(Dynamic) Kinetic Resolution of Enamines/Imines: Enantioselective N-Heterocyclic Carbene Catalyzed [3+3] Annulation of Bromoenals and Enamines/Imines

Article abstract of DOI:10.1002/anie.201813047

The enantioselective N-heterocyclic carbene catalyzed [3+3] annulation of α-bromoenals by dynamic kinetic resolution (DKR) of enamines and normal resolution of α,α-disubstituted imines were developed. The corresponding substituted dihydropyridones were isolated in good yields with excellent diastereo- and enantioselectivities, and a high selective factor (up to 83) was realized for the resolution of α,α-disubstituted imines.

Full text of DOI:10.1002/anie.201813047

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: (Dynamic) Kinetic Resolution of Enamines/Imines:
Enantioselective N-Heterocyclic Carbene-Catalyzed [3+3]
Annulation of Bromoenals and Enamines/Imines
Authors: Kun-Quan Chen, Zhong-Hua Gao, and Song Ye
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813047
Angew. Chem. 10.1002/ange.201813047
Link to VoR: http://dx.doi.org/10.1002/anie.201813047
http://dx.doi.org/10.1002/ange.201813047

10.1002/anie.201813047
Angewandte Chemie International Edition
COMMUNICATION
(Dynamic)
Kinetic
Resolution
of
Enamines/Imines:
Enantioselective
N-Heterocyclic
Carbene-Catalyzed
[3+3]
Annulation of Bromoenals and Enamines/Imines
Kun-Quan Chen, Zhong-Hua Gao and Song Ye*
Dedication ((optional))
Abstract: The enantioselective N-heterocyclic carbene-catalyzed
[3+3] annulation of α-bromoenals via dynamic kinetic resolution
(DKR) of enamines and normal resolution of α,α-disubstituted imines
were developed. The corresponding substituted dihydropyridones in
good yields with excellent diastereo- and enantioselectivities, and
high selective factor (up to 83) was realized for the resolution of -
disubstituted imines.
communication, we report an NHC-catalyzed DKR of enamines
via its [3+3] annulation with bromoenals and normal kinetic
resolution with α,α-disubstituted imines for the enantioselective
construction of dihydropyridone, which is an important motif in
numerous alkaloids and pharmaceutical compounds (Scheme 1,
reaction g).[14]
In the past decades, N-heterocyclic carbenes (NHCs)
have been demonstrated as powerful organocatalysts,
especially for the enantioselective cyclization reactions.[1]
Compared to the well-established NHC-catalyzed construction
of new stereocenters, the NHC-catalyzed dynamic kinetic
resolutions (DKRs) were far less developed. In 2012, Scheidt et
al. reported the pioneering NHC-catalyzed DKR of substituted
ketones for the synthesis of -lactones (Scheme 1, reaction a).[2]
Lately, the NHC-catalyzed DKR of -substituted ketones were
then successfully established for [3+2][3] and [4+2] [4] annulation
with enals and -methylenals for the synthesis of - and -
lactones, respectively (Scheme 1, reactions b & c). The NHC-
catalyzed DKR of substituted ketones via benzoin reaction[5] and
the DKR of -substituted esters via transesterification[6] were
also developed (Scheme 1, reactions d & e). In addition, the
NHC-catalyzed DKR of pyranone-dervied hemiacetals via
esterification was reported (Scheme 1, reaction f).[7]
Compared to the reported NHC-catalyzed DKR of
carbonyl compounds, the DKR of imines or enamines is very
challenging due to imine/enamine tautomerization and
regioselectivity. To the best of our knowledge, the reported
catalytic DKR of imines or enamines relys on the hydrogenation
reaction.[8]. Recently, the NHC-catalyzed generation of -
unsaturated acyl azoliums[9] and its following annulation with
various bisnucleophiles, such as 1,3-dicarbonyl compounds,[10]
enolizable aldehydes/ketones,[11] imines,[12] and enamines,[13]
were very successful. Inspired by those reports, particularly the
reaction with enamines, we envisioned that the NHC-catalyzed
annulation via -unsaturated acyl azolium intermediate may
offer a good opportunity for DKRs of imines or enamines. In the
Scheme 1. NHC-catalyzed dynamic kinetic resolution (DKR).
Initially, the reaction of enamines 1 with different N-
protective groups and -bromocinnamaldehyde 2a was
investigated as model reaction under chiral NHC catalysis
(Table 1). Although there was no desired cyclopropane-fused
dihydropyridones formed when enamines 1a-1c (PG = Ph, Bn,
Ac) were used (entries 1-3), the reaction with enamine 1d (PG =
Ts) gave cycloadduct 3a in 77% yield with 3:1 dr and 87% ee
(major diastereomer) in the presence of aminoindanol-derived
[15]
tetracyclic triazolium A
as the NHC catalyst precursor (entry
[*]
K.-Q Chen, Dr. Z.-H. Gao, Prof. Dr. S. Ye
4). Control experiment revealed that the cis- or trans-3a could
not be isomerized under the condition with Et3N as the base. To
further improve the stereoselectivity, NHC precursors B[16] and
C[17] with different N-aryl group were tested, and preNHC C with
N-(2-isopropyl)phenyl resulted in better diastereo- and
enantioselectivity (entries 4-6). Screening of the solvents
revealed that the reaction worked better in MeCN than in DCM,
toluene and THF (entries 6‒19). Reducing the catalyst loading
led to some loss of enantioselectivity (entry 10), and adding LiCl
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
E-mail: songye@iccas.ac.cn (S. Ye)
K.-Q. Chen, Prof. Dr. S. Ye
University of Chinese Academy of Sciences, Beijing 100049, China
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813047
Angewandte Chemie International Edition
COMMUNICATION
as the Lewis acid additive showed no notable improvement in
term of selectivity but led to some loss of yield (entry 11).
Table 1 Condition optimization for the DKR of enamines
yield
[%][b]
ee
Entry
1
preNHC
solvent
dr[d]
[%][c]
1
2
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
A
A
A
A
B
C
C
C
C
C
C
DCM
DCM
0
/
/
/
0
/
3
DCM
0
/
/
4
DCM
77
51
58
64
68
88
90
68
3:1
3:1
9:1
9:1
9:1
9:1
10:1
8:1
87
93
95
93
95
94
83
95
5
DCM
6
DCM
7
toluene
THF
8
9
MeCN
MeCN
MeCN
10[e]
11[f]
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv), preNHC A-C
(0.02 mmol, 10 mol %). [b] Isolated yield. [c] Determined by HPLC analysis
using a chiral stationary phase. [d] Determined by 1H NMR of the crude
reaction mixture. [e] 5 mol % of C was used. [f] 10 mol % of LiCl was added.
Scheme 2. Scope of enamines.
With the optimized conditions in hand, the scope of
enamines was briefly investigated (Scheme 2). Variation of N-
protecting groups of the enamines showed that different
sulfinates, such as benzenesulfinate, 4-methylbenzenesulfinate
and 4-nitrobenzenesulfinate, all worked well for the reaction to
give the corresponding products (3a‒3c) in good yields with
good diastereo- and high enantioselectivities. However, N-(2-
methyl
benzenesulfonyl)
enamine
resulted
in
low
diastereoselectivity (2:1 dr), presumably owing to the steric
effect of the ortho-substituent (3d). Enamines with different ester
groups (R = Me, i-Pr, n-Bu) showed no significant change, giving
desired dihydropyridones (3e‒3g) in good yields with high
enantioselectivities. Notably, besides the cyclopetene-derived
enamines, the cyclohexene- and cycloheptene-derived
enamines
worked well to give the corresponding
dihydropyridones (3h‒3i) in good yields with excellent
stereoselectivities. In addition, piperidine was also tolerated,
affording the interesting piperidine-fused dihydropyridone 3j in
55% yield, with16:1 dr and 95% ee. Furthermore, the reaction of
acyclic enamine was also feasible to provide the corresponding
dihydropyridone 3k in good yield with good diastereo- and high
enantioselectivity.
Scheme 3. Scope of α-bromoenals.
The scope of -bromoenals was shown in Scheme 3. It was
found that -bromoenals with electron-donating (Ar = 4-MeC6H4
and 4-MeOC6H4) and electron-withdrawing groups (Ar = 4-FC6H4,
4-ClC6H4, and 4-BrC6H4) were tolerable to afford the desired
product in high yields with high diastereo- and
enantioselectivities (3l‒3p). Both -bromoenals with meta-
This article is protected by copyright. All rights reserved.

10.1002/anie.201813047
Angewandte Chemie International Edition
COMMUNICATION
substituent (Ar = 3-ClC6H4) and ortho-substituent (Ar = 2-
OMeC6H4 and 2-BrC6H4) performed well under the standard
reaction conditions (3q‒3s). However, alkyl bromoenals were
unsuitable substrates, giving no desired cycloaddition products
under current reaction conditions.
The standard kinetic resolution (non-DKR) of -
disubstituted imine was also investigated (Scheme 4). After
optimization of the conditions, we were happy to find high
enantioselectivities were achieved for both the cycloadduct and
the recovered disubstituted imine with high
S
factor[18]
(Supporting Information, Table S1). It was found that reaction of
bromoenals with different -aryl group (Ar = 4-MeC6H4, 4-ClC6H4,
4-BrC6H4) afforded the cyclopentene-fused dihydropyridones 5c-
5d with quaternary stereocenter in good yield with good
diastereo- and enantioselectivities. The resolution reaction of
imine 4b (R = i-Pr) gave cycloadduct 5e with 91% ee and
recovered (R)-4b with 87% ee.
Scheme 5. Gram-scale reaction and further transformations.
The absolute configuration of 3a was unambiguously
established by X-ray analysis of its crystal structure (See
supporting information).
Scheme 4. Reactions of cyclic -disubstituted imines.
The annulation reaction could be scaled up to 1.0 gram
without decrease of yield or stereoselectivity under the optimal
conditions (Scheme 5, reaction a). The resulting bicyclic
dihyropyridones with highly functional groups present
opportunities for many further chemical transformations. For
example, hydrogenation of 3a under Pd(OH)2/C gave
cyclopentane-fused pyridone
6
in quantitative yield with
Figure 1. Proposed mechanism.
excellent diastereoselectivities (Scheme 5, reaction b). The N-
tosyl group could be removed by Na/Naphthalene in DME at -78
oC to give the corresponding product 7 in 82% yield and 96% ee
(Scheme 5, reaction c).[19] Ring-opening reduction of 3a with
NaBH4/I2 afforded enamine alcohol 8 in 67% yield, with 20:1 dr
and 96% ee (Scheme 5, reaction d).[20]
A plausible catalytic cycle for the NHC-catalyzed dynamic
kinetic resolution of enamines is depicted in Figure 1. The
addition of NHC catalyst to the -bromoenal 2a gives the
corresponding Breslow intermediate I, which is tautomerized to
bromoacyl azolium II. The leaving of bromide generates the key
-unsaturated
acyl
azolium
intermediate
III.[10b]
Tautomerization of cyclic enamine 1 forms its racemic isomer 1’.
The (S)-1’ is kinetically favored over (R)-1d’ for its Michael
addition to the -unsaturated acyl azolium intermediate III to
This article is protected by copyright. All rights reserved.

10.1002/anie.201813047
Angewandte Chemie International Edition
COMMUNICATION
give adduct IV. The subsequent lactamization affords the final
dihydropyridones 3 and regenerates the free NHC catalyst.
7421; b) R. C. Johnston, D. T. Cohen, C. C. Eichman, K. A. Scheidt, P.
H.-Y. Cheong, Chem. Sci. 2014, 5, 1974; c) S. Mondal, S. Mukherjee, T.
K. Das, R. Gonnade, A. T. Biju, ACS Catal. 2017, 7, 3995.
[3] C. G. Goodman, M. M. Walker, J. S. Johnson, J. Am. Chem. Soc. 2015,
137, 122.
[4] Z. Wu, F. Li, J. Wang, Angew. Chem. Int. Ed. 2015, 54, 1629; Angew.
Chem. 2015, 127, 1649.
[5] C. G. Goodman, J. S. Johnson, J. Am. Chem. Soc. 2014, 136, 14698.
[6] X. Chen, J. Z. M. Fong, J. Xu, C. Mou, Y. Lu, S. Yang, B.-A. Song, Y. R.
Chi, J. Am. Chem. Soc. 2016, 138, 7212.
[7] C. Zhao, F. Li, J. Wang, Angew. Chem. Int. Ed. 2016, 55, 1820; Angew.
Chem. 2016, 128, 1852.
[8] a) Z.-Y. Han, H. Xiao, L.-Z. Gong, Bioorg. Med. Chem. Lett. 2009, 19,
3729; b) V. N. Wakchaure, J. Zhou, S. Hoffmann, B. List, Angew. Chem.
Int. Ed. 2010, 49, 4612; Angew. Chem. 2010, 122, 4716; c) J. Han, S.
Kang, H.-K. Lee, Chem. Commun. 2011, 47, 4004; d) M.-W. Chen, X.-F.
Cai, Z.-P. Chen, L. Shi, Y.-G. Zhou, Chem. Commun. 2014, 50, 12526;
e) B. Song, M.-W. Chen, Y.-G. Zhou, Org. Chem. Front. 2018, 5, 1113.
[9] a) J. Guin, S. De Sarkar, S. Grimme, A. Studer, Angew. Chem. Int. Ed.
2008, 47, 8727; Angew. Chem. 2008, 120, 8855; b) S. J. Ryan, L.
Candish, D. W. Lupton, J. Am. Chem. Soc. 2009, 131, 14176; c) J.
Kaeobamrung, J. Mahatthananchai, P. Zheng, J. W. Bode, J. Am.
Chem. Soc. 2010, 132, 8810; d) Z. Q. Zhu, J. C. Xiao, Adv. Synth.
Catal. 2010, 352, 2455.
Figure 2. Possible transition states.
Based on the stereochemical outcome, two transition states
A and B were proposed for the addition of enamine (S)-1’ and
(R)-1’ to -unsaturated acyl azolium intermediate III,
respectively (Figure 2). TS A with (S)-1’ is kinetically favoured
over TS B with (R)-1’ due to the steric repulsion between the
ester group in (R)-1’ and the catalyst. The less reactive (R)-1’ is
transformed to (S)-1’ via achiral isomeric enamine 1 under basic
condition, and thus furnishes the dynamic kinetic resolution.
In conclusion, we developed a dynamic kinetic resolution of
enamines via NHC-catalyzed enantioselective [3+3] annulation
reactions of -bromoenals with enamines. The reaction worked
well for cyclopentene-, cyclohexene- and cycloheptene-derived
enamines, and as well as the acyclic enamines. The
corresponding highly functionalized dihydropyridones were
obtained in good yields, with good diastereoselectivities and
excellent enantioselectivities. In addition, the normal kinetic
resolution with α,α-disubstituted imines gave both the
dihydropyridones and the recovered α,α-disubstituted imines
with high enantioselectivities (S factor up to 83). Other related
NHC-catalyzed (dynamic) kinetic resolution reactions are
underway in our laboratory.
[10] a) S. De Sarkar, A. Studer, Angew. Chem. Int. Ed. 2010, 49, 9266; Angew.
Chem. 2010, 122, 9452; b) F.-G. Sun, L.-H. Sun, S. Ye, Adv. Synth.
Catal. 2011, 353, 3134; c) C. Yao, D. Wang, J. Lu, T. Li, W. Jiao, C. Yu,
Chem. Eur. J. 2012, 18, 1914; d) J. Xu, W. Zhang, Y. Liu, S. Zhu, M.
Liu, X. Hua, S. Chen, T. Lu, D. Du, RSC Adv. 2016, 6, 18601.
[11] a) L. Candish, D. W. Lupton, Org. Lett. 2010, 12, 4836; b) D. Du, Z. Hu, J.
Jin, Y. Lu, W. Tang, B. Wang, T. Lu, Org. Lett. 2012, 14, 1274; c) Y. Lu,
W. Tang, Y. Zhang, D. Du, T. Lu, Adv. Synth. Catal. 2013, 355, 321; d)
S. R. Yetra, T. Kaicharla, S. S. Kunte, R. G. Gonnade, A. T. Biju, Org.
Lett. 2013, 15, 5202; e) Q. Ni, X. Song, G. Raabe, D. Enders, Chem.
Asian J. 2014, 9, 1535; f) G. T. Li, Z.-K. Li, Q. Gu, S.-L. You, Org. Lett.
2017, 19, 1318.
[12] a) A. G. Kravina, J. Mahatthananchai, J. W. Bode, Angew. Chem. Int. Ed.
2012, 51, 9433; Angew. Chem. 2012, 124, 9568; b) J. Cheng, Z. Huang,
Y. R. Chi, Angew. Chem. Int. Ed. 2013, 52, 8592; Angew. Chem. 2013,
125, 8754; c) Y.-J. Yang, H.-R. Zhang, S.-Y. Zhu, P. Zhu, X.-P. Hui,
Org. Lett. 2014, 16, 5048; d) H.-M. Zhang, W.-Q. Jia, Z.-Q. Liang, S. Ye,
Asian J. Org. Chem. 2014, 3, 462; e) Z. Zhang, X. Zeng, D. Xie, D.
Chen, L. Ding, A. Wang, L. Yang, G. Zhong, Org. Lett. 2015, 17, 5052;
f) W. Xia, H. Yao, D. Liu, L. Zhao, Y. Zhou, H. Liu, Adv. Synth. Catal.
2016, 358, 1864; g) L. Yi, Y. Zhang, Z.-F. Zhang, D. Sun, S. Ye, Org.
Lett. 2017, 19, 2286.
Acknowledgements ((optional))
Financial support from the National Natural Science Foundation
of China (Nos 21425207, 21521002), and the Chinese Academy
of Sciences is greatly acknowledged.
[13] a) B. Wanner, J. Mahatthananchai, J. W. Bode, Org. Lett. 2011, 13, 5378;
b) S. R. Yetra, A. Bhunia, A. Patra, M. V. Mane, K. Vanka, A. T. Biju,
Adv. Synth. Catal. 2013, 355, 1089.
Conflict of interest
[14] a) C. Chen, A. P. Kozikowski, P. L. Wood, I. J. Reynolds, R. G. Ball, Y. P.
Pang, J. Med. Chem. 1992, 35, 1634; b) M. D. Meyer, J. F.
DeBernardis, A. A. Hancock, J. Med. Chem. 1994, 37, 105; c) M.
Elhallaoui, M. Laguerre, A. Carpy, F. C. Ouazzani, j. mol. model 2002,
8, 65; d) J. Singh, R. Singh, P. Gupta, S. Rai, A. Ganesher, P.
Badrinarayan, G. N. Sastry, R. Konwar, G. Panda, Biorg. Med. Chem.
2017, 25, 4452.
The authors declare no conflict of interest.
Keywords: N-heterocyclic carbene catalysis • kinetic resolution
• enamines • imines • dihydropyridones
[1] a) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606; b) A.
Grossmann, D. Enders, Angew. Chem. Int. Ed. 2012, 51, 314; Angew.
Chem. 2012, 124, 320; c) J. W. Bode, Nat. Chem. 2013, 5, 813; d) X.-Y.
Chen, S. Ye, Synlett 2013, 24, 1614; e) S. De Sarkar, A. Biswas, R. C.
Samanta, A. Studer, Chem. - Eur. J. 2013, 19, 4664; f) S. J. Ryan, L.
Candish, D. W. Lupton, Chem. Soc. Rev. 2013, 42, 4906; g) M. N.
Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485;
h) J. Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47, 696; i)
D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem.
Rev. 2015, 115, 9307; j) R. S. Menon, A. T. Biju, V. Nair, Chem. Soc.
Rev. 2015, 44, 5040; k) M. H. Wang, K. A. Scheidt, Angew. Chem. Int.
Ed. 2016, 55, 14912; Angew. Chem. 2016, 128, 15134; l) E. Reyes, U.
Uria, L. Carrillo, J. L. Vicario, Synthesis 2017, 49, 451; m) C. Zhang, J.
F. Hooper, D. W. Lupton, ACS Catal. 2017, 7, 2583.
[15] M. He, J. R. Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128, 8418.
[16] M. S. Kerr, J. Read de Alaniz, T. Rovis, J. Org. Chem. 2005, 70, 5725.
[17] Z. Xiao, C. Yu, T. Li, X.-S. Wang, C. Yao, Org. Lett. 2014, 16, 3632.
[18] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1998, 18, 249.
[19] E. Lorthiois, M. Meyyappan, A. Vasella, Chem. Commun. 2000, 1829.
[20] N. Boechat, J. C. S. da Costa, J. de Souza Mendonça, P. S. M. de
Oliveira, M. Vinıcius Nora De Souza, Tetrahedron Lett. 2004, 45, 6021.
́
[2] a) D. T. Cohen, C. C. Eichman, E. M. Phillips, E. R. Zarefsky, K. A. Scheidt,
Angew. Chem. Int. Ed. 2012, 51, 7309; Angew. Chem. 2012, 124,
This article is protected by copyright. All rights reserved.

10.1002/anie.201813047
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
(Dynamic) Kinetic resolution: The
Kun-Quan Chen, Zhong-Hua Gao and
Song Ye*
enantioselective
N-heterocyclic
carbene-catalyzed [3+3] annulation of
α-bromoenals via dynamic kinetic
resolution (DKR) of enamines and
normal resolution of -disubstituted
Page No. – Page No.
(Dynamic) Kinetic Resolution of
Enamines/Imines: Enantioselective N-
Heterocyclic Carbene-Catalyzed [3+3]
Annulation of Bromoenals and
Enamines/Imines
imine
were
developed.
The
corresponding
substituted
dihydropyridones was isolated in good
yields with excellent diastereo- and
enantioselectivities, and high selective
factor was realized for the resolution
of -disubstituted imines.
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.