A novel chiral aliphatic-aromatic diamine promoted direct, highly enantio- and diastereoselective Michael addition of cyclohexanone to nitroolefins under solvent-free conditions

Article abstract of DOI:10.1002/chir.20847

A series of new highly efficient chiral aliphatic-aromatic diamine catalysts have been designed and successfully applied to the asymmetric Michael addition of cyclohexanone with nitroolefins under solvent-free conditions without any acidic additives. The desired adducts were obtained in high yields with excellent enantio- and diastereoselectivities of syn products (up to >99% ee, >99:1 dr).

Full text of DOI:10.1002/chir.20847

CHIRALITY 22:855–862 (2010)
A Novel Chiral Aliphatic–Aromatic Diamine Promoted Direct,
Highly Enantio- and Diastereoselective Michael Addition of
Cyclohexanone to Nitroolefins Under Solvent-Free Conditions
*
SHIFENG MIAO, JINJIN BAI, JIN YANG, AND YAWEN ZHANG
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, People’s Republic of China
ABSTRACT
A series of new highly efficient chiral aliphatic–aromatic diamine cata-
lysts have been designed and successfully applied to the asymmetric Michael addition
of cyclohexanone with nitroolefins under solvent-free conditions without any acidic addi-
tives. The desired adducts were obtained in high yields with excellent enantio- and dia-
stereoselectivities of syn products (up to >99% ee, >99:1 dr). Chirality 22:855–862,
C
VV
2010.
2010 Wiley-Liss, Inc.
KEY WORDS: aliphatic–aromatic diamine; asymmetric; Michael addition; nitroolefin;
solvent free
INTRODUCTION
the chiral pyrrolidine unit covalently adhered to aromatic
amine moiety, so that the former could activate the donor
ketone through forming enamine intermediate and the lat-
ter chiral-induce the acceptor b-nitroolefin via NꢀꢀH hydro-
gen bonding and steric hindrance.
Very recently, much attention has been paid to asym-
metric reactions using small organic molecules as cata-
lysts, which is mainly due to environmental concern where
use of metals in the reactions would be avoided.1–9 The
Michael addition reaction represents one of the most gen-
eral and versatile methods for carbon–carbon bonds for-
mation in modern synthetic organic chemistry.10–12
Among the variants of asymmetric conjugate additions,13
nitroolefin-dependent Michael reactions are of special in-
terest as these processes are the vital steps in the forma-
tions of amine, nitrile oxide, ketone, carboxylic acid, etc.,
which are recognized as synthetically interesting com-
pounds.14,15 In recent years, a great deal of effort has gone
into the optimization of the structure of the chiral catalyst
so as to achieve excellent selectivity and catalytic activ-
ity.16–26 Of the developed organocatalysts in asymmetric
catalysis, chiral diamines27–35 derived from natural amino
acids and cinchona alkaloids, which contain primary–sec-
ondary, primary–tertiary, secondary–secondary, and sec-
ondary–tertiary diamine catalysts, have proven to be
powerful and been applied successfully to asymmetric cat-
alytic Michael additions.
EXPERIMENTAL SECTION
General
Analytical thin layer chromatography was performed
using glass plates precoated with 200–400 mesh silica gel
impregnated with a fluorescent indicator (254 nm). Silica
gel (200–400 mesh) and HG silica gel from Yantai Silica
Gel Factory were used for chromatography. IR spectra
were recorded on a Varian FT-1000 spectrophotometer
using KBr optics. NMR spectra were recorded on Varian
Inova-400 or Varian System-300 NMR spectrometer. High
resolution mass spectra (HRMS) were obtained using
MicroMass TOF-MS spectrometer (EI). Optical rotations
were measured at 589 nm (Na D line) on a Autopol V Auto-
matic polarimeter. The enantiomeric excesses of the prod-
ucts were determined by HPLC analysis on a Chiralpak AS-
H or AD-H column using 2-propanol/hexane as the eluent.
To the best of our knowledge, the recent inspiring suc-
cessful applications of diamines in the enamine cata-
lytic36,37 conjugate addition of ketones or aldehydes with
nitroolefins were almost aliphatic–aliphatic diamines. Only
few examples38 were described for the use of aliphatic–aro-
matic diamine catalysts in the conjugate addition of
ketones or aldehydes to nitroolefins to date. As List39 and
Barbas’40 pioneering works of the organcatalytic asymmet-
ric Michael addition of ketone with nitroolefins, the cyclic
five-membered secondary amine structure is now regarded
as one of the ‘‘privileged’’ backbones in the design of orga-
nocatalysts.17 Therefore, in this article, we disclose such a
Material
Commercial reagents were used as received, unless oth-
erwise stated. All reactions unless otherwise noted were
Contract grant sponsor: Key Laboratory of Organic Synthesis of Jiangsu
Province.
*Correspondence to: Yawen Zhang, Key Laboratory of Organic Synthesis
of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, People’s Republic
of China. E-mail: zhangyw@suda.edu.cn
Received for publication 6 October 2009; Accepted 8 January 2010
DOI: 10.1002/chir.20847
Published online 12 April 2010 in Wiley Online Library
set of new diamine catalysts (Fig. 1), which comprise of (wileyonlinelibrary.com).
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2010 Wiley-Liss, Inc.

856
MIAO ET AL.
to the known methods,46,48 which was directly subjected
to the next step without further purification.
Compound 14 (4.80 g, 17.5 mmol) in THF (20 mL) was
slowly added to a THF (40 mL) suspension of LiAlH4 (2.0
g, 52.5 mmol) at 08C under an argon atmosphere and the
mixture was refluxed for 18 h. Then saturated Na2SO4 so-
lution was added to the mixture at 08C. After removal of
the inorganic material by filtration, the filtrate was dried
with anhydrous K2CO3. Removal of the solvent in vacuo
and purification from column chromatography to afford 5
as a rufous oil (3.28 g, 72%).49,50 1H NMR (300 MHz,
CDCl3) d (ppm): 7.13–7.00 (m, 3H), 3.43–3.24 (m, 3H),
2.96 (t, J 5 6.7 Hz, 2H), 2.85 (dd, J 5 4.6, 11.5 Hz, 1H),
2.73 (dd, J 5 8.3, 11.5 Hz, 1H), 2.39–1.49 (m, 5H), 1.43 (dt,
J 5 6.1, 12.2 Hz, 1H), 1.24 (d, J 5 6.8 Hz, 12H) 13C NMR
(75 MHz, CDCl3) d: 143.62, 142.57, 123.67, 123.63, 58.96,
Fig. 1. Evaluated aliphatic–aromatic diamine catalysts.
56.65, 46.69, 29.65, 27.70, 26.07, 24.45 ppm; IR (film) vmax
:
3343, 3061, 2961, 2868, 1685, 1590, 1458, 1362, 1256, 1112
cm–1; HRMS (EI) calcd for C17H28N2 260.2252, found:
260.2257; [a]D25 5 126.2 (c 5 1.02, CH2Cl2).
carried out directly under air. THF was dried and distilled
from sodium benzophenone under nitrogen just before
use. Catalyst 1 is commercially available, catalysts 2,41
3,38 and 442 are known, which were prepared according
to the literature methods or modification of the known pro-
cedures. The trans-substituted nitroolefins were synthe-
sized according to the known procedure.42–45
(S)-N-benzyl-4-methoxy-N-(pyrrolidine-2-ylmethyl)aniline
(6) was prepared according to the procedure described
above (46% yield, colorless oil). 1H NMR (300 MHz,
CDCl3): d (ppm) 7.34–7.14 (m, 5H), 6.83–6.68 (m, 4H),
4.63–4.46 (m, 2H), 3.73 (s, 3H), 3.50–3.23 (m, 3H), 3.01–
2.79 (m, 2H), 2.36 (brs, 1H), 1.96–1.62 (m, 3H), 1.46–1.30
(m, 1H) 13C NMR (75 MHz, CDCl3) d: 151.56, 143.29,
138.93, 128.25, 126.71, 126.48, 114.90, 114.45, 57.19, 57.09,
56.17, 55.37, 45.97, 29.30, 24.70. ppm; IR (film) vmax: 2954,
2870, 1513, 1452, 1242, 1042 cm–1; HRMS calcd for
C19H24N2O 296.1889, found: 296.1889; [a]D25 5 114.7
(c 5 1.02, CH2Cl2).
Preparation of Pyrrolidine–Aromatic Diamine
Bifunctional Organocatalysts 3, 5, and 6
(S)-4-Nitro-N-(pyrrolidin-2-ylmethyl)aniline (3). (S)-
N-(4-nitrophenyl)pyrrolidine-2-carboxamide (10) was pre-
pared from L-proline, according to the literature proce-
dures,46 which was directly subjected to the next step
without further purification.
General Procedure for the Michael Addition of
Cyclohexanone to Nitroolefins Catalyzed by
Chiral Diamine 5
To a suspension of 10 (0.48 g, 2 mmol) and NaBH4
(1.14 g, 30 mmol) in THF (40 mL) in an ice-water bath
was added acetic acid (1.72 mL, 30 mmol) in THF (8 mL).
The reaction mixture was then refluxed for 6 h. The sol-
vent was removed and the residue was dissolved in chloro-
form (50 mL), washed with water, dried over anhydrous
K2CO3, and concentrated.47 The residue was dissolved in
THF (80 mL) and 6 N HCl (8 mL) was added dropwise at
08C. After refluxing for 8 h, the reaction mixture was
cooled to 08C, and water (10 mL) was added under stir-
ring. The mixture was basified with 4 N NaOH solution
and extracted with EtOAc (3 3 20 mL). The combined or-
ganic layers were dried with anhydrous K2CO3, filtered
and concentrated. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/MeOH 5 15/
1) to give a yellow solid diamine 3 (0.15 g, 33%).32 1H
NMR (300 MHz, CDCl3) d (ppm): 8.11 (d, J 5 9.2 Hz, 2H),
6.65 (d, J 5 9.2 Hz, 2H), 5.02 (brs,1H), 3.88 (brs, 1H),
3.73–3.61 (m, 1H), 3.50–3.21 (m, 3H), 2.99 (dq, J 5 8.1,
16.3 Hz, 1H), 2.32–2.18 (m, 1H), 2.15–1.98 (m, 1H), 1.98–
1.80 (m, 1H), 1.77–1.62 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) d: 154.25, 136.08, 126.31, 110.90, 63.82, 54.27,
43.74, 29.25, 22.45 ppm.
To a solution of cyclohexanone (0.62 mL, 6.0 mmol, 20
eq) and nitroolefin (0.3 mmol) was added catalyst 5 (7.8
mg, 10 mol%). The resulting mixture was stirred at room
temperature. After the reaction was completed (monitored
by TLC), the mixture was purified by column chromatog-
raphy (eluent: petroleum ether/AcOEt 5 10/1 to 5/1) to
give the desired product.
Relative and absolute configurations of the products
were determined by comparison with the known 1H NMR,
chiral HPLC analysis, and optical rotation values. Com-
pounds reported in Table 2 are all known in the litera-
tures.14,16,17,32,51
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (18a).14
White solid, 99% yield; syn/anti 5 98/2, ee (major) 5 97%,
determined by HPLC analysis (Chiralpak AS-H, i-PrOH/
hexane 5 10/90, flow rate 10 mL/min, k 5 210.5 nm, tr
(minor) 5 8.92 min, tr (major) 5 12.17 min; [a]D25
5
1
–18.1 (c 5 0.23, CH2Cl2) H NMR (400 MHz, CDCl3) d
(ppm): 7.36–7.27 (m, 3H), 7.20–7.15 (m, 2H), 4.95 (dd,
J 5 4.5, 12.5 Hz, 1H), 4.63 (dd, J 5 10.0, 12.5 Hz, 1H),
(S)-2,6-Diisopropyl-N-(pyrrolidin-2-ylmethyl)ani- 3.81–3.72 (m, 1H), 2.75–2.64 (m, 1H), 2.53–2.34 (m, 2H),
line (5). (S)-N-(2,6-diisopropyl-phenyl) pyrrolidine-2-car- 2.15–2.03 (m, 1H), 1.83–1.50 (m, 4H), 1.24 (qd, J 5 3.5,
boxamide (14) was synthesized from L-proline, according 12.1 Hz, 1H).
Chirality DOI 10.1002/chir

NOVEL CHIRAL ALIPHATIC–AROMATIC DIAMINE
857
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohex- 23.40 min, [a]D25 5 –15.0 (c 5 0.21, CH2Cl2); 1H NMR
anone (18b).32 White solid, 92% yield; syn/anti > 99:1, (300 MHz, CDCl3) d (ppm): 7.22–6.92 (m, 4H), 4.93 (dd, J
ee (major) 5 99%, determined by HPLC analysis (Chir- 5 4.5, 12.5 Hz, 1H), 4.60 (dd, J 5 10.1, 12.4 Hz, 1H), 3.77
alpak AS-H, i-PrOH/hexane 5 10/90, flow rate 1.0 mL/ (td, J 5 4.5, 9.9 Hz, 1H), 2.73–2.58 (m, 1H), 2.53–2.30 (m,
min, k 5 210.5 nm, tr (minor) 5 19.37 min, tr (major) 5 2H), 2.15–2.03 (m, 1H), 1.83–1.52 (m, 4H), 1.31–1.14 (m,
22.11 min; [a]D25 5 –14.3 (c 5 0.64, CH2Cl2); 1H NMR 1H).
(300 MHz, CDCl3) d (ppm): 7.30 (d, J 5 8.4 Hz, 2H), 7.12
(S)-2-((R)-2-Nitro-1-p-tolylethyl)cyclohexanone
(d, J 5 8.4 Hz, 2H), 4.93 (dd, J 5 4.5, 12.6 Hz, 1H), 4.61
(18h).14 White solid, 99% yield; syn/anti 5 99:1, ee
(major) 5 91%, determined by HPLC analysis (Chiralpak
AS-H, i-PrOH/hexane 5 20/80, flow rate 10 mL/min, k 5
(dd, J 5 10.2, 12.3 Hz, 1H), 3.82–3.70 (m, 1H), 2.72–2.58
(m, 1H), 2.53–2.30 (m, 2H), 2.16–2.01 (m, 1H), 1.86–1.58
(m, 4H), 1.31–1.14 (m, 1H).
211.7 nm, tr (minor) 5 7.26 min, tr (major) 5 10.76 min,
(S)-2-((R)-1-(2-Chlorophenyl)-2-nitroethyl)cyclohex- [a]D25 5 –15.0 (c 5 0.21, CH2Cl2); 1H NMR (300 MHz,
anone (18c).14 White solid, 99% yield; syn/anti > 99:1, ee CDCl3) d (ppm): 7.12 (d, J 5 7.9 Hz, 2H), 7.04 (d, J 5 8.0
(major) 5 90%, determined by HPLC analysis (Chiralpak Hz, 2H), 4.92 (dd, J 5 4.5, 12.3 Hz, 1H), 4.61 (dd, J 5 9.9,
AS-H, i-PrOH/hexane 5 20/80, flow rate 10 mL/min, k 5 12.3 Hz, 1H), 3.78–3.65 (m, 1H), 2.74–2.59 (m, 1H), 2.53–
210.5 nm, tr (minor) 5 8.66 min, tr (major) 5 11.14 min; 2.35 (m, 2H), 2.31 (s, 3H), 2.14–2.02 (m, 1H), 1.83–1.61
[a]D25 5 –36.7 (c 5 1.04, CH2Cl2); 1H NMR (300 MHz, (m, 4H), 1.31–1.15 (m, 1H).
CDCl3) d (ppm): 7.43–7.14 (m, 4H), 4.89 (d, J 5 6.5 Hz,
2H), 4.36–4.21 (m, 1H), 2.99–2.83 (m, 1H), 2.53–2.30
(m, 2H), 2.16–2.02 (m, 1H), 1.86–1.49 (m, 4H), 1.41–1.23
(m, 1H ).
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclo-
hexanone (18i).32 White solid, 93% yield; syn/anti 5
97:3, ee (major) 5 92%, determined by HPLC analysis
(Chiralpak AD-H, i-PrOH/hexane 5 20/80, flow rate 05
(S)-2-((R)-1-(2,4-Dichlorophenyl)-2-nitroethyl)cy- mL/min, k 5 223.4 nm, tr (minor) 5 17.04 min, tr (major)
clohexanone (18d).51 White solid, 93% yield; syn/anti > 5 20.11 min, [a]D25 5 –11.2 (c 5 0.61, CH2Cl2); H NMR
1
99:1, ee (major) > 99%, determined by HPLC analysis (300 MHz, CDCl3) d (ppm): 7.08 (d, J 5 8.6 Hz, 2H), 6.85
(Chiralpak AD-H, i-PrOH/hexane 5 10/90, flow rate 10 (d, J 5 8.6 Hz, 2H), 4.91 (dd, J 5 4.6, 12.3 Hz, 1H), 4.59
mL/min, k 5 210.5 nm, tr (minor) 5 8.78 min, tr (major) (dd, J 5 10.0, 12.2 Hz, 1H), 3.78 (s, 3H), 3.76–3.65 (m,
5 11.47 min; [a]D25 5 241.1 (c 5 0.35, CH2Cl2); H NMR 1H), 2.71–2.58 (m, 1H), 2.53–2.31 (m, 2H), 2.15–2.02 (m,
1
(300 MHz, CDCl3) d (ppm): 7.41 (d, J 5 1.9 Hz, 1H), 7.26– 1H), 1.85–1.58 (m, 4H), 1.31–1.14 (m, 2H).
7.14 (m, 2H), 4.88 (d, J 5 6.9 Hz, 2H), 4.25 (dt, J 5 7.0, 9.4
(S)-2-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)cyclo-
Hz, 1H), 2.94–2.80 (m, 1H), 2.53–2.31 (m, 2H), 2.18–2.06
(m, 1H), 1.88–1.52 (m, 4H), 1.42–1.23 (m, 1H).
hexanone (18j).17 White solid, 99% yield; syn/anti 5
97:3, ee (major) > 99%, determined by HPLC analysis
(S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)cyclohexa- (Chiralpak AS–H, i-PrOH/hexane 5 15/85, flow rate 10
none (18e).32 White solid, 90% yield; syn/anti 5 98:2, ee mL/min, k 5 211.7 nm, tr (minor) 5 9.99 min, tr (major)
(major) 5 92%, determined by HPLC analysis (Chiralpak 5 11.14 min, [a]D25 5 –25.4 (c 5 0.45, CH2Cl2); H NMR
1
AS-H, i-PrOH/hexane 5 20/80, flow rate 05 mL/min, k 5 (300 MHz, CDCl3) d (ppm): 7.23 (d, J 5 6.4 Hz, 1H), 7.09
210.5 nm, tr (minor) 5 19.96 min, tr (major) 5 30.32 min; (d, J 5 6.5 Hz, 1H), 6.89 (t, J 5 7.7 Hz, 2H), 4.91–4.76 (m,
[a]D25 5 –12.7 (c 5 1.05, CH2Cl2); 1H NMR (300 MHz, 2H), 4.02–3.90 (m, 1H), 3.84 (s, 3H), 3.06–2.90 (m, 1H),
CDCl3) d (ppm): 7.46 (d, J 5 8.3 Hz, 2H), 7.06 (d, J 5 8.3 2.54–2.30 (m, 2H), 2.15–2.00 (m, 1H), 1.81–1.54 (m, 4H),
Hz, 2H), 4.93 (dd, J 5 4.5, 12.6 Hz, 1H), 4.60 (dd, J 5 10.0, 1.30–1.11 (m, 1H).
12.5 Hz, 1H), 3.75 (td, J 5 4.5, 9.9 Hz, 1H), 2.71–2.59 (m,
1H), 2.53–2.31 (m, 2H), 2.15–2.04 (m, 1H), 1.87–1.58 (m,
4H), 1.31–1.14 (m, 1H).
(S)-2-((R)-2-Nitro-1-(4-nitrophenyl)-ethyl)cyclohex-
anone (18k).14 Brown oil, 96% yield; syn/anti 5 88:12, ee
(major) 5 84%, determined by HPLC analysis (Chiralpak
(S)-2-((R)-1-(2-Bromophenyl)-2-nitroethyl)cyclohexa- AD-H, i-PrOH/hexane 5 10/90, flow rate 10 mL/min, k 5
none (18f).16 White solid, 90% yield; syn/anti > 99:1, ee 210.5 nm, tr (minor) 5 14.34 min, tr (major) 5 29.67 min,
(major) 5 92%, determined by HPLC analysis (Chiralpak [a]D25 5 –22.1 (c 5 0.46, CH2Cl2); 1H NMR (300 MHz,
AS-H, i-PrOH/hexane 5 10/90, flow rate 08 mL/min, k 5 CDCl3) d (ppm): 8.20 (d, J 5 8.6 Hz, 2H), 7.40 (d, J 5 8.6
212.0 nm, tr (minor) 5 17.49 min, tr (major) 5 22.80 min;. Hz, 2H), 5.00 (dd, J 5 4.4, 13.0 Hz, 1H), 4.70 (dd, J 5 10.1,
[a]D25 5 –37.4 (c 5 1.01, CH2Cl2); 1H NMR (300 MHz, 12.9 Hz, 1H), 4.00–3.88 (m, 1H), 2.81–2.64 (m, 1H), 2.55–
CDCl3) d (ppm): 7.58 (d, J 5 8.0 Hz, 1H), 7.35–7.09 (m, 2.31 (m, 2H), 2.19–2.06 (m, 1H), 1.76–1.55 (m, 3H), 1.38–
3H), 5.01–4.82 (m, 2H), 4.38–4.24 (m, 1H), 3.01–2.81 (m, 1.15 (m, 2H).
1H), 2.54–2.32 (m, 2H), 2.16–2.04 (m, 1H), 1.88–1.61 (m,
(S)-2-((R)-1-(Naphthalen-2-yl)-2-nitroethyl)cyclohex-
4H), 1.45–1.31 (m, 1H).
anone (18l).32 White solid, 88% yield; syn/anti 5 99:1, ee
(S)-2-((R)-1-(4-Fluorophenyl)-2-nitroethyl)cyclohex- (major) 5 90%, determined by HPLC analysis (Chiralpak
anone (18g).32 White solid, 92% yield; syn/anti 5 98:2, AS-H, i-PrOH/hexane 5 50/50, flow rate 07 mL/min, k 5
ee (major) 5 90%, determined by HPLC analysis (Chir- 223.4 nm, tr (minor) 5 9.11 min, tr (major) 5 14.94 min,
alpak AS-H, i-PrOH/hexane 5 10/90, flow rate 1.0 mL/ [a]D25 5 221.1 (c 5 0.43, CH2Cl2); H NMR (300 MHz,
1
min, k 5 210.5 nm, tr (minor) 5 15.93 min, tr (major) 5 CDCl3) d (ppm): 7.86 – 7.74 (m, 3H), 7.63 (s, 1H), 7.53–
Chirality DOI 10.1002/chir

858
MIAO ET AL.
2.17–2.03 (m, 1H), 1.98–1.79 (m, 2H), 1.75–1.58 (m, 2H),
1.32 (td, J 5 3.6, 15.9 Hz, 1H).
(S)-2-((S,E)-1-Nitro-4-phenylbut-3-en-2-yl)cyclohex-
anone (18o).25 Yellow solid, 94% yield; syn/anti 5 >99,
1, ee (major) 5 88%, determined by HPLC analysis (Chir-
alpak AS-H, i-PrOH/hexane 5 15/85, flow rate 10 mL/
min, k 5 250.0 nm): tr (minor) 5 14.10 min, tr (major) 5
18.78 min, [a]D25 –21.4 (c 5 0.67, CH2Cl2); H NMR (400
1
MHz, CDCl3) d (ppm): 7.35–7.22 (m, 5H), 6.49 (d, J 5 15.8
Hz, 1H), 6.02 (dd, J 5 9.6, 15.8 Hz, 1H), 4.68(dd, J 5 4.6,
11.9 Hz, 1H), 4.57 (dd, J 5 8.5, 11.9 Hz, 1H), 3.39–3.31 (m,
1H), 2.58–2.51 (m, 1H), 2.47–2.32 (m, 2H), 2.19–2.05 (m,
2H), 1.92–1.90 (m, 1H), 1.74–1.65 (m, 2H), 1.45 (qd, J 5
3.3, 12.5 Hz, 1H).
(S)-5-Nitro-4-phenylpentan-2-one (18q).51 White
solid, 77% yield; ee 5 34%, determined by HPLC analysis
(Chiralpak AS-H, i-PrOH/hexane 5 25/75, flow rate 10
mL/min, k 5 210.5 nm): tr (minor) 5 39.76 min, tr (major)
5 44.67 min, [a]D25 –4.7 (c 5 0.13, CH2Cl2); H NMR (300
1
MHz, CDCl3) d (ppm): 7.35–7.28 (m, 3H), 7.16–7.12 (m,
2H), 4.60–4.44 (m, 2H), 3.95 (p, J 5 7.1 Hz, 1H), 2.92–2.72
(m, 2H), 1.57 (s, 3H).
RESULTS AND DISCUSSION
The newly designed chiral aliphatic–aromatic diamines
were synthesized from L-proline through simple conver-
sions (Scheme 1) and evaluated as catalysts for the model
reaction between cyclohexanone (16) and (E)-(2-nitrovi-
nyl)benzene (17a). The reaction was conducted using chi-
ral diamines 1–6, respectively, in an excess of cyclohexa-
none at room temperature, and only the syn-product was
obtained despite the various catalysts used.
Initially, a comparison was made among catalysts 1–3
bearing different kinds of subsistent groups in the aryl
ring. The results showed that modulating NꢀꢀH acidity of
aromatic amine through altering substituent groups plays
a key role in achieving good conversions and high level of
steroselectivities. As shown in Table 1, catalyst 2 contain-
ing powerful electron-donating group is a tolerable catalyst
for this reaction (Table 1, entry 2). To test the steric
effects of aryl ring moiety, catalyst 4 were prepared and
applied in the model reaction. To our delight, excellent
diasteroselectivty (up to 99:1) and enantioselectivity (up to
97% ee) were obtained. However, the only dissatisfied as-
pect was the low yield (Table 1, entry 4). Based on the ex-
perimental results described above, we hypothesized that
an appropriate combination of electron-donating and steric
Scheme 1. Synthesis of catalysts 3, 5, and 6.
7.42 (m, 2H), 7.33–7.27 (m, 1H), 5.03 (dd, J 5 4.5, 12.5 Hz,
1H), 4.74 (dd, J 5 10.1, 12.4 Hz, 1H), 4.01–3.89 (m, 1H),
2.84–2.73 (m, 1H), 2.57–2.33 (m, 2H), 2.14–2.02 (m, 1H),
1.82–1.58 (m, 4H), 1.34–1.19 (m, 1H).
(S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl)cyclohexanone
(18m).32 Clear and clorless oil, 97% yield; syn/anti 5
98:2, ee (major) 5 97%, determined by HPLC analysis
(Chiralpak AD-H, i-PrOH/hexane 5 5/95, flow rate 10
mL/min, k 5 210.5 nm, tr (major) 5 13.84 min, tr (minor)
5 17.06 min, [a]D25 5 28.0 (c 5 0.28, CH2Cl2); H NMR
1
(300 MHz, CDCl3) d (ppm): 7.35 (d, J 5 1.0 Hz, 1H), 6.29
(dd, J 5 1.9, 3.0 Hz, 1H), 6.18 (d, J 5 3.0 Hz, 1H), 4.79
(dd, J 5 4.8, 12.5 Hz, 1H), 4.67 (dd, J 5 9.3, 12.4 Hz, 1H),
3.97 (td, J 5 4.9, 9.1 Hz, 1H), 2.86–2.65 (m, 1H), 2.56–2.25
(m, 2H), 2.20–1.98 (m, 1H), 1.90–1.58 (m, 4H), 1.29 (qd, J
5 3.8, 12.4 Hz, 1H).
(S)-2-((S)-2-Nitro-1-(thiophen-2-yl)-ethyl)cyclohexa- bulky elements in a chiral scaffold could result in a poten-
none (18n).32 White solid, >99% yield; syn/anti 5 92:8, tial bifunctional organocatalyst. Therefore, we synthesized
ee (major) 5 89%; determined by HPLC analysis (Chir- the chiral catalyst 5, in which the isopropyl groups at posi-
alpak AD-H, i-PrOH/hexane 5 5/95, flow rate 10 mL/min, tions 2 and 6 not only function as effective bulky group but
k 5 231.6 nm): tr (minor) 5 14.10 min, tr (major) 5 18.78 also as electron-donating group, and the catalytic activity
min, [a]D25 –15.1 (c 5 0.98, CH2Cl2); H NMR (CDCl3, 300 of which in the asymmetric direct Michael addition reac-
1
MHz) d (ppm): 7.22 (d, J 5 4.9 Hz, 1H), 6.94 (dd, J 5 3.6, tion was investigated. As expected, the model reaction
4.9 Hz, 1H), 6.87 (d, J 5 2.9 Hz, 1H), 4.89 (dd, J 5 4.8, took place smoothly to give the desired adduct in 96%
12.6 Hz, 1H), 4.66 (dd, J 5 9.3, 12.5 Hz, 1H), 4.13 (td, J 5 yield with an 93% ee and 98:2 syn/anti ratio (Table 1, entry
4.8, 9.1 Hz, 1H), 2.75–2.61 (m, 1H), 2.53–2.29 (m, 2H), 5). Increasing the catalyst loading to 20 mol % could dra-
Chirality DOI 10.1002/chir

NOVEL CHIRAL ALIPHATIC–AROMATIC DIAMINE
859
TABLE 1. Catalysts screening in the direct asymmetric nitro-Michael addition reaction of cyclohexanonea
Entry
Catalysts
Catalyst loading (mol %)
Additives
Time(h)
Yield (%)b
Drc (syn:anti)
Ee (%)dsyn
1
2
3
4
5
6
7
8
9
1
2
3
4
5
5
5
6
5
5
5
5
10
10
10
10
10
20
5
10
10
10
10
10
–
–
–
–
–
–
–
–
TFA
48
24
48
24
24
12
54
72
48
48
24
20
57
90
68
78
96
98
87
69
<5
<5
96
92
98:2
98:2
94:6
>99:1
98:2
97:3
98:2
94:6
nde
92
92
73
97
93
84
90
21
nde
nde
92
92
10
11
12
pTsOH
HOAc
PhCOOH
nde
97:3
98:2
aThe reactions were performed with 16 (3 mmol), 17a (0.3 mmol), and catalyst in CHCl3 (0.5 mL) at room temperature, unless otherwise specified.
bIsolated yields after column chromatography.
cDiastereoselectivities were determined by 1H NMR of the crude mixture or HPLC analysis.
dEe’s value were determined by HPLC using a Chiralpak AS-H or AD-H column. Absolute configuration was determined by comparison of the measured
optical rotation with the reported data.
eNot determined.
matically accelerate the reaction rate, but the enatioselec- and hexane, the Michael addition reaction ran smoothly to
tivity dropped. While decreased catalyst loading (5 mol %), give product 18a in moderate to excellent conversions
resulted in slow reaction and low enantioselectivity (Table with good to high enantioselectivities (Table 2, entries 3–
1, entries 6–7). Removal of the hydrogen-bond donor
TABLE 2. Screening solventsa
group by N-benzylation leads to a sharp reduction of the
enatioselectivity (Table 1, entry 8, only 21% ee was
observed). This provides a valid proof for demonstrating
that the NꢀꢀH bond of the new catalyst has a profound
influence on the steroselectivities.
It is worth mentioning here that, thus far, for all reported
nitro-Michael addition mediated by chiral diamine catalysts,
a suitable Brønsted acid must be used as a cocatalyst.52,53
However, to our surprise, the reaction between cyclohexa-
none and trans-b-nitroolefin 17a catalyzed by our alphatic–
aromatic diamine catalysts proceeded smoothly, giving the
conjugate adducts g-nitro ketone in good yields and high
steroselectivities without any additives.
Time
(h)
Yieldb
(%)
Dr
Ee
(%)dsyn
Entry
Solvent
(syn:anti)c
1
2
3
4
5
6
7
8
9
DMF
108
96
96
96
24
24
24
15
72
12
72
<5
<5
57
71
96
93
91
90
95
99
79
nd
nd
nd
nd
93
86
93
93
90
90
91
97
90
iPrOH
CH3CN
THF
98:2
96:4
98:2
98:2
96:4
97:3
95:5
98:2
98:2
Meanwhile, we also investigated the effects of some
acid additives on the reaction yield and the stereoselecti-
vites. As shown in Table 1 (entries 9–10), strong Brønsted
acid TFA and pTsOH could not promote the Michael addi-
tion. And, no improvement in catalytic activity or selectiv-
ity was observed when relatively weak acid, such as HOAc
and PhCOOH was employed as an additive (Table 1,
entries 11ꢁ12).
CHCl3
DCM
DCE
toluene
hexane
solvent-free
water
10e
11
aThe reactions were performed with 16 (10 equiv), 17a (0.3 mmol), 5 (10
mol %), and solvent (0.5 mL) at room temperature, unless stated other-
wise.
Screening of solvents with the best organocatalyst 5 has
shown that solvent-free conditions (Table 2, entry 10) gave
the highest yield and enantioselectivity. All solvents tested
were dramatically disappointing. As shown in Table 2, in
strong polar solvents such as DMF and i-PrOH, only a
trace amount of the desired adduct was observed (Table 2,
entries 1 and 2). Whereas, in less polar and nonpolar sol-
bIsolated yields after column chromatography.
cDiastereoselectivities were determined by 1H NMR of the crude mixture
or HPLC analysis.
dEe values were determined by HPLC analysis using a Chiralpak AS-H or
AD-H column. Absolute configuration was determined by comparison of
the measured optical rotation with the reported data.
vents, such as CH3CN, THF, chlorinated solvents, toluene, e20 equiv cyclohexanone was used under solvent-free conditions.
Chirality DOI 10.1002/chir

860
MIAO ET AL.
TABLE 3. Scope of the reactiona
Entry
R
Adduct
Time (h)
Yieldb (%)
Drc (syn/anti)
Eed (%) syn
1
2
3
4
5
6
7
8
9
10
11e
12
13
14
15
16
Ph
4-ClC6H4
2-ClC6H4
18a
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
18m
18n
18o
18p
12
12
12
10
12
12
12
10
10
10
12
12
12
12
16
48
99
92
>99
93
90
90
92
>99
93
>99
96
88
98:2
>99:1
>99:1
>99:1
98:2
>99:1
98:2
99:1
97:3
97:3
88:12
99:1
98:2
97
99
90
>99
92
92
90
91
92
>99
84
2,4-Cl2C6H3
4-BrC6H4
2-BrC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
2-CH3OC6H4
4-NO2C6H4
2-naphthyl
2-furyl
90
91
89
97
>99
94
2-thienyl
92:8
CH¼CHPh
>99:1
88
(CH3)2CH
<5
ndf
ndf
aReaction conditions: 16 (20 equiv), 17 (0.3 mmol), 5 (10 mol %), rt.
bIsolated yields after column chromatography.
cDiastereoselectivities were determined by 1H NMR of the crude mixture or HPLC analysis.
dEe’s value were determined by HPLC using a Chiralpak AS-H or AD-H column. Absolute configuration was determined by comparison of the measured
optical rotation with the reported data.
e0.5 mL CHCl3 was added as solvent.
fNot determined.
9). Interestingly, the reaction could also conducted in corresponding products with good to excellent steroselec-
water.19,34,51,54–56 But, to our regret, giving a lower yield tivities in high yields (Table 3, entries 12–14). Moreover,
and enantioselectivity (Table 2, entry 11). Under solvent- alkenyl substituted nitroolefin can also be employed suc-
free conditions, the reaction occurred fastest, giving the cessfully; the same good diastereo- and enantioselectivity
desired adduct quantitively with the highest ee (97%) and were observed as those found in the aryl substituted ones
excellent diastereoselectivity (98: 2 dr) (Table 2, entry 10). (Table 3, entry 15). However, aliphatic aldehyde derived
Under the optimized conditions, a variety of nitroolefins nitroolefin appeared to be an inappropriate candidate.
with different structures were investigated, and the results
The asymmetric addition of acetone to nitrostyrene 17a
are summarized in Table 3. Various styrene-type nitroole- using 5 as a catalyst was also investigated. As shown in
fins reacted efficently with cyclohexanone and excellent Scheme 2, which gave the desired product in 77% yield
yields, diasteroselectivities and enantioselectivities were with 34% ee.
achieved. Generally, aryl groups containing electron-donat-
On the basis of the experimental results described
ing and halogenated substituents (Table 3, entries 1–10) above, a possible stereochemical model was depicted to
marginally influenced the results, especially in diastero- account for the sterochemical outcome of the present reac-
meric ratio (97:3 to >99:1 syn/anti) and enantiomeric tion. As shown in Figure 2, the pyrrolidine ring firstly
excess (90% to >99% ee). Strong electron withdrawing
group nitro attached to benzene ring slightly lowered dia-
steroselectivetity and enantioselectivity (Table 3, entry
11). Naphthyl and heterocyclic nitroolefins also gave the
Scheme 2. Reaction of acetone and nitroolefin 17a.
Chirality DOI 10.1002/chir
Fig. 2. Proposed transition state.

NOVEL CHIRAL ALIPHATIC–AROMATIC DIAMINE
861
17. Tan B, Zeng X, Lu Y, Chua PJ, Zhong G. Rational design of organoca-
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orientated the nitro group via a hydrogen bond so that the
enamine could attack the nitroolefin from re-face to give
the highly enantio- and diasteroselective adduct. The ex-
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