Download Copper-Catalyzed Coupling Reactions Using Carbon

Copper-Catalyzed Coupling Reactions Using Carbon-Hydrogen Bonds Woo-Jin Yoo
A thesis submitted to McGiIl University in partial fulfillment of the requirements for the
degree of
Doctor of Philosophy
Department of Chemistry Mc Gill University, Montreal May 2009
© Woo-Jin Y00, 2009
Catalyse au Cuivre Reaction de Couplage Utilisant des Liaisons Carbone­
Hydrogene
Woo-Jin Yoo
Universite Mc Gill
Superviseur: Prof. Chao-Jun Li
Cette these est une investigation sur l'utilisation des liaisons carbone­
hydro gene (C-H) en tant que substrats dans les procedes de formation de liaisons
carbone-carbone et carbone-heteroatome.
Dans la premiere partie de cette these, une reaction de couplage oxydant
est decrite entre la liaison C-H adjacent it l'atome d oxygene d'ethers cycliques
benzyliques et la liaison C-H de malonates. Ce procede, utilisant I' oxygene
comme oxydant terminal, est catalyse par un melange de trois catalyseurs: le
triflate de cuivre (Il), le chlorure d'indium (Ill), et le N-hydroxyphthalimide.
Dans la deuxieme partie de cette these, une serie de reactions de couplages
oxydants est decrite entre des liaisons C-H acyles et une variete d'heteroatomes
nucleophiles tel qu'enoles, alcools, et amines pour la synthese d'esters et
d'amides. Cette methode emploie l'hydroperoxide de tert-butyle comme oxydant,
ce dernier etant active par une quantite catalytique de sel de cuivre.
Dans la troisieme et derniere partie de cette these, une reaction de
couplage multicomposants entre alcynes, aldehydes, amines et dioxyde de
carbone it pression atmospherique, est presentee. Cette catalyse au cuivre procede
via une reaction tandem A3 -coupling/cyclisation-carboxylation pour la synthese
simple et efficace d'oxazolidines.
Table of Contents
Table of Contents ..................................................................................................... i Acknowledgements ................................................................................................. v List of Abbreviations ................ :............................................................................ vi List of Tables ......................................................................................................... ix List of Figures ........................................................................................................ xi Part I - Copper-Catalyzed Oxidative Alkylation of Cyclic Benzyl Ethers
Using Oxygen Gas as the Terminal Oxidant
Chapter 1 - Introduction to Oxidative Cross-Coupling Reactions .................. 1 1.1 Oxidative Coupling ofthe C-H Bond Adjacent to Heteroatoms ...................... 2 1.2 Oxidative Coupling of the Allylic and Benzylic C-H Bond ............................. 5 1.3 Oxidative Coupling of Alkane C-H Bonds ....................................................... 9 References for Chapter 1....................................................................................... 11 Chapter 2 - Oxidative Alkylation of Cyclic Benzyl Ethers with Malonates Using Oxygen Gas as the Terminal Oxidant ............ 13 2.1 Background ..................................................................................................... 13 2.2 Optimization of Reaction Conditions ............................................................. 15 2.3 Scope of the Oxidative Alkylation of Malonates with Benzyl Ethers ............ 16 2.4 Proposed Reaction Mechanism ....................................................................... 17 2.5 Conclusion ...................................................................................................... 20 2.6 Experimental Section ...................................................................................... 20 References for Chapter 2 ....................................................................................... 26 Part 11 - Copper-Catalyzed Oxidative Esterification and Amidation of
Aldehydes
Chapter 3 - Introduction of Oxidative Esterification and Amidation of Aldehydes.............. ...................................................................... 28 3.1 Oxidative Esterification of Aldehydes Mediated by Oxidants ....................... 28 3.2 Metal-Catalyzed Oxidative Esterification of Aldehydes ................................ 31 3.3 Carbene-Catalyzed Oxidative Esterification of Aldehydes ............................ 34 3.4 Oxidative Amidation of Aldehydes Mediated by Oxidants ............................ 36 3.5 Metal-Catalyzed Oxidative Amidation of Aldehydes ..................................... 39 3.6 Carbene-Catalyzed Oxidative Amidation of Aldehydes ................................. 41 References for Chapter 3 ....................................................................................... 43 Chapter 4 - Copper-Catalyzed Oxidative Esterification of Aldehydes with ~-Dicarbonyl Compounds ..................................................... 46 4.1 Background ..................................................................................................... 46 4.2 Optimization of Reaction Conditions ............................................................. 47 4.3 Scope of the Copper-Catalyzed Oxidative Esterification of Aldehydes with ~-Dicarbonyl Compounds....................................................................... 51 4.4 Proposed Reaction Mechanism ....................................................................... 52 4.5 Conclusion ...................................................................................................... 54 4.6 Experimental Section ...................................................................................... 54 References for Chapter 4 ....................................................................................... 61 Chapter 5 - Copper-Catalyzed Oxidative Esterification of Alcohols with Aldehydes Activated by Lewis Acids ................................... 62 5.1 Background ..................................................................................................... 62 5.2 Optimization of Reaction Conditions ............................................................. 63 ii
5.3 Scope of the Copper-Catalyzed Oxidative Esterification of Aldehydes with Alcohols .................................................................................................. 65 5.4 Proposed Reaction Mechanism ....................................................................... 66 5.5 Conclusion ...................................................................................................... 67 5.6 Experimental Section ...................................................................................... 67 References for Chapter 5 ....................................................................................... 74 Chapter 6 - Copper-Catalyzed Oxidative Amidation of Aldehydes with Amine Hydrochloride Salts .................................................. 75 6.1 Background ..................................................................................................... 75 6.2 Optimization of Reaction Conditions ............................................................. 75 6.3 Scope of the Oxidative Amidation of Aldehydes with Amine Hydrochloride Salts ......................................................................................... 81 6.4 Development of a 2 nd Generation Oxidative Amidation Protocol .................. 82 6.5 Scope of the 2 nd Generation Copper- and Silver-Catalyzed Oxidative Amidation Reactions of Aldehydes with Amine HCI Salts ............................ 83 6.6 Proposed Reaction Mechanism ....................................................................... 85 6.7 Conclusion ...................................................................................................... 85 6.8 Experimental Section ...................................................................................... 86 References for Chapter 6 ....................................................................................... 94 Part III - Copper-Catalyzed Multi-Component Coupling Reactions with CO 2
Chapter 7 - Introduction to the Applications of CO 2 in Organic Synthesis. 95 7.1 Synthesis of Carboxylic Acids Using CO2 ..................................................... 95 7.2 Heterocyclic Synthesis with CO 2 .................................................................... 98 7.3 References for Chapter 7............................................................................... 101 iii
Chapter 8 - Copper-Catalyzed Four-component Coupling between Aldehydes Amines, Alkynes and C02 ...... .................................. 103 8.1 Background ................................................................................................... 103 8.2 Optimization of Reaction Conditions ........................................................... 104 8.3 Scope of the Copper-Catalyzed Four-component Coupling Reaction of Alkynes, Aldehydes, Arnines, and CO 2 •••••••••••..•••.•••••••••••.••••••••••••••••••••••• 106 8.4 Proposed Reaction Mechanism ..................................................................... 107 8.5 Conclusion .................................................................................................... 109 8.6 Experimental Section .................................................................................... 109 References for Chapter 8 ..................................................................................... 119 Conclusions and Claims to Original Knowledge ............................................ 120 iv
Acknowledgements
The successful completion of this thesis and degree would not be made
possible without the support and assistance of a number of individuals whom I
had the privilege of knowing.
First and foremost, I would like to thank Prof. Chao-Jun Li for his support,
guidance, and patience throughout my Ph.D. studies. Thank you for accepting me
as your graduate student and providing the tools necessary to become a successful
chemist.
I would also to like thank the past and present members of the Li group for
their assistance and friendship through the last four years. I would especially like
to acknowledge Dr. Zhiping Li, Dr. Yuhua Zhang, Dr. Xiaoquan Yao, Dr. Nicolas
Eghbali, Dr. Rene-Viet Nguyen, Liang Zhao, Olivier Basle, and Camille Correia
•
for helpful discussions during my Ph.D. studies.
I am also grateful to the
Gleason, Amdtsen, Bohle, Auclair, and Moitessier Labs for allowing me to
borrow a variety of chemicals and equipment throughout my studies. I would also
like to acknowledge the help of the support staff of the chemistry department.
I would also like to thank some of my former colleagues and friends (Dr.
Robert Jordan, Dr. Geoff Tranmer, Dr. Karine Villeneuve, Nicole Riddell, Petar
Duspara, Kevin "Mister Awesome" Anderson) for their support and friendship
throughout my undergraduate and graduate studies. I would also like to thank my
former M.Sc. advisor, Prof. William Tam, for his advice, support and guidance.
I would finally like to thank my family for their understanding and
patience during my graduate studies.
v
List of Abbreviations
Ac
acetyl
acac
acetyl acetone
Ar
aryl
Bn
benzyl
BOC
tert-butoxycarbonyl
BQ
l,4-benzoquinone
n-butyl
tert-butyl
Cl
one carbon
cap
caproI actamate
C-C
carbon-carbon
C-H
carbon-hydrogen
COD
1,5-cyclooctadiene
Cy
cyclohexyl
d
doublet (IH NMR)
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DCE
1,2-dichloroethane
DDQ
2,3 -dichloro-5, 6-dicyano-l ,4-benzoquinone
BHT
2,6-di-tert-butyl-4-methyl phenol
DIB
(diacetoxyiodo )benzene
DMBQ
2,6-dimethyl-l,4-benzoquinone
DME
1,2-dimethoxyethane
vi
DMSO
dimethyl sulfoxide
dppb
bis(diphenylphosphino )butane
dppe
bis( diphenylphosphino )ethane
dppp
bis( diphenylphosphino )propane
ee
enantiomeric excess
Et
ethyl
eqmv.
equivalence
HOAt
I-hydroxy-7 -azabenzotriazole
IR
infrared spectroscopy
m
multiplet (IH NMR) or medium (IR)
Me
methyl
m.p.
melting point
NHPI
N -hydroxyphthalimide
NMR
nuclear magnetic resonance spectroscopy
HRMS
high-resolution mass spectroscopy
nOe
nuclear Overhauser effect
Nu
nucleophile
[0]
oxidation
OTf
trifluoromethanesulfonate
2KHS0 5- KHS04-K2S04
Ph
phenyl
PINO
phthalimido-N -oxyl
PMP
para-methoxyphenyl
ppm
parts per million
vii
isopropyl
q
quartet eH NMR)
rt
room temperature
s
singlet eH NMR) or strong (IR)
SET
single electron transfer
t
triplet ('H NMR)
TBHP
tert-butyl hydroperoxide
temp.
temperature
THF
tetrahydrofuran
T-HYDRO®
tert-butyl hydroperoxide, 70 wt% in water
TIPS
tri -iso-propylsilyl
TLC
thin-layer chromatography
Ts
tosyl
w
weak (IR)
Xantphos
4,5-bis( diphenylphosphino )-9,9-dimethylxanthene
viii
List of Tables
Table 1. Optimization of the Oxidative Alkylation Reaction of Isochroman 29a with Dimethyl Malonate 31a ..................................... 16 Table 2. Optimization of the Oxidative Esterification of Aldehyde 90a with ~-Diketone 88a through Screening Copper Salts ......................... 47 Table 3. Optimization of the Oxidative Esterification of Aldehyde 90a with ~-Diketone 88a by Screening the Oxidant ................................... 48 Table 4. Optimization of the Oxidative Esterification of Aldehyde 90a with ~-Diketone 88a by Changing the Temperature ............................ 49 Table 5. Optimization of the Oxidative Esterification of Aldehyde 90a with ~-Diketone 88a Through the Introduction of a Solvent ............... 50 Table 6. Scope of the Copper-Catalyzed Oxidative Esterification of Aldehydes ......................................................................................... 51 Table 7. Optimization of the Oxidative Esterification of Aldehyde 90a with Alcohol 94a by Screening Metal Salts ......................................... 63 Table 8. Optimization of the Oxidative Esterification of Aldehyde 90a with Alcohol 94a by Examining the Effect of Increasing the Equivalence of Alcohol 94a ........................................................... 64 Table 9. Optimization of the Oxidative Esterification of Aldehyde 90a with Alcohol 94a by Screening Copper Salts ....................................... 65 Table 10. Scope of the Oxidative Esterification of Aldehydes with Alcohols ...................................................................................... 66 Table 11. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine HCI Salt 97a by Screening Copper Salts ........................ 76 Table 12. Optimization ofthe Oxidative Amidation of Aldehyde 90a with Amine HCl Salt 97a by Screening Metal Salts ........................... 77 Table 13. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine HCl Salt 97a by the Addition ofNaHC03 ...................... 78 Table 14. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine HCI Salt 97a by the Addition of a Base .......................... 79 ix
Table 15. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine HCl Salt 97a by Screening Copper Salts ........................ 79 Table 16. Optimization ofthe Oxidative Amidation of Aldehyde 90a with Amine HCl Salt 97a by Screening Oxidants .............................. 80 Table 17. Optimization ofthe Oxidative Amidation of Aldehyde 90a with Amine HCl Salt 97a by Varying Catalyst Loading .................... 81 Table 18. Scope of the Oxidative Amidation of Aldehyde 90a with Amine HCl Salts 97a-f................................................................ 81 Table 19. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine HCl Salt 97f .................................................................... 83 Table 20. Scope of the 2nd Generation Oxidative Amidation Reaction .............. 84 Table 21. Optimization of the Four-Component Coupling between Alkyne 122a, Aldehyde 90a, Amine 123a, and C02 ........................ 105 Table 22. Scope of the Copper-catalyzed Four-Component Coupling between Alkyne, Aldehyde, Amine, and CO2 .................................. 106 x
List of Figures
Figure 1. Various Strategies for the Synthesis of Biaryl Compounds .................. 1 Figure 2. Structures ofNHPI and PINO ............................................................. 15 Figure 3. Direct Oxidative Esterification and Amidation of Aldehydes............. 28 xi
Part I - Copper-Catalyzed Oxidative Alkylation of Cyclic Benzyl Ethers Using Oxygen as the Terminal Oxidant Chapter 1 - Introduction to Oxidative Cross-coupling Reactions
The development of efficient strategies towards the formation of carbon­
carbon (C-C) bonds is of great interest.
A common route into C-C bond
formation occurs through the coupling between nucleophiles and electrophiles.
However, in most cases, these activated coupling partners are often derived from
less reactive starting materials. The direct use of carbon-hydrogen (C-H) bonds to
form C-C bonds 1.2 would be highly desirable since it would eliminate pre­
activation of the substrate and improve the overall efficiencies in synthetic routes
by removing needless synthetic steps (Figure 1).
[
Ar-B(OHh + Ar'- X ]
[ Ar-H +
Both coupling partners must
be pre-activated (synthesized)
Ar'-x]
Only the electrophile must
be pre-activated (synthesized)
~-----------.
~
Suzuki Crossl.....::...:...
coupling Reaction
Direct Arylation
Reaction
1 Oxidative Cross-coupling
[ Ar-H + Ar'-H 1
Neither coupling partners must
be pre-activated (synthesized)
Figure 1. Various Strategies for the Synthesis of Biaryl Compounds.
Oxidative coupling reactions with C-H bonds are quite challenging due to
the relative strong C-H bond, along with the associated selectivity issues with the
myriad of C-H bonds that are available for the coupling reaction.
While
challenging, chemists have strived to develop new synthetic methodologies that
incorporate the use of C-H bonds as substrates for C-C bond formation processes.
In this chapter, a concise review of oxidative cross-coupling reactions relevant to
this thesis will be presented. Furthermore, the examples will be focused heavily
on the use of organic peroxides as the oxidant, with select examples of other types
1
of oxidants.
The stoichiometric use of metal salts as the oxidant has been
excluded in this discussion.
1.1 - Oxidative Coupling of the C-H Bond Adjacent to Heteroatoms
It has been previously established by Murahashi and co-workers that the
C-H bond adjacent to the nitrogen atom in tertiary amines 1 can be selectively
oxidized with tert-butyl hydroperoxide (TB HP) using catalytic amounts of
RuCb(PPh3)3 (Scheme 1).3a
TBHP, benzene, rt
R1
OOtBu
R2
R3
'N-(
2
Scheme 1. Ruthenium-Catalyzed Oxidation of Tertiary Amines with TBHP.
Murahashi believed that a-tert-butyldioxyamines 2 were derived from
iminium ion intermediates that were trapped by a tert-butyl peroxyl anion.
Various peroxides in combination with catalytic amounts of ruthenium provided
similar oxygenated products for the tertiary amines. 3 Murahashi and co-workers
later demonstrated that selective oxidative C-C bond formation was possible
through a ruthenium-catalyzed oxidative cyanation of tertiary amines (Scheme
2).4
cat. RuCI 3
1
O2 (1 atm) or H2 0 2
AcOH, MeOH, 60°C
3
Scheme 2. Ruthenium-Catalyzed Oxidative Cyanation of Tertiary Amines with
Sodium Cyanide.
Synthesis of a-aminonitriles 3 was achieved with a simple ruthenium
chloride salt as catalyst with either oxygen gas or hydrogen peroxide as the
2
oxidant.
The role of acetic acid was to act as a proton source to generate
hydrogen cyanide in situ from sodium cyanide.
Employing a similar strategy, Doyle and co-workers utilized dirhodium
caprolactamate (Rh2(cap )4) as catalyst for the oxidative coupling of tertiary
amines 1 with 2-siloxyfurans 4 to generate y-butyrolactones 5 (Scheme 3).5
R1,
N\
R2
+
R3
(J-o OTIPS
1
cat. Rh 2(cap)4
T-HYDRO®, MeOH 60°C R:
N
po
0
R2
R3
5
4
Scheme 3. Rhodium-Catalyzed Oxidative Mannich Reaction of Tertiary Amines
with 2-Siloxyfuranes.
Cross-dehydrogenative coupling reaction of tertiary ammes 1 with a
variety of nucleophiles has been extensively studied by Li and co-workers
(Scheme 4). 6
R1,
cat. CuBr
+
N\
R2
H-Nu
R3
TBHP
1
Nu
=
=
Nu
R'
'N-<
R2
R3
10
R
,
ro
R
~
N
0
;N02 ,
R
0
RO~OR
H
6
7
8
9
Scheme 4. Cross-Dehydrogenative Coupling Reactions of Tertiary Amines.
Through the catalytic use of CuBr and TBHP as the stoichiometric
oxidant, the in situ generated iminium ion was captured with various carbon­
based nucleophiles such as alkynes 6/ indoles 7,8 nitromethane 8,9 and malonates
9 10 to provide the desired a-substituted tertiary amines 10.
3
Furthermore, an
asymmetric oxidative alkylation reaction of cyclic tertiary amines was
demonstrated through the use of chiral bisoxazolines as ligands. 11
Asymmetric oxidative alkylation of BOC protected tertiary ammes 11
with malonates 9 were recently described by Sodeoka and co-workers (Scheme
5).12
catalyst
9
11
~Ar2
Pd +(OHh
catalyst =
2
PAr2
Ar
=3,5-Me2CsH3
12
Scheme 5. Palladium-Catalyzed Asymmetric Oxidative Alkylation BOC­
Protected Amines. Through the use of a chiral cationic palladium(II) speCIes 12, the
asymmetric
oxidative
alkylation
was
achieved
with
good
yields
and
enantioselectivity. The reaction is believed to occur through the in situ generation
of the iminium ion achieved by the slow addition of2,3-dichloro-5,6-dicyano-l,4­
benzoquinone (DDQ) dissolved in CH2Ch.
The oxidative alkynylation of secondary amines was recently achieved by
Li and co-worker using CuBr as catalyst and TBHP as the oxidant.
Unlike
tertiary amines, the C-H bond was required to be adjacent to both the nitrogen
atom and an amide.
This stringent requirement proved quite useful since it
allowed for a highly selective oxidative coupling of phenylacetylene to dipeptide
13 (Scheme 6).13
4
H
PMP'N~N~ /COOEt
11
~
H
cat. CuBr
+
=
0
Ph
TBHP, DCE, 70°C
13
Scheme 6. Site-Specific Oxidative Alkynylation of a Dipeptide.
Analogous to the oxidative coupling reactions of tertiary amines, the C-H
bond of benzylic ethers 14 was shown by Li and co-worker to be amenable to
undergo oxidative coupling reactions with malonates 9 using Cu(OT£)2 and InCh
as catalyst (Scheme 7).14
cat. Cu(OTfh, cat. InCI 3
14
9
Scheme 7. Oxidative Alkylation of Benzyl Ethers with Malonates.
Due to higher oxidation potential of ethers compared to tertiary amines,
TBHP was found to be insufficient for the generation of the desired oxonium ions
from ethers. However, DDQ was previously reported to react with benzyl ethers
to generate oxonium ions and ultimately prevailed as the oxidant of choice.
Furthermore, simple ketones were shown to undergo oxidative coupling reactions
with benzyl ethers under metal-free conditions with DDQ.15
1.2 - Oxidative Coupling of the Allylic and Benzylic C-H Bond
Selective oxidation of allylic and benzylic C-H bonds over aliphatic C-H
bonds has been well reported. 16 The selectivity can be attributed to the relative
weak bond strength of allylic and benzylic C-H bonds. Unlike simple oxidation
reactions, selective oxidative coupling reactions of allylic and benzylic C-H bonds
have only been recently disclosed.
5
The palladium-catalyzed allylic alkylation (Tsuji-Trost) reaction is an
important transformation that allows for the forn1ation of a single C-C bond from
an allylic carboxylate (or another leaving group) with various nucleophiles. 17 The
Tsuji-Trost reaction can proceed through the allylic C-H bond over two steps with
the use of palladium(II). However, due to the difficulty associated with in situ
reoxidation of palladium(O) into palladium(II), the reaction was stoichiometric
with the palladium(II) acting as both a catalyst and oxidant. 18 Following upon
their previous work utilizing TB HP as an oxidant, Li and co-worker recently
reported an oxidative allylic alkylation reaction between activated methylene
nucleophiles 15 (such as diketones and ketoesters) with cyclic alkenes 16
catalyzed by CuBr and CoCh (Scheme 8).19
cat. CuBr, cat. CoCI 2
TBHP, BODC
15
16
17
Scheme 8. Oxidative Allylic Alkylation of Cyclic Alkenes.
Excess cyclic alkene 16 was required to furnish the desired alkylated
product 17 in good yields due to the competing oxidation of 16 to its
corresponding allylic alcohol and ketone.
Following the work by Li, Shi and co-workers reported both an inter- and
intramolecular oxidative allylic reaction utilizing palladium(II) complex 18 as
catalyst using a combination of l,4-benzoquinone (BQ) and oxygen gas as the
oxidant (Scheme 9)?O
White and co-worker also reported an intermolecular
oxidative allylic alkylation reaction with a similar palladium(II) complex 19
(Scheme 1O)? I
Due to the propensity of soft nucleophiles to undergo addition reactions to
BQ, White chose to use 2,6-dimethyl-l,4-benzoquinone (DMBQ) as the oxidant.
6
Furthennore, the reaction required the use of highly acidic nuc1eophiles (pKa < 6)
for the reaction to occur smoothly.
~Ph
catalyst =
catalyst
)j O}­
l)--'
Ph
BQ, O2 (1 at m)
toluene, 60°C
O~ /\/,,0
Bn/ S • S'Bn Pd(OAch 18
Scheme 9. Palladium(II)-Catalyzed Intramolecular Oxidative Allylic Alkylation.
Ar~
catalyst
+
DMBQ, AcOH
dioxane/DMSO, 45°C
R =COOMe, C(O)Ph, S02Ph
catalyst =
O~/\,p
Ph/ S • S'Ph Pd(OAch 19
Scheme 10. Palladium(II)-Catalyzed Intennolecular Oxidative Allylic Alkylation. The oxidative cross-coupling reaction between activated methylene 15
with benzylic C-H bonds of 20 was reported by Li and co-workers using a simple
FeCb salt as catalyst (Scheme 11).22
cat. FeCI 2
20
15
Scheme 11. Iron(II)-Catalyzed Oxidative Alkylation of Benzylic C-H Bonds.
7
Powell and co-worker also demonstrated that peroxides can mediate the
oxidative coupling reaction of activated methylene 15 with benzyl aromatics 20
(Scheme 12).23 Powell believed that the reaction proceeds through the in situ
generation of benzoate 22 which then undergoes a coupling reaction with 15. The
key evidence supporting this hypothesis was the observation of this intermediate
in the initial stages of the reaction (via IH NMR). Furthermore, l-phenylethyl
benzoate 22 (Ar
Ph and RI
=
=
Me) was synthesized independently and the
benzoate was shown to undergo the cross-coupling reaction to generate the
alkylated product 21.
Ar/'--R1 +
cat. Cu(CI04 h
cat. bathophenanthroline
o
0
11
11 R2~R3
20
tBuOOBz, 60°C 15
21
Intermediate
=[
9 1
BZ
Ar./"-..R1
22
Scheme 12. Copper(II)-Catalyzed Oxidative Benzylic Alkylation.
Bao and co-workers recently reported a metal-free oxidative coupling
reaction of benzylic/allylic C-H bonds with activated methylene 15 using DDQ as
the oxidant (Scheme 13).24
+
o 0
R1~R2
15
Scheme 13. Oxidative Alkylation Mediated by DDQ.
Furthermore, Bao and co-worker extended this methodology to include
benzylic/propargylic C-H bonds as oxidative coupling partners to 1,3-dicarbonyl
compounds?5
8
1.3 - Oxidative Coupling of Alkane C-H Bonds
The oxidative cross-coupling reaction of simple aliphatic C-H bonds
remains to be a challenging problem. However, it has been well established that
simple aliphatic C-H bonds can undergo oxidation to alcohols and ketones under
Fenton26 and Gif1 7 conditions. With this in mind, Li and co-worker attempted to
achieve cross-coupling reactions with simple alkanes through the interceptions of
the Fenton and Gif intermediates with C-H bond nucleophiles. Indeed, using
iron(II) chloride as a catalyst, simple cyclic alkanes 23 were shown to undergo
cross-coupling reactions with various ~-ketoesters 24 (Scheme 14).28
24
23
25
Scheme 14. Oxidative Cross-Coupling Reaction Between Cyclic Alkanes and
Ketoesters.
p­
Li believed that a cyclic alkane radical was generated from the hydrogen
abstraction by a tert-butoxy radical that arose from the iron-catalyzed
decomposition of tert-butyl peroxide. The cyclic alkane radical in turn reacts
with ketoester 24 to form the alkylated product 25.
To extend the concept of trapping alkane radicals with other types of C-H
bonds, Li and co-workers showed that aromatic C-H bonds of 26, with the aid of
pyridine directing group, can undergo oxidative cross-coupling reactions with
cyclic alkanes 23 in the presence of tert-butyl peroxide and catalytic amounts of
dichloro(p-cymene )ruthenium(II) dimer (Scheme 15).29
9
+
0)
b
n _
_ __
cat. [Ru(p-cymene)CI
2
+
tBuOO tBu.135°C
23
26
Scheme 15. Ruthenium(II)-Catalyzed Oxidative Alkylation of2-Phenylpyridines
with Cycloalkanes.
Finally, Itami, Li, and co-workers also demonstrated that pyridine N­
oxides 27 can be alkylated with cycloalkanes 23 simply with the use of tert-butyl
peroxide as the oxidant (Scheme 16).30
27
Scheme 16. Oxidative Cross-Coupling ofPyridine N-Oxide Derivatives with
Cycloalkanes.
Although alkylation was shown to prefer the C-H bond adjacent to the
nitrogen atom, the oxidative coupling reaction was not completely selective and
the trialkylation was also observed.
10 References for Chapter 1
1. For recent reviews on direct arylation reactions, see: (a) Li, B.-J.; Yang, S.­
D.; Shi, Z.-J. Synlett 2007,949. (b) Seregin: I. V.; Gevorgyan, V. Chem. Soc.
Rev. 2007,36, 1173. (c) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichimica Acta 2007,40,35. (d) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007,107, 174. (e) Daugulis, 0.; Zaitsev, V. G.; Shabashov, D.;
Pham, Q.-N.; Lazareva, A. Synlett 2006,3382. (t) Campeau, L.-C.; Fagnou,
K. Chem. Commun. 2006, 1253.
2. For reviews on oxidative cross-coupling reactions, see: (a) Li, c.-J. Acc.
Chem. Res. 2009,42,335. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318.
3. (a) Murahashi, S.-I.; Naota, T.; Yonemura, K. JAm. Chem. Soc. 1988,110,
8256. (b) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi,
H.; Akutagawa, S. JAm. Chem. Soc. 1990,112, 7720.
4. (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. JAm. Chem. Soc.
2003,125,1532. (b) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew. Chem.
Int. Ed 2005,44,6931. (c) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya,
N. JAm. Chem. Soc. 2008, 130, 11005.
5. Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. JAm. Chem. Soc.
2006, 128, 5648.
6. Li, Z.; Bohle, D. S.; Li, c.-J. Proc. Natl. Acad Sci. US.A. 2006, 103, 8928.
7. Li, Z.; Li, C.-J. JAm. Chem. Soc. 2004,126, 11810.
8. Li, Z.; Li, c.-J. JAm. Chem. Soc. 2005,127,6968.
9. Li, Z.; Li, c.-J. JAm. Chem. Soc. 2005,127,3672.
10. Li, Z.; Li, c.-J. Eur. J Org. Chem. 2005,3173.
11. (a) Li, Z.; MacLeod, P. D.; Li, c.-J. Tetrahedron: Asymmetry 2006, 17, 590.
(b) Li, Z.; Li, c.-J. Org. Lett. 2004,6,4997.
12. (a) Dubs, c.; Hamashima, Y.; Sasamoto, N.; Seidel, T. M.; Suzuki, S.;
Hashizume, D.; Sodeoka, M. J Org. Chem. 2008, 73,5859. (b) Sasamoto,
11 N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. JAm. Chem. Soc. 2006, 128,
14010.
13. Zhao, L.; Li, c.-J. Angew. Chem. Int. Ed. 2008,47, 7075.
14. Zhang, Y.; Li, C.-J. Angew. Chem. Int. Ed. 2006,45, 1949.
15. Zhang, Y.; Li, c.-J. JAm. Chem. Soc. 2006, 128,4242.
16. Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1981.
17. For a recent review, see: Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921.
18. Trost, B. M.; Strege, P. E.; Weber, L.; Fullerton, T. J. Dietsche, T. J. JAm.
Lnem. Soc. 1978,100,3407.
19. Li, Z.; Li, C.-J. JAm. Chem. Soc. 2006, 128,56.
20. Lin, S.; Song, c.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. JAm. Chem. Soc.
2008, 130, 12901.
21. Young, A. J.; White, M. C. JAm. Chem. Soc. 2008, 130, 14090.
22. Li, Z.; Cao, L.; Li, c.-J. Angew. Chem. Int. Ed. 2007,46,6505.
23. Borduas, N.; Powell, D. A. J Org. Chem. 2008, 73, 7822.
24. Cheng, D.; Bao, W. Adv. Synth. Catal. 2008,350, 1263.
25. Cheng, D.; Bao, W. J Org. Chem. 2008, 73,6881.
26. For reviews on Fenton chemistry, see: (a) Sawyer, D. T.; Sobkowiak, A.;
Matsushita, T. Acc. Chem. Res. 1996,29,409. (b) Walling, C. Acc. Chem.
Res. 1998, 31, 155.
27. For reviews on Gif chemistry, see: (a) Stavropoulos, P.; <;elenligil-<;etin, R.;
Tapper, A. E. Acc. Chem. Res. 2001,34, 745. (b) Barton, D. H. R.; Doller, D.
Ace. Chem. Res. 1992,25,504.
28. Zhang, y.; Li, c.-J. Eur. J Org. Chem. 2007,4654.
29. Deng, G.; Zhao, L.; Li, c.-J. Angew. Chem. Int. Ed. 2008,47,6278.
30. Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, c.-J. Chem. Eur. J 2009,
15,333.
12 Chapter 2 - Oxidative Alkylation of Cyclic Benzyl Ethers with Malonates
Using Oxygen Gas as the Terminal Oxidant
As illustrated in chapter 1, a variety of peroxides and quinones have been
shown to act as powerful mediators for the oxidative coupling between various
nucleophiles with allylic and benzylic C-H bonds. While these reagents are quite
powerful and efficient, they do not represent the most ideal oxidant. Oxygen gas
is highly desired as an oxidant due to its availability and cost.
2.1 - Background
Murahashi I and Li2 have recently disclosed improved protocols of
oxidative coupling reactions between C-H bonds adjacent to nitrogen of tertiary
amines 1 and various nucleophiles utilizing oxygen gas under atmospheric
pressure as the terminal oxidant (Scheme 17).
R2
R4
R1,N~N02
cat. CuBr
R3
O2 (1 atm)
H20, 60°C
COOR 5
R2
R1,N~COOR5
1
R3
Scheme 17. Copper-Catalyzed Oxidative Coupling Reactions of C-H Bonds Adjacent to Nitrogen Using Oxygen as the Terminal Oxidant. We were interested in developing additional oxidative C-C coupling
reactions using oxygen gas as the oxidant and looked towards the oxidative
coupling reaction between benzyl ethers 14 with malonates 9 (Scheme 18).3
cat. Cu(OTfh, cat. InCI 3
14
9
Scheme 18. Oxidative Alkylation of Benzyl Ethers with Malonates.
13
Our approach towards this challenge was to initially seek a known catalyst
system that could selectively oxidize the C-H bond of benzyl ethers 14 using
oxygen gas as the oxidant.
We hypothesized that the intermediate of the
oxidation product could be intercepted with malonates 9 to provide our desired
alkylation product 28 (Scheme 19).
catalyst
14
Scheme 19. Our Approach towards the Development of an Oxidative Alkylation
Reaction Using Oxygen Gas as the Oxidant.
A catalyst that is well known to oxidize Sp3-hybridized C-H bonds with
oxygen gas is N-hydroxyphthalimide (NHPI). For example, Ishii and co-workers
reported the use of NHPI as a catalyst to selectively oxidize isochroman 29a into
its corresponding ester 30 using oxygen gas as the oxidant (Scheme 20).4
co
cat. NHPI
O 2 (1 atm). PhCN
100°C CQ
o
30 29a
Scheme 20. Selective C-H Bond Oxidation Using NHPI as Catalyst.
NHPI is a cheap and non-toxic compound that is an effective catalyst for
C-H bond activation by hydrogen abstraction. 5
14 It acts as a precursor of
phthalimido-N-oxyl (PINO) radical and this radical IS the active speCIes that
abstracts hydrogen atoms of C-H bonds (Figure 2).
o
C<N-OH
o
NHPI
PINO
Figure 2. Structures ofNHPI and PINO.
The PINO radical is believed to anse from the abstraction of the N­
hydroxyl hydrogen ofNHPI by the diradical oxygen gas. Additionally, Ishii and
co-workers demonstrated that catalytic amounts of metals such as cobalt can
promote the formation of the PINO radical more effectively.6
2.2 - Optimization of Reaction Conditions
We began the
optimization process by exammmg the
original
copper/indium-catalyzed oxidative coupling reactions between malonate 29a and
benzyl ether 31a mediated by DDQ (Table 1). Our initial attempt at utilizing
NHPI and oxygen gas instead of DDQ did not provide the desired product 32a
(entry 1) and only the oxidation product 30 was observed. Increasing the amount
of isochroman available to the system did not produce any positive results (entry
2).
However, by increasing the temperature, the desired oxidative coupling
product 32a was obtained with a moderate yield (entry 3). The yield of 32a
improved when the reaction was performed under neat conditions (entry 4).
Selective removal of each of the catalyst components showed that both the copper
and indium salts were necessary to achieve a successful oxidative coupling
reaction (entries 6-7).
Increasing the amount of NHPI in the system did not
improve the reaction (entry 10), while replacing the oxygen with air decreased the
yield of the reaction (entry 11).
15 Table 1. Optimization of the Oxidative Alkylation Reaction oflsochroman 29a
with Dimethyl Malonate 31a.a
MeO
u
CO:
0
OMe +
29a
~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
Ih-
0
MeO
O 2 (1 atm), temp.
o
31a
OMe
0
32a
I
Entry
I
1c,o
2°
3d
4
5
6
7
Cu(OTf)2
(mol%)
InCh
(mol%)
NHPI
(mol%)
Temp.
(QC)
Yield
(%)b
5
5
5
5
5
10
5
5
5
5
5
20
20
20
20
20
20
20
20
10
40
20
rt
rt
0
0
41
8
9
2.5
5
10
lIe
5
5
10
2.5
5
5
5
55
55
75
55
55
55
55
55
55
77
57
31
20
72
64
76
17
Malonate 26a (0.5 mmo!), benzyl ether 24a (2.5 mmo!).
b Determined by 'H NMR using mesitylene as an internal standard.
c Malonate 26a (0.6 mmol), benzyl ether 24a (0.5 mmol).
d CH 2CIz (2.0 mL).
e Air instead of oxygen gas.
a
2.3 - Scope of the Oxidative Alkylation of Malonates with Benzyl Ethers
With the optimized reaction conditions in hand, the scope of the oxidative
alkylation of malonates 29a-f with benzyl ethers 31a-c was examined (Scheme
21). Overall, a variety of malonates were found to be good substrates for the
oxidative coupling reaction, although substitution on the a-position decreased the
yield of the reaction as shown with substrates 27e and 27f.
On the other hand,
only cyclic benzyl ethers were found to be good substrates for the oxidative
coupling reaction. The use of non-cyclic benzyl ethers, such as benzyl methyl
ether, provided the desired product in small quantities that proved to be difficult
to separate from the undesired side products.
16 Other activated methylene
substrates such as 2,4-pentanedione were attempted with the optimized conditions
and a complex reaction mixture was observed along with the desired product.
Although not discussed in this thesis, oxidative coupling of simple ketones was
successful with the optimized reaction conditions with a slight increase in
temperature. 7
5.0 mol% Cu(OTfh, 5.0 mol% InCI 3
20 mol% NHPI
O2 (1 atm), 55°C
29a-f
o
o
31a-c
32a-h
~
I/-o
MeO
o
OMe
0
co
EtOyYOEt
o
~
I/-o
iprO
o
0
OiPr
co
snoyYosn
o
0
0
32a
32b
32c
32d
(77%)
(83%)
(68%)
(77%)
~
I/-
0
Me
OMe
l
Meo
o
0
co
CC(
MeO~OMe
o
MeoyYOMe
o
0
0
~
--..::::::O
/-
OMe
MeO
o
32e
32f
32 9
32h
(42%)
(60%)
(61%)
(41%)
0
Scheme 21. Scope of the Oxidative Alkylation of Malonates with Cyclic Benzyl
Ethers.
2.4 - Proposed Reaction Mechanism
Although the exact role of the metal catalysts in the oxidative alkylation
reaction is unknown, we hypothesized that cyclic benzyl alcohol 33 could be a
17 possible intermediate. Even though benzyl alcohol 33 was not observed during
the optimization process, we considered it to be a potential intermediate since
benzylic alcohols are known to undergo alkylation with malonates and diketones
in the presence of metal salts. 8 To test this hypothesis, 33 was independently
synthesized through a two-step procedure that involved a DDQ-mediated
oxidative dimerization of 31a which is followed by an acid-catalyzed cleavage
reaction (Scheme 22).9
1. DDQ, CH 2 CI 2/H 20
2. TsOH, H2 0
~
OH
31a
33
Scheme 22. Synthesis of Cyclic Benzyl Alcohol.
When benzyl alcohol 33 was used as a substrate instead of isochroman
31a, the alkylation product was observed, albeit at a slightly lower yield (Scheme
23).
o
0
MeO~OMe
29a
+
~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
O2 (1 atm), 55°C
(60%)
OH
~
I~
0
MeO
33
o
OMe
0
32a
Scheme 23. Alkylation of Cyclic Benzyl Alcohol.
With this experimental result, along with what is known about NHPI
catalyzed oxidation of C-H bonds, a likely reaction pathway for the oxidative
alkylation of malo nates with cyclic benzyl ethers is proposed (Scheme 24).
The reaction can be envisioned to proceed through the initial radical­
induced hydrogen abstraction of cyclic benzyl ether 31a to give benzyl radical 34.
The key radical species responsible for the hydrogen abstraction, PINO, was
18 generated through the interaction between NHPI and oxygen gas. Next, benzyl
radical 34 can be trapped by oxygen gas and in the presence of hydrogen donors
(31a, NHPI, etc.) produces hydroperoxide 35. Metal-induced decomposition of
35 would then form the key alcohol intermediate 33, which can follow two
possible reaction pathways. 5 The undesired pathway is the over oxidation of
alcohol 33 to its corresponding lactone 30.
Alternatively, 30 can also be
generated directly from 35 through the loss of water. 10
The other potential
reaction pathway is the metal-catalyzed alkylation of malonate 29a to provide the
desired oxidative coupling product 32a.
o
o
-OH cGN
cGN-Oo
o
PINO NHPI
CC) ---~-="'-~/=-------. CC) •
31a 34
j
CC) ~
MeO~OMe
[Cu]/[In] o
0
.
[Cu]/[In]
0
MeohoMe o
0,. H-dono'
OH
33 29a
j
32a [0]
CQ
o
30
Scheme 24. Proposed Reaction Pathway for the Oxidative Alkylation of Isochromans with Dimethyl Malonates. 19
From this proposed mechanism, the large excess of the cyclic benzyl ether
31a required for the oxidative alkylation reaction can be easily explained since
there are two potential pathways towards the formation of the undesired cyclic
lactone 30.
2.5 - Conclusion
In summary, an oxidative alkylation of cyclic benzyl ethers with
malonates was demonstrated through the use of indium and copper salts as
catalysts. Furthern1ore, the addition ofNHPI as a co-catalyst allowed the reaction
to precede using oxygen gas at atmospheric pressure to act as the terminal
oxidant. In addition, it was shown that a potential intermediate for this oxidative
coupling reaction could be the benzylic alcohol derived from the oxidation of the
cyclic benzyl ether.
2.6 - Experimental Section
General Information Relating to All Experimental Procedures
All experimental procedures were carried out under an atmosphere of
oxygen gas. Standard column chromatography was performed on 20-60 Ilm silica
gel (obtained from Silicycle Inc.) using standard flash column chromatography
techniques.
IH and
l3 C
NMR spectra were recorded on a 400 MHz NMR
spectrometer. Chemical shifts for IH NMR spectra were reported in parts per
million (ppm) from tetramethylsilane with the solvent resonance as the internal
standard (chloroform: () 7.26 ppm). Chemical shifts for
l3 C
NMR spectra were
reported in parts per million (ppm) from tetramethylsilane with the solvent as the
internal standard (deuterated chloroform: () 77.0 ppm). All reagents purchased
were used without further purification. 3-Methylisochroman (31 b) was prepared
by the literature method. I I
20 MeO
u
+~
~(
OMe
29a
cat. CU(OTf)2, cat. InCI 3
cat. NHPI
~ I
0
h-
MeO
OMe
o
31a
0
32a
General Procedure for the Oxidative Alkylation of Cyclic Benzyl Ethers with
Malonates. In a sealable test-tube equipped with a magnetic stir bar was charged
Cu(OT±)2 (9.5 mg, 0.026 mmol, 5.0 mol%), InCh (5.8 mg, 0.026 mmol, 5.0
mol%), and NHPI (17.1 mg, 0.105 mmol, 20.0 mol%). The reaction vessel was
sealed and flushed with O2 gas. The tube was attached to a balloon of 02 and
charged with malonate 29a (60.0 ilL, 0.524 mmol) and isochroman 31a (0.33 mL,
2.6 mmol). The test-tube was placed in an oil bath set at 55°C and was allowed to stir overnight. The reaction mixture was allowed to cool to room temperature and the crude reaction mixture was purified by silica gel column chromatography (EtOAc:hexanes = 1:4) to provide the desired alkylation product 32a (107.1 mg, 0.405 mmol, 77%) as a clear colourless oil. Dimethyl 2-(3,4-dihydro-1H-isochromen-l-yl)malonate (32a).
(EtOAc:hexanes
=
Rf
=
0.33 1:4); lH NMR (CDCh, 400 MHz, ppm): 87.18-7.08 (m, 3H), 6.99 (d,J= 7.6 Hz, IH), 5.45 (d,J=6.0Hz, IH), 4.15 (dddd,J= 11.2,4.8,4.8,
1.6 Hz, IH) 3.98 (dd, J= 6.0, 2.0 Hz, IH), 3.80-3.73 (m, IH), 3.73 (d, J= 2.0 Hz,
3H), 3.63 (d, J = 2.0 Hz, 3H), 3.01-2.94 (m, IH), 2.69 (d, J = 16.4 Hz, IH);
l3 C
NMR (CDCh, 100 MHz, ppm) 8 168.2, 167.3, 134.8, 134.6, 129.3, 127.4, 126.5,
124.7, 74.3, 63.7, 58.2, 53.0, 52.7, 28.8. This is a known compound and the
spectral data is consistent with those reported in literature. 3
EtO
u
29b
OEt
+
0l
~co
cat. Cu(OTf)2, cat. InCI 3
cat. NHPI
sx
I
h-
0
EtO
OEt
o
31a
0
32b
Diethyl 2-(3,4-dihydro-1H-isochromen-l-yl)malonate (32b).
Following the
above general procedure with malonate 29b (76.0 ilL, 0.496 mmol) and cyclic
21 benzyl ether 31a (0.31 mL, 2.5 mmol). The crude reaction mixture was purified
by column chromatography (EtOAc:hexanes
=
1:4) to provide 32b (120.7 mg,
0.413 mmol, 83%) as a clear colourless oil. Rf = 0.36 (EtOAc:hexanes = 1:4); lH
NMR (CDCh, 400 MHz, ppm): 8 7.17-7.07 (m, 3H), 7.03 (d, J
=
7.6 Hz, IH),
5.45 (d, J = 6.4 Hz, 1H), 4.22-4.08 (m, 5H), 3.95 (dd, J = 6.4, 1.2 Hz, IH), 3.80­
3.73 (m, 1H), 3.01-2.94 (m, 1H), 2.69 (ddd, J= 16,7.6,3.6 Hz, IH), 1.21 (dt, J=
7.2, 1.2 Hz, 3H), 1.12 (dt, J
=
7.2, 1.2 Hz, 3H);
l3 C
NMR (CDCh, 100 MHz,
ppm) 8 167.8, 167.0, 135.1, 134.6, 129.2, 127.3, 126.4, 124.9, 74.3, 63.6, 61.9,
61.5, 58.4, 28.8, 14.2, 14.1. This is a known compound and the spectral data is
consistent with those reported in literature. 3
·~~·+CO~O
'PrO~O/Pr
29c
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
//
..
~
1.&
0
iprO
o
31a
OiPr
0
32c
Diisopropyl 2-(3,4-dihydro-1H -isoch romen-l-yl)malonate (32c).
Following
the above general procedure with malonate 29c (95.0 ilL, 0.495 mmol) and cyclic
benzyl ether 31a (0.31 mL, 2.5 mmol). The crude reaction mixture was purified
by column chromatography (EtOAc:hexanes
=
1:4) to provide 32c (108.5 mg,
0.339 mmol, 68%) as a clear colourless oil. Rf = 0.33 (EtOAc:hexanes = 1:4); IH
NMR (CDCi), 400 MHz, ppm): 0 7.14-7.07 (m, 4H), 5.43 (d, J
=
5.6 Hz, 1H),
5.09-5.03 (m, IH), 5.01-4.95 (m, IH), 4.17-4.14 (m, IH), 3.89 (dd, J
Hz, IH), 3.79-3.74 (m, IH), 2.98-2.94 (m, IH), 2.70 (d, J
(dd, J
=
6.0, 2.0 Hz, 3H), 1.17 (dd, J
=
=
=
6.4, 2.4
16.4 Hz, IH), 1.22
6.0, 2.0 Hz, 3H), 1.16-1.12 (m, 6H);
13 C
NMR (CDCi), 100 MHz, ppm) 0 167.4, 166.6, 135.4, 134.5, 129.2, 127.2, 126.3,
125.0, 74.2, 69.4, 68.9, 63.6, 58.7, 28.8, 21.8, 21.6. This is a known compound
and the spectral data is consistent with those reported in literature. 3
22 u
BnO
OBn
+~
~(
~ I~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
BnO
(OBn
o
31a
29d
0
0
32d
Dibenzyl 2-(3,4-dihydro-l H -isochromen-l ~yl)malonate (32d). Following the
above general procedure with malonate 29d (125.0 /J.L, 0.500 mmol) and cyclic
benzyl ether 31a (0.31 mL, 2.5 mmol). The crude reaction mixture was purified
by column chromatography (EtOAc:hexanes
=
1:4) to provide 32d (161.0 mg,
0.387 mmol, 77%) as a clear colourless oil. Rr = 0.33 (EtOAc:hexanes = 1:4); IH
NMR (CDCh, 400 MHz, ppm): cS 7.34-7.29 (m, 8H), 7.19-7.16 (m, 3H), 7.09­
7.06 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 5.53 (d, J = 6.0 Hz, IH), 5.22 (d, J = 12.8
Hz, IH), 5.16 (d, J= 12.0 Hz, IH), 5.11 (s, 2H), 4.17-4.11 (m, 2H), 3.79-3.73 (m,
IH), 2.90 (ddd, J = 15.2, 8.8, 5.6 Hz, IH), 2.66 (d, J = 16.4 Hz, IH);
13 C
NMR
(CDCh, 100 MHz, pp m) cS 167.6, 166.7, 135.6, 135.4, 134.9, 134.7, 129.4, 128.8,
128.7, 128.6 (2 peaks), 128.5, 128.4, 127.3, 126.5, 124.8, 74.4, 67.6, 67.3, 63.8,
58.3, 28.8. This is a known compound and the spectral data is consistent with
those reported in literature. 3
MeOYOMe +
2ge
CO
~
I~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
0
MeO
o
31a
OMe
0
32e
Dimethyl
2-(3,4-dihydro-lH-isochromen-l-yl)-2-methylmalonate
(32e).
Following the above general procedure with malonate 2ge (67.0 /J.L, 0.498 mmol)
and cyclic benzyl ether 31a (0.31 mL, 2.5 mmol). The crude reaction mixture
was purified by column chromatography (EtOAc:hexanes
=
1:4) to provide 32e
(58.7 mg, 0.211 mmol, 42%) as a clear colourless oil. Rf = 0.36 (EtOAc:hexanes
= 1:4); IH NMR (CDCh, 400 MHz, ppm): 07.17-7.09 (m, 3H), 7.03 (d, J= 7.6
Hz, IH), 5.72 (s, IH), 4.12 (dd, J = 11.2,5.6 Hz), 3.77 (s, 3H), 3.76 (s, 3H), 3.64
(dt, J= 11.2, 1.6 Hz, 1H), 3.00 (ddd, J= 16.0,11.2,5.6 Hz, IH), 2.54 (d, J= 16.0
23 Hz, 1H), 1.21 (s, 3H);
l3 C
NMR (CDCh, 100 MHz, ppm) 8 171.4, 170.6, 136.1,
134.2,129.3,127.1,126.4,125.8,78.2,64.6,60.9,53.1, 53.0, 29.7,15.0. This is
a known compound and the spectral data is consistent with those reported in
literature. 3
IJl
MeO-
'(
'OMe
+CO~
0
//
~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
I
0
h-
Cl
MeO
Cl
o
29f
31a
OMe
0
32f
Dimethyl
(32t).
2-(3,4-dihydro-1H -isochromen-l-yl)-2-chloromalonate
Following the above general procedure with malonate 29f (68.0 ilL, 0.501 mmol)
and cyclic benzyl ether 31a (0.31 mL, 2.5 mmol). The crude reaction mixture
was purified by column chromatography (EtOAc:hexanes
=
1:4) to provide 32f
(90.5 mg, 0.303 mmol, 60%) as a clear colourless oil. Rf = 0.29 (EtOAc:hexanes
= 1:4); lH NMR (CDCh, 400 MHz, ppm): 8 7.25-7.19 (m, 2H), 7.16-7.11 (m,
2H), 5.92 (s, 1H), 4.23 (dddd, J= 10.8,4.4,3.6,1.6 Hz, 1H), 3.85 (d, J= 1.6 Hz,
3H), 3.83 (d, J= 1.6 Hz, 3H), 3.71 (ddt, J= 10.4,3.6,1.6 Hz, IH), 3.03 (ddd, J=
16.6, 9.2, 5.2 Hz, 1H), 2.68-2.63 (m, 1H);
l3 C
NMR (CDCh, 100 MHz, ppm) 8
166.6,165.4,136.2,132.3,129.1,127.8,126.4,126.1,78.4, 64.0, 54.4, 54.3, 29.1.
This is a known compound and the spectral data is consistent with those reported
in literature. 3
U
MeO
29a
OMe
+
(;b
~6
~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
I
0
h-
MeO
OMe
o
31b
0
329
Dimethyl
2-(3-methyl-3,4-dihydro-1H-isochrornen-l-yl)malonate
(32g).
Following the above general procedure with malonate 29a (57.0 ilL, 0.497 mmol)
and cyclic benzyl ether 31 b (368.3 mg, 2.49 mmol). The crude reaction mixture
was purified by column chromatography (EtOAc:hexanes
24 =
1:4) to provide 32g
(84.9 mg, 0.305 mmol, 61%) as a 1:1 mixture of two diastereoisomers that was a
clear colourless oil. Rf= 0.36 (EtOAc:hexanes = 1:4); The first isomer: IH NMR
(CDCh, 400 MHz, ppm): & 7.18-7.12 (m, 2H), 7.08-7.06 (m, IH), 7.00-6.98 (m,
1H), 5.46 (d, J= 5.6 Hz, 1H), 3.91 (d, J= 6.0 Hz, IH), 3.82-3.76 (m, 1H), 3.74 (s,
16.0, 10.8 Hz, IH), 2.62 (dd, J
3H), 3.64 (s, 3H), 2.74 (dd, J
=
IH), 1.30 (d, J= 6.0 Hz, 3H);
13 C
=
15.6, 2.4 Hz,
NMR (CDCh, 100 MHz, ppm) & 168.3, 167.5,
135.3,135.1, 129.0, 127.2, 126.5, 124.2,75.2,71.1,58.9,52.9,52.6,36.6,21.9;
The second isomer: IH NMR (CD Ch, 400 MHz, ppm): & 7.20-7.04 (m, 4H),
5.56 (d, J= 9.6 Hz, IH), 4.15-4.10 (m, 1H), 4.04 (dd, J= 9.6,1.2 Hz, IH), 3.78
(d, J= 1.6 Hz, 3H), 3.71 (d, J= 1.6 Hz, 3H), 2.77 (dd, J= 16.4,3.6 Hz, 1H), 2.64
(dd, J = 16.0, 10.4 Hz, 1H), 1.23 (dd, J = 6.0, 1.6 Hz, 3H); l3C NMR (CDCh, 100
MHz, pp m) & 168.0, 167.3, 134.6, 133.6, 129.4, 127.7, 126.3, 125.4, 73.7, 65.9,
58.7, 53.0, 52.9, 35.7, 21.6.
This is a known compound and the spectral data is
consistent with those reported in literature. 3
u
MeO
OMe +
~O
~
cat. Cu(OTfh, cat. InCI 3
cat. NHPI
~
~
0
OMe
,9
MeO
o
29a
0
31c
32h
Dimethyl 2-(1,3-dihydroisobenzofuran-l-yl)malonate (32h).
Following the
above general procedure with malonate 29a (57.0 ilL, 0.497 mmol) and cyclic
benzyl ether 31c (0.28 mL, 2.5 mmol). The crude reaction mixture was purified
by column chromatography (EtOAc:hexanes = 1:4) to provide 32h (51.4 mg,
0.206 mmol, 41%) as a clear colourless oil. Rf = 0.23 (EtOAc:hexanes = 1:4); IH
NMR (CDCh, 400 MHz, ppm): & 7.26-7.14 (m, 4H), 5.82 (d, J = 7.6 Hz, IH),
5.10 (dd, J= 12.8, 1.6 Hz, IH), 5.00 (d, J
12.4 Hz, IH), 3.68-3.66 (m, 7H);
l3 C
NMR (CDCh, 100 MHz, ppm) & 167.5, 167.4, 139.7, 138.6, 128.6, 127.7, 122.3,
121.3, 82.2, 73.2, 58.2, 52.9,52.8.
This is a known compound and the spectral
data is consistent with those reported in literature. 3
25 References for Chapter 2
1. Ca) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. JAm. Chem. Soc.
2008, 130, 11005. Cb) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J
Am. Chem. Soc. 2003,125, 1532.
2. Basle, 0.; Li, c.-J. Green Chem. 2007,9, 1047.
3. Zhang, y.; Li, c.-J. Angew. Chem. 1nt. Ed. 2006,45, 1949.
4. Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama, T.; Nishiyama,
Y. J Org. Chem. 1995, 60, 3934.
5. For reviews on the use of NHPI as catalyst, see: Ca) Galli, c.; Gentil, P.;
Lanzalunga, O. Angew. Chem. 1nt. Ed. 2008, 47, 4790.
Cb) Recupero, F.;
Punta, C. Chem. Rev. 2007, 107, 3800. Cc) Sheldon, R. A.; Arends, I. W. C.
E. J Mol. Cat. A: Chem. 2006,251,200. Cd) Sheldon, R. A.; Arends, I. W. C.
E. Adv. Synth. Catal. 2004,346,1051. Ce) Ishii, Y.; Sakaguchi, S.; Iwahama,
T. Adv. Synth. Catal. 2001, 343, 393.
6. For representative examples metal-catalyzed oxidation of C-H bonds with
NHPI and oxygen gas, see:
Ca) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y.
Angew. Chem. Int. Ed. 2004, 43, 1120. Cb) Hara, T.; Iwahama, T.; Sakaguchi,
S.; Ishii, Y. J Org. Chem. 2001, 66, 6425. (c) Sakaguchi, S.; Nishiwaki, Y.;
Kitamura, T.; Ishii, Y. Angew. Chem. Int. Ed. 2001, 40, 222. (d) Kato, S.;
Iwahama, T.; Sakaguchi, S.; Ishii, Y. J Org. Chem. 1998, 63, 222. (e) Ishii,
Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J Org. Chem.
1996, 61, 4520.
7. The results obtained were recently published along with the results for the
oxidative coupling reactions of cyclic benzyl ethers with simple ketone. For
further information, see:
Yoo, W.-J.; Correia, C. A.; Zhang, Y.; Li, c.-J.
Synlett 2009, 138.
8. For recent examples, see: (a) Noji, M.; Konno, Y.; Ishii, K. J Org. Chem.
2007, 72, 516l. (b) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron
Lett. 2007, 48, 3969. (c) Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.;
Beller, M. Adv. Synth. Catal. 2007, 349, 865. (d) Rueping, M.; Nachtsheim,
26 B. J.; Kuenkel, A. Org. Lett. 2007,9, 825. (e) Yasuda, M.; Somyo, T.; Baba,
A. Angew. Chem. Int. Ed. 2006,45,793.
9. For the preparation of benzylic alcohol 33, see:
Xu, Y. C.; Lebeau, E.;
Gillard, 1. W.; Attardo, G. Tetrahedron Lett. 1993,34,3841.
10. lones, C. W. Application of Hydrogen Peroxide and Derivatives, The Royal
Society of Chemistry: Cambridge, 1999.
11. DeNinno, M. P.; Pemer, R. J.; Morton, H. E.; DiDomenico, S., Jr. J. Org.
Chem. 1992,57, 7115.
27 Part II - Copper-Catalyzed Oxidative Esterification and Amidation of Aldehydes Chapter 3 - Introduction to Oxidative Esterification and Amidation of
Aldehydes
Esters and amides are ubiquitous in organic compounds and can be found
from simple solvents to complex natural products and polymers.
The most
prevalent strategy towards ester and amide bond formation relies heavily upon the
nucleophilic addition of alcohols and amines to activated carboxylic acid
derivatives.
An alternative method towards esters and amides can be achieved through
the direct oxidative esterification and amidation between aldehydes with alcohols
and amines. This approach has recently generated increasing attention and has
become a conceptually attractive alternative to traditional strategies (Figure 3).1
oxidative
amidation
oxidative
esterification
o
HNR3R4' [0]
I
R20H, [0]
R)lH
j
[0]
o
R)lOH
I
R20H
0
• R)lOR 2
Figure 3. Direct Oxidative Esterification and Amidation of Aldehydes.
In this chapter, recent developments into oxidative esterification and
amidation of aldehydes will be presented. Furthermore, examples will be limited
to oxidative coupling reactions of aldehydes with alcohols and amines.
3.1 - Oxidative Esterification of Aldehydes Mediated by Oxidants
One of the first reported examples of an oxidative esterification of aldehydes
was reported by Corey and co-workers in which aldehydes 36 were converted to
methyl esters 37 through a one pot, two-step process (Scheme 25).2
28
0
NaCN, AcOH, Mn02
0
RAH
MeOH, 20-25°C
• RAOMe
37
36
I
I
+
/
HCN
HO CN
RXH
, , MeOH
0
- - - - .....
Mn02 R)lCN
38
39
Scheme 25. Oxidative Esterification of Aldehydes via Cyanohydrin Intermediate.
The reaction is believed to arise from the initial formation of cyanohydrin
intermediate 38, which is then oxidized to acyl cyanide 39 and finally trapped by
methanol to generate the methyl ester 37. In the absence of an external oxidant,
a,~-unsaturated
aldehydes 40 undergo oxidative esterification reaction through an
internal redox process (Scheme 26)?
N5(H
o
Ar~H
,,
45
Et3N, ROH •
40
0
Ar~OR
41
I
HO CN
Ar~H
42
---.
43
44
Scheme 26. Cyanide-Mediated Esterification and Reduction of a,~-Unsaturated
Aldehydes with alcohols.
Mechanistically, the reaction proceeds through the initial formation of
cyanohydrin 42, which after migration of the double bond, forms intermediate 43.
Tautomerization to acyl cyanide 44 and subsequent addition of the alcohol
furnishes the desired ester. Furthermore, under the same reaction conditions, aryl
aldehydes can undergo oxidative esterification with alcohols using acetone
29 cyanohydrin 45 as a mediator. This is believed to proceed through a hydrogen
transfer process between cyanohydrin intermediate 38 and the acetone that was
liberated from acetone cyanohydrin 45. 3a
While the oxidation of cyanohydrin intermediates allows for the oxidative
esterification of aldehydes, an alternate route into esters would be through the
oxidation of hemiacetals and acetals. A great deal of oxidants have been shown
to mediate the oxidative esterification reaction of aldehydes with alcohols. For
example, iodine and bromine have been shown to act as mild oxidants to generate
ester 46 from aldehydes 36 (Scheme 27).4
\
~
I
1-0 OR2
R1«H ---.. _ I
48
Scheme 27. Iodine-Mediated Oxidative Esterification of Aldehydes.
The reaction is believed to proceed through the initial formation of the
hemiacetal intermediate 47, which in the presence of iodine generates hemiacetal
hypoiodite 48 and then collapses to ester 46. Various similar reactions conditions
have been reported using halogens and their derivatives as oxidants. For example,
oxidative esterifications of aldehydes have been achieved using sodium
hypochlorite,5
N-iodosuccinimide,6
pyridinium
hydrobromide
perbromide,7
sodium metaperiodate,8 and h with diacetoxyiodobenzene. 9
Inorganic peroxides such as Oxone® (2KHSOseKHS04eK2S04) and
peroxymonosulfuric acid (H2S05) have been used as mediators for oxidative
esterification reactions of aldehydes. The desired ester is formed readily from the
Baeyer-Villiger type oxidation of hemiacetal intermediate 47 (Scheme 28).10
30 KHSO s
R2 0H, 25-66 0 C·
0
R)lOR 2
46
t
47
Scheme 28. Oxidative Esterification of Aldehydes Mediated by Oxone.
Oxidative esterification can also be achieved through electrochemical
methods using catalytic amounts of potassium iodide and sodium cyanide. 11 One
of the potential advantages of using electrons as reagents is the general tolerance
for various functional groups and the avoidance of strong oxidants.
3.2 - Metal-Catalyzed Oxidative Esterification of Aldehydes
The use of metals for catalysis has been well established for a wide array
of organic transfomlations and various metals have been employed as catalysts
for the oxidative esterification reaction of aldehydes. For example, Patel and co­
worker demonstrated an oxidative esterification of aldehydes catalyzed by
vanadium(V) oxide (Scheme 29).12
The vanadium-catalyzed oxidative esterification is believed to proceed
through the initial formation of the hemiacetal 47 that reacts with vanadium
peracid 49 to form vanadium hemiacetal intermediate 50.
The subsequent
elimination of 50 provides the desired ester 46 and regenerates the vanadium
catalyst. Similar early transition metals such as vanadium and titanium have been
shown to activate hydrogen peroxide to catalyze the oxidative esterification
reaction. I3
31 °
R)lH
36
+
R2 0H
°
cat. V2 0 S
R)lOR 2
H2 0 2 , SOC or reflux
\
46
I
\
\
OH
R1+H
R2 0
q, ,OH
O,N,O
49
------~
",
~Fti OH
o ~
R1
47
SO
V2 0 S
+
3 H2 0 2
0, ,OH
2
'V
HO" 'OOH
+
1/2 O2
49
Scheme 29. Vanadium-Catalyzed Oxidative Esterification of Aldehydes with
Alcohols.
The use of middle to late transition metals has been shown to catalyze the
oxidative esterification reaction without the use of external oxidants. Instead, the
transition metals allow for the esterification of aldehydes with alcohols to occur
through the use of hydrogen acceptors or by the direct liberation of hydrogen
gas. 14 While attractive, some of the problems associated with these catalysts is
the poor yields that are obtained due to competing oxidative dimerization of the
alcohols and the aldehyde substrates acting as the hydrogen acceptor. However,
an efficient oxidative esterification reaction has been demonstrated when a
rhodium(I) complex was used as a catalyst for an oxidative esterification of 4­
alkynals 51 (Scheme 30).15
The esterification occurs through a tandem process in which the rhodium
catalyst is believed to insert into the acyl C-H bond of 4-alkynals 51 to generate
intermediate 53. Hydrometallation of 53 furnishes the metallocycle 54, which
then is trapped by the alcohol to provide the esterification product 52 and
regenerate the catalyst.
32 cat. [Rh(dppe)b(BF4h
DCE,25-80o C
51
I
"
52
I
I
53
Scheme 30. Rhodium(I)-Catalyzed Oxidative Esterification of 4-Alkynals with Alcohols. A similar tandem process involving oxidative esterification was reported
by Wu and co-workers who demonstrated that palladium can act as catalyst for a
tandem oxidative esterification/hydroarylation process of 2-alkynyl aldehydes 55
(Scheme 31).16
o
o
~H
~R
+
~OMe
Arl
R
Ar
56
55
+
: - [Pd]
[Pd] + Arl - - Ar-[Pd]-I
I
I
H~Me
0,\
~
I
'-':::
h-
I
R
~OMe
'-':::
0
[Pd]-I'- - - - --
I
I
h-
R
Ar
57
58
[Pd] - - - - -­
Ar
~OMe
~[Pdl-H
R
Ar
59
Scheme 31. Palladium-Catalyzed Tandem Oxidative Esterification and Hydroarylation of2-Alkynyl Aldehydes. 33
The reaction begins with the hydrometallation of alkynyl 55 with the aryl
palladium(II) species that was generated from the oxidative addition of
palladium(O) with aryl iodide. Nucleophilic addition of methanol to intermediate
57 liberates HI and the resulting metallocycle 58 undergoes
to form 59.
~-hydride
elimination
Reductive elimination of 59 provides the desired ester 56 and
regenerates the palladium(O) catalyst.
3.3 - Carbene-Catalyzed Oxidative Esterification of Aldehydes
N-Heterocyclic carbenes have gained considerable attention in organic
synthesis and has been used in the chemistry of carbonyl compounds, including
oxidative esterification reactions.
For example, Eisfeld and co-workers
demonstrated that indazole carbene 60 can act as a mediator for the oxidative
esterification reaction of aromatic aldehydes in refluxing alcohol based solvents
(Scheme 32).17
Me
I
O=;~-Me 60
ROH, reflux
Scheme 32. Oxidative Esterification of Aldehydes with Alcohols Mediated by N­
Heterocyclic Carbenes of Indazole.
N-Heterocyclic carbenes have been used as catalyst for oxidative
esterification of aldehydes through an internal redox-type reaction. IS Bode and
co-workers demonstrated an oxidative esterification reaction of
a,~-epoxy
aldehyde 61 using thiazolium salt 62 as a catalyst (Scheme 33).19
The reaction is believed to proceed initially through the addition of the
active carbene catalyst formed in situ through the deprotonation of the thiazolium
salt 62 and then undergoes a nucleophilic addition to the
34 a,~-epoxy
aldehyde 61.
The epoxide nng of intermediate 64 then undergoes a ring-opening and is
followed by a hydride shift which results in the activated carboxylated
intermediate 65. Trapping intermediate 65 with the alcohol nuc1eophile provides
the desired P-hydroxyester 63 and regenerates the carbene catalyst.
Bn
N+
cat. f-(-Me, cat. DIPEA
Me
62
63
61
I
"
I
I
-
o0
Bn
R1~N;-Me
R2
S-\
-----..
Me
65
64
Scheme 33. Stereoselective Synthesis of P-Hydroxyesters from Epoxyaldehydes.
The use ofN-heterocyclic carbenes as catalyst has been applied to various
aldehydes such as a-bromoaldehydes,20 a,p-unsaturated aldehydes,21 alkynyl
aldehydes,22 and forn1ylcyclopropanes 23 to obtain esters in good yields.
Similarly,
oxidative esterification of aldehydes
catalyzed by N­
heterocyc1ic carbenes can be achieved through the use of an external oxidant.
Castells and co-workers described the use of thiazolium salts such as 62 to
catalyze the esterification of aldehydes using nitrobenzene as an oxidant (Scheme
34)?4
The N-heterocyclic carbene-catalyzed oxidative esterification reaction of
aldehydes has been shown with other oxidants such as MnOl 5 and through
electrochemical oxidation. 26
35
Bn
N+
cat.
J~6
r~Me
Me
62
H
Et3N, nitrobenzene,
MeOH,60oC
o
~OMe
~6
Scheme 34. N -Heterocyclic Carbene Catalyzed Oxidative Esterification of
Aldehydes.
3.4 - Oxidative Amidation of Aldehydes Mediated by Oxidants
Unlike oxidative esterification reactions, oxidative amidation of aldehydes
is not as common. One of the first examples of oxidative amidation of aldehydes
was the work presented by Nakagawa and co-workers in which they demonstrated
the direct amidation of aromatic and allylic aldehydes with ammonia in the
presence of nickel peroxide. 27 Since their seminal work, various groups have
reported the direct oxidative amidation reaction of aldehydes with amines in the
presence of an external oxidant. For example, Wolf and co-worker reported the
direct oxidative amidation of aldehydes 36 with secondary amines 66 using TBHP
as the oxidant (Scheme 35).28
o
~
R1AH
36
+
1A N, ,R
R2'N,R 3 - - - -__
• R
H
TBHP, 80°C
2
R3
67
66
I
; [0]
I
I. _ _ _ _
____ I
Scheme 35. Oxidative Amidation of Aldehydes with Secondary Amines
Mediated by TBHP.
36
Assumed to operate analogous to the oxidative esterification reaction,
Wolf believed that the oxidative amidation reaction proceeded through the
oxidation of the carbinolamine intermediate 68 to provide the desired amide 67.
Using TBHP as the oxidant, Reddy and co-workers demonstrated the
oxidative amidation reaction of aldehydes 36 with aliphatic primary amines 69
using potassium iodide as a catalyst (Scheme 36).29
°
R1
)l
cat. KI
H
+ H2N-R2 - - - - - - ­
• R1
TBHP, H20, 80D
e
36
)l0
N' R2
H
69
Scheme 36. Potassium Iodide-Catalyzed Oxidative Amidation of Aldehydes with
Primary Amines with TB HP as the Oxidant.
The oxidative amidation reaction appeared to work best using aromatic
aldehydes while the use of aliphatic aldehydes provided moderate to low yields.
Furthermore, oxidative coupling reactions with amino acid derivatives was
demonstrated by Reddy and co-workers, and no loss of chirality was observed
when enantiomerically pure an1ino esters were utilized as substrates. The authors
also found that the reaction is catalyzed by iodine, which is generated in situ from
the oxidation ofr by TBHP.
Wang and co-workers reported an oxidative amidation reaction of
aldehydes 36 with aniline derivatives 70 using Oxone® as the oxidant under
mechanical milling conditions (Scheme 37).30
°
R./'..H
11
36
+
H2N-Ar
Oxone®, MgS04
ball milling (30 Hz),
rt
•
~
R./'..N,Ar
H
70
Scheme 37. Oxone® Mediated Oxidative Amidation of Aldehydes with Aromatic
Amines.
37
Employing mechanical milling techniques,31 Wang was able to rapidly
prepare amides from aldehydes under solvent- and metal-free conditions with
moderate to good yields. Although an investigation of the reaction mechanism
was not made, the transamidation reaction with carboxylic acids from the
oxidation of aldehydes was ruled out through control experiments.
Oxidative amidation reactions of aldehydes have been recently reported
using iodine based oxidants. Bao and co-workers demonstrated that hypervalent
iodine(III) reagents such as (diacetoxyiodo )benzene (DIB) were competent
mediators of the oxidative amidation reaction between aldehydes 36 and aliphatic
amines 69 (Scheme 38).32
°
11
+ H2 N-R 2
R1AH
36
DIB
H2 0, CHCI 3 , rt
69
Scheme 38. Oxidative Amidation of Aldehydes with Aliphatic Primary Amines
Mediated by (Diacetoxyiodo)benzene.
An interesting application of the oxidative amidation reaction was recently
reported by Compain and co-workers in which protected sugars 71 were
oxidatively converted to amides 72 using h as an oxidant under basic conditions
(Scheme 39)?3
('OBn
<,OBn
~o
BnO-~OH
~OH
Bno-~NHR
+
71
72
°
Scheme 39. Iodine Mediated Oxidative Amidation of Aldoses with Amines.
Compain and co-workers examined vanous types of ammes as
nuc1eophiles and found that only primary amines were viable substrates and aryl
amines and secondary amines were unsuitable under their optimized reaction
38 conditions.
Furthermore, ammo alcohols were shown to be better substrates
compared to the simple aliphatic amines since excess amine and longer reaction
times were required for the simple amines.
3.5 - Metal-Catalyzed Oxidative Amidation of Aldehydes
Like the oxidative esterification reaction of aldehydes, metals have been
utilized to catalyze the oxidative transformation of aldehydes to amides. One of
the earliest examples of a metal-catalyzed oxidative amidation reaction with
aldehydes was reported by Yoshida and co-workers (Scheme 40).34
°
R)lH
36
+
(0)
cat. Pd(OAch. cat. PPh 3
N
H
ArBr. K2 C0 3 • DME. 85°C
,
°
R)lNl
~O
,I
,,
OH 1 \
°
78
RkN
HLJ
73
75
Ar-Pd(II)-Br
74
+
..~
,
,
Ar-Pd(II)-H
76
.
,
ArBr ­
""" . '. Pd(O)
--(
77
\
ArH
Scheme 40. Palladium-Catalyzed Oxidative Transformation of Aldehydes to Amides. The oxidative amidation reaction with aldehydes 36 and morpholine is
believed to arise from the initial formation of the carbinolamine 73 which
undergoes a base-assisted ligand exchange with the bromide of aryl palladiunl(II)
complex 74 to generate intermediate 75.
p-Hydride elimination of the
palladium(II) intermediate 75 provides the desired amide 78 and the aryl hydride
palladium(II) species 76. Reductive elimination of 76 results in the formation of
39 palladium(O) 77 and oxidative addition of aryl bromide to 77 regenerates aryl
palladium(II) bromide 74.
Recently Torisawa and co-workers reported a palladium-catalyzed
oxidative amidation of aldehydes using hydrogen peroxide as the oxidant
(Scheme 41).35
cat. PdCI 2 • cat. Xantphos
36
69
Scheme 41. Palladium-Catalyzed Oxidative Amidation Using H20 2 as the Oxidant. Unlike the palladium-catalyzed example by Yoshida and co-workers, the
oxidative amidation using hydrogen peroxide as an oxidant was amenable to
primary aliphatic amines 69 as substrates, but not secondary amines. Control
studies suggested that mechanism does not go through a P-hydride elimination
process and the authors suggested a palladium hydroperoxide species as the key
intermediate.
Other transition metals have been shown to catalyze the oxidative
amidation reactions with aldehydes.
For example, Beller and co-workers
demonstrated a rhodium-catalyzed protocol for the conversion of aldehydes 36 to
amide 67 with secondary amines 66 (Scheme 42).36
The oxidative amidation is believed to proceed through the oxidative
insertion of the rhodium(I) catalyst 78 to the aminol 68 to generate the
rhodium(III) hydride complex 79.
p-Hydride elimination of 79 provides the
desired amide 67 and rhodium(III) dihydrogen 80.
The active catalyst 78 is
regenerated through the removal of the hydrogen by the action of an external
oxidant such as N-methylmorpholine N-oxide or in the absence of the oxidant,
either the aldehyde 36 and/or carbinolamine 68. Similar types of the oxidative
amidation reactions have been reported invoking the formation of a metal
40 dihydride species using rhodium37 and ruthenium 38 catalysts.
Often these
oxidative amidation reactions involve the coupling between an alcohol and an
amine in which the alcohol is first oxidized to the aldehyde, which then undergoes
the oxidative coupling reaction.
cat. [Rh(CODh]BF 4
cat. K2C0 3 , cat. PPh 3
N-methylmorpholine N-oxide
PhMe or THF, 140°C
36
66
,,
. ______ .J
,
Rh(l)
78
t
t
~ ~
- --
H-Rh(III)-H
80
Scheme 42. Rhodium-Catalyzed Oxidative Amidation of Aldehydes.
3.6 - Carbene-Catalyzed Oxidative Amidation of Aldehydes
Similar to the oxidative esterification chemistry, NHCs have been utilized
for the oxidative amidation of aldehydes. Rovis and co-worker demonstrated the
amidation of aldehydes with amines through an internal redox process (Scheme
43).39
o
cat. 81, cat. HOAt
PhYH
Cl Cl
+
Et3N, tsuOH, THF, 25°C
66
82
F.
F
BF4 F
F
•
Ph
Yo
Cl
R2
N, '
R1
83
a)*F
81
Scheme 43. Oxidative Amidation of a-Chloroaldehydes.
41
While a variety of nuc1eophiles have been shown to participate in the
internal redox coupling process with aldehydes, amines have been particularly
difficult, with only aniline being a viable partner. 20b
Rovis and co-worker
managed to couple a,a-dichloroaldehyde 82 with amines 66 to generate amide 83
using carbene 81 and HOAt (l-hydroxybenzotriazole) in catalytic amounts. This
method was extended to a,p-epoxy, a,p-aziridino, and conjugated aldehydes.
A very similar protocol was reported by Bode and co-worker in which a­
functionalized aldehydes were converted to amides using catalytic amounts of
NHC 84 (Scheme 44).
o
EtOOC",
V
'l H
.",
cat. 84, cat. DBU
+ H2 N-Bn - - - - - - - ­
imidazole, THF, 40°C
85
o
,
L _ _ _ _ _ _ _ _ _ .....
0
EtO~N~
o
0
EtO~NHBn
•
87
~N
86
Scheme 44. N-Heterocyc1ic Carbene Catalyzed Amidation of Aldehydes.
A variety of ammes were coupled with formyl cyc1opropanes, a­
chloroaldehydes, and a,p-unsaturated aldehydes. Bode was able to show by IH
NMR studies that cyc1opropyl aldehyde 85 in the presence of carbene 84, DBU,
and imidazole, acyl intermediate 86 was present. When benzyl amine was added
to 86, amide 87 was observed.
42 References for Chapter 3
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2. (a) Lai, G.; Anderson, W. K. Synth. Commun. 1997,27, 1281. (b) Corey, E. J.;
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Am. Chem. Soc. 1968, 90, 5618. (c) Corey, E. J.; Gilman, N. W.; Ganem, B.
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H.; Hayashi, M. Tetrahedron Lett. 2002, 43, 5645.
4. Mori, N.; Togo, H. Tetrahedron 2005,61,5915.
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6. McDonald, C.; Holcomb, H.; Kennedy, K.; Kirkpatrick, E.; Leathers, T.;
Vanemon, P. J Org. Chem. 1989,54, 1213.
7. Sayama, S.; Onami, T. Synlett 2004,2739.
8. Shaikh, T. M. A.; Emmanuvel, L.; Sudalai, A. Synth. Commun. 2007, 37,
2641.
9. Karade, N. N.; Budhewar, V. H.; Katkar, A. N.; Tiwari, G. B. ARK/VOC
2006, 162.
10. (a) Travis, B. R.; Sivakumar, M.; Hollist, 0.; Borhan, B. Org. Left. 2003, 5,
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11. (a) Okimoto, M.; Chiba, T. J Org. Chem. 1988, 53, 218.
(b) Shono, T.;
Matsumura, y.; Hayashi, J.; Inoue, K.; Iwasaki, F.; Itoh, T. J Org. Chem.
1985, 50, 4967.
(c) Chi ba, T.; Okimoto, M.; Nagai, H.; Takata, Y. Bull.
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12. Gopinath, R.; Patel, B. K. Org. Lett. 2000,2,577.
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(b) Chavan, S. P.; Dantale, S. W.; Govande, C. A.;
Venkatraman, M. S.; Praveen C. Synlett 2002,267.
43 14. (a) Kiyooka, S.-I.; Wada, Y.; Ueno, M.; Yokoyarna, T.; Yokoyarna, R.
Tetrahedron 2007, 63, 12695.
(b) Kiyooka, SA.; Ueno, M.; Ishii, E.
Tetrahedron Lett. 2005,46,4639. (c) Espenson, J. H.; Zhu, Z.; Zauche, T. H.
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Y.; Yarnarnoto A. Bull. Chem. Soc. Jpn. 1982, 55, 504.
(i) Grigg, R.;
Mitchell, T. R. B.; Sutthivaiyakit, S. Tetrahedron 1981, 37, 4313.
G)
Yarnashita, M.; Watanabe, Y.; Mitsudo, T.; Takegarni, Y. Bull. Chem. Soc.
Jpn. 1976, 49, 3597.
(k) Hidai, M.; Ishirni, K.; Iwase, M.; Tanaka, E.;
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15. Tanaka, K.; Fu, G. C. Angew. Chem. Int. Ed. 2002,41,1607.
16. Wei, L.-L.; Wei, L.-M.; Pan, W.-B.; Wu, M.-J. Synleft 2004, 1497.
17. Schrnidt, A.; Habeck, T.; Snovydovych, B.; Eisfeld, W. Org. Left. 2007, 9,
3515.
18. Zeitler, K. Angew. Chem. Int. Ed. 2005,44, 7506.
19. Chow, K. Y.-K.; Bode, J. W. JAm. Chem. Soc. 2004,126,8126.
20. (a) Reynolds, N. T.; Rovis, T. JAm. Chem. Soc. 2005,127,16406.
(b)
Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. JAm. Chem. Soc. 2004, 126,
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44 24. (a) CastelIs, J.; Pujol, F.; Llitj6s, H.; Moreno-Mafias, M. Tetrahedron 1982,
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25. (a) MaId, B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (b) Noonan,
c.;
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(b)
Nakagawa, K.; Mineo, S.; Kawamura, S.; Horikawa, M.; Tokumoto, T. Mori,
O. Synth. Commun. 1979,9,529.
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Org. Chem. 2008,3619.
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45 Chapter 4 - Copper-Catalyzed Oxidative Esterification of Aldehydes with J3­
Dicarbonyl Compounds
As illustrated in chapter 3, aldehydes can undergo oxidative esterification
with alcohols in the presence of an oxidant. In this chapter, the discovery and
development of a copper-catalyzed oxidative esterification reaction of aldehydes
with p-dicarbonyl compounds such as diketones and ketoesters will be discussed.
4.1 - Background
As discussed in Chapter 1, a great deal of interest has been generated in
the use of C-H bonds as substrates for C-C bond formation processes. Previously,
our group developed an oxidative alkylation reaction between activated
methylene nucleophiles with cyclic alkenes catalyzed by CuBr and CoCh using
TB HP as an oxidant. 1 During the course of our investigations on the oxidative
alkylation reaction between p-diketone 88a and cyclic alkene 89, an unknown
product was isolated that possessed the exact mass as the expected alkylation
product (Scheme 45).
o
0
~
88a
2.5 mol% CuBr, 10.0 mol% CoCI 2
+
TBHP (2.0 equiv.), 80a C
208 m/e
89
(5.0 equiv.)
Scheme 45. Oxidative Coupling of J3-Diketone 88a with Cyclic Alkene 89.
Although the exact structure of the product was unknown, we assumed it
was an oxidative coupling reaction between the two substrates with the loss of
two hydrogens. In order to determine if the reaction occurred with the allylic C-H
bond or the C-H bond of the aldehyde, benzaldehyde 90a was used as a substrate.
The major spot determined by visual inspection of the TLC plate of the crude
reaction mixture was isolated and later was confirmed to be the oxidative
esterification product 91a 2 (Scheme 46).
46
o
0
Ph)lH +
90a
2.5 mol% CuBr, 10.0 mol% CoCI 2
0
AA
TBHP (2.0 equiv.), aooc
88a
(1.1 equiv.)
91a
Scheme 46. Oxidative Esterification of Aldehyde 90a with p-Diketone 88a.
4.2 - Optimization of Reaction Conditions
To begin the study, the effects of the various reaction parameters on the
oxidative esterification of benzaldehyde 90a with p-diketone 88a were examined
(Table 2).
Table 2. Optimization of the Oxidative Esterification of Aldehyde 90a with p­
Diketone 88a Through Screening Copper Salts. a
0
0
0
Ph)lH +
90a
0
catalyst
AA
0
Ph)lO
Ph)lO
TBHP, 80°C
0
~
+
AA
8aa
91a
Entry
Catalyst
lC
2c
CuBr/CoCh
CuBr
CuBr
CuBr
CuCl
CuI
CuBr2
Cu(OAc)2
Cu(OTf)2
CuOTf
3
4°
5
6
7
8
9
10
Yield (%)
of91ab
51
51
92
Yield (%)
of92 b
10
10
64
7
53
10
18
54
26
54
49
0
0
9
7
19
0
0
Benzaldehyde 90a (0.92 mmol), 2,4-pentanedlOne 88a (0.97 mmol), TBHP
(1.4 mmol), cobalt(II) chloride (0.097 mmol), and copper salt (0.025 mmol).
b Determined by IH NMR using mesitylene as an internal standard.
c TBHP (1.8 mmol).
d TBHP (1.0 mmol).
a
47
Using the conditions reported for the oxidative coupling reaction of allylic
C-H bonds with activated methylene compounds, CuBr and CoCh were initially
examined as co-catalysts (entry 1). Subsequently, it became apparent that CoCh
was not required for the oxidative esterification reaction (entry 2). Furthermore,
decreasing the amount of TBHP from 2.0 to 1.5 equiv. improved the yield (entry
3). After a variety of copper(I) and copper(II) salts were screened, CuBr was
found to be the most effective (entries 3 and 5-10).
Attempts were made to improve the overall yield through screenmg
different types of peroxide as oxidants (Table 3).
In general, there does not
appear to be any trend to the effectiveness of the peroxides based on the bond
dissociation energies (HO OH, i1H! = 47 kcallmol, TB HP, i1Ht = 41 kcallmol,
CBUO)2, i1H! = 36 kcallmol).3 From the initial screening processes, it appeared
that the oxidative esterification reaction was sensitive to the nature of the oxidant
since the yield suffered even when T-HYDRO® (70 wt% of TBHP in H20) was
used as an oxidant (entry 2).
Table 3. Optimization of the Oxidative Esterification of Aldehyde 90a with
Diketone 88a by Screening the Oxidant. a
0
0
0
Ph)lH
+
90a
0
cat. CuBr
AA
0
Ph)lO
Ph)lO
oxidant, BOoC
0
~
+
AA
0
88a
91a
Entry
Oxidant
Yield (%)
of91a b
1
2
3
4
5
TBHP
T-HYDRO@
H 20 2 (30 wt% in H 2O)
tBuOOtBu
tButyl peroxybenzoate
Curnene hydroperoxide
CH3COOOH
tBuCOOOH
64
6
7
8
31
0
2
24
37
5
12
92
Yield (%)
of92 b
7
3
0
1
25
11
0
9
Benzaldehyde 90a (0.92 mmol), 2,4-pentanedlOne 88a (0.97 mmol), copper(I)
bromide (0.025 mmol), and oxidant (1.4 mmol).
b Determined by IH NMR using mesitylene as an internal standard.
a
48
~­
Next, the temperature was varied for the oxidative esterification reaction
(Table 4).
Table 4. Optimization of the Oxidative Esterification of Aldehyde 90a with
Diketone 88a by Changing the Temperature. a
~­
0
0
0
PhAH +
90a
cat. CuBr
0
~
TBHP, temp.
0
PhAO
PhAO
91a
Temp. (OC)
1
2
3
25
50
80
100
4
+
~
88a
Entry
0
Yield (%)
of91ab
2
12
64
30
~
92
Yield (%)
of92 b
0
0
7
30
Benzaldehyde 90a (0.92 mmol), 2,4-pentanedione 88a (0.97 mmol),
copper(I) bromide (0.025 mmol), and TBHP (lA mmol).
b Determined by IH NMR using mesitylene as an internal standard.
a
With lower reaction temperatures, the yield of the oxidative coupling
reaction decreased (entry 1-2).
However, increasing the temperature of the
reaction above 80°C did not improve the overall yield and the stereoselectivity
observed previously was lost (entry 4). Finally, different solvents were examined
(Table 5).
In most cases, the yield and stereoselectivity did not vary greatly when a
solvent was introduced into the reaction conditions (entries 2-6). However, since
the addition of solvents did not appear to improve the yield of the reaction, the
oxidative esterification reaction was run neat.
•
49 Table 5. Optimization of the Oxidative Esterification of Aldehyde 90a
Diketone 88a through the Introduction of a Solvent. a
with~­
0
0
0
0
PhAH +
0
~
cat. CuBr
TBHP, 80°C
~
+
0
AA
Solvent
90a
PhAO
PhAO
88a
91a
Entry
1
2
3
4
5
6
Solvent
92
Yield (%)
of91ab
Yield (%)
of92 b
64
64
64
66
67
66
7
4
dioxane
DCE
DMSO
cyclohexane
toluene
9
4
11
7
Benzaldehyde 90a (0.92 mmol), 2,4-pentanedione 88a (0.97 mmol),
copper(I) bromide (0.025 mmol), and TBHP (lA mmol) in a solvent
(0.25 mL).
bDetermined by lH NMR using mesitylene as an internal standard.
a
4.3 - Scope of the Copper-catalyzed Oxidative Esterification of Aldehydes
with ~-Dicarbonyl Compounds
Under the optimized reaction conditions, various
~-dicarbonyl
compounds
88a-f were used as substrates for the oxidative esterification of aldehydes 90a-f
(Table 6).
In general, the oxidative esterification reaction proved to be highly
stereoselective for the (Z)-enol esters 91a-j, and the level of stereoselectivity was
dependent on the nature of the
~-dicarbonyl
substrates. With
level of stereoselectivity varies (entries 1-2). However, with
~-diketones,
~-ketoesters
the
88c-e,
the oxidative esterification was shown to be highly stereoselective to furnish one
stereoisomer exclusively (entries 3-10). The stereoselectivity of the reaction was
determined by the examination of the crude I H NMR spectra of the crude reaction
mixture and the stereoisomers were found to be the (Z)-enol ester by NOE
experiments on the purified products. Both aliphatic and aromatic aldehydes were
50 amenable to the reaction conditions and the electronic nature of the aldehydes did
not appear to greatly influence the yield of the reaction (entries 6-10). When the
reaction was extended to simple primary alcohols, such as I-butanol, the
oxidative esterification also proceeded, albeit at a much lower yield (Scheme 47).
Table 6. Scope of the Copper-Catalyzed Oxidative Esterification of Aldehydes. a
90a-f
88a-e
91a-j
Entry
1
2
3
4
5
6
7
8
9
10
Aldehyde
RI
90a
90a
90a
90a
90a
90b
90c
90d
90e
90f
Ph
Ph
Ph
Ph
Ph
4-F-C 6H4
4-0Me-C6H4
pentyl
cycIohexyl
CH(CH2CH3)2
Rl
RJ
Me
Et
Me
CH2 CI
Ph
Me
Me
Me
Me
Me
Me
Et
OMe
OEt
OEt
OMe
OMe
OMe
OMe
OMe
~-Dicar-
bonyl
88a
88b
88c
88d
88e
88c
88c
88c
88c
88c
Product Yield b
(%)
57 c
91a
80
91b
84
91c
49
91d
86
91e
81
9lf
91g
81
72
91h
80
9li
89
91j
Aldehyde 90a-f (l equiv.), p-dicarbonyl 88a-e (1.1 equiv.), copper(I) bromide (2.5 mol%), and
TBHP (1.5 equiv.).
b Isolated yields were based on the aldehyde.
C The (E)-stereoisomer was also isolated with a yield of 9%.
a
nBuOH
cat. CuBr
TBHP, BOoC
(33%)
Scheme 47. Oxidative Esterification of I-Butanol.
Furthermore, when a cyclic
~-diketone
was subjected to the optimized
reaction conditions, esterification was not observed.
Thus, it appears that
substrates that can bind to the copper metal in a bidentate fashion, such as linear
~-diketones
and
~-ketoesters,
are good substrates for the esterification reaction.
51 4.4 - Proposed Reaction Mechanism
A plausible reaction mechanism to explain the results of the copper­
catalyzed oxidative esterification of aldehydes with
~-dicarbonyl
compounds is
proposed in Scheme 48. Copper enolate 92 generated from a copper salt and
~­
dicarbonyl compounds 88a-e could potentially add to aldehydes 90a-f to form a
copper hemiacetal complex 93. Hydrogen abstraction of copper complex 93 by a
radical generated from the copper-catalyzed decomposition of TBHP followed by
a single-electron transfer (SET) of the hemiacetal radical to the copper metal
would lead to the desired esters 91a-j.
o
o
0
R2~HxR3 ~
88a~
[Cu]X
~
~
~
R)lo 0
R2~R3
+ tBuOH
+ H20
91a-j
TBHP
+ HX
o-[Cu]
[CuI
6 b
R1~O 0
R2~R3
92
93
R2~R3
Scheme 48. Proposed Reaction Pathway for the Copper-Catalyzed Oxidative Esterification of Aldehydes. The initial fommtion of the copper enolate is believed to occur due to the
high stereoselectivity experienced by the oxidative esterification reaction. This
also explains why 1,3-cyc1ic diketones, which cannot undergo bis-chelation4 with
metals, were found to be poor substrates for the oxidative esterification reactions
with aldehydes. Although the exact mechanism of the oxidation of the copper
complex 93 is not well understood, a SET of the hemiacetal radical to the copper
metal is proposed due to similar intermediates proposed for the oxidation of
alcohols
to
aldehydes
mediated
by
(TEMPO) radicals (Scheme 49). 5
52
2,2,6,6-tetramethyl-I-piperidinyloxy
l' '\
-
:1
~
QV
/
Cu(l)
N-CU(II)"----r-~
\
/
N
o
\.
+
0/
\
R/-H H
Scheme 49. Copper-TEMPO Radical Oxidation of Alcohols to Aldehydes.
The SET of ketyl radical intermediates have also been proposed in the
oxidation of a1cohols to aldehydes by galactose oxidases and these enzymes
utilize copper metals as co-factors for the oxidation reaction. 6
In the case of the copper-catalyzed esterification reaction with
~­
dicarbonyl compounds, copper-catalyzed homolytic decomposition of TBHP is
believed to be the major source of the radical required for the oxidation reaction
(Scheme 50).7
Reduction:
Oxidation
+O-OH
+O-OH
+
+
+ -OH +
Cu(lI)
Cu(l)
..
Cu(lI)
Cu(l)
+
+
H
·o-f
+
Scheme 50. Copper-Catalyzed Decomposition of TB HP
Evidence that radical-type intermediates are possibly involved in the
reaction was found when a radical scavenger, 2,6-di-tert-butyl-4-methyl phenol
(BHT) was introduced between aldehyde 90a and
~-diketone
88a. The addition
of BHT prevented the esterification process and provided only trace amount of the
esterification product 91a
«
5% by IH NMR) with near quantitative recovery of
the unreacted aldehyde 90a.
53 4.5 - Conclusion
In conclusion, a copper-catalyzed oxidative esterification between an
aldehyde and
~-dicarbonyl
compound was achieved using TBHP as an oxidant.
The reaction was found to be highly stereoselective to provide the (Z)-enol ester
in good yields.
4.6 - Experimental Section
General Information Relating to All Experimental Procedures
All reactions were carried out under an atmosphere of dry nitrogen at
ambient temperature unless otherwise stated. Standard column chromatography
was perforn1ed on 20-60 !lm silica gel (obtained from Silicycle Inc.) using
standard flash column chromatography techniques. Infrared analyses of liquid
compounds were recorded as a thin film on NaCI plates and solid compounds as
KBr pellets.
IH and
l3 C
NMR spectra were recorded on a 400 MHz NMR
spectrometer. Chemical shifts for IH NMR spectra were reported in parts per
million (ppm) from tetramethylsilane with the solvent resonance as the internal
standard (chloroform: cS 7.26 ppm). Chemical shifts for l3C NMR spectra were
reported in parts per million (ppm) from tetramethylsilane with the solvent as the
internal standard (deuterated chloroform: cS 77.0 ppm). All reagents purchased
were used without further purification.
0
0
0
+
0
0
Ph)l.H
~
90a
88a
PhAO
cat. CuBr
TBHP, BOOC
PhAO
0
AA
91a
+
~
0
92
General Procedure for the Copper-Catalyzed Oxidative Esterification of
Aldehydes with
~-Dicarbonyl
Compounds. To a mixture of CuBr (3.3 mg,
0.025 mmol, 2.5 mol%), aldehyde 90a (100.0 !lL, 0.985 mmol), and p-diketone
54 88a (0.11 mL, 1.1 mmol) was added tert-butyl hydroperoxide (TBHP, 5.5 M in
decanes, 0.27 mL, 1.5 mmo1) under an inert atmosphere of nitrogen gas at room
temperature. The reaction vessel was capped and allowed to stir overnight at
80°C. The crude reaction mixture was purified by column chromatography on
silica gel (EtOAc: hexane = 1:4) to provide 92 (18.3 mg, 0.0896 mmo1, 9%) and
91a (114.0 mg, 0.558 mmol, 57%) as clear colourless oils.
(E)-4-0xopent-2-en-2yl benzoate (92). Rf = 0.44 (EtOAc: hexane = 1:4); IH
NMR (CDCi), 400 MHz, ppm): 8 8.08-8.06 (m, 2H), 7.64-7.61 (m, IH), 7.50­
7.747 (m, 2H), 6.23 (s, IH), 2.45 (s, 3H), 2.26 (s, 3H);
J3 C
NMR (CDCi), 100
MHz, ppm): 8 197.1, 163.7, 162.7, 133.7, 129.9, 128.9, 128.5, 116.5,32.3, 18.8.
This is a known compound and the spectral data is consistent with the reported
literature data?
(Z)-4-0xopent-2-en-2-yl benzoate (91a) (Table 6, entry 1). Rf = 0.30 (EtOAc:
hexane= 1:4); IHNMR(CDCh, 400 MHz,ppm): 88.20-8.18 (m,2H), 7.72-7.67
(m, IH), 7.58-7.54 (m, 2H), 5.99 (s, IH), 2.29 (s, 3H), 2.25 (s, 3H); l3C NMR
(CDCi), 100 MHz, ppm):
8 195.0, 163.1, 157.8, 133.5, 129.9, 128.7, 128.4,
117.1,31.0,21.5. This is a known compound and the spectral data is consistent
with the reported literature data. 2
o
Ph)lH
90a
0
+
0
)lJl Et Et
cat. CuBr TBHP, BO°C
88b (Z)-S-Oxohept-3-en-3-yl benzoate (9tb) (Table 6, entry 2).
Following the
above general procedure with aldehyde 90a (100.0 ilL, 0.985 mmo1) and
~­
diketone 88b (0.15 mL, 1.1 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 1:4) to provide 91b (183.4 mg, 0.789
mmol, 80%) as a clear colourless oil. Rf= 0.45 (EtOAc: hexane = 1:4); IR (neat,
NaCl): 3064 (w), 2978 (s), 2940 (m), 2881 (m), 1740 (s), 1702 (s), 1668 (s), 1634
(s), 1452 (s), 1263 (s) cm-I; IH NMR (CDCh, 400 MHz, ppm): 8 8.11-9.09 (m,
2H), 7.61-7.57 (m, IH), 7.49-7.45 (m, 2H), 5.96 (s, IH), 2.50 (q, 2H, J= 7.2 Hz),
55 2.43 (q, 2H, J = 7.6 Hz), 1.17 (t, 3H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.6 Hz);
I3 C
NMR(CDCh, 100MHz,ppm): 8197.7,163.3,161.6,133.3,130.0,129.1,128.4,
113.7, 37.0, 28.4, 10.6, 7.8; HRMS (El):
calculated for C14H1603:
[M+·] =
232.1099 m/z; found: [M+e] = 232.1108 m/z.
o
Ph)lH
0
+
0
~OMe
90a
cat. CuBr
TBHP, BOOC
SSc
(Z)-4-Methoxy-4-oxobut-en-2-yl benzoate (91c) (Table 6, entry 3). Following
the above general procedure with aldehyde 90a (100.0
~L,
0.985 mmol) and
~­
ketoester 88c (0.12 mL, 1.1 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 1:4) to provide 91c (182.2 mg, 0.827
mmol, 84%) as a white solid (m.p. = 40-41 QC). Rf= 0.47 (EtOAc: hexane
1:4);
IR (neat, KBr): 3026(s), 2997 (s), 2845 (w), 1734 (s), 1600 (s), 1584 (s), 1432
(s), 1378 (s), 1313 (s) cm-I; IH NMR (CDCh, 400 MHz, ppm): 88.12-8.09 (m,
2H), 7.60-7.56 (m, IH), 7.48-7.44 (m, 2H), 5.69 (s, IH), 3.59 (s, 3H), 2.14 (s,
3H);
I3 C
NMR (CDCh, 100 MHz, ppm): 8 163.9, 163.4, 160.2, 133.4, 130.1,
129.1, 128.4, 108.2, 51.3, 21.8; HRMS (El): calculated for C 12 H 12 0 4 : [M+e] =
220.0736 mlz; found: [M+·] = 220.0732 mlz.
o
Ph)lH
0
+
90a
0
~OEt
Cl
cat. CuBr
TBHP, BOOC
SSd
91d
(Z)-1-Chloro-4-ethoxy-4-oxobut-2-en-2yl benzoate (91d) (Table 6, entry 4).
Following the above general procedure with aldehyde 90a (1 00.0
mmol) and
~-ketoester
88d (0.16 mL, 95%, 1.1 mmol).
~L,
0.985
The crude reaction
mixture was purified by column chromatography (EtOAc: hexane = 1:4) to
provide 91d (129.6 mg, 0.482 mmol, 49%) as a clear colourless oil. Rf = 0.43
(EtOAc: hexane = 1:4); IR (neat, NaCI): 3427 (w), 3073 (m), 2983 (s), 2905 (m),
56 2873 (w), 1970 (w), 1914 (w), 1760 (s), 1733 (s), 1674 (s), 1452 (s), 1262 (s) cm­
I; IH NMR (CDCh, 400 MHz, ppm): 8 8.14-8.12 (m, 2H), 7.64-7.60 (m, IH),
7.51-7.47 (m, 2H), 6.04 (s, 1H), 4.24 (s, 2H), 4.10 (q, 2H, J= 7.2 Hz), 1.13 (t, 3H,
J
=
7.2 Hz); 13C NMR (CDCh, 100 MHz, ppm): 8 163.2, 162.8, 155.6, 133.7,
130.2, 128.5, 128.4, 110.0, 60.6, 43.3, 14.1; HRMS (El):
C13H 13 CI04: [M+e]
=
268.0502 m/z; found: [M+e]
=
calculated for
268.0496 m/z.
o
cat. GuBr
PhAO
TBHP, BOOG
Ph~OEt
88e
90a
0
91e
(Z)-3-Ethoxy-3-oxo-l-phenylprop-l-enyl benzoate (91e) (Table 6, entry 5).
Following the above general procedure with aldehyde 90a (100.0 JlL, 0.985
mmol) and p-ketoester 88e (0.21 mL, 90%, 1.1 mmol).
The crude reaction
mixture was purified by column chromatography (EtOAc: hexane = 1:4) to
provide 91e (251.9 mg, 0.850 mmol, 86%) as a white solid (m.p. = 77-78°C). Rf
=
0.43 (EtOAc: hexane
=
1:4); IR (neat, KBr): 3065 (w), 2986 (w), 2932 (w),
1742 (s), 1733 (s), 1636 (s), 1450 (m), 1392 (m), 1334 (s), 1241 (s), 1068 (s),
1039 (m) cm-I; IH NMR (CDCh, 400 MHz, ppm): 8 8.25-8.23 (m, 2H), 7.66­
7.64 (m, 3H), 7.55-7.50 (m, 2H), 7.43-7.40 (m, 3H), 6.39 (s, 1H), 4.15 (q, 2H, J=
7.2 Hz), 1.17 (t, 3H, J = 7.2 Hz);
13 C
NMR (CDCh, 100 MHz, ppm): 8 163.8,
163.6, 157.6, 133.5, 133.3, 130.8, 30.2, 128.9, 128.7, 128.5, 125.8, 106.7, 60.4,
14.2; HRMS (El): calculated for C1sH1604: [M+e]
=
=
296.1049 mlz; found: [M+-]
296.1046 mlz.
d
I~
~
o
o
00
H+~
cat. GuBr
OMe
TBHP, BOOG
F
90b
88c
~O
0
F~ ~OMe
91f
(Z)-4-Methoxy-4-oxobut-2-en-2-yl 4-fluorobenzoate (91f) (Table 6, entry 6).
Following the above general procedure with aldehyde 90b (100.0 JlL, 98%, 0.929
mmol) and p-ketoester 88c (0.10 mL, 0.93 mmol). The crude reaction mixture
57 was purified by column chromatography (EtOAc: hexane = 1:4) to provide 9lf
(178.3 mg, 0.748 mmol, 81 %) as a clear colourless oil. Rf = 0.43 (EtOAc: hexane
=
1:4); IR (neat, NaCl): 3438 (w), 3116 (m), 3081 (m), 2953 (s), 2921 (m),2845
(m), 2124 (w), 1755 (s), 1606 (s), 1508 (s), 1442 (s), 1380 (s) cm-I; IH NMR
(CDCh, 400 MHz, ppm): 8 8.15-8.11 (m, 2H), 7.16-7.12 (m, 2H), 5.70 (s, IH),
3.61 (s, 3H), 2.15 (s, 3H); I3C NMR (CDCh, 100 MHz, ppm): 8 167.1, 164.6,
162.4, 161.9 (d, J = 365.0 Hz), 132.6 (d, J = 9.2 Hz), 125.4, 115.6 (d, J = 22.2
Hz), 108.1,51.2,21.7; HRMS (El): calculated for C\2H II F04: [M+e] = 238.0641
mlz; found: [M+e]
Meo
~H
4
=
238.0637 mlz.
o
o
+
0
~OMe
cat. GuBr
TBHP, aOOG
88c
90c
~O 0
Meo4
~OMe
91 9
(Z)-4-Methoxy-4-oxobut-2-en-2-yl 4-methoxybenzoate (91g) (Table 6, entry
7). Following the above general procedure with aldehyde 90c (100.0 ilL, 98%,
0.805 mmol) and
~-ketoester
88c (0.10 mL, 0.93 mmol). The crude reaction
mixture was purified by column chromatography (EtOAc: hexane
provide 91g (162.9 mg, 0.651 mmol, 81 %) as a white solid (m.p.
=
=
1:4) to
29-30°C). Rf
= 0.37 (EtOAc: hexane = 1:4); IR (neat, KBr): 2952 (w), 2842 (w), 1731 (s),
1676 (s), 1607 (s), 1512 (s), 1442 (s), 1370 (m), 1262 (s), 1165 (s) cm-I; IH NMR
(CDCh, 400 MHz, ppm): 88.06 (dm, 2H, J= 9.0 Hz), 6.94 (dm, 2H, J= 9.0 Hz),
5.67 (s, 1H), 3.85 (s, 3H), 3.59 (s, 3H), 2.14 (s, 3H); I3C NMR (CDCh, 100 MHz,
ppm): 8 163.8, 163.6, 163.0, 160.4, 132.1, 121.4, 113.6, 108.0, 55.4, 51.1, 21.8;
HRMS (El): calculated for C13HI 40 S: [M+e]
=
250.0841 mlz; found: [M+e] =
250.0832 mlz.
o
~H
gOd
o
+
0
~OMe
o
cat. GuBr
TBI-IP, BOOG
88c
~oo
~OMe
9h
58
(Z)-4-Methoxy-4-oxobut-2-en-2-yl hexanoate (91h) (Table 6, entry 8).
Following the above general procedure with aldehyde 90d (100.0 ilL, 98%, 0.814
mmol) and
~-ketoester
88c (0.10 mL, 0.93 mmol). The crude reaction mixture
was purified by column chromatography (EtOAc: hexane = 1:4) to provide 91h
(125.2 mg, 0.584 mmol, 72%) as clear colourless oil. Rf= 0.61 (EtOAc: hexane =
1:4); IR (neat, NaCl): 2957 (s), 2934 (s), 2863 (m), 1764 (s), 1729 (s), 1678 (s),
1442 (m), 1379 (m), 1282 (m), 1219 (m), 1096 (s) cm-I; IH NMR (CDCi), 400
MHz, ppm): 8 5.56 (s, IH), 3.63 (s, 3H), 2.48 (t, 2H, J = 7.6 Hz) 1.98 (s, 3H),
1.70-1.67 (m, 2H), 1.36-1.30 (m, 4H), 0.89 (t, 3H, J= 7.2 Hz);
l3 C
NMR (CDCi),
100 MHz, ppm): 8 170.3,163.8,160.1,107.7,51.1,34.1,31.2,24.2,22.3,21.7,
13.9; HRMS (El): calculated for C ll H IS 0 4 : [M+e] = 214.1205 mlz; found: [M+e]
= 214.1202 mlz.
o
+
0
cat. CuBr
AAoMe
90e
TBHP,
88c
aooc
~O
U AA
0
oMe
91i
(Z)-4-Methoxy-4-oxobut-2-en-2-yl cyclohexanecarboxylate (9li) (Table 6,
entry 9). Following the above general procedure with aldehyde 90e (100.0 ilL,
98%, 0.814 mmol) and
~-ketoester
88c (0.10 mL, 0.93 mmol).
The crude
reaction mixture was purified by column chromatography (EtOAc: hexane = 1:4)
to provide 9li (146.9 mg, 0.649 mmol, 80%) as clear colourless oil. Rf = 0.58
(EtOAc: hexane = 1:4); IR (neat, NaCl): 3079 (w), 2993 (m), 2935 (s), 2857 (s),
1762 (s), 1719 (s), 1701 (s), 1434 (s), 1379 (m), 1282 (m), 1076 (s) cm-I; IH
NMR (CDCi), 400 MHz, ppm): 85.55 (s, IH), 3.62 (s, 3H), 2.47 (tt, IH, J = 8.0,
3.6 Hz), 2.03-2.01 (m, 2H), 1.97 (s, 3H), 1.78-1.75 (m, 2H), 1.65-1.63 (m, IH),
1.54-1.45 (m, 2H), 1.34-1.21 (m, 4H);
l3 C
NMR (CDCi), 100 MHz, ppm): 8
172.3, 163.8, 160.1, 107.7, 51.0, 43.0, 28.7, 25.7, 25.4, 21.6; HRMS (El):
calculated for C\2H Is04 : [M+e] = 226.1205 m/z; found: [M+e] = 226.1212 m/z.
59 o
+
0
~OMe
cat. CuBr
TBHP,80 o C
~O
) AAoMe
SBc
90f
0
91j
(Z)-Methyl-3-(2-ethylbutanoyloxy)but-2-enoate (91j) (Table 6, entry 10).
Following the above general procedure with aldehyde 90f (100.0 ilL, 92%, 0.748
mmol) and p-ketoester 88c (0.10 mL, 0.93 mmol). The crude reaction mixture
was purified by column chromatography (EtOAc: hexane
=
1:4) to provide 91j
(142.4 mg, 0.665 mmol, 89%) as clear colourless oil. R f = 0.57 (EtOAc: hexane =
1:4); lR (neat, NaCl): 3080 (w), 2967 (s), 2939 (s), 2879 (m), 1756 (s), 1736 (s),
1679 (s), 1461 (m), 1336 (m), 1267 (m), 1218 (s) cm-I; IH NMR (CDCh, 400
MHz, ppm):
(5
5.54 (s, IH), 3.61 (s, 3H), 2.37-2.32 (m, 1H), 1.98 (s, 3H), 1.76­
1.67 (m, 2H), 1.61-1.51 (m, 2H), 0.94 (t, 6H, J= 7.6 Hz); l3C NMR (CDCh, 100
MHz, ppm):
(5
172.5, 163.7, 159.6, 108.2,51.0,48.3,24.3,21.4,11.6; HRMS
(El): calculated for CIIHIS04: [M+e] = 214.1205 m/z; found: [M+e] = 214.1211
mlz.
60 References for Chapter 4
1. Li, Z.; Li, c.-J. JAm. Chem. Soc. 2006, 128, 56. 2. Enol esters 91a and 92 are known compounds and the spectral data eH,
l3c
NMR) is consistent with the reported data, see: Negishi, E.; Liou, S.; Xu, C.;
Shimoyama, 1.; Makabe, H. J Mol. Catal. Chem. A. 1999,143,279.
3. Bach, R. D.; Ayala, P. Y.; Schlegel, H. B. JAm. Chem. Soc. 1996, 118, 12758. 4. Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4,269.
5. (a) Arends, 1.; Gamez, P.; Sheldon, R. A. Adv. inorg. Chem. 2006, 58, 235. (b) Sheldon, R. A.; Arends, 1. J Mol. Catal. A 2006, 251, 200. 6. (a) Himo, F.; Eriksson, L. A.; Maseas, F.; Siegbahn, P. E. M. JAm. Chem. Soc. 2000, 122, 8031. (b) Whittaker, M. M.; Ballou, D. P.; Whittaker, J. W. Biochemistry 1998, 37, 8426. (c) Wachter, R. M.; Montague-Smith, M. P.; Branchaud, B. P. JAm. Chem. Soc. 1997,119, 7743. 7. Sheldon, R. A.; Kochi, J. K. Metal-catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1981.
61 Chapter 5 - Copper-catalyzed Oxidative Esterification of Alcohols with
Aldehydes Activated by Lewis Acids
In chapter 4, p-dicarbonyl compounds were shown to undergo oxidative
esterification reactions with aldehydes in the presence of TBHP and catalytic
amounts of a copper salt.
However, simple alcohols such as I-butanol were
shown to be poor substrates for the esterification reaction under the optimized
reaction conditions. In this chapter, the development of an oxidative esterification
reaction of aldehydes with simple alcohols will be discussed.
5.1 - Background
As illustrated in chapter 3, a variety of protocols have been developed for
the oxidative esterification of aldehydes with alcohols. However, many of these
protocols call for excess reagents and/or expensive catalyst.
Furthermore,
competing side reactions such as the oxidation of the alcohol and the aldehyde
substrates complicate the oxidative esterification and limit the application of this
functional group transformation. Unlike most oxidative esterification protocols,
the copper-catalyzed oxidative esterification with p-dicarbonyl compounds using
TBHP as an oxidant does not suffer from these disadvantages (Scheme 51).1
o
0
R2~R3
90a-f
cat. CuBr
TBHP, 80°C
•
88a-e
91a-j
Scheme 51. Copper-catalyzed Stereoselective Oxidative Esterification of
Aldehydes with p-Dicarbonyl Compounds.
Thus, we became interested in developing a copper-catalyzed system to
induce the oxidative esterification to occur with aldehydes and simple alcohols
while avoiding the limitations faced by most oxidative esterification protocols.
62 5.2 - Optimization of Reaction Conditions
From our prevIOus expenences with the copper-catalyzed oxidative
esterification reaction, we were aware that alcohols that cannot chelate with the
copper metal were poor substrates. However, we believed that if the aldehyde
was activated with a Lewis acid, then the oxidative esterification reaction was
possible. Thus, we began our study by screening a variety of high-valent metal
salts as co-catalyst for the oxidative esterification of benzaldehyde 90a with 1­
butanol 94a (Table 7).
Table 7. Optimization of the Oxidative Esterification of Aldehyde 90a with
Alcohol 94a by Screening Metal Salts. a
nBuOH
90a
Entry
1
2
3
4
5
6
7
8
9
10
11
12
cat. CuBr, cat. [M]
0
TBHP, BOOC
• Ph)lonBU
94a
95a
[M]
RhCh-H2O
AuBr3
AuCI
AgCI0 4
AgI
Ga(OTf)3
GaBr3
Gal3
InCh
InBr3
InI3
Yield b
(%)
33
44
50
59
57
56
58
50
46
47
58
47
Aldehyde 90a (0.92 mmol), alcohol 94a (1.0 mmol), TBHP
(1,0 mmol), CuBr (0,046 mmol), and metal salt (0,046 mmol),
b Determined by IH NMR using mesitylene as an internal standard,
a
Table 7 represents some of the screened metal salts that showed an
improvement over just the copper(I) bromide-catalyzed oxidative esterification
reaction. Since most oxidative esterification reactions reported in the literature
use the alcohol as both a reagent and solvent, we examined the effect of slightly
63 increasing the amount of alcohol 94a from 1.1 equivalence to 1.5 equivalence
(Table 8).
Table 8. Optimization of the Oxidative Esterification of Aldehyde 90a with
Alcohol 94a by Examining the Effect of Increasing the Equivalence of Alcohol
94a. 3
nBuOH
90a
Entry
1
2
3
4
5
6
cat. CuBr, cat. [M]
0
TBHP, BODC
• Ph)lonBU
94a
95a
[M]
Yield b (%)
AuCI
AgCI0 4
AgI
RhCh-H 2O
Ga(OTf)3
InBr3
44
40
47
49
64
62
Aldehyde 90a (0.92 mmol), a1cohol94a (lA mmol), TBHP
(1.0 mmol), CuBr (0.046 mmol), and metal salt (0.046 mmol).
b Determined by 'H NMR using mesitylene as an internal standard.
a
Some of the better performing metal salts found in table 7 were subjected
to the excess alcohol with catalytic amounts of CuBr and TBHP. With the silver
and gold catalysts (entries 1-3) lead to a decrease in yield, while the other metal
salts (entries 4-6) showed slight improvement. Next, the copper salt was screened
while the metal additive was kept constant. Indium(III) bromide was chosen as
the co-catalyst due to cost oflnBr3 relative to Ga(OTf)3 (Table 9).
Screening of the various copper salts showed copper(II) perchlorate
emerging as the best catalyst (entry 14). Finally, increasing the temperature of the
reaction proved to be useful and provides the desired ester 95a with a high yield
(entry 15). Additional attempts at improving the yield of the reaction through the
introduction of a solvent (toluene, acetonitrile, water, etc.) or a different oxidant
(02, H202, cumene hydroperoxide, tert-butyl peroxybenzoate, etc.) failed.
64 Table 9. Optimization ofthe Oxidative Esterification of Aldehyde 90a with Alcohol 94a by Screening Copper Salts. a nBuOH
cat. InBr3' cat. [CuI
TBHP, BODC
90a
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 c
94a
[Cu]
CuBr
CuCl
CuI
CuSCN
Cu(MeCN)4PF 6
CuOTf
CuCh
CuBr2
Cu(OTf)2
CuO
Cu(acach
Cu(OAc)2
Cu(CF3COOh
Cu(C104)2·6H2O
Cu(CI04h·6H20
Yield tl (%)
62
64
57
57
59
56
62
62
67
63
54
60
67
78
91
Aldehyde 90a (0.92 mmol), alcohol 94a (1.4 mmol), TBHP
(1.0 mmol), [nBr3 (0.046 mmol), and copper salt (0.046 mmol). b Determined by 'H NMR using mesitylene as an internal standard. a
c
1000e.
5.3 - Scope of the Copper-Catalyzed Oxidative Esterification of Aldehydes
with Alcohols
With the optimized reaction condition in hand, the scope of the copper and
indium catalyzed oxidative esterification of aldehydes 90a, c-h with alcohols 94a­
e was examined (Table 10).
In general, the copper- and indium-catalyzed oxidative esterification
reaction occurs smoothly to provide the desired esters 95a-k in good yields.
Sterically hindered alcohols diminish the effectiveness of the reaction with lower
yields experienced with secondary and tertiary alcohols (entries 4-5).
The
oxidative esterification was amenable to both electron-rich and electron-poor
65 aromatic aldehydes (entries 6-9). More gratifying was the compatibility of the
reaction with primary and secondary aliphatic aldehydes as substrates (entries lO­
11).
Unfortunately, due to the oxidative nature of the reaction conditions,
substrates that contain functional groups that readily oxidize, such as allylic
alcohols and sulfides, were shown to be poor substrates for the oxidative
esterification reaction.
Table 10. Scope of the Oxidative Esterification of Aldehydes with Alcohols. a
cat. Cu(CI0 4h.6H 2 0, cat. InBr3
TBHP, 80°C
0
•
94a-e
R)lOR 2
95a-k
Entry
Aldehyde
RI
Alcohol
RL
Product
1
2
3
90a
90a
90a
90a
90a
90f
90c
90g
90h
90d
90e
Ph
Ph
Ph
Ph
Ph
4-Me-C 6H4
4-MeO-C 6H4
4-CI-C 6H4
4-CN-C 6H4
pentyl
cyclohexyl
94a
94b
94c
94d
94e
94a
94a
94a
94a
94a
94a
nBu
95a
95b
95c
95d
95e
95f
95g
95h
95i
95j
95k
4
5
6
7
8
9
10
11
Me
Et
ipr
tBu
nBu
nBu
nBu
nBu
nBu
nBu
Yieldo
(%)
91
83
89
57
<5 e
87
65
81
42
91
85
Aldehyde 90a, c-b (1 equiv.), alcohol 94a-e (1.5 equiv.), Cu(CI04)2-6H20 (5.0 mol%), InBr3
(5.0 mol%), and TBHP (1.5 equiv.). b Isolated yields based on the aldehyde. C Determined by lH NMR using mesitylene as an internal standard. The ester was not isolated. a
5.4 - Proposed Reaction Mechanism
The
mechanism
of the copper-
and indium-catalyzed
oxidative
esterification reaction is believed to proceed through the same mechanism as
illustrated in chapter 4.
Initial formation of the hemiacetal intermediate 96,
followed by oxidation from the radical generated from a metal-induced
decomposition of the TBHP is believed to be the reaction pathway towards the
desired esters (Scheme 52).
66
cat. Cu(CI0 4h.6H 2 0, cat. InBr3
TBHP, BOoC
[Cutin]
0
•
R)lOR 2
[Cutin]
.-----------­ ,
1- _ _ _ _ _ _ _ _ _ _ _ _ _ ....­
TBHP
96
Scheme 52. Proposed Reaction Mechanism for the Oxidative Esterification of Aldehydes with Alcohols. The indium(lII) bromide is believed to aid in the formation of the hemi­
acetal intermediate 96, while the copper is the catalysts that facilitates the
decomposition of the TB HP to the radicals responsible for the oxidation of
intermediate 96. Evidence for a radical mechanism was once again demonstrated
when a radical scavenger, BHT, was introduced into the system, the oxidative
esterification reaction was inhibited.
5.5 - Conclusion
In summary, an oxidative esterification reaction between aldehydes and
alcohols was developed using a combination of Cu(CI04h-6H 20 and InBr3 as
catalyst and TBHP as the oxidant. Both aliphatic and aromatic aldehydes were
shown to be compatible to the reaction conditions and large excess of alcohol was
not required to obtain the desired ester in high yields.
5.6 - Experimental Section
General Information Relating to All Experimental Procedures
All reactions were carried out under an atmosphere of dry nitrogen at
ambient temperature unless otherwise stated. Standard column chromatography
was performed on 20-60 Ilm silica gel (obtained from Silicycle Inc.) using
standard flash column chromatography techniques. Infrared analyses of liquid
67 compounds were recorded as a thin film on NaCI plates and solid compounds as
KBr pellets.
H and
1
\3 C
NMR spectra were recorded on a 400 MHz NMR
spectrometer. Chemical shifts for 1H NMR spectra were reported in parts per
million (ppm) from tetramethylsilane with the solvent resonance as the internal
standard (chloroform: 8 7.26 ppm). Chemical shifts for
\3 C
NMR spectra were
reported in parts per million (ppm) from tetramethylsilane with the solvent as the
internal standard (deuterated chloroform: 8 77.0 ppm). All reagents purchased
were used without further purification.
+ nBuOH
cat. Cu(CI04h-6H 2 0, cat. InBr3
0
TBHP, 100°C
• Ph)lons U
94a
95a
General Procedure for the Oxidative Esterification of Aldehydes with
Alcohols. To a mixture of Cu(CI04h-6H 20 (17.1 mg, 0.0462 mmol, 5.0 mol%),
InBr3 (16.4 mg, .0463 mmol, 5.0 mol%), aldehyde 90a (94.0 ilL, 0.926 mmol),
and alcohol 94a (0.13 mL, 1.42 mmol) was added tert-butyl hydroperoxide
(TBHP, 5.5 M in decanes, 0.18 mL, 0.99 mmol) under an inert atmosphere of
nitrogen gas at room temperature. The reaction vessel was capped and allowed to
stir overnight at 100°C.
The crude reaction mixture was purified by column
chromatography on silica gel (EtOAc: hexane = 1: 19) to provide 95a (150.1 mg,
0.842 mmol, 91 %) as clear colourless oil.
Butyl benzoate (95a) (Table 10, entry 1). Rr= 0.57 (EtOAc: hexane
=
1: 19); IH
NMR (CDCh, 400 MHz, ppm): 8 8.06-8.03 (m, 2H), 7.54 (tt, IH, J = 6.8, 1.6
Hz), 7.43 (tm, 2H, J= 8.0 Hz), 4.33 (t, 2H, J= 6.8 Hz), 1.80-1.73 (m, 2H), 1.54­
1.45 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz);
\3 C
NMR (CDCh, 100 MHz, ppm): 8
166.4, 132.6, 130.4, 129.4, 128.1,64.8, 30.9, 19.4, 13.9. This is a commerically
available compound and the spectral data is consistent with the reported data. 2
68 o
+ MeOH )l
Ph
H
90a
cat. Cu(CI0 4h.6H 20, cat. InBr3
TBHP,100oC
0
Ph)lOMe
•
94b
95b
Methyl benzoate (95b) (Table 10, entry 2).
Following the above general
procedure with aldehyde 90a (94.0 JlL, 0.926 mmol) and alcohol 94b (0.06 mL,
1.4 mmol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1:19) to provide 95b (105.0 mg, 0.771 mmol, 83%) as a clear
colourless oil. Rr= 0.32 (EtOAc: hexane = 1:19); IH NMR (CDCh, 400 MHz,
ppm): cS 8.03 (dm, 2H, J = 6.8 Hz), 7.54 (tm, 1H, J = 7.2 Hz), 7.42 (tm, 2H, J =
7.6 Hz), 3.90 (s, 3H);
13 C
NMR (CDCh, 100 MHz, ppm): cS 167.0, 132.8, 130.1,
129.5, 128.2, 52.0. This is a commerically available compound and the spectral
data is consistent with the reported data?
o
+ EtOH
)l
Ph
H
90a
cat. Cu(CI0 4h.6H2 0, cat. InBr3
TBHP,100oC
0
•
Ph)lOEt
94c
95c
Ethyl benzoate (95c) (Table 10, entry 3).
Following the above general
procedure with aldehyde 90a (94.0 JlL, 0.926 mmol) and alcohol 94c (0.08 mL,
1.4 mmol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1:19) to provide 95c (123.6 mg, 0.823 mmol, 89%) as a clear
colourless oil. Rr= 0.39 (EtOAc: hexane = 1:19); IH NMR (CDCh, 400 MHz,
ppm): cS 8.05 (dm, 2H, J = 7.2 Hz), 7.54 (tm, 1H, J = 6.8 Hz), 7.43 (tm, 2H, J =
7.6 Hz), 4.38 (q, 2H, J= 7.2 Hz), 1.39 (t, 3H, J= 7.2 Hz);
MHz, ppm):
13 C
NMR (CDCh, 100
cS 166.5, 132.7, 130.4, 129.5, 128.2, 60.9, 14.3.
This is a
commerically available compound and the spectral data is consistent with the
reported data?
cat. Cu(CI0 4 h.6H 2 0, cat. InBr3
TBHP, 100°C
94d
0
•
Ph)lOipr
95d
69
2-Propyl benzoate (95d) (Table 10, entry 4).
Following the above general
procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and alcohol 94d (0.11 mL,
1.4 mmol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1: 19) to provide 95d (86.0 mg, 0.524 mmol, 57%) as a clear
colourless oil. Rr = 0.41 (EtOAc: hexane = 1: 19); 1H NMR (CDCh, 400 MHz,
ppm): () 8.04 (dm, 2H, J= 7.6 Hz), 7.56 (tm, 1H, J= 7.2 Hz), 7.43 (tm, 2H, J=
8.0 Hz), 5.26 (septet, 1H, J= 6.4 Hz), 1.37 (d, 6H, J= 6.4 Hz); l3C NMR (CDCh,
100 MHz, ppm): () 166.1, 132.6, 130.9, 129.4, 128.2,68.3,21.9. This is a known
compound and the spectral data is consistent with the reported literature data. 3
+ nBuOH
90t
9St
94a
Butyl4-methylbenzoate (95f) (Table 10, entry 6). Following the above general
procedure with aldehyde 90f (100.0 ilL, 0.823 mmol) and alcohol 94a (0.11 mL,
1.2 mmol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1:19) to provide 95f (138.3 mg, 0.719 mmol, 87%) as a clear
colourless oil. Rr= 0.47 (EtOAc: hexane = 1:19); IH NMR (CDCh, 400 MHz,
ppm): () 7.94 (d, 2H, J = 7.6 Hz), 7.22 (d, 2H, J = 7.6 Hz), 4.31 (t, 2H, J = 6.8
Hz), 2.39 (s, 3H), 1.78-1.71 (m,2H), 1.52-1.45 (m, 2H), 0.98 (t, 3H, J= 7.6 Hz);
l3C NMR (CDCh, 100 MHz, ppm): () 166.6, 143.3, 129.4, 128.9, 127.7, 64.5,
30.7, 21.5, 19.2, 13.7.
This is a known compound and the spectral data is
consistent with the reported literature data. 4
~H
cat. Cu(CI0 4h-6H 20, cat. InBr3
+ "BuOH
TBHP, 100°C
Meo)()
90c
94a
95 9
Butyl 4-methoxybenzoate (95g) (Table 10, entry 7).
Following the above
general procedure with aldehyde 90f (100.0 ilL, 0.805 mmol) and alcohol 94a
(0.11 mL, 1.2 mmol).
The crude reaction mixture was purified by column
70 chromatography (EtOAc: hexane = 1:9) to provide 95g (111.2 mg, 0.534 rnrnol,
65%) as a clear colourless oil.
Rr = 0.44 (EtOAc: hexane = 1:9); IH NMR
(CDCh, 400 MHz, ppm): 87.99 (dm, 2H, .1= 8.8 Hz), 6.90 (dm, 2H, .1= 8.8 Hz),
4.28 (t, 2H, .1= 6.4 Hz), 3.83 (s, 3H), 1.76-1.69 (rn, 2H), 1.51-1.41 (rn, 2H), 0.97
(t,3H,J=7.2Hz); I3CNMR (CDCh, 100MHz,ppm): 8166.3,163.2,131.4,
122.9, 113.4,64.4,55.3,30.7, 19.2, 13.7. This is a known compound and the
spectral data is consistent with the reported literature data. 5
o
c,
~H
+ nBuOH
N
o
~onBu
cat. Cu(CI0 4h.6H 20, cat. InBr3
TBHP, 100°C
c,
90g
N
95h
94a
Butyl 4-cblorobenzoate (95b) (Table 10, entry 8). Following the above general
procedure with aldehyde 90g (130.0 mg, 0.897 mmol) and alcohol 94a (0.13 mL,
1.35 mmol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1:19) to provide 95b (154.8 mg, 0.728 mmol, 81%) as a clear
colourless oil. Rf= 0.43 (EtOAc: bexane = 1:19); IH NMR (CDCh, 400 MHz,
ppm): 8 7.96 (d, 2H, .1 = 8.4 Hz), 7.38 (d, 2H, .1 = 8.4 Hz), 4.30 (t, 2H, J = 6.8
Hz), 1.77-1.69 (rn, 2H), 1.50-1.41 (m, 2H), 0.96 (t, 3H, J = 7.2 Hz); I3C NMR
(CDCh, 100 MHz, ppm): 8 165.7, 139.1, 130.8, 128.9, 128.6,65.0,30.6, 19.2,
13.7. This is a known compound and the spectral data is consistent with the
reported literature data. 6
~H
NcN
90h
o
~onBu
cat. Cu(CI0 4h.6H 20, cat. InBr3
+ 'BuOH
TBHP, 100°C
NC
M
95i
94a
Butyl 4-cyanobenzoate (95i) (Table 10, entry 9). Following the above general
procedure with aldehyde 90b (120.0 mg, 0.869 rnrnol) and alcohol 94a (0.12 mL,
1.3 rnrnol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1:19) to provide 95i (154.8 mg, 0.728 mmol, 81%) as a white
solid (m.p. = 54-55°C). Rf = 0.24 (EtOAc: hexane = 1:19); IH NMR (CDCb, 400
71 MHz, ppm): 88.12 (dm, 2H, J= 8.6 Hz), 7.73 (dm, 2H, J= 8.6 Hz), 4.34 (t, 2H,
J = 6.7 Hz), 1.78-1.71 (m,2H), 1.51-1.41 (m, 2H), 0.97 (t, 3H, J = 7.0 Hz); 13C
NMR (CDCl), 100 MHz, ppm): 8 164.9, 134.2, 132.1, 130.0, 117.9, 116.2, 65.6,
30.5, 19.1, 13.6. This is a known compound and the spectral data is consistent
with the reported literature data. 5
o
~H
+ nBuOH
90d
95j
94a
Butyl hexanoate (95j) (Table 10, entry 10).
Following the above general
procedure with aldehyde 90d (100.0 JlL, 0.796 mmol) and alcohol 94a (0.11 mL,
1.2 mmol). The crude reaction mixture was purified by column chromatography
(EtOAc: hexane = 1:19) to provide 95j (124.7 mg, 0.724 mmol, 91%) as a clear
colourless oil. Rf= 0.48 (EtOAc: hexane = 1:19); IH NMR (CDCl), 400 MHz,
ppm): 8 4.04 (t, 2H, J = 6.8 Hz), 2.26 (t, 2H, J = 7.6 Hz), 1.63-1.54 (m, 4H),
1.40-1.22 (m, 6H), 0.92 (t, 3H, J = 7.6 Hz), 0.86 (t, 3H, J = 7.2 Hz); 13C NMR
(CDCl), 100 MHz, ppm): 8 173.9, 64.0, 34.3, 31.3, 30.6, 24.6, 22.2, 19.1, 13.8,
13.6. This is a known compound and the spectral data is consistent with the
reported literature data. 7
cat. Cu(CI0 4h.6H 2 0. cat. InBr3
TBHP.100oC
90e
o
ci'O"BU
95k
94a
Butyl cyclohexanecarboxylate (95k) (Table 10, entry 11). Following the above
general procedure with aldehyde 90e (100.0 JlL, 0.814 mmol) and alcohol 94a
(0.11 mL, 1.2 mmol).
The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 1: 19) to provide 95k (127.9 mg, 0.694 mmol,
85%) as a clear colourless oil.
Rf = 0.52 (EtOAc: hexane = 1:19); IH NMR
(CDCi], 400 MHz, ppm): 8 4.02 (t, 2H, J = 6.4 Hz), 2.25 (tt, IH, J = 11.6, 3.6
Hz), 1.87-1.84 (m, 2H), 1.73-1.69 (m, 2H), 1.62-1.53 (m, 2H), 1.44-1.15 (m, 8H),
72 0.89 (t, 3H, J = 7.6 Hz); l3C NMR (CDCi), 100 MHz, ppm): 8 176.1,63.8,43.2, 30.6, 29.0, 25.7, 25.4, 19.1, 13.6. This is a known compound and the spectral data is consistent with the reported literature data. 8 73 References for Chapter 5
1. Yoo, W.-l.; Li, C.-l.J Org. Chem. 2006,71,6266.
2. Commerically available from Sigma-Aldrich® with spectral data available
online at http://www.sigmaaldrich.com/
3. Jackson, L. B.; Waring, A. J. J Chem. Soc. Perkin Trans. 21990,907.
4. Magerlein, W.; Indolese, A. F.; Beller, M. J Organomet. Chem. 2002, 641,
30.
5. Schoenberg, A.; Bartoletti, I.; Heck, R. F. J Org. Chem. 1974,39,3318.
6. Jacobson, R. M. Synth. Commun. 1978, 8, 33.
7. Huang, Z.; Reilly, 1. E.; Buckle, R. N. Synlett 2007, 1026.
8. Hans, 1. J.; Driver, R. W.; Burke, S. D. J Org. Chem. 2000,65,2114.
74 Chapter 6 - Copper-Catalyzed Oxidative Amidation of Aldehydes with
Amine Hydrochloride Salts
In the previous two chapters, copper-catalyzed protocols were developed
for the oxidative esterification of aldehydes using TBHP as the oxidant. In this
chapter, the development of a copper-catalyzed oxidative amidation of aldehydes
will be discussed.
6.1- Background
The amide functional group is important and ubiquitous in orgamc
chemistry.l The most prevalent strategy towards the formation of amide bonds
relies heavily upon the interconversion of activated carboxylic acid derivatives
with an amine. 2 As illustrated in chapter 3, new developments have been made
for amide bond synthesis through the oxidative amidation of aldehydes.
However, prior to the development of this work, only a few examples of oxidative
ainidation of aldehydes were reported. 3
Most examples utilized expensive
transition metal catalysts and often the substrate scope was poor. With our recent
success in the oxidative esterification reaction,4 we looked to develop the much
more challenging amidation reaction of simple aldehydes with amines.
6.2 - Optimization of Reaction Conditions
Our preliminary studies on the oxidative amidation reaction began by
attempting to couple benzaldehyde 90a with benzyl amine (Scheme 53).
+
cat. CuBr
TBHP, 80°C
90a
o
Ph)lN/'...Ph
H
(33%)
Scheme 53. Initial Attempt at the Oxidative Amidation of Aldehydes with Benzylamine. 75
Surprisingly, the first attempt at the oxidative amidation of aldehyde 90a
was successful to provide the amide with 33% yield (determined by IH NMR of
the crude reaction mixture).
However, control studies showed that the
benzylamine is susceptible to oxidation and undergoes oxidative dimerization
(Scheme 54).
)l0
cat. CuBr
TBHP,80oC
•
Ph
N/"'-,.Ph
H
(33%)
H20
---------------~
Scheme 54. Oxidative Dimerization of Benzyl Amine. Table 11. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine HCI Salt 97a by Screening Copper Salts.a Ph
)l
°
90a
Entry
1
2
3
4
5
6
7
8
9
+
cat. [Cui
EtNH 2eHCI
TBHP, BOoC
H
97a
[Cu]
CuCI
CuBr
CuI
CuBr2
Cu(OAc)2
Cu(acach
CU(OTf)2
Cu(CI04 h-6H20
(MeCN)4CuPF 6
Yield!> (%)
28
30
35
28
38
39
26
30
32
Aldehyde 90a (0.93 mmol), amme HCI 97a (lA mmol), TBHP
(1.0 mmo\), and copper salt (0.046 mmol).
b Determined by IH NMR using mesitylene as an internal standard
after quenching the reaction mixture with sat. NaHC0 3 •
a
76 In order to prevent the oxidative dimerization of the amine, we considered
the use of amine hydrochloride salts as the amine source. Thus, we began our
optimization study using benzaldehyde 90a and amine hydrochloride 97a (Table
11).
Initially, copper salts were screened and Cu(acac)2 (entry 6) was found to
be the best. Following our earlier work with the oxidative esterification reactions,
various metal salts were screened to see if a co-catalyst would have any effect. A
variety of metal salts were screened and the ones which improved the yield of the
amidation are shown in Table 12.
Table 12. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine
HCI Salt 97a by Screening Metal Salts.a
cat. Cu(acacb, cat. [M]
TBHP,
90a
Entry
1
2
3
4
5
6
7
8
9
10
11
12
aooc
97a
[M]
InBr3
InI3
GaCl]
GaBr3
Ga(acac)3
AgCI0 4
AgI0 3
AuBr3
AuI
Coh
CoF2
CoF3
Yield b (%)
42
52
48
56
55
46
48
42
50
45
54
50
Aldehyde 90a (0.93 mmol), amme HCl 97a (1.4 mmol), TBHP
(1.0 mmol), Cu(acac)2 (0.046 mmol) and metal salt (0.046 mmol).
b Determined by IH NMR using mesitylene as an internal standard
after quenching the reaction mixture with sat. NaHC0 3 .
a
Although the amine HCI was believed to be a good substrate due to its
resistance to oxidation, the ability of the amine HCI salt to add to the aldehyde
would be poor.
We hypothesized that the addition of a base might help the
77 reaction and the best performing metal salts from table 12 were screened along
with 1.1 equivalence ofNaHC03 as a base (Table 13).
Table 13. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine
HCI Salt 97a by the Addition ofNaHC03.a
cat. Cu(acach. cat.
[M]
NaHC03 • TBHP. 80°C
90a
Entry
1
2
3
4
5
97a
[M]
YieldD (%)
GaBr3
AgI03
AuI
COF2
61
72
73
61
63
Aldehyde 90a (0.93 mmol), amme HCl 97a (lA mmol), TBHP
(1.0 mmol), Cu(acac)2 (0.046 mmol), metal salt (0.046 mmol),
NaHC0 3 (1.0 mmol).
b Determined by I H NMR using mesitylene as an internal standard.
a
Next, the base was screened using a catalytic amount of Cu(acac)2 and
AgI03 (Table 14). The silver salt was chosen over GaBr3 since it is an easier
reagent to work with.
As shown in table 14, the type of base plays an important role, with
inorganic bases performing better than the amine-type bases (entries 8-10).
Although NaOH provided yields similar to NaHC0 3, the bicarbonate was chosen
since it is not as hydroscopic as NaOH. Next, we re-examined the copper salts in
order to improve the yield of the oxidative amidation reaction of aldehydes (Table
15).
While the screening of the copper salt did not dramatically improve the
overall yield of the amidation reaction, slight improvements were observed with
various copper(I) and copper(II) salts.
Copper(I) iodide was chosen as the
catalyst for further optimization since it was one of the best catalysts, coupled
with the fact that it is very easy to handle and is a very inexpensive reagent.
78 Table 14. Optimization ofthe Oxidative Amidation of Aldehyde 90a with Amine
HCl Salt 97a by the Addition of a Base. a
cat. Cu(acach, cat. AgI0 3
[base], THBP, BOoC
90a
97a
Entry
1
2
3
4
5
6
7
8
9
10
[base]
NaHC0 3
Na2C03
NaH2P04-H20
K2HP04
Na3P04
KOAc
NaOH
Et3N
(iPrhNEt
pyridine
Yield!> (%)
73
67
68
44
24
36
72
42
8
44 Aldehyde 90a (0.93 mmol), amine HC197a (lA mmol), TB HP (l.0 mmol), Cu(acac)2 (0.046 mmol), AgI0 3 (0.046 mmol),
base (1.0 mmol).
b Detennined by IH NMR using mesitylene as an internal standard.
a
Table 15. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine
HCl Salt 97a by Screening Copper Salts.a
o
)l.
Ph
+
H
90a
Entry
1
2
3
4
5
6
7
8
9
cat. [Cu], cat. AgI0 3
EtNH 2eHCI - - - - - - - NaHC03 , TBHP, BOoC
97a
[Cu]
Cu(acac)2
CuBr
CuI
CuOTf
CuCh
CuBr2
CU(OTt)2
Cu(CI0 4h-6H2O
Cu(OAch
Yield!> (%)
73
75
78
68
79
60
74
75
71
Aldehyde 90a (0.93 mmol), amme HCI 97a (lA mmol), TBHP
(l.0 mmol), Ag103 (0.046 mmol), copper salt (0.046 mmol),
NaHC0 3 (1.0 mmol).
b Determined by IH NMR using mesitylene as an internal standard.
a
79
Next, various oxidants were screened (Table 16).
Table 16. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine
HCI Salt 97a by Screening Oxidants. a
o
)l
Ph
+
EtNH 2eHCI cat. Cui, cat. AgI0 3
NaHC0 3 , [oxidant], 80°C H
90a
97a
Entry
1
2
3
4
5
6
Yield b (%)
78
0
0
50
44
84
[oxidant]
TBHP
H20 2 (30 wt% in H2O)
tBuOOtBu
tBuCOOAc
tButyl peroxybenzoate
Cumene hydroperoxide
Aldehyde 90a (0.93 mmol), amme HCI 97a (l.4 mmol), CuI
(0.046 mmol), AgI0 3 (0.046 mmol), NaHC0 3 (l.0 mmol), and
oxidant (1.0 mmol).
b Detennined by lH NMR using mesitylene as an internal standard.
a
Screening of peroxides showed cumene hydroperoxide to be the best
oxidant. Furthermore, by increasing the amount of cumene hydroperoxide from
1.1 equivalences to 1.5 leads to a quantitative yield of the desired amide 98a.
However, the IH NMR yields obtained using cumene hydroperoxide as an oxidant
did not translate to similar isolated yields (Scheme 55).
o
)l
Ph
90a
+
EtNH 2eHCI cat. Cui, cat. AgI0 3
NaHC0 3 , [oxidantj, 80°C H
97a
Cumene hydroperoxide: 99% 1H NMR yield
57% isolated yield
tert-butyl hydroperoxide: 78% 1H NMR yield
78% isolated yield
Scheme 55. Oxidative Amidation of Aldehydes with Amine HCI Salts Using Cumene Hydroperoxide as an Oxidant. 80
Attempts at isolation of amide 98a were difficult due to a variety of
impurities that were difficult to separate from 98a.
However, for the TBHP­
mediated reaction, the IH NMR yield and the isolated yield corresponded well.
When the catalyst loading of the reaction was decreased, surprisingly the yield of
the oxidative amidation increased, with a catalyst loading of 1.0 mol% providing
a quantitative yield of the desired amide 98a (Table 17).
Table 17. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine
HCl Salt 97a by Varying Catalyst Loading.a
o
)l
Ph
cat. Cui, cat. AgI0 3
+ EtNH 2eHCI - - - - - - - - - - - H
NaHC0 3 , TBHP, BODC 90a
•
97a
Entry
1
2
3
4
Mol%
10.0 5.0 2.5 1.0 Yield o (%)
79
78
90
99
Aldehyde 90a (0.93 mmol), amme HCI97a (lA mmol), CuI
(0.009-0.093 mmol), AgI0 3 (0.009-0.093 mmol), NaHC0 3
(1.0 mmol), and oxidant (1.0 mmol).
b Determined by I H NMR using mesitylene as an internal standard.
a
6.3 - Scope of the Oxidative Amidation of Aldehydes with Amine
Hydrochloride Salts
Using the optimized conditions, the scope of the copper and silver catalyzed
oxidative amidation of aldehyde 90a with various amine HCl salts 97a-e was
examined (Table 18).
As shown in table 18, simple aliphatic amine HCl salts were found to be
good substrates under the optimized reaction conditions (entries 1-3). However,
other amine HCI salts containing ester and chloride group failed to provide the
desired amide in good yields (entries 5-6). Examination of the TLC plate and IH
NMR of the crude reaction mixture showed the presence of a variety of
unidentified side products.
Thus, while a protocol was developed for the
81
oxidative amidation reaction of aldehydes; further improvement upon the catalyst
system was desired.
Table 18. Scope of the Oxidative Amidation of Aldehyde 90a with Amine HCI Salts 97a-C cat. Cui, cat. AgI0 3
NaHC0 3 , TBHP, BOOC
90a
Entry
I
2
3
4
5
6
Aldehyde
90a
90a
90a
90a
90a
90a
97a-f
RI
Ph
Ph
Ph
Ph
Ph
Ph
Amine
HCI
97a
97b
97c
97d
97e
97f
RL
Product
Yield o
(%)
Et
Bn
cyclohexyl
t Bu
CH 2CH2CI
CH2COOEt
98a
98b
98c
98d
98e
98f
87
68
95
30
13
28
Aldehyde 90a (l eqUlv.), amme HCI97a-f(1.5 eqUlv.), CuI (1.0 mol%), AgI0 3 (1.0 mol%), NaHC0 3 (1.1 equiv.) and TBHP (1.1 equiv.). b Isolated yields based on the aldehyde. a
6.4 - Development of a 2 nd Generation Oxidative Amidation Protocol
With our desire to develop an oxidative amidation reaction that tolerates a
variety of different functional groups, we examined the system using the amino
ester HCl salt 97f as the amidation reagent (Table 19).
Examination of the I H NMR of the crude reaction mixture showed a great
number of peaks around 3.5-4.5 ppm region along with the desired amide 98f.
However, in the absence of the base, the undesirable unknown peaks were not
detected. Unfortunately, from our previous optimization studies, the base was
shown to be critical for the success of the amidation reaction. Thus, we attempted
to utilize a very insoluble base, such as CaC03 (entry 2). Although the yield of
amide 98f was low using CaC03 as a base, the reaction was free of the unknown
impurities. The low yield observed was rationalized as an inability of the reaction
mixture to stir properly since many solid reagents were present. Thus, solvents
82 were introduced into the system in order to provide a medium for efficient stirring
(entries 3-6). The most dramatic improvement was observed when the solvent in
the oxidant was switched from decane to water (entry 7). The reaction conditions
were further optimized and were shown to be complete in 6 hours at 40°C.
Table 19. Optimization of the Oxidative Amidation of Aldehyde 90a with Amine
HCI Salt 97f.a
cat. Cui, cat. AgI0 3
[base], [oxidant], [solvent]
90a
80°C
97f
Entry
Base
1
2
3
4
5
6
7
NaHC0 3
CaC03
CaC03
CaC03
CaC0 3
CaC0 3
CaC0 3
Solvent
Oxidant
cyclohexane
MePh
H2O
MeCN
MeCN
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
T-HYDROQ!!
Yield b
(%)
39
35
34
50
44
69
93
a Aldehyde
90a (0.93 mmol), amine HCl97a (1.4 mmol), CuI (0.009 mmol),
AgI03 (0.009 mmol), base (1.0 mmol), and oxidant (1.0 mmol) in solvent
(0.2 mL). b Determined by 'H NMR using anisole as an internal standard. 6.5 - Scope of the 2nd Generation Copper- and Silver-Catalyzed Oxidative
Amidation Reaction of Aldehydes with Amine HCl Salts
With the development of a new set of reaction conditions for the oxidative
amidation reaction, the scope of the reaction was explored with aldehydes 90a, c,
e-g, i and amine hydrochloride salts 97a-g (Table 20).
In general, the oxidative amidation reaction proceeds well to provide the
desired amides 98a-1 in good yields. Steric effects of the amine HCl salts may
play a role since a bulky group, such as tert-butyl, provided the amide 98e with a
low yield (entry 5). Remarkably, the amidation reaction occurred even in the
presence of other electrophiles, such as alkyl chloride (entry 6) and ester (entries
83 7-12). The oxidative amidation was also compatible with a variety of electron­
rich and electron-poor aryl aldehydes (entries 8-11). When aliphatic aldehyde 90e
was utilized as a coupling partner, the desired amide 981 was obtained with a low
yield (entry 12). In fact, aliphatic aldehydes (such as hexanal, valeraldehyde)
were found to be poor substrates for the oxidative amidation reaction due to
competing aldol condensation reactions.
Interestingly, when the oxidative
amidation reaction was applied to optically active amine ester 97h, the reaction
proceeded smoothly in high yields without racemization of the chiral center
(Scheme 56).
Table 20. Scope of the 2nd Generation Oxidative Amidation Reaction. a
cat. Cui, cat. AgI0 3
90a, c, e-g, i
97a-g
Entry
Aldehyde
RI
1
2
3
4
90a
90a
90a
90a
90a
90a
90a
90f
90c
90g
90i
90e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-C 6H4
4-MeO-C 6H4
4-CI-C6H4
4-N02-C6H4
cyclohexyl
5
6
7
8
9
10
11
12
.
CaC0 3 , T-HYDRO®
MeCN,40oC
Amine
HCI
97a
97b
97g
97c
97d
97e
97f
97f
97f
97f
97f
97f
Rl
Product
Et
Bn
CH2Bn
cyclohexyl
tBu
CH2CH2CI
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH 2COOEt
CH2COOEt
98a
98b
98c
98d
98e
98f
98g
98h
98i
98j
98k
981
Yield b
(%)
91
71
89
73
39
89
91
91
78
81
49
39
Aldehyde 90a, C, e-g, I (1 eqUlv.), amme HCl 94a-g (1.5 eqUlv.), CuI (1.0 mol%), AgI0 3
(1.0 mol%), and TBHP (1.1 equiv.) in MeCN (0.2 mL). b Isolated yields based on the aldehyde. a
0
+
Ph)lH
90a
X
MeOOC
NH 2-HCI
cat. Cui, cat. AgI0 3
CaC0 3, T-HYDRO®
MeCN,40oC
97h
(91%)
99% ee
O~
Ph)lN~COOMe
H
98m
99%ee
Scheme 56. Oxidative Amidation of an Enantiopure Amino Ester HCI Salt.
84
6.6 - Proposed Reaction Mechanism
The mechanism of the oxidative amidation reaction of aldehydes is
believed to occur through a similar route as the oxidative esterification reactions
(Scheme 57).
base
[0]
Scheme 57. Proposed Reaction Pathway Towards Amides From Aldehydes and
Amine Hel Salts.
The initial deprotonation of the amine Hel salt to the free amine, followed
by the nucleophilic addition of the amine to the aldehyde would generate
carbinolamine intermediate 99.
Oxidation of intermediate 99 by a radical
generated from the copper-induced decomposition of TBHP would result in the
formation of the desired amide. Evidence for a radical mechanism was once
again demonstrated by the inhibition of the oxidative amidation reaction in the
presence of the radical scavenger, BHT. Mechanistically, it is also plausible that
the amide formation may arise from a transamination reaction with a carboxylic
acid derived from the direct oxidation of the aldehyde.
However, when
benzaldehyde was replaced with benzoic acid, the expected amide was not
observed under the optimized reaction conditions.
6.7 - Conclusion
In conclusion, a copper- and silver-catalyzed oxidative amidation reaction
between aldehydes and amine Hel salts was developed using THBP as the
oxidant. The initially developed oxidative amidation protocol provided amides in
high yields from aldehydes, but was limited in scope with only simple aliphatic
amine Hel salts providing good yields.
85 Studies into the development of a
modified version to overcome this limitation lead to the discovery of a milder and
more functional group compatible protocol.
6.8 - Experimental Section
General Information Relating to All Experimental Procedures
All reactions were carried out under an atmosphere of dry nitrogen at
ambient temperature unless otherwise stated. Standard column chromatography
was performed on 20-60 !lm silica gel (obtained from Silicycle Inc.) usmg
standard flash column chromatography techniques. Infrared analyses were
recorded as KBr pellets. IH and
l3 C
NMR spectra were recorded on a 400 MHz
NMR spectrometer. Chemical shifts for 1H NMR spectra were reported in parts
per million (ppm) from tetramethylsilane with the solvent resonance as the
internal standard (chloroform:
i)
7.26 ppm).
Chemical shifts for
l3 C
NMR
spectra were reported in parts per million (ppm) from tetramethylsilane with the
solvent as the internal standard (deuterated chloroform:
cS 77.0 ppm).
All
reagents purchased were used without further purification.
o
11
Ph~H
90a
+
EtNH 2eHCI
cat. Cui, cat. AgI0 3
CaC0 3 T-HYDRO®'
97a
MeCN,40oC
General Procedure for the Copper- and
Silver-catalyzed Oxidative
Amidation of Aldehydes with Amine HCI Salts. To a mixture of CuI (1.8 mg,
0.0095 mmol, 1.0 mol%), AgI0 3 (2.6 mg, 0.0092 mmol, 1.0 mol%), amine HCI
salt 97a (113.2 mg, 1.388 mmol) and CaC03 (101.9 mg, 1.011 mmol) in MeCN
(0.2 mL), aldehyde 90a (94.0 !lL, 0.926 mmol) and T-HYDRO® (70 wt% of
TB HP in H20, 0.15 mL, 1.05 mmol) was added under an inert atmosphere of
nitrogen gas at room temperature. The reaction vessel was capped and allowed to
stir for 6h at 40°C.
The crude reaction mixture was purified by column
86 chromatography (EtOAc: hexane = 2:3) to provide 98a (125.8 mg, 0.843 mmol, 91 %) as a white solid (m.p. = 71-72°C). N-Ethylbenzamide (98a) (Table 20, entry 1). Rf= 0.27 (EtOAc: hexane = 2:3); lH NMR (CDCh, 400 MHz, ppm): (37.77-7.75 (m, 2H), 7.41 (tt, 1H, J = 7.2, 1.2
Hz), 7.34 (mt, 2H, J= 7.2 Hz), 6.89 (bs, IH), 3.46-3.39 (m, 2H), 1.19 (t, 3H, J=
7.2 Hz);
13 C
NMR (CDCh, 100 MHz, ppm): (3 167.2, 134.4, 130.9, 128.1, 126.7,
34.8, 14.8. This is a known compound and the spectral data are identical to those
reported in the literature. 5
o
)l
Ph
+
BnNH, HCI
H
90a
97b
cat. CuI, cat. AgI0 3
CaC0 3 T-HYDRO®"
MeCN,40oC
N-Benzylbenzamide (98b) (Table 20, entry 2). Following the above general
procedure with aldehyde 90a (94.0 j..lL, 0.926 mmol) and amine HCI salt 97b
(139.2 mg, 1.340 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 2:3) to provide 98b (139.2 mg, 0.659 mmol,
71 %) as a white solid (m.p. = 104-106°C). Rf= 0.45 (EtOAc: hexane = 2:3); IH
NMR (CDCh, 400 MHz, ppm): (37.80-7.78 (m, 2H), 7.51-7.26 (m, 8H), 6.72 (bs,
IH), 4.61 (d, 2H, J= 5.2 Hz);
13 C
NMR (CDCh, 100 MHz, ppm): (3167.7,138.5,
134.6,131.8,129.0,128.8,128.1,127.8,127.3,44.3. This is a known compound
and the spectral data are identical to those reported in the literature. 6
cat. CuI, cat. AgI0 3
90a
979
.
CaC0 3 . T-HYDRO®
MeCN,40oC
o
)l
Ph
~
/'-...
Bn
98c
N-Phenethylbenzamide (98c) (Table 20, entry 3). Following the above general
procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and amine HCI salt 97g
(218.9 mg, 1.390 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 2:3) to provide 98c (171.4 mg, 0.811 mmol,
88%) as a white solid (m.p. = 113-114°C). Rf= 0.37 (EtOAc: hexane = 2:3); IH
NMR (CDCh, 400 MHz, ppm): (37.72-7.70 (m, 2H), 7.47 (tm, 1H, J= 7.2 Hz),
87 7.39 (tm 2H, J = 7.2 Hz), 7.32 (tm, 2H, J = 7.6 Hz), 7.24 (tm 3H, J = 7.6 Hz),
6.39 (bs, 1H), 3.73-3.68 (m, 2H), 2.93 (t, 2H, J = 6.8 Hz); I3C NMR (CD Cb, 100
MHz, ppm): D 167.4, 138.8, 134.5, 131.3, 128.7, 128.6, 128.5, 126.8, 126.5,41.1,
35.6. This is a known compound and the spectral data are identical to those
reported in the literature. 7
cat. Cui, cat. AgI0 3
90a
97c
.
CaC0 3, T-HYDRO@
MeCN,40oC
N-Cyclohexylbenzamide (98d) (Table 20, entry 4).
Following the above
general procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and amine HCI salt
97c (188.3 mg, 1.390 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 2:3) to provide 98d (137.0 mg, 0.674 mmol,
73%) as a white solid (140-141°C). Rr= 0.30 (EtOAc: hexane = 1:4); IH NMR
(CDCb, 400 MHz, ppm): D 7.78-7.73 (m, 2H), 7.47-7.34 (m, 3H), 6.24 (bd, IH, J
= 6.4 Hz), 3.99-3.89 (m, IH), 2.01-1.97 (m, 2H), 1.75-1.59 (m, 3H), 1.43-1.11
(m, 5H);
l3 C
NMR (CDCb, 100 MHz, ppm): D 166.6,135.0,131.1,128.3, 126.8,
48.6, 33.1, 25.4, 24.9.
This is a known compound and the spectral data are
identical to those reported in the literature. 8
cat. Cui. cat. AgI0 3
90a
97d
.
CaC0 3 , T-HYDRO®
MeCN.40oC
N-tert-Butylbenzamide (98e) (Table 20, entry 5). Following the above general
procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and amine HCI salt 97d
(152.2 mg, 1.390 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 2:3) to provide 98e (63.2 mg, 0.357 mmol,
39%) as a white solid (132-133°C). Rf= 0.57 (EtOAc: hexane = 1:4); IH NMR
(CDCh, 400 MHz, ppm): D 7.72-7.69 (m, 2H), 7.44 (tm, IH, J = 7.2 Hz), 7.38
(tm, 2H, J = 7.2 Hz), 6.01 (bs, IH), 1.46 (s, 9H); I3C NMR (CDCh, 100 MHz,
88 ppm): 3 166.8, 135.8, 131.0, 128.4, 126.6,51.5,28.8. This is a known compound
and the spectral data are identical to those reported in the literature. 9
o
Ph
)l
+
H
CI~NH2·HCI
cat. Cui, cat. AgI0 3
)l0
-C-a-C-O--T--H-YD-R-O---=®--Ph
N~CI
3
MeCN, 40°C
90a
H
97e
98f
N-(2-Chloroethyl)benzamide (98g) (Table 20, entry 6). Following the above
general procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and amine HCI salt
97e (161.1 mg, 1.390 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 2:3) to provide 98f (151.1 mg, 0.823 mmol,
89%) as a white solid (m.p. = 104-105°C). Rf= 0.34 (EtOAc: hexane = 2:3); IH
NMR (CDCh, 400 MHz, ppm): 3 7.80-7.77 (m, 2H), 7.50 (tm, 1H, J = 7.6 Hz),
7.42 (tm, 2H, J= 7.6 Hz), 6.79 (bs, IH), 3.80-3.76 (m, 2H), 3.73-3.70 (m, 2H);
13C NMR (CDCh, 100 MHz, ppm): 3 167.7, 134.0, 131.7, 128.6, 126.9, 44.0,
41.6. This is a known compound and the spectral data are identical to those
reported in the literature. 10
o
cat. Cui, cat. AgI0 3
CaC0 3 T-HYDRO®
90a
,
MeCN,40oC
97f
Ethyl 2-benzamidoacetate (98g) (Table 20, entry 7).
)l
Ph
N
H
./"-...
COOEt
98g
Following the above
general procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and amine HCI salt
97f (193.8 mg, 1.390 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane
=
2:3) to provide 98g (174.6 mg, 0.843 mmol,
91 %) as a white solid (60-61°C). Rc = 0.30 (EtOAc: hexane
=
2:3); IH NMR
(CDCh, 400 MHz, ppm): 3 7.80-7.78 (m, 2H), 7.47 (tm, IH, J = 7.6 Hz), 7.38
(tm, 2H, J= 7.6 Hz), 6.98 (bs, 1H), 4.20 (q, 2H, J= 6.8 Hz), 4.18 (d, 2H, J= 5.2
Hz), 1.27 (t, 3H, J = 6.8 Hz); 13C NMR (CDCh, 100 MHz, ppm): 3 170.0, 167.5,
133.5, 131.6, 128.4, 127.0, 61.5, 41.7, 14.0. This is a known compound and the
spectral data are identical to those reported in the literature. I I
89
o
cat. Cui, cat. AgI0 3
. ff~"'COOEt
CaC0 3 , T-HYDRO®
MeCN,40oC
90t
97t
98h
EthyI2-(4-methylbenzamido)acetate (98h) (Table 20, entry 8). Following the
above general procedure with aldehyde 90f (100.0 j.lL, 0.823 mmol) and amine
HCI salt 97f (172.2 mg, 1.234 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 2:3) to provide 98h (165.4 mg, 0.748
mmol, 91 %) as a white solid (68-69°C). Rf = 0.30 (EtOAc: hexane = 2:3); IR
(KBr) cm-I 3300 (s), 3068 (w), 2998 (w), 2906 (w), 1752 (s), 1624 (s), 1545 (s),
1505 (s), 1329 (m), 1206 (s), 1162 (m), 1021 (m); IH NMR (CDCh, 400 MHz,
ppm): 87.77 (d, 2H,J= 8.0 Hz), 7.25 (d, 2H,J= 8.0 Hz), 7.14 (bs, 1H), 4.27 (q,
2H, J = 6.8 Hz), 4.24 (d, 2H, J = 5.2 Hz), 2.43 (s, 3H), 1.34 (t, 3H, J = 6.8 Hz);
l3 C
NMR (CDCh, 100 MHz, ppm): 8 170.1, 167.4, 141.9, 130.7, 129.0, 127.0,
61.3, 41.6, 21.3, 14.0; HREI calculated for C 12H 1SN03 : [M+e] = 221.1052 mlz;
found: [M+e] = 221.1054 mlz.
o
~H+
Meo
N
90c
97t
98i
EthyI2-(4-methoxybenzamido)acetate (98i) (Table 20, entry 9). Following the
above general procedure with aldehyde 90c (100.0 j.lL, 0.805 mmol) and amine
HCI salt 97f (168.6 mg, 1.208 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 2:3) to provide 98i (149.9 mg, 0.632
mmol, 78%) as a white solid (m.p. = 92-93°C). Rf= 0.18 (EtOAc: hexane = 2:3);
IR (KBr) cm- l 3328 (s), 2976 (w), 2949 (w), 2841 (w), 1755 (s), 1637 (s), 1606
(s), 1547 (s), 1508 (s), 1376 (m), 1184 (s), 1032 (m); IH NMR (CDCh, 400 MHz,
ppm): 87.74 (dm, 2H, J = 7.2 Hz), 6.90 (bs, IH), 6.85 (dm, 2H, J = 8.8 Hz), 4.19
(q, 2H, J
= 7.2 Hz), 4.14 (d, 2H, J = 5.2 Hz), 3.79 (s, 3H), 1.25 (t, 3H, J = 7.2
90 Hz); 13C NMR (CDCh, 100 MHz, ppm): 0 170.2, 166.9, 162.2, 128.8, 125.9,
113.6,61.4, 55.2, 41.7, 14.0; HREI calculated for C 12 H 1SN0 4 : [M+·] = 237.1001
m/z; found: [M+·] = 237.0999 mlz.
CI
rJH
M
90g
o
cat. Cui, cat. AgI0 3
+ EtOOC/'..NH 2 eHCI - - - - - - ­
CaC0 3 , T-HYDRO®
MeCN,40oC
CI
~~~COOEt
M
98j
97f
Ethyl 2-(4-chlorobenzamide)acetate (98j) (Table 20, entry 10). Following the
above general procedure with aldehyde 90g (130.0 mg, 0.897 mmol) and amine
HCI salt 97f (193.6 mg, 1.387 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 2:3) to provide 98j (176.4 mg, 0.730
mmol, 81 %) as a white solid (Ill-112°C). Rf= 0.32 (EtOAc: hexane = 2:3); IR
(KBr) cm- 1 3269 (s), 3090 (m), 2981 (m), 1747 (s), 1647 (s), 1599 (s), 1556 (s),
1487 (m), 1408 (m), 1376 (m), 1205 (s), 850 (s); IH NMR (CDCh, 400 MHz,
ppm): 07.69 (dm, 2H, J= 8.8 Hz), 7.32 (dm, 2H, J= 8.8 Hz), 7.13 (bs, IH), 4.19
(q, 2H, J= 6.8 Hz), 4.13 (d, 2H, J= 5.2 Hz), 1.25 (t, 3H, J= 6.8 Hz);
l3 C
NMR
(CDCh, 100 MHz, ppm): 0170.0,166.4,137.8, 13l.9, 128.6, 128.4, 6l.5, 4l.7,
14.0; HREI calculated for CIIHI23SC1N03: [M+-] = 24l.0506 m/z; found: [M+·] =
237.0999 m/z, for C ll H1237 CIN03:
[M+·] = 243.0476 mlz; found:
[M+·] =
243.0460 m/z.
90i
98k
97f
Ethyl 2-(4-nitrobenzamido)acetate (98k) (Table 20, entry 11). Following the
above general procedure with aldehyde 90i (140.0 mg, 0.907 mmol) and amine
HCl salt 97f (194.0 mg, 1.390 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 2:3) to provide 98k (111.4 mg, 0.442
91 mmol, 49%) as a white solid (m.p. = 140-141 DC). Rr = 0.53 (EtOAc: hexane =
2:3); IR (KBr) cm- 1 3316 (s), 3108 (w), 2989 (w), 2911 (w), 1735 (s), 1642 (s),
1604 (s), 1524 (s), 1344 (s), 1222 (s), 1109 (m), 876 (m); IH NMR (CDCi}, 400
MHz, ppm): 8 8.37 (d, 2H, J = 8.4 Hz), 7.96 (d, 2H, J = 8.4 Hz), 6.94 (bs, 1H),
4.28-4.22 (m, 4H), 1.31 (q, 3H, J = 7.2 Hz);
13 C
NMR (CDCl), 100 MHz, ppm):
8 170.0, 165.7, 150.0, 139.5, 128.6, 124.1, 62.2, 42.3, 14.4; HREI calculated for
CllH12NOs: [M+e] = 252.0746 m/z; found: [M+e] = 252.0749 mlz.
o
cat. Cui, cat. AgI0 3
EtOOC.............. NH 2 ·HCI - - - - - ­ CaC0 3 , T-HYORO®
MeCN,40oC
+
90e
~~/'-.COOEI
981
97f
Ethyl 2-(cyclohexanecarboxamido)acetate (981)
(Table
20,
entry
12).
Following the above general procedure with aldehyde 90e (100.0 /J.L, 0.814
mmol) and amine HCl salt 97f (170.5 mg, 1.222 mmol).
The crude reaction
mixture was purified by column chromatography (EtOAc: hexane = 2:3) to
provide 981 (72.2 mg, 0.318 mmol, 39%) as a white solid (m.p. = 74-75 DC). Rf=
0.29 (EtOAc: hexane = 2:3); IR (KBr) cm- 1 3316 (s), 2987 (w), 2927 (s), 2852
(m), 1743 (s), 1633 (s), 1546 (s), 1438 (m), 1243 (s), 1212 (s), 1030 (w); IH NMR
(CDCl), 400 MHz, ppm): 86.10 (bs, IH), 4.18 (q, 2H, J= 7.2 Hz), 3.99 (d, 2H, J
=
5.2 Hz), 2.13 (tt, IH, J
1.27-1.17 (m, 5H);
13 C
=
8.4, 3.6 Hz), 1.86-1.63 (m, 6H), 1.46-1.37 (m, 2H),
NMR (CDCl), 100 MHz, ppm): 8 176.2, 170.2, 61.4,
45.1, 41.1, 29.4, 25.62, 25.56, 14.0; HREI calculated for CllHI9N03: [M+·]
=
213.1365 m/z; found: [M+·] = 213.1369 mlz.
o
PhAH
+
X
MeOOC
cat. Cui, cat. AgI0 3
NH 2 .HCI -C-a-C-O­
3 , -T--HY-O-R-O-®"·
MeCN,40oC
90a
98m
97h
(R)-Methyl 2-benzamido-3-methylbutanoate (98m).
Following the above
general procedure with aldehyde 90a (94.0 /J.L, 0.926 mmol) and amine HCI salt
92 97h (232.8 mg, 1.389 mmol). The crude reaction mixture was purified by column
chromatography (EtOAc: hexane = 2:3) to provide 98m (197.6 mg, 0.840 mmol,
91 %) as a white solid (m.p. = 87-88°C). Rf= 0.45 (EtOAc: hexane = 2:3); HPLC
(Daicel Chiral AD-H, hexane/isopropanol = 95:5, flow rate = 0.5 mLlmin) tR =
22.745, tR = 29.896 min, Ee = 99%; IR (KBr) cm- 1 3348 (s), 2968 (s), 1739 (s),
1642 (s), 1522 (s), 1491 (m), 1361 (m), 1204 (m), 1153 (m); IH NMR (CDCh,
400 MHz, ppm): 87.79 (dm, 2H, J = 7.2 Hz), 7.48 (tm IH, J = 7.2 Hz), 7.41 (tm,
2H, J = 7.2 Hz), 6.69 (bd, IH, J = 8.4 Hz), 4.76 (dd, IH, J = 8.8, 8.8 Hz), 3.74 (s,
3H), 2.30-2.13 (m, IH), 1.00-0.96 (m 6H); BC NMR (CDCb, 100 MHz, ppm): 8
72.6, 167.2, 134.0, 131.6, 128.5, 127.0, 57.3, 52.1, 31.5, 18.9, 17.9; HREI
calculated for C BH17N03: [M+e] = 235.1208 mlz; found: [M+e] = 235.1210 mlz.
X
MeOOC
90a
NH 2 eHCI
cat. Cui, cat. AgI0 3
CaC0 3 . T-HYDRO®
MeCN,40oC
rac-98m
rac-97h
rac-Methyl 2-benzamido-3-methylbutanoate (rac-98m). Following the above
general procedure with aldehyde 90a (94.0 ilL, 0.926 mmol) and amine HCI salt
rac-97h (232.8 mg, 1.389 mmol). The crude reaction mixture was purified by
column chromatography (EtOAc: hexane = 2:3) to provide rac-98m (203.7 mg,
0.870 mmol, 94%) as a white solid (m.p. = 87-88°C). Rf = 0.45 (EtOAc: hexane =
2:3); HPLC (Daicel Chiral AD-H, hexane/isopropanol = 95:5, flow rate = 0.5
mLlmin) tR = 22.753, tR = 29.858 min, Ee = 0%; IH NMR (CDCb, 400 MHz,
ppm): 8 7.79 (dm, 2H, J = 7.2 Hz), 7.48 (tm IH, J = 7.2 Hz), 7.41 (tm, 2H, J =
7.2 Hz), 6.69 (bd, IH, J = 8.4 Hz), 4.76 (dd, IH, J = 8.8, 8.8 Hz), 3.74 (s, 3H),
2.30-2.13 (m, IH), 1.00-0.96 (m 6H); BC NMR (CDCh, 100 MHz, ppm): 8 72.6,
167.2,134.0,131.6,128.5,127.0,57.3,52.1,31.5,18.9,17.9.
93 References for Chapter 6
1. Humpbrey, 1. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243.
2. Larock, R. C. Comprehensive Organic Transformation; VCH: New York,
1999.
3. (a) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983, 474. (b) Naota, T.;
Murahashi, S. Synlett 1991, 693. (c) Tillack, A.; Rudloff, I.; Beller, M. Eur. J
Org. Chem. 2001,523.
4. (a) Yoo, W.-l.; Li, C.-l. J Org. Chem. 2006, 71,6266. (b) Yoo, W.-l.; Li, C.­
1. Tetrahedron Lett. 2007,48, 1033.
5. Wang, X.; Widenhoefer, R. A. Organometallics 2004, 23, 1649.
6. Shangguan, N.; Katukojuala, S.; Greenberg, R.; Williams, L. 1. JAm. Chem.
Soc. 2003,125,7754.
7. Kita, Y.; Akai, S.; Ajimara, N.; Yoshigi, M.; Tsugoshi, T.; Yasuda, H.;
Tamura, Y. J Org. Chem. 1986,51,4150.
8. Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004,6,4619.
9. Nakagawa, H.; Nagano, T.; Higuchi, T. Org. Lett. 2001, 3, 1805.
10. Shibata, I.; Nakamura, K.; Baba, A.; Matsuda, H. Bull. Chem. Soc. Jpn. 1989,
62,853.
11. Hans, 1. 1.; Driver, R. W.; Burke, S. D. J Org. Chem. 2000,65,2114.
94 Part III - Copper-Catalyzed Multi-Component Coupling Reactions with CO2
Chapter 7 - Introduction to the Applications of CO 2 in Organic Synthesis
With diminishing levels of petroleum as a source of chemical feedstock,
there has been great effort into seeking new sources of simple organic substrates
to fuel the chemist's need for synthesis.) One potential source is the use of carbon
dioxide as a Cl feedstock. Indeed, carbon dioxide is advantageous to use as a
chemical feed stock since it is non-toxic, abundant, and inexpensive. However,
one of the main disadvantages of utilizing carbon dioxide as a substrate is the fact
that it is a relatively low energy molecule (most oxidized state of carbon) and thus
requires high energy input in order for it to be incorporated into useful organic
molecules.
However,
while
carbon
dioxide
IS
considered
to
be
thermodynamically and kinetic ally stable, the carbon atom is electron deficient.
Thus, carbon dioxide has great affinity towards nucleophiles and reacts readily
with water, alkoxides, amines, and organometallic nucleophiles. In this chapter,
recent reports on the use of carbon dioxide as a substrate will be highlighted.
7.1 - Synthesis of Carboxylic Acids Using CO2
Strong carbon-based nucleophiles such as Grignard and organolithium
reagents are well known to add to carbon dioxide gas to generate carboxylic
acids. 2
However, these reactive nucleophiles possess poor functional group
compatibility and limit their use in synthesis. Recently, several research groups
have shown that less reactive organometallic nucleophiles can react with carbon
dioxide gas. Iwasawa and co-workers reported a rhodium-catalyzed protocol for
the addition of aryl- and alkenylboronic esters 100 to carbon dioxide (Scheme
58)?
The rhodium was shown to facilitate the addition of boronic esters 100 to
carbon dioxide to generate carboxylic acids 101 in the presence of functional
groups such as esters and cyanides. However, functional groups on the arene such
as halides, alkynes, and olefins were found to be incompatible to the rhodium
95 catalyst. An improved protocol was recently reported by Iwasawa using copper(I)
iodide as a catalyst with a bisoxazoline ligand to overcome these limitations. 4
cat. [Rh(OH)(COD)h
cat. dppe or (p-MeO)dppp
+ CO 2
R-COOH
CsF, dioxane, 60 DC
(1 atm)
101
Scheme 58. Rhodium-Catalyzed Carboxylation of Aryl- and Alkenylboronic Esters with CO2. Dong and co-worker reported that both palladium and nickel could
catalyze the carbonylation of organozinc reagents 102 with carbon dioxide with
the aid of an electron-rich phosphine ligand (Scheme 59). 5
RZnX
(in THF)
+
CO 2
cat. [Ni(PCY3hb(N 2) or cat. Pd(OAch, cat. PCY3 R-COOH
THF,ODC
(1 atm)
101
102
Scheme 59. Carbonylation of Organozinc Reagents with C02.
Dong demonstrated that carbonylation of organozinc 102 allows for the
synthesis of carboxylic acids 101 in the presence of various functional groups
such as esters, ketones, cyanides, and halides.
Carbonylation with carbon dioxide has been demonstrated with 7t-systems
such as alkynes and dienes under metal-mediated processes (Scheme 60).6
[M]
R
•
___
:r>=
[M]-O 0
W
-
R
~COOH
Scheme 60. Metal-Mediate Carbonylation of 7t-Bonds.
These metal-mediated processes can be rendered catalytic usmg
stoichiometric amounts of dialkyl zinc reagents through the regeneration of the
96 low valent metal via reductive elimination. 7 For example, Mori and co-workers
demonstrated a nickel-catalyzed regioselective synthesis of carboxylic alkenes
103 through an alkylative carboxylation of alkynes 104 using dialkyl zinc
reagents 105 under atmospheric carbon dioxide (Scheme 61).7a
R1
=
TMS
+
104
cat. Ni(CODh
R2 2Zn - - - - - - - - ­
DBU, CO 2 (1 atm), THF
105
rt
R1
TMS
R2
COOH
>=<
103
•
t
R1
TMS~·
>=
~N::'1-0
0
107
106
Scheme 61. Regioselective Alkylative Carboxylation of Alkynes with Dialkyl
Zinc Nudeophiles.
The reaction is believed to occur through the initial formation of the
metallocyde 106, followed by the addition of the zinc reagent 105 to provide the
organonickel intermediate 107.
Reductive elimination of 107 provides the
carboxylic alkene 103 and regenerates the nickel catalyst.
Similarly, nickel has been shown to catalyze the reductive carboxylation
reaction of alkenes 108 with carbon dioxide using diethyl zinc as a reducing
reagent (Scheme 62). 8
Ar~
108
+
CO 2
(1 atm)
cat. Ni(acach
CS 2 C0 3 , Et2Zn, THF
23°C
Scheme 62. Nickel-Catalyzed Reductive Carboxylation of Alkenes Using CO 2 •
Rovis and co-workers found that the reaction was regioselective and
worked best with aromatic alkenes. The diethyl zinc acted as a hydride source
through p-hydride elimination to provide the nickel hydride and ethene gas.
97 7.2 - Heterocyclic Synthesis with CO2
One of the most extensive studies into the use of carbon dioxide as a
substrate is in cyclic carbonate synthesis. Cyclic carbonates are often obtained
through the coupling of epoxides with carbon dioxide and serves as an important
intermediate for polycarbonate synthesis (Scheme 63).9
[M]
Scheme 63. Cyclic Carbonate Synthesis via Coupling Between Epoxides and CO2 . Since epoxides are often synthesized from the oxidation of olefins, several
groups have looked towards cyclic carbonate synthesis through the oxidative
coupling reaction with alkenes and carbon dioxide. For example, Li and co­
worker recently reported the conversion of alkenes 109 into cyclic carbonates 110
using hydrogen peroxide in water (Scheme 64).10
r
+
CO 2
(475 psi)
109
[Br-]
= NBS, NaBr, or TBAB
110
Scheme 64. Bromide-Catalyzed Oxidative Coupling of Temlinal Alkenes with C02 in Water. Another strategy into the incorporation of carbon dioxide into cyclic
carbonates is through the carboxylative cyclization of propargyl alcohols. 11 For
example,
Yamada and
co-workers
recently
reported
a silver-catalyzed
carboyxlative cyclization of propargylic alcohol 111 to generate cyclic carbonates
112 (Scheme 65).lla
98 o
O~
cat. AgOAc
1--f--1U
DBU, MePh, rt·
CO 2 (1 MPa)
R
'l.R
R2
3
112
Scheme 65. Silver-Catalyzed Synthesis of Cyclic Carbonates from Propargylic Alcohols. Similar to cyclic carbonate synthesis, oxazolidinones can be obtained from
the coupling of carbon dioxide with the appropriate nitrogen precursor. 12 Thus,
propargylic amines can undergo cyclization with carbon dioxide to generate the
corresponding oxazolidinones (Scheme 66).12a
o
NHMe
~
R
CO 2 (10 MPa)
100°C
MeN.J(
0
\\
113
l{
R
114
Scheme 66. Carboxylative Cyclization ofPropargylamines with Supercritial CO2• Transition metals have been well established in catalyzing the fixation of
carbon dioxide gas into heterocycles. One of the first examples was reported by
Inoue and co-workers in which symmetric alkynes 115 were coupled with carbon
dioxide to provide lactones 116 (Scheme 67).13
cat. Ni(CODh, cat. dppb
R--===--R
CO 2 (50 bar), 120°C
115
(\
o
0
116
Scheme 67. Nickel-Catalyzed Synthesis of Lactones with Alkynes and CO2 .
99 Similarly, other unsaturated 1t-systems, such as dienes,14 allenes,15 and
diynes, 16 were shown to fix carbon dioxide into heterocyclic frameworks with the
aid of transition metals.
Recently, Yoshida, Kunai, and co-workers demonstrated that in situ
generated benzynes 119 can undergo coupling reactions with imines 117 and
carbon dioxide gas to provide benzoxazinones 118 (Scheme 68).17
R2
D:;
I
KF, 18-crown-6
CO 2 (1 atm),
aoe
NyAr
R1-'­
I
h-
0
o
118
117
•
117
119
120
Scheme 68. Three-Component Coupling of Benzynes, Imines, and C02.
The three-component coupling reaction is believed to occur through the
nucleophilic addition of the imine to benzyne 119 to generate the zwitterionic
species 120.
Next, trapping of the carbon dioxide gas by 120 leads to
intermediate 121, which then collapses into the desired product 118. Other than
imines, Yoshida also demonstrated that amines can also act as a nucleophile to
benzynes in carbon dioxide atmosphere to generate anthranilic acids. 18
100 References for Chapter 7
1. For recent reviews on the use of CO 2 gas in organic synthesis, see:
(a)
Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365. (b) Yin,
X.; Moss, J. R. Coord. Chem. Rev. 1999, 181, 27. (c) Gibson, D. H. Chem.
Rev. 1996,96,2063. (d) Braunstein, P.; Matt, D.; Nobel, D. Chem. Rev. 1988,
88, 747.
2. Kharasch, M.
S.; Reinmuth, O. Grignard Reactions of Nonmetallic
Substances; Prentice-Hall: New York, 1954; p 5.
3. Ukai, K.; Aoki, M.; Takaya, J.; Iwasawa, N. JAm. Chem. Soc. 2006, 128,
8706.
4. Takaya, J.; Tadarni, S.; Ukai, K. Iwasawa, N. Org. Lett. 2008,10,2697.
5. Yeung, C. S.; Dong, V. M. 1. Am. Chem. Soc. 2008,130, 7826.
6. For representative examples, see: (a) Takimoto, M.; Mizuno, T.; Mori, M.;
Sato, Y. Tetrahedron 2006, 62, 7589. (b) Aoki, M.; Kaneko, M.; Izumi, S.;
Ukai, K.; Iwasawa, N. Chem. Commun. 2004, 2568. (c) Takimoto, M.; Mori,
M. JAm. Chem. Soc. 2001, 123, 2895.
7. (a) Shimizu, K.; Takimoto, M.; Sato, Y.; Mori, M. Org. Lett. 2005, 7, 195. (b)
Takimoto, M.; Kawamura, M.; Mori, M.; Sato, Y. Synlett 2005, 2019. Cc)
Takimoto, M.; Nakamura, Y.; Kimura, K.; Mori, M. JAm. Chem. Soc. 2004,
126,5956. (d) Takimoto, M.; Mori, M. JAm. Chem. Soc. 2002, 124, 10008.
8. Williams, C. M.; Johnson, J. B.; Rovis, T. JAm. Chem. Soc. 2008, 130,
14936.
9. For a review on coupling of epoxides and CO 2 , see:
Darensbourg, D. J.;
Holtcamp, M. W. Coord. Chem. Rev. 1996,153,155.
10. Eghbali, N.; Li, C.-J. Green Chem. 2007,9,213.
11. (a) Yamada, W.; Sugawara, Y.; Cheng, H. M.; Ikeno, T.; Yamada, T. Eur. J
Org. Chem. 2007, 2604. Cb) Kayaki, Y.; Yarnamoto, M.; Ikariya, T. J Org.
Chem. 2007, 72, 647. (c) Gu, Y.; Shi, F.; Deng, Y. J Org. Chem. 2004, 69,
391.
101 12. (a) Kayaki, Y.; Yamamoto, T.; Suzuki, T.; Ikariya, T. Green Chem. 2006, 8, 1019.
(b) Feroci, M.; Orsini, M.; Sotgiu, G.; Rossi, L.; Inesi, A. J Org. Chem. 2005, 70, 7795. (c) Shi, M.; Shen, Y.-M. J Org. Chem. 2002, 67, 16. (d) Costa, M.; Chiusoli, G. P.; Rizzardi, M. Chem. Commun. 1996, 1699. (e) Mitsudo, T.; Hori, Y.; Yamakawa, Y.; Watanabe, Y. Tetrahedron Let!. 1987, 28,4417. 13. Inoue, Y.; Itoh, Y.; Kazama, H.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1980, 53,3329. 14. (a) Behr, A.; Brehme, V. A. J Mol. Catal. A: Chem. 2002, 187,69. (b) Behr,
A.; Jusazk, K. D. J Organomet. Chem. 1983,255, 263.
15. Tsuda, T.; Yamamoto, T.; Saegusa, T. J Organomet. Chem. 1992,429,46.
16. (a) Takavec, T. N.; Arif, A. M.; Louie, J. Tetrahedron 2004,60,7431. (b) Louie, J.; Gibby, J. E.; Famworth, M. V.; Tekavec, T. N. JAm. Chem. Soc. 2002, 124, 15188. (c) Tsuda, T.; Maruta, K.; Kitaike, Y. JAm. Chem. Soc. 1992,114, 1498. 17. Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. JAm. Chem. Soc. 2006, 128, 11040. 18. Yoshida, H.; Takami, M.; Ohshita, J. Org. Lett. 2008,10,3845.
102 Chapter 8 - Copper-Catalyzed Four-Component Coupling between
Aldehydes, Amines, Alkynes, and C02
As illustrate in chapter 7, there has been increased attention to the use of
carbon dioxide gas as an inexpensive Cl feedstock.
In this chapter, the
development of a copper-catalyzed four-component coupling between aldehydes,
amines, alkynes and carbon dioxide will be discussed.
8.1 - Background
One method in which carbon dioxide has been utilized as a substrate is
through the carboxylative cyclization of propargylic amines to generate
oxazolidinones (Scheme 69).
Scheme 69. Carboxylative Cyclization of Propargylic Amines.
While a variety of protocols have been reported, these methods are often
limited by the use of high carbon dioxide pressure and/or restricted to propargyl
amines that bear terminal alkynes.
A simple and effective entry into propargylic amines is through a three­
component coupling reaction between alkynes, aldehydes, and amines (we termed
as A3-coupling) (Scheme 70). I
Scheme 70. Propargyl Amine Synthesis through the A3-Coupling Reaction.
103 Recently, a variety of research groups including ourselves, have
demonstrated that various metal salts and organometallic complexes can catalyze
the A3 -coupling reaction to generate the corresponding propargyl amines in good
yields. As a natural extension into the A 3 -coupling reaction, our group has begun
to explore the possibility of incorporating the A 3 -coupling reaction into tandem
processes. With respect to this goal, a five-component double A 3-coupling2 and
six-component double A 3-couplingl[2+2+2] cyc1oaddition reaction was recently
reported (Scheme 71).3
cat. RuCI 3 , cat. CuBr
/r------===--R 2
- - - - ' - - - - - - . RLN
H20, rt
\'------===--R2
Scheme 71. A3-Coupling in Multi-component Tandem Reactions.
With our group's earlier success in multi-component tandem reactions, we
looked towards developing a tandem A 3 -coupling and a carboxylative cyc1ization
reaction through the four-component coupling of alkynes, aldehydes, amines, and
carbon dioxide gas.
8.2 - Optimization of Reaction Conditions
Preliminary attempts began with the CuBr/RuCh-catalyzed A3-coupling of
phenyl acetylene, benzaldehyde, and aniline under atmospheric and high pressure
CO2 (750 psi).4 However, in both cases, only the propargyl amine was formed.
These results suggested that either CuBr and RuCh does not catalyze the
cyc1ization step or the carbon dioxide does not bind well to the aromatic
propargylic amine. Thus, a more basic amine, such as butylamine was utilized
with the understanding that it would provide a propargyl amine that would bind
well to the carbon dioxide. Although it had not been well established if aliphatic
104 ammes are viable substrates for the A3-coupling reaction, the tandem A3_
coupling/carboxylative cyclization was nevertheless attempted (Table 21).
Table 21. Optimization of the Four-Component Coupling between Alkyne 122a,
Aldehyde 90a, Amine 123a, and C02.a
o
Ph
=
Ph-CHO
+
122a
90a
+
catalyst
n
Bu-NH 2 123a
nBUNAo
Ph~Ph
CO 2 (1 atm), solvent, 65°C 124a
Entry
1
2
3
4
5
6
7
8
9
10
11<1
12<1
Catalyst
RuChe, CuBr
CuBr
CuCI
CuI
CuSCN
CuBr2
CuI
CuI
CuI
CuI
CuI
CuI
Solvent
Yield b (%)
41
38
34
86
6
37
THF
H2O
EtOAc
EtOH
EtOAc
EtOH
59
62
80
78
78
89
• Alkyne 122a (0.89 111mol), aldehyde 90a (1.8 111mol), amme 123a (1.8 mmo1)
and copper salt (0.29 111mol) in solvent (0.18 111L) with CO 2 (1 atm).
b Determined by IH NMR using mesitylene as an internal standard.
c RuCl 3 (0.027 11111101)
d750C.
The initial reaction between alkyne 122a, aromatic aldehyde 90a, and
aliphatic amine 123a provided the desired oxazolidinone 124a with a modest
yield (entry 1). It was determined that RuCh was not an essential co-catalyst for
the successful synthesis of the desired product 124a.
In fact, this was quite
surprising since in the original A3-coupling involving aromatic amines, RuCh
provided a substantial increase in yield (60%) for the propargyl aromatic amine
when used as a co-catalyst with CuBr. Screening various copper salts revealed
CuI to be an excellent catalyst for the four-component coupling reaction (entry 3­
6). Although the reaction proceeded well under solvent-free conditions, a solvent
105 was deemed a necessity since some starting materials and products generated
from the tandem A 3 -coupling/carboxylative cyclization reaction would be solids.
While most solvents decreased the yield, EtOAc and EtOH were found to be the
best solvents (entry 7-10). Finally, increasing the reaction temperature slightly
improved the yield of the reaction when EtOH was used as the solvent (entry 12).
8.3 - Scope of the Copper-Catalyzed Four-Component Coupling Reaction of
Alkynes, Aldehydes, Amines, and C02
With the optimized reaction conditions, the scope of the four-component
tandem A 3 -coupling/carboxylative cyclization reaction was examined (Table 22).
Table 22. Scope of the Copper-Catalyzed Four-Component Coupling between Alkyne, Aldehyde, Amine, and CO2.a o
R1
•
=
+
122a-d
RLCHO +
90a, d, f,
cat. Cui
RLNH2 123a-c
CO 2 (1 atm), EtOH, 75°C
h, j-k
R3
'N
)(
0
\...-.-1.,
R2 ~R1
124a-k
Entry
Rl
RL
RJ
Product
Yieldo
(%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-C 6H4
4-MeO-C I OH6
hexyl
Ph
4-Me-C 6H4
4-NMe2-C 6H4
4-CN-C 6H4
4-Br-C 6H4
pentyl
Ph
Ph
Ph
Ph
Ph
nBu
nBu
nBu
nBu
nBu
nBu
CH2CH2Bn
allyl
nBu
nBu
nBu
124a
124b
124c
124d
124e
124f
124g
124h
124i
124j
124k
85
78
55
38
2
3
4
5
6
7
8
9
10
11
71
56
58
70
91
58
0
Alkyne 122a-d (1 eqUlv.), aldehyde 90a, d, C, h, j-k (2.0 eqUlv.), amme 123a-c (2.0 eqUlv.),
and CuI (30 mol%) in EtOH (0.18 mL) with CO 2 (1 atm).
b Isolated yields were based on the alkyne.
a
The scope was examined by first looking at the effect of varying the
aldehyde component of the reaction (entries 1-6). In general, it appears that the
106
four-component coupling reaction is very sensitive to the electronic properties of
the aldehyde.
Deviation from the phenyl substituent to more electron-rich or
electron-poor aromatic aldehyde decreased the yield. Aliphatic aldehydes such as
hexanal was also found to be a viable substrate and provided the desired
oxazolidinone in modest yield.
Next, the amine component was examined
(entries 7-8). Basic primary amines were good substrates, but once again, varying
the substrate from the optimized reaction conditions to other types of aliphatic
amines proved to diminish the yield.
Finally, the alkyne component of the
tandem reaction was examined (entries 9-11). When aromatic alkynes were used
as substrates, the corresponding oxazolidinones were obtained.
aliphatic alkynes were poor substrates.
However,
This was somewhat expected since
aliphatic alkynes are rarely utilized as a coupling partner in the A3-coupling
reactions. 5
8.4 - Proposed Reaction Mechanism
The four-component, tandem A3-coupling/carboxylative cyclization of
alkynes, aldehydes, amines, and carbon dioxide is believed to proceed through the
reaction pathway shown in Scheme 72.
The reaction is believed to begin by the initial formation of copper
acetylene 125, which then adds to imine 126 to generate the A3 -coupling product
127. The propargyl amine 127 then adds to carbon dioxide to form intermediate
128. The copper catalyst is believed to coordinate to the acetylene bond of 128 to
facilitate the intramolecular addition of the carbamate on to the n-bond to form
129. Protonolysis of the copper-carbon bond leads to the desired oxazolidinone
124a and regenerates the copper catalyst.
To confirm the reaction pathway for the four-components coupling
reaction, the tandem reaction was performed in separate stages.
Under the
optimized reaction conditions excluding carbon dioxide, the expected propargyl
amine 127 was synthesized with a moderate yield of 63% (isolated yield of 55%).
107 Subsequently, the A 3-coupling product 127 was subjected to the optimized
reaction conditions to furnish oxazolidinone 124a with a IH NMR yield of 48%.
However, when amine 123a was introduced with the propargyl amine 127, the
cyclization was achieved with a high yield (Scheme 73).
=
Ph
1220
Ph-CHO
90a
n
+ Bu-NH 2
123a
BUjt
n
Ph
l
r
[Cui
0
Bu, ~
n
Ph~Ph
[Cui
129
125
~[Cu]
H
126
124a
CO 2 + [Cui
nB
u'NH
~
Ph~
-----"'----.
Ph
nB
)l0
u'N
OH
Ph~~
[CuI' 'Ph
127
128
Scheme 72. Proposed Reaction Mechanism of the Copper-Catalyzed Four­
Component Coupling Reaction.
From these results, it appears that a symbiotic relationship exists between
the amine and carbon dioxide. For the one-pot tandem A 3 -coupling/carboxylative
cyclization reaction, heterocycle 124a was obtained with a yield of 85%, which
translates to an average of 92% per step. Thus, it appears that CO 2 promotes the
A3-coupling reaction. A potential reason to explain the poor performance of the
A3-coupling reaction with aliphatic amines is that the electron-rich amine may
coordinatively saturate the copper salt.
However, in the presence of carbon
dioxide, the amine would likely react with carbon dioxide to form carbamic acid
that ultimately reduces the amount of free amine in solution and free up the
copper catalyst.
Conversely, the formation of the carbamic acid essentially
increases the effective concentration of carbon dioxide in solution and aids in the
carboxylative cyclization step.
108
NH'Bu
Ph
=
122a
+
Ph-CHO + nBu-NH2
90a
cat. Cui
Ph~
123a
Ph
127
(63%)
cat. Cui
CO 2 (1 atm), EtOH
75°C
o
nBUNA O
Ph~Ph 124a
without 123a (48%)
with 123a (100%)
Scheme 73. Stepwise Synthesis of Oxazolidinone 124a.
8.5 - Conclusion
In summary, a facile synthesis of oxazolidinones bearing exocyclic
alkenes was demonstrated through a copper-catalyzed four-component coupling
between alkynes, aldehydes, amines, and carbon dioxide under atmospheric
pressure. Carbon dioxide appears to be an important substrate for the success of
the A3-coupling reaction, while the excess amine present in the reaction was
found to play an important role in facilitating the carboxylative cyclization step.
8.6 - Experimental Section
General Information Relating to All Experimental Procedures
All reactions were carried out in an atmosphere of carbon dioxide at
ambient temperature unless otherwise stated. Standard column chromatography
was performed on 20-60 /lm silica gel (obtained from Silicycle Inc.) using
109 standard flash column chromatography techniques. Infrared analyses were
recorded as a thin film on NaCl plates and solid compounds as KBr pellets. 'H
and
l3 C
NMR spectra were recorded on a 400 MHz NMR spectrometer.
Chemical shifts for IH NMR spectra were reported in parts per million (ppm)
from tetramethylsilane with the solvent resonance as the internal standard
(chloroform: 07.26 ppm). Chemical shifts for I3C NMR spectra were reported in
parts per million (ppm) from tetramethylsilane with the solvent as the internal
standard (deuterated chloroform: 077.0 ppm). All reagents purchased were used
without further purification.
o
Ph
=
+
122a
Ph-CHO
90a
+
n
Bu-NH 2
123a
cat. Cui
11
- - - - - - - _ nBuNA O
\......1
CO 2 (1 atm), EtOH, 75°C
ptf
~Ph
124a
General Procedure for the Copper-Catalyzed Coupling between Aldehydes,
Amines, Alkynes, and C02. In a sealable test-tube equipped with a magnetic stir
bar was charged with CuI (51.0 mg, 0.268 mmol). The reaction vessel was sealed
and flushed with CO2. The tube was attached with a balloon of C02 and charged
with EtOH (0.18 mL), aldehyde 90a (0.18 mL, 1.8 mmol), and amine 123a (0.18
mL, 1.8 mmol).
The reaction mixture was allowed to stir slowly at room
temperature for approximately 30 sec. (caution: reaction is slightly exothermic
and will release C02) and then alkyne 122a (0.100 mL, 0.892 mmol) was added.
The test-tube was placed in an oil bath set at 75°C and was allowed to stir
overnight. The reaction mixture was allowed to cool to room temperature and
was placed through a plug of silica gel. The crude reaction mixture was further
purified by silica gel column chromatography (EtOAc:hexane
=
1:9) to provide
the desired oxazolidinone 124a (235.8 mg, 0.767 mmol, 85%) as a pale yellow
solid (m.p. = 99-100°C).
(Z)-5-Benzylidene-3-butyl-4-phenyloxazolidin-2-one (124a) (Table 22, entry
1). Rf = 0.27 (EtOAc:hexane = 1:9); IR (KBr): 2956 (m), 2929 (m), 1781 (s),
1689 (s), 1458 (m), 1415 (m), 1313 (m), 1103 (m), 1048 (s), 1002 (m), 941 (m)
110 765 (m) cm-I; IH NMR (CDCi), 400 MHz, ppm): 0
=
7.54-7.52 (m, 2H), 7.46­
7.39 (m, 3H), 7.35-7.26 (m, 4H), 7.20-7.17 (m, IH), 5.38 (d, IH, J= 2.0 Hz), 5.26
(d, IH, J= 2.0 Hz), 3.52 (td, IH, J= 14.1,7.8 Hz), 2.83 (td, IH, J= 14.1,6.3 Hz),
1.50-1.42 (m, 2H), 1.34-1.24 (m, 2H), 0.89 (t, 3H, J= 7.4 Hz); BC NMR (CDCh,
100 MHz, ppm): 0 = 154.9, 147.6, 137.2, 133.3, 129.21, 129.17, 128.3, 128.2,
127.7, 126.8, 104.3, 63.7, 41.4, 28.8, 19.6, 13.5; HRMS (El): calculated for
C2oH2IN02Na: [M+·]
=
330.4675 mlz; found: [M+·]
o
Ph
=
~H+
+
)l)
122a
=
cat. Cui
n
Bu-NH 2
330.1465 m/z.
•
CO 2 (1 atm), EtOH
75°C
123a
90f
124b
(Z)-5-Benzylidene-3-butyl-4-tolyloxazolidin-2-one (124b) (Table 22, entry 2).
•
Following the above general procedure with alkyne 122a (0.100 mL, 0.892
mmol), aldehyde 90f (0.21 mL, 1.78 mmol), and amine 123a (0.18 mL, 1.8
mmol). The crude reaction mixture was filtered through a plug of silica and then
further purified by column chromatography (EtOAc:hexane
=
1:9) to provide
124b (224.8 mg, 0.699 mmol, 78%) as a pale yellow oil.
(EtOAc:hexane
=
Rf
=
0.27
1:9); IR (neat, NaCl): 3056 (w), 2932 (s), 2873 (m), 1783 (s),
1692 (s), 1495 (m), 1413 (s), 1309 (m), 1245 (m), 1098 (m) cm-I; IH NMR
(CDCh, 400 MHz, ppm): ()
=
7.54-7.52 (m, 2H), 7.31-7.16 (m, 7H), 5.35 (d, IH,
J= 2.0 Hz), 5.25 (d, IH, J= 2.0 Hz), 3.50 (td, IH, J= 14.1,7.8 Hz), 2.82 (td, IH,
J= 14.5, 7.4 Hz), 2.38 (s, 3H), 1.50-1.42 (m, 2H), 1.33-1.24 (m, 2H), 0.90 (t, 3H,
J= 7.0 Hz);
l3 C
NMR (CDCh, 100 MHz, ppm): 0 = 154.8, 147.8, 139.1, 134.1,
133.4,129.8,128.2,128.1,127.6,126.6,104.1,63.4, 41.3, 28.7, 21.1,19.6,13.5;
HRMS (El): calculated for C21H23N02Na: [M+·]
= 344.1621 mlz.
111 =
334.1623 mlz; found: [M+e]
cat.Cul
Ph
n
=
Bu-NH2 CO 2 (1 atm), EtOH
75°C
123a
90j
122a
124c
(Z)-5-Benzylidene-3-butyl-4-(4-( dim ethylamino )phenyl)oxazolidin-2-one
(124c) (Table 22, entry 3). Following the above general procedure with alkyne
122a (0.100 mL, 0.892 mmol), aldehyde 90j (266.3 mg, 1.8 mmol), and amine
123a (0.18 mL, 1.8 mmol). The crude reaction mixture was filtered through a
plug of silica and
then further
purified
by
column
chromatography
(EtOAc:hexane = 1:4) to provide 124c (171.8 mg, 0.490 mmol, 55%) as a pale
yellow solid (m.p. = 107-108°C). Rf = 0.32 (EtOAc:hexane = 1:4); IR (KBr):
3022 (w), 2959 (m), 2871 (m), 1770 (s), 1687 (s), 1615 (m), 1526 (m), 1420 (m),
1360 (m), 1185 (m), 1045 (s), 813 (s) cm-I; IH NMR (CDCI), 400 MHz, ppm): 8
•
= 7.55-7.53 (m, 2H), 7.31-7.27 (m, 2H), 7.19-7.16 (m, 3H), 6.73-6.71 (m,2H),
5.31 (s, IH), 5.27 (s, IH), 3.47 (td, IH, J= 14.1, 7.8 Hz), 2.98 (s, 6H), 2.83 (td,
IH, J= 14.5,7.0 Hz), 1.50-1.43 (m, 2H), 1.35-1.21 (m, 2H), 0.90 (t, 3H, J= 7.0
Hz); 13C NMR (CDCI), 100 MHz, ppm): 8 = 154.8, 150.8, 148.6, l33.7, 128.8,
128.2, 128.1, 126.5, 123.8, 112.3, 103.8,63.4,41.2,40.2,28.8, 19.7, l3.5; HRMS
calculated for C22H27N202:
(El):
[M+e ]
=
351.2062 mlz; found:
[M+ e ]
=
351.2067 mlz.
o
Ph
=
+
~H+
cat. Cui
nBu-NH2
CO 2 (1 atm), EtOH
75°C
NCJl)
122a
90h
123a
124d
(Z)-4-(5-Benzylidene-3-butyl-2-oxooxazolidin-4-yl)benzonitrile (124d) (Table
22, entry 4). Following the above general procedure with alkyne 122a (0.100
mL, 0.892 mmol), aldehyde 90h (234.1 mg, 1.78 mmol), and amine 123a (0.18
mL, 1.8 mmol). The crude reaction mixture was filtered through a plug of silica
112 and then further purified by column chromatography (EtOAc:hexane = 1:4) to
provide 124d (112.2 mg, 0.338 mmol, 38%) as a pale yellow oil. Rf
0.23
=
(EtOAc:hexane = 1:4); IR (neat, NaCI): 3059 (w), 2933 (s), 2874 (m), 2230 (s),
1785 (s), 1609 (m), 1502 (m), 1449 (s), 1410 (s), 1244 (s), 1202 (m) cm-I; IH
NMR (CDCh, 400 MHz, ppm):
(5 =
7.76-7.74 (m, 2H), 7.49-7.7.45 (m, 4H),
7.30-7.25 (m, 2H), 7.20-7.17 (m, IH), 5.44 (s, IH), 5.22 (s, IH), 3.53 (td, IH, J =
14.5, 7.8 Hz), 2.73 (td, IH, J = 14.1, 7.4 Hz), 1.48-1.33 (m, 2H), 1.31-1.22 (m,
2H), 0.88 (t, 3H, J
=
7.4 Hz); l3C NMR (CDCb, 100 MHz, ppm):
= 154.7,
(5
146.1, 142.4, 133.1, 132.8, 128.4, 128.3, 128.2, 127.2, 117.9, 113.2, 105.2, 63.0,
41.8, 28.8, 19.6, 13.4; HRMS (El):
355.1418 m/z; found: [M+·]
=
calculated for C21H20N202Na:
[M+·]
=
355.1417 m/z.
o
0
Ph
=
+
Br
122a
ffH
nBUNAo
cat. Cui
+
n
Bu-NH 2
~
CO, (1 aIm), EIOH'
75°C
123a
90k
~Ph
Y
Br
124e
(Z)-5-Benzylidene-4-(4-bromophenyl)-3-butyloxazolidin-2-one (124e) (Table
22, entry 5). Following the above general procedure with alkyne 122a (0.100
mL, 0.892 mmol), aldehyde 90k (330.3 mg, 1.78 mmol), and amine 123a (0.18
mL, 1.8 mmol). The crude reaction mixture was filtered through a plug of silica
and then further purified by column chromatography (EtOAc:hexane
provide 124e (244.7 mg, 0.633 mmol, 71%) as a pale yellow oil.
=
Rf
I :9) to
=
0.20
(EtOAc:hexane = 1:9); IR (neat, NaCl): 3059 (w), 2932 (s), 2873 (m), 1780 (s),
1692 (s), 1592 (m), 1489 (s), 1417 (s), 1309 (s), 1201 (m), 1097 (m) cm-I; IH
NMR (CDCh, 400 MHz, ppm):
(5 =
7.57-7.50 (m, 4H), 7.31-7.17 (m, 5H), 5.34
(s, IH), 5.23 (s, IH), 3.50 (td, IH, J = 14.1, 7.8 Hz), 2.81 (td, IH, J = 14.5, 7.4
Hz), 1.48-1.39 (m, 2H), 1.37-1.23 (m, 2H), 0.89 (t, 3H, J
(CDCh, 100 MHz, ppm):
(5 =
=
7.0 Hz); l3C NMR
154.7, 147.0, 136.2, 133.1, 132.4, 129.3, 128.3,
128.2, 126.9, 123.3, 104.6, 63.0, 41.5, 28.7, 19.6, 13.5; HRMS (El): calculated
for C2oH20N02BrNa: [M+·]
=
408.05702 mlz; found: [M+·]
113 =
408.05696 mlz.
Ph
=
o
+~H
cat. Cui
n
+ Bu-NH 2
75°C
123a
90d
122a
CO 2 (1 atm), EtOH
124f
(Z)-5-Benzylidene-3-butyl-4-pentyloxazolidin-2-one (124f) (Table 22, entry
6). Following the above general procedure with alkyne 122a (0.100 mL, 0.892
mmol), aldehyde 90d (0.22 mL, 1.78 mmol), and amine 123a (0.18 mL, 1.8
mmol). The crude reaction mixture was filtered through a plug of silica and then
further purified by column chromatography (EtOAc:hexane = 1:4) to provide 124f
(149.3 mg, 0.495 mmol, 56%) as a pale yellow oil. Rf = 0.51 (EtOAc:hexane =
1:4); IR (neat, NaCI): 3058 (w), 2933 (s), 2863 (s), 1783 (s), 1692 (s), 1496 (m),
1422 (s), 1329 (m), 1246 (m), 1112 (m) cm-I; IH NMR (CDCh, 400 MHz, ppm):
8
=
7.59 (d, 2H, J= 7.4 Hz), 7.32 (t, 2H, J= 7.4 Hz), 7.19 (t, IH, J= 7.4 Hz),
5.47 (s, IH), 4.52 (s, IH), 3.59 (td, IH, J= 14.5,7.4 Hz), 3.04-2.97 (m, IH), 1.89­
1.83 (m, IH), 1.71-1.47 (m, 3H), 1.41-1.20 (m, 8H), 0.95 (t, 3H, J= 7.0 Hz), 0.87
(t, 3H, J= 7.0 Hz);
13 C
NMR (CDCh, 100 MHz, ppm): 8
=
155.1, 146.9, 133.5,
128.3, 128.1, 126.6, 102.1, 58.3, 40.9, 31.9, 31.4, 29.1, 22.3, 21.8, 19.8, 13.8,
13.5; HRMS (El):
calculated for C19H28N02:
[M+e]
=
302.2112 mlz; found:
[M+e] = 302.2115 m/z.
cat. Cui
Ph
=
+
CO 2 (1 atm), EtOH
75°C
122a
90a
o
~N)(O
Ph
123b
\J..-J
Pt!
~Ph
1249
(Z)-5-Benzylidene-4-phenyl-3-(3-phenylpropyl)oxazolidin-2-one
(124g)
(Table 22, entry 7). Following the above general procedure with alkyne 122a
(0.100 mL, 0.892 mmol), aldehyde 90a (0.18 mL, 1.8 mmol), and amine 123b
(0.25 mL, 1.8 mmol). The crude reaction mixture was filtered through a plug of
silica and then further purified by column chromatography (EtOAc:hexane
to provide 124g (187.2 mg, 0.507 mmol, 58%) as a pale yellow solid (m.p.
114 =
=
1:4)
68­
70°C). Rf = 0.35 (EtOAc:hexane = 1:4); IR (KBr): 3027 (m), 2928 (m), 1788 (s),
1701 (m), 1685 (m), 1560 (m), 1458 (m), 1063 (m), 945 (m), 750 (m) cm-I; IH
NMR (CDCh, 400 MHz, ppm): 8 = 7.53-7.51 (m, 2H), 7.43-7.41 (m, 3H), 7.32­
7.24 (m, 6H), 7.21-7.19 (m, 2H), 7.17-7.10 (m, 2H), 5.32 (d, 1H, J = 2.0 Hz), 5.24
(d, 1H, J
=
2.0 Hz), 3.53 (td, 1H, J
=
14.1, 7.8 Hz), 2.95-2.89 (m, 1H), 2.58 (dt,
2H, J= 7.8, 3.9 Hz), 1.85-1.76 (m, 2H);
l3 C
NMR (CDCh, 100 MHz, ppm): 8 =
154.9, 147.5, 140.8, 137.1, 133.3, 129.34, 129.27, 128.40, 128.37, 128.3, 128.1,
127.8, 126.9, 126.0, 104.6, 63.9, 41.6, 32.8, 28.4; HRMS (El): calculated for
C2sH23N02Na: [M+e]
Ph
=
=
392.1625 mlz; found: [M+e]
=
cat. Cui
+
392.1621 m/z.
.
CO 2 (1 atm). EtOH
75°C
123c
90a
122a
124h
(Z)-3-AlIyl-5-benzylidene-4-phenyloxazolidin-2-one (124h) (Table 22, entry
8). Following the above general procedure with alkyne 122a (0.100 mL, 0.892
mmol), aldehyde 90a (0.18 mL, 1.8 mmol), and amine 123c (0.13 mL, 1.8 mmol).
The crude reaction mixture was filtered through a plug of silica and then further
purified by column chromatography (EtOAc:hexane
=
1:4) to provide 124h
(182.4 mg, 0.626 mmol, 70%) as a pale yellow solid (m.p. = 94-95°C). Rf = 0.39
(EtOAc:hexane
=
1:4); IR (KBr): 3088 (w), 2980 (w), 1782 (s), 1691 (s), 1495
(m), 1438 (m), 1405 (s), 1349 (m), 1241 (m), 1057 (m), 929 (m) cm-I; IH NMR
(CDCh, 400 MHz, ppm): 8
=
7.55-7.53 (m, 2H), 7.46-7.39 (m, 3H), 7.34-7.28
(m, 4H), 7.22-7.17 (m, 1H), 5.78-5.68 (m, 1H), 5.39 (d, 1H, J
=
2.0 Hz), 5.33 (d,
1H, J= 2.0 Hz), 5.26-5.22 (m, IH), 5.14-5.09 (m, IH), 4.29-4.23 (m, 1H), 3.32­
3.26 (m, IH); l3C NMR (CDCh, 100 MHz, ppm): 8 = 154.6, 147.4, 136.8, 133.2,
130.7,129.2,129.1,128.3,128.2,127.8,126.8,119.4, 104.6,63.0,44.1; HRMS
(El): calculated for CI9HISN02: [M+e]
=
292.1333 mlz; found: [M+e]
mlz.
115 =
292.1332
o
cat. Cui
n
122b
Bu-NH 2
- - - - - - - . nBuN
cO 2 (1 atm), EtOH
75°C
A0
K
pt{
F\_
~
123a
90a
124i
(Z)-5-( 4-Methylbenzylidene)-3-butyl-4-phenyloxazolidin-2-one (124i) (Table
22, entry 9). Following the above general procedure with alkyne 122b (0.100
mL, 0.765 mmol), aldehyde 90a (0.16 mL, 1.5 mmol), and amine 123a (0.15 mL,
1.5 mmol). The crude reaction mixture was filtered through a plug of silica and
then further purified by column chromatography (EtOAc:hexane
=
1:4) to provide
124i (224.4 mg, 0.698 mmol, 91 %) as a pale yellow solid (m.p. = 119-120°C). Rf
=
0.49 (EtOAc:hexane
=
1:4); IR (KBr): 3030 (w), 2960 (m), 1780 (s), 1684 (s),
1513 (m), 1458 (m), 1410 (s), 1310 (s), 1102 (m), 1046 (s) cm-I; IH NMR
(CDCh, 400 MHz, ppm): cS
=
7.46-7.32 (m, 7H), 7.12-7.10 (m, 2H), 5.37 (d, IH,
J= 1.6 Hz), 5.23 (d, IH, J= 2.0 Hz), 3.50 (td, IH, J= 14.1, 7.8 Hz), 2.83 (td, IH,
J= 14.1, 7.4 Hz), 2.32 (s, 3H), 1.50-1.38 (m, 2H), 1.35-1.21 (m, 2H), 0.89 (t, 3H,
J= 7.0 Hz);
l3 C
NMR (CDCh, 100 MHz, ppm): cS
=
155.0, 146.8, 137.3, 136.6,
130.5, 129.2, 129.1, 129.0, 128.1, 127.7, 104.3,63.7,41.5,28.8,21.1, 19.7, 13.5;
HRMS (El): calculated for C21H24N02: [M+e]
=
322.1803 mlz; found: [M+e]
=
322.1802 m/z.
MeO
~
~ f ~ _ +
_
-
Ph
Jl
90a
122c
cat. Cui
+ nBu-NH2 CO 2 (1 aIm), EtOH
H
750C
123a
124j
(Z)-3-Butyl-5-«6-methoxylnaphthalene-2-yl)methylene)-4-phenyloxazolidin­
2-one (124j) (Table 22, entry 10). Following the above general procedure with
alkyne 122c (170.0 mg, 0.9156 mmol), aldehyde 90a (0.19 mL, 1.8 mmol), and
amine 123a (0.18 mL, 1.8 mmol).
The crude reaction mixture was filtered
through a plug of silica and then further purified by column chromatography
•
(EtOAc:hexane
=
1:4) to provide 124j (205.2 mg, 0.530 mmol, 58%) as a white
solid (m.p. = 148-150°C). Rf = 0.32 (EtOAc:hexane = 1:4); IR (KBr): 2931 (m),
116 2870 (w), 1763 (s), 1685 (m), 1603 (w), 1427 (m), 1272 (m), 1239 (m), 1101 (m),
1028 (m), 859 (m) cm-I; IH NMR (CD Ch, 400 MHz, ppm): 0
7.85 (s, IH),
=
7.72-7.65 (m, 3H), 7.44-7.40 (m, 5H), 7.13-7.08 (m, 2H), 5.39 (s, 1H), 5.37 (s,
1H), 3.89 (s, 3H), 3.53 (td, 1H, J= 14.1, 7.4 Hz), 2.84 (td, 1H, J= 14.5, 7.0 Hz),
1.50-1.43 (m, 2H), 1.35-1.25 (m, 2H), 0.90 (t, 3H, J= 7.4 Hz);
100 MHz, ppm): 0
=
l3 C
NMR (CDCh,
157.6, 155.1, 147.2, 137.3, 133.3, 129.5, 129.2, 128.85,
128.79, 127.7, 127.0, 126.9, 126.7, 118.9, 105.5, 104.6, 63.8, 55.2, 41.5, 28.8,
19.7, 13.5 (one missing carbon peak due to overlaps in the aromatic region);
HRMS (El): calculated for C2sH26N03: [M+e]
=
388.1911 mlz; found: [M+e]
=
388.1907 mlz.
NH'Bu
Ph
=
122a
+
Ph-GH~
cat.Gul
+ Bu-'NH 2 - - - -
EtOH, 75°G
~
Ph
~
~
Ph
123a
90a
127
In a sealable test-tube equipped with a magnetic stir bar was charged CuI (51.0
mg, 0.268 mmol). The reaction vessel was sealed and flushed with N2. The test­
tube was charged with EtOH (0.18 mL), aldehyde 90a (0.18 mL, 1.8 mmol), and
amine 123a (0.18 mL, 1.8 mmol). The reaction mixture was allowed to stir at
room temperature for approximately 30 sec. and then alkyne 122a (0.100 mL,
0.892 mmol) was added. The test-tube was placed in an oil bath set at 75°C and
was allowed to stir overnight. The reaction mixture was allowed to cool to room
temperature and was filtered through a plug of silica gel. The crude reaction
mixture was further purified by silica gel column chromatography (EtOAc:hexane
=
2:5) to provide the desired propargyl amine 127 (130.4 mg, 0.495 mmol, 55%)
as a pale yellow oil.
N-(1,3-Diphenylprop-2-ynyl)butan-1-amine (127). Rf = 0.11 (EtOAc:hexane
=
1:4); IR (neat, NaCl): 3314 (w), 3062 (m), 2929 (s), 2866 (s), 2204 (w), 1949
(w), 1805 (w), 1598 (m), 1490 (s), 1443 (s), 1273 (m), 1070 (m) cm-I; IH NMR
(CDCh, 400 MHz, ppm): ()
=
7.66-7.64 (m, 2H), 7.54-7.52 (m, 2H), 7.44-7.33
(m, 6H), 4.86 (s, 1H), 2.91 (td, 1H, J = 11.0, 7.0 Hz), 2.77 (td, 1H, J = 11.3, 6.7
Hz), 1.63-1.53 (m, 3H), 1.48-1.39 (m, 2H), 0.98 (t, 3H, J
117 =
7.4 Hz);
l3 C
NMR
(CDCh, 100 MHz, ppm): 8 = 140.5, 131.6, 128.4, 128.1, 128.0, 127.6, 127.5,
123.1, 89.5, 85.1, 54.6, 47.0, 32.0, 20.4, 13.9; HRMS (El):
CI9H22N: [M+e ] = 264.1751 mlz; found: [M+-] = 264.1747 mlz.
118 calculated for
References for Chapter 8
1. For reviews on the A3 -coupling reaction, see: (a) Wei, C.; Li, c.-J. Synlett
2004, 1472. (b) Zani, L.; Bolm, C. Chem. Cammun. 2006,4263.
2. Bonfield, E. R.; Li, C.-J. Org. Biama!. Chem. 2007,5,435.
3. Bonfield, E. R.; Li, c.-J. Adv. Synth. Catal. 2008,350,370.
4. Li, c.-J.; Wei, C. Chem. Cammun. 2002,268.
119 Conclusions and Claims to Original Knowledge
The oxidative alkylation of cyclic benzyl ethers with malonates was
developed using a combination of catalyst: Cu(OTf)2, InCh, and NHPI. The use
of NHPI as a catalyst allowed the reaction to occur using 02 gas as the oxidant.
This represents an improvement over the original DDQ-mediated protocol by
replacing the organic oxidant with a cheap, safe, and readily available gas.
A series of oxidative esterification and amidation reactions were
developed between aldehydes and heteroatom nucleophiles using copper saIts as
catalyst and THBP as an oxidant. The copper-catalyzed oxidative esterification of
~-dicarbonyl
substrates was to the best of our knowledge, the first of its kind and
was found to be highly stereoselective for the (Z)-enol ester. For the oxidative
esterification of aldehydes with simple a1cohols, an additional Lewis acidic co­
catalyst was required. While a variety of protocols have already been reported for
this transformation, the reaction conditions reported in this thesis represents one
of the few examples in which large excess amount of the alcohol is not required.
Finally, an oxidative amidation reaction was developed between aldehydes and
amine hydrochloride salts. This copper- and silver-catalyzed amidation reaction
was found to be very mild and required very low catalyst loading to achieve good
yields.
A copper-catalyzed four-component coupling between alkynes, aldehydes,
amines, and CO2 gas under atmospheric pressure was developed to synthesize
oxazolidinones.
This reaction was found to be very efficient and atom­
economical with water being the only by-product.
This multi-component
coupling reaction is believed to occur through a tandem A3-coupling and
carboxylative cyclization reaction.
During the course of this thesis, the following articles were published:
1. Yoo, W.-J.; Li, c.-J. J. Org. Chem. 2006, 71,6266.
2. Yoo, W.-J.; Li, c.-J. J. Am. Chem. Soc. 2006, 128, 6266.
120
3. Yoo, W.-J.; Li, c.-J. Tetrahedron Lett. 2007,48, 1033.
4. Yoo, W.-J.; Li, C.-J. Adv. Synth. Catat. 2008,350, 1503.
5. Yoo, W.-J.; Correia, C. A.; Zhang, Y.; Li, c.-J. Synlett 2009, 138. 121