N-Heterocyclic Carbene Catalyzed Cyclocondensation of α,β-Unsaturated Carboxylic Acids: Enantioselective Synthesis of Pyrrolidinone and Dihydropyridinone Derivatives

Article abstract of DOI:10.1002/anie.201407469

The catalytic cyclocondensation of in situ activated α,β-unsaturated carboxylic acids was developed. N-heterocyclic carbenes efficiently catalyzed the generation of α,β-unsaturated acyl azolium intermediates from α,β-unsaturated carboxylic acids via in situ generated mixed anhydrides for the enantioselective [3+2] and [3+3] cyclocondensation with α-amino ketones and alkyl(aryl)imines, respectively. The corresponding pyrrolidinones and dihydropyridinones were isolated in good yields with high to excellent enantioselectivities. Into the mix: N-Heterocyclic carbenes (NHCs) catalyze the generation of α,β-unsaturated acyl azoliums from α,β-unsaturated carboxylic acids via in situ generated mixed anhydrides for the enantioselective [3+2] and [3+3] cyclocondensation with sulfonylated α-amino ketones and alkyl(aryl)imines, respectively. The corresponding pyrrolidinones and dihydropyridinones were isolated in good yields with high to excellent enantioselectivities.

Full text of DOI:10.1002/anie.201407469

Angewandte
Chemie
DOI: 10.1002/anie.201407469
Organocatalysis
N-Heterocyclic Carbene Catalyzed Cyclocondensation of a,b-
Unsaturated Carboxylic Acids: Enantioselective Synthesis of
Pyrrolidinone and Dihydropyridinone Derivatives**
Xiang-Yu Chen, Zhong-Hua Gao, Chun-Yu Song, Chun-Lin Zhang, Zhi-Xiang Wang,* and
Song Ye*
Dedicated to Professor Li-Xin Dai on the occasion of his 90th birthday
Abstract: The catalytic cyclocondensation of in situ activated
a,b-unsaturated carboxylic acids was developed. N-heterocy-
clic carbenes efficiently catalyzed the generation of a,b-
unsaturated acyl azolium intermediates from a,b-unsaturated
carboxylic acids via in situ generated mixed anhydrides for the
enantioselective [3+2] and [3+3] cyclocondensation with a-
amino ketones and alkyl(aryl)imines, respectively. The corre-
sponding pyrrolidinones and dihydropyridinones were isolated
in good yields with high to excellent enantioselectivities.
I
n recent years, N-heterocyclic carbenes (NHCs) have
emerged as one of the most powerful organocatalysts for
the reactions of various substrates[1] such as aldehydes,[2]
ketenes,[3] esters,[4] and Michael acceptors.[5] As an important
1,3-biselectrophile intermediate, the NHC-catalyzed genera-
tion of a,b-unsaturated acyl azoliums (I; see Scheme 1) from
enals,[6] ynals,[7] a-bromoenals,[8] a,b-unsaturated acyl fluo-
rides,[9] and a,b-unsaturated esters[10] have been well estab-
lished. Apparently, most of the carboxylate derivatives are
prepared from carboxylic acids, which are readily available
and easy to handle. However, the direct NHC-catalyzed
reaction of a carboxylic acid instead of its derivatives is of
great value but remains unexplored. We envisioned that the
in situ formed mixed anhydride may afford an alternative
direct pathway to generate the NHC-bound a,b-unsaturated
acyl azolium (Scheme 1).
Scheme 1. The NHC-catalyzed generation of a,b-unsaturated acyl azo-
liums from carboxylic acids and its derivatives.
the generation of the a,b-unsaturated acyl ammonium com-
pounds from a,b-unsaturated anhydrides,[13] acyl chlorides,[14]
and acyl cyanides[15] have also been successfully explored. We
envision that the b-functionalization of a,b-unsaturated
carboxylic acids is also possible when the proper nucleophilic
catalyst is employed.
Considering the wide applications of chiral g-butyrolac-
tams,[16,17] we are interested in employing a-amino ketones as
the possible 1,2-bis(nucleophile) to react with the in situ
generated a,b-unsaturated acyl azolium intermediate from an
a,b-unsaturated acid, for the synthesis of g-butyrolactams.
Initially, the isothiourea DHPB (3,4-dihydro-2H-pyrimido-
[2,1-b]benzothiazole; A) was employed as the catalyst for the
reaction of cinnamic acid (1a) with the a-amino ketone 2a in
the presence of pivaloyl chloride as the reagent for generating
the mixed anhydride (Scheme 2). However, the reaction
catalyzed by A, which works well for the a-functionalization
of carboxylic acids,[12] gave none of the desired cycloconden-
sation product 4a, but the amide 3a was generated in 89%
yield. Interestingly, the same reaction catalyzed by the NHC
B1[18] afforded the desired cycloadduct 4a in 49% yield
without the formation of 3a. We proposed that the relatively
unfavored amidation of the NHC-bound acyl azolium com-
pared to isothiourea-bound one makes the cyclocondensation
feasible.[19]
The direct catalytic a-functionalizations of carboxylic
acids using an amine-based nucleophilic catalyst were well
established by Romo et al.[11] and Smith et al.[12] Very recently,
[*] X.-Y. Chen, Z.-H. Gao, C.-L. Zhang, Prof. Dr. S. Ye
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190 (China)
E-mail: songye@iccas.ac.cn
C.-Y. Song, Prof. Dr. Z.-X. Wang
College of Chemistry and Chemical Engineering
University of Chinese Academy of Sciences
Beijing 100049 (China)
E-mail: zxwang@gucas.ac.cn
[**] Financial support from the Ministry of Science and Technology of
China (2011CB808600), National Science Foundation of China
(21272237) are greatly acknowledged.
The NHC-catalyzed model reaction was then optimized
(Table 1). The yield was improved to 60% when the reaction
was carried out at 408C (entry 1). The screening of solvents
revealed that the reaction gave the best results in toluene as
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407469.
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Table 2: Enantioselective [3+2] cyclocondensation.
Scheme 2. Catalyst-dependent reaction results. DIPEA=N,N-diisopro-
pylethylamine, PivCl=pivaloyl chloride, Ts=4-toluenesulfonyl.
Table 1: Optimization of reaction conditions.
Entry
Cat.
Solvent
Yield [%][a]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
B1
B1
B1
B1
B2
B3
B4
B5
C
CH2Cl2
CHCl3
THF
toluene
toluene
toluene
toluene
toluene
toluene
60
trace
31
64
trace
9
7
20
trace
3:1
–
4:1
5:1
–
n.d.
n.d.
3:1
–
93
–
93
96
–
n.d.
n.d.
79
–
[a] Used 1 (2.0 equiv) and PivCl (2.4 equiv).
for the reaction (Table 2). Both electron-donating (4-
MeC6H4) and electron-withdrawing groups (4-ClC6H4 and 4-
BrC6H4) were tolerated and gave the desired pyrrolidinones
4b–d in good yields with high enantioselectivities. Cinnamic
acids having a meta-substituent (3-MeOC6H4, 3-BrC6H4, and
3-ClC6H4) also worked well (4e–g). Reaction of a disubsti-
tuted cinnamic acid derivative (3,4-Cl2C6H3) gave the desired
pyrrolidinone 4h in 67% yield with d.r. = 5:1 and 95% ee.
Notably, the reaction of challenging ortho-substituted sub-
strates (2-MeOC6H4, 2-MeC6H4, 2-BrC6H4, and 2-ClC6H4)
were also successful (4i–l). The scope of the reaction with
respect to the amino ketones was also examined. Amino
ketones with electron-withdrawing or electron-donating sub-
stituents (4-MeC6H4, 4-ClC6H4, and 4-BrC6H4) were tolerated
and gave the desired pyrrolidinones 4m–o in good yields with
excellent enantioselectivities. The reaction of an amino
ketone with a 2-naphthyl group gave the corresponding
pyrrolidinone 4p in moderate yield with excellent diastereo-
selectivity and enantioselectivity. However, it should be noted
that the alkyl a,b-unsaturated carboxylic acids did not work
under the current reaction conditions. The 4R,5S configura-
[a] Yield of the isolated mixture of two diastereoisomers. [b] Determined
by 1H NMR (300 MHz) spectroscopy of the unpurified reaction mixture.
[c] Determined by HPLC using a chiral stationary phase. Mes=2,4,6-
trimethylphenyl, n.d.=not determined, TBS=tert-butyldimethylsilyl.
compared to that in dichloromethane, chloroform, and
tetrahydrofuran (entries 2–4). A series of NHCs (B1–B5)
with different N-aryl groups was investigated, thus showing
that the NHCs B2–B5, having N-phenyl, benzyl, 2-isopropyl-
phenyl, and 2,6-diethylphenyl groups, respectively, were
inferior to B1 which bears an N-mesityl group (entries 4–8).
The NHC C derived from pyroglutamic acid was not effective
for the reaction under the current reaction conditions
(entry 9).
With the optimized reaction conditions in hand, a variety
of a,b-unsaturated carboxylic acids were briefly investigated
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Table 3: Enantioselective [3+3] cyclocondensation with sulfamate-
Table 4: Enantioselective [3+3] cyclocondensation with sultam-derived
derived cyclic imines.
cyclic imines.
tion of the cycloadduct 4k was determined by the X-ray
analysis of a single crystal.[20]
[a] The reaction was carried in CH2Cl2 at RT. [b] Determined by 1H NMR
spectroscopy (300 MHz) of the unpurified reaction mixture.
The NHC-catalyzed direct functionalization of a,b-unsa-
turated carboxylic acids was then extended to the [3+3]
cyclocondensation with sulfamate-derived cyclic imines to
give dihydropyridinones (Table 3). It was found that the
optimized reaction conditions for the [3+2] cyclocondensa-
tion with a-amino ketones also worked well for the [3+3]
reaction with cyclic imines. A range of a,b-unsaturated
carboxylic acids with electron-donating (4-MeC6H4) and
electron-withdrawing groups (4-ClC6H4) reacted smoothly
with the cyclic imine 5a to give the corresponding dihydro-
pyridinones (6b and 6c) in good yields with excellent
enantioselectivities. ortho-Substituted (2-MeC6H4 and 2-
BrC6H4) or meta-substituted substrates (3-MeC6H4, 3-
OMeC6H4 and 3-BrC6H4) showed no negative effect for the
reaction (6d–h). The cyclic imine 5b having a methyl
substituent also worked well to give the desired cycloadduct
6i in 58% yield and 95% ee. The S configuration of 6c was
determined by the X-ray analysis of a single crystal.[20]
The [3+3] cyclocondensation with sultam-derived cyclic
imines 7 were also investigated under the optimized reaction
conditions (Table 4).[6d] As expected, a range of a,b-unsatu-
rated carboxylic acids reacted well with the cyclic imine 7a to
give the desired cycloadduct in good yields with high
enantioselectivities (8a–e). Cinnamic acid with a 3,4,5-trime-
thoxyphenyl group also worked well albeit with decreased
yield and enantioselectivity (8 f). Notably, the reaction of b,b-
disubstituted a,b-unsaturated carboxylic acids were successful
and gave the desired cycloadducts 8g and 8h, bearing chiral
quaternary carbon centers, in good yields with high enantio-
selectivities. In addition, the a,b-disubstituted a,b-unsatu-
rated carboxylic acid also worked well to give 8i in 52% yield
with excellent diastereo- and good enantioselectivity. The
sultam-derived cyclic imine 7b with an n-butyl group was also
examined. Under the standard reaction conditions in toluene,
the reaction went very slow with only trace amounts of
product observed, while the reaction in dichloromethane gave
the cycloadduct 8j in 68% yield with 85% ee.
Besides the cyclic imines 6 and 7, the reaction with the
acyclic imine 9 also proceeded to give the cycloadduct 10 in
77% yield with 96% ee (Scheme 3).[10b]
A plausible catalytic cycle for the NHC-catalyzed [3+2]
cyclocondensation of a,b-unsaturated acid is depicted in
Figure 1. The addition of NHC to the mixed anhydride 1’,
which is formed in situ from the a,b-unsaturated acid, gives
the corresponding a,b-unsaturated acyl azolium intermediate
I. In presence of a base, the Michael addition of the a-amino
ketone 2 to II gives the adduct II, with a subsequent proton
transfer to afford the intermediate III. The intramolecular
lactamization affords the final cycloadduct 4 and regenerates
the NHC catalyst.
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Figure 1. Plausible catalytic cycle.
In summary, the NHC-catalyzed enantioselective [3+2]
cyclocondensation of in situ activated a,b-unsaturated car-
boxylic acids with a-amino ketones, and [3+3] cycloconden-
sation with imines were developed.[21] A variety of pyrrolidi-
nones and dihydropyridinones were obtained in good yields
with high to excellent enantioselectivities. The ready avail-
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carboxylic acids makes it a favorable starting material for
the NHC-catalyzed generation of a,b-unsaturated acyl azo-
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reactions of carboxylic acids are underway in our laboratory.
Received: July 22, 2014
Published online: September 9, 2014
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Keywords: cyclization · heterocycles · N-heterocyclic carbenes ·
organocatalysis · synthetic methods
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[20] CCDC 997053 (4k) and 997054 (6c) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[21] During the resubmission of the manuscript, Scheidt et al.
reported an NHC-catalyzed enantioselective annulation for
dihydroquinolones by in situ generation of azolium enolates
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Angew. Chem. Int. Ed. 2014, 53, 11611 –11615
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