Organocatalytic enantioselective Michael addition of malononitrile to nitroolefins catalyzed by bifunctional thiourea

Article abstract of DOI:10.1002/chir.20956

A novel enantioselective Michael addition of malononitrile to trans-β-nitroolefins in the presence of bifunctional amine thiourea organocatalyst is developed. The Michael reaction catalyzed by amine thioureas containing both central and axial chiral eleme

Full text of DOI:10.1002/chir.20956

CHIRALITY 23:514–518 (2011)
Organocatalytic Enantioselective Michael Addition of
Malononitrile to Nitroolefins Catalyzed by Bifunctional Thiourea
1
1
2
HAI-MING GUO,1 JIAN-GUO LI, GUI-RONG QU, XIAO-MEI ZHANG, AND WEI-CHENG YUAN2
*
1College of Chemistry and Environmental Science, Key Laboratory of Green Chemical Media and Reactions of Ministry of Education,
Henan Normal University, Xinxiang, Henan, People’s Republic of China
2Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, China
ABSTRACT
A novel enantioselective Michael addition of malononitrile to trans-b-nitroole-
fins in the presence of bifunctional amine thiourea organocatalyst is developed. The Michael
reaction catalyzed by amine thioureas containing both central and axial chiral elements pro-
ceeded smoothly and provided the desired adducts with high yields (up to 96% yield) and mod-
erate enantioselectivities (up to 83% enantiomeric excess). Chirality 23:514–518, 2011.
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2011 Wiley-Liss, Inc.
KEY WORDS: organocatalysis; Michael addition; malononitrile; nitroolefins; bifunctional
thiourea
INTRODUCTION
EXPERIMENTAL
Michael addition to electron-deficient nitroolefins is one of
Melting points are recorded with an XRC-1 micro-melting point appara-
1
tus and uncorrected. H and 13C NMR spectra were recorded on Brucker-
the important reactions in organic synthesis that provides
access to useful functionalized nitroalkanes,1,2 which are
readily converted into other useful compounds such as nitrile
oxide,3,4 amine,5–7 ketone,8 carboxylic acid,9 or other func-
tionalized compounds.10
400 and 2300 instruments. Proton chemical shifts (d) are given in ppm
relative to tetramethylsilane (d 0.00 ppm) in CDCl3 or to the residual pro-
ton signals of the deuterated solvent CD3OD. Silica gel (200–300 mesh)
(from Qingdao Haiyang Chemical Company) was used for column chro-
matography. All reactions were monitored by thin layer chromatography.
Chiral high performance liquid chromatography (HPLC) analyses were
carried out on a Hewlett Packard Series 1100 instrument. High resolution
mass spectrometer (HRMS) were obtained in electron impact (EI) mode
using a Bruker Esquire 3000 mass spectrometer. Elemental analyses
were performed on an EA-1110 instrument. All regents and solvents were
purchased from commercial sources and purified commonly before used
by standard procedures as specified in Ref. 55.
In the last few years, asymmetric organocatalysis has
proved to be a practical and powerful tool for the stereoselec-
tive preparation of chiral molecules in the field of natural or
biologically active compounds.11–18 Recently, the development
of organocatalytic asymmetric Michael addition reactions of
nitroolefins has received growing attention.1 Various organo-
catalysts activating the nucleophile or the electrophile via for-
mation of covalent bonds or weaker interactions, such as ion
pairing hydrogen bonding, have been reported.11–18 Among
them, the development of chiral bifunctional thioureas as
powerful hydrogen-bond-donating organocatalysts has rapidly
developed19–21 since Jacobsen and coworkers22–26 successfully
developed an efficient chiral Schiff base-thiourea catalyzed
asymmetric Strecker reaction. Takemoto and coworkers27,28
reported the first example of a thiourea-organocatalyzed
asymmetric Michael addition to nitroolefins by tertiary amine
thiourea bifunctional catalyst. Primary amine thiourea catalyst
developed by Jacobsen and coworkers29 also demonstrated
excellent catalytic activity in the asymmetric Michael addition
of ketones to nitroolefins. Ma and coworkers30,31 reported an
efficient organocatalyst for the asymmetric addition of aceto-
phenone to nitroolefins with saccharide-derived bifunctional
thiourea. In addition, other type of thiourea catalysts such as
cinchona alkaloid-based thioureas,32–34 pyrrolidine-thiour-
eas,35,36 and 4-dimethylaminopyridine-thioureas37 have been
found to be useful for Michael addition reactions. Recently,
the enantioselective addition reactions of aldehydes and
ketones,38–43 malonate esters,44,45 b-keto esters,46,47 and
1,3-diketone48,49 to nitroolefins have been presented. More-
over, malononitrile and cyanoacetate have been used as
Michael donors.50–54 To the best of our knowledge, addition
reactions of malononitrile to nitroolefins catalyzed by bifunc-
tional thiourea have been rarely explored.
Synthesis of Chiral Amine Thiourea Catalysts (1)
(R)-2,20-Di(bromomethyl)-1,10-binaphthyl and phthalic anhydride-
monoprotected (1S,2S)-cyclohexyldiamine were prepared by modified lit-
erature procedure.54,56
To a solution of primary amine (392 mg, 1 mmol) in dry tetrahydro-
furan (5 ml), a solution of 3,5-bis (trifluoromethyl)phenyl isothiocyanate
(271 mg, 182 ll, 1 mmol) in dry tetrahydrofuran (5 ml) was added under
nitrogen atmosphere. After the mixture was stirred for 12 h at room tem-
perature, the mixture was concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel to give the
bifunctional thiourea catalyst 1 (white solid, 591 mg, 81% yield).
Characterization of Bifunctional Thiourea Catalyst 1
Mp 149–1518C; 1H NMR (300 MHz, CDCl3): d 7.89 (d, J 5 8.2 Hz,
2H), 7.82 (d, J 5 8.2 Hz, 2H), 7.58 (s, 2H), 7.49 (s, 1H), 7.45 (m, 4H),
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant numbers: 20802016, 21072047
Contract grant sponsor: Program for New Century Excellent Talents in Uni-
versity of Ministry of Education; Contract grant numbers: NCET-09-0122
*Correspondence to: H.-M. Guo, College of Chemistry and Environmental
Science, Key Laboratory of Green Chemical Media and Reactions of Ministry
of Education, Henan Normal University, Xinxiang, Henan, People’s Republic
of China. Eail: ghm@henannu.edu.cn
Received for publication 23 March 2010; accepted in revised form 18 January
2011; Accepted 4 February 2011
DOI: 10.1002/chir.20956
Published online 19 April 2011 in Wiley Online Library
(wileyonlinelibrary.com).
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2011 Wiley-Liss, Inc.

ADDITION REACTION OF MALONONITRILE TO NITROOLEFINS
515
7.39 (d, J 5 8.4 Hz, 2H), 7.27–7.25 (m, 2H), 6.72 (br s, 1H), 4.09 (br s,
1H), 3.78–3.72 (m, 2H), 3.62 (d, J 5 12.3 Hz, 2H), 2.95 (t, J 5 8.4 Hz,
1H), 1.87–1.80 (m, 1H), 1.75–1.71 (m, 3H), 1.37–1.27 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 178.8, 141.7, 134.0, 132.2, 130.3, 128.1, 127.4, 126.4,
126.2, 125.1, 124.8, 123.3, 120.6, 117.8, 68.5, 54.7, 32.2, 28.8, 27.1, 27.0,
24.4, 23.7.
NMR (100 MHz, CDCl3): d 133.2, 130.5, 130.2, 128.6, 127.4, 126.8, 109.5,
109.2, 72.9, 38.9, 28.8; mass spectrometer (EI, 70 eV): m/z (%) 5 248.5
(M1); Anal. calcd for C11H8ClN3O2: C, 52.92; H, 3.23; N, 16.83. Found:
C, 52.51; H, 3.43; N, 16.36.
2-(2-Nitro-1-p-tolylethyl) malononitrile (4f). White solid; Mp
99–1018C; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-PrOH 5
85:15, flow rate: 1.0 ml/min, 25 8C, UV: k 5 254 nm, t (minor) 5 10.7
min, t (major) 5 13.0 min.
1H NMR (400 MHz, CDCl3): d 728–7.22 (m, 4H), 4.93 (m, 2H), 4.42
(d, J 5 6.0 Hz, 1H), 4.07–4.02 (m, 1H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 139.6, 129.6, 127.8, 126.6, 109.7, 109.6, 74.1, 42.5, 26.8, 20.3;
mass spectrometer (EI, 70 eV): m/z (%) 5 228.7 (M1); Anal. calcd for
C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.77; H, 4.84; N,
17.59.
General Procedure for Organocatalytic
Micheal Addition Reaction
Malononitrile 2 (13.2 mg, 0.2 mmol) was added to a solution of cata-
˚
lyst 1 (6.6 mg, 0.01 mmol, 10 mol %), 4 A molecular sieve (12–15 mg),
and trans-b-nitrostyrene 3a (14.9 mg, 0.1 mmol) in toluene (1 ml) at
2108C. After 8 h, the resulting mixture was diluted with chloroform (2
ml) and washed with water (10 ml). The combined organic phase was
washed with brine and dried over anhydrous Na2SO4. Evaporation of the
solvents gave the crude product, which was purified by column chroma-
tography on silica gel (petro ether-ethyl acetate) to afford the desired
product 4a (15.05 mg, 70% yield).
2-(1-(4-Methoxyphenyl)-2-nitroethyl) malononitrile (4g). White
solid; Mp 83–858C; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-
PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (minor) 5
27.6 min, t (major) 5 29.7 min.
1H NMR (400 MHz, CDCl3): d 7.28 (d, J 5 8.8 Hz, 2H), 6.97 (d, J 5
8.8 Hz, 2H), 4.92 (m, 2H), 4.40 (d, J 5 5.6 Hz, 1H), 4.07–4.02 (m, 1H),
3.83 (s, 3H); 13C NMR (100 MHz, CDCl3): d 160.9, 129.0, 123.4, 115.2,
110.6, 110.5, 75.1, 55.4, 43.1, 27.8; mass spectrometer (EI, 70 eV): m/z
(%) 5 244.4 (M1); Anal. calcd for C12H11N3O3: C, 58.77; H, 4.52; N,
17.13. Found: C, 58.87; H, 4.51; N, 16.17.
Characterization of Micheal Addition Products
White solid; Mp 54–568C; HPLC analysis: Daicel Chiralcel AD-H, n-
Hexane-i-PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t
(minor) 5 11.3 min, t (major) 5 13.3 min.
1H NMR (400 MHz, CDCl3): d 7.49–7.47 (m, 3H), 7.37–7.35 (m, 2H),
4.95 (m, 2H), 4.44 (d, J 5 6.0 Hz, 1H), 4.11–4.06 (m, 1H); 13C NMR (100
MHz, CDCl3): d 131.5, 130.1, 129.6, 127.4, 110.1, 110.0, 74.6, 43.4, 29.4;
mass spectrometer (EI, 70 eV): m/z (%) 5 214.6 (M1); Anal. calcd for
2-(1-(2-Methoxyphenyl)-2-nitroethyl) malononitrile (4h). White
solid; Mp 90–928C; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-
PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (minor)
5 10.9 min, t (major) 5 12.1 min.
C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 60.89; H, 4.31; N,
19.22.
1H NMR (400 MHz, CDCl3): d 7.46–7.42 (m, 1H), 7.287–7.26 (m, 1H),
7.07–6.99 (m, 2H), 5.00 (m, 2H), 4.55 (d, J 5 8.4 Hz, 1H), 4.45–4.41 (m,
1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3): d 155.8, 130.6, 128.7,
120.8, 118.9, 110.7, 110.0, 73.4, 54.8, 39.4, 24.4; mass spectrometer (EI,
70 eV): m/z (%) 5 244.5 (M1); Anal. calcd for C12H11N3O3: C, 58.77; H,
4.52; N, 17.13. Found: C, 58.87; H, 4.39; N, 16.19.
2-(2-Nitro-1-(4-nitrophenyl) ethyl) malononitrile (4b). Yellow
solid; Mp 142–1448C; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-
PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (minor) 5
28.1 min, t (major) 5 34.1 min.
1H NMR (400 MHz, CD3OD): d 8.33 (d, J 5 8.8 Hz, 2H), 7.77 (d, J 5
8.8 Hz, 2H), 5.20 (d, J 5 7.2 Hz, 1H), 4.53 (d, J 5 7.2 Hz, 1H), 3.61 (q, J
5 6.8 Hz, 2H); 13C NMR (100 MHz, CD3OD): d 150.0, 142.4, 131.0,
125.3, 112.8, 112.6, 76.0, 44.0, 27.6; mass spectrometer (EI, 70 eV): m/z
(%) 5 259.6 (M1); Anal. calcd for C11H8N4O4: C, 50.77; H, 3.10; N, 21.53.
Found: C, 50.44; H, 3.22; N, 21.29.
2-(1-(4-(Dimethylamino) phenyl)-2-nitroethyl) malononitrile
(4i). Yellow solid; Mp 84–868C; HPLC analysis: Daicel Chiralcel AD-
H, n-Hexane-i-PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254
nm, t (major) 5 17.5 min, t (minor) 5 24.3 min.
1H NMR (400 MHz, CDCl3): d 7.81 (d, J 5 8.8 Hz, 1H), 7.47 (s, 1H),
7.18 (d, J 5 8.8 Hz, 2H), 4.90 (m, 2H), 4.37 (d, J 5 5.6 Hz, 1H), 4.01–3.96
(m, 1H), 2.98 (s, 6H); 13C NMR (100 MHz, CDCl3): d 157.3, 150.4, 132.9,
117.1, 110.0, 109.9, 74.4, 57.6, 39.3, 27.1; mass spectrometer (EI, 70 eV):
m/z (%) 5 257.3 (M1); Anal. calcd for C13H14N4O2: C, 60.45; H, 5.46; N,
21.69. Found: C, 61.38; H, 5.41; N, 20.46.
2-(2-Nitro-1-(3-nitrophenyl) ethyl) malononitrile (4c). Light
yellow solid; Mp 126–1288C; HPLC analysis: Daicel Chiralcel AD-H, n-
Hexane-i-PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm,
t (minor) 5 21.5 min, t (major) 5 23.2 min.
1H NMR (400 MHz, CDCl3): d 8.38(d, J 5 6.8 Hz, 1H), 8.28 (s, 1H),
7.45 (d, J 5 7.6 Hz, 2H), 5.02 (m, 2H), 4.51 (d, J 5 6 Hz, 1H), 4.27 (d, J
5 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 150.1, 137.6, 135.7, 131.8,
125.5, 124.6, 112.8, 112.7, 76.1, 44.0, 28.1; mass spectrometer (EI, 70
eV): m/z (%) 5 259.5 (M1); Anal. calcd for C11H8N4O4: C, 50.77; H, 3.10;
N, 21.53. Found: C, 50.48; H, 3.05; N, 20.41.
2-(1-(Furan-2-yl)-2-nitroethyl) malononitrile (4j). Yellow oil;
HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-PrOH 5 85:15, flow
rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (major) 5 14.0 min, t (minor)
5 16.0 min.
1H NMR (400 MHz, CDCl3): d 7.50 (s, 1H), 6.54 (d, J 5 3.2 Hz, 1H),
6.45 (d, J 5 3.2 Hz, 1H), 4.93 (d, J 5 6.4 Hz, 2H), 4.47 (d, J 5 6.0 Hz,
1H), 4.32–4.28 (m, 1H); 13C NMR (100 MHz, CDCl3): d 144.6, 144.5,
111.2, 111.0, 110.2, 110.0, 73.3, 38.2, 25.9; mass spectrometer (EI, 70
eV): m/z (%) 5 204.7 (M1); Anal. calcd for C9H7N3O3: C, 52.69; H, 3.44;
N, 20.48. Found: C, 52.36; H, 3.46; N, 20.28.
2-(1-(4-Chlorophenyl)-2-nitroethyl) malononitrile (4d). White
solid; Mp 89–918C; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-
PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (minor) 5
12.8 min, t (major) 5 16.3 min.
1H NMR (400 MHz, CDCl3): d 7.47 (d, J 5 8.8 Hz, 2H), 7.32 (d, J 5
8.8 Hz, 2H), 4.94 (m, 2H), 4.43 (d, J 5 6.0 Hz, 1H), 4.11–4.06 (m, 1H);
13C NMR (100 MHz, CDCl3): d 135.8, 129.3, 128.2, 109.4, 109.3, 73.8,
42.2, 26.6.; mass spectrometer (EI, 70 eV): m/z (%) 5 248.7 (M1); Anal.
calcd for C11H8ClN3O2: C, 52.92; H, 3.23; N, 16.83. Found: C, 52.53; H,
3.03; N, 16.24.
2-(1-Cyclohexyl-2-nitroethyl) malononitrile (4k). Colorless liq-
uid; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-PrOH 5 85:15,
flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (major) 5 11.7 min, t
(minor) 5 13.3 min.
1H NMR (400 MHz, CDCl3): d 4.63 (m, 2H), 4.26 (d, J 5 5.2 Hz, 1H),
2.79–2.73 (m, 1H), 1.87–1.71 (m, 6H), 1.35–1.14 (m, 4H); 13C NMR (100
MHz, CDCl3): d 110.5, 110.4, 72.7, 42.3, 37.9, 29.9, 27.9, 25.1, 23.4; mass
spectrometer (EI, 70 eV): m/z (%) 5 220.6 (M1); Anal. calcd for
2-(1-(2-Chlorophenyl)-2-nitroethyl) malononitrile (4e). White
solid; Mp 84–868C; HPLC analysis: Daicel Chiralcel AD-H, n-Hexane-i-
PrOH 5 85:15, flow rate: 1.0 ml/min, 258C, UV: k 5 254 nm, t (minor) 5
12.5 min, t (major) 5 17.2 min.
1H NMR (400 MHz, CDCl3): d 7.556–7.53 (m, 1H), 7.44–7.40 (m, 3H),
5.01 (m, 2H), 4.78 (q, J 5 6.8 Hz, 1H), 4.55 (d, J 5 6.8 Hz, 1H); 13C
C11H15N3O2: C, 59.71; H, 6.83; N, 18.99. Found: C, 59.35; H, 6.83; N,
18.36.
Chirality DOI 10.1002/chir

516
GUO ET AL.
TABLE 1. Screening of different reaction solvents and
temperatures for the addition of malononitrile 2 to
nitrostyrene 3a using catalyst 1a
RESULTS AND DISCUSSION
The effect of solvents was initially studied for the orga-
nocatalytic Michael addition of malononitrile 2 and nitro-
styrene 3a using amine thiourea 1 as the catalyst (Fig. 1
and Table 1). It was found that the reaction performed
best in toluene, providing high yield (83%) and moderate
enantioselectivity (42%) within 3 h at room temperature
(Table 1, entry 1). In other solvents, the adducts were
obtained with lower enantioselectivities (Table 1, entries
2–6). However, the enantioselectivity could be increased
from 42 to 58% by lowering the reaction temperature to
08C (entry 7). If the temperature was further decreased,
the reaction proceeded with lower enantioselectivity and
reaction rate (entry 8).
Entry Solvent Temperature (8C) Time (h) Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Toluene
CH2Cl2
Xylene
Mesitylene
Et2O
25
25
25
25
25
25
0
210
210
210
210
3
3
3
3
3
3
6
8
8
8
8
83
80
77
80
74
72
73
71
80
70
71
42
29
41
42
17
28
58
54
65
68
55
THF
It is interesting to note that the addition of different acti-
vated molecular sieves (MSs) gave different improvements in
Toluene
Toluene
Toluene
Toluene
Toluene
the enantiomeric excess (ee).57–60 Addition of 5 A MS did not
9d
10e
11f
˚
˚
improve the enantioselectivity (Table 1, entry 11), and 3 A
MS gave the product 4a with 65% ee (Table 1, entry 9). How-
˚
ever, the use of 4 A MS gave the product 4a with 68% ee (Ta-
aExperimental conditions (unless stated otherwise): a mixture of 2 (0.2
mmol), 3a (0.1 mmol), and catalyst 1 (10 mol %) in solvent (1 ml) was per-
formed at room temperature.
˚
ble 1, entry 10). Thus, 4 A MS was used at 2108C to promote
the reaction.
bIsolated yields.
To evaluate the generality of the reaction, a wide range of
nitroalkenes bearing electron-donating, electron-withdrawing,
electron-neutral, heteroaromatic, or alkyl groups were investi-
gated (Table 2). The substituent at different position of the
aromatic ring of nitrostyrenes exhibited a strong impact on
the enantioselectivity. For example, the use of 4-NO2-trans-b-
nitrostyrene led to a higher enantioselectivity (Table 2, entry
2) when compared with 3-NO2-trans-b-nitrostyrene (Table 2,
entry 3). Moreover, steric hindrance on ortho-methoxy sub-
strate 3h provided a high yield (96%) and good enantioselec-
tivity (80% ee). Likewise, the employment of ortho-chloro
substituent 3e obtained moderate enantioselectivity (Table 2,
entry 5). However, para-chloro substituent 3d as electron-
withdrawing groups resulted in a marked loss of enantiose-
lectivity (Table 2, entry 4). As for other nitroolefin substrates,
the introduction of either an electron-donating or electron-
neutral aryl group at the para-position of aromatic ring or het-
erocyclic group favored the reaction. The corresponding
conjugate addition products were obtained with moderate
enantioselectivities (Table 2, entries 6, 7, and 10). In addition,
the substrate of cyclohexyl 3k also afforded the product with
an alkyl nitroolefin with high enantioselectivity (Table 2,
entry 11). Although the enantioselectivity of some products
is not so high, this is the first example of enantioselective
Michael addition of malononitrile to nitroolefins.
cDetermined by chiral HPLC analysis.
d
˚
˚
˚
3 A molecular sieve was used.
4 A molecular sieve was used.
5 A molecular sieve was used.
e
f
ourea organocatalyst with high yields and moderate to
˚
high enantioselectivities. Moreover, 4 A MS was found to
have positive effects on the reaction. Modification of these
organocatalysts and their use in other asymmetric reac-
tions is underway in our laboratory.
TABLE 2. Organocatalytic enantioselective addition
of malononitrile to various nitroolefins catalyzed by
amine thioureasa
Entry
R
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph (3a)
70
77
57
67
94
87
90
96
85
59
93
68
83
47
43
64
66
50
80
43
62
82
4-NO2-C6H4 (3b)
3-NO2-C6H4 (3c)
4-Cl-C6H4 (3d)
2-Cl-C6H4 (3e)
4-CH3-C6H4 (3f)
4-CH3O-C6H4 (3g)
2-CH3O-C6H4 (3h)
4-N(CH3)2-C6H4 (3i)
Furyl (3j)
CONCLUSION
In summary, we have presented the first addition reac-
tion of malononitrile to nitroolefins catalyzed by amine thi-
9
10
11d
Cyclohexyl (3k)
aExperimental conditions (unless stated otherwise): a mixture of 2 (0.2
˚
mmol), 3a (0.1 mmol), 4 A molecular sieve (MS) (12 mg), and catalyst 1 (10
mol %) in toluene (1 ml) was performed.
bIsolated yields.
cDetermined by chiral HPLC analysis.
dThe reaction mixture was consumed completely for 44 h.
Fig. 1. Bifunctional amine thiourea catalyst 1.
Chirality DOI 10.1002/chir

ADDITION REACTION OF MALONONITRILE TO NITROOLEFINS
517
29. Huang H, Jacobsen EN. Highly enantioselective direct conjugate addition
of ketones to nitroalkenes promoted by a chiral primary amine2thiourea
catalyst. J Am Chem Soc 2006;128:7170–7171.
LITERATURE CITED
1. Tsogoeva SB. Recent advances in asymmetric organocatalytic 1,4-conju-
gate additions. Eur J Org Chem 2007;2007:1701–1716.
30. Liu K, Cui H-F, Nie J, Dong K-Y, Li X-J, Ma J-A. Highly enantioselective
Michael addition of aromatic ketones to nitroolefins promoted by chiral
bifunctional primary amine-thiourea catalysts based on saccharides. Org
Lett 2007;9:923–925.
2. Berner AM, Tedeschi L, Enders D. Asymmetric Michael additions to
nitroalkenes. Eur J Org Chem 2002;2002:1877–1894.
3. Kumaran G, Kulkarni GH. A facile conversion of nitro olefins to function-
alised hydroximoyl chlorides as nitrile oxide precursors. Tetrahedron
Lett 1994;35:5517–5518.
31. Li X-J, Liu K, Ma H, Nie J, Ma J-A. Highly enantioselective Michael
addition of malonates to nitroolefins catalyzed by chiral bifunctional
tertiary amine-thioureas based on saccharides. Synlett 2008;2008:3242–
3246.
4. Mukaiyama T, Hoshino T. The reactions of primary nitroparaffins with
isocyanates. J Am Chem Soc 1960;82:5339–5342.
5. Poupart MA, Fazal G, Goulet S, Mar LT. Solid-phase synthesis of peptidyl
trifluoromethyl ketones. J Org Chem 1999;64:1356–1361.
32. Gu C-L, Liu L, Sui Y, Zhao J-L, Wang D, Chen Y-J. Highly enantioselec-
tive Michael additions of a-cyanoacetate with chalcones catalyzed by
bifunctional cinchona-derived thiourea organocatalyst. Tetrahedron:
Asymmetry 2007;18:455–463.
6. Lloyd DH, Nichols DE. Nickel boride/hydrazine hydrate reduction of
aromatic and aliphatic nitro compounds. Synthesis of 4-(benzyloxy)indole
and a-alkyltryptamines. J Org Chem 1986;51:4294–4295.
33. McCooey SH, Connon SJ. Urea- and thiourea-substituted cinchona alka-
loid derivatives as highly efficient bifunctional organocatalysts for the
asymmetric addition of malonate to nitroalkenes: inversion of configura-
tion at C9 dramatically improves catalyst performance. Angew Chem Int
Ed Engl 2005;44:6367–6370.
7. Barrett AGM, Spilling CD. Transfer hydrogenation: a stereospecific
method for the conversion of nitro alkanes into amines. Tetrahedron Lett
1988;29:5733–5734.
8. Ballini R, Petrini M. Recent synthetic developments in the nitro to
carbonyl conversion (Nef reaction). Tetrahedron 2004;60:1017–1047.
34. Ye J, Dixon DJ, Hynes PS. Enantioselective organocatalytic Michael addi-
tion of malonate esters to nitro olefins using bifunctional cinchonine
derivatives. Chem Commun 2005;35:4481–4483.
9. Kamlet MJ, Kaplan LA, Dacons JC. Reactions of polynitroalkanes with
hot mineral acids. J Org Chem 1961;26:4371–4375.
35. Cao Y, Lai Y, Wang X, Li Y, Xiao W. Michael additions in water
of ketones to nitroolefins catalyzed by readily tunable and bifunc-
tional pyrrolidine–thiourea organocatalysts. Tetrahedron Lett 2007;48:
21–24.
10. Tamura R, Kamimura A, Ono N. Displacement of aliphatic nitro groups
by carbon and heteroatom nucleophiles. Synthesis 1991;6:423–434.
11. Connon SJ. Asymmetric catalysis with bifunctional cinchona alkaloid-
based urea and thiourea organocatalysts. Chem Commun 2008;22:2499–
2510.
36. Cao C, Ye M, Sun X, Tang Y. Pyrrolidine–thiourea as a bifunctional orga-
nocatalyst: highly enantioselective Michael addition of cyclohexanone to
nitroolefins. Org Lett 2006;8:2901–2904.
12. Melchiorre P, Marigo M, Carlone A, Bartoli G. Asymmetric aminocataly-
sis-gold rush in organic chemistry. Angew Chem Int Ed Engl
2008;47:6138–6171.
37. Rabalakos C, Wulff WD. Enantioselective organocatalytic direct Mi-
chael addition of nitroalkanes to nitroalkenes promoted by
a
13. Dondoni A, Massi A. Asymmetric organocatalysis: from infancy to adoles-
cence. Angew Chem Int Ed Engl 2008;47:4638–4660.
unique bifunctional DMAP-thiourea.
13524–13525.
J Am Chem Soc 2008;130:
14. Pellissier H. Asymmetric organocatalysis. Tetrahedron 2007;63:9267–
9331.
38. Jiang X-X, Zhang Y-F, Chan ASC, Wang R. Highly enantioselective syn-
thesis of g-nitro heteroaromatic ketones in a doubly stereocontrolled
manner catalyzed by bifunctional thiourea catalysts based on dehydroa-
bietic amine: a doubly stereocontrolled approach to pyrrolidine carbox-
ylic acids. Org Lett 2009;11:153–156.
15. Almasi D, Alonso DA, Najera C. Organocatalytic asymmetric conjugate
additions. Tetrahedron: Asymmetry 2007;18:299–365.
16. Vicario JL, Badia D, Carrillo L. Organocatalytic enantioselective Michael
and hetero-Michael reactions. Synthesis 2007;2065–2092.
39. Xiong Y, Wen Y, Wang F, Gao B, Liu X, Huang X, Feng X. A chiral func-
tionalized salt-catalyzed asymmetric Michael addition of ketones to nitro-
olefins. Adv Synth Catal 2007;349:2156–2166.
17. Doyle AG, Jacobsen EN. Small-molecule H-bond donors in asymmetric
catalysis. Chem Rev 2007;107:5713–5743.
40. Lalonde MP, Chen Y, Jacobsen EN. A chiral primary amine thiourea
catalyst for the highly enantioselective direct conjugate addition of a,a-
disubstituted aldehydes to nitroalkenes. Angew Chem Int Ed Engl
2006;45:6366–6370.
18. Dalko PI, Moisan L. In the golden age of organocatalysis. Angew Chem
Int Ed Engl 2004;43:5138–5175.
19. Taylor MS, Jacobsen EN. Asymmetric catalysis by chiral hydrogen-bond
donors. Angew Chem Int Ed Engl 2006;45:1520–1543.
41. Yalalov DA, Tsogoeva SB, Schmatz S. Chiral thiourea-based bifunctional
organocatalysts in the asymmetric nitro-Michael addition: a joint experi-
mental-theoretical study. Adv Synth Catal 2006;348:826–832.
20. Connon SJ. Organocatalysis mediated by (thio)urea derivatives. Chem
Eur J 2006;12:5418–5427.
21. Takemoto Y. Recognition and activation by ureas and thioureas: stereose-
lective reactions using ureas and thioureas as hydrogen-bonding donors.
Org Biomol Chem 2005;3:4299–4306.
42. Tsogoeva SB, Wei S. Highly enantioselective addition of ketones to nitro-
olefins catalyzed by new thiourea–amine bifunctional organocatalysts.
Chem Commun 2006;13:1451–1453.
22. Sigman MS, Jacobsen EN. Schiff base catalysts for the asymmetric
Strecker reaction identified and optimized from parallel synthetic libra-
ries. J Am Chem Soc 1998;120:4901–4902.
43. Tsogoeva SB, Yalalov DA, Hateley MJ, Weckbecker C, Huthmacher K.
Asymmetric organocatalysis with novel chiral thiourea derivatives:
bifunctional catalysts for the Strecker and nitro-Michael reactions. Eur J
Org Chem 2005;70:4995–5000.
23. Sigman MS, Vachal P, Jacobsen EN. A general catalyst for the asymmet-
ric Strecker reaction. Angew Chem Int Ed Engl 2000;39:1279–1281.
44. Hoashi Y, Yabuta T, Yuan P, Miyabe H, Takemoto Y. Enantioselec-
tive tandem Michael reaction to nitroalkene catalyzed by bifunctional
thiourea: total synthesis of (2)-epibatidine. Tetrahedron 2006;62:365–
374.
24. Vachal P, Jacobsen EN. Enantioselective catalytic addition of HCN to
ketoimines. Catalytic synthesis of quaternary amino acids. Org Lett
2000;2:867–890.
25. Su JT, Vachal P, Jacobsen EN. Practical synthesis of a soluble Schiff base
catalyst for the asymmetric Strecker reaction. Adv Synth Catal
2001;343:197–200.
45. McCooey SH, McCabe T, Connon SJ. Stereoselective synthesis of highly
functionalized nitrocyclopropanes via organocatalyic conjugate addition
to nitroalkenes. J Org Chem 2006;71:7494–7497.
26. Vachal P, Jacobsen EN. Structure-based analysis and optimization of a
highly enantioselective catalyst for the Strecker reaction. J Am Chem Soc
2002;124:10012–10013.
46. Miyabe H, Tuchida S, Yamauchi M, Takemoto Y. Reaction of nitroor-
ganic compounds using thiourea catalysts anchored to polymer support.
Synthesis 2006;3295–3300.
27. Okino T, Hoashi Y, Takemoto Y. Enantioselective Michael reaction of
malonates to nitroolefins catalyzed by bifunctional organocatalysts. J Am
Chem Soc 2003;125:12672–12673.
47. Kim SM, Lee JH, Kim DY. Enantioselective direct amination of a-cyano-
ketones catalyzed by bifunctional organocatalysts. Synlett 2008;2659–
2662.
28. Okino T, Hoashi Y, Furukawa T, Xu X, Takemoto Y. Enantio- and dia-
stereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroole-
fins catalyzed by a bifunctional thiourea. J Am Chem Soc 2005;127:
119–125.
48. Peng F-Z, Shao Z-H, Fan B-M, Song H, Li G-P, Zhang H-B. Organocata-
lytic enantioselective Michael addition of 2,4-pentandione to nitroalkenes
promoted by bifunctional thioureas with central and axial chiral elements.
J Org Chem 2008;73:5202–5205.
Chirality DOI 10.1002/chir

518
GUO ET AL.
49. Wang J, Li H, Duan W, Zu L, Wang W. Organocatalytic asymmetric Mi-
chael addition of 2,4-pentandione to nitroolefins. Org Lett 2005;7:4713–4716.
55. Armarego WLF, Perrin DD. Purification of laboratory chemicals, 4th ed.
Butterworth Heinemann; 1997;330–346.
´
50. Jung S-H, Kim DY. Catalytic enantioselective electrophilic a-hydrazina-
tion of b-ketoesters using bifunctional organocatalysts. Tetrahedron Lett
2008;49:5527–5530.
56. Kaik M, Gawronski J. Facile monoprotection of trans-1,2-diaminocyclo-
hexane. Tetrahedron: Asymmetry 2003;14:1559–1563.
57. Li X-J, Zhang G-W, Wang L, Hua M-Q, Ma J-A. Molecular-sieves con-
trolled diastereo- and enantioselectivity: unexpected effect in the organo-
catalyzed direct aldol reaction. Synlett 2008;1255–1259.
51. Inokuma T, Hoashi Y, Takemoto Y. Thiourea-catalyzed asymmetric
Michael addition of activated methylene compounds to a,b-unsaturated
imides: Dual activation of imide by intra- and intermolecular hydrogen
bonding. J Am Chem Soc 2006;128:9413–9419.
58. Hasegawa M, Ono F, Kanemasa S. Molecular sieves 4A work to mediate
the catalytic metal enolization of nucleophile precursors: application to
catalyzed enantioselective Michael addition reactions. Tetrahedron Lett
2008;49:5220–5223.
52. Liu T-Y, Long J, Li B-J, Jiang L, Li R, Wu Y, Ding L-S, Chen Y-C. Enantio-
selective construction of quaternary carbon centre catalysed by bifunc-
tional organocatalyst. Org Biomol Chem 2006;4:2097–2099.
59. Palomo C, Pazos R, Oiarbide M, Garc´ıa J. Catalytic Enantioselective con-
jugate addition of nitromethane to a0-hydroxy enones as surrogates of
a,b-unsaturated carboxylic acids and aldehydes. Adv Synth Catal
2006;348:1161–1164.
53. Hoashi Y, Okino T, Takemoto Y. Enantioselective Michael addition to
a,b-unsaturated imides catalyzed by a bifunctional organocatalyst. Angew
Chem Int Ed Engl 2005;44:4032–4035.
54. Ooi T, Kameda M, Maruoka K. Design of N-spiro C2-symmetric chiral
quaternary ammonium bromides as novel chiral phase-transfer catalysts:
synthesis and application to practical asymmetric synthesis of a-amino
acids. J Am Chem Soc 2003;125:5139–5151.
60. Garcia JM, Maestro MA, Oiarbide M, Odriozola JM, Razkin J, Palomo C.
Conjugate addition of nitroalkanes to an acrylate equivalent. Stereocon-
trol at C-a of the nitro group through double catalytic activation. Org Lett
2009;11:3826–3829.
Chirality DOI 10.1002/chir