One-pot synthesis of optically enriched 2-piperidinones from aliphatic aldehydes and cyanoacrylamides

Article abstract of DOI:10.1021/ol401951g

A highly stereoselective one-pot reaction of aliphatic aldehydes and cyanoacrylamides has been developed. The one-pot reaction includes an organocatalytic Michael addition followed by an intramolecular hemiaminalization. After reduction, optically enriched 2-piperidinones with three contiguous chiral centers were obtained in up to 95% yield and 9:1 dr with 99% ee.

Full text of DOI:10.1021/ol401951g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Synthesis of Optically Enriched
2‑Piperidinones from Aliphatic Aldehydes
and Cyanoacrylamides
Ying He,† Tai-Ran Kang,*,†,‡ Quan-Zhong Liu,*,† Lian-Mei Chen,† Yi-Lian Tu,†
Ya-Jun Liu,† Tang-Bin Chen,† Zhi-Qiang Wang,† Jie Liu,‡ Yong-Mei Xie,‡
Jin-Liang Yang,‡ and Long He*,†
Chemical Synthesis and pollution Control Key Laboratory of Sichuan Province,
College of Chemistry and Chemical Engineering, China West Normal University,
Nanchong, 637009, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu, 610041, China
kangtairan@sina.com; quanzhongliu@sina.com; longhe@mail.ustc.edu.cn
Received May 17, 2013
ABSTRACT
A highly stereoselective one-pot reaction of aliphatic aldehydes and cyanoacrylamides has been developed. The one-pot reaction includes an
organocatalytic Michael addition followed by an intramolecular hemiaminalization. After reduction, optically enriched 2-piperidinones with three
contiguous chiral centers were obtained in up to 95% yield and 9:1 dr with 99% ee.
The rapid construction of CꢀC and CꢀN bonds has
has been achieved over the past few years.1 Formation of
several bonds in a one-pot reaction is highly desirable since
the laborious purification procedures and protection/
deprotection protocols may thus be avoided.2 2-Piperidi-
nones, nitrogen-containing six-membered heterocycles, have
especially attracted much attention from many synthetic
recently received great attention and significant progress
† China West Normal University.
‡ Sichuan University.
(1) For selected examples, see: (a) Lin, H.; Tan, Y.; Liu, W.-J.; Zhang,
Z.-C.; Sun, X.-W.; Lin, G.-Q. Chem. Commun. 2013, 49, 4024. (b)
Sengupta, T.; Gayen, K. S.; Pandit, P.; Maiti, D. K. Chem.;Eur. J.
2012, 18, 1905. (c) Dhara, D.; Gayen, K. S.; Khamarui, S.; Pandit, P.;
Ghosh, S.; Maiti, D. K. J. Org. Chem. 2012, 77, 10441. (d) Cheng, H.-G.;
Lu, L.-Q.; Wang, T.; Yang, Q.-Q.; Liu, X.-P.; Li, Y.; Deng, Q.-H.; Chen,
J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2013, 52, 3250. (e) Valero, G.;
Schimer, J.; Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron Lett.
2009, 50, 1943. (f) Breistein, P.; Johansson, J.; Ibrahem, I.; Lin, S. Z.;
Deiana, L.; Sun, J. L.; Cordova, A. Adv. Synth. Catal. 2012, 354, 1156. (g)
Takasu, K.; Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem. 2005, 70,
3957. (h) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (i) Bøgevig, A.; Juhl,
K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem.,
(2) For reviews, see: (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (b) Guo, H.; Ma, J. Angew.
Chem., Int. Ed. 2006, 45, 354. (c) Pellissier, H. Tetrahedron 2006, 62,
2143. (d) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
€
(e) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
2007, 46, 1570.
(3) For selected examples, see: (a) Lucas, B. S.; Fisher, B.; McGee,
L. R.; Olson, S. H.; Medina, J. C.; Cheung, E. J. Am. Chem. Soc. 2012,
134, 12855. (b) Rew, Y.; et al. J. Med. Chem. 2012, 55, 4936. (c)
Middleton, D. S.; MacKenzie, A. R.; Newman, S. D.; Corless, M.;
Warren, A.; Marchington, A. P.; Jones, B. Bioorg. Med. Chem. Lett.
2005, 15, 3957. (d) MacKenzie, A. R.; Marchington, A. P.; Middleton,
D. S.; Newman, S. D.; Jones, B. C. J. Med. Chem. 2002, 45, 5365. (e)
Kaiser, A .; Ulmer, D.; Goebel, T.; Holzgrabe, U.; Saeftel, M.; Hoerauf,
A. Mini-Rev. Med. Chem. 2006, 6, 1231. (f) Pei, Z.; et al. J. Med. Chem.
2007, 50, 1983. (g) Nara, S.; Tanaka, R.; Eishima, J.; Hara, M.;
Takahashi, Y.; Otaki, S.; Foglesong, R. J.; Hughes, P. F.; Turkington,
S.; Kanda, Y. J. Med. Chem. 2003, 46, 2467. For review of synthesis of
2-piperidinones, see: (h) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953.
ꢀ
Int. Ed. 2002, 41, 1790. (j) Marigo, M.; Schulte, T.; Franzen, J.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 15710. (k) Jiang, H.; Nielsen, J. B.;
Nielsen, M.; Jørgensen, K. Chem.;Eur. J. 2007, 13, 9068. (l) Chandler, C.;
Galzerano, P.; Michrowska, A.; List, B. Angew. Chem., Int. Ed. 2009, 48,
1978. (m) Desmarchelier, A.; Marrot, J.; Moreau, X.; Greck, C. Org.
Biomol. Chem. 2011, 9, 994. (n) Coeffard, V.; Desmarchelier, A.; Morel, B.;
Moreau, X.; Greck, C. Org. Lett. 2011, 13, 5778. (o) Desmarchelier, A.;
Coeffard, V.; Moreau, X.; Greck, C. Chem.;Eur. J. 2012, 18, 13222. (p)
Kano, T.; Sakamoto, R.; Yamaguchi, Y.; Itoh, K.; Maruoka, K. Chem.
Commun. 2013, 49, 1118. For selected reviews, see: (q) Nicolaou, K. C.;
Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993.
r
10.1021/ol401951g
XXXX American Chemical Society

chemists because they are key structural motifs prevalent
in numerous natural compounds and in biologically active
synthetic drugs as exemplified by the molecules shown in
Figure 1.3 Moreover, they also served as the chiral building
blocks or intermediates in the synthesis of polysubstituted
piperidines and medicinally relevant compounds.3,4 Thus
numerous ingenious approaches for the synthesis of sub-
stituted 2-piperidinones have been reported,5 including
the DielsꢀAlder reaction,5aꢀc ring-closing metathesis,5d,e
amination reaction5fꢀh and the general cyclization of
amino acids or esters.5i,j Due to most approaches having
their own disadvantages and the versatility of 2-piperidinone
derivatives in both pharmaceuticals and organic synthesis,
the development of efficient methods to access optically pure
multifunctionalized 2-piperidinones is still an attractive goal
in organic synthesis.6
and unsaturated ketone or ester10 is likewise applied in the
synthesis of complicated molecules. To our knowledge,
however, R,β-unsaturated amides have been seldom em-
ployed in the conjugate addition probably due to the low
reactivity of amides compared to other systems.1h In
connection with our interest in the synthesis of nitrogen-
containing heterocycle compounds11 and the wide range of
biological activities associated with the 2-piperidinones
moiety, herein we wish to report the one-pot synthesis of
functionalized 3,4,5-trisubstituted 2-piperidinones by the
reaction of aliphatic aldehydes with cyanoacrylamide.
Initially, the reaction of (E)-N-benzyl-3-phenylacryla-
mide and propionaldehyde 3a was investigated using pro-
line as the catalyst. Unfortunately, the reaction did not
proceed at all (see Supporting Information (SI)). We
thought that this may be attributed to the inherent low
reactivity of acrylamide resulting in the failed reaction. To
solve the problem, we introduced a cyano functionality to
the R-position of the acrylamide and investigated whether
(E)-cyanoacrylamide 2a would be more amenable to this
reaction.12 To our delight, the reaction led to desired
hemiaminalization product 7a in 94% yield, but in a
disappointing mixture of diastereoisomers by using 20
mol % proline 1a in THF at rt.13 After reduction of 7a
using Et3SiH/BF3 Et2O at 0 °C for 0.5 h, all trans 2-piper-
3
idinone derivative 4a as the major isomer resulted. The
enantioselectivity of 4a was determined to be 25% ee
(Table 1, entry 1). This promising result encouraged us
to further improve the enantioselectivity of the reaction.
Figure 1. Examples of bioactive 2-piperidinones.
Recently, the organocatalytic cascade reactions were
widely employed in the synthesis of structurally diverse
molecules.7 Conjugate addition of aliphatic aldehydes to
unsaturated systems such as nitroolefins,8 vinyl sulfones,9
(8) For selected examples, see: (a) Garcia-Garcia, P.; Ladepeche, A.;
Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 47, 4719. (b) Hayashi,
Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47,
4722. (c) Watt, J.; Luu, L.; Mckee, V.; Carey, E.; Kellehera, F. Adv.
Synth. Catal. 2012, 354, 1035. (d) Chi, Y.; Guo, L.; Kopf, N. A.;
Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608. (e) Ishikawa, H.;
Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem.;Eur. J. 2010,
16, 12616. (f) Shen, H.; Yang, K.-F.; Shi, Z.-H.; Jiang, J.-X.; Lai, G.-Q.;
Xu, L.-W. Eur. J. Org. Chem. 2011, 26, 5031. (g) Hayashi, Y.; Okano, T.;
Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922. (h)
Zhang, X.; Zhang, S.; Wang, W. Angew. Chem., Int. Ed. 2010, 49, 1481.
(i) Mao, Z.; Jia, Y.; Xu, Z.; Wang, R. Adv. Synth. Catal. 2012, 354, 1401.
(j) Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett.
2008, 10, 4557.
(4) (a) Maekawa, Y.; Sakaguchi, T.; Tsuchikawa, H.; Katsumura, S.
Tetrahedron Lett. 2012, 53, 837. (b) Krishna, P. R.; Kumar, P. V. A.;
Mallula, V. S.; Ramakrishna, K. V. S. Tetrahedron 2013, 69, 2319. (c)
Xiao, K. J.; Liu, L. X.; Huang, P. Q. Tetrahedron: Asymmetry 2009, 20,
1181.
(5) (a) Chen, Z.; Lin, L.; Chen, D.; Li, J.; Liu, X.; Feng, X. Tetra-
hedron Lett. 2010, 51, 3088. (b) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2006, 45, 4796. (c) Kipassa, N. T.; Okamura, H.;
Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815. (d) Lee,
J. H.; Shin, S.; Kang, J.; Lee, S. J. Org. Chem. 2007, 72, 7443. (e) Deitel’s,
A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (f) Wasa, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 14058. (g) Rice, G. T.; White, M. C. J. Am.
Chem. Soc. 2009, 131, 11707. (h) Tsuchikawa, H.; Maekawa, Y.;
Katsumura, S. Org. Lett. 2012, 14, 2326. (i) Chen, B.-F.; Tasi, M.-R.;
Yang, C.-Y.; Chang, J.-K.; Chang, N.-C. Tetrahedron 2004, 60, 10223.
(j) Majik, M. S.; Parameswaran, P. S.; Tilve, S. G. J. Org. Chem. 2009,
74, 6378.
(9) For selected examples, see: (a) Murphy, J. J.; Quintard, A.;
McArdle, P.; Alexakis, A.; Stephens, J. C. Angew. Chem., Int. Ed.
2011, 50, 5095. (b) Zhu, Q.; Lu, Y.-X. Org. Lett. 2008, 10, 4803. (c)
ꢀ
Mosse, S.; Alexakis, A.; Mareda, J.; Bollot, G.; Bernardinelli, G.;
Filinchuk, Y. Chem.;Eur. J. 2009, 15, 3204.
(10) For selected examples, see: (a) Chi, Y.; Gellman, S. H. Org. Lett.
2005, 7, 4253. (b) Wen, L.; Shen, Q.; Lu, L. Org. Lett. 2010, 12, 4655. (c)
ꢀ
Wang, J.; Ma, A.; Ma, D. Org. Lett. 2008, 10, 5425. (d) Sulzer-Mosse, S.;
Tissot, M.; Alexakis, A. Org. Lett. 2007, 9, 3749.
(11) (a) Kang, T. R.; Chen, Y.; He, L.; Ye, J.; Liu, Q. Z. Tetrahedron
Lett. 2012, 53, 2552. (b) Chen, Y.; Liu, Y. N.; Ye, J.; He, L.; Kang, T. R.;
Liu, Q. Z. Tetrahedron Lett. 2012, 53, 6775.
(6) For selected examples, see: (a) Breistein, P.; Johansson, J.;
Ibrahem, I.; Lin, S.-Z.; Deiana, L.; Sun, J.-L.; Cordova, A. Adv. Synth.
Catal. 2012, 354, 1156. (b) Chakrabarky, M.; Karmakar, S.; Arima, S.;
Harigaya, Y. Heterocycles 2007, 73, 795. (c) Sosnicki, J. G. Synlett 2003,
11, 1673. (d) White, N. A.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc.
2013, 135, 8504.
(7) For selected reviews, see: (a) Moyano, A.; Rios, R. Chem. Rev.
2011, 111, 4703. (b) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237. (c)
Zhou, J. Chem.;Asian J. 2010, 5, 422. (d) Roca-Lopez, D.; Sadaba, D.;
Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron: Asymmetry
2010, 21, 2561. (e) Mielgo, A.; Palomo, C. Chem.;Asian J. 2008, 3, 922.
(f) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, K. A.
Acc. Chem. Res. 2012, 45, 248. (g) List, B. Chem. Rev. 2007, 107, 5413. (h)
Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969. (i)
Wende, R. C.; Schreiner, P. R. Green Chem. 2012, 14, 1821. (j) Bonne,
D.; Constantieux, T.; Coquerel, Y.; Rodriguez, J. Org. Biomol. Chem.
(12) For a review on unsaturated nitriles, see: (a) Fleming, F. F.;
Wang, Q. Chem. Rev. 2003, 103, 2035. For selected examples about the
reaction of acrylonitrile, see: (b) Yeh, L. F.; Anwar, S.; Chen, K.
Tetrahedron 2012, 68, 7317. (c) Landa, A.; Maestro, M.; Masdeu, C.;
Puente, A.; Vera, S.; Oiarbide, M.; Palomo, C. Chem.;Eur. J. 2009, 15,
1562. (d) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.; Sambri,
L.; Bartoli, G.; Melchiorre, P. Chem.;Eur. J. 2008, 14, 4788. (e) Das,
U.; Huang, C. H.; Lin, W. W. Chem. Commun. 2012, 48, 5590. (f) Zhao,
G. L.; Dziedzic, P.; Ullah, F.; Eriksson, L.; Cordova, A. Tetrahedron
Lett. 2009, 50, 3458. (g) Wang, X. J.; Fang, T.; Tong, X. F. Angew.
Chem., Int. Ed. 2011, 50, 5361. (h) Fusco, C. D.; Tedesco, C.; Lattanzi,
A. J. Org. Chem. 2011, 76, 676. (i) Meninno, S.; Croce, G.; Lattanzi, A.
Org. Lett. 2013, 15, 3436.
ꢀ ꢁ
2012, 10, 3969. (k) Helene, P. Tetrahedron 2013, 69, 7171.
(13) 7a as a mixture of 1.3/1 dr.
B
Org. Lett., Vol. XX, No. XX, XXXX

Catalyst diarylprolinol and silyl ether studies showed that
silyl has a considerable effect on the stereochemistry (entry
2 vs 4 and 3 vs 5). A significant increase of ee was observed
when prolinol 1b or 1c (20 mol %) was employed as the
catalyst in the presence of 20 mol % 4-nitrobenzoic acid
(entries 2ꢀ3). We were pleased to observe that the ee of 4a
further increased to 86% when the chiral diphenylprolinol
silyl ether 1d was used (entry 4). The most optimal catalyst
turned out to be diarylprolinol silyl ether 1e, affording a
94% yield and 93% ee after 48 h (entry 5). All catalysts
afforded similar diastereoselectivities for the reaction. A
screening of different acids revealed that the yield and
enantioselectivity are both dependent on the acid em-
ployed (entries 6ꢀ9). The screening of different solvents
Table 2. Scope of the Reactiona
time
yield
(%)c
entry
R1/R2
Ph/Me
(h)b
4
drd
eee
1
12
12
72
12
12
12
12
24
48
12
12
36
12
96
4a
4b
4c
4d
4e
4f
94
90
88
92
92
91
89
95
94
90
90
91
83
trace
6:1
6:1
6:1
9:1
6:1
6:1
6:1
6:1
6:1
8:1
6:1
6:1
6:1
ꢀ
94/97
99/99
98/99
98/ꢀ
99/99
97/99
99/99
96/99
96/99
96/ꢀ
96/ꢀ
96/99
92/ꢀ
ꢀ
2
4-MeC6H4/Me
4-MeOC6H4/Me
4-ClC6H4/Me
4-BrC6H4/Me
4-CF3C6H4/Me
4-FC6H4/Me
3-MeC6H4/Me
3-MeOC6H4/Me
3-ClC6H4/Me
3-BrC6H4/Me
2-MeOC6H4/Me
2-ClC6H4/Me
3,4,5-(MeO)3-
C6H2/Me
3
4
5
6
7
4g
4h
4i
Table 1. Optimization of the Michael
AdditionꢀHemiaminalization Reaction of the (E)-N-Benzyl-2-
8
cyano-3-phenylacrylamide 2a and Propionaldehyde 3aa
9
10
11
12
13
14
4j
4k
4l
4m
ꢀ
15
16f
17
18
19
20
21
2-furyl/Me
12
48
48
48
48
48
96
4n
4o
4p
4q
4r
4s
ꢀ
80
6:1
3:1
6:1
5:1
5:1
5:1
ꢀ
93/ꢀ
68/73
94/ꢀ
94/ꢀ
95/ꢀ
92/ꢀ
ꢀ
4-BrC6H4/H
C6H5/Et
80
time
(h)b
yield
(%)c
85
entry
cat.
solvent
drd
eee
C6H5/nC3H7
C6H5/nC4H9
C6H5/Bn
65
62
1f
2
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
THF
48
48
48
48
48
48
48
48
48
36
36
48
48
48
12
93
5:1
5:1
5:1
6:1
6:1
6:1
6:1
nd
25
60
61
86
93
83
87
nd
nd
89
93
85
nd
nd
94
60
THF
73
C6H5/iPr
trace
3
THF
67
a Reaction conditions: 0.1 mmol of 2, 0.2 mmol of 3. b The time
required for the first step. c Isolated yields of 4. d Determined by crude 1H
NMR. e Determined by chiral HPLC analysis, and the second ee is for
the minor diastereomer. f At 0 °C, 4 mmol of 3.
4
THF
90
5
THF
94
6g
7h
8i
9j
THF
90
THF
97
THF
<10
<10
90
THF
nd
were tolerated under the present conditions affording the
desired 3,4,5-trisubstituted 2-piperidinone derivatives
(4aꢀm) in good yields and diastereoselectivities with ex-
cellent enantioselectivities (entries 2ꢀ13, 88ꢀ99% ee,
Table 2). However, cyanoacrylamide bearing the highly
electron-rich 3,4,5-trimethoxylphenyl substitutent was not
reactive, providing only a trace amount of product after a
long reaction time (entry 14). This may have resulted from
the electronic effect. It should be mentioned that the
heteroaromatic furan substituted cyanoacrylamide was
tolerated under the present catalytic system, likewise with
excellent stereoselectivity (entry 15). The current protocol
can also be applied to other linear aliphatic aldehydes.
Acetaldehyde was able to participate in this reaction in
80% yield, but with moderate 3/1 diastereoselectivity and
68% ee (entry 16). When butyraldehyde was surveyed, the
2-piperidinone derivative 4p was isolated in 85% yield and
6:1 dr with 94% ee, although a long reaction time was
required (entry 17). The longer chain valeraldehyde and
hexaldehyde were also investigated, affording 2-piperidi-
none 4q and 4r in moderate yield with 94% and 95% ee,
respectively (entries 18ꢀ19). The 3-phenylpropanal
worked in this transformation giving 4s in 60% yield and
5:1 dr with 92% ee (entry 20). Unfortunately, no desired
10
11
12
13
14
15
CH2Cl2
CHCl3
MeOH
DMF
DMSO
dioxane
5:1
3:1
3:1
nd
94
55
<10
<10
94
nd
6:1
a Unless otherwise noted, reactions were carried out with 2a
(0.1 mmol), propionaldehyde 3a (0.2 mmol), and catalyst 1 (0.02 mmol,
20 mol %) and 20 mol % of 4-nitrobenzoic acid in 0.5 mL of solvent
indicated. b The time required for the first-step reaction. c Isolated yield
of 4a. d Determined by crude 1H NMR. e ee of major diastereomer
determined by chiral HPLC analysis. f No additives used. g Benzoic acid
(20 mol %) used. h 20 mol % acetic acid used. i Trifluoroacetic acid
(20 mol %) used. j Triflic acid (20 mol %) used.
indicated that 1,4-dioxane was the optimal choice (entries
10ꢀ15). To the best of our knowledge, this result presents
the first highly stereoselective reaction initiated by a Mi-
chael addition of aliphatic aldehydes to cyanoacrylamides.
With the optimal conditions for the reaction established
above, we next examined the generality of the protocol for
various cyanoacrylamides 2 and aliphatic aldehydes 3. As
summarized in Table 2, the electronic nature of the aro-
matic ring attached to the β-position of cyanoacrylamides
had little effect on the reaction. Various cyanoacrylamides
Org. Lett., Vol. XX, No. XX, XXXX
C

product was isolated when the branched isovaleraldehyde
was used (entry 21).
Scheme 2. A Millimole-Scale Synthesis and Absolute
Configuration of 4k
Scheme 1. Synthetic Transformations of 7a
The unreduced hemiaminal 7a could be converted smoothly
into other valuable compounds14 (Scheme 1). Upon oxida-
tion with PCC (pyridinium chlorochromate), piperidine-
2,6-dione 9 was produced in 88% yield, 6/1 dr and with
94%ee. When7awas treatedwithH2SO4 (35%, 2equiv) in
water for 24 h, the corresponding dehydration product 8
was formed in 95% yield and 6/1 dr with 94% ee with the
cyano functionality unaffected (Scheme 1).
Scheme 3. A Plausible Mechanism for the One-Pot Reaction
The present protocol could be scaled up to a millimole
scale with almost no reduction in yield and with very subtle
erosion in enantioselectivity (Scheme 2). For example, the
reaction between 1 mmol of 3-bromophenyl substituted
cyanoacrylamide 2k with propionaldehyde proceeded
smoothly to afford 2-piperidinone 4k in 88% yield with
94% ee and 5:1 dr. The compound 4k could be grown to a
crystal suitable for X-analysis after a simple recrystalliza-
tion from the mixture solvent of hexane/ethyl acetate. The
absolute configuration of 4k was thus assigned to be 3R,
4R and 5R by single crystal X-ray diffraction analysis15
(see Supporting Informaition). The absolute configura-
tions of other products were tentatively assigned by analogy.
Based on the absolute configuration observed in the
experiment and previous literature,7e,f a plausible mechan-
ism for the one-pot reaction was proposed (Scheme 3).
Propionaldehyde first reacts with catalyst 1e to form a
stereodefined enamine intermediate A, which would react
with 2a to generate B by a Michael reaction, to afford a
mixture of diastereomers C after hydration and diaster-
eoselective protonation.7e,f Then C undergoes an intramo-
lecular hemiaminalization in which C3-epimerization
could occur, thereby generating7a as major diastereomers.
Removal of the 6-hydroxy group of 7a using Et3SiH/
and cyanoacrylamides, which proceeds through a Michael
addition followed by an intramolecular hemiaminaliza-
tion, and after reduction of the products, the correspond-
ing highly functionalized 2-piperidinones were obtained in
high yield and moderate diastereoselectivity with excellent
enantioselectivity. The one-pot reaction can lead to rapid
access to 2-piperidinone derivatives with three new stereo-
centers under mild reaction conditions. Studies toward the
application of this methodology in the synthesis of struc-
turally diversified molecules are ongoing.
Acknowledgment. We are grateful for the financial
support from National Natural Science Foundation of
China (21102116) and Science & Technology Department
of Sichuan Province (2013JY0095).
BF3 Et2O affords the desired product 4a.
In summary, we have developed a highly stereoselective
organocatalytic one-pot reaction of linear aliphatic aldehydes
3
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Han, B.; Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen, Y.-C. Angew.
Chem., Int. Ed. 2008, 47, 9971.
(15) CCDC 936011 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.can.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Center, 12 Union Road, Cambridge, CB21EZ, U.K.;
Fax: (þ44)1223-336033; or deposit@ccdc.cam.ac.uk).
The authors declare no competing financial interest.
D
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