Highly efficient catalytic system for enantioselective Michael addition of aldehydes to nitroalkenes in water

Article abstract of DOI:10.1002/anie.200704161

(Chemical Equation Presented) Organocatalysis: A highly effective catalytic procedure for the Michael addition of aldehydes to nitroalkenes is achieved by combining the excellent asymmetric induction ability of o-TMS-protected diphenylprolinol compounds, the quick formation of enamines in the presence of benzoic acid, and the highly concentrated organic phase in water (see scheme; TMS=trimethylsilyl).

Full text of DOI:10.1002/anie.200704161

Angewandte
Chemie
DOI: 10.1002/anie.200704161
Nucleophilic Additions
Highly Efficient Catalytic System for Enantioselective Michael
Addition of Aldehydes to Nitroalkenes in Water**
Shaolin Zhu, Shouyun Yu, and Dawei Ma*
Since Betancort and Barbas reported the first organocatalytic
asymmetric Michael addition of aldehydes to nitroalkenes,[1]
2 mol% of catalyst for the known substrates) was discovered.
Herein, we disclose our results.
a
great effort has been devoted to the development of more
selective and efficient catalytic systems for this synthetically
useful transformation,[2–4] and significant progress has been
made.Especially, the use of o-TMS-protected diphenylproli-
nol (1; TMS = trimethylsilyl)[3e] or pyrrolidine sulfonamide
(2)[3d,h] as catalysts has given rise to excellent enantioselectiv-
The required b-nitroacrylate compounds were easily
accessible by the condensation of glyoxylic acid with nitro-
methane and subsequent esterification and elimination.
Initially, we conducted our Michael addition under the
conditions reported by Hayashi et al.[3e] We found that after
24 h, the desired adduct 5 and its epimer were produced with
good diastereoselectivity and enantioselectivity (entry 1,
Table 1).However, the conversion was incomplete, which
prompted us to vary the reaction conditions.Changing the
Table 1: Effect of the additive and the solvents on the Michael addition of
n-pentanal to methyl 3-nitroacrylate (catalyzed by amine 4).[a]
ities in the reactions.However, for a long time, these reactions
required a large excess of donor source (up to 10 equivalents
of aldehyde) as well as high catalyst loadings (between 10 and
20 mol%), and they gave poor results when alkyl-substituted
nitroalkenes were employed.These problems were efficiently
solved by Palomo and co-workers by using the newly designed
catalyst 3.[3j] However, a loading of more than 5 mol% of this
catalyst was still required in their experiments (although, at
the time, this represented the lowest catalyst/substrate ratio
employed in any enamine-based Michael addition with
excellent enantioselectivity).While catalyst design has been
the subject of several studies, little attention has been paid to
exploring functionalized nitroalkene compounds as substra-
tes.[3b,n] Such studies would be of immense benefit for
expanding the scope of application of this reaction in organic
synthesis.We recently found that b-nitroacrylate compounds
are suitable acceptors for this reaction, the products of which
are the precursors of biologically important b-amino acids[5]
and b-lactams.[6] Accompanying this study, a more efficient
catalytic system (which works in water and requires only 0.5–
Entry
Solvent
Benzoic acid
[mol%]
t [h]
Yield
[%][b]
syn/anti[c]
ee
[%][d]
1
2
n-hexane
toluene
0
water
water
water
water
0
0
24
24
67
1.5
2
65[e]
80
91:9
91
90
88
95:5
67:33
94
94
3water
22
100
50
50
25
97
4
5
6
7
53:47
97:3
64:36
98:2
>99
>99
>99
>99
1.5
4
82
[a] Reaction conditions: methyl 3-nitroacrylate (1 mmol), n-pentanal
(2 mmol), 10 mol% 4 (5 mol% 4 was used for entries 5 and 7), 2 mL of
solvent, 08C for 1 h, then RT for the indicated time. [b] Yield of isolated
product. [c] Determined by means of 1H NMR measurements performed
on the crude product. [d] Determined by means of chiral-phase HPLC
analysis of the syn product. [e] About 10% of methyl 3-nitroacrylate was
not consumed (determined by 1H NMR spectroscopy).
solvent to toluene led to a faster reaction, but the diastereo-
selectivity decreased significantly (entry 2, Table 1).Barbas
and co-workers recently reported that water and brine were
good media for organocatalytic reactions.[3k,7a] We were
pleased to see that our reaction worked well in water to
afford compound 5 with a high enantioselectivity (97% ee)
and good diastereoselectivity (entry 3, Table 1).Since it had
been observed that the addition of some Brønsted acids could
promote the formation of enamines, thereby accelerating
amine-catalyzed reactions,[3a,8] we conducted the reaction in
the presence of benzoic acid.When benzoic acid (100 mol%)
was added, the reaction was greatly accelerated, although
poor diastereoselectivity was observed (entry 4, Table 1).
Interestingly, the selectivity was greatly improved by reducing
the catalyst loading to 5 mol% and adding 50 mol% of
[*] S. Zhu, Dr. S. Yu, Prof. Dr. D. Ma
State Key Laboratory of Bio-Organic and Natural Products
Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (P.R. China)
Fax: (+86)21-64166128
E-mail: madw@mail.sioc.ac.cn
[**] The authors are grateful to the Chinese Academy of Sciences and the
National Natural Science Foundation of China (grant 20621062) for
their financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 545 –548
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
545

Communications
benzoic acid (entry 5, Table 1), whereas simply reducing the
amount of benzoic acid still gave poor diastereomeric ratios
(entry 6, Table 1).These results indicated that high catalyst
loadings, which lead to quick conversion, could decrease the
overall diastereoselectivity.This phenomenon has also been
observed in some organocatalytic reactions.[9] Since using
5 mol% of catalyst 4 and 25 mol% of benzoic acid slowed
down the reaction (entries 5 and 7, Table 1), we decided to use
a ratio of 1:10 for the catalyst and the additive in the
subsequent studies.
Scheme 1. Synthesis of amino acid 13. Reagents and conditions:
a) Pd(OH)2, H2, MeOH; then benzyl chloroformate, Et3N, DMAP,
CH2Cl2, 54%; b) aq. LiOH, MeOH, THF; then Pd/C, H2, MeOH, 90%.
Using the optimized reaction conditions we examined a
number of b-nitroacrylate and aldehyde compounds
(Table 2).In most cases, good yields and excellent diastereo-
and enantioselectivities were observed.When 2-phenylpro-
logue of the anticonvulsant pregabalin have been disclosed to
date[10]—our route being shorter and more convenient.
The excellent performance of our procedure in Michael
additions of aldehydes to b-nitroacrylate compounds also
encouraged us to check if it could provide improved results
when simple aryl- and alkyl-substituted nitroalkenes were
employed.Gratifyingly, for aryl nitroalkenes, excellent results
were obtained by using only 1 mol% of the catalyst in less
than 12 h (entries 1–6, 8, and 9, Table 3).Further reduction of
the catalyst loading still gave satisfactory results (entry 7,
Table 3).To our knowledge, these results represent the lowest
suitable catalyst loadings reported to date for Michael
additions and for several other organocatalyst-mediated
reactions.[11]
Reaction of b-nitrostyrene with 2-methylpropanal pro-
duced adduct 21 (with 97% yield and 92% ee), although a
prolonged reaction time and increased catalyst loading were
required (entry 10, Table 3).This is—to date—the highest
ee value achieved for this Michael adduct, thus providing
further evidence of the excellent asymmetric induction ability
of o-TMS-protected diphenylprolinol 4 and its enantiomer 1.
In the case of less-reactive alkyl nitroalkene compounds, a
catalyst loading of 2 mol% was necessary to ensure complete
conversion within 2–12 h.Variation of the aldehyde and alkyl
nitroalkene species did not alter the excellent yield, diaste-
reoselectivity, and enantioselectivity (entries 11–15, Table 3).
To investigate the suitability of our system for multigram-
scale synthesis, some reactions were carried out on a 10-mmol
scale using a slight excess of aldehyde (entries 4 and 13,
Table 3).In general, we obtained satisfactory results, although
in one case both the diastereoselectivity and the enantiose-
lectivity were slightly diminished (entries 3 and 4, Table 3).
Thus, our procedure is quite promising for pharmaceutical
and industrial applications.
Table 2: Enantioselective Michael addition of aldehydes to 3-nitroacry-
lates.[a]
Entry
Product
t [h]
Yield
[%][b]
syn/anti[c]
ee
[%][d]
1
2
3
6
2
7
90
86
74
97:3
98:2
97:3
>99
>99
98
4
2.5
8398:2
>99
5
6
2
81
81
96:4
>99
15
81:19
96
[a] Reaction conditions: 3-nitroacrylate (1 mmol), aldehyde (2 mmol),
5 mol% 4, 50 mol% benzoic acid, 2 mL of water, 08C for 1 h, then RT for
the indicated time. [b] Yield of isolated product. [c] Determined by means
1
of H NMR measurements performed on the crude product. [d] Deter-
mined by means of chiral-phase HPLC analysis of the syn product.
panal was used, the diastereoselectivity dropped dramatically.
Noteworthy is that the tert-butyl and benzyl ester moieties in 6
and 7 can be cleaved by acid treatment and hydrogenolysis,
respectively, to furnish the corresponding acids in a specific
manner, and that the olefinic double bond in 10 can be further
modified to afford molecules of higher complexity.
To demonstrate the utility of our reaction, adduct 9 was
transformed into the known amino acid 13[10] by means of a
four-step procedure (Scheme 1).Hydrogenation of 9, fol-
lowed by protection with benzyl chloroformate, provided
pyrrolidine 12, which was then subjected to deprotection to
afford 13 (with an overall yield of 48%).The analytical data
obtained for this compound were identical to the reported
values, which confirms the stereochemistry of adduct 9.Two
routes for assembling this conformationally restricted ana-
In conclusion, we have developed a new procedure for the
asymmetric Michael addition of aldehydes to nitroalkenes,
which provides an excellent solution to the problems asso-
ciated with this reaction.The diarylprolinol ether catalyst
used herein is simple and easily accessible.These advantages
make this procedure more suitable for practical use.Mech-
anistically, the progress may result from a combination of the
excellent asymmetric induction ability of the o-TMS-pro-
tected diphenylprolinol compounds,[12] the quick formation of
enamine species in the presence of benzoic acid, and the
highly concentrated organic phase directed by the aqueous
medium.[7] These observations may prepare the ground for
the development of more effective conditions for other
enamine-based reactions catalyzed by o-TMS-protected
diphenylprolinol compounds.Investigations in this direction,
546
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 545 –548

Angewandte
Chemie
acrylate was consumed (the course of the reaction was monitored by
Table 3: Enantioselective Michael addition of aldehydes to aryl- and
alkyl-substituted nitroalkenes.[a]
means of thin-layer chromatography, TLC).The reaction was then
quenched by adding saturated NaHCO3, and the resultant mixture
was extracted with ethyl acetate.The combined organic layers were
dried over Na2SO4 and concentrated.Purification by flash column
chromatography (silica gel, petroleum ether/AcOEt) afforded the
Michael adduct (195 mg, 90%) as a colorless oil.A ratio of 97:3 for
the syn and anti isomers was determined by performing 1HNMR
measurements on the crude mixture.The ee value (> 99%) was
measured by means of high-performance liquid chromatography
(HPLC) on a chiral stationary phase: Chiralpak IC column, l =
214 nm, EtOH/hexane 10:90, tR = 23.4 min (major), 28.5 min (minor).
Entry Product
Catalyst t [h] Yield syn/anti[c] ee
[mol%]
[%][b]
[%][d]
1
2
1
6
96
98:2
>99
1
1387
96:4
>99
3
4
1
1
4
24
98
95:5
92:8
>99
>99
95[e]
Received: September 10, 2007
Published online: November 23, 2007
5
1
12
86
97:3
>99
Keywords: aldehydes · asymmetric catalysis ·
diastereoselectivity · Michael addition · nitroalkenes
.
6
7
1
0.5
2
6
95
96
98:2
98:2
>99
>99
[1] J.M.Betancort, C.F.Barbas III, Org. Lett. 2001, 3, 3737.
[2] For recent reviews, see: a) J.L.Vicario, D.Badía, L.Carrillo,
Synthesis 2007, 2065; b) S.B.Tsogoeva, Eur. J. Org. Chem. 2007,
8
1
5
86
96:4
>99
1701; c) D.Enders, C.Grondal, M.R.M.Hüttl,
Angew. Chem.
2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46, 1570.
[3] a) N.Mase, R.Thayumanavan, F.Tanaka, C.F.Barbas III,
Org.
Lett. 2004, 6, 2527; b) O.Andrey, A.Vidonne, A.Alexakis,
Tetrahedron Lett. 2003, 44, 7901; c) O.Andrey, A.Alexakis, A.
Tomassini, G.Bernardinelli, Adv. Synth. Catal. 2004, 346, 1147;
9
1
7
96
97:3
–
>99
92
d) W.Wang, J.Wang, H.Li,
Angew. Chem. 2005, 117, 1393;
10
10
60
97
Angew. Chem. Int. Ed. 2005, 44, 1369; e) Y.Hayashi, H.Gotoh,
T.Hayashi, M.Shoji, Angew. Chem. 2005, 117, 4284; Angew.
Chem. Int. Ed. 2005, 44, 4212; f) C.E.T.Mitchell, A.J.A.Cobb,
S.V.Ley, Synlett 2005, 611; g) Y.Xu, W, Zhou, H.SundØn, I.
Ibrahem, A.Córdova, Adv. Synth. Catal. 2006, 348, 418; h) J.
[f]
11
12
2
2
2
8394:6
>99
12
88
94:6[f]
94:6[f]
>99
>99
[e]
Wang, H.Li, B.Lou, L.Zu, H.Guo, W.Wang,
Chem. Eur. J.
132
44
78
2006, 12, 4321; i) S.Luo, X.Mi, L.Zhang, S.Liu, H.Xu, J-.P.
Cheng, Angew. Chem. 2006, 118, 3165; Angew. Chem. Int. Ed.
2006, 45, 3093; j) C.Palomo, S.Vera, A.Mielgo, E.Gomez-
Bengoa, Angew. Chem. 2006, 118, 6130; Angew. Chem. Int. Ed.
2006, 45, 5984; k) N.Mase, K.Watanabe, H.Yoda, K.Takabe, F.
Tanaka, C.F.Barbas III, J. Am. Chem. Soc. 2006, 128, 4966; l) S.
14
2
2
2.5 81
96:4
>99
>99
15
5
85
94:6[f]
Mosse, M.Laars, K.Kriis, T.Kanger, A.Alexakis,
2006, 8, 2559; m) S.Mosse, A.Alexakis, Org. Lett. 2006, 8, 3577;
n) E.Reyes, J.L.Vicario, D.Badia, L.Carrillo, Org. Lett. 2006,
8, 6135; o) S.H.McCooey, S.J.Connon, Org. Lett. 2007, 9, 599;
p) M.T.Barros, A.M.F.Phillips, Eur. J. Org. Chem. 2007, 178;
Org. Lett.
[a] Reaction conditions: 3-nitroalkene (1 mmol), aldehyde (2 mmol),
0.5–2 mol% 4, 5–20 mol% benzoic acid, 2 mL of water, 08C for 1 h, then
room temperature for the indicated time. [b] Yield of isolated product.
q) S.Sulzer-MossØ, A.Alexakis, Chem. Commun. 2007, 3123.
[4] For Michael reactions involving tandem processes, see: a) D.
Enders, M.R.M.Hüttl, C.Grondal, G.Raabe, Nature 2006, 441,
861; b) D.Enders, M.R.M.Hüttl, J.Runsink, G.Raabe, B.
Wendt, Angew. Chem. 2007, 119, 471; Angew. Chem. Int. Ed.
2007, 46, 467; c) Y.Hayashi, T.Okano, S.Aratake, D.Hazelard,
Angew. Chem. 2007, 119, 5010; Angew. Chem. Int. Ed. 2007, 46,
4922.
1
[c] Determined by means of H NMR measurements performed on the
crude product. [d] Determined by means of chiral-phase HPLC analysis
of the syn product. [e] The reaction was carried out on a 10-mmol scale
using 1.5 equivalents of aldehyde. [f] Determined by means of chiral-
phase HPLC analysis after purification.
[5] a) S.H.Gellman, Acc. Chem. Res. 1998, 31, 173; b) D.Seebach,
S.Abele, K.Gademann, B.Jaun, Angew. Chem. 1999, 111, 1700;
Angew. Chem. Int. Ed. 1999, 38, 1595; c) S.H.Lee, J.S.Park,
B.M.Kim, S.H.Gellmann, J. Org. Chem. 2003, 68, 1575.For
recent synthetic studies, see: d) M.A.Swiderska, J.D.Stewart,
Org. Lett. 2006, 8, 6131; e) H.Huang, X.Liu, J.Deng, Z.Zheng,
Org. Lett. 2006, 8, 3359; f) J.E. Beddow, S.G. Davies, A.D.
Smith, A.J.Russell, Chem. Commun. 2004, 2778.
as well as studies on the application of the above results to the
synthesis of more complex molecules, are currently under.
Experimental Section
Typical Procedure: n-Pentanal (213 mL, 2.0 mmol) was added to a
suspension of catalyst 4 (16 mg, 0.05 mmol), methyl 3-nitroacrylate
(131 mg, 1.0 mmol), and benzoic acid (61 mg, 0.5 mmol) in water
(2.0 mL) at 08C.After 1 h at 0 8C, the reaction mixture was allowed to
warm to room temperature and then stirred until methyl 3-nitro-
[6] a) M.M-.C.Lo, G.C.Fu,
J. Am. Chem. Soc. 2002, 124, 4572;
b) R.Fernꢀndez, A.Ferrete, J.M.Lassaletta, J.M.Llera, E.
Martín-Zamora, Angew. Chem. 2002, 114, 859; Angew. Chem.
Int. Ed. 2002, 41, 831, and references therein.
Angew. Chem. Int. Ed. 2008, 47, 545 –548
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
547

Communications
[7] a) N.Mase, Y.Nakai, N.Ohara, H.Yoda, K.Takabe, F.Tanaka,
Marigo, K.A.Jørgensen, Angew. Chem. 2007, 119, 2029; Angew.
Chem. Int. Ed. 2007, 46, 1983.
[9] a) Y.Chi, S.H.Gellman, Org. Lett. 2005, 7, 4253; b) B.List, J.
Am. Chem. Soc. 2002, 124, 5656.
C.F.Barbas III, J. Am. Chem. Soc. 2006, 128, 734; b) Y.Hayashi,
T.Sumiya, J.Takahashi, H.Gotoh, T.Urushima, M.Shoji,
Angew. Chem. 2006, 118, 972; Angew. Chem. Int. Ed. 2006, 45,
958; c) D.G.Blackmond, A.Armstrong, V.Coombe, A.Wells,
Angew. Chem. 2007, 119, 3872; Angew. Chem. Int. Ed. 2007, 46,
3798.
[10] a) R.Ling, I.V.Ekhato, J.R.Rubin, D.J.Wustrow,
Tetrahedron
2001, 57, 6579; b) R.Galeazzi, G.Martelli, G.Mobbili, M.
Orena, S.Rinaldi, Tetrahedron: Asymmetry 2003, 14, 3353.
[11] For recent reviews, see: a) P.I.Dalko, L.Moisan, Angew. Chem.
2004, 116, 5248; Angew. Chem. Int. Ed. 2004, 43, 5138; b) H.
Pellissier, Tetrahedron 2007, 63, 9267.
[12] For a review on diarylprolinol ether catalyzed reactions, see: C.
Palomo, A.Mielgo, Angew. Chem. 2006, 118, 8042; Angew.
Chem. Int. Ed. 2006, 45, 7876.
[8] For selected references, see: a) K.Sakthivel, W.Notz, T.Bui,
C.F. Barbas III, J. Am. Chem. Soc. 2001, 123, 5260; b) M.
Nakadai, S.Saito, H.Yamamoto, Tetrahedron 2002, 58, 8167;
c) N.Mase, F.Tanaka, C.F.Barbas III, Angew. Chem. 2004, 116,
2474; Angew. Chem. Int. Ed. 2004, 43, 2420; d) Y.Xu, A.
Córdova, Chem. Commun. 2006, 460; e) P.DinØr, M.Nielsen, M.
548
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 545 –548