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A study of palladium-catalyzed amination of benzylic carbonates via η3-benzyl metal complexes, utilizing N-heterocyclic carbene ligands and microwave acceleration

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A STUDY OF PALLADIUM-CATALYZED AMINATION OF
BENZYLIC CARBONATES VIA TI 3 -BENZYL METAL COMPLEXES, UTILIZING
N-HETEROCYCLIC CARBENE LIGANDS AND MICROWAVE ACCELERATION.
A Thesis
Presented to the
Faculty of
California State University, Fullerton
In Partial Fulfillment
of the Requirements for the Degree
Master of Science
in
Chemistry
By
Elaine J. Mina
Approved by:
Christopher J.T. Hyland, Committee Chair
Department of Chemistry and Biochemistry
Date
H.J. Petei/de Lijser, Member
Department of Chemistry and Biochemistry
Date
1 l\ll^oo*\
Kami Sorasaened, Member
Department of Chemistry and Biochemistry
Date
UMI Number: 1468532
Copyright 2009 by
Mina, Elaine J.
INFORMATION TO USERS
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ABSTRACT
-3
While palladium r| -benzyl complexes have been reported as intermediates in
reactions, they are not as well known or well studied as palladium r|3-allyl complexes. A
study of the palladium-catalyzed amination of benzyl carbonates via r|3-benzyl complexes
has been carried out, utilizing biphosphine and N-heterocyclic carbene (NHC) ligands
with microwave heating. These new conditions significantly enhance the practicality of
this reaction. A carbene catalyzed decarbonylation was noted as a significant sidereaction and conditions have been found to reduce this, with size of the NHC ligand
being found to be a significant factor in determining product distributions. A variety of
methods to generate the active catalyst have been investigated and by altering the NHC
by producing a silver complex of itself proved to be the optimum process. Reaction
times have varied by the different methods, but a trend showing a decrease in both
reaction time and temperature occurs when administering the silver complexes.
11
TABLE OF CONTENTS
ABSTRACT
ii
LIST OF FIGURES
iv
LIST OF SCHEMES.
v
LIST OF TABLES
vii
ABBREVIATIONS...
.
ix
ACKNOWLEDGMENTS
xii
Chapter
1. INTRODUCTION
>
1
N-Heterocyclic Carbenes as Ligands for Palladium Catalysts
28
Proposed Research
33
2.
MATERIALS AND METHODS
35
3.
RESULTS AND DISCUSSION
75
Microwave Accelerated Amination of Benzylic Carbonates with Palladium
N-Heterocyclic Carbene Catalysts
Microwave Accelerated Amination of Benzylic Carbonates with Palladium
N-Heterocyclic Silver Carbene Catalysts
Conclusion
Future Work
Microwave Accelerated Heck reactions of Benzylic Carbonates with
Palladium Phosphine Catalysts
iii
82
92
109
110
110
LIST OF FIGURES
Figure
1.
Palladium-catalyzed coupling reactions of benzylic derivatives
2.
Models for r\ -allyl and r\ -benzyl intermediate complexes and the naphthalene
system
2
4
3.
r| -Benzyl complex produced from naphthylmethyl ester
4.
5.
Inhibitors of breast cancer cell growth
Biphosphine ligands studied in palladium-catalyzed substitution reactions of
benzylic derivatives
7
14
20
6.
Structures of C-S and C-N containing compounds
24
7.
Imidazolium salts and Pd-NHC catalysts
29
8.
NHCs employed in our investigations
84
9.
Generation of silver NHCs
93
;
IV
LIST OF SCHEMES
Scheme
1.
Oxidative addition of benzyl halides to palladium(O) complexes
3
2.
Palladium-catalyzed reactions of allylic substrates
6
3.
Cycloaddition of allyl silane
6
4.
Palladium-catalyzed nucleophilic substitution of naphthylmethyl and 1naphthylethyl esters
7
5.
6.
Mechanism for asymmetric palladium-catalyzed nucleophilic substitution of
1-naphthylethyl acetates
11
Enantioselective palladium-catalyzed substitution of l-(2-naphthyl)ethyl
acetate
12
7.
Palladium-catalyzed amination of acetates
13
8.
Formation of benzylformamide product
14
9.
Reactivity of quinoline- and isoquinoline-based heteroaromatic substrates
15
10. Different pathways in the case of acetates
17
11.
19
Catalytic benzylation of dimethyl malonate and 2-substituted malonates
12. Catalytic benzylic amination of benzylic esters
21
13.
22
Possible reaction mechanism of catalytic benzylation
14. Palladium-catalyzed benzylation of active methine compounds
23
15. Palladium-catalyzed sulfonylation of benzylic carbonates
23
v
16. Palladium-catalyzed C-N bond formation
25
17. Mechanism for amination of aryl halides
26
18. Buchwald-Hartwig amination
30
19. Cross-coupling of substituted anilines with aryl chlorides...
30
20. Buchwald-Hartwig amination involving Pd-NHC complex
31
21. Tsuji-Trost methodology with Pd-NHC ligands
32
22. Formation of alcohol byproduct by nucleophilic attack of water on the
r|3-benzyl palladium intermediate
81
23. Allylic substitution of allylic acetates
83
24. Suzuki-Miyaura cross-coupling of benzylic carbonates with arylboronic acids.. 110
25. Oxidative addition of carboxylate to palladium(O)
111
26. The Heck reaction
112
VI
LIST OF TABLES
Table
1.
2.
Palladium-catalyzed substitution of enantiomerically pure 2-naphthylmethyl
carbonate
8
Asymmetric palladium-catalyzed nucleophilic substitution of racemic
naphthylethyl esters
9
3.
Products from reactions of quinoline and isoquinoline acetates
16
4.
Hartwig's study of relative rates
76
5.
Benzylic amination of 9 utilizing DPEphos with microwave heating
78
6.
Benzylic amination of 9 with morpholine utilizing N-heterocyclic carbene
ligands and BuLi
Benzylic amination of 9 with morpholine utilizing N-heterocyclic carbene
ligands and cesium carbonate with varying temperature
,
87
8.
Benzylic amination of 9 with morpholine utilizing N-heterocyclic carbene
ligands and cesium carbonate at constant temperature
'
90
9.
Benzylic amination of 9 with morpholine utilizing silver N-heterocyclic
carbene ligands
94
10. Benzylic amination of 9 with morpholine utilizing silver N-heterocyclic
carbene ligands in a mixed solvent system
99
7.
11.
Benzylic amination of 9 with morpholine utilizing silver N-heterocyclic
carbene ligands in acetone
12. Benzylic amination of 9 with dibutylamine utilizing silver N-heterocyclic
carbene ligand
vii
85
100
102
13. Benzylic amination of 9 with piperidine utilizing silver N-heterocyclic carbene
ligand
105
14. Benzylic amination of 9 with pyrrolidine utilizing silver N-heterocyclic carbene
ligand
107
15. Benzylic carbon-carbon bond formation of 9 with acrylonitrile by Heck
reaction
viii
112
ABBREVIATIONS
[Pd(allyl)Cl]2
palladium allyl chloride
2[Pd(C3H5)(diene)]BF4
r|3-allyl( 1,5-cyclooctadiene)palladium(II) tetrafluoroborate
Ag 2 0
silver (I) oxide
AgBF4
silver (I) tetrafluoroborate
AgCl
silver chloride
BDPP
2,4-bis(diphenylphosphino)pentane
BINAP
2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl
BIPHEP
2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-l,r-biphenyl
BSA
N,0-bis(trimethylsilyl) acetamide
CH2CI2
methylene chloride, dichloromethane
CHCI3
chloroform
CHIRAPHOS
bis(diphenylphosphino)butane
CO
carbon monoxide
COD
1,5-cyclooctadiene
Cs 2 C0 3
cesium carbonate
DIOP
isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane
IX
DME
dimethoxyethane
DMF
dimethyl formamide
DMPU
i^JV-dimethylpropyleneurea
DMSO
dimethylsulfoxide
DPEphos
bis(2-diphenylphosphinophenyl)ether
DPPB
l,4-bis(diphenylphosphino)butane
Dppbenzene
1,2-bis(diphenylphosphino)benzene
DPPE
l,2-bis(diphenylphosphino)ethane
DPPF
1,1 '-bis(diphenylphosphino)ferrocene
Dppm
1,1 -bis(diphenylphosphino)methane
DPPP
1,3 -bis(diphenylphosphino)propane
DPPPent
1,3-bis(diphenylphosphino)pentane
DUPHOS
2,5-diisopropylphospholano benzene
ee
enantiomeric excess
Et3N
triethylamine
EtOAc
ethyl acetate
GCFID
gas chromatography flame ionization detector
GCMS
gas chromatography mass spectrometer
H 2 S0 4
sulfuric acid
K2CO3
potassium carbonate
MeCN
acetonitrile
X
MeOH
methanol
NaHC0 3
sodium bicarbonate
OC0 2 Me
methyl carbonate
OCOMe
acetate
Pd(dba)2
bis(dibenzylideneacetone)palladium(0)
Pd(dba)3
tris(dibenzylideneacetone)palladium(0)
Pd(OAc)2
palladium(II) acetate
Pd(PPh3)4
palladium(O) tetrakis
Pd2(dba)3
tris(dibenzylideneacetone)dipalladium(0)
PdCl2
palladium(II) chloride
PPh3
triphenylphosphine
PROPHOS
l,2-bis(diphenylphosphino)propane
THF
tetrahydrofuran
TiCl4
titanium(IV) tetrachloride
Xantphos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
XI
ACKNOWLEDGMENTS
First and foremost, I would like to express my gratitude to Dr. Christopher
Hyland for his continuous guidance and support throughout my graduate school career
and laboratory research. Without his patience, motivation, and enthusiasm I could not
have written this thesis. I could not have asked for a more amazing experience or better
advisor.
I would like to thank my committee members, Dr. de Lijser and Dr. Sorasaenee.
Without Dr. de Lijser's guidance, I would not have been so lucky to end up in the organic
chemistry laboratory that I did. His assistance throughout the years has been greatly
appreciated. Thank you to Dr. Sorasaenee for his support in such a short time. He has
been an inspiration to always be uplifting and hardworking. I thank my fellow labmates
who have been there every step of the way; thanks for all the talks, laughs, and lunches.
Thank you Raymond and Linh, we will always be the OG P-Carbs!
I am grateful to all my friends, most importantly JEEJ90. Thank you for the
amazing adventure. You will always be my roomies and my brothers. Jonathan, you
have always inspired me to reach for the stars. Eugene, you have been an incredible
support throughout the years, both emotionally and physically. I could not have done it
without your love and care. Jeffrey, you have taught me that NOTHING is impossible.
xii
Thank you to my sister Melissa. Ness, you are so incredible and I am so blessed
to have you to look up to and to lean on. I love you. To my brother Jeffrey, thank you
for your love and support.
Last but definitely not least, I thank the two most important people in my life, my
mom and dad (Nick and Imelda Mina). I am forever indebted to you. Thank you for
your endless patience and never ending encouragement. Thank you for supporting all my
educational endeavors. God has blessed me with the most amazing parents ever. Thank
you for loving me and always being a constant spiritual guidance. This work is dedicated
to you. I love you!
xiii
CHAPTER 1
INTRODUCTION
Transition metal-catalyzed reactions continue to provide a fresh approach for
discovering new synthetic methods. Such methodology has lead to a wide range of
carbon-carbon bond or carbon-heteroatom bond forming reactions. Many of these
reactions play important roles in contributing to total syntheses of important compounds
in areas of medicinal chemistry, natural products synthesis, chemical biology, and
materials science.'
The research contained in this thesis covers the palladium-catalyzed amination of
benzyl carbonates, which proceed via r)3-benzyl complexes. This introduction is split
into the following three sections: catalytic reactions via r\ -benzyl-palladium complexes,
Buchwald-Hartwig amination, and N-heterocyclic carbene ligands.
A wide range of comprehensive studies have been performed utilizing allylic
compounds, olefins, and aryl halides. However, less investigated substrates have been
benzylic derivatives for cross-coupling reactions employing palladium catalysts. Such
substrates hold potential usefulness and have interested the likes of Heck, Suzuki, Stille,
and Sonagashira to report carbon-carbon bond forming reactions of benzylic derivatives
1
Transition Metals in the Synthesis of Complex Organic Molecules; Hegedus, L. S.; University Science
Books: Ed. 2: Sausalitc-,1999.
1
while carbon-nitrogen bond formations have been reported by Buchwald and Hartwig
(Figure l). 2
EWG
Sonogashira
R2N
Buchwald-Hartwig
Figure 1. Palladium-catalyzed coupling reactions of benzylic derivatives.
One of the earliest studies of cross-coupling reactions with benzylic derivatives
was demonstrated by Stille and co-workers in 1976.3 They investigated the mechanism
behind oxidative addition of aryl halides to palladium(O) complexes. It was first believed
that such a reaction occurred by a-n rearrangement or a free-radical process. However,
Stille et al. went on to perform two major reactions with (5}-(-)-bromoethyl 1 benzene
that confirmed inversion of configuration at the asymmetric carbon center (Scheme 1).
2
3
Liegault, B.; Renaud, J-L.; Bruneau, C. Chem. Soc. Rev. 2008, 37, 290.
Lau, K. S. Y; Wong, P. K.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 5832.
PPh3
Me
Br
\ ±:""Ph
Pd(PPh3)2(CO)
PdA
OX
o c ' Vph 3 H
C 6 H 6 , r.t.
Me
PPh3
Ph
PhaP-
II Me
DDh- W
PPh,H
1.Br 2 l -78°C
2. MeOH, r.t.
CO (1 atm)
i vie
(PPh3)2
Pd(PPh3)4
•
/
Pd
/ \
Ph3P
Me0 2 C^\'Ph
Me
Br
^ — •
C 6 H 6 , r.t.
J*.,OK
+
Pd(PPh3)2
'
Ph
H
PPh3
Scheme 1. Oxidative addition of benzyl halides to palladium(O) complexes.
First, a reaction of 1 with Pd(PPh3)2(CO) in benzene produced benzylpalladium
complex 2. With this reaction, inversion of configuration from an S configuration to an R
configuration takes place. Next, the carbonyl is incorporated into the intermediate by
insertion between the Pd-carbon cj-bond of 2. Finally, a work-up of bromine and
methanol yield the ester 5.
The second reaction incorporated the reaction of 1 with Pd(PPh3)4, a palladium(O)
species. Oxidative addition of Pd(PPh3)4 to 1 yielded the benzylpalladium complex 4,
again resulting from an inversion of configuration in the oxidative addition step. The
benzylpalladium complex then undergoes ligand exchange with carbon monoxide.
Again, after bromine cleavage and a work-up with methanol, the ester 5 is formed. The
oxidative addition of the benzyl bromide reagent to the palladium(O) species suggests an
SN2-type mechanism where palladium(O) is the nucleophile. Erosion of stereochemistry
suggests an inversion process via r)3-benzyl palladium complexes. It's probable that
Stille's proposal of the SN2-type mechanism actually involves attack of Pd(0) on a benzyl
Pd complex, leading into future suggestions about the mechanism. This reaction utilizing
a benzylic derivative and transition-metal palladium launched a new wave of ideas of its
true mechanism. However, before considering the mechanism for benzylic derivatives,
Tsuji and Trost proposed that with transition-metal catalysts, nucleophilic addition
reactions occur by way of r|3-intermediates for allylic substrates.4 There are a wide range
of palladium-catalyzed reactions that proceed via r|3-allyl complexes A (Figure 2).
Although, r|3-benzyl complexes B have been reported as intermediates in reactions, they
are not as well-known or well-studied as T|3-al!yl complexes A.5
,(-Pd(L)2
(-Pd(L) 2
B
L -Ligand
Figure 2. Models of r|3-allyl and r|3-benzyl intermediate complexes, and the naphthalene
system.
4
Lau, K. S. Y; Wong, P. K.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 5832.
Transition Metals in the Synthesis of Complex Organic Molecules; Hegedus, L. S.; University Science
Books: Ed. 2: Sausalito,1999.
5
5
One of the most well-known reactions incorporating r| -intermediates is the TsujiTrost reaction. Tsuji et al. reported a reaction that required stoichiometric amounts of
palladium while Trost et al. reported catalytic conditions involving allylic compounds
and conjugated dienes that react with palladium(O) complexes to form n3-allylpalladium
intermediate complexes.6 The complex forms in situ to react with carbonucleophiles,
producing carbon-carbon bonds. The first detailed synthesis of an r|3-allylpalladium
chloride complex used PdCb and allyl chloride. Oxidative addition of the allyl
compound to palladium(O) generated from PdCh forms the n3-allyl complex (Scheme
2).7 This methodology has been applied to allylic alkylation. For example, Brengal and
Meyers reported a cycloaddition to allyl silane with good yield (Scheme 3).8 With the
success of these reactions Legros, Fiaud, and Toffano began investigation of related
naphthyl systems C (Figure 2).
6
.7
'
Trost, B. M. Ace. Chem. Res. 1980,13, 385.
Transition Metals in the Synthesis of Complex Organic Molecules; Hegedus, L. S.; University Science
Books: Ed. 2: Sausalito,1999.
8
Brengel G. P.; Meyers, A. I. J. Org. Chem. 1996,61, 3230
jf^s'
^^Pd(")-X
ligand
association
oxidative
addition
./
Pdflh
LnPd(O)
Nuc"
dissociation
Nuc'
i .... nucleophilic
^ ° > attack
Ln
,./
Pd(ll)
ligand
exchange
Scheme 2. Palladium-catalyzed reactions of allylic substrates.
MeT
4 r Tr
Me
O
Me
1
TiCI4
R = c-C5H9, CH2t-Bu
"Si-Tr
Me
55-65%
70-80%
Scheme 3. Cycloaddition of allyl silane.
Legros and Fiaud reported a palladium-catalyzed nucleophilic substitution of
naphthylmethyl and 1-naphthylethyl esters with sodium dimethyl malonate as the
nucleophile (Scheme 4).9 The difference between these reactions and the Tsuji-Trost
reaction is that formation of a ri3-allylpalladium intermediate complex is not possible.
-1
Legros and Fiaud proposed the substitution reaction comes about by formation of an r|
1
Legros, J. Y.; Fiaud, J. C. Tetrahedron Lett. 1992, 33, 2509.
naphthylpalladium intermediate complex (Figure 3), which is analogous to the r| -allyl
intermediate in the Tsuji-Trost reaction. Importantly, they also showed that the reaction
is highly regioselective since no addition to the ring structure was observed, in order to
preserve aromaticity. This was thefirstreport of t|3-aryl complexes being identified as
intermediates in Pd-catalyzed reactions.
2 mol% Pd(dba)2, 3 mol% dppe
CH(C02CH3)2
NaCH(C02CH3)2
DMF, 24 h
73 - 88%
R = H or CH3
Scheme 4. Palladium-catalyzed nucleophilic substitution of naphthylmethyl and 1naphthylethyl esters.
PdLn
Figure 3. n3-Benzyl complex producedfromnaphthylmethyl ester.
A few years after this finding, Legros, Toffano, and Fiaud continued in this area
of research. Still using sodium dimethyl malonate as a carbon nucleophile, they carried
out substitution reactions on 1-naphthylmethyl or 2-naphthylmethyl carbonates and
8
acetates. Working with enantiomerically pure carbonates and acetates yielded
enantiomerically pure substitution products (Table l).10
Table 1. Palladium-catalyzed substitution of enantiomerically pure 2-naphthylmethyl
carbonate.
O
O
0.5 mol% Pd(dba)2
i
0
—• ^^^\^A^A /
1.5 mol% dppe
DMF, 60 °C, 48 H
+
Na
(| ^ [
i|
[
°
\ ^ \ ^
O^SD
I
entry
1
substrate
(S)-2-naphthyl
X
OCOMe
ligand
DPPE
T(°C)
80
yield (%)
78
ee(%)
50
2
(S)-2-naphthyl
OC02Me
DPPE
80
90
68
Here, Legros et al. studied more of the stereochemistry of the reaction. It was
determined that in comparing the carbonate and acetate leaving groups, the carbonate
leaving group was more favorable for retention of configuration. This reaction also
proved to be advantageous because the reaction proceeded with a loading of only 0.5
mol% palladium catalyst as opposed to 2 mol% from their previous work.
Legros et al. began working with racemic substrates to perform stereoselective
substitutions. To do this, they investigated chiral ligands in order to develop a dynamic
kinetic resolution. When studying racemic mixtures 1-naphthylethyl and 2-naphthylethyl
esters, Legros and co-workers looked at modifying several variables of the reaction to
optimize ee. They varied chiral ligands, temperature, and leaving group of the substrates
Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51, 3235.
investigated. First, they screened chiral ligands including (/?)- BINAP, (i?)-PROPHOS,
(5,5)-DIOP, (S,S)-CHIRAPHOS, and (S,5)-BDPP while also varying reaction
temperature. Ligands BDPP and CHIRAPHOS gave the best results where a reaction at
20°C still gave a marginal 13 to 9.5% ee, respectively. As mentioned before, when
studying the leaving group of the substrate, the carbonate is superior to the acetate
leaving group. The reaction scheme shows the optimal conditions to obtain 61.5% ee
(Table 2)."
Table 2. Asymmetric palladium-catalyzed nucleophilic substitution of racemic
naphthylethyl esters.
Me
^—X
+ NaC(R)E2
2 mol% Pd(dba)2
2.5 mol% ligand
(E = C0 2 Me)
DMF, °C, 48 h
entry
substrate
1
2
3
4
5
6
2-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
1-naphthyl
1-naphthyl
OC0 2 Me
OC0 2 Me
OC0 2 Me
OC02Me
OCOMe
OCOMe
ligand
T (°C)
yield (%)
ee (%)
H
(R)-BINAP
20
10
13
H
H
H
H
Me
(R)-CHIRAPHOS
(R)-CHIRAPHOS
(R)-CHIRAPHOS
(S.S)-BDPP
(S,S)-BDPP
20
40
60
60
60
90
98
91
82
37
9.5
8
10
27.5
61.5
As before, Legros and Fiaud proposed the substitution reaction comes about by
formation of an n3-benzylpalladium intermediate complex similar to the r)3" Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron: Asymmetry 1995, 6, 1899.
10
allylpalladium intermediate complex of the Tsuji-Trost reaction (Figure 2). These latest
studies provided additional evidence that the mechanism of these reactions were also
analogous to that of the Tsuji-Trost reaction mechanism. The intermediacy of a r|3benzylpalladium helps to explain the enantioselectivity of the reaction as it likely did in
Stille's seminal work. Beginning with enantiomerically pure 1-naphthylmethyl acetate
and (S.S'J-BDPP, equilibration can occur between the two diastereomeric intermediates
where a racemic mixture of the two products can form. This needs to be avoided in order
to acquire an enantiomerically pure product.
Employing a chiral ligand, like the biphosphine ligands they investigated,
harnesses the equilibration route to enable a dynamic kinetic resolution of racemic
substrates. Thus, nucleophilic attack of the malonate ion at the exocylic position occurs
faster with one diastereomeric complex over the other (Scheme 5). Beginning with a
racemic mixture of 1-naphthylmethyl acetate, an interconversion of the two
diastereomeric malonate cationic complexes must occur rapidly to enable a dynamic
kinetic resolution to take place. This interconversion (a nucleophilic exchange process,
as postulated by Stille) is proposed to occur via nucleophilic attack by Pd(0) on the
existing Pd-benzyl complex.
In order to obtain one enantiomer over the other, Legros et al. chose to slow down
the rate of the nucleophilic attack since there was no apparent way to direct the
equilibration process. They studied two reactions, one using sodium dimethyl
methylmalonate and the other sodium dimethyl malonate as the nucleophile. Sodium
11
dimethyl methylmalonate is a bulkier nucleophile and should slow down the rate of
nucleophilic attack. The yield may have decreased, but the enantioselectivity doubled in
the reaction with the bulkier nucleophile (Table 2, Entries 5 and 6).
CH(C02Me)2
OCOMe
Pd(0)
*-
-CH(C02Me)2
CH(C02Me)2
OCOMe
Pd(0)
•CH(C02Me)2
S
R
Scheme 5. Mechanism for asymmetric palladium-catalyzed nucleophilic substitution of
1-naphthylethyl acetates.
Legros et al. continued with an analogous study of enantioselectivity by studying
an asymmetric palladium-catalyzed nucleophilic substitution of l-(2-naphthyl)ethyl
acetate.
12
12
Again, the nucleophile used was dimethyl malonate anion.
Legros, J. Y.; Boutros, A.; Fiaud, J. C; Toffano, M. J. Mol. Catal. A: Chem. 2003,196, 21.
12
(S.S)-BDPP
(R,R)-Me-DUPHOS
Scheme 6. Enantioselective palladium-catalyzed substitution of l-(2-naphthyI)ethyl
acetate.
Palladium-catalyzed substitution reaction of l-(2-naphthyl)ethyl acetate with
dimethyl malonate anion produced dimethyl 2-[l-(2-naphthyl)ethyl]propanedioate in up
to 74% ee in the presence of a chiral ligand (Scheme 6).
After studying the sodium malonate carbo-nucleophile, an amine nucleophile also
underwent investigation. Now, Legros, Toffano, and Fiaud looked at coupling
naphthylmethyl acetates with morpholine and benzylamine. Palladium-catalyzed
amination of acetates produced either A^-(naphthylmethyi)morpholines or N,Ndimethylnapthylmethylamines in good yield (Scheme 7a,b). Again, they hypothesized
that the reaction occurs by way of the r|3-benzylpalladium intermediate complex like that
of the Tsuji-Trost reaction for allylic compounds.1
Legros, J. Y.; Toffano, M ; Fiaud, J. C. Tetrahedron Lett. 1997, 38, 77.
13
2 mol% Pd(dba)2
3 mol% dppe
^.
(a)
DMPU, 80 °C, 96 h
1a: 1-naphthyl
2a: 2-naphthyl
1b: 70% yield
2b: 66% yield
2 mol% Pd(dba)2
3 mol% dppe
DMF, 80°C,48h
1a: 1-naphthyl
2a: 2-naphthyl
K^A^
i
+
:T
Ks^
r
H-^0
1c: 85% yield
2c: 78% yield
Scheme 7. Palladium-catalyzed amination of acetates, (a) Palladium-catalyzed
nucleophilic substitution of naphthylmethyl acetates with amine morpholine. (b)
Palladium-catalyzed nucleophilic substitution of naphthylmethyl acetates with
benzylamine.
A benzylformamide by-product that occurs with the benzylamine substitution
comes about when the decomposition of DMF reacts with benzylamine (Scheme 8).
DMF decomposes to dimethyl amine and carbon monoxide. The dimethyl amine and
carbon monoxide undergo a formylation reaction to produce JV, JV-dimethylformamide.
This readily reacts with benzylamine to create the benzylformamide product.
w
14
y$rjx>
o9©
N-
•N
H
H
\Jb
©NH
/ H
O.
^
NH +
/
^-N
/
H
LI
H
Scheme 8. Formation of benzylformamide product.
Continuing with the r)3-benzylpalladium intermediate complex formation in
palladium-catalyzed substitution reactions, Legros and co-workers also investigated
quinoline- and isbquinoline-based heteroaromatic substrates (Scheme 9).14 This class of
compounds has shown potential usefulness as anticancer agents. The chemical
compounds erlotinib and PD153 03 5 have been shown to inhibit the growth of breast
cancer cells (Figure 4) 15
HN
Erlotinib
Br
PD153035
Figure 4. Inhibitors of breast cancer cell growth.
14
Legros, J. Y.; Primault, G.; Toffano, M.; Riviere, M. A.; Fiaud, J. C. Org. Lett. 2000, 2, 433.
Li, H-H.; Huang, H,; Zhang, X-H.; Luo, X-M,; Lin, L-P.; Jiang, H-L.; Ding, J.; Chen, K.; Liu, H.
Acta Pharmacol. Sin. 2008,12, 1529.
15
15
^Y^
R
- ^0^ R
r,
0Y C
1^kv*Y
MCHE2
— •
2 mol% Pd(dba)2
R
V-^Ljr-
CYn
^ A
V
^ Y
3 mol% dppe
DMF, 80 °C
X,Y = N, CH or CH, N
M = Na, K or Cs
R = H, or CH 3
E = C0 2 CH 3
Scheme 9. Reactivity of quinoline- and isoquinoline-based heteroaromatic substrates.
Their study began with the reaction of primary acetates. 2- and 3-quinolyl
acetates gave the expected substitution products of the 2- and 3-methylquinoline dimethyl
esters when reacted with the dimethylmalonate reagent by palladium(0)-catalysis (Table
3). However, side products 3- and 4-methylquinolines were also formed during the
reaction. These resulted from a reductive elimination process (Scheme 10, path b).
During the elimination process, an intermediate hydrido complex is formed to yield the
final reduction products. The solvent DMF is necessary for the formation of the
complex, but the exact nature of the hydride source is yet to be resolved. The yields
stated depend upon the substitution pattern that occurs, substrate, and metal counterion
involved in the reaction.
16
Table 3. Productsfromreactions of quinoline and isoquinoline acetates.
substrate
substitution product
side product
C0 2 CH 3
f|
primary acetate
cd
0Ac
X = N or CH
Y = CHorN
|
"1 C0 2 CH 3
23 - 80%
\
/C0 2 CH 3
ay
13-78%
0 - 74%
ay
3 - 29%
secondary acetate
After studying primary acetates, secondary acetates 3-quinolyl and 3-isoquinolyl
were also reacted with dimethylmalonate ion to form 3-ethylquinolyl and 3ethylisoquinolyl dimethyl esters. The reaction of secondary acetates led to the formation
of side products vinylquinolines and isovinylquinolines (Table 3). These come about by
an elimination pathway as opposed to a reduction process (Scheme 10, path c).
17
OAc
Pd(0)Ln
-OAc
PdLn
PdHU
R = CH3
-^
base
R= H
inDMF
N
CH(C02CH3)2
path b
-Pd(0)Ln
path a
-Pd(0)Ln
pathc
X0 2 CH 3
^
C0 2 CH 3
R = HorCH 3
Scheme 10. Different pathways in the case of acetates.
Looking closer at the different reaction pathways, it becomes apparent of how not
only the substitution product forms, but also the side products (Scheme 10). The first
step in forming the substitution product is oxidative addition to form the r|3benzylpalladium intermediate. Then, nucleophilic attack of the dimethylmalonate anion
occurs on this intermediate, leading to the substitution product. The reduction product,
which is formed by P-hydride elimination is only obtained in DMF with primary acetates,
18
and is not observed in THF. In contrast, with secondary acetates when the substituent is a
methyl group, an E2 type elimination from the r|3-benzylpalladium intermediate occurs to
give the conjugated side products. The palladium(O) species is eliminated producing the
vinylquinoline side product. It is worth mentioning that the reaction pathway is identical
to the substitution and elimination pathways of 1-naphtylethyl acetates mentioned earlier
by Legros et al. (Scheme 10).
It is important to note that all of the above studies were limited to naphthyl
systems as the related benzyl complexes are less reactive towards substitution due to the
greater disruption in aromaticity. While the aromaticity of naphthyl systems are only
partially disturbed in one of the conjoined ring systems, the aromaticity of the sole benzyl
ring is disrupted completely during nucelophilic substitution. In 2003, over a decade
later from the initial proposal that the substitution reaction comes about by formation of
r|3-arylpalladium intermediates, Kuwano etal. determined which palladium catalytic
complexes are favorable for substitution reactions of benzyl esters with malonates and
amines.16 This discovery represented a significant advance in the field of benzylic
substitutions and more specifically, r|3-intermediates.
16
Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,125, 12104.
19
X
O
mol % cat
[Pd] - Ligand
OMe + R^COjR 2 -
base
THF, 80 °C, 3 h
reactions with dimethylmalonate R1 = H and R2 = C0 2 Me
reactions with 2-substituted malonates R1 = Me, Ph, AcNH, or MeO
R2 = C0 2 Et
* second substitution product only occurs during dimethylmalonate substitution
Scheme 11. Catalytic benzylation of dimethyl malonate and 2-substituted malonates.
Kuwano et al. reported the usefulness of such systems and has determined that
palladium-catalyzed nucleophilic benzylic substitution of benzylic esters is dependent
upon the palladium catalyst employed along with its stabilizing ligand. The first reaction
that illustrated this dependence was benzylic alkylation of benzyl methyl carbonate with
dimethylmalonate. Simply changing the palladium source or phosphine ligand resulted in
dramatic changes in the yield of product. Studies of biphosphine ligands included DPPE,
DPPP, DPPB, DPPF, DPEphos, and Xantphos, in order of increasing bite angle (Figure
5).17a Palladium catalysts employed included Pd(dba)2, [Pd(n3-C3H5)C1]2, and [Pd(n3C3H5)(cod)]BF4. The highest yield of the desired product made use of 5 mol % [Pd(r| C3H5)(cod)]BF4, DPPF, and the base BSA producing 74% yield of the corresponding
substitution product (Scheme 11). It is noteworthy to recognize that the bite angle of
phosphine-Pd-phosphine has been studied and it has been shown that bite angle has a
20
significant effect on reaction rate.17b'c However, while DPEphos and Xantphos afforded
larger bite angles, DPPF was still the most effective ligand for enhancing the substitution
reaction
18
.PPh,
Ph ? P'
v
Ph 2 P'
Ph,P'
DPPE
DPPP
DPPB
86°
91°
95°
PPh2
O^PPh2
Fe
PPh,
PPh,
PPh,
DPPF
DPEphos
99°
102°
PPh2
PPh2
Xantphos
112°
X° = Natural Bite Angle
Figure 5. Biphosphine ligands studied in palladium-catalyzed substitution reactions of
benzylic derivatives.
The next investigation was the reaction of benzyl methyl carbonate with 2substituted malonates. Varying the substituents on the malonate did not considerably
alter the rate or yield of the nucleophilic substitution reaction. Substrates studied were
benzyl methyl carbonate, 4-methoxybenzyl methyl carbonate, and 2-methylbenzyl methyl
17
(a) Bite angle refers to the chelation angle (P-M-P bond angle) determined by the biphosphine ligand
backbone (b) Steffen, W. L.; Palenik, G. J. Inorg. Chem. 1976,15,2432. (c) Hayashi, T.; Konishi, M.;
Kobori, Y.; Kumada, M; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984,106,158.
18
Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.;
Fraanje, J. Organometallics 1995,14, 3081.
21
carbonate. The reactions were done with 1 mol % of [Pd(r|3-C3H5)(cod)]BF4-DPPF
catalyst. The yields ranged from 61 to >99%, with the 4-methoxybenzyl methyl
carbonate substrate yielding >99% of the corresponding product. All reactions were done
at 80° C; therefore, it is important to take note that the reaction rate of benzyl methyl
carbonates is slower than that of naphthylmethyl esters. While benzyl methyl carbonate
systems took three hours for reaction completion, naphthylmethyl esters completed in
only one hour.
0
(X
II
CT^OMe
R1
+ HN
R2
1 mol% cat
[Pd]-DPEPhos
!
•
DME,80°C
ff^r^N'
U^J
R2
amine 1: R = R' = Bu
amine 2: morpholine
amine 3: R = Ph, R' = H
Scheme 12. Catalytic benzylic amination of benzylic esters. The ratio of benzyl methyl
carbonate (1.0 mmol): amine: [Pd(Ti3-C3H5)(cod)]BF4: DPEphos was 100:1.10:1:1.1.
Lastly, the reaction of palladium-catalyzed benzylic amination of benzylic esters
was carried out. Several substituted benzyl carbonate substrates were reacted with
dibutylamine, morpholine, or phenylamine. A palladium-DPEphos catalyst was used to
promote the reaction. The corresponding benzylic amine was produced in high yields
ranging from 73 - 98% (Scheme 12). It is important to be aware that unlike the benzylic
alkylations of malonates, benzylic amination proceeded without additional base.
22
[Pd(Ti3-C3H5)(cod)]+
+
DPPF
r T ^
^OCOMe
"OCOMe
II
O
co 2
MeO
8
C0 2 R
<
C0 2 R
- •
(DPPF)Pd
(DPPF)Pd0
11 J^Pd+(DPPF)
7
6
C0 2 R
K^
C02R
C0 2 R
Scheme 13. Possible reaction mechanism of catalytic benzylation.
As Kuwano et al. continued their work with benzyl carbonates, they were able to
hypothesize a plausible mechanism for catalytic benzylation (Scheme 13).19 First, DPPF
and [Pd(r|3-C3H5)(cod)]BF4, combine to form (r|3-allyl)palladium(II) 6. The malonate
anion attacks the positively-charged complex to reduce the Pd(II) species to Pd(0) 7. The
active Pd(0) species 7 can then undergo oxidative addition to the benzyl methyl carbonate
8 to form the (t| -benzyl)palladium species. It is this species that has the ability to react
with soft nucleophiles, such as malonates. Following oxidative addition, methoxide is
generated and can now deprotonate the malonate species. With this mechanistic insight,
Kuwano et al. developed a new method of alkylating benzylic esters by palladium
catalysis without using an additional base (Scheme 14). The new conditions consisted
only of substrate, nucleophile, Pd catalyst, DPPF ligand, cyclooctadiene, and solvent.
19
Kuwano, R.; Kondo, Y. Org. Lett. 2004, 6, 3545.
23
1-2% cat
1
R
?
fiW^tAoMe
R
+ H-C-R 2
R3
(Cp)(113-C3H5)Pd-DPPF
•
10% 1,5-cyclooctadiene
R
R1
(r\^^C'R
\^?
R3
2
Scheme 14. Palladium-catalyzed benzylation of active methine compounds without base.
The authors proposed that the role of 1,5-cyclooctadiene was to avoid formation
of DPPF-palladium(O) complex clusters that decreases catalytic activity. Not only was
the cluster formation repressed, but lifetime of the catalyst was also enhanced; this in turn
led to high yields of benzylation products.
Kuwano et al. also studied the nucleophilic substitution of benzylic carbonates by
palladium-catalysis using arene sulfinates. The carbon-sulfur bond was formed at the
benzylic position (Scheme 15).20
^L
^
ifCV^
i^}
0
cat.
[Pd(ri3- C3H5)CI]2
O
A
OMe
+
R2S02Na
DPEPhos
R\.
•
DMSO,80°C
\ ^
.
R2
f^Y^K
o/N0
72 - 99%
R1 = 2-Me, 4-OMe, 4-CI, 4-C02Me; 2,4,6-Me; 2-Me; 3-OMe; 3-NH2 3-OTBDPS; or Ph
R2 = Ph, 4-MeCeH4, 4-CIC6H4, or Me
Scheme 15. Palladium-catalyzed sulfonylation of benzylic carbonates.
Kuwano, R.; Kondo, Y.; Shirahama, T. Org. Lett. 2005, 7, 2973.
24
As mentioned earlier, for the alkylation reactions of benzylic esters, the DPPF
biphosphine ligand had the optimal bite angle for these reactions. However, even though
DPPF promoted sulfonylation, a study with the biphosphine ligand DPEphos showed a
better conversion of carbonate to sulfonate (Scheme 15). The reactions in DMSO also
enhanced the reaction rate.
Forming carbon-sulfur bonds, and more specifically sulfones, is a useful synthetic
process. Sulfones can be converted into other functional groups and they can be removed
under reductive conditions. Thus, they are often found as key synthetic intermediates for
the preparation of natural products. One recent example of this is in the total synthesis of
(-)-Siccanin, where Trost et al. made use of a pyridinyl sulfone D as one of the
intermediate complexes (Figure 6).21
C0 2 Me
Ph
Figure 6. Structures of C-S and C-N containing compounds.
Focusing on forming carbon-heteroatom bonds, developing carbon-nitrogen
bonds are an essential part of organic chemistry. Synthetic applications of C-N bond
formation is extremely wide-ranging and includes drug synthesis for pharmaceuticals and
21
Trost, B. M.; Shen, H. C; Surivet, J-P. J. Am. Chem. Soc. 2004,126, 12565.
25
conducting plastics for the polymer industry.22 For example, the amine derivative
cyclazocine E was synthesized as an analgesic to help prevent relapse of heroin
addiction. Another amine derivative 1,2-aziridinomitosene F was developed as an
antitumor antibiotic. Polysubstituted phenazines G are naturally occurring products
which have several biological applications. All of these compounds have been made
synthetically in the laboratory (Figure 6).
R
Br
R2
Rl
.,
+
Pd, Base
N
->p3
H
VR2
/ L
•
fi
Toluene, A
j
(a)
^ ^
Buchwald: Pd = [(o-tolyl)3P]2PdCI2 or [Pd(dba)2]/2P(o-tolyl)3
Base = NaOtBu
Hartwig: Pd = [(o-tolyl)3P]2Pd or [(o-toiyl)3P]2PdX2; X = CI, Br
Base = LiN(SiMe3)2, NaOtBu, LiOtBu
H
N
-Bn
Cat. Pd
NaOffiu, K 2 C0 3
Toluene, A
^
^ - Y\
jn
\^~-N
(b)
Bn
Scheme 16. Palladium-catalyzed C-N bond formation, (a) Conversion of aryl bromides
to aryl amines, (b) Intramolecular aromatic amination.
Probably one of the most important palladium catalyzed C-N bond forming
methodologies is the Buchwald-Hartwig coupling. Independently of one another,
22
Kurti, L.; Czak, B. Strategic Applications of Named Reactions in Organic Synthesis: Background and
Detailed Mechanisms; Elsevier Inc.: Burlington, Massachusetts, 2005.
26
Buchwald and Hartwig reported the palladium-catalyzed synthesis of arylamines by
utilizing aryl bromides and stoichiometric amounts of base (Scheme 16a).23 Extensive
studies have led to a detailed explanation for the Buchwald and Hartwig reaction
mechanism. The pathway proposed by Buchwald validated the mechanism proposed by
Hartwig and vice versa. It is from these collective analyses that the approved
mechanistic pathway is understood today (Scheme 17).24
PhBr
amine
+ base
[PdL2]
^
[PdL(PhBr)]
[PdL]
^
Br
-[PdL(dba)]
Ph
[PdL]2(dba)]
[PdL(dba)]
amine
+ base
HNRR"
NaOR"
LP(<.
Ph-NRR'
NRR'
ROH + NaBr
Scheme 17. Mechanism for amination of aryl halides.
The first step of the catalytic cycle is oxidative insertion of the bromoarene onto
the ligated palladium complex. The ligated palladium complex [PdL] is actually
generated by the dissociation of [PdL2] which occurs outside of the catalytic cycle. Now
that the [Pd(L)(Ph)(Br)] complex is formed, it can react with the amine to form an
23
Guram, A. S.; Rennels, R. A.; Buchwald, S. L.; Barta, N. S.; Pearson, W .H. Chemtracts: Inorg.
Chem. 1996, 8, 1.
24
Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2006,128, 3584.
27
arylpalladium ami do complex. The last step of the cycle is reductive elimination to
regenerate the [PdL] complex and yield the arylamine.
N-Heterocyclic Carbenes as Ligands for Palladium Catalysts
Most of the reactions discussed above have employed phosphine ligands with
transition metals for catalytic reactions. However, more recently N-heterocyclic carbene
ligands (NHCs) have become increasingly used as alternative ligands in conjunction with
transition metals.25 In comparison to the more traditional phosphine ligands, NHCs have
a much stronger a-electron-donating ability than even the most electron-donating
phosphines. This property enhances oxidative insertion of the Pd-NHC complex into
challenging substrates. Another important property of NHCs is their bulkiness and
distinct physical characteristics that facilitate a rapid reductive elimination process. One
of the main contributing factors to the stability of carbene ligands is the aromatic
heterocyclic structure with a-electron-withdrawing, 7i-electron-donating heteroatoms.
This framework stabilizes the nucleophilic state of the carbene (Figure 7a). Another
important stabilization factor comes about by employing bulky substituents like
adamantyl groups on the nitrogen atoms. Lastly, the robust palladium-NHC bond helps
stabilize the activated complex, which increases lifetime of the catalyst, even at hightemperatures as well as allowing low ligand-to-palladium catalyst loadings. The appeal
of employing N-heterocyclic carbenes is not only limited to their excellent catalytic
ability, but also due to their commercial availability and relative ease of preparation and
handling.
Kantchev, E. A. B.; O'Brien, C. J.; Organ, M. G. Angew. Chem. Int. Ed. 2007, \6,2768.
29
R-NP^R
*2 o
R2
a. nucleophilic state
B F
R2
«R2
H R1 = H, R2 = iPr, SIPr-HBF4
I R1, R2 = Me
SMes-HBF4
f=\
R-N
N-R
c, P( M
MR = iPr
N R = SIPr
Figure 7. Imidazolium salts and Pd-NHC catalysts
Several groups including Hartwig, Nolan, Caddick and Cloke, have studied
Buchwald-Hartwig amination utilizing the Pd-NHC complex (Scheme 18, Figure 7). The
first investigations of amination of aryl halides using N-heterocyclic carbenes formed the
Pd-NHC complex in situ. Common Pd sources [Pd(dba)2] or [Pd2(dba)3] were employed
with H, I, J, and K carbene ligands to construct the Pd-NHC complex. The reactions
were usually run with either KO/Bu or NaCtfBu for the sources of base. Popular solvents
used were DME and dioxane. Reaction temperatures ranged from room temperature to
110° C.
Ar—X
+
1
R -N
/H
X
/R 1
NHC-Pd cat. (1 mol%)
•
R2
conditions
1.1-1.2 equiv
Ar—N
X
p2
31 examples
56 -100% yield
Scheme 18. Buchwald-Hartwig amination. Method A: H (0.08-2 mol%), [Pd(dba)2]
(0.08-2 mol%), NaOfBu, DME, RT -> 55 °C. Method B: I (2-4 mol%), [Pd2(dba)3] (1
mol%), dioxane, 100 °C. Method C: J (4 mol%), [Pd2(dba)3] (1 mol%), LiHMDS, THF,
RT. Method D: K (4 mol%), [Pd2(dba)3] (4 mol%), NaO/Bu, dioxane, 100-110 °C.
Caddick and Cloke continued to improve upon Buchwald-Hartwig aminations by
working with in situ generated [(NHC)2Pd] complexes formed from the imidazolium salt
and base. Beginning at room temperature and increasing to 100 °C push the reaction in
the forward manner. Caddick and Cloke investigated cross-coupling both JV-mono and
jV,iV-disubstituted anilines with aryl chlorides (Scheme 19, Figure 7).
Ar—X
+
1
R -N
/H
X
/R 1
NHC-Pd cat. (1 mol%)
•
R2
1.1-1.2 equiv
conditions
Ar—N
N
R2
31 examples
73-100% yield
Scheme 19. Cross-coupling of substituted anilines with aryl chlorides. Pd-NHC
catalysts: L, M,N, orO Base: KCMBu, NaOfBu, or NaO/Am. Solvent: DME, dioxane,
or toluene at RT to 100 °C. /Am = tert-amyl.
Also compounding upon the intramolecular Buchwald-Hartwig amination, Nolan
and co-workers were able to synthesize cryptauswoline and cryptowoline utilizing a Pd-
31
NHC complex (Scheme 20). These compounds are medicinally significant and are used
to treat leukemia and tumors.
[(IMes)Pd(7t-allyl)CI] (6 mol%)
DME or toluene
NaOfBu, 80 °C
MeO
cryptausWoline R = CH 3
cryptowoline
R = -CH 2 -
Scheme 20. Intramolecular Buchwald-Hartwig amination involving Pd-NHC complex.
Total synthesis of cryptauswoline and cryptowoline.
Thefirstpeople to explore r)3-allyl intermediates with Pd-NHC complexes were
Mori, Sato, and Yoshino. They explored the Tsuji-Trost alkylation of allylic acetates.
Using Pd(0)-IPr NHC catalysts generated in-situ from PdCl2 and IPr-HCl/base. They
were successful to afford 6 different examples with yields ranging from 46 - 94%.
Several substrates were investigated such as an unsymmetrical allylic acetate, cyclic
acetates or lactones, and P-ketoesters (Scheme 21). Interestingly, Mori et al. determined
that allylic carbonates failed to undergo amination reactions, with this catalyst system.
32
conditions
(a) Ph-
"OAc
•
v
Ph'
CH(COOMe)2
55%
OAc
CH(COOMe)2
conditions
(b)
83%
CH(COOMe)2
conditions
:
(c)
O
CH2N2
•
»•
94%
(d)
^\^OAc
(2 equiv)
+
,/\L-COOEt
conditions
\ ^
72%
Scheme 21. Tsuji-Trost methodology with Pd-NHC ligands. (a) unsymmetrical allylic
acetate (b) cyclic acetate (c) lactone (d) P-ketoester. Conditions: IPr-HCl (5 mol%),
[Pd2(dba)3]-CHC13 (2.5 mol%), CH2(COOMe)2 (2 equiv), Cs 2 C0 3 , THF, reflux. NaH
was added.
The mechanism of Pd-NHC Mechanistic studies for palladium-catalyzed
reactions with N-heterocyclic carbenes are still under investigation.
33
Proposed Research
As discussed in the introduction Kuwano and co-workers reported palladiumcatalyzed nucleophilic substitution of benzylic esters in high yields utilizing the
2[Pd(C3H5)(diene)]BF4/DPEphos catalyst system.26 Their protocol for use of amine
nucleophiles required heating at 80 °C for up to 96 hours.
This report prompted our study to accelerate the amination of benzylic esters
using microwave heating as well as investigate non-phosphine based catalytic systems
such as NHCs. While Kuwano et al. reported the amination of a benzyl carbonate
substrate by conventional heating in 96 hours we wished to find conditions that would
make the reaction more practical. As discussed, efficient amination procedures are very
important for the synthesis of biologically active compounds.
Microwave reactors are becoming more common-place in synthetic organic
laboratories as a tool to heat chemical reactions.27 Reactions that have taken several days
or hours are decreased in time to take only several minutes. As implied, the microwave
works at fixed levels of 2.45 GHz. This frequency provides microwave energy which is
translated to thermal energy. This is achieved by a built-in magnetron that supplies
frequencies to heat up chemical reactions. The microwave also provides a pressurized
system so that solvents may be heated at temperatures higher than their boiling points.
26
Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,125, 12104.
Microwave Assisted Organic Synthesis ; Tierney, J. P., Lidstrom, P., Eds.;Blackwell Publishing:
Oxford, 2005.
27
34
The microwave works by the following two methods: dipolar polarization and
ionic conduction. Substances with a dipole moment when irradiated will produce heat.
This occurs because the dipole moment of the molecules will want to align with the
external electric field provided by the magnetron. Manipulating the frequency of the
electric field to be constantly changing does not give the dipole moments of the
molecules sufficient time to fully align with one another. The dipoles constantly trying to
re-orient themselves with the changing frequency create molecular collisions. Thus,
molecular collisions releasing energy create heat which was translated from microwave
energy. Ionic conduction is performed with solvents that contain ions. A solution with
ions will be attracted or repelled by the electromagnet depending upon the frequency that
is applied. Therefore, a solution with ions will move throughout the solution under the
influence of the electric field. The increasing movement causes an increased rate of
particle collisions. Again, molecular collisions create heat by releasing energy.
We also wish to use N-heterocyclic carbenes as ligands for our palladiumcatalyzed benzylic reactions. They are exceptional for our kind of research since they
-J
can accelerate oxidative insertion of the r| -benzyl complex. They also help with
stabilizing the palladium at the high temperatures in the microwave.
CHAPTER 2
MATERIALS AND METHODS
General and Materials. *H and ,3C NMR spectra were measured with Bruker AVANCE
II400 MHz spectrometer in base washed CDCI3 (from Acros) unless otherwise noted.
Spectra were calibrated using the residual chloroform peak. The following abbreviations
were used to describe peak patterns when appropriate: br = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet. Coupling constants, J, were reported in
Hertz (unit Hz). Reaction progress was monitored by Varian Saturn 2100T GC/MS fitted
with a Varian factor FOUR capillary column (30 x 0.25 x 0.39). GC yield measured with
Agilent Technologies 7890A GC/FID system performed with J&W Scientific Agilent
Technologies high resolution gas chromatography column (30 x 0.32 x 0.32). Helium
was used as carrier gas for both GC instruments. Analyses were carried out at least twice
to ensure consistency of results. Conversions were obtained by integration of the starting
material area.
Microwave heat carried out with Biotage Initiator 2.0 performed with Biotage
microwave vials (0.5 - 2 ml size), oven dried and sealed with 20 mm aluminum seal caps,
0.125" thick teflon faced silicone septa purchasedfromChemglass.
35
36
Thin layer chromatography was carried out with Silica Gel XHL, TLC plates with
UV254 purchased from Sorbent Technologies (Support: Glass backed, Thickness: 250
urn, Dimensions: 20 x 20 cm). Flash column chromatography was performed with Silica
Gel Standard Grade purchased from Sorbent Technologies (Porosity: 60 A, Particle Size:
40-63 urn or 230 x 400 mesh, Surface Area: 500-600 m2/g, Bulk Density: 0.4 g/ml, pH
range: 6.5-7.5). TLC stains to help monitor reaction progress included the following:
Hannessian's, potassium permanganate, vanillin, and ninhydrin.
All reactions were conducted under argon atmosphere. Acetonitrile, toluene,
DME, DMF, and DMSO were purchased from DriSolv and handled under argon using
standard syringe techniques. Acetone was distilled over molecular sieves (Activated,
type 4A, 8-12 mesh, J.T. Baker). Methylene chloride was distilled over calcium hydride.
THF was distilled over sodium benzophenone-ketyl.
Pd2(dba)3 and 2[Pd(C3H5)(diene)]BF4 were prepared according to literature.28'29
PdCl2, [Pd(allyl)Cl]2, and Pd(OAc)2 were purchased from Sigma-Aldrich. Cesium
carbonate was purchased from Alfa Aesar. Butyl lithium was purchasedfromAcros and
was titrated in triplicate against diphenylacetic acid.
Alcohol precursors to synthesize the carbonate starting material were purchased
from Sigma-Aldrich and used without further purification. Pyridine was purchased from
EM Science. Methyl chloroformate was purchasedfromAcros. Dibutylamine was
purchased from Spectrum. Morpholine and piperidene were purchasedfromSigma28
Organometallics in Synthesis; M. Scholosser, Eds.; 2nd Edition; John Wiley & Sons, Ltd: Chichester,
2004.
29
White, D. A. Inorganic Synthesis, 1972,13, 55.
>
'
Aldrich. Imidazolium salts were purchased from Sigma-Aldrich. Silver NHCs were
prepared according to literature.30
General procedure A for microwave heating. After determining volume and
concentration of reaction mixture, an appropriately-sized oven-dried microwave vial
equipped with stir bar was prepared with the reaction materials (Too dilute or too
concentrated reactions will give inaccurate microwave readings.) All solid particles were
flushed off the sides of the microwave vials walls with the appropriate solvent. The
microwave vial was capped with an appropriate seal and the length of time and
temperature for the reaction were programmed into the microwave. For our purposes,
reactions required 10 minute heat intervals and temperatures ranging from 100 °C to 160
°C.
General procedure B for synthesis of benzvlaminated products.31 Sodium carbonate (500
mg, 6 mmol, 1.0 equiv), sodium dodecyl sulfate (20 mg, 0.06 mmol, 1.0 equiv), and
amine (5 mmol, 0.88 equiv) were dissolved in DIH2O (20 ml). The reaction mixture was
heated at 80 °C for 5 minutes. The benzylic halide (6 mmol, 1.0 equiv) was then added
to reaction mixture and heated for 1 hour. The solution was allowed to cool to room
temperature. The organic layer was extracted 5 times with ethyl acetate. The crude
organic solution was passed through a short column of silica using 20:80 ethyl
30
31
Bonnet, L. G.: Douthwaite, R. E. Organometallics, 2003, 22, 4187.
Singh, C. B.; Kavala, V.; Samal, A. K.; Patel, B. K. Eur. J. Org. Chert. 2007, 1369.
38
acetate:hexane mixture. The solvent was removed under reduced pressure to yield a
yellow oil.
General procedure C to synthesize silver N-heterocyclic carbene complexes.
A solution
of imidazolium salt (230 mg, 0.5 mmol, 1.0 equiv) and Ag20 (60 mg, 0.2 mmol, 0.5
equiv) were stirred in CH2G2 under argon overnight with the exclusion of light. The
reaction mixture was then passed through celite and rinsed with CH2CI2. Methylene
chloride was removed under reduced pressure yielded an off-white solid. This was stored
in foil-covered vial under argon.
Synthesis of Pd?(dba^.33 To a flame-dried and evacuated Schlenk flask dibenzylidene
acetone (4.6 g, 0.01 mol) was stirred in MeOH (150 ml) at 50 °C for 5 minutes. PdCl2
(1.05 g, 5 mmol) was added to the mixture and was left stir at 40 °C for another 4 hours.
Using vacuum filtration, the precipitate that was formed was collected by a sintered
funnel. The precipitate was rinsed once with DIH2O and rinsed again with acetone. A
purple solid was obtained (Pd(dba)2). CHCI3 (80 ml) was added to a flame-dried flask
and the solution was heated, but not to boiling. The purple solid was then added to the
solution and was readily dissolved. The solution was then filtered immediately,
collecting the filtrate in another round bottom flask. After the addition of ether (120 ml),
the flask was then placed in an ice bath to ensure crystallization. The crystals were
32
33
2004.
Bonnet, L. G.: Douthwaite, R. E. Organometallics, 2003, 22, 4187.
Organometallics in Synthesis; M. Scholosser, Eds.; 2nd Edition; John Wiley & Sons, Ltd: Chichester,
filtered off and a purple solid was collected. Recrystallization of crude Pd2(dba)3 with
CHCI3 yielded pure Pd2(dba)3.
Synthesis of r\ -Allyl(1.5-cvclooctadiene)palladium(II) Tetrafluoroborate
(2rPd(C3HO(diene)lBF^.34 [{(C3H5)Pd}2Cl2] (400 mg, 1.0 mmol) and AgBF4 (426 mg, 2
mmol) were stirred in CH2CI2 (10 ml) for 15 minutes. Then followed the addition 1,5cyclooctadiene (0.4 ml) and the reaction was stirred for another 2 minutes. The AgCl salt
crashed out. This was thenfilteredoff and washed twice with CH2CI2. The addition of
ether to the filtrate caused a gray precipitate to crash out of solution. The gray solid was
filtered off and washed 3 times with ether. The solid was then dissolved in CH2CI2 and
filtered through a cotton-plugged pipette. The plug was washed with CH2CI2. The
addition of ether to the liquid phase yielded a white precipitate. The white solid was
filtered off and dried by high-vacuum line.
Synthesis of rCHNCH-Bu21Br2.35 2,6-Dibromopyridine (3.2 g, 0.01 mol) and 1butylimidazole (3.3 mg, 0.02 mmol) were stirred neat under argon 150 °C for 20 hours.
The reaction was set to cool for 1 hour and a brown solid appeared. The solid was
dissolved in chloroform (50 ml). The addition of ether (250 ml) yielded a yellow
precipitate. To purify, the yellow solid was dissolved in methanol (50 ml). Addition of
35
700.
White, D. A. Inorganic Synthesis, 1972,13, 55.
Loch, J. A.; Albrecht, M ; Peris, E.; Mata, J.; Faller, J. W.; Crabtree, R.H. Orgcmometallics, 2002, 21,
40
ether (250 ml) yielded an off-white precipitate. The ether solution was filtered off to
obtain an off-white solid. The solid was dried by high-vacuum line.
Synthesis of rPdBr(CNC-Bu?WBr1.36 [CHNCH-Bu2]Br2 (0.4 g) and [Pd(OAc)2] (0.2 g,
0.9 mmol) were stirred in DMSO (8 ml) for 3 hours at room temperature. The
temperature was then increased to 50 °C and the reaction was set to stir another 12 hours.
The temperature was then raised to 155 °C and left to stir an additional hour. The
solution was cooled to room temperature. The reaction mixture was then transferred to 20
ml CH2CI2 and the addition of ether (200 ml) afforded an orange solid. The solvent was
filtered off to obtain the orange solid which was then dissolved in CH3CI (20 ml). The
addition of ether (200 mis) yielded a yellow precipitate. The precipitate was washed two
more times with ether to obtain the purified product.
General procedure D to synthesize Benzyl methyl carbonate substrates. Around-bottom
flask was flame-dried and purged with argon. In this flask, methyl chloroformate (0.02
mol, 1.2 equiv) was added dropwise to a stirring solution of methylene chloride (50 ml),
benzyl alcohol (0.01 mol, 1.0 equiv), and pyridine (0.05 mol, 2.0 equiv) chilled in an ice
bath. After 5 minutes stirring, the ice bath was removed to let reaction warm to room
temperature. The reaction was left to stir until benzyl alcohol was consumed. The
reaction was monitored by TLC (EtOAc:Hexane 20:80). Once the alcohol was consumed
36
700.
Loch, J. A.; Albrecht, M.; Peris, E.; Mata, J.; Faller, J. W.; Crabtree, R.H. Organometallics, 2002,21,
41
the reaction was quenched with methylene chloride (100 ml). The reaction mixture was
washed twice with 1 M H2S04 (100 ml) and twice with saturated NaHC03 (100 ml), then
dried over magnesium sulfate. The methylene chloride was removed under reduced
pressure to yield the crude product. This was purified by flash column chromatography
with silica gel (EtOAc:Hexane 20:80) to give desired benzyl carbonate product.
General procedure E to synthesize corresponding benzvlmorpholine product employing
phosphine ligand. In an oven-dried microwave vial, 2[Pd(C3H5)(diene)]BF4 (3.5 mg, 10
umol, 0.01 equiv) and DPEphos (30 mg, 54 umol, 0.05 equiv) were added to a stirring
solution of DME (1 ml). The reaction was left stir for 5 minutes and then the benzyl
carbonate substrate (1 mmol, 1.0 equiv) and morpholine (68 ul, 1.1 mmol, 1.1 equiv)
were added to the reaction mixture. After a period of further stirring for 5 minutes the
reaction mixture was then heated in the microwave for 10 minute intervals at 160 °C.
Reaction progress was monitored by GCFID and/or GC/MS.
General procedure F to synthesize corresponding benzvlmorpholine product employing
butyl lithium and N-heterocvclic carbene ligands. In an oven-dried microwave vial,
PdCl2 (1.7 mg, 0.01 mmol, 0.025 equiv), NHC (5.4 mg, 0.02 mmol, 0.04 equiv), and
butyl lithium (0.88 ml, 0.7 mmol, 0.03 equiv of a 1.6 M solution in hexanes) were added
to a stirring solution of THF (1 ml). The reaction was stirred for 5 minutes and then the
37
Appropriate heating times are given in Table 5 in the experimental for each individual compound.
benzyl carbonate substrate (1 mmol, 1.0 equiv) and morpholine (0.07 ml, 0.8 mmol, 1.1
equiv) were added to the reaction mixture. After stirring for another 5 minutes the
reaction mixture was heated in the microwave for 5 minute intervals at 140 °C.38
Reaction progress was monitored by GCFID and/or GC/MS.
General procedure G to synthesize corresponding benzylmorpholine product employing
cesium carbonate and N-heterocyclic carbene ligands. In an oven-dried microwave vial,
Pd2(dba)3 (9 mg, 0.009 mmol, 0.025 equiv), NHC (6.3 mg, 0.015 mmol, 0.05 equiv), and
cesium carbonate (258 mg, 0.8 mmol, 0.04 equiv) were added to a stirring vial of the
appropriate solvent (1 ml). The reaction was stirred for 5 minutes and the benzyl
carbonate substrate (0.4 mmol, 1.0 equiv) and morpholine (0.8 mmol, 2.0 equiv) were
added to the reaction mixture. After stirring for another 5 minutes the reaction mixture
was heated in the microwave in a stepwise fashion of 10 minute intervals at 100 °C, 120
°C, 140 °C, and 160 °C.39 Reaction progress was monitored by GCFID and/or GC/MS.
General procedure H to synthesize corresponding benzylmorpholine product employing
l,3-Bis(l-adamantyl)-imidazolium silver tetrafluoroborate. In an oven-dried microwave
vial, Pd2(dba)3 (9.0 mg, 0.009 mmol, 0.025 equiv) and l,3-Bis(l-adamantyl)-imidazolium
silver tetrafluoroborate (7.5 mg, 0.015 mmol, 0.04 equiv) were combined with the
appropriate solvent (1 ml). The mixture was allowed to stir for 5 minutes, after which
38
39
Appropriate heating times are given in Table 6 in the experimental for each individual compound.
Appropriate heating times are given in Tables 7 in the experimental for each individual compound.
43
time the benzyl carbonate substrate (0.3 mmol, 1.0 equiv) and morpholine (68 ul, 0.8
mmol, 2.0 equiv) were added. The reaction was allowed to stir another 5 minutes and was
then heated in microwave for 10 minute intervals at 140 °C.40 The reaction progress was
monitored by GC/FID and/or GC/MS.
General procedure I to synthesize corresponding benzyldibutylamine product employing
l,3-Bis(l-adamantyO-imidazolium silver tetrafluoroborate. In an oven-dried microwave
vial Pd2(dba)3 (9.0 mg, 0.009 mmol, 0.025 equiv) and l,3-Bis(l-adamantyl)-imidazolium
silver tetrafluoroborate (9.4 mg, 0.02 mmol, 0.05 equiv) were combined to a stirring vial
of appropriate solvent (1 ml). The mixture was allowed to stir 5 minutes after which time
the benzyl carbonate substrate (0.3 mmol, 1.0 equiv) and dibutylamine (135 ul, 0.8
mmol, 2.0 equiv) were added. The reaction was allowed to stir another 5 minutes and
then was heated in the microwave for 10 minute intervals at 160 °C.41 The reaction
progress was monitored by GC/FID and/or GC/MS.
General procedure J to synthesize corresponding benzylpiperidine product employing
1,3-Bisd-adamantyD-imidazolium silver tetrafluoroborate. In an oven-dried microwave
vial Pd2(dba)3 (9.0 mg, 0.009 mmol, 0.025 equiv) and l,3-Bis(l-adamantyl)-imidazolium
silver tetrafluoroborate (9.4 mg, 0.02 mmol, 0.05 equiv) were combined to a stirring vial
of solvent (1 ml). The mixture was allowed to stir 5 minutes after which time the benzyl
40
Appropriate heating times are given in Tables 9, 10, and 11 in the experimental for each individual
compound.
41
Appropriate heating times are given in Table 12 in the experimental for each individual compound.
44
carbonate substrate (0.3 mmol, 1.0 equiv) and piperidine (78 ul, 0.8 mmol, 2.0 equiv)
were added. The reaction was allowed to stir another 5 minutes and then was heated in
the microwave for 10 minute intervals at 100 °C.42 The reaction progress was monitored
by GC/FID and/or GC/MS.
General procedure K to synthesize corresponding benzylpyrrolidine product employing
l,3-Bis(l-adamantyl)-imidazolium silver tetrafluoroborate. In an oven-dried microwave
vial, Pd2(dba)3 (9.0 mg, 0.009 mmol, 0.025 equiv) and l,3-Bis(l-adamantyl)-imidazolium
silver tetrafluoroborate (9.4 mg, 0.02 mmol, 0.05 equiv) were added to a stirring solution
of solvent (1 ml). The reaction was stirred for 5 minutes. Benzyl carbonate substrate
(0.3 mmol, 1.0 equiv) and pyrrolidine (65 ul, 0.8 mmol, 2.0 equiv) were added to the
reaction mixture and left to stir another 5 minutes. The reaction mixture was heated in
the microwave for 10 minute intervals at 100 °C.43 The reaction progress was monitored
by GC/FID and/or GC/MS.
Appropriate heating times are given in Table 13 in the experimental for each individual compound.
Appropriate heating times are given in Table 14 in the experimental for each individual compound.
45
O
cAo'
Benzyl methyl carbonate 9a 4 was prepared according to general procedure D employing
5 grams of benzyl alcohol. 7.4 g 96% of a colorless oil was obtained. *H NMR (400
MHz, CDC13) 8 7.47 (m, 5H), 5.14 (s, 2H), 3.70 (s, 3H). 13C NMR (101 MHz, CDCI3) 8
155.5, 135.9, 128.9, 128.6, 127.3, 71.3,
54.1.
f
V
— , — . — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — • — 1 — 1 — , — , — 1 — , —
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
r
— . — 1 — . — 1 — • — 1 — . — 1 — 1 — 1 — • — 1 — . — 1 — 1 — 1 — 1 — 1 — 1 — i — 1 — 1 — 1 — ( — < — 1 —
5.8
S.6
5.4
fl (ppm)
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.6
3.6
3.4
3.2
Reported in the literature. Yu, C; Zhou, B.; Su, W.; Xu, Z. Synth. Comm., 2007, 37, 647.
46
-1700
-1600
-150O
1400
1300
1200
1100
1000
-900
300
-200
j.
—200
-300
160
155
150
145
140
135
130
125
120
115
110
105
100
95
o
^ T "crA,
"o
F3C
4-Trifluoromethylbenzyl methyl carbonate 9d45 was prepared according to general
procedure D employing 2.5 grams of 4-trifluoromethylbenzyl alcohol. 1.5 g 45% of a
colorless oil was obtained. 'H NMR (400 MHz, CDC13) 5 7.66 (d, J= 8.0 Hz, 2H), 7.52
(d, J= 8.0 Hz, 2H), 5.24 (s, 2H), 3.90 (s, 3H). 13C NMR (101 MHz, CDCI3) 5 157.8,
141.2,139.2, 132.3, 128.1, 126.2,
II
Lil
rn— 1
>
7.8
45
1
7.6
>
1
7.4
'
1
7.2
'
1
7.0
1
1
6.8
'
1
6.6
1
1
6.4
1
1
6.2
r — 1
6.0
1
1
5.8
'
1
1
5.6
f l (ppm)
1
5.4
1
1
5.2
'
1
5.0
'
1
4.8
'
1
4.6
'
I
4.4
•
1
4.2
•
1
4.0
'
1
3.8
'
1
3.6
•
1
3.4
Reported in the literature. Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,125,
12104.
48
150
145
140
135
130
125
120
115
110
105
100
95
fl(ppm)
90
85
75
70
65
60
55
50
45
40
CC
oV
2-Methylbenzyl methyl carbonate 9i46 was prepared according to general procedure D
employing 2.5 grams of 2-methylbenzyl alcohol, l.lg 30% of a colorless oil was
obtained. !H NMR (400 MHz, CDC13) 5 7.43 - 7.15 (m, 4H), 5.22 (s, 2H), 3.82 (s, 3H),
2.40 (s,3H). 13CNMR(101 MHz, CDC13)5 158.2, 139.3, 133.9, 131.5, 129.3, 129.4,
126.0,68.1,54.8,18.8.
-2E+05
L
-2E+05
f
—
•
r~
|
-2E+05
—
/
-2E+05
1
-2E+05
f
J
•
j
.
-1E+05
-1E+05
-1E+05
"
-1E+05
-1E+05
_-
-90000
-80000
-70000
-60000
-50000
-40000
-30000
-20000
ik
-10000
1
-0
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
5.4
5.2
5.0
4.8
fl (ppm)
"
4.6
4.4
4.2
4.0
--10000
3.8
!
'
: 3.(10
T
1'
3.6
3.4
3.2
3.0
2.8
2.6
2.4
Reported in the literature. Yu, C; Zhou, B.; Su, W.; Xu, Z. Synth. Comm., 2007, 37, 647.
50
^n*«t|g^^^^^M^^^^^^|^
160
150
140
130
120
110
100
90
50
40
51
MeO
4-Methoxycarbonyloxybenzyl methyl carbonate 9g47 was prepared according to general
procedure D employing 2.5 grams of 4-acetatebenzyl alcohol. 0.9 g 30% of white crystals
were obtained. *H NMR (400 MHz, CDC13) 8 8.06 (d, J = 8.2 Hz, 2H) 7.47 (d, J =1.9
Hz, 2H), 5.24 (s, 2H), 3.95 (s, 3H), 3.84 (s, J = 1.4,3H). I3C NMR (101
MHz, CDC13) 6
168.4, 156.8, 141.2, 129.8, 129.4, 127.6, 69.8, 56.9, 54.0.
— 1 — 1 — 1 — • — 1 — 1 — 1 — . — , — . — 1 — • — 1 — 1 — 1 — 1 — 1 — • — 1 — . — 1 — 1 — 1 — . — 1 — > — 1 — • — 1 — < — 1 — 1 — 1 — 1 — 1 — > — 1 — '
B.2
47
8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
S.8
fl
5.6
(ppm)
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
Reported in the literature. Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003, 725,
12104.
52
170
165
160
155
150
145
140
135
130
125
120
115
110
105
fl (ppm)
100
o
ci
4-Chlorobenzyl methyl carbonate 9h48 was prepared according to general procedure D
employing 2.5 grams of 4-chlorobenzyl alcohol. 1.5 g 43% of a colorless oil was
obtained. 'H NMR (400 MHz, CDC13) 8 7.43 (d, J = 0.9,2H), 7.35 (d, J= 1.5,2H), 5.15
(s, 2H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCI3) 5 156.9, 135.2, 132.6, 129.6,128.0,
68.7, 54.9.
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.6
5.6
5,4
fl <ppm)
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
Reported in the literature. Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,125,
12104.
54
160
1S5
L50
145
135
130
125
120
115
110
105
55
0
4-Methylbenzyl methyl carbonate 9e49 was prepared according to general procedure D
employing 2.5 grams of 4-methylbenzyl alcohol. 1.2 g 32% of a colorless oil was
obtained. *H NMR (400 MHz, CDC13) 8 7.29 (d, J - 5.3 Hz, 2H), 7.19 (d, J = 4.8 Hz,
2H) 5.15 (s, 2H), 3.83 (s, 3H), 2.35 (s, 2H). 13C NMR (101 MHz, CDC13) 5 156.9, 139.3,
131.4, 129.4, 128.9, 78.6, 69.6, 54.8, 21.1.
-2E+05
-2E+0S
T2E+0S
-2E+05
2E+05
2E+0S
-2E+05
-2E+05
2E+05
-2E+0S
-2E+0S
-1E+0S
- 1E+05
-1E+05
-1E+05
-1E+05
90000
60000
70000
60000
50000
40000
30000
il
-20000
10000
0
"V
-10000
--20000
1 — ' — I — ' — I — ' — I — ' — I — ' — 1 — ' — 1 — ' — I — ' — I — ' — I — ' — I — < — I — ' — I — ' — I — ' — I — 1 — I — ' — I — ' — I — ' — I — • — 1 — ' — I — ' — I — ' — I — ' — \ — ' — I — ' — I — ' — I — 1 — 1 — ' — I — ' — I —
8.2
8.0
49
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
5.4 5.2 5.0
fl (ppm)
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
T
2.4
Reported in the literature. Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,125,
12104.
56
-300
-400
^
o
A,"o
"o"
02N
4-Nitrobenzyl methyl carbonate 9b50 was prepared according to general procedure D
employing 5 grams of 4-nitrobenzyl alcohol. 2.1 g 45% of pale yellow crystals were
obtained. 'H NMR (400 MHz, CDC13) 8 8.26 (d, J = 4.0, 2H), 7.58 (d, J = 4.5,2H), 5.28
(s, 2H), 3.84 (s, 3H). 13C NMR (101 MHz, CDCI3) 5 156.1, 142.8, 142.6, 128.4, 123.8,
67.9, 55.2.
-800
-600
S
T—'—1"'
9.0 8.8
S
S
i • "1 • T • r " • i '' 1 • i ' i ' i • i '< i • i ' i ' i • i ' 1 ' 1 ' i ' r '
6.6 8.4 8.2
8.0 7.8
7.6 7.4 7.2
7.0 6.B 6.6 6.4 6.2 6.0 5.8
5.6 5.4 5.2
5.0
S
1—r~i—• i ' i "' 1 '" 1 • i ' i •
4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4
Prepared according to literature. Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51, 3235.
58
mmmmmmmi^
160
155
150
145
140
135
130
125
120
115
110
105
100
fl (ppm)
95
90
-|
80
>
1
75
•
1
70
'
1
65
'
1
60
'
1
55
'
1—
50
59
O
MeO
4-Methoxybenzyl methyl carbonate 9c51 was prepared according to general procedure D
employing 5 grams of 4-methoxybenzyl alcohol. 5.9 g 83% of white crystals were
obtained. ]H NMR (400 MHz, CDC13) 5 7.41 (d, J = 4.9 Hz, 2H), 6.98 (d, J = 5.2 Hz
2H), 5.10 (s, 2H), 3.95 (s, 3H), 1.58 (s, 3H), I3C NMR (101 MHz, CDCI3) 5 161.8, 156.4,
130.2,127.8,113.9,69.5,55.0,54.8.
T — • — 1 — 1 — 1 — • — 1 — > — 1 — 1 — 1 — • — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — < — 1 — > — 1 — 1 — 1 — ' — 1 — • — 1 — • — 1 — ' — 1 — • — 1 — ' — 1 — ' — 1 — • — 1
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
•
1
3.4
•
1
3.2
'
r
3.0
f l (ppm)
51
Reported in the literature. Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,125,
12104.
60
61
O
MeO
cAcr
3-Methoxybenzyl methyl carbonate 9f52 was prepared according to general procedure D
employing 1.9 grams of 3-methoxybenzyl alcohol. 0.85 g 32% of a colorless oil was
obtained. ]H NMR (400 MHz, CDC13) 8 7.41- 7.36 (m, 2H), 7.04- 6.78 (m, 2H), 5.16 (s,
2H), 4.05 (s, 6H). 13C NMR (101 MHz, CDC13) 5 160.2, 156.1,137.3, 129.6,120.4,
113.8,112.6, 69.5, 56.0, 55.2.
-2E+05
-2E+05
-2E+05
-2E+05
-2E+05
-2E+0S
j
J
-2E+05
-1E+05
-1E+05
-1E+0S
-1E+05
-1E+05
-9O0OO
-80000
-70000
-60000
-50000
-40000
-30000
-20000
I
>V
-10000
.
"V
HT
-0
--10000
Prepared according to literature. Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51, 3235.
62
~1
150
i
1
145
1
1
140
1
1
135
1
1
130
1
|
125
1
1
120
1
1
115
•
|
110
•
1
105
fl (ppm)
•
,
100
1
1
95
•
,
90
.
1
85
.
J-
80
— i
75
• — I
1
70
1 — • — I — >
65
60
1
55
'
—
I
50
—
63
N
Benzyl morpholine 11a53 was prepared according to general procedure B employing 1 g
of benzyl bromide. 0.33 g 31% of a yellow oil was obtained. (Impurity in 13C NMR
spectra, a peak corresponding to acetonitrile solvent occurs at -100 ppm.) *H NMR (400
MHz, CDC13) 5 7.58 (m, 5H), 3.81 (m, 4H), 3.54 (s, 2H), 2.56 (m, 4H). 13C NMR (101
MHz, CDCI3) 6 129.3,128.1,127.2,126.2, 67.2,63.6, 53.8.
JUL
S
5.0
f l (ppm)
Reported in the literature. Fujita, K-L; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
64
wmW0H^^
135
130
125
120
115
110
105
100
95
90
85
75
70
65
60
55
50
65
N
0,N
4-Nitrobenzyl morpholine lib 5 4 was prepared according to general procedure B
employing 1.2 g of 4-nitrobenzyl bromide. 0.57 g 42% of yellow crystals were obtained.
*H NMR (400 MHz, CDC13) 8 8.20 (d, J= 7.3,2H), 7.55 (d, J= 7.3,2H), 3.75 (s, 4H),
3.68 (s, 2H), 2.49 (s, 4H). 13C NMR (101 MHz, CDC13) 6 141.9,136.8,129.4,125.5,
68.2,64.1,55.6.
-20000
1
f
1
i
-19000
-18000
1
r
1
1
r
-17000
1
A
) -
-160OO
j
-1S0OO
-14000
-130OO
-12000
-11000
-10000
-9000
-8000
-7000
-5000
^5000
-4000
-3000
-2000
.
,
A,
-
I
.
K.
J
tJ
54
1 '1'
8.0
7.5
7.0
6.5
6.0
5,5
5.0
4.5
4.0
3.5
-1000
-i
1
T
8.S
j
1V
--1000
a
3.0
2.S
2.0
Reported in the literature. Fujita, K-I.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
66
67
N
F,C
4-Trifluoromethylbenzyl morpholine lid 55 was prepared according to general procedure
B employing 1.4 g of 4-trifluorobenzyl bromide. 0.35 g 23% of a yellow oil was
obtained. 'H NMR (400 MHz, CDC13) 8 7.61 (d, J= 7.3, 2H), 7.55 (d, J = 8.0, 2H), 3.83
(s, 4H), 3.59 (s, 2H), 2.49 (s, 4H). 13C NMR (101 MHz, CDC13) 6 129.9,125.6,125.3,
123.2,120.1,67.6,63.4,53.9.
20000
-19000
18000
17000
16000
15000
-1«00
13000
12000
11000
-10000
9000
8000
7000
6000
-5000
4000
3000
-2000
10O0
<A
^J
s
s
JLJL
"-r*
Reported in the literature. Fujita, K-L; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
68
135
130
125
120
115
110
105
100
95
90
85
75
70
65
-i
60
<
1
55
•
1
50
'
1—
45
N'
4-Methylbenzyl morpholine lie 56 was prepared according to general procedure B
employing 1.1 g of 4-methylbenzyl bromide. 0.28 g 24% of a yellow oil was obtained.
(Impurity in 13C NMR spectra, a peak corresponding to benzyl bromide reagent occurs at
-128 ppm.) 'H NMR (400 MHz, CDC13) 8 7.27 (d, J = 4.5,2H), 7.16 (d, J = 4.2,2H),
3.74 (s, 4H), 3.50 (s, 2H), 2.47 (s, 4H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCI3) 5
136.8, 135.2,129.3,129.1, 66.9, 63.8, 53.5,21.1.
JUL
1 '• T ' 1 ' 1 ' i •' r T ' i — • — r - r ' - r — i - i — » 1 » t 1 i • i -T 1 » 1 1 1—1 1 1 r > 1 1 1 • 1. 1—-—1—' 1 • 1—• "J • T ' 1 ' 1—• 1 • i
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 S.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6
fl (ppm)
Reported in the literature. Fujita, K-L; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64,1943.
J
70
71
Benzyldibutylamine 13a57 was prepared according to general procedure B employing 1.0
g of benzyl bromide. 0.28 g 21% of a yellow oil was obtained. (Impurity in 13C NMR
spectra, a peak corresponding to pentane solvent occurs at -65 ppm.) "H NMR (400
MHz, CDC13) 5 7.32 (m, 5H), 4.73 (s, 1H), 3.59 (s, 2H), 2.45 (m, 4H), 0.98 (s, 2H). 13C
NMR (101 MHz, CDCI3) 5 140.8,128.8,128.1, 126.6, 58.6, 53.5, 30.1,20.6, 14.1.
i
1
r
•nr .
7.5
ILL
7.0
6.5
6.0
5.0
4.5
3.0
2.5
2.0
1.5
1.0
Reported in the literature. Fujita, K-L; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
72
73
u v
3-Methoxybenzyl morpholine llf58 was prepared according to general procedure B
employing 1.2 g of 3-methoxybenzyl bromide. 0.54 g 43% of a yellow oil was obtained.
(Impurity in *H NMR spectra, a peak corresponding to benzyl bromide reagent occurs at
-3.8 ppm.) !H NMR (400 MHz, CDC13) 5 7.27 (m, 1H), 6.94 (m, 2H), 6.83 (m, 1H), 3.84
(s, 3H), 3.76 (s, 1H), 2.50 (s, 2H). 13C NMR (101 MHz, CDC13) 8 160.5, 146.6, 130.3,
129.6, 121.6, 115.6, 65.8, 63.8, 55.5, 53.7.
1
Ir
I / '
j 1
1
f
Y
V
.Lii
T TT
— I — 1 — 1 — 1 — 1 — > — 1 — « — l — • — l — ' — 1 — - " — l — « — 1 — « — 1 — • — 1 — 1 — 1 — 1 — 1 — > — 1 — • — 1 — « — 1 — « — l — ' — l — ' — I —
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
5.4
5.2
5.0 4.8
f 1 (ppm)
4.6
4.4
4.2
r
~ l — ' — l — ' — l — ' — l — ' — l — ' — l — « — l — ' — 1 — ' — 1 — ' — l —
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
Reported in the literature. Fujita, K-L; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
74
- i — . — | — i — | — i — j -
160
155
150
145
140
135
130
125
120
115
110
105
100
fl (ppm)
1—'—I—'—r95
90
75
70
65
60
55
50
45
CHAPTER 3
RESULTS AND DISCUSSION
As described in the introduction of this thesis, the formation of benzylic carboncarbon and carbon-heteroatom bonds have occurred by palladium(0)-catalyzed
nucleophilic substitutions or benzylic substrates via r|3-complexes. These investigations
included the study of r|3-naphthyl, r|3-allyl, and r|3-benzyl complexes. However, it was
interesting that the r| -benzyl systems were not as well-studied like the other two systems.
Hartwig did a study of the relative reaction rates of r)3-complexes.59 His study concluded
that r|3-benzyl systems react more quickly than r)3-allyl systems (Table 4, Entries 1-5).
The study showed the effect of steric and electronic components on the rate. Adding
steric bulkiness to a napthyl group slowed down the reaction rate by four times (Table 4,
Entries 1 and 2). This occurs because the addition of the methyl group creates steric
hindrance, making it more difficult for the nucleophile to attack thereby decreasing
reaction rate. However, the opposite occurs for the r|3-allyl system, where addition of
two methyl groups increases the reaction rate by four times (Table 4, Entries 4 and 5). It
Johns, A. M.; Tye, J. W.; Hartwig, J. F. J. Am. Chem. Soc. 2006,128, 16010.
75
76
is understood that these groups help stabilize the positively charged rj -intermediate
complex and thus the forward reaction can occur more quickly.
Table 4. Hartwig's study of relative rates.
>7~**
50PhNH2
60 °C, PhCCPh
F-'-i
Ph
HN
f\
^
?
or
Pd°
)— NH
R
Ph
R = H, Me
entry
1
2
3
4
5
T)3electrophile
OJ
(XT
(J
a.
^
^
t-i/2 min
kob.(Ox10J
11
1.0
42
0.27
185
0.062
570
0.020
2200
0.0052
As mentioned previously, Kuwano began investigations of palladium-catalyzed
benzylic animation.60 His reactions were more or less successful, having the reactions go
to completion, but on the order of at least 3 to 96 hours.
60
Kuwano, R.; Kondo, Y.; Matsuyama, Y.; J. Am. Chem. Soc. 2003,125, 12104.
Our research propositions were the following: 1) speed up palladium-catalyzed
benzylic amination by utilizing microwave conditions; 2) develop a suitable catalyst
system; and 3) utilize N-heterocyclic carbenes as ligands.
The following results and discussion section encompasses all three areas of
interest and describes the overall success of the research study. The investigations of
utilizing NHC ligands along with microwave acceleration have also offered a new
pathway for the Heck reaction.
78
Table 5. Benzylic animation of 9 utilizing DPEphos with microwave heating. a
O
H
b j
p
R.
R2
io
9
9a: R = H
9b:R = 4-N0 2
9c: R = 4-OMe
? . : !? " ^ ' P / 3
9e: R = 4-Me
9f: R = 3-OMe
«
R1
Pd-DPEphos
DME,[Ar]
microwave heating, 160 °C
R
^
12
13
14
11a: R = H, R1,R2 = 0(CH2CH2-)2
11b: R = 4-N0 2 , R1,R2 = 0(CH2CH2-)2
11 c: R = 4-OMe, R1, R2 = 0(CH2CH2-)2
11d: R = 4-CF3, R1,R2 = 0(CH2CH2-)2
11e: R = 4-Me, R1,R2 = 0(CH2CH2-)2
11f: 3-OMe, R1,R2 = 0(CH2CH2-)2
12a: R = H, R1,R2 = CH2(CH2CH2-)2
13a: R = H, R1 = R2 = Bu
14a: R = H, R1,R2 = CH2(CH2-)2
10a: morpholine
10b: piperidine
10c: R2 = R1 = Bu
10d:
Pyrrolidine
h j
9
10
time, m
11
15
1"
9a
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9f
10a
10a
10a
10a
10a
10b
10c
10d
10a
10a
10a
10a
10a
20
20
10
20
10
20
20
20
20
20
20
20
20
11a
11a
11a
11a
11a
12a
13a
14a
11b
11c
11d
11e
11f
15a
15a
15a
15a
15a
15a
15a
15a
15b
15c
15d
15e
15f
bd
3
4
5e
6
7
8
9
10
11
12
13
L
R
R
entry
<yb,c,d
OH
2
C
/
15
15a: R = H
15b: R = 4-N02
15c: R = 4-OMe
15d: R = 4-CF3
15e: R = 4-Me
15f: R = 3-OMe
°Meld) 9 %
11
62
37
11:15
''''
97:3
-
89(51)
-
59
-
50 (28)
97:3^
95:5"
85
95 (47)
96:4'
89 (58)
80:20
92 (63)
98:2
94 (80)
98:2
93 (35)
84 (44)
-
"Reactions were conducted in DME (1.0 M) with microwave heating at 160 °C unless otherwise
noted. The ratio of 9 (1 mmol):morpholine:Pd:ligand = 100:110:1:5 unless otherwise noted. [Pd]
= 2[Pd(C3H5)(diene)]BF4. b 1.1 mol% DPEphos ligand was used . c 4 mol% of Pd catalyst was used.
6
Microwave heating at 150 °C.e Microwave heating at 180 °C.f Determined by GCMS.
9
Isolated yield. h The ratios were calculated from the GC areas.'"-" denotes >99% conversion of
corresponding benzylamine produced. ' ratio of 12:15. k ratio of 13:15.' ratio of 14:15.
79
Thefirstresearch proposal was to increase reaction rate of palladium-catalyzed
benzylic amination. Compounding upon Kuwano's work, we first followed his
methodology, but this time utilizing the microwave reactor.
Various reactions of benzylic carbonate 9 and morpholine were carried out in
DME at 160 °C with 2[Pd(C3H5)(diene)]BF4 as a catalyst in conjunction with the
DPEphos ligand with an in situ catalyst formation. Microwave heating enhanced the
production of the corresponding aminated products 11 with little or no production of the
alcohol byproduct 15 as shown in Table 5. Initial investigations for generating the
aminated product were analogous to the report of Kuwano et al. which employed 1.1
mol% DPEphos ligand. This method proved successful to produce the corresponding
aminated product in 11% conversion, but was still not comparable to the high yields of
previous studies (Table 5, Entry 1). Both increasing the catalyst loading and decreasing
the microwave heating temperature demonstrated an increased conversion to benzyl
morpholine 11a, thereby suggesting the sensitivity of the catalyst to high temperatures
(Table 5, Entries 2 and 3). However, when the amount of DPEphos ligand was increased
to 5 mol% while keeping Pd at 1.1 mol% a significant gain in conversion to 89% of 11a
took place (Table 5, Entry 4). It is believed that the increased amount of phosphine
ligand helps stabilize the catalyst at the relatively high temperatures employed in the
microwave, thereby preventing the formation of metallic palladium. It should be noted
that when 1.1 mol% of the ligand was employed a significant amount of metallic black
palladium was observed. Increasing the microwave temperature to 180 °C from 160 °C
and decreasing time of reaction showed a lowering in conversion to 11a (Table 5, Entry
5). As evidenced by black metallic palladium formation, this low conversion is thought to
be a result of catalyst instability at this higher temperature, despite the additional
phosphine being present. Electron-rich and electron-poor benzylic substrates were
examined, illustrating that the/>ara-substituent on the aromatic ring does not hinder
benzylic amination (Table 5, Entries 9, 10, and 11). The most effective/>ara-substituent
on the aromatic ring proves to be the 4-trifluoromethyl group which provided a
conversion of 95% to lid (Table 5, Entry 11). It is believed that the electronwithdrawing group increases the reactivity of the r|3-benzyl complex more so than the
electron-donating methoxy group. However, the 4-nitro group illustrates a discrepancy
by giving a significantly lower conversion to lib than the 4-trifluoromethyl and 4methoxy groups as well as a significant amount of benzyl alcohol as a byproduct. There
may be coordination between the nitro group and palladium hindering the amination
reaction.
The new reaction conditions were also applicable to other amines; piperidine,
dibutylamine, and pyrrolidine all being effective nucleophiles (Table 5, Entries 6, 7, 8).61
In all cases the conversions exceeded 90%. A small but not significant amount of benzyl
alcohol was also formed in each case. Interestingly, extending the nucleophile scope to
primary amines, such as allyl amines, did not yield the corresponding benzyl amine.
However, the short investigation of primary amines leads to future work to determine
61
A Hammet correlation study may be the subject of future studies with relative rate studies between
the electron-rich and electron-poor benzylic substrates.
81
what is formed in the reaction. Even though the corresponding benzyl amine was not
formed, a white solid precipitated out of the reaction mixture. It is believed to be the
formation of the rion-nucleophilic amine salt which then hinders the nucleophile from
further reaction.
It is postulated that the benzyl alcohol by-products 15a-f are likely a result of
trace moisture in the reaction. It is plausible that water attacks the n3-benzyl intermediate
as control studies have shown that in the absence of Pd no alcohol is observed (Scheme
22).
H_„H
.0.
O
H J
f
*~ U J'. Pd-L
O
*~
rT "V^ OH
X -J
MeO
0:
-a
Scheme 22. Formation of alcohol byproduct by nucleophilic attack of water on the r\ benzyl palladium intermediate.
82
Microwave Accelerated Amination of Benzylic Carbonates with Palladium
N-Heterocvclic Carbene Catalysts
Following onfromour successful work with the DPEphos ligand we began to
utilize N-heterocyclic carbene catalyst systems. As stated previously, in comparison to
the more traditional phosphine ligands, NHCs have a much stronger a-electron-donating
ability than even the most electron-donating phosphines. This property enhances
oxidative insertion of the Pd-NHC complex into challenging substrates, like that of
benzylic carbonates. In addition, NHC ligands are less kinetically labile than their
phosphine counterparts and so should be more robust under microwave heating.62 This
property can also allow for a lower loading amount of NHC than phosphines due to the
increased Pd-NHC stability.
As discussed in the introduction, allylic substitution utilizing NHCs was
investigated by Mori and co-workers when they reported palladium-catalyzed
nucleophilic substitution of allylic acetates in high yields (Scheme 23).63 This gave us a
starting point for our investigations.
Kantchev, E. A. B.; O'Brien, C. J.; Organ, M. G. Angew. Chem. Int. Ed. 2007, 46, 2768.
Sato, Y.; Yoshino, T.; Mori, M. Org. Lett. 2003, 5, 31.
83
R
Pd2dba3 • CHCI3
/
QAc
RI /
\
r
Nu
nucleophile (Nu-H)
Cs 2 C0 3 , THF
50 °C, 2 - 37 hours
R = Ph
6-100% yield
Scheme 23. Allylic substitution of allylic acetates.
Our initial experiments with benzylic ester substrates paralleled Mori and coworkers by following their experimental procedures utilizing butyl lithium and cesium
carbonate as sources of base to deprotonate the imidazolium salt in order to generate the
free NHC in-situ in the presence of palladium. Microwave heating was then used to carry
out the amination reactions as was the case for the phosphine system. Our work
incorporated the five following NHCs: A, 1,3-Diisopropyl-imidazolium
tetrafluoroborate; B, l,3-Bis-(2,6-diisopropylphenyl)-imidazolinium chloride; C, 1,3Bis(l-adamantyl)- imidazolium tetrafluoroborate; D, 1,3-Di-terf-butyl-imidazolinium
tetrafluoroborate; and E, l,3-Bis-(2,4,6-trimethylphenyl)-imidazolinium chloride (Figure
8). These NHCs were chosen since they have proven successful in many other Pd
catalyzed reactions and came packaged together in a readily-available kit from SigmaAldrich.
84
BF4
A
BF4
BF;
D
E
Figure 8. NHCs employed in our investigations.
85
Table 6. Benzylic amination of 9 with morpholine utilizing N-heterocyclic carbene
ligands and BuLi.a
0
PdCI2-Ligand
Q^O^OMe
R
:
— •
THF, Butyl Lithium, [Ar]
microwave heating, 140 °C
«
9a: R = H
9b: R = 4-N02
9c: R = 4-OMe
R
R
11
11a: R = H
11b:R = 4-N02
11c: R = 4-OMe
entry
9
1
2"
3C
4
5
6
7
8d
9d
9a
9a
9a
9a
9a
9a
9a
9b
^fJT
ligand
A
A
A
B
C
D
E
E
9c
E
15
15a: R = H
15b: R = 4-N02
15c: R = 4-OMe
time, m
11
15
convn (9), %e
11:15'
5
5
5
5
5
5
5
10
10
11a
11a
11a
11a
11a
11a
11a
11b
11c
15a
15a
15a
15a
15a
15a
15a
15b
15c
54
25
5
22
45
27
33
68
66
68:31
72:28
2:98
50:45
73:24
77:22
81:18
48:51
63:36
"Reactions were conducted in THF (1.0 M) with microwave heating at 140 °C unless otherwise
noted. The ratio of 9 (1 mmol):morpholine:base:Pd:ligand = 100:110:3:7:7. Carbene ligand A,
1,3-Diisopropyl-imidazoliumtetrafluoroborate; B, l,3-Bis-(2,6-diisopropylphenyl)-imidazolinium
chloride; C, l,3-Bis(l-adamantyl)- imidazolium tetrafluoroborate; D, 1,3-Di-tert-butylimidazolinium tetrafluoroborate; E, l,3-Bis-(2,4,6-trimethy|phenyl)-imidazolinium chloride. h
Cooled reaction to 0 °C before microwave heat. c Stirred overnight at room temperature before
microwave heat. d Microwave heat at 160 °C.e Determined by GCMS. 'The ratios were
calculated from the GC areas.
Several reactions of benzyl carbonate 9 were executed utilizing the «BuLi to
generate the free carbene from the imidazolium salts and these are summarized in Table
6. Of the five NHCs investigated, l,3-Bis-(2,4,6-trimethylphenyl)-imidazolinium
chloride (E) gave the highest ratio of benzyl morpholine to benzyl alcohol, but in
relatively low conversion (Table 6, Entry 7). In contrast, carbenes B, C, and D also
86
produced slightly more benzyl alcohol in only moderate conversions (Table 6, Entries 46).
An investigation was done with carbene A at room temperature, and a significant
amount of alcohol was formed (Table 6, Entry 3). As mentioned earlier in our study,
alcohol formation can occurfromexcess moisture. However, it can also be postulated
that alcohol formation can occur due to the moisture-sensitive imidazolium salt. The
addition of imidazolium salt attracts moisture molecules thereby increasing the chance of
forming the alcohol byproduct. It may also be an NHC catalyzed process.
The optimal NHC E was then used with the substrates 4-nitro and 4methoxybenzyl methyl carbonates (Table 6, Entries 8 and 9). Unfortunately, the
reactions showed an increased Conversion to benzyl alcohol and like the reactions with
the DPEphos ligand, the 4-nitrobenzyl methyl carbonate produced the greatest amount of
alcohol byproduct.
87
Table 7. Benzylic amination of 9 with morpholine utilizing N-heterocyclic carbene
ligands and cesium carbonate with varying temperature.3
0
Pd2(dba)3-Ligand
A
^ ^ / ^
R
"O
OMe
9a: R == H
9b: R ==94-N02
9c: R == 4-OMe
9d:R == 4-CF3
entry
9
1
9a
carbene
ligand
A
2
9a
9a
B
E
9a
9a
9a
8
9a
9b
E
E
E
E
E
9
9b
D
10"
11 c
9b
9c
9d
3
4
5C
6
l6
12
~0* i
^^Solvent
Cesium Carbonate, [Ar]
microwave heating
R
R
11
11a: R = H
11b:R = 4-N02
11c: R:= 4-OMe
11d:R = 4-CF3
15
15a: R = H
15b: R = 4-N02
15c: R = 4-OMe
15d: R = 4-CF3
solvent
11
15
convn (9), %e
11:15*°
MeCN
11a
15a
84
20:79
MeCN
MeCN
11a
11a
15a
15a
86
88
CH2CI2
11a
11a
11a
15a
15a
15a
15a
0
Toluene
THF
MeCN
15:83
86:13
-
0.1
38
MeCN
11a
11b
15b
18
0
MeCN
11b
15b
40
A
MeCN
11b
E
MeCN
11c
15b
15c
31
2
E
MeCN
11d
15d
69
40:60
43:54
8:91
0
Reactions were conducted in MeCN (0.4 M) with microwave heating of a stepwise fashion of 10
minute intervals at 100 °C, 120 °C, 140 "C, and 160 °C unless otherwise noted. The ratio of 9 (0.4
mmol):morpholine:base:Pd:ligand = 100:200:4:2.5:5. A, 1,3-Diisopropyl-imidazolium
tetrafluoroborate; B, l,3-Bis-(2,6-diisopropylphenyl)-imidazolinium chloride; C, 1,3-Bis(ladamantyl)- imidazolium tetrafluoroborate; D, 1,3-Di-tert-butyl-imidazolinium
tetrafluoroborate; E, l/3-Bis-(2,4,6-trimethylphenyl)-imidazolinium chloride. b Used 2 mol%
Cesium Carbonate.c Stepwise fashion of 10 minute heat intervals at 100 °C and 120 "C only.
d
Used [PdBr(CNC-Bu2)][Br]. determined by GCMS. xThe ratios were calculated from the GC
areas.g "-" denotes >99% conversion of corresponding benzylamine produced.
Following Mori's work, the next part of the study involved decreasing the
concentration of the solution from 1.0 M to 0.4 M. This simply allowed us to work on a
88
smaller scale of the reaction, and did not affect reactivity of materials. Mori also reported
that cesium carbonate could be used as the base to deprotonate the imidazolium salts in
order to form the N-heterocyclic carbene in-situ and so a study of this method was carried
out. Another reason we wished to look at cesium carbonate is that it is non-flammable
unlike wBuLi. A number of reactions with benzylic carbonate 9 and morpholine were
carried out by microwave heating of a stepwise fashion of 10 minute intervals at 100 °C,
120 °C, 140 °C, and 160 °C using the conditions shown in Table 7. The reason for the
stepwise fashion was to determine which temperature would yield the optimal conversion
to benzyl amine. The main focus was on carbene E as the coordinating NHC ligand
source since in the previous studies with wBuLi, it was determined to be the most
effective amongst the imidazolium salts.
i
Several attempts were made to improve the conversion of 9 to 11, including the
assessment of various solvent systems in which to run the reaction. Of the five solvents
investigated, acetonitrile gave the highest conversion of 9a to 11a (88%) along with a
relatively minor amount of benzyl alcohol (Table 7, Entry 3). Of the other solvents
employed only THF gave a conversion (38%) to product.
Substrate scope was also investigated; however, in one case (9b) conversion was
almost entirely to the undesired benzyl alcohol (Table 7, Entry 8). The other substrates
were less promising and did not give much insight into whether an electron-rich or
electron-poor substrate accelerated the reaction (Table 7, Entries 8, 11, and 12).
Unfortunately, substrate scope was inconclusive.
89
These investigations lead us to believe 140 °C is the optimal microwave
temperature as indicated by analysis of the GC conversions. Also, to be certain that the
reaction did actually proceed by catalysis, a blank reaction was carried out with only
benzyl methyl carbonate substrate and morpholine in MeCN. The reaction mixture was
heated at 140 °C for 30 min and <3% conversion to the corresponding amine was
observed.
Varying solvent systems were also tested in pursuit of optimum conditions (Table
7, Entries 3-6). The outcome of these studies were that MeCN, a polar solvent gave the
highest conversion (Table 7, Entry 3), while non-polar solvents THF, CH2CI2 and toluene
gave poor or no conversion (Table 7, Entries 4, 5, and 6). This is expected given the fact
that these are poor solvents for the microwave since polar solvents are required for the
manipulation of its particles created by altering the magnetic frequency.
90
Table 8. Benzylic amination of 9 with morpholine utilizing N-heterocyclic carbene
ligands and cesium carbonate at constant temperature.0
yCY
"c
OMe
+
-'
9
9a: R = H
entry
9
1
2
3
4
5
9a
9a
9a
9a
9a
HN
--\
Pd2(dba)3-Ligand
k^O
Y
7W
^
V
J
R
11
(
— •
MeCN
Cesium Carbonate, [Ar]
|
Microwave 140 °C
carbene
ligand
E
A
B
C
D
..
11a
11a
11a
11a
11a
+
(
^Y^0H
R
15
VJ
11a: R = H
15a: R = H
15
convn (9), %"
11:15°
15a
15a
15a
15a
15a
71
64
49
60
62
61:43
59:40
51:48
70:30
79:20
0
Reactions were conducted in MeCN (0.4 M) with microwave heating of 30 min total heat for 10
min intervals at 140 °C. The ratio of 9 (0.4 mmol):morpholine:base:Pd:ligand = 100:200:4:2.5:4.
A, 1,3-Diisopropyl-imidazolium tetrafluoroborate; B,l,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride; C, l,3-Bis(l-adamantyl)- imidazolium tetrafluoroborate; D, 1,3-Di-tertbutyl-imidazolinium tetrafluoroborate; E, l,3-Bis-(2,4,6-trimethylphenyl)-imidazolinium chloride.
b
Determined by GCMS. cThe ratios were calculated from the GC areas.
Altering the protocol, the microwave heating time was set to three intervals often
minutes each at 140 °C, thus getting rid of the stepwise heating pattern having
determined the optimal microwave temperature. Each N-heterocyclic carbene was tested
against benzyl methyl carbonate. This time, the NHC with the best overall conversion of
9a in 71% was still carbene E (Table 8, Entry 1). However, the NHCs with the best
conversion to 11a were carbenes C and carbene D, showing high product:alcohol ratios
of 70:30 and 79:20, respectively (Table 8, Entries 4 and 5). It is deduced that steric
bulkiness of the R group of the NHC ligand has a direct effect on the conversion of 9a.
In accordance, investigations of carbenes A and B showed a low ratio of product to
91
alcohol where the carbene was not as sterically bulky as carbenes C and D (Table 8,
Entries 1 and 2). Having also altered the microwave heating process, it was deduced that
a gradual heating protocol is better for the amination reaction.
Microwave Accelerated Amination of Benzylic Carbonates with Palladium
N-Heterocyclic Silver Carbene Catalysts
The nBuLi method of carbene generation proved to be cleaner than the cesium
carbonate method. It was not necessary to wait for the base to dissolve in solvent since it
added quite cleanly as a clear liquid to the reaction mixture. However, working with
«BuLi is unfavorable because it is highly corrosive and flammable. Also, wBuLi limits
solvent choices, as any solvent needs to be compatible with alkyl lithium reagents.
Working with cesium carbonate proved to be more problematic when carrying out
microwave reactions as it would often stick to the walls of the microwave vial, which
would often lead to vial bursts.
Douthwaite et al. compounded upon Mori's work with N-heterocyclic carbenes
by developing an enantioselective variant of the allylic substitution reaction that
employed a chiral N-heterocyclic carbene (NHC)-imine ligand derived from trans-1,2diaminocyclohexane.64 Douthwaite and co-workers had found that transfer of the
carbene ligand to palladium was easily achieved by transmetallation from the silver(I)
halide complexes of the NHC, a procedure originally developed by Wang et al.65
Therefore, given the handling issues of both the cesium carbonate and wBuLi methods in
conjunction with the significant production of benzyl alcohol our attention turned to the
use of silver carbenes.
Bonnet, L. G.: Douthwaite, R. E. Organometallics, 2003, 22, 4187.
Wang, H. M. J.; Lin, I. J. B. Organometallics 1998,17, 972.
93
R-N
R-N
N-R
BF4
Ag20
— •
N-R
/ BF4
If
Ag
Ag
\
R-N^N-R
R R
r-N
/
l >=Ag
\
Ag-BF 4
BF4
Figure 9. Generation of silver NHCs.
BF 4
/=\
2 R-N
N- R
T
Ag
BF4
94
Table 9. Benzylic amination of 9 with morpholine utilizing silver N-heterocyclic carbene
ligands."
^R2
Ri
+
HN-^
.
Pd2(dba)3-Ligand
Solvent, [Ar]
Microwave, 140 °C
9
OH
Ri
9a: Ri = H, R2 = OC02Me
98^ Ri = H, R2 = OC02fBoc
9a 2 : Ri = H, R2 = OCOMe
9a3: Ri = H, R2 = OC02Et
entry
1°
b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16" c
171b,6
18"-'
19b
20"
21"
22"
23"
24"
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9ai
9ai
9a2
9a2
9a3
9a3
carbene ligand
Ag
Ag
Ag
Ag
Ag
Ag
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-C
Ag-D
Ag-C
Ag-D
Ag-C
Ag-D
11
11a: R = H
solvent
MeCN
MeCN
DME
DMSO
DMF
toluene
THF
CH2CI2
90:10 toluene:MeCN
acetone
80:20 toluene:MeCN
50:50 toluene:MeCN
25:75 toluene:MeCN
10:90 toluene:MeCN
20:80 toluene: MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
convn(9), %'
54
49
35
53
61
12
13
4
33
96
44
55
54
57
99
26
36
>1
16
12
7
3
28
31
Ri
15
15a: R = H
11 a: 15agjr
77:22
83:16
77:22
66:32
85:14
94:5
96:4
92:7
94:5
86:13
62:38
60:39
0.2:0.04
68:31
58:41
"Reactions were conducted in solvent (0.4 M) with microwave heating of 10 minute intervals at
140 °C for 40 minutes unless otherwise noted. All reactions utilized l,3-Bis(l-adamantyl)imidazolium silver tetrafluoroborate unless otherwise noted. The ratio of 9 (0.4
mmol):morpholine:Pd:silver carbene = 100:200:2.5:4." Microwave heating of 10 minute
intervals at 140 °C for 60 minutes. c Used [Pd(allyl)CI]2. "Used PdCI2.e Used Pd(OAc)2.
f
Determined by GCMS. 9The ratios were calculated from the GC areas. h "-" denotes >99%
conversion of corresponding benzylamine produced.
95
Towards this goal we synthesized 1,3-bis (l-adamantyl)-imidazolium silver
tetrafluoroborate (Ag-C) and 1,3-di-tert-butyl-imidazolinium silver tetrafluoroborate
(Ag-D). As far as stability is concerned, silver carbene Ag-C was more air stable and
easily stored in a vial in the absence of light. Silver carbene Ag-D was not air stable and
had to be stored in an evacuated schlenk flask filled with argon in the absence of light.
These two NHCs were chosen for preparation and further analysis because of the
conclusions drawn from the previous investigations that they were the two most optimal
ligands in reaction for the conversion of 9a to 11a with little or no conversion to 15a.
These carbenes were prepared by combining silver(I) oxide and the imidazolium salt
itself set to stir overnight in DCM with the exclusion of light. All subsequent animation
reactions were carried out with microwave heating of 10 minute intervals at 140 °C for
40 minutes. The following areas of interest were the main focuses of our investigation
with the silver NHCs: 1) varying the leaving group of the carbonate substrate; 2)
determining which NHC would prove superior for conversion of 9 to 11a; 3)
determining an optimal solvent system in which to run the reaction; and 4) investigating
other sources of Pd(II) catalysts.
Investigations of benzyl substrate leaving groups included 9a, 9ai, 9a2, and 9a3.
Investigations were carried out in MeCN solvent and utilizing silver carbene Ag-C. Of
the four substrates, 9a2 and 9a3 yielded benzyl morpholine with no alcohol formation
(Table 9, Entries 21 and 23). Benzyl substrate 9ai yielded benzyl morpholine, but almost
half of the conversion was the alcohol byproduct, due to sterics of the substrate (Table 9,
Entry 19). As of yet, the best substrate to yield benzyl morpholine was 9a, with the
highest overall conversion with some alcohol formation (Table 9, Entry 2).
Investigations were continued by utilizing silver carbene Ag-D. The outcome was
analogous to previous work where 9a2 and 9a3 yielded benzyl morpholine in low
conversion with no alcohol production (Table 9, Entries 22 and 23). Benzyl substrate 9ai
had high conversion to benzyl alcohol, and again, 9a was the best substrate for benzylic
amination (Table 9, Entries 1 and 20).
These investigations indicate that 9a is the best leaving group for increased
reaction rate. These findings are also consistent with leaving group ability where
phosphonates are the best leaving groups, then carbonates and lastly, acetates. Also, the
best NHC was silver carbene Ag-C. While reactions with silver carbene Ag-D showed a
greater overall conversion of 9, reaction with silver carbene Ag-C yielded greater
production of 11a with smaller amounts of alcohol byproduct (Table 9, Entries 1 and 2).
Having determined the best substrate and NHC for benzylic amination, attention
was turned to the effect of the reaction solvent. As stated previously, the microwave
operates by dipolar polarization or ionic conduction. Thus, polar solvents would enhance
rate of reaction over nqnpolar solvents. In our investigations, several nonpolar and polar
solvents were assessed under identical microwave conditions. The nonpolar solvents
included toluene, THF, and DCM (Table 9, Entries 6-8). These solvents inefficiently
produced benzyl morpholine, but did suppress the formation of benzyl alcohol. The polar
solvents analyzed were DME, DMSO, DMF, and acetone (Table 9, Entries 3-5, and 9).
97
In contrast, these solvents showed much higher conversions to benzyl morpholine and
afforded some benzyl alcohol. Acetone was the best solvent showing the highest
conversion to benzyl morpholine. From these trials, it was shown that microwave
suitable polar solvents showed optimal conditions for benzylic amination. It was
worthwhile to try a mixed solvent system with toluene and MeCN, to see the outcome if a
nonpolar solvent could suppress the alcohol byproduct formation while the polar solvent
could promote the amination process. Testing several solvent systems by mixing
different volumes of toluene and MeCN, the reaction was most favorable when the ratio
of toluene:MeCN was 20:80 (Table 9, Entries 10-15), while decreasing the amount of
MeCN decreased conversion. Obviously, decreasing the amount of polar solvent also
lowered the solvent ability for reaction performance. The outcome drawn from testing
solvent scope confirmed that acetone and the toluene-MeCN solvent mixtures to be the
best solvent systems for amination.
The last variable to test was the Pd source. Pd2(dba)3 is a readily available, air
stable Pd(0) source, but Pd(II) sources have the ability to form Pd(0) in the presence of a
base. Of the Pd(II) sources readily available, [Pd(allyl)Cl]2, PdCl2, and Pd(OAc)2 were
tested against Pd2(dba)3 (Table 9, Entries 2, 16-18). [Pd(allyl)Cl]2, PdCl2, and
Pd(OAc)2 exhibited low conversions of 9 (26%, 36%, and <1%, respectively), with high
formation of byproduct benzyl alcohol. Pd2(dba)3 largely surpass these percentages with
an overall conversion of 49% (Table 9, Entry 2). Pd2(dba)3 was by far the most superior
catalyst for benzylic amination, with the precatalyst already in the zero oxidation state.
98
Having determined the optimal substrate, ligand, solvent system, and Pd(II)
source, the next component of the reaction was to study substrate scope. Several
substrates with the methyl carbonate leaving group were reacted under our optimized
conditions with morpholine. The reactions were carried out in 20:80 toluene:MeCN at
140 °C with the Pd2(dba)3 pre-catalyst and silver carbene Ag-C. The first set of
substrates were tested with the 20:80 toluene:MeCN solvent system. Benzyl methyl
carbonate was the most favorable substrate to couple with morpholine (Table 10, Entry
1). All other substrates showed very poor conversion to the corresponding amine
product. The best substrates of the trials were 9c, 9f, and 91 (Table 10, Entries 3,6, and
9), indicating that electron-donating substituents favor substitution over electronwithdrawing substituents in the case of the NHC-Pd catalyst system. However, the
unsubstituted substrate continues to be the best substrate for palladium catalyzed benzylic
amination. All other substrates showed significantly lower conversion of 9, but still
favorably with no alcohol production. The absence of benzyl alcohol is likely due to the
fact there is unlikely to be free carbene present in comparison to the in-situ carbene
generation methods described above.
99
Table 10. Benzylic amination of 9 with morpholine utilizing silver N-heterocyclic
carbene ligands in a mixed solvent system."
R
Pd2(dba)3/F4
-*
0
^
^
y^R
1
A
*/Ie
+
9
-"i
-r
w
\
\y
R"'
P
Wf^
k/0 .20:80 Toluene: MeCN, [Ar]
— * •
microwave heating
140 °C, 60 min
9a: R = H
9b: R = 4-N02
9c: R = 4-OMe
9d: R = 4-CF3
9e: R = 4-Me
9f: R = 3-OMe
9g: R = 4-C02Me
9h: R = 4-CI
9i: R = 2-Me
R
/ \ ^
'=1D
L-^-~-~J
+
•w
fYT^
w
w iT^T^
R
11
11a: R = H
11b:R = 4-N02
11c: R = 4-OMe
11d:R = 4-CF3
11e:R = 4-Me
11f: R = 3-OMe
11g:R = 4-C02Me
11h:R = 4-CI
11i:R = 2-Me
R
15
15a: R = H
15b: R = 4-N02
15c: R = 4-OMe
15d:R = 4-CF3
15e:R = 4-Me
15f: R = 3-OMe
15g:R = 4-C02Me
15h: R = 4-CI
15i: R = 2-Me
11:15*'"
15a
convn 9, %"(yield)c
(99 (36)
11b
15b
6
9c
11c
15c
15
75:25
-
4
9d
11d
-
9e
9f
11e
11f
15d
15e
15f
4
5
6
7
9g
9h
9i
11g
11h
11i
15g
15h
15i
10
28
3
7
15
-
entry
9
11
15
1
9a
11a
2
9b
3
8
9
0H
86:13
"Reactions were conducted in 20:80Toluene:MeCN solvent (0.4 M) with microwave heating of
10 minute intervals at 140 °Cfor60 minutes. All reactions utilized l,3-Bis(l-adamantyl)imidazolium silver tetrafluoroborate. The ratio of 9 (0.4 mmol):morpholine:Pd:silver carbene =
100:200:2.5:4. " Determined by GCMS.c Isolated yield. d The ratios were calculated from the GC
areas. e "-" denotes >99% conversion of corresponding benzylamine produced.
100
Table 11. Benzylic amination of 9 with morpholine utilizing silver N-heterocyclic
carbene ligands in acetone.0
R
Pd 2 (dba) 3 /F 4 BAg^(
O
, 0AOMe
,
k ^
+
R
HN^
'' » ( f Y T ^
k^O
1
\
Acetone, [Ar]
9
microwave heating
%^
R
V
+
fVOH
;
V^
0
11
R
140 °C, 60 min
9a:R = H
9b:R = 4-N0 2
9c:R = 4-OMe
9d:R = 4-CF 3
9e:R = 4-Me
9f: R = 3-OMe
9g: R = 4-C0 2 Me
9h: R = 4-CI
9i: R = 2-Me
.
11a: R = H
11b:R = 4-N0 2
11c:R = 4-OMe
11d:R = 4-CF3
11e:R = 4-Me
11f: R = 3-OMe
11g: R = 4-C0 2 Me
11h:R = 4-CI
11i:R = 2-Me
/x
R =
\T^\
JJJ
t^-J
15a: R = H
15b:R = 4-N0 2
15c: R = 4-OMe
15d:R = 4-CF3
15e:R = 4-Me
15f: R = 3-OMe
15g: R = 4-C0 2 Me
15h:R = 4-CI
15i: R = 2-Me
entry
9
11
15
convn 9, % (yield)0
11:15'd,e
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9g
9h
9i
11a
11b
11c
11d
11e
11g
11h
11i
15a
15b
15c
15d
15e
15g
15h
15i
96 (58)
94:5
13
27
21
30
24
27
51
28:66
73:26
41:58
48:51
82:17
0
Reactions were conducted in acetone solvent (0.4 M) with microwave heating of 10 minute
intervals at 140 °C for 60 minutes. All reactions utilized l,3-Bis(l-adamantyl)- imidazolium silver
tetrafluoroborate. The ratio of 9 (0.4 mmol):morpholine:Pd:silver carbene = 100:200:2.5:4.b
Determined by GCMS.cIsolated yield. d The ratios were calculated from the GC areas. e "-"
denotes >99% conversion of corresponding benzylamine produced.
The same analyses were done but this time with acetone the other optimal solvent.
It was evidentfromthis study that the reactions in acetone showed a higher conversion to
the benzyl alcohol byproducts where, in contrast, reactions with the mixed solvent
systems showed lower conversions to the benzyl amine overall. However, with concern
that the acetone may bring about side reactions via imine formation, further
investigations utilized the 20:80 toluene:MeCN solvent system for the animation of
benzyl carbonate substrates. To further determine the scope of the reaction, other amino
nucleophiles were analyzed with the various benzylic substrates to see how they would
perform under the optimal reaction conditions.
102
Table 12. Benzylic amination of 9 with dibutylamine utilizing silver N-heterocyclic
carbene ligand."
Ri
Pd2(dba)3/F4BAg^((
O
R ^
R'
20:80 toluene: MeCN, [Ar]
microwave heating
R
160 °C, 60 min
13a: R = H
13b:R = 4-N02
13c: R = 4-OMe
13d:R = 4-CF3
13e: R = 4-Me
13f: R = 3-OMe
13g: R = 4-C02Me
13h: R = 4-CI
13i: R = 2-Me
9
9a: R H
9b: R 4-N02
9c R = 4-OMe
9d: R = 4-CF3
9e: R = 4-Me
9f: R = 3-OMe
9g: R = 4-C02Me
9h: R = 4-CI
9i: R = 2-Me
entry
* b,c,d
0
15>
R
15a: R = H
15b:R = 4-N02
15c: R = 4-OMe
15d: R = 4-CF3
15e:R = 4-Me
15f: R = 3-OMe
15g:R = 4-C02Me
15h: R = 4-CI
15i: R = 2-Me
13
15
convn9, % f (yield)3
13:1s"''
81:18
9a
13a
15a
80(51)
2
d
9a
13a
15a
52
3
9b
13b
15b
90
4
9c
13c
15c
84
5
9d
13d
15d
35
6
9e
13e
15e
37
7
9f
13f
15f
44
8
9g
9h
13g
15g
27
13h
15h
82
9i
13i
15i
90
9
10
*0?
74:25
37:62
37:62
54:45
Reactions were conducted in 20:80 Toluene:MeCN solvent (0.4 M) with microwave heating of
10 minute intervals at 160 °C for 60 minute total heat time unless otherwise stated. All
reactions utilized l,3-Bis(l-adamantyl)- imidazolium silver tetrafluoroborate. The ratio of 9 (0.4
mmol):dibutylamine:Pd:silver carbene = 100:200:2.5:5.b Used acetone for solvent. c Used 4
mol% ligand. d microwave heating of 10 minute intervals at 140 °C for 90 minutes. e microwave
heating of 10 minute intervals at 140 °G for 60 minutes. f Determined by GCMS.s Isolated yield. h
The ratios were calculated from the GC areas.'"-" denotes >99% conversion of corresponding
benzylamine produced.
The first amine nucleophile tested was dibutylamine with microwave heating at
140 °C with the Pd2(dba)3 catalyst and 1,3-Bis (l-adamantyl)-imidazolium silver
tetrafluoroborate ligand. The first few reactions (Table 12, Entries 1 and 2) were to
further optimize the conditions and it was found that for efficient conversion increased
temperatures were required.
Use of the 20:80 toluenerMeCN solvent mixture gave a greater conversion to
benzyl morpholine. There was also a concern that the acetone solvent can react with
amines and result in byproduct formation. Therefore, without further trial, the mixed
solvent system of 20:80 toluene:MeCN was assumed to be the optimal solvent system to
use in subsequent reactions.
Two major factors were brought to mind that could be hindering the forward
reaction. Of course thefirstmain factor would be decreased nucleophilicity of acyclic
dibutylamine vs. morpholine. Therefore, reactions with this amine should be expected to
be slower and require an increased temperature in the microwave. A control experiment
was performed without the palladium catalyst or silver carbene ligand in 20:80
toluene:MeCN and microwave heated at 160 °C, which did not produce any substitution.
Therefore, it was established that the reaction is a catalytic reaction where the addition of
palladium catalyst with silver carbene are necessary for the reaction to go forward. More
importantly, the catalyst is stable at the higher microwave temperature of 160 °C. The
following reactions investigating the substrate scope with dibutylamine and carbonates
9b-i were then heated at 160 °C for 60 minutes (Table 12, Entries 3-10).
Previous reactions with benzyl methyl carbonate have shown the highest
conversion of 9a, regardless of the amine nucleophile, (Table 10, Entry 1). However it
was an anomaly that this did not hold true and it became more evident that dibutylamine
is a more challenging nucleophile to react with the benzyl substrate. With morpholine,
overall the electron-rich substrates showed a higher conversion to the corresponding
amine product when compared to the electron-poor substrates. For the reactions with
dibutylamine, the favorable substrates to produce the amine product varied amongst
electron-poor and electron-rich substrates.
The substrates with the highest conversion of 9 were benzyl methyl carbonate and
4-nitrobenzyl methyl carbonate (Table 12, Entries 1 and 3). The electron-poor 4-nitro
substrate showed the highest overall conversion of 90% with moderate formation of
alcohol byproduct. Electron- rich substrate benzyl methyl carbonate showed an overall
conversion of 80%. However, this reaction was done in acetone which also generates the
alcohol byproduct. In comparison to the other electron-rich substrates (9c, 9f, 9i), it did
not give the most conversion of 9, but did give the highest conversion to 13 with no
formation of alcohol.
Overall, one of the best benzylic derivatives was 4-chlorobenzyl methyl carbonate
giving 82% conversion of 9 and no formation of alcohol byproduct (Table 10, Entry 9).
105
Table 13. Benzylic animation of 9 with piperidine utilizing silver N-heterocyclic earbene
ligand."
Pd2(dba)3/ F4BAg
HN
o„. o u
9a:R = H
9b: R = 4-N02
9c:R = 4-OMe
9d: R = 4-CF3
9e:R = 4-Me
9f: R = 3-OMe
9g:R = 4-C02Me
9h: R = 4-CI
9i: R = 2-Me
0
R'
20:80 toluene: MeCN, [Ar]
microwave heating
100 °C, 120 min
12a: R = H
15a: R = H
12b: R = 4-N02
15b: R = 4-N02
12c:R = 4-OMe
15c: R = 4-OMe
12d: R = 4-CF3
15d: R = 4-CF3
12e:R = 4-Me
15e:R = 4-Me
12f: R = 3-OMe
15f: R = 3-OMe
12g: R = 4-C02Me 15g: R = 4-C02Me
12h:R = 4-CI
15h: R = 4-CI
12i:R = 2-Me
15i: R = 2-Me
entry
9
12
15
convn 9, %" (yield)0
12:15 de
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
99
9h
9i
12a
12b
12c
12d
12e
12f
12g
12h
12i
15a
15b
15c
15d
15e
15f
15g
15h
15i
76 (48)
-
44
27
12
11
14
23
17
53
83:16
90:7
82:11
-
"Reactions were conducted in 20:80 Toluene:MeCN solvent (0.4 M) with microwave heating of
10 minute intervals at 100 °C for 120 minute total heat time. All reactions utilized 1,3-Bis(ladamantyl)- imidazolium silver tetrafluoroborate. The ratio of 9 (0.4 mmol):piperidine:Pd:silver
earbene = 100:200:2.5:5. b Determined by GCMS. isolated yield. d The ratios were calculated
from the GC areas. e "-" denotes >99% conversion of corresponding benzylamine produced.
The next part in the scope of the reaction was to look at the piperidine
nucleophile. A control was executed without palladium catalyst or silver earbene at 100
°C. The outcome was a 7% conversion to 12. Higher temperatures, such as 120 °C and
106
140 °C showed conversions over 10%. Again, the reaction is catalytic and the reasoning
for decreasing the microwave temperature is due to piperidine being a stronger
nucleophile than morpholine or dibutylamine resulting in a higher background reaction.
Therefore, a reaction with piperidine would not need as vigorous reaction conditions.
However, because the reaction temperature was decreased, a longer heating time was
necessary for the reaction to occur.
The results of the reactions were very much analogous to reactions with
morpholine. The substrate that showed the best conversion of 9 with no alcohol
production benzyl methyl carbonate (Table 13, Entry 1). Like the reactions with
morpholine, the best substrates of the trials were 4-methoxybenzyl methyl carbonate and
2-methylbenzyl methyl carbonate (Table 13, Entries 3 and 9). Overall conversion to 12
was greater with piperidine than with morpholine, as morpholine did not react
significantly at 100 °C, thus proving piperidine to be a better nucleophile over
morpholine.
107
Table 14. Benzylic amination of 9 with pyrrolidine utilizing silver N-heterocyclic
carbene ligand."
Pd2(dba)3/F4BAg^(0]
o
T>
R ^
9
•$ro
20:80 toluene: MeCN, [Ar]
microwave heating
100 °C, 120 min
R
9a: R = H
9b:R = 4-N02
9c: R = 4-OMe
9d: R = 4-CF3
9e: R = 4-Me
9f: R = 3-OMe
9g: R = 4-C02Me
9h: R = 4-CI
9i: R = 2-Me
!
14
14a: R == 4-N0
H 2
14b:R
14c: R = 4-OMe
14d: R = 4-CF3
14e:R = 4-Me
14f: R = 3-OMe
14g: R = 4-C02Me
14h: R = 4-CI
14i:R = 2-Me
+
QT 0 H
1D
R
15a:
H 2
15b: R
R == 4-N0
15c: R = 4-OMe
15d:R = 4-CF3
15e:R = 4-Me
15f: R = 3-OMe
15g:R = 4-C02Me
15h: R = 4-CI
15i: R = 2-Me
entry
9
14
15
convn 9, %" (yield)0
1
14a
14b
15a
15b
54 (35)
24
3
9a
9b
9c
9d
15c
15d
59
14
55:44
4
14c
14d
2
14:15*e
78:21
-
5
9e
14e
15e
22
6
7
9f
14f
14g
85
41
92:8
32:67
14h
15f
15g
15h
22
71:29
14i
15i
38
71:28
8
9g
9h
9
9i
0
Reactions were conducted in 20:80 Toluene:MeCN solvent (0.4 M) with microwave heating of
10 minute intervals at 100 °C for 120 minute total heat time. All reactions utilized 1,3-Bis(ladamantyl)- imidazolium silver tetrafluoroborate. The ratio of 9 (0.4 mmol):pyrrolidine:Pd:silver
carbene = 100:200:2.5:5.b Determined by GCMS.c Isolated yield. d The ratios were calculated
from the GC areas. e "-" denotes >99% conversion of corresponding benzylamine produced.
Pyrrolidine was the last nucleophile tested to investigate the substrate scope. A
control was executed without palladium catalyst or silver carbene at 100 °C. The
108
outcome was a 7% conversion of 9a to 14a. Like with piperidine, higher temperatures
such as 120 and 140 showed greater conversion to 14 in over 10 % in the absence of Pd
catalyst.
The reaction results were analogous to reactions with morpholine and piperidine.
The substrate that showed the best conversion of 9 with no alcohol production was benzyl
methyl carbonate 9a (Table 14, Entry 1). Like previous analyses, 4methoxycarbonyloxybenzyl and 2-methylbenzyl methyl carbonate have the best
conversions to 14. 4-Acetatebenzyl methyl carbonate 9g has the second highest
conversion, but only 32% of that is l4g; the majority conversion to 15g.
109
Conclusion
In conclusion, palladium complexes with bisphosphine ligand DPEphos, NHCs,
and silver NHCs were found to catalyze nucleophilic benzylic substitution of benzylic
esters via ri3-benzylpalladium intermediates. Increasing the amount of DPEphos ligand
brought about a significant improvement in yields of the desired benzylaminated product.
NHCs clearly showed an improvement over the use of DPEphos where lower loading of
ligand still produced the corresponding benzylaminated product; the reactions still went
forward with a lower Pd to ligand ratio. The most optimal catalyst system included the
generated in situ Pd(0)-silver NHC complex. This system also proved useful for benzylic
amination in the absence of additional base since transfer of the carbene ligand to
palladium was easily achieved by transmetallation from the silver(I) halide complexes of
the NHC. Further studies to expand the scope of this reaction and apply this method to
other cross-coupling synthesis reactions are ongoing. There are several advantages of the
silver(I) halide complexes of the NHC over phosphine ligands. NHCs have a much
stronger a-electron-donating ability than even the most electron-donating phosphines.
This property enhances oxidative insertion of the Pd-NHC complex into challenging
substrates. Another important stabilization factor comes about by employing bulky
substituents like adamantyl groups on the nitrogen atoms. Lastly, the sturdy palladiumNHC bond helps stabilize the activated complex, which increases lifetime of the catalyst,
even at high-temperatures as well as allowing low ligand-to-palladium catalyst loadings.
Furthur studies also include more investigations on the substrate scope of the reaction.
110
Future Work
Microwave Accelerated Heck reactions of Benzylic Carbonates with Palladium
Phosphine Catalysts
Now that a suitable catalytic system has proven to be successful for benzylic
amination, it is worthwhile to utilize the catalyst for Heck Reactions. Similar to the Heck
reaction are the investigations done by Kuwano and Yokogi when they studied SuzukiMiyaura cross-coupling of benzylic carbonates with arylboronic acids (Scheme 24).66 In
this study, cross-coupling was accomplished by using benzylic carbonates as
electrophiles. They employed [Pd(r|3-C3H5)C1]2 metal and DPPpent biphosphine catalyst
to generate the palladium (0) complex in situ. They were able to form various examples
of the corresponding diarylmethane in high yields.
1-2% cat.
R1
\^
^
A?
R
^
[Pd]-DPPPent
K2C03, DMF
80 °C
19 examples
78 -99% yield
Scheme 24. Suzuki-Miyaura cross-coupling of benzylic carbonates with arylboronic
acids.
The reaction cross-couples organometallic compounds with unactivated aryl
chlorides. The acyl C - O bond of carboxylate is cleaved by the palladium (0) complex
(Scheme 25). Then, an aryl carboxylate is used in catalytic acylation of organometallic
66
Kuwano, R.; Yokogi, M. Organic Letters, 2005, 7, 945.
Ill
compounds (path a). Oxidative addition of carboxylate can also occur where palladium
inserts iteslf between the oxygen-alkyl bond (path b). However, this is less likely since
there is difficulty in activating a low-valent metal complex.
O
PR
O
1
Pd
N
Pd°
-<
OR
2
?t
,
C
R
a'
N
b
o1- v'r^
path a
R
°
PCR1
Pd°
*~
Pd
path b
R2
Scheme 25. Oxidative addition of carboxylate to palladium(O).
Heck reactions are similar to this style of reaction. They are palladium-catalyzed
coupling reactions first done with alkenes and electron-deficient substrates for carboncarbon bond formation in the presence of base (Scheme 26).67'68
67
68
Liegault, B.; Renaud, J-L.; Bruneau, C; Chem. Soc. Rev. 2008, 37, 290.
Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533.
112
H
R—X
+
v_ /
>=(
R
cat. Pd°
+ Base
- •
v _ /
>=(
+ Base-HX
R = Aryl, vinyl
X = I, Br, OTf
Scheme 26. The Heck reaction.
Table 15. Benzylic carbon-carbon bond formation of 9 with acrylonitrile by Heck
reaction."
0
Pd(OAc)2- Ligand
^ A
O
R
OMe
+
Et 3 N
MeCN, [Ar]
microwave heating
^ C N
9
•
O
16
9a: R == H
entry
3
4
5
6
7
8
9
9a
9a
9a
9a
9a
9a
9a
9a
i
ligand
DPEphos
DPEphos
BIPHEP
XANTPhos
dppbenzene
dppm
dppb
dppe
convn 9, %e
14
19
29
31
35
0
12
0
"Reactions were conducted in MeCN solvent (0.4 M) with microwave heating of 20 minute
intervals at 160 "C for 60 minute total heat time. The ratio of 9 (0.4
mmol):acrylonitrile:Pd:ligand:Et3N = 100:200:5:10:250. "Used 2[Pd(C3H5)(diene)]BF4.
c
Microwave heating of 10 minute intervals at 160 °C for 20 minute total heat time. d Microwave
heating of 10 minute intervals at 120 °C for 20 minute total heat time. c Determined by GCMS.
The most apparent approach to utilizing our catalytic system along with the Heck
reaction was to begin our studies by the initial investigation of phosphine ligands. The
113
benzylic substrate tested was benzyl carbonate with acrylonitrile employing Pd(OAc)2
catalyst and microwave heating. The phosphine was the variable of the reaction. The
reactions did not show high conversions, however, favorable was the lack of alcohol
byproduct formation. With the investigations completed, it can be seen that the DPEphos
ligand which was found favorable for benzylic amination is not the optimal ligand for the
Heck reaction. Rather, the phosphine ligands dppbenzene, XANTphos, and BIPHEP
show the highest conversions to desired product.
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