A simple primary amine thiourea catalyzed highly enantioselective conjugate addition of α,α-disubStituted aldehydes to maleimides

Article abstract of DOI:10.1002/chem.201001207

(Figure Presented) Branch point: A simple primary amine thiourea catalyzed highly enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides has been developed. The biologically useful chiral disubstituted α-branched succinimides are attained with the generation of two contiguous quaternary and/or tertiary stereogenic centers in one step with excellent enantioselectivities and in high yields under mild reaction conditions (see scheme).

Full text of DOI:10.1002/chem.201001207

COMMUNICATION
DOI: 10.1002/chem.201001207
A Simple Primary Amine Thiourea Catalyzed Highly Enantioselective
Conjugate Addition of a,a-Disubstituted Aldehydes to Maleimides
Fei Xue,[a] Lu Liu,[a] Shilei Zhang,[a] Wenhu Duan,*[a, b] and Wei Wang*[a, b, c]
Conjugate addition reactions are powerful and versatile
enantiomeric excess (ee)) were obtained when a-branched
isobutyraldehyde was used.
À
processes for the formation of C C bonds in organic synthe-
sis as a result of a wide variety of substances that can serve
as electrophiles and nucleophiles and, consequently, a di-
verse array of products can be generated.[1,2] Notably, in
recent years, organocatalytic, enantioselective conjugate re-
actions have been subject to intensive investigations. The
general observation is that enals, enones, and nitroolefins
are often used as Michael acceptors.[2] In sharp contrast, the
Because of significant steric hindrance and less reactivity,
examples of a,a-disubstituted aldehydes 1 as potential nu-
cleophilic partners in organocatalytic asymmetric conjugate
reactions are very limited.[8] So far, the successful systems
mainly rely on the use of highly active nitroolefins as effec-
tive Michael acceptors.[8] Notably, we,[8a,b] Barbas et al.,[8c,d]
and others[8e–g] have reported chiral amine promoted, highly
enantioselective conjugate additions of a,a-disubstituted al-
dehydes to nitroolefins. Moreover, the groups of Jacobsen[9a]
and Yan[9b] disclosed elegant chiral primary amines as pro-
moters for the process. Although the employment of malei-
mides for a direct, catalytic, asymmetric conjugate addition
reaction with a,a-disubstituted aldehydes presents an ap-
pealing approach to valuable chiral a-branched succini-
mides, the realization of the process faces formidable chal-
lenges of generating contiguous quaternary and/or tertiary
stereogenic centers with the highly hindered, less reactive
substrates (Scheme 1). Herein, we report a simple primary
amine thiourea promoted conjugate addition of aldehydes,
including a,a-disubstituted substrates, to maleimides in high
yields and with high enantioselectivities.
The unsatisfactory results (e.g., low enantioselectivity) of
chiral secondary amine catalyzed conjugate addition of a,a-
disubstituted aldehydes to maleimides[7,10] prompted us to
seek new alternative catalytic systems. It is recognized that
chiral primary amines have been demonstrated as unique
promoters for the activation of enolizable carbonyl com-
pounds to form enamines for nucleophilic additions.[11,12] Ac-
cordingly, we probed a model Michael reaction of isobutyr-
aldehyde (1a) with maleimide (2a) in the presence of a bi-
functional chiral primary amine (15 mol%) and H2O
(15 mol%) in CHCl3 at RT (Table 1). Among the primary
amine catalysts surveyed, catalysts I and II, which are simi-
lar to the Takamoto catalyst[13] were found to induce particu-
larly high enantioselectivities (Table 1, entries 1 and 2). Fur-
thermore, notably, they promoted the conjugate addition
process very quickly and the reaction was accomplished in
less than 1 h in high yields. We decided to select the simple
use of maleimides 2,[3–5] for C C bond formation remains
À
elusive, despite the broad synthetic and biological utilities of
chiral a-branched succinimides 3 (Scheme 1).[6] To the best
Scheme 1. Catalytic enantioselective conjugate addition of aldehydes to
maleimides.
of our knowledge, only a single study reported by Cꢀrdova
and co-workers describes an enantioselective conjugate ad-
dition of aldehydes to maleimides catalyzed by a pyrrolidine
silyl ether.[7] However, the reaction has a significant limita-
tion. A low yield (40%) and poor enantioselectivity (51%
[a] F. Xue, L. Liu, Dr. S. Zhang, Prof. Dr. W. Duan, Prof. Dr. W. Wang
School of Pharmacy, East China University of Science
Shanghai 200237, China
[b] Prof. Dr. W. Duan, Prof. Dr. W. Wang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
555 Zuchongzhi Road, Shanghai 201203 (China)
Fax : (+86)21-5080-6032
E-mail: whduan@mail.shcnc.ac.cn
[c] Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, MSC03 2060
Albuquerque, NM 87131-0001 (USA)
Fax : (+1)505-277-2609
E-mail: wwang@unm.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001207.
Chem. Eur. J. 2010, 16, 7979 – 7982
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7979

Table 1. Optimization of reaction conditions for the catalytic enantiose-
The reaction was also applicable to an aliphatic maleimide
(Table 2, entry 5). The reactions of cyclopentanecarbalde-
hyde (Table 2, entry 6) or cyclohexanecarbaldehyde
(Table 2, entry 7) with N-phenylmaleineimide displayed un-
expected reaction behavior. Under the same reaction condi-
tions, either low reaction yields or low enantioselectivities
were observed. Therefore, we used 15 mol% of I for both
cases and reactions occurred much faster. Furthermore, it
was found that slow addition of the solution of N-phenylma-
leineimide to cyclopentanecarbaldehyde was crucial to ach-
ieve high efficiency (Table 2, entry 6). It was essential to
change the addition sequence of starting materials for the
reaction of cyclohexanecarbaldehyde (Table 2, entry 7).
Slow addition of the cyclohexanecarbaldehyde to the reac-
tion solution of N-phenylmaleineimide and I resulted in a
good yield and high enantioselectivity. The I-catalyzed con-
jugate addition reactions were also applicable to linear alde-
hydes without a-branch side chains. High enantioselectivi-
ties and good yields were obtained despite low diastereose-
lectivities (Table 2, entries 8 and 9). Finally, we probed un-
symmetrical a,a-disubstituted aldehydes using 5 mol% of I.
Notably, two contiguous quaternary and tertiary stereogenic
centers were created in one step with excellent enantioselec-
tivities in spite of relatively low diastereoselectivities
(Table 2, entries 10–12).
lective Michael reaction of isobutyraldehyde (1a) with maleimide (2a).[a]
Entry
Cat.
Solvent
t [h]
0.67
0.67
1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
I
CHCl3
CHCl3
CHCl3
CHCl3
THF
93
96
96
66
87
85
89
89
98
93
87
87
97
94
77
88
81
53
62
91
96
97
97
97
II
III
IV
I
I
I
24
1.25
1.67
0.5
0.67
2
2.5
22
70
iPrOH
H2O
8[d]
9[e]
10
11
12
I
I
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
I[f]
I[g]
I[h]
[a] Unless specified, see the Experimental Section. [b] Isolated yields.
[c] Determined by HPLC analysis (Chiralcel OD-H). [d] Without
15 mol% H2O. [e] Reaction performed at 48C. [f] 5 mol% used.
[g] 1 mol% used. [h] 0.5 mol% used.
It is noted that the nice feature of the I-catalyzed Michael
reaction is that the process proceeded cleanly to give an
adduct in high purity. For example, simple evaporation of
the reaction solvents and volatile compounds gave product
amine thiourea I for further optimization reaction condi-
tions. While variation of solvents had a pronounced effect
on enantioselectivity (Table 1, entries 1 and 5–7), high yields
were obtained in all cases. Moreover, we observed that
water as the additive was beneficial to the enantioselectivity
of the reaction (Table 1, entry 1 vs. entry 8). It appeared that
reaction temperature had a limited impact on both yield and
enantioselectivity (Table 1, entry 9). Finally, the effect of
catalyst loading on reaction efficiency was evaluated
(Table 1, entries 10–12). Remarkably, the reaction proceed-
ed smoothly even at catalyst with a loading as low as
0.5 mol% without loss of yield and enantioselectivity (87%
yield and 97% ee, entry 12,). From operational convenience
point of view, the use of 1 mol% I ensured a high level of
reaction efficiency and enantioselectivity while maintaining
reasonable reaction time (Table 1, entry 11).
1
3c in more than 95% purity based on H NMR spectroscop-
ic analysis (Table 2, entry 3 and Figure S1 in the Supporting
Information). The absolute configuration of the products
was determined by single-crystal X-ray analysis of 3l
(Figure 1).[14]
Encouraged by these promising results, we next examined
the scope and limitation of the I-promoted conjugate addi-
tion reactions with a variety of aldehydes and maleimides
(Table 2). As demonstrated, the process served as a general
approach to the formation of highly valuable, chiral disubsti-
tuted, a-branched succinimides 3 in high yields and with ex-
cellent enantioselectivities. The reactions of maleimides with
electron-neutral, -donating and -withdrawing groups with
isobutyraldehyde proceeded smoothly to give structurally di-
verse succinimides 3 (Table 2, entries 1–4) It was found that
the electron-withdrawing group in 2 slowed down the reac-
tion; however, the use of higher catalyst loading (15 mol%)
dramatically enhanced the reaction rate (Table 2, entry 4).
Figure 1. X-ray structure of compound 3l.
In summary, an unprecedented primary amine thiourea
promoted, direct, highly efficient conjugate addition reac-
tion of a,a-disubstituted aldehydes and maleimides has been
developed. The approach serves as a powerful tool for the
preparation of synthetically and biologically important
chiral disubstituted, a-branched succinimides. This structur-
ally simple catalyst exhibits high catalytic activity and enan-
tioselectivity towards a variety of aldehydes and maleimides
with significant structural variations under mild reaction
conditions. Furthermore, remarkably, two contiguous quater-
7980
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7979 – 7982

Enantioselective Conjugate Addition
COMMUNICATION
Table 2. Scope of I promoted enantioselective conjugate addition reactions of aldehydes 1 with maleimides 2.[a,10]
Entry Product
t [h] Yield [%][b] ee [%][c] d.r.[d] Entry Product 3
t [h] Yield [%][b] ee [%][c]
d.r.[d]
1
22
20
87
93
97
95
–
–
8
48
48
70
79
68
79
96 (major)
98 (minor)
1.3:1
2
3
18
86
98
–
9
95 (major)
1.2:1
4[e]
0.83 87
95
99
–
–
91 (minor)
98 (major)
5
18
91
69
10[h]
2.3:1
6[f]
6
96
95
–
–
96 (minor)
11[h]
84
81
99 (major)
96 (minor)
99 (major)
75 (minor)
7[g]
12
72
11:2
12[g]
84
91
5:1
[a] Unless specified, see the Experimental Section. [b] Isolated yields. [c] Determined by chiral HPLC analysis (Chiralcel OD-H, OJ-H, Chiralcel AS-H,
or AD-H). [d] Determined by 1H NMR spectroscopic analysis of the crude reaction mixture. [e] 15 mol% I used. [f] 15 mol% I and 10 equiv of cyclopen-
tanecarbaldehyde used. [g] 15 mol% I and 8 equiv of cyclopentanecarbaldehyde used. [h] 5 mol% I used.
Chem. Eur. J. 2010, 16, 7979 – 7982
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7981

W. Duan, W. Wang et al.
Tan, Angew. Chem. 2009, 121, 3681; C.-H. Tan, Angew. Chem. 2009,
121, 3681; Angew. Chem. Int. Ed. 2009, 48, 3627.
[5] We reported the first example of organocatalytic enantioselective
cascade Michael–aldol reaction involving maleimides: L. Zu, H. Xie,
H. Li, J. Wang, W. Jiang, W. Wang, Adv. Synth. Catal. 2007, 349,
1882.
[6] a) S. Ahmed, Drug Discovery 1996, 14, 77; b) A.-S. S. Hamad Elgaz-
wy, Molecules 2000, 5, 665; c) A. Mitchenson, A. Nadin, J. Chem.
Soc. Perkin Trans. 1 2000, 2862; d) M. L. Curtin, R. B. Garland,
H. R. Heyman, R. R. Frey, M. R. Michaelides, J. Li, L. J. Pease,
K. B. Glaser, P. A. Marcotte, S. K. Davidsen, Bioorg. Med. Chem.
Lett. 2002, 12, 2919; e) R. Ballini, G. Bosica, G. Cioci, D. Fiorini, M.
Petrini, Tetrahedron 2003, 59, 3603; f) J. Pohlmann, T. Lampe, M.
Shimada, P. G. Nell, J. Pernerstorfer, N. Svenstrup, N. A. Brunner,
G. Schiffer and C. Freiberg, Bioorg. Med. Chem. Lett. 2005, 15,
1189.
nary and/or tertiary stereogenic centers can be efficiently
generated in one step with excellent enantioselectivities.
Further efforts on exploration of new organic transforma-
tions using these types of catalysts and evaluation of the bio-
logical properties of the intriguing succinimides are under-
way in our laboratory.
Experimental Section
General procedure (Table 2 entry 1 as an example): Unless specifically
stated, N-phenylmaleimide (2a, 0.2 mmol) was added to a solution of iso-
butyraldehyde (1a) (0.4 mmol) in the presence of catalyst
I
(0.002 mmol), water (0.15 equiv) and chloroform (0.5 mL), and the result-
ing solution was stirred at room temperature. The reaction mixture was
directly purified by silica gel chromatography without workup and frac-
tions were collected and concentrated in vacuo to provide the pure de-
sired product 3a used for compound characterization and chiral HPLC
analysis.
[7] G.-L. Zhao, Y. Xu, H. Sundꢃn, L. Eriksson, M. Sayah A. Cꢀrdova,
Chem. Commun. 2007, 734.
[8] For examples of a,a-disubstituted aldehydes in organocatalytic
enantioselective conjugation addition to nitroolefins, see: a) W.
Wang, J. Wang, H. Li, Angew. Chem. 2005, 117, 1393; Angew. Chem.
Int. Ed. 2005, 44, 1369; b) J. Wang, H. Li, B. Lou, L. Zu, H. Guo, W.
Wang, Chem. Eur. J. 2006, 12, 4321; c) N. Mase, R. Thayumanavan,
F. Tanaka, C. F. Barbas III, Org. Lett. 2004, 6, 2527; d) N. Mase, K.
Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas III, J. Am.
Chem. Soc. 2006, 128, 4966; e) S. Mossꢃ, M. Laars, K. Kriis, T.
Kanger, A. Alexakis, Org. Lett. 2006, 8, 2559; f) C.-L. Cao, M.-C.
Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901; g) Z. Zheng, B. L.
Perkins, B. Ni, J. Am. Chem. Soc. 2010, 132, 50; h) S. Brandes, B.
Niess, M. Bella, A. Prieto, J. Overgaard, K. A. Jørgensen, Chem.
Eur. J. 2006, 12, 6039; an example of aldol reaction: i) M. Markert,
U. Scheffler, R. Mahrwald, J. Am. Chem. Soc. 2009, 131, 16642.
[9] a) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew. Chem. 2006, 118,
6514; Angew. Chem. Int. Ed. 2006, 45, 6366; b) X.-J. Zhang, S.-P.
Liu, J.-H. Lao, G.-J. Du, M. Yan, A. S. C. Chan, Tetrahedron: Asym-
metry 2009, 20, 1415.
Acknowledgements
Financial support of this research is supported by the China 111 Project
(grant B07023) and the “thousands of talents” program (W.W.) is grate-
fully acknowledged.
Keywords: aldehydes · maleimides · Michael addition ·
organocatalysis
[10] For a nonasymmetric approach, see: J. Nçth, K. J. Frankowski, B.
Neuenswander, J. Aubꢃ, O. Reiser, J. Comb. Chem. 2008, 10, 456.
[11] For recent reviews of primary amine catalyzed reactions, see: a) Y.-
C. Chen, Synlett 2008, 1919; b) L.-W. Xu, J. Luo, Y.-X. Lu, Chem.
Commun. 2009, 1807.
[1] For reviews of conjugate addition reactions, see: a) P. Perlmutter,
Conjugate Addition Reactions in Organic Synthesis, Pergamon,
Oxford, 1992; b) M. Sibi, S. Manyem, Tetrahedron 2001, 57, 8033;
c) J. Christoffers, A. Baro, Angew. Chem. 2003, 115, 1726; Angew.
Chem. Int. Ed. 2003, 42, 1688; d) R. Ballini, G. Bosica, D. Fiorini, A.
Palmieri, M. Petrini, Chem. Rev. 2007, 107, 933.
[2] For recent reviews of organocatalyzed conjugate addition reactions,
see: a) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem.
2002, 1877; b) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118,
1550; Angew. Chem. Int. Ed. 2006, 45, 1520; c) D. Almas¸i, D. A.
Alonso, C. Nꢂjera, Tetrahedron: Asymmetry 2007, 18, 299; d) S. B.
Tsogoeva, Eur. J. Org. Chem. 2007, 1701; e) S. Mukherjee, J. W.
Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; f) P. Mel-
chiorre, M. Marigao, A. Carlone, G. Bartoli, Angew. Chem. 2008,
120, 6232; Angew. Chem. Int. Ed. 2008, 47. 6138; g) S. Bertelsen,
K. A. Jørgensen, Chem. Soc. Rev. 2009, 38, 2178.
[3] Examples of chiral Lewis acid catalyzed Michael additions, see:
a) J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999, 121, 8959;
b) S. Harada, N. Kumagai, T. Kinoshita, S. Matsunaga, M. Shibasaki,
J. Am. Chem. Soc. 2003, 125, 2582; c) R. Shintani, K. Ueyama, I.
Yamada, T. Hayashi, Org. Lett. 2004, 6, 3425; d) R. Shintani, W.-L.
Duan, T. Nagano, A. Okada, T. Hayashi, Angew. Chem. 2005, 117,
4687; Angew. Chem. Int. Ed. 2005, 44, 4611; e) R. Shintani, W.-L.
Duan, T. Hayashi, J. Am. Chem. Soc. 2006, 128, 5628.
[12] For selected examples, see: a) H. Huang, E. N. Jacobsen, J. Am.
Chem. Soc. 2006, 128, 7170; b) K. Liu, H.-F. Cui, J. Nie, K.-Y. Dong,
X.-J. Li, J.-A. Ma, Org. Lett. 2007, 9, 923; c) S. B. Tsogoeva, S. Wei,
Chem. Commun. 2006, 1451; d) J.-W. Xie, L. Yue, W. Chen, W. Du,
J. Zhu, J.-G. Deng, Y.-C. Chen, Org. Lett. 2007, 9, 413; e) J.-W. Xie,
W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu,
J.-G. Deng, Angew. Chem. 2007, 119, 393; Angew. Chem. Int. Ed.
2007, 46, 389; f) S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9,
599; g) S. S. V. Ramasastry, H. Zhang, F. Tanaka, C. F. Barbas III, J.
Am. Chem. Soc. 2007, 129, 288; h) P. Ricci, A. Carlone, G. Bartoli,
M. Bosco, L. Sambri, P. Melchiorre, Adv. Synth. Catal. 2008, 350, 49;
i) R. P. Singh, K. Bartelson, Y. Wang, H. Su, X. Lu, L. Deng, J. Am.
Chem. Soc. 2008, 130, 2422; j) X. Wang, C. M. Reisinger, B. List, J.
Am. Chem. Soc. 2008, 130, 6070; k) P. Li, Y. Wang, X. Liang, J, Ye,
Chem. Commun. 2008, 3302; l) Q. Zhu, L. Cheng, Y.-X. Lu, Chem.
Commun. 2008, 6315; m) K. Mei, M. Jin, S.-L. Zhang, P. Li, W.-J.
Liu, X.-B. Chen, F. Xue, W.-H. Duan, W. Wang, Org. Lett. 2009, 11,
2864; n) Q. Zhu, Y.-X. Lu, Chem. Commun. 2010, 46, 2235.
[13] T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672.
[4] For limited examples for using maleimides in organocatalysis, see:
a) G. Bartoli, M. Bosco, A. Carlone, A. Cavalli, M. Locatelli, A.
Mazzanti, P. Ricci, L. Sambri, P. Melchiorre, Angew. Chem. 2006,
118, 5088; Mazzanti, P. Ricci, L. Sambri, P. Melchiorre, Angew.
Chem. 2006, 118, 5088; Angew. Chem. Int. Ed. 2006, 45, 4966; b) W.
Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh, C.-H. Tan,
Adv. Synth. Catal. 2007, 349, 2454; c) Z. Jiang, W. Ye, Y. Yang, C.-
H. Tan, Adv. Synth. Catal. 2008, 350, 2345; d) Z. Jiang, Y. Pan, Y.
Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang, M. W. Wong; C.-H.
[14] The structure of compound derived from molecule 3l was deter-
mined by X-ray crystal analysis. CCDC-772788 contains the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: May 5, 2010
Published online: June 10, 2010
7982
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7979 – 7982