Gold(I)-catalyzed, stereocontrolled enamide synthesis from primary amides and propargyl aldehydes using a tandem strategy

Article abstract of DOI:10.1021/ol503055x

A novel strategy for enamide synthesis from primary amides and propargyl aldehydes via Au(I)-catalyzed tandem amide addition and Meyer-Schuster rearrangement is described. In situ generated hemiaminals were successfully converted to the desired products u

Full text of DOI:10.1021/ol503055x

Letter
pubs.acs.org/OrgLett
Gold(I)-Catalyzed, Stereocontrolled Enamide Synthesis from Primary
Amides and Propargyl Aldehydes Using a Tandem Strategy
Sang Min Kim, Dabon Lee, and Soon Hyeok Hong*
Center for Nanoparticle Research, Institute for Basic Science (IBS), Gwanak-gu, Seoul 151-742, Republic of Korea
Department of Chemistry, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-747,
Republic of Korea
S
* Supporting Information
ABSTRACT: A novel strategy for enamide synthesis from primary amides and propargyl aldehydes via Au(I)-catalyzed tandem
amide addition and Meyer−Schuster rearrangement is described. In situ generated hemiaminals were successfully converted to
the desired products under the optimized conditions. Enamide stereochemistry was controlled simply by changing solvents and
adding a catalytic amount of acid. The developed synthetic strategy provides a new method to synthesize various β-substituted
α,β-unsaturated carbonyl compounds.
Scheme 1. Novel Synthetic Strategy for β-Substituted
α,β-Unsaturated Ketones via Tandem Nucleophilic Addition
and Meyer−Schuster Rearrangement
namides are very common organic compounds and
encompass numerous natural products and drug candidates.1
E
In addition, enamides are highly valuable synthetic intermediates
for the synthesis of chiral amines,2 heterocycles,3 and cross-
coupling reagents.4 Several synthetic methods for the preparation
of enamides have already been developed, such as the dehydration
of hemiaminals,5 condensation of compounds containing carbonyl
functional groups with amides,6 and acylation of imines;7 however,
these conventional methods require harsh reaction conditions and
provide poor stereoselective control. Recently, diverse transition
metal-catalyzed reactions have been developed utilizing Ru,8,9
Rh,8 Fe,8 Pd,10 Au,11 and Cu,12 which provide significant
advantages over traditional methods. Nevertheless, these reactions
are also limited due to difficulties in preparing the necessary
starting materials, requirement of particular reaction conditions,
and confined scope of the enamide products. Therefore, new,
simple synthetic strategies are still needed.
The Meyer−Schuster rearrangement of propargylic alcohols
is a powerful tool to make α,β-unsaturated ketones,13 allowing
for the synthesis of many β-functionalized compounds from
diverse substrates. Within the past decade, many Au(I)- and
Au(III)-catalyzed Meyer−Schuster rearrangement reactions
have been developed.14 However, the propargylic alcohols are
mostly confined to alkyl or aryl substitution at the propargylic
position. Applying this reaction to the more inherently unstable
substrates with a carbon-heteroatom bond at the propargylic
position, such as propargylic hemiaminal, would significantly
extend the synthetic possibilities. To overcome the limitation,
we envisioned the use of in situ generation of heteroatom-
substituted propargylic alcohols from readily available nucleo-
philes and propargyl aldehydes (Scheme 1). In this regard,
Received: October 18, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Amide Substrate Scope
b
yield
solvent (%) Z/E
b
entry
catalyst
additive
1
2
3
4
5
6
7
8
9
AuCl3
AuCl
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
DMF
19
29
40
44
56
55
69
71
56
43
38
29
89
5.6
5.4
4.8
4.8
4.7
5.2
4.9
6.6
5.7
5.7
AuCl/AgOTf
(IPr)AuCl/AgOTf
Ph3PAuCl/AgOTf
BrettPhosAuCl/AgOTf
LAuCl/AgOTf
LAuCl/AgOTs
LAuCl/AgBF4
10 LAuNTf2
11 LAuCl/AgOTf
12 LAuCl/AgOTf
19
0.7
4.9
c
13 LAuCl/AgOTf
1.0 equiv of H2O and THF
0.5 equiv of EtOH
c
14 LAuCl/AgOTs
1.0 equiv of H2O and THF
0.5 equiv of EtOH
85
5.0
a
Reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2a (0.25 mmol,
b
1.0 equiv), catalyst (5 mol %), solvent (0.5 mL), 24 h. Yield of
isomeric mixtures and Z/E ratio determined by H NMR. Mesitylene
was used as an internal standard. 2a (0.30 mmol, 1.2 equiv) was used.
1
c
a
Reaction conditions: (step 1) 1 (0.25 mmol, 1.0 equiv), 2a (0.30 mmol,
1.2 equiv), LAuCl (0.0125 mmol, 5 mol %), AgOTf (0.0125 mmol,
5 mol %), H2O (0.25 mmol, 1.0 equiv), EtOH (0.125 mmol, 0.5 equiv),
THF (0.5 mL), 75 °C, 24 h; (step 2) 4 M HCl in dioxane
(0.0125 mmol, 5 mol %), DCM (0.5 mL), room temperature, 40 min.
b
c
Isolated yield. 2a (0.50 mmol, 2.0 equiv) was used.
Table 2. Stereocontrolled Isomerization of Enamides
also can mediate the Meyer−Schuster rearrangement of
propargylic alcohols.14
A model reaction between benzamide (1a) and 2-octynal
(2a) was first used to determine the required catalytic
conditions (Table 1), beginning by determining the ideal Au
catalyst. The simpler Au(I) and Au(III) chloride catalysts
showed low activity (entries 1 and 2), while the addition of
AgOTf increased the yield slightly to 40% (entry 3). While the
N-heterocyclic carbene (NHC)-based Au catalyst (IPr)AuCl
did not result in a meaningful improvement in yield (entry 4),
Ph3PAuCl showed significantly greater activity, producing the
enamide in 56% yield (entry 5). This result suggested that
phosphine-based Au complexes might provide the best results;
testing of several of these catalysts identified Me4-t-
BuXPhosAuCl (LAuCl) as the best candidate (entries 6 and 7).
Further testing of the Ag additive confirmed triflate and tosylate
to be the best counterions (entries 7−10). Meanwhile, solvent
testing revealed that THF gave the highest yields (entries 7, 11,
and 12). Interestingly, decreasing solvent polarity increased the
Z/E ratio of the product; while DCM yielded the highest ratio
of 19 (entry 11), DMF gave the E-enamide as the major isomer
(entry 12). Water and ethanol additives increased the yield to
89%, an observation that is consistent with previous results;14
because AgOTf gave a slightly better yield than AgOTs under
a
entry
solvent
Z/E
1
2
3
4
5
6
DCM
THF
19:1
5:1
MeOH
DMA
DMF
1.1:1
1:1.3
1:1.5
1:8.6
DMSO
1
a
Z/E ratio was determined by H NMR.
the rearrangement of propargylic hemiaminals synthesized
from primary amides and propargyl aldehydes would yield
particularly valuable enamides. Au catalysis appeared to be
most promising to achieve this goal, given that it can activate
propargyl aldehydes to yield more electrophilic species15 and
B
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Organic Letters
Letter
a,b
Next, aldehyde substrate scope was investigated with
benzamide (Scheme 3). As opposed to the amides, aliphatic
substitution gave higher yields than aryl substitution, even for
sterically hindered substrates (3aa−ad); aryl propargyl aldehydes
only gave yields up to 73% (3ae−ai). Notably, the aryl aldehyde
4-(3-oxo-1-propyn-1-yl)benzaldehyde (2i) only allowed for
reaction at the propargyl aldehyde site (3ai).
Scheme 3. Aldehyde Substrate Scope
The developed isomerization method was then applied
to obtain E-enamides from the various Z-enamides (Table 3).
a
Table 3. E-Selective Enamide Isomerization
b
entry
R
R′
E/Z
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
t-Bu
p-MeOC6H4
t-Bu
3.4
4.0
6.2
8.6
9.9
3.8
7.0
11
Ph
n-C5H11
o-FC6H4
n-C5H11
n-C5H11
n-C5H11
n-C5H11
a
p-MeOC6H4
n-C5H11
Reaction conditions: (step 1) 1a (0.25 mmol, 1.0 equiv), 2 (0.30 mmol,
1.2 equiv), LAuCl (0.0125 mmol, 5 mol %), AgOTf (0.0125 mmol,
5 mol %), H2O (0.25 mmol, 1.0 equiv), EtOH (0.125 mmol,
0.5 equiv), THF (0.5 mL), 75 °C, 24 h; (step 2) 4 M HCl in dioxane
(0.0125 mmol, 5 mol %), DCM (0.5 mL), room temperature, 40 min.
m-CF3C6H4
17
a
Reaction conditions: Z-enamide (1.0 equiv), 4 M HCl in dioxane
(10 mol %), DMSO (0.5 mL), 6 h. Determined by H NMR.
b
1
b
Isolated yield.
As expected, all chosen enamides showed good E-selectivity
in DMSO. Generally, electron-deficient enamides gave higher
E/Z ratios, presumably due to weaker intramolecular hydrogen
bonding.
Finally, the reaction pathway was investigated to confirm that
hemiaminals are produced as intermediates in this reaction
(Scheme 4). An isolable hemiaminal (5) afforded the desired
the optimized conditions, it was selected for further study
(entries 13 and 14).
Given the observed stereoselective solvent dependency in
the screening experiments, additional solvents were tested
to further improve the reaction utility (Table 2). A catalytic
amount of HCl was added to facilitate isomerization through
protonation of the carbonyl oxygen. As previously reported,
DCM predominantly gave the Z-isomer due to intramolecular
hydrogen bonding between the amide proton and the carbonyl
oxygen of the ketone group;10e unfortunately, less polar
solvents could not be tested due to solubility issues. On the
other hand, polar solvents, particularly DMSO, disrupted that
intramolecular hydrogen bond by competing with the substrate,
favoring the E-isomer as a result. Chang and co-workers
reported that some E-enamides could be obtained by photo-
isomerization of the corresponding Z-enamides with moderate
efficiency and selectivity by using 350 nm UV light.10e In our
case, a simple workup involving catalytic addition of HCl and
careful solvent selection produce a similar, more selective result
without any loss of the enamide product.
Scheme 4. Proposed Reaction Pathway and Intermediate
Study
With the above results in hand, we investigated substrate
scope with a one-pot procedure including Au-catalyzed enamide
synthesis and enamide isomerization to obtain Z-enamide
selectively. First, amide substrate scope with 2a was examined
(Scheme 2). Several substituted benzamides afforded
Z-enamides in reasonably high yields, including both those
that contained electron-donating and electron-withdrawing
groups (3aa−ia). Hydroxy and halide substituents were both
well tolerated by the reaction (3ea,ga−ha), while aliphatic
amides gave good yields when two equivalents of aldehyde
were used (3ja−la). While cinnamamide and furanamide
afforded moderate yields (3ma−na), nicotinamide showed no
reactivity (3oa).
enamide product in 91% yield after 6 h under the optimized
conditions, providing further support for the proposed
mechanism.
In summary, a novel enamide synthesis has been developed
that combines primary amides and propargyl aldehydes via
Au(I)-catalyzed tandem amide addition and Meyer−Schuster
C
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Letter
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rearrangement. Enamide stereoselectivity was controlled simply
by changing solvents and through the addition of a catalytic
amount of acid. The developed synthetic strategy provides
a new approach by which to synthesize various β-substituted
α,β-unsaturated carbonyl compounds.
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(d) Marion, N.; Carlqvist, P.; Gealageas, R.; de Fremont, P.; Maseras,
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ASSOCIATED CONTENT
* Supporting Information
(g) Ramon
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Details of experimental procedure and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
́ ́
Chem. 2011, 76, 1479. (j) Gomez-Suarez, A.; Oonishi, Y.; Meiries, S.;
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: soonhong@snu.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF-2014R1A2A1A11050028) and
the Institute for Basic Science (IBS-R006-D1), funded by the
Korean Government.
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