC-
250 ºC at 20 ºC/min., 250 ºC holds for 15 min. and the solvent used was chloroform. (HP-5 5% phenyl
methyl siloxane, capillarity 30 m * 320 μm *0.25 μm nominal).
55
4.3 SYNTHESES
4.3.1 Synthesis of different Fischer Carbenes complexes
4.3.1.1 Synthesis of Phenyl Fischer Carbene Complex
Inside of the dry box, 3gr (13.6 mmol, 1 equiv) of chromium hexacarbonyl were weighed on a
round bottom flask equipped with a stir bar, air free adaptor, and septum. Subsequent addition of 15 mL
of dry Dichloromethane (DCM) was done under N2 atmosphere. Then, under nitrogen atmosphere,
phenyl lithium (11.5 mL, 1.8M solution in t-Bu2O, 20.4 mmol, 1.5 equiv) was carefully added drop wise
via syringe over a period of 5-10 minutes at 0°C (ice bath). The solution turned gradually from yellow to
brown. The reaction was left under ice bath and stirring for 2 hours, time after which it adopted a dark
brown, and the chromium hexacarbonyl crystals were disappeared. The solvent was removed under
reduce pressure.
In another 50 mL round bottom flask equipped with a stir bar and septum were placed 4.07 gr
(27.2mmol, 2 equiv) of tetramethylammonium bromide (TMA) under Nitrogen atmosphere. Then, 20
mL of H2O (O2 free) were added and stirred until the TMA was completely dissolved. Under nitrogen
atmosphere this mixture was transfer to the previous round bottom flask via cannula. The new mixture
was stirred 1 hour long under ice bath. The next step was an extraction of the compound with DCM,
three times 50 mL of DCM each. Dried with magnesium sulfate and filtered. The solvent was removed
under reduce pressure.
The solid formed was placed under N2 atmosphere and dissolved with 10 mL of dry
dichloromethane. The solution was cooled to -40°C using a slush bath made from the mixture of liquid
nitrogen and isopropanol. Once the desired temperature was reached, 1.41 mL (20.4 mmol, 1.5 equiv) of
acetyl chloride dissolved in 10 mL of DCM was slowly added drop wise. The solution was left stirring
for approximately 1 hour until its color turned from orange to dark red. The appearance of the dark red
56
color is characteristic of the formation of the acetylated carbene complex. Afterwards, the solvent was
removed under reduce pressure. In the mean time, 1350 mg of PL-Wang resin (1.7 mmol/g bead,
loading) were pre swell with 10 mL of dry dichloromethane under N2 atmosphere. The next step was
transfer the red compound to the beads container. Since the red compound is O2 and moisture sensitive,
the acetoxy Fischer carbene complex is transferred via cannula, all under a N2 atmosphere. The flask
was then placed on a wrist-action shaker for 120 minutes and the beads were shaken until they “link” the
red compound. The beads were then washed with 3x5 mL of dry and N2 saturated dichloromethane and
3x5 mL of dry and N2 saturated methanol. In the end, they retained a bright red color. This product has
to be stored under N2 atmosphere and low temperature to avoid decomposition. Loading by weight:
100%. (2.295 mmol, MW= 297, gr loaded = 681.6) FT-IR (KBr thin film): 1933, 2060 (Cr-CO),
(Scheme 4).
4.3.1.2 Synthesis of 2-Methoxyphenyl Fischer Carbene Complex
Inside of the hood and under nitrogen atmosphere was placed a 100 mL round bottom flask
equipped with stir bar, air free adaptor, and septum. 10 mL of THF were added and subsequent addition
of 2-Bromo Anisol (3ml, 2.41x 10-2mol, 1 equiv). The mixture was cooled down to -40 °C (Isopropanol
and N2 liquid). Next, tert-buthyl lithium (25ml, 4.82 x 10-2 mol, 1.7M, 2 equiv.) was added. The mixture
was stirred for a period of 45 min from -40 °C to room temperature and an extra 20 min of stirring on
water bath.
While time inside of the dry box, 3gr (13.6 mmol, 1eq) of chromium hexacarbonyl were weighed
on a round bottom flask equipped with a stir bar, air free adaptor, and septum. Subsequent addition of 15
mL of dry Dichloromethane (DCM) was done under N2 atmosphere.
The mixture of 2-Br-anisol was carefully added via cannula over a period of 5-10 minutes at 0°C
(ice bath) to the chromium mixture. The solution turned gradually from yellow to brown. The reaction
57
was left under ice bath and stirring for 2 hours, time after which it adopted a dark brown, and the
chromium hexacarbonyl crystals were disappeared. The solvent was removed under reduce pressure.
In another 50 mL round bottom flask equipped with a stir bar and septum were placed 4.07 gr
(27.2mmol, 2 equiv) of Tetramethylammonium Bromide (TMA) under Nitrogen atmosphere. Then, 20
mL of H2O (O2 free) were added and stirred until the TMA was completely dissolved. Under nitrogen
atmosphere this mixture was transfer to the previous round bottom flask via cannula. The new mixture
was stirred 1 hour long under ice bath. The next step was an extraction of the compound with DCM,
three times 50 mL of DCM each. Dried with magnesium sulfate and filtered. The solvent was removed
under reduce pressure.
The solid formed was placed under N2 atmosphere and dissolved with 10 mL of dry
dichloromethane. The solution was cooled to - 40°C using a slush bath made from the mixture of liquid
nitrogen and isopropanol. Once the desired temperature was reached, 1.41 mL (20.4 mmol, 1.5 equiv) of
acetyl chloride dissolved in 10 mL of DCM was slowly added drop wise. The solution was left stirring
for approximately 1 hour until its color turned from orange to dark red. The appearance of the dark red
color is characteristic of the formation of the acetylated carbene complex. Afterwards, the solvent was
removed under reduce pressure. In the mean time, 1350 mg of PL-Wang resin (1.7 mmol/g bead,
loading) were pre swell with 10 mL of dry dichloromethane under N2 atmosphere. The next step was
transfer the red compound to the beads container. Since the red compound is O2 and moisture sensitive,
the acetoxy Fischer carbene complex is transferred via cannula, all under a N2 atmosphere. The flask
was then placed on a wrist-action shaker for 120 minutes and the beads were shaken until they “link” the
red compound. The beads were then washed with 3x5 mL of dry and N2 saturated dichloromethane and
3x5 mL of dry and N2 saturated methanol. In the end, they retained a bright red color. This product has
to be stored under N2 atmosphere and low temperature to avoid decomposition. Loading by weight:
58
100%. (2.3112 mmol, MW= 327, gr loaded = 755gr) FT-IR (KBr thin film): 1922, 2061 (Cr-CO),
(Scheme 15).
4.3.1.3 Synthesis of Furan Fischer Carbene Complex
Inside of the hood and under nitrogen atmosphere was placed a 100 mL round bottom flask
equipped with stir bar, air free adaptor, and septum. 30 mL of Ether were added and 8.12 mL (98 mmol,
2 equiv) of Tetramethylethylenediamine (TMEDA). Subsequent addition of Furan (5.74ml, 9.8x 102
mol, 2 equiv). The mixture was cooled down to 0 °C (ice bath). Next, n-butyl lithium (14.26 mL, 7.82 x
10-2 mol, 1.5 equiv) was added drop wise. The mixture was stirred for a period of 90 min from under
Nitrogen atmosphere on ice bath.
While time inside of the dry box, 5gr (49 mmol, 1equiv) of chromium hexacarbonyl were
weighed on a round bottom flask equipped with a stir bar, air free adaptor, and septum. Subsequent
addition of 5 mL of dry Terahydrofuran (THF) was done under N2 atmosphere.
The mixture of Furan was carefully added via cannula over a period of 5-10 minutes at 0°C (ice
bath) to the chromium mixture. The solution turned gradually from yellow to brown. The reaction was
left under ice bath and stirring for 2 hours, time after which it adopted a dark brown, and the chromium
hexacarbonyl crystals were disappeared. The solvent was removed under reduce pressure.
In another 50 mL round bottom flask equipped with a stir bar and septum were placed 4.2 g
(27.5mmol, 1.1 equiv) of Tetramethylammonium Bromide (TMA) under Nitrogen atmosphere. Then, 20
mL of H2O (O2 free) were added and stirred until the TMA was completely dissolved. Under nitrogen
atmosphere this mixture was transfer to the previous round bottom flask via cannula. The new mixture
was stirred 1 hour long under ice bath. The next step was extractions of the compound with DCM, three
times 50 mL of DCM each, dried with magnesium sulfate and filtered. The solvent was removed under
reduce pressure.
59
The solid formed was placed under N2 atmosphere and dissolved with 10 mL of dry DCM. The solution
was cooled to – 40 °C using a slush bath made from the mixture of liquid nitrogen and isopropanol.
Once the desired temperature was reached, 2.66 mL (37.5 mmol, 1.5 equiv) of acetyl chloride dissolved
in 10 mL of DCM was slowly added drop wise. The solution was left stirring for approximately 1 hour
until its color turned from orange to purple. The appearance of the purple color is characteristic of the
formation of the acetylated carbene complex. Afterwards, the solvent was removed under reduce
pressure. In the mean time, 2.517 g of PL-Wang resin (1.7 mmol/g bead, loading) were pre swell with
10 mL of dry dichloromethane under N2 atmosphere. The next step was transfer the purple compound to
the beads container. Since the purple compound is O2 and moisture sensitive, the acetoxy Fischer
carbene complex is transferred via cannula, all under a N2 atmosphere. The flask was then placed on a
wrist-action shaker for 120 minutes and the beads were shaken until they “link” the purple compound.
The beads were then washed with 3x5 mL of dry and N2 saturated dichloromethane and 3x5 mL of dry
and N2 saturated methanol. In the end, they retained a bright purple color. This product has to be stored
under N2 atmosphere and low temperature to avoid decomposition. Loading by weight: 100% (4.279
mmol, MW= 287, gr loaded = 1228gr) FT-IR (KBr thin film): 1958, 2041 (Cr-CO), (Scheme 21).
4.3.2 Synthesis of 2,3-Disubstitured-1,4-Naphthoquinones Incorporating Amino and
Carboxyl groups
4.3.2.1 Synthesis of Tert-Butyl Ester NH-Propargylcarbamate [1] and Bis-tert-Butyl Ester
N-Propargylcarbamate [2]
A solution of propargylamine (2.482 mmol) in dry CH2Cl2 (DCM) 8 mL was treated under N2
atmosphere with (Boc)2O (4.784 mmol), DMAP (0.745 mmol), and Et3N (2.5 mmol). The reacton
mixture was stirred at room temperature for 6 h, diluted with ether, and washed with aqueous HCl,
saturated NaHCO3 solution, and brine (H2O-NaCl). The organic layer was dried (MgSO4), and the
60
residue was purified by chromatography on SiO2. (Hexanes/Ethyl acetate 9:1) to yield (1.4 mmol) of the
desired mono and bis- tert-butyl ester N-propargylcarbamate [3 and 4] as a light yellow oil (Table 1,
Scheme 5).
Analysis Section: Synthesis of Mono- tert-butyl ester N-propargylcarbamate [3]
IR (neat): Vmax/(cm-1) 3328 (s), 2127, 2930 (s), 1792 (d), 1600 (none)
13
C NMR (300 MHz; CDCl3) δc : 151.6, 83.1, 79.6, 70.5, 35.7, 28.
1
H NMR (CDCl3; 300 MHz) δ = 4.49 (broads S, 2H), 2.29 (broads, 1H), 1.57 (S, 18H).
HPLC; Retention Time: 6.779 min, 80%.
Synthesis of Bis- tert-butyl ester N-propargylcarbamate [4]
IR (neat): Vmax/(cm-1) 3275 (s), 2150, 2980 (s), 1790 (d), 1600 (none)
13
C NMR (300 MHz; CDCl3) δc : 151.6, 83.1, 79.6, 70.5, 35.7, 28.
1
H NMR (CDCl3; 300 MHz) δ = 4.33 (broads S, 2H), 2.17 (broads, 1H), 1.57 (S, 18H).
HPLC; Retention Time: 6.959 min, 86%.
4.3.2.2 Synthesis of Different Alkynes [3a-h] by Sonogashira Coupling
Cuprous iodine (0.05 mmol) was added to a mixture of bis(triphenylphosphine)palladium
dichloride (0.1 mmol) and diethylamine solution (60 mL) of alkyl iodobenzoates (10 mmol) under
nitrogen atmosphere in a flask equipped with a gas inlet tube and a magnetic stirrer. A slow addition of
mono or bis-tert-butyl ester N-propargylcarbamate [1a-b] was performed at room temperature. The
mixture was stirred for 6 h. After removal of diethylamine under reduced pressure, water was added to
the residue. The mixture was extracted with DCM, which was removed under reduced pressure. The
concentrated was passes over a silica column to remove the catalyst and any byproduct to give the
expected disubstituted alkyne in excellent yield (entries 1-8) (Table 2, Scheme 6).
Analysis of the Alkynes [3a-h]
[3a]. 1H NMR (CDCl3; 300 MHz) δ = 7.95 (d, 2H), 7.45 (d, 2H), 4.59 (s, 2H), 4.35 (m, 2H), 1.53 (s,
18H), 1.37 (t, 3H). 13C NMR (300 MHz; CDCl3) δc : 168, 152, 132, 131,130, 128, 88, 83, 82, 61, 36, 28,
61
14. IR (neat): Vmax/(cm-1) 3331 (N-H none), 2952(d), 1721 (s), 1552 (s), 796 (s). HPLC; Retention
Time: 6.964 min, 91%. [3b]. 1H NMR (CDCl3; 300 MHz) δ = 7.95 (d, 2H), 7.44 (d, 2H), 4.59 (s, 2H),
4.37 (m, 2H), 1.53 (s, 18H), 1.37 (t, 3H). 13C NMR (300 MHz; CDCl3) δc : 168, 152, 134, 132, 131,
130, 127, 123, 88, 83, 82, 61, 36, 28, 14. IR (neat): Vmax/(cm-1) 3421 (N-H none), 2980(d), 1722 (s),
1565 (s), 747 (s). HPLC; Retention Time: 6.979 min, 80%. [3c]. 1H NMR (CDCl3; 300 MHz) δ = 7.95
(d, 1H), 7.73 (m, 2H), 7.43 (d, 1H), 4.58 (s, 2H), 4.35 (m, 2H), 1.52 (s, 18H), 1.36 (t, 3H). 13C NMR
(300 MHz; CDCl3) δc: 168, 152, 134, 133, 132, 129,128, 123, 88, 83, 82, 61, 36, 28, 14. IR (neat):
Vmax/(cm-1) 3346 (N-H none), 2978(d), 1730 (s), 1584 (s), 744 (d). HPLC; Retention Time: 6.966 min,
85%. [3d]. 1H NMR (CDCl3; 300 MHz) δ = 7.99 (d, 1H), 7.8 (d, 1H), 7.45 (m, 1H), 7.15 (m, 1H), 4.65
(s, 2H), 3.95 (d, 3H), 1.55 (s, 18H). 13C NMR (300 MHz; CDCl3) δc : 168, 152, 134, 133, 132, 129,128,
123, 88, 83, 82, 52, 36, 28. IR (neat): Vmax/(cm-1) 3418 (N-H none), 2980(s), 1735 (s), 1596 (m), 759
(s). HPLC; Retention Time: 6.974 min, 82%. [3e]. 1H NMR (CDCl3; 300 MHz) δ = 7.95 (d, 2H), 7.45
(d, 2H), 4.59 (s, 2H), 4.35 (m, 2H), 2.15 (s, 1H), 1.53 (s, 9H), 1.36 (t, 3H). 13C NMR (300 MHz; CDCl3)
δc: 168, 155, 132, 131,130, 128, 88, 83, 82, 61, 37, 28, 14. IR (neat): Vmax/(cm-1) 3331 (N-H, s),
2981(d), 1719 (s), 1524 (s), 757 (d). HPLC; Retention Time: 6.779 min, 80%. [3f]. 1H NMR (CDCl3;
300 MHz) δ = 7.95 (d, 2H), 7.44 (d, 2H), 4.76 (s, 2H), 4.36 (m, 2H), 2.15 (s, 1H), 1.53 (s, 9H), 1.36 (t,
3H). 13C NMR (300 MHz; CDCl3) δc : 168, 155, 134, 132, 131, 130, 127, 123, 88, 83, 82, 61, 37, 28, 14.
IR (neat): Vmax/(cm-1) 3333 (N-H, s), 2981 (s), 1723 (s), 1524 (s), 787 (d). HPLC; Retention Time:
6.788 min, 84%. [3g]. 1H NMR (CDCl3; 300 MHz) δ = 7.95 (d, 1H), 7.73 (m, 2H), 7.43 (d, 1H), 4.8 (s,
2H), 4.45 (m, 2H), 1.52 (s, 9H), 2.15 (s, 1H), 1.36 (t, 3H). 13C NMR (300 MHz; CDCl3) δc: 168, 155,
134, 133, 132, 129,128, 123, 88, 83, 82, 61, 37, 28, 14. IR (neat): Vmax/(cm-1) 3330 (N-H, s), 2982(d),
1720 (s), 1523 (s), 757 (s). HPLC; Retention Time: 6.756 min, 65%. [3h]. 1H NMR (CDCl3; 300 MHz)
δ = 7.99 (d, 1H), 7.8 (d, 1H), 7.45 (m, 1H), 7.15 (m, 1H), 4.65 (s, 2H), 3.95 (d, 3H), 2.15 (s, 1H), 1.55
(s, 9H). 13C NMR (300 MHz; CDCl3) δc: 168, 155, 134, 133, 132, 129,128, 123, 88, 83, 82, 52, 37, 28.
62
IR (neat): Vmax/(cm-1) 3333 (N-H, s), 2952(d), 1721 (s), 1552 (s), 786 (s). HPLC; Retention Time:
6.715 min, 76%.
4.3.2.3 Synthesis of 2,3-Disubstitured-1,4-Naphthoquinones[4a-h]
100 mg of Wang resins with the supported Phenyl Fischer Carbene Complex [A] and 5
equivalent of the alkyne [3a-h] from the Sonogashira coupling (0.575 mmol) were taken in microwave
vial under nitrogen atmosphere; 2 mL of Bu2O were added. This mixture was set up in the microwave
apparatus at 90 ºC for 20 minutes (Dötz Benzannulation). Cleavage of the bead. First of all, the beads
were cleaned with DCM. The cleavage was achieve by adding 10 Equivalents of CAN (1.15 mmol), 2
mL of water, and 5 mL of DCM as solvent, and shaking for 6 h. Then the solution was filtered and
extracted with more DCM. The solvent was removed under reduced pressure. TLC were taken to check
the spots and calculated the possible product spot, followed by Pre TLC to purified the expected
products (2,3-disubstituted-1,4-naphthoquinones[4a-h]). (Table 3, Scheme 7).
Analysis of the Dötz products [4a-h]
[4a]. 1H NMR (CDCl3; 300 MHz) δ = 8.1 (d, 2H), 8.0 (d, 1H), 7.6 (d, 1H), 7.5 (m, 3H), 7.4 (d, 1H), 4.4
(m, 2H), 1.3 (s, 18H). [4b]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 2H), 7.6 (d, 2H), 7.51 (m, 3H), 7.33
(m, 1H), 4.38 (m, 2H), 1.27 (s, 18H). [4c]. 1H NMR (CDCl3; 300 MHz) δ = 8.12 (d, 2H), 7.65 (d, 2H),
7.51 (m, 3H), 7.33 (m, 1H), 4.4 (m, 2H), 1.26 (s, 18H). [4d]. 1H NMR (CDCl3; 300 MHz) δ = 8.13 (d,
2H), 7.65 (d, 2H), 7.52 (t, 3H), 7.33 (m, 1H), 4.36 (m, 2H), 1.25 (s, 18H). [4e]. 1H NMR (CDCl3; 300
MHz) δ = 8.16 (d, 2H), 7.8 (d, 1H), 7.65 (d, 2H), 7.53 (m, 3H), 4.39 (m, 2H), 2.27 (t, 1H), 1.26 (s, 9H).
[4f]. 1H NMR (CDCl3; 300 MHz) δ = 8.1 (d, 2H), 7.6 (m, 2H), 7.55 (d, 2H), 7.33 (m, 2H), 4.36 (m, 2H),
2.54 (t, 1H), 1.26 (s, 9H). [4g]. 1H NMR (CDCl3; 300 MHz) δ = 8.1 (d, 2H), 7.65 (m, 2H), 7.55 (m,
3H), 7.33 (s, 1H), 4.36 (m, 2H), 2.26 (t, 1H), 1.23 (s, 9H). [4h]. 1H NMR (CDCl3; 300 MHz) δ = 8.13
(d, 2H), 7.62 (m, 2H), 7.51 (m, 3H), 7.33 (m, 1H), 4.36 (m, 2H), 2.54 (t, 1H), 1.26 (s, 9H).
63
4.3.3 Optimization of Dötz Benzannulation with Diynes and Different Fischer
Carbene Complexes in Solid-Phase Organic Synthesis
4.3.3.1 Dötz Benzannulation with Phenyl Fischer Carbene Complex
100 mg of Wang resins with the Phenyl Fischer carbene complex [A] and 5 equivalents of the
diynes (0.575 mmol) were taken in different microwave vials under nitrogen atmosphere; 2 mL of DCM
were added. This mixture was set up in the microwave apparatus at different temperatures for different
times (Dötz Benzannulation). Cleavage of the bead. First of all, the beads were cleaned with DCM,
THF, Methanol, THF, and DCM again. The cleavage was achieve by adding 10 Equivalents of CAN
(1.15 mmol), 1mL of water, and 2 mL of DCM as solvent, and shaking for 7 h. Then the solution was
filtered and extracted with more DCM, and three extractions were performed with NaOH 10 % to
eliminate the formed benzoic acid during the Dötz benzannulation. MgSO4 was added to dry the
solution, the solution was filtered and the solvent was removed under reduced pressure (Scheme 7).
Analysis of the Dötz Optimization products [Table 4, entries 1-24]
[Entry 3]. 1H NMR (CDCl3; 300 MHz) δ = 8.206 (d, 2H), 7.809 (d, 2H), 7.57 (m, 4H), 7.38 (m, 6H).
GC; Retention Time: 13.139 min. [Entry 13]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 2H), 7.6 (m,
2H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 24H), 0.88 (t, 3H).
GC; Retention Time: 17.747 min. [Entry 23]. 1H NMR (CDCl3; 300 MHz) δ = 8.189 (d, 2H), 7.658
(d, 2H), 4.379 (m, 2H), 3.86 (m, 2H), 1.946 (s, 2H). GC; Retention Time: 12.526 min.
4.3.3.2 Dötz Benzannulation with 2-Methoxyphenyl Fischer Carbene Complex
100 mg of Wang resins with the 2-Methoxyphenyl Fischer Carbene Complex (0.111mmol) and 5
equivalents of the diynes (0.555 mmol) were taken in different microwave vials under nitrogen
atmosphere; 2 mL of DCM were added. This mixture was set up in the microwave at different
64
temperatures for different times (Dötz Benzannulation). Cleavage of the bead. First of all, the beads
were cleaned with DCM, THF, Methanol, THF, and DCM again. The cleavage was achieved adding 10
equiv of CAN (1.11 mmol), 1mL of water, and 2 mL of DCM as solvent, and shaking for 7 h. Then the
solution was filtered and extracted with more DCM, and three extractions were performed with NaOH
10 % to let loose the formed benzoic acid during the Dötz Benzannulation. MgSO4 was added to dry the
solution, the solution was filtered and the solvent was removed under reduced pressure (Scheme 16).
Analysis of the Dötz Optimization products [Table 11, entries 1-24]
[Entry 3]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 1H), 7.56 (d, 1H), 7.55 (m, 4H), 7.37 (m, 6H), 7.02
(m, 1H), 4.05 (s, 3H). GC; Retention Time: 13.156 min. [Entry 13]. 1H NMR (CDCl3; 300 MHz) δ =
8.19 (d, 1H), 7.6 (m, 1H), 7.05 (m, 1H), 3.94 (s, 3H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m,
4H), 1.31 (m, 2H), 1.25 (s, 24H), 0.88 (t, 3H). GC; Retention Time: 18.376 min. and GC; Retention
Time: 18.760 min.(1-2). [Entry 23]. 1H NMR (CDCl3; 300 MHz) δ = 8.22 (d, 1H), 7.6 (d, 1H), 7.09 (d,
1H), 4.379 (m, 2H), 4.1 (s, 3H), 3.86 (m, 2H), 1.946 (s, 2H). GC; Retention Time: 15.035 min.
4.3.3.3 Dötz Benzannulation of Diynes [6a-i]
100 mg of Wang resins with 2-methoxyphenyl (Scheme 4), phenyl, or furan supported Fischer
carbene complex and 5 equivalents of different diynes [6a-i] were taken in different microwave vials
under nitrogen atmosphere; 3 mL of DCM were added. This mixture was set up in the microwave
apparatus at 85 ºC for 25 minutes (Dötz Benzannulation). Cleavage of the bead. First of all, the beads
were cleaned with DCM, THF, Methanol, THF, and DCM again. The cleavage was achieved adding 10
Equivalents of CAN, 1mL of water, and 2 mL of DCM, followed by shaking for 7 h. Then the solution
was filtered and extracted with more DCM, and three extractions were performed with NaOH 10 % to
remove the formed benzoic acid during the Dötz Benzannulation. MgSO4 was added to dry the solution,
the solution was filtered and the solvent was removed under reduced pressure.
65
Analysis of the Dötz Benzannulation with 2-Methoxyphenyl FCC [Table 12, entries 1-9]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 1H), 7.56 (d, 1H), 7.55 (m, 4H), 7.37 (m, 6H), 7.02
(m, 1H), 4.05 (s, 3H). GC; Retention Time: 16.710 min. [Entry 2]. 1H NMR (CDCl3; 300 MHz) δ = 8.2
(d, 1H), 7.56 (d, 1H), 7.55 (m, 4H), 7.37 (m, 6H), 7.02 (m, 1H), 4.94 (s, 4H), 4.05 (s, 3H). [Entry 3]. 1H
NMR (CDCl3; 300 MHz) δ = 8.22 (d, 1H), 7.6 (d, 1H), 7.09 (d, 1H), 4.379 (m, 2H), 4.1 (s, 3H), 3.86
(m, 2H), 1.946 (s, 2H). GC; Retention Time: 12.183 min. [Entry 4]. 1H NMR (CDCl3; 300 MHz) δ =
8.1 (d, 2H), 7.652 (d, 1H), 4.05 (s, 3H), 2.97 (m, 2H), 2.89 (m, 2H), 2.18 (m, 4H), 1.26 (m, 4H), 0.92 (s,
6H). GC; Retention Time: 12.223min. [Entry 5]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 1H), 7.6 (m,
1H), 7.05 (m, 1H), 3.94 (s, 3H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H),
1.25 (s, 20H), 0.89 (t, 3H). [Entry 6]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 1H), 7.6 (m, 1H), 7.05
(m, 1H), 3.94 (s, 3H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s,
24H), 0.88 (t, 3H). GC; Retention Time: 13.759 min.
Analysis of the Dötz Benzannulation with Phenyl FCC [Table 5, entries 1-9]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 8.206 (d, 2H), 7.809 (d, 2H), 7.57 (m, 4H), 7.38 (m, 6H).
GC; Retention Time: 13.114 min. [Entry 2]. 1H NMR (CDCl3; 300 MHz) δ = = 8.2 (d, 2H), 7.56 (d,
2H), 7.55 (m, 4H), 7.37 (m, 6H), 4.94 (s, 4H). [Entry 3]. 1H NMR (CDCl3; 300 MHz) δ = 8.189 (d,
2H), 7.658 (d, 2H), 4.379 (m, 2H), 3.86 (m, 2H), 1.946 (s, 2H). GC; Retention Time: 11.655 min.
[Entry 4]. 1H NMR (CDCl3; 300 MHz) δ = 1H NMR (CDCl3; 300 MHz) δ = 8.1 (d, 2H), 7.652 (d, 1H),
2.97 (m, 2H), 2.89 (m, 2H), 2.18 (m, 4H), 1.26 (m, 4H), 0.92 (s, 6H). GC; Retention Time: 12.935min.
[[Entry 5]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 2H), 7.6 (m, 2H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63
(m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 20H), 0.88 (t, 3H). [Entry 6]. 1H NMR (CDCl3; 300 MHz)
δ = 8.19 (d, 2H), 7.6 (m, 2H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H),
1.25 (s, 24H), 0.88 (t, 3H).
66
Analysis of the Dötz Benzannulation Furan FCC [Table 16, entries 1-9]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 7.579 (d, 1H), 7.463 (d, 1H), 7.075 (m, 10H), GC;
Retention Time: 12.882min. [Entry 2]. 1H NMR (CDCl3; 300 MHz) δ = 7.6 (d, 1H), 7.45 (d, 1H), 7.3
(m, 5H), 6.99 (m, 5H), 4.94 (s, 4H). [Entry 3]. 1H NMR (CDCl3; 300 MHz) δ = 7.89 (d, 1H), 7.13 (d,
1H), 3.91 (s, 4H), 2.84 (s, 2H). [Entry 4]. 1H NMR (CDCl3; 300 MHz) δ = 7.8 (d, 1H), 6.98 (d, 1H),
4.91 (s, 3H), 2.83 (s, 2H), 2.46 (m, 2H), 1.26 (m, 8H), 0.89 (s, 6H).
4.3.4 CLICK CHEMISTRY
4.3.4.1 Click Chemistry in solid Phase Organic Synthesis
100 mg of the compound [D] (0.115mmol) (Table 6, Scheme 10), compound [E] (0.111mmol)
(Table 13, Scheme 18) or compound [F] (0.116mmol) (Table 17, Scheme 23) from previous Dötz
benzannulation were cleaned with DCM, THF, Methanol, THF, and DCM. Then the beads with the
correspondent Fischer carbene complex were taken in a microwave vial under N2 atmosphere, different
azides [S] (0.575 mmol, 5 equiv.) were suspended in a 2:1 mixture of CH3CN and Et3N (3mL) in the
same vial equipped with a small magnetic stirring bar. To this was added copper iodide (0.0575 mmol,
10mg). The mixture was then irradiated at different temperatures and different periods of time in a
microwave machine, after completion of the reaction; the vial was cooled down to 50 ºC. It was then
filtered and washed with DCM, THF, Methanol, THF, and DCM again. The beads were dry under
reduce pressure.
After clean the beads, they were place on a 4 mL vial where a solution ([CAN 0.575mmol, 5
equiv, 320 mg] and 0.5 mL H20, after shake the solution, 2 mL of DCM were added) was pre-prepared.
The vial was place to shake for a period of time of 12 h, then the beads were filtered down using DCM
67
to extract the organic product, 3 extractions were performed with NaOH 10% to clean the product from
benzoic acid.
Analysis of click chemistry with Phenyl FCC [Table 6, entries 1-34]
[Entry 1 and 24]. 1H NMR (CDCl3; 300 MHz) δ = 8.12 (d, 2H), 7.87 (d, 2H), 7.35 (m, 2H), 6.92 (m,
2H), 5.13 (s, 3H), 4.36 (m, 2H), 3.83 (m, 2H), 1.87 (s, 2H). GC; Retention Time: 11.650 min. [Entry 3
and 31]. 1H NMR (CDCl3; 300 MHz) δ = 8.12 (d, 2H), 7.65 (d, 2H), 7.57 (m, 4H), 7.38 (m, 6H), 7.35
(m, 2H), 6.92 (m, 2H), 3.9 (s, 2H), 3.75 (s, 3H). GC; Retention Time: 12.51 min. [Entry 5]. 1H NMR
(CDCl3; 300 MHz) δ = 8.20 (d, 2H), 7.81 (d, 2H), 7.61 (m, 4H), 7.51 (m, 6H), 7.37 (m, 4H). [Entry 6
and 17]. 1H NMR (CDCl3; 300 MHz) δ = 8.1 (d, 2H), 7.652 (d, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 3.9 (s,
2H), 3.75 (s, 3H), 2.97 (m, 2H), 2.89 (m, 2H), 2.18 (m, 4H), 1.26 (m, 4H), 0.92 (s, 6H). GC; Retention
Time: 12.954min. [Entry 8 and 16]. 1H NMR (CDCl3; 300 MHz) δ = 8.189 (d, 2H), 7.658 (d, 2H), 7.35
(m, 4H), 2.97 (m, 2H), 2.89 (m, 2H), 2.18 (m, 4H), 1.26 (m, 4H), 0.92 (s, 6H). [Entry 9 and 28]. 1H
NMR (CDCl3; 300 MHz) δ = 8.19 (d, 2H), 7.6 (m, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 3.9 (s, 2H), 3.75 (s,
3H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 24H), 0.88 (t, 3H).
[Entry 10]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 2H), 7.6 (m, 2H), 7.35 (m, 4H), 2.35 (m, 2H), 2.26
(m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 24H), 0.88 (t, 3H).
Analysis of click chemistry with 2-Methoxyphenyl FCC [Table 13, entries 1-16]
[Entry 11]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 1H), 7.6 (m, 1H), 7.05 (m, 1H), 7.35 (m, 2H), 6.92
(m, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 3.94 (s, 3H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H),
1.31 (m, 2H), 1.25 (s, 24H), 0.88 (t, 3H). GC; Retention Time: 13.738min. [Entry 12]. 1H NMR
(CDCl3; 300 MHz) δ = 8.19 (d, 1H), 7.6 (m, 1H), 7.05 (m, 1H), 3.94 (s, 3H), 2.35 (m, 2H), 2.26 (m,
4H), 1.93 (m, 6H), 1.8 (m, 3H), 1.53 (m, 6H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 24H),
0.88 (t, 3H). GC; Retention Time: 14.319 min. [Entry 13]. 1H NMR (CDCl3; 300 MHz) δ = 8.19 (d,
1H), 7.6 (m, 1H), 7.05 (m, 1H), 7.01 (m, 4H), 3.94 (s, 3H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H),
68
1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 24H), 0.88 (t, 3H). GC; Retention Time: 17.416 min. [Entry 14]. 1H
NMR (CDCl3; 300 MHz) δ = 8.2 (d, 1H), 7.56 (d, 1H), 7.55 (m, 4H), 7.37 (m, 6H), 7.02 (m, 1H), 7.35
(m, 2H), 6.92 (m, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 4.05 (s, 3H). GC; Retention Time: 19.923 min. [Entry
15]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 1H), 7.56 (d, 1H), 7.55 (m, 4H), 7.37 (m, 6H), 7.02 (m,
1H), 4.05 (s, 3H), 1.93 (m, 6H), 1.8 (m, 3H), 1.53 (m, 6H). GC; Retention Time: 20.653 min. [Entry
16]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 1H), 7.56 (d, 1H), 7.55 (m, 4H), 7.37 (m, 6H), 7.02 (m,
1H), 7.35 (m, 4H), 4.05 (s, 3H). GC; Retention Time: 19.885 min.
4.3.4.2 Click chemistry but In Situ Formation of Catalyst
100 mg of the compound [D] (0.115mmol) (Table 7, Scheme 11) from previous Dötz
benzannulation were cleaned with DCM, THF, Methanol, THF, and DCM. Then the beads with the
phenyl Fischer carbene complex were taken in a microwave vial under N2 atmosphere, different azides
[S] (0.575 mmol, 5 equiv) were suspended in a 2:1 mixture of CH3CN and Et3N (3mL) in the same vial
equipped with a small magnetic stirring bar. To this was added copper turnings (50mg) and copper
sulfate solution (1M, 200 µl) 47 . The mixture was then irradiated for 25 min at 85 ºC in a microwave
instrument, after completion of the reaction; the vial was cooled down to 50 ºC. It was then filtered and
washed with DCM, THF, Methanol, THF, and DCM again. The beads were dry under reduce pressure.
After clean the beads, they were place on a 4 mL vial were a solution ([CAN 0.5mmol, 5 equiv,
320 mg] and 0.5 mL H20, after shake the solution 2 mL of DCM was added) was pre-prepared. The vial
was place to shake for a period of time of 12 h, then the beads were filtered down using DCM to extract
the organic product, 3 extractions were performed with NaOH 10% to clean the product from benzoic
acid.
Analysis of click chemistry with Phenyl FCC [Table 7, entries 1-6]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 8.12 (d, 2H), 7.87 (d, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 5.13
(s, 3H), 4.36 (m, 2H), 3.83 (m, 2H), 1.87 (s, 2H). [Entry 2]. 1H NMR (CDCl3; 300 MHz) δ = 8.12 (d,
69
2H), 7.65 (d, 2H), 7.57 (m, 4H), 7.38 (m, 6H), 7.35 (m, 2H), 6.92 (m, 2H), 3.9 (s, 2H), 3.75 (s, 3H).
[Entry 3]. 1H NMR (CDCl3; 300 MHz) δ = 8.12 (d, 2H), 7.87 (d, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 5.13
(s, 2H), 1.87 (s, 2H), 1.26 (m, 12H).
4.3.4.3 Click chemistry but In Situ Formation of Catalyst and Polar Solvents
100 mg of the compound [D] (0.115mmol) (Table 8, Scheme 12), compound [E] (0.111mmol)
(Table 14, Scheme 19) or compound [F] (0.116mmol) (Table 18, Scheme 24) were cleaned with DCM,
THF, Methanol, THF, and DCM , then the beads with the correspondent Fischer carbene complex were
taken in a microwave vial under N2 atmosphere, different azides [S] (0.575 mmol, 5 equiv) were
suspended in a 1:1 mixture of H2O and t-BuOH (1.5mL each) in the same vial equipped with a small
magnetic stirring bar. To this was added copper turnings (50 mg) and copper sulfate solution (1M, 200
µl) 48 . The mixture was then irradiated for 25 min at 85 ºC in a microwave machine, after completion of
the reaction; the vial was cooled down to 50 ºC. It was then filtered and washed with DCM, THF,
Methanol, THF, and DCM again. The beads were dry under reduce pressure.
After clean the beads, they were place on a 4 mL vial were a solution ([CAN 0.5mmol, 5 equiv,
320 mg] and 0.5 mL H20, after shake the solution 2 mL of DCM was added) was pre-prepared. The vial
was place to shake for a period of time of 12 h, then the beads were filtered down using DCM to extract
the organic product, 3 extractions were performed with NaOH 10% to clean the product from benzoic
acid.
Analysis of click chemistry with Phenyl FCC [Table 8, entries 1-4]
[Entry 2 and 3]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 2H), 7.89 (d, 2H), 7.65 (m, 5H), 7.41 (m, 5H),
6.96 (m, 5H), 4.52 (s, 2H).
70
Analysis of the Dötz Benzannulation Furan FCC [Table 18, entries 1-3]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 8.144 (d, 1H), 7.868 (d, 1H), 7.635 (m, 4H), 7.423
(m, 8H), 7.132 (m, 8H).
4.3.4.4 In Situ Click chemistry Using different Halides and NaN3 to form different
Azides and In Situ Formation of Catalyst and Polar Solvents
100 mg of phenyl Fischer carbene complex [D] (0.115mmol) (Table 9, Scheme 13) or 2Methoxyphenyl Fischer carbene complex [E] (0.111mmol) (Table 15, Scheme 20) from Dötz
benzannulation using 1,4-diphenyl butadiyne were cleaned with DCM, THF, Methanol, THF, and DCM.
Then, the beads with the Fischer Carbene Complex were taken in a microwave vial under N2
atmosphere, sodium azide (0.6 mmol) and different halides [T] (0.5 mmol) were suspended in a 1:1
mixture of H2O and t-BuOH (1.5mL each) in the same vial equipped with a small magnetic stirring bar. .
To this was added copper turnings (50mg) and copper sulfate solution (1M, 200 µl) 49 . The mixture was
then irradiated for different times at different temperatures in a microwave machine, after completion of
the reaction; the vial was cooled down to 50 ºC. It was then filtered and washed with DCM, THF,
Methanol, THF, and DCM again. The beads were dry under reduce pressure.
After clean the beads, they were place on a 4 mL vial were a solution ([CAN 0.5mmol, 5 equiv,
320 mg] and 0.5 mL H20, after shake the solution 2 mL of DCM was added) was pre-prepared. The vial
was place to shake for a period of time of 12 h, then the beads were filtered down using DCM to extract
the organic product, 3 extractions were performed with NaOH 10% to clean the product from benzoic
acid.
Analysis of click chemistry with Phenyl FCC [Table 9, entries 1-2]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 2H), 7.89 (d, 2H), 7.65 (m, 5H), 7.41 (m, 5H), 6.96
(m, 5H), 4.52 (s, 2H). [Entry 2]. H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 2H), 7.6 (m, 2H), 6.96 (m,
71
5H), 4.52 (s, 2H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31 (m, 2H), 1.25 (s, 20H),
0.88 (t, 3H).
Analysis of click chemistry with 2-methoxyphenyl FCC [Table 15, entries 1-2]
[Entry 1]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 1H), 7.89 (d, 2H), 7.65 (m, 5H), 7.41 (m, 5H), 6.96
(m, 5H), 4.52 (s, 2H), 3.93 (s, 2H). [Entry 2]. H NMR (CDCl3; 300 MHz) δ = 8.19 (d, 1H), 7.6 (m, 2H),
6.96 (m, 5H), 4.52 (s, 2H), 3.93 (s, 2H), 2.35 (m, 2H), 2.26 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31
(m, 2H), 1.25 (s, 20H), 0.88 (t, 3H).
4.3.4.5 Click chemistry Using different Halides, NaN3, and CuI
100 mg of phenyl Fischer carbene complex [D] (0.115mmol) (Table 10, Scheme 14) from Dötz
benzannulation using different diynes (0.1mmol, 1 equiv) were cleaned with DCM, THF, Methanol,
THF, and DCM again, and then the beads with the correspondent Fischer carbene complex were taken in
a microwave vial under N2 atmosphere, sodium azide (0.6mmol, 6 equiv) and the correspondent halide
[T] (0.5 mmol, 5 equiv) were suspended in a 2:1 mixture of CH3CN and Et3N (3 mL) in the same vial
equipped with a small magnetic stirring bar. To this was added copper iodide (0.0575 mmol, 10mg). The
mixture was then irradiated for 25 min at 130 ºC in a microwave machine, after completion of the
reaction; the vial was cooled down to 50 ºC. It was then filtered and washed with DCM, THF, Methanol,
THF, and DCM again. The beads were dry under reduce pressure.
Analysis of click chemistry with Phenyl FCC [Table 10, entries 1-8]
[Entry 1 and 4]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 2H), 7.89 (d, 2H), 7.65 (m, 5H), 7.41 (m, 5H),
6.96 (m, 5H), 4.52 (s, 2H). [Entry 2]. 1H NMR (CDCl3; 300 MHz) δ = 8.2 (d, 2H), 7.89 (d, 2H), 7.65
(m, 5H), 7.41 (m, 5H), 6.99 (s, 5H), 5.02 (s, 1H), 2.25 (s, 3H). [Entry 3]. 1H NMR (CDCl3; 300 MHz) δ
= 8.0 (d, 2H), 7.8 (d, 2H), 7.60 (m, 4H), 7.49 (m, 4H), 6.98 (m, 2H), 4.33 (t, 2H), 2.47 (m, 2H), 2.27 (m,
2H), 1.42 (m, 2H), 1.33 (m, 14H), 0.96 (s, 3H). [Entry 5]. 1H NMR (CDCl3; 300 MHz) δ = 8.0 (d, 2H),
72
7.8 (m, 2H), 6.96 (m, 5H), 4.67 (s, 2H), 2.34 (m, 2H), 2.05 (m, 4H), 1.63 (m, 2H), 1.49 (m, 4H), 1.31
(m, 2H), 1.25 (s, 20H), 0.88 (t, 3H). [Entry 6]. 1H NMR (CDCl3; 300 MHz) δ = 8.0 (d, 2H), 7.58 (d,
2H), 7.48 (m, 2H), 7.39 (m, 3H), 4.92 (d, 1H), 2.56 (s, 3H), 1.57 (m, 4H), 1.53 (m, 4H), 1.46 (m, 4H),
1.31 (m, 2H), 1.26 (s, 20H), 0.89 (t, 3H).
4.3.4.6 Cleavage of the Click Chemistry Product
After clean the beads, they were place on a 4 mL vial were a solution ([CAN 0.5mmol, 5 equiv,
320 mg] and 0.5 mL H20, after shake the solution 2 mL of DCM was added) was pre-prepared. The vial
was place to shake for a period of time of 12 h, then the beads were filtered down using DCM to extract
the organic product, 3 extractions were performed with NaOH 10% to clean the product from benzoic
acid.
73
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46
The peaks due to the resin decomposition are: 1HNMR (300MHz, CDCl3) δ = 1.55 (s), 1.26 (s), 0.89
(m). This was proved by an experiment were a 100 mg of Wang resin were treated at the same
condition for cleavage that all experiments (CAN = 320 mg, 0.5 mmol) DCM/H2O.
47
Frokin Prasad et al, Organic letters, 2004, Vol. 6, 23, 4224.
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Frokin Prasad et al, Organic letters, 2004, Vol. 6, 23, 4224.
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Organometallic Chemistry II, 1995, 12, 469-547
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79
CURRICULUM VITAE
Alejandro Bugarin was born in Zacatecas, Mexico, on February 29, 1980. Second
son of Mr. Noe Bugarin and Mrs. Clementina Cervantes. After completing his studies at
CBTa # 137 High School, Tepechitlan, Zacatecas, in 1998. He entered at The
Autonomous University of Zacatecas in 1998, and received his Bachelor of Science
degree (biology chemistry and pharmacy) in 2003. In August 2003, he joined the
Graduate School of the University of Texas at El Paso.
Upon graduation, He will attend Texas A&M University, College Station, Texas,
in the Department of Chemistry, in pursuit of a Ph.D. in Organic Chemistry.
Permanent Address:
6840 N Millmark Ave.
Long Beach, CA, 90805.
This thesis was typed by Alejandro Bugarin.
80
Waste Disposal Information
All toxic materials were disposed of in accordance with “Prudent Practices in the
Laboratory”; National Academy Press; Washington, DC 1995.
81
Solid-phase Organic Synthesis of 2-tridecanyl
1,4-naphthoquinone and 2-tridecanyl 1,4naphtadiol that form Redox-active Micelles
Alejandro Bugarin, Juan J. Camacho, Itzia Cruz, Juan C. Noveron,
Luis E. Martinez*
Department of Chemistry, University of Texas at El Paso, El Paso, TX 79912 U.S.A.
luisem@utep.edu, jcnoveron@utep.edu
Received Date (will be automatically inserted after manuscript is accepted)
ABSTRACT
R
R
R = O or OH
A new amphiphilic compound is reported. It is based on a newly designed 1,4-naphtoquinone derivatives that
contains polar and no polar properties that self-assembles.
are insoluble in water and require the addition of cosolvents such as DMSO to generate aqueous solutions
suitable for biological applications. Another common
strategy for their aqueous administration is to introduce
hydrophilic groups into the core structure, but this approach
has a significant impact on the biodistribution and activity
of such derivatives. Herein we report the solid-phase
organic synthesis of amphiphilic naphthoquinones that
posses a single hydrocarbon chain at the second position
and are able to generate vesicles in water with chemicallyswitchable headgroups. This solid-phase strategy serves as a
core method to incorporate new solvent-exposed functional
groups on vesicles of this type and generate large libraries
of varying biological activity.
Naphthoquinones and their derivatives have been studied
for many years in an effort to understand their biological
activity 1 . They are naturally occurring quinones that possess
a variety of pharmacological effects towards bacteria, fungi,
as well as having cytostatic effects. 2 Their biological
activity arises primarily from the redox active quinone that
interferes with biochemical oxidation processes, 3
particularly microsomal lipid peroxidation. In view of their
potential role in medicine, a myriad of derivatives of
naphthoquinones have been reported and reviewed
recently. 4 However, many derivatives of these compounds
1
Lavigene, J. J.; Anslyn, E. V. Angew. Chem., Int. Ed.
1999, 38, 3666-3669.
2 Molina Portela Mp, Pahn Em De, Galeffi C, Stoppani Aom Rev Arg Microbio 1991. 23:
,
.
The Fisher carbene complex in solid-phase (FCC-SPOS)
was used to develop a core synthesis for amphiphilic
naphthoquinones. It is based on immobilized Fischer
carbene complexes, which allows for regioselective
formation of naphthoquinones with predetermined
substitutions. 5 This approach also allows for the formation
of single benzannulation products from alkynes, which is an
1-14.
3
a) Dubin et al, Biochem Pharmacol , 1990, 39: 1151-1160.
b) Molina Portela et al, Biochem Pharmacol , 1996, 51:
275-283. c) Molina Portela et al Biochem Pharmacol ,
1996, 52: 1875-1882.
4
a) Ferreira de Santana et al., Revta Inst Antibiot Univ
Recife, 1968, 8: 89-94. b) Chau et al, Free Radical Biol
Med, 1998, 24: 660-670. c) Frydman et al, Cancer Res,
1997, 57:620-627. d) Dolan et al., , Anti-cancer Drugs,
1998, 9: 437-448.
5
Wulff, W. D. in Comprehensive Organometallic
Chemistry II, Abel, E.W.; Stone, R.G.A.; Wilkinson, G.,
Eds.; Pergamon Press, 1995, Vol. 12, 469.
82
Cr(CO) 5
Cr(CO) 5
O Li
C r (CO ) 6 / TH F
O N Me 4
2
1
Cl
Br N M e 4 H 2 0 (O 2 Free)
0 ºC / 1 h
0 'C / 2 hr
3
R
Cr(CO) 5
Cr(CO) 5
HO
PL- W ang RESIN
O
-73
+
O
DC
M/
O
ºC,
Ac
Yield 98%
Link
90
min
Li
DCM / Shake 5 h
5
6
R = -CH 2 (CH 2 ) 11 CH 3
4
Yield 100%
loading
O
z
ot
D
85
n
io
at
ul
nn
in
za
m
en
B
35
ºC
w
M
OH
Link
O
O
NaBH 4
CAN
R
(OC) 3 Cr
OH
R
2-PROPA NOL/ THF
H 2 O / D CM
Shaking 12 h
R
7
O
8
Yiel d 63 %
OH
9
Yield 52 %
Scheme 1. Solid-phase synthesis of 2-tridecanyl-1,4-naphthoquinone and 2-tridecanyl-1,4-naphthadiol.
added advantage since in the absence of the solid-support,
the reaction would generate several products with different
configurations that would require extensive purification
techniques.
The amphiphilic naphthoquinone was prepared by a
modified method originally developed by Connor. 6 The
synthesis of polymer-supported Fischer carbene complex
was obtained in four steps (Scheme 1) from commercially
available chromium hexacarbonyl and phenyllithium by Oacylation of [tetramethylammonium][(2phenyl)oxidocarbene]pentacarbonylchromium 3 with acetyl chloride
followed by reaction with PL-Wang resin (Polymer
Laboratories, 1% crosslinked 1.7 mmol/g) to produce resinbound Fischer carbene complex 5 with 100% loading.
Resin loading of the carbene complex can be easily
monitored qualitatively by colorimetric analysis, the beads
turn a dark red color. The appearance of characteristic CrCO stretches at 2060 and 1933 cm-1 in the IR spectrum of 5
correspond to CO stretches found in analogous aryl carbene
complexes. 7 Under optimized conditions, the Dötz
benzannulation of 5 was performed with 1-pentadecyne 6
followed by the oxidative cleavage of the resulting resinbound naphthol in overall good yield (63%). The
corresponding of 2-tridecanyl-1,4-naphthadiol 9 was
obtained by isopropanol/THF reaction of sodium
borohydride with 8.
5 nm
Figure 1. Atomic Force Microscopy of 8 in mica.
The self-assembly properties of the resulting amphiphilic
naphthoquinones were studied in water. Aqueous solutions
of compound 8 (1%, wt) were sonicated for 30 min. and
then diluted to give solutions of varying concentrations. At
low concentrations, 8 forms micelles with diameter of 5 nm,
as indicated with Atomic Force Microscopy, Figure 1. This
is to be expected since amphiphiles with high-volume head
groups have a preference to organize into micelles due to
their conical shape. However, when 2 is dispersed at higher
concentration >0.5% wt, they give vesicles of 264 nm.
Aqueous solutions of compound 9 result in vesicle
formation of similar size (260 nm, see Supplementary
Material). These solutions were treated with phenoxazine
dye nile red indicator, which is a fluorescent indicator used
to localize lipid phases within membranes. Nile red alone is
6
(a) Connor, J. A.; Jones, E. M. J. Chem. Soc. A, 1971,
1974. . (b) Connor, J.A.; Jones, E. M. J. Chem. Soc., Chem
Commun., 1971, 570
7
(a) McCallum, J.S.; Kunng, F.A.; Gilbertson, S.R.; Wulff,
W.D. Organometallics 1988, 7, 2346. (b) Hafner, A.;
Hegedus, L.S.; deWeck, G.; Hawkins, B.; Dötz, K.H. J. Am.
Chem. Soc. 1988, 25, 8413.
83
Figure 2. Optical microcopy of vesicles of 8 before (a) and after (b) staining with Nile red indicator.
Inset: DLC distribution of 8.
almost non-fluorecent in water, but undergoes fluorescent
enhancement with blue shift in hydrophobic environments.
When vesicles formed with 8 are stained with Nile red in
water, they reveal a homogeneous dispersion of vesicles.
In conclusion, the solid-support synthesis and
characterization of 2-tridecanyl-1,4-naphthoquinone and 2tridecanyl-1,4-naphthadiol was reported. These molecules,
depending on the concentration, self-assemble into micelles
and liposomes in water and exhibit redox-active properties.
The method used for the synthesis of these amphiphilic
molecules can be employed to form further derivatives that
present new functional groups on the surface of liposomes
or micelles.
Cyclic
voltammetry
measurements
of
8
in
dichloromethane revealed a quasi reversible redox potential
of 0.504 V, Figure 1, suggesting that the redox active
properties are retain in the molecule.
Acknowledgement.
Figure 3. Cyclic voltammetry of 8.
Supplementary Material.
84
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