Asymmetric cooperative catalysis in the conjugate addition of pyrazolones to nitroolefins and subsequent dearomative chlorination

Article abstract of DOI:10.1007/s11426-013-5017-3

Over the past decade many bifunctional amine-thioureas have been developed as active metal-free organocatalysts. Cooperative catalysis of these amino-thioureas allows high reaction rates and excellent transfer of stereochemical information. Despite these impressive advances, the design of new high-performance catalysts for applications in asymmetric catalytic reactions is of ongoing interest in organic chemistry. Herein we describe a cooperative catalyst system consisting of a chiral aminethiourea and an achiral organic acid that promotes the conjugate addition of 4-nonsubstituted pyrazolones to nitroolefins and subsequent dearomative chlorination. The corresponding adducts and the subsequent products were obtained in high to excellent yields (up to 99%) and high stereoselectivities (up to 99/1 dr, 98% ee) under mild reaction conditions. These transformations provide an easy access to enantio-enriched pyrazole derivatives, which could possess potential pharmaceutical activity.

Full text of DOI:10.1007/s11426-013-5017-3

SCIENCE CHINA
Chemistry
February 2014 Vol.57 No.2: 265–275
doi: 10.1007/s11426-013-5017-3
• ARTICLES •
· SPECIAL ISSUE · The Frontiers of Chemical Biology and Synthesis
Asymmetric cooperative catalysis in the conjugate addition of
pyrazolones to nitroolefins and subsequent dearomative
chlorination
ZHANG KeFeng, LI Feng, NIE Jing & MA JunAn*
Department of Chemistry, Tianjin University, Tianjin 300072, China
Received August 25, 2013; accepted September 15, 2013; published online November 22, 2013
Over the past decade many bifunctional amine-thioureas have been developed as active metal-free organocatalysts. Coopera-
tive catalysis of these amino-thioureas allows high reaction rates and excellent transfer of stereochemical information. Despite
these impressive advances, the design of new high-performance catalysts for applications in asymmetric catalytic reactions is
of ongoing interest in organic chemistry. Herein we describe a cooperative catalyst system consisting of a chiral amine-
thiourea and an achiral organic acid that promotes the conjugate addition of 4-nonsubstituted pyrazolones to nitroolefins and
subsequent dearomative chlorination. The corresponding adducts and the subsequent products were obtained in high to excel-
lent yields (up to 99%) and high stereoselectivities (up to 99/1 dr, 98% ee) under mild reaction conditions. These transforma-
tions provide an easy access to enantio-enriched pyrazole derivatives, which could possess potential pharmaceutical activity.
cooperative catalysis, conjugate addition, amine-thioureas, pyrazolone, nitroolefin, chlorination
acids. We hypothesized that if a suitable acid is used, the
1 Introduction
thiourea and the protonated amine could play different roles
in a reaction system, leading to new types of reactions. On
the basis of this hypothesis, we were interested in exploring
an amine-thiourea/organic acid cooperative strategy in ca-
talysis [3].
Asymmetric transformations catalyzed by chiral bifunction-
al amine-thioureas have become a quickly growing field
over the past decade [1]. Since 2007, our group has focused
on the design of saccharide-based amine-thioureas and the
exploration of new asymmetric reactions by amine-thiourea
catalysis [2]. We have developed two families of catalysts
(primary and tertiary amine-thioureas, as in Figure 1) and
successfully applied these small organic molecules to the
Michael additions, aldol condensations, and Mannich reac-
tions that efficiently afford versatile products that have good
enantioselectivity. Of these catalysts, the dual hydrogen-
bond donors can direct the assembly of the reactants, while
the saccharide moiety can modify the electronic and steric
nature of the amine-thioureas. The corresponding amine
groups are basic and thus could be compatible with organic
Figure 1 Saccharide-based amine thiourea catalysts.
*Corresponding author (email: majun_an68@tju.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2013
chem.scichina.com link.springer.com

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Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
Pyrazolone and its enol structure are present in many
instrument with hexane and isopropyl alcohol as eluents.
Tetrahydrofuran (THF), diethyl ether, and toluene were
distilled from sodium/benzophenone prior to use; CH2Cl2,
ClCH2CH2Cl (DCE), CHCl3, and xylene were distilled from
CaH2; EtOH was distilled from sodium; and CH3CN was
distilled from P2O5. DMF was obtained from commercial
sources. All purchased reagents were used without further
purification. Analytical thin-layer chromatography was per-
formed on 0.20 mm Qingdao Haiyang silica gel plates. Sil-
ica gel (200–300 mesh) from Qingdao Haiyang Chem. Co-
mpany, Ltd. was used for flash chromatography. Pyrazolin-
5-ones were prepared according to or in analogy to the re-
ported procedures [8].
drugs, agrochemicals, and voltage-sensitive dyes [4, 5], inc-
luding allonal, veramon, novalgin, edaravone, and phena-
zone and its analogues, as well as dye RH1691. Their im-
portance has recently inspired the development of diverse
methods for their enantioselective transformations, includ-
ing transition-metal catalysis and organocatalysis [6].
However, the stereocenter flanked by pyrazol-5-ol may lose
its stereochemical integrity as a result of rapid tautomeriza-
tion. Consequently, little progress has been made in the use
of 4-nonsubstituted pyrazolones for the asymmetric synthe-
sis of enantioenriched pyrazol-5-ol derivatives [7]. In addi-
tion, asymmetric access to chlorinated pyrazolones has not
yet been documented. We have previously observed the
formation of intermediate pyrazol-5-ols in the presence of
organic acid during an investigation of the mechanism of
the thiourea-catalyzed one-pot subsequent addition/fluorin-
ation transformation of pyrazolones [2e]. Herein we wish to
report a cooperative catalyst system (Figure 1, III), consist-
ing of a chiral aminothiourea and an achiral organic acid,
which promotes the conjugate addition of 4-nonsubstituted
pyrazolones to nitroolefins and subsequent dearomative
chloroination (Scheme 1). In these asymmetric transfor-
mations, high yields and stereoselectivities were achieved
for a wide range of nitroolefins.
2.2
General procedure for the thiourea-catalyzed
asymmetric Michael addition of pyrazolin-5-ones to ni-
troolefins
Pyrazolin-5-one (0.1 mmol), nitroolefin (0.15 mmol),
PhCO2H (0.02 mmol), and the catalyst (0.01 mmol) were
placed in a 10 mL Schlenk equipped with a magneton. The
vial was refilled with Ar three times. Toluene (1.0 mL) was
then added and the resulting mixture was stirred at room
temperature under an Ar atmosphere for the stated time.
Then the reaction solution was concentrated in vacuo and
the crude was purified by flash chromatography with ethyl
acetate/petroleum ether (1/2, v/v) to afford the 1H-pyrazol-
5-ols 3.
2 Experimental
2.1 Materials and methods
1H and 13C NMR were recorded on Bruker instruments at
400 MHz (1H NMR) and 100 MHz (13C NMR). Chemical
shifts were reported in ppm from the solvent resonance as
the internal standard (CDCl3,  : 7.26 ppm, 77.1 ppm). Mul-
tiplicity was indicated as follows: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), dd (doublet of doublet),
and br (broad). Coupling constants were reported in Hertz
(Hz). LRMS were recorded on a VGZAB-HS spectrometer
with an ESI resource. HRMS were recorded on an IonSpec
Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS mass
spectrometer with an ESI resource. IR spectra were record-
ed on an AVATAR 360 FT-IR spectrometer. HPLC anal-
yses were carried out on a Hewlett Packard Model HP 1200
3-Methyl-4-(2-nitro-1-phenylethyl)-1-phenyl-1H-pyrazol-5-
ol (3a)
32.0 mg, 99% yield, 96% ee, []2D0 = 129.4° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 15/85), 254 nm UV
detector, 1.0 mL/min, tR = 13.463 min (minor), 18.527 min
(major)]; 1H NMR (400 MHz, CDCl3)  1.86 (s, 3H), 4.40 (t,
J = 6.8 Hz, 1H), 4.76 (dd, J = 12.8 Hz, 6.8 Hz, 1H), 5.17
(dd, J = 12.8 Hz, 5.2 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 7.07
(t, J = 7.2 Hz, 2H), 7.197.29 (m, 7H); 13C NMR (100 MHz,
CDCl3)  161.6, 146.9, 139.2, 135.6, 128.8, 127.5, 126.1,
120.7, 103.2, 77.3, 39.6, 36.6, 29.7, 24.6, 10.6, 10.5; IR
(KBr) ν 3062, 2929, 1608, 1552, 1500, 1377, 1306, 757,
696 cm1; MS (ESI) m/z 324.16 [M+H]+.
4-(1-(4-Methoxyphenyl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3b)
33.9 mg, 96% yield, 96% ee, []2D0 = 104.0° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
mL/min, tR = 6.232 min (minor), 10.716 min (major)]; H
Scheme 1 Asymmetric addition of 4-nonsubstituted pyrazolones to ni-
troolefins and subsequent dearomative chloroination.
1

Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
267
(KBr) ν 3063, 2914, 1608, 1552, 1496, 1409, 1368, 1091,
759 cm1; MS (ESI) m/z 358.13 [M+H]+.
NMR (400 MHz, CDCl3)  1.90 (s, 3H), 3.72 (s, 3H), 4.37
(t, J = 7.6 Hz, 1H), 4.78 (dd, J = 12.0 Hz, 6.4 Hz, 1H), 5.16
(dd, J = 17.6 Hz, 9.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.02
(t, J = 6.8 Hz, 1H), 7.09 (d, J = 5.6 Hz, 2H), 7.227.36 (m,
4H); 13C NMR (100 MHz, CDCl3)  158.8, 147.0, 135.7,
131.3, 128.8, 128.6, 126.0, 120.7, 114.0, 103.9, 103.7, 77.2,
55.3, 55.2, 39.0, 29.7, 24.6, 10.6; IR (KBr) ν 3063, 2924,
1706, 1613, 1552, 1511, 1373, 1244, 1035, 753 cm1; MS
(ESI) m/z 354.13 [M+H]+.
4-(1-(4-Bromophenyl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3f)
39.4 mg, 98% yield, 95% ee, []2D0 =110.2° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel Chi-
ralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm UV de-
tector, 1.0 mL/min, tR = 4.972 min (minor), 8.986 min (ma-
jor)]; 1H NMR (400 MHz, CDCl3)  2.04 (s, 3H), 4.42 (t, J =
7.2 Hz, 1H), 4.87 (dd, J = 13.2 Hz, 6.8 Hz, 1H), 5.29 (dd, J =
13.2 Hz, 9.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0
Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.387.41 (m, 4H), 9.22 (s,
1H); 13C NMR (100 MHz, CDCl3)  161.6, 146.6, 138.3,
135.4, 131.9, 129.3, 128.8, 126.3, 121.4, 121.0, 102.3, 76.4,
39.0, 29.7, 10.5; IR (KBr) ν 3068, 2925, 1613, 1557, 1491,
1372, 1075, 1014, 756 cm1; MS (ESI) m/z 401.76 [M–H]–.
3-Methyl-4-(2-nitro-1-(p-tolyl)ethyl)-1-phenyl-1H-pyrazol-
5-ol (3c)
33.1 mg, 98% yield, 97% ee, []2D0 = 157.9° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel Chira-
lpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 5.476 min (minor), 8.192 min (major)]; H
NMR (400 MHz, CDCl3)  1.95 (s, 3H), 2.28 (s, 3H), 4.40
(t, J = 7.6 Hz, 1H), 4.81 (dd, J = 12.8 Hz, 6.8 Hz, 1H), 5.25
(dd, J = 12.4 Hz, 9.2 Hz, 1H), 7.04 (d, J = 7.6 Hz, 3H), 7.13
(t, J = 7.6 Hz, 2H), 7.24 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 10.4
Hz, 2H), 10.07 (s, 1H); 13C NMR (100 MHz, CDCl3) 
171.5, 147.3, 137.1, 136.2, 135.8, 129.5, 128.8, 127.4,
125.9, 120.4, 119.3, 104.3, 76.8, 39.4, 21.0, 20.9, 10.7; IR
(KBr) ν 3042, 2914, 1618, 1546, 1495, 1372, 1305, 1012,
752 cm1; MS (ESI) m/z 338.15 [M+H]+.
3-Methyl-4-(2-nitro-1-(4-nitrophenyl)ethyl)-1-phenyl-1H-
pyrazol-5-ol (3g)
35.0 mg, 95% yield, 95% ee, []2D0 = 95.4° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 5.902 min (minor), 22.853 min (major)]; H
NMR (400 MHz, CDCl3):  2.02 (s, 3H), 4.52 (t, J = 7.6 Hz,
1H), 4.90 (dd, J = 13.2 Hz, 6.8 Hz, 1H), 5.19 (dd, J = 13.2
Hz, 8.8 Hz, 1H), 7.067.11 (m, 1H), 7.19 (t, J = 7.6 Hz, 2H),
7.33 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 8.05 (d, J
= 8.4 Hz, 2H), 10.20 (s, 1H); 13C NMR (400 MHz, CDCl3):
δ 171.3, 147.3, 146.2, 139.8, 136.1, 136.0, 133.7, 130.1,
129.7, 129.3, 129.2, 128.7, 128.4, 124.5, 124.1, 120.2, 75.9,
39.6, 29.6; IR (KBr): ν 3063, 2923, 1617, 1552, 1498, 1376,
1306, 1013, 753 cm1; MS (ESI): m/z 369.09 [M+H]+.
4-(1-(4-Fluorophenyl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3d)
33.4 mg, 98% yield, 95% ee, []2D0 = 122.8° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 5.033 min (minor), 7.285 min (major)]; H
NMR (400 MHz, CDCl3)  1.90 (s, 3H), 4.40 (t, J = 8.4 Hz,
1H), 4.78 (dd, J = 12.8 Hz, 7.2 Hz, 1H), 5.12 (dd, J = 12.8
Hz, 8.8 Hz, 1H), 6.92 (t, J = 8.8 Hz, 2H), 7.027.13 (m, 3H),
7.257.30 (m, 4H); 13C NMR (100 MHz, CDCl3)  163.2,
160.7, 146.7, 135.4, 135.1, 135.0, 130.0, 129.2, 128.8,
126.2, 120.9, 115.7, 115.5, 102.8, 76.9, 38.9, 36.6, 24.6,
10.5; IR (KBr) ν 3067, 2909, 1618, 1552, 1506, 1378, 1224,
885, 752 cm1; MS (ESI) m/z 342.13 [M+H]+.
4-(1-(2-Chlorophenyl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3h)
34.3 mg, 96% yield, 97% ee, []2D0 = 168.9° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 3.990 min (minor), 10.616 min (major)]; H
NMR (400 MHz, CDCl3)  1.97 (s, 3H), 4.52 (t, J = 5.2 Hz,
1H), 4.95 (dd, J = 9.6 Hz, 5.2 Hz, 1H), 5.26 (dd, J = 12.4
Hz, 10.4 Hz, 1H), 7.007.22 (m, 7H), 7.33 (t, J = 6.8 Hz,
1H), 7.60 (t, J = 7.6 Hz, 1H), 10.75 (s, 1H); 13C NMR (100
MHz, CDCl3)  162.1, 147.3, 136.1, 135.4, 132.8, 129.7,
128.8, 127.1, 126.1, 120.7, 101.5, 75.1, 35.7, 10.7; IR (KBr)
ν 3072, 2919, 1613, 1556, 1500, 1377, 1310, 1034, 752
cm1; MS (ESI) m/z 358.12 [M+H]+.
4-(1-(4-Chlorophenyl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3e)
35.4 mg, 99% yield, 94% ee, []2D0 = 100.4° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 4.845 min (minor), 8.014 min (major)]; H
NMR (400 MHz, CDCl3)  1.99 (s, 3H), 4.41 (t, J = 7.2 Hz,
1H), 4.84 (dd, J = 13.2 Hz, 6.8 Hz, 1H), 5.23 (dd, J = 13.2
Hz, 9.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.167.22 (m, 4H),
7.307.36 (m, 4H), 9.82 (s, 1H); 13C NMR (100 MHz,
CDCl3)  161.5, 146.8, 137.7, 135.5, 133.3, 130.0, 128.9,
126.3, 120.8, 102.9, 76.5, 39.0, 29.6, 24.6, 10.5, 1.0; IR
4-(1-(2-Bromophenyl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3i)
37.8 mg, 94% yield, 97% ee, []2D0 = 182.9° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel

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Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
mL/min, tR = 4.056 min (minor), 10.322 min (major)]; H
(t, J = 7.6 Hz, 2H), 7.487.58 (m, 4H), 7.68 (d, J = 8.0 Hz,
2H), 8.06 (d, J = 8.4 Hz, 2H), 8.51 (t, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3)  162.3, 148.4, 136.0, 131.6,
130.9, 129.8, 129.7, 128.9, 128.8, 128.6, 125.9, 124.9,
120.4, 118.9, 105.7, 33.3, 11.4; IR (KBr) ν 3048, 2919,
1610, 1552, 1498, 1374, 732 cm1; MS (ESI) m/z 424.16
[M+H]+.
1
NMR (400 MHz, CDCl3)  2.00 (s, 3H), 4.61 (t, J = 5.2 Hz,
1H), 4.95 (dd, J = 10.0 Hz, 5.2 Hz, 1H), 5.28 (dd, J = 12.8
Hz, 10.4 Hz, 1H), 7.017.14 (m, 5H), 7.24 (t, J = 4.4 Hz,
2H), 7.52 (dd, J = 6.4 Hz, 1.2 Hz ,1H), 7.65 (t, J = 0.8 Hz,
1H), 10.64 (s, 1H); 13C NMR (100 MHz, CDCl3)  147.5,
137.9, 135.5, 133.0, 130.0, 129.1, 128.8, 127.8, 126.1,
123.5, 120.7, 101.9, 75.2, 38.6, 11.0, 11.0; IR (KBr) ν 3067,
2919, 1613, 1557, 1495, 1367, 1316, 1024, 901, 752 cm1;
MS (ESI) m/z 401.81 [M–H]–.
4-(1-(Furan-2-yl)-2-nitroethyl)-3-methyl-1-phenyl-1H-pyrazol-
5-ol (3m)
29.8 mg, 95% yield, 93% ee, []2D0 = 121.7° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
3-Methyl-4-(2-nitro-1-(3-phenoxyphenyl)ethyl)-1-phenyl-1H-
pyrazol-5-ol (3j)
39.9 mg, 96% yield, 96% ee, []2D0 = 138.1° (c = 1.0,
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 4.188 min (minor), 4.943 min (major)]; H
NMR (400 MHz, CDCl3)  1.93 (s, 3H), 4.63 (t, J = 7.6 Hz,
1H), 4.78 (dd, J = 13.2 Hz, 6.8 Hz, 1H), 4.93 (dd, J = 12.8
Hz, 8.4 Hz, 1H), 6.00 (d, J = 3.2 Hz, 1H), 6.22 (d, J = 5.2
Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 2H),
7.33 (t, J = 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3)  170.3, 151.1, 147.0, 141.8, 141.8,
135.6, 130.0, 128.8, 128.4, 126.1, 120.7, 110.5, 106.9,
106.9, 100.4, 74.7, 33.0, 10.6, 10.5; IR (KBr) ν 3067, 2919,
1607, 1556, 1495, 1377, 1305, 1013, 742 cm1; MS (ESI)
m/z 314.11 [M+H]+.
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 5.558 min (minor), 6.255 min (major)]; H
NMR (400 MHz, CDCl3)  1.88 (s, 3H), 4.39 (t, J = 7.2 Hz,
1H), 4.82 (dd, J = 6.4 Hz, 1.6 Hz, 1H), 5.18 (dd, J = 12.4
Hz, 9.2 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.927.00 (m,
3H) 7.017.13 (m, 5H), 7.147.18 (m, 1H), 7.227.29 (m,
4H); 13C NMR (100 MHz, CDCl3)  157.5, 156.8, 141.2,
135.6, 135.5, 129.8, 128.8, 123.4, 122.3, 120.7, 118.8,
117.4, 103.3, 75.6, 39.5, 36.6, 24.6, 10.6; IR (KBr) ν 3067,
2919, 1608, 1552, 1485, 1367, 1239, 753, 691 cm1; MS
(ESI) m/z 416.14 [M+H]+.
3-Methyl-4-(1-nitropentan-2-yl)-1-phenyl-1H-pyrazol-5-ol
(3n)
21.4 mg, 74% yield, 90% ee, []2D0 = +119.3° (c = 1.0,
3-Methyl-4-(1-(naphthalen-2-yl)-2-nitroethyl)-1-phenyl-1H-
pyrazol-5-ol (3k)
36.6 mg, 98% yield, 96% ee, []2D0 = 108.8° (c = 1.0,
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 20/80), 254 nm, 1.0
1
mL/min, tR = 5.743 min (minor), 10.471 min (major)]; H
CH2Cl2), [determined by HPLC analysis with Daicel
NMR (400 MHz, CDCl3)  0.87 (t, J = 7.2 Hz, 3H),
1.211.28 (m, 2H), 1.381.47 (m, 1H), 1.751.83 (m, 1H),
2.06 (s, 3H), 3.173.22 (m, 1H), 4.44 (dd, J = 12.4 Hz, 5.6
Hz, 1H), 4.84 (dd, J = 21.2 Hz, 5.6 Hz, 1H), 7.14 (t, J = 7.2
Hz, 1H), 7.287.42 (m, 2H), 7.49 (d, J = 8.0 Hz, 2H), 9.29
(s, 1H); 13C NMR (100 MHz, CDCl3)  148.5, 136.3, 129.0,
128.9, 125.6, 119.8, 118.8, 108.6, 105.2, 74.6, 34.2, 31.8,
20.6, 13.7, 10.9; IR (KBr) ν 3072, 2919, 1625, 1551, 1496,
1368, 1310, 1014, 752 cm1; MS (ESI) m/z 300.14 [M+H]+.
Chiralpak AD-H, i-PrOH/hexane (v/v = 30/70), 254 nm, 1.0
1
mL/min, tR = 6.347 min (minor), 7.324 min (major)]; H
NMR (400 MHz, CDCl3)  1.90 (s, 3H), 4.56 (t, J = 7.2 Hz,
1H), 4.91 (dd, J = 13.2 Hz, 6.8 Hz, 1H), 5.27 (dd, J = 13.2
Hz, 8.8 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.6 Hz,
2H), 7.247.27 (m, 2H), 7.397.46 (m, 3H), 7.677.74 (m,
4H); 13C NMR (100 MHz, CDCl3)  161.8, 147.1, 136.6,
135.7, 133.3, 132.6, 130.0, 128.8, 128.7, 127.7, 127.6,
126.3, 125.7, 120.6, 103.6, 65.3, 39.8, 23.3, 10.7, 10.7; IR
(KBr) ν 3062, 2934, 1618, 1551, 1495, 1367, 1305, 742,
686 cm1; MS (ESI) m/z 374.18 [M+H]+.
3-Methyl-4-(4-methyl-1-nitropentan-2-yl)-1-phenyl-1H-
pyrazol-5-ol (3o)
23.7 mg, 78% yield, 88% ee, []2D0 = +111.2° (c = 1.0,
4-(1-(Anthracen-10-yl)-2-nitroethyl)-3-methyl-1-phenyl-1H-
pyrazol-5-ol (3l)
40.6 mg, 96% yield, 90% ee, Mp. 205–206 °C, []2D0
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 20/80), 254 nm, 1.0
mL/min, tR = 5.884 min (minor), 10.866 min (major)]; 1H
NMR (400 MHz, CDCl3)  0.82 (dd, J = 10.0 Hz, 6.4 Hz,
6H), 1.081.14 (m, 1H), 1.321.38 (m, 1H), 1.681.75 (m,
1H), 1.98 (s, 3H), 3.216.26 (m, 1H), 4.29 (dd, J = 12.4 Hz,
5.6 Hz, 1H), 4.61 (dd, J = 13.2 Hz, 10.0 Hz, 1H), 7.10 (t,
J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 8.0 Hz,
=
117.7° (c = 1.0, CH2Cl2), [determined by HPLC analysis
with Daicel Chiralpak OJ-H, i-PrOH/hexane (v/v = 10/90),
254 nm, 1.0 mL/min, tR = 30.297 min (minor), 35.631 min
1
(major)]; H NMR (400 MHz, CDCl3)  1.44 (s, 3H), 5.11
(dd, J = 14.0 Hz, 6.8 Hz, 1H), 6.35 (t, J = 6.8 Hz, 1H), 6.47
(dd, J = 13.6 Hz, 7.2 Hz, 1H), 7.24 (t, J = 7.2 Hz, 2H), 7.44

Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
269
2H); 13C NMR (100 MHz, CDCl3)  147.2, 135.8, 128.8,
125.8, 120.6, 102.5, 77.6, 38.4, 32.2, 25.4, 23.1, 21.6, 10.5,
10.5; IR (KBr) ν 3062, 2929, 1623, 1551, 1496, 1369, 1310,
1015, 753 cm1; MS (ESI) m/z 304.16 [M+H]+.
2.3
General procedure for catalytic asymmetric
onepot subsequent conjugate addition/dearomative
chlorination
4-(2-Nitro-1-phenylethyl)-1,3-diphenyl-1H-pyrazol-5-ol
(3p)
36.6 mg, 95% yield, 98% ee, []2D0 = 89.9° (c = 1.0,
Pyrazolin-5-one (0.12 mmol), nitroolefins (0.1 mmol),
PhCO2H (0.02 mmol), and the amine-thiourea catalyst (0.01
mmol) were added to a 10 mL Schlenk tube equipped with a
magneton. The vial was refilled with Ar three times. Tolu-
ene (1.0 mL) was then added and the resulting mixture was
stirred at room temperature under an Ar atmosphere for the
appropriate time until 2 was consumed (monitored by TLC).
Then NCS (0.2 mmol) was added and the mixture was
stirred at the same temperature (monitored by TLC). The
reaction solution was concentrated in vacuo and the residue
was purified by flash chromatography with ethyl acetate/
petroleum ether (1/20, v/v) to afford the chlorinated product
4.
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm, 1.0
1
mL/min, tR = 19.635 min (minor), 28.967 min (major)]; H
NMR (400 MHz, CDCl3)  4.30 (t, J = 4.8 Hz, 1H), 4.88
(dd, J = 14.4 Hz, 5.2 Hz, 1H), 5.78 (dd, J = 14.4 Hz, 9.6 Hz,
1H), 7.11 (t, J = 7.2 Hz, 2H), 7.177.32 (m, 5H), 7.347.47
(m, 8H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3)  158.1,
157.8, 136.8, 136.7, 132.1, 131.9, 129.4, 129.2, 129.1,
129.1, 128.5, 128.4, 128.4, 126.3, 121.3, 121.0, 120.6,
119.1, 118.9, 74.0, 58.0, 34.9, 33.7; IR (KBr) ν 3062, 2929,
1603, 1552, 1500, 1409, 1365, 1034, 754 cm1; MS (ESI)
m/z 386.14 [M+H]+.
3-(4-Methoxyphenyl)-4-(2-nitro-1-phenylethyl)-1-phenyl-1H-
pyrazol-5-ol (3q)
39.9 mg, 96% yield, 92% ee, []2D0 = 112.4° (c = 1.0,
4-Chloro-3-methyl-4-(2-nitro-1-phenylethyl)-1-phenyl-1H-
pyrazol-5-one (4a)
33.4 mg, 95% yield, 93% ee, 99:1 dr, []2D0 =65.7° (c =
CH2Cl2), [determined by HPLC analysis with Daicel
1.0, CH2Cl2), [determined by HPLC analysis Daicel Chi-
ralpak AD-H, hexane/i-PrOH (v/v = 90/10), 254 nm UV
detector, 1.0 mL/min, tR = 7.775 min (major) and tR = 8.946
Chiralpak AD-H, i-PrOH/hexane (v/v = 15/85), 254 nm, 1.0
1
mL/min, tR = 11.026 min (minor), 13.318 min (major)]; H
NMR (400 MHz, CDCl3)  3.92 (s, 3H), 4.27 (t, J = 4.8 Hz,
1H), 4.87 (dd, J = 14.4 Hz, 5.2 Hz, 1H), 5.78 (dd, J = 14.8
Hz, 9.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.8
Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.167.20 (m, 2H),
7.287.38 (m, 4H), 7.63 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 8.8
Hz, 2H); 13C NMR (100 MHz, CDCl3)  171.4, 161.7, 156.6,
137.3, 133.3, 129.0, 128.7, 128.6, 128.2, 127.7, 125.7,
122.7, 119.6, 114.7, 74.1, 55.4, 50.6, 43.2, 40.2; IR (KBr): ν
3068, 2918, 1601, 1552, 1495, 1372, 1305, 1075, 753 cm1;
MS (ESI) m/z 416.15 [M+H]+.
1
min (minor)]; H NMR (400 MHz, CDCl3)  2.23 (s, 3H),
4.18 (t, J = 7.2 Hz, 1H), 5.44 (d, J = 7.2 Hz, 2H), 7.227.30
(m, 6H), 7.41 (t, J = 8.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3)  168.0, 156.8, 136.6, 131.7,
129.6, 129.3, 128.9, 127.8, 126.1, 119.2, 74.5, 65.4, 48.9,
13.1; IR (KBr) ν 2965, 2927, 1710, 1656, 1630, 1401, 1370,
1286, 758, 702 cm1; HRMS (ESI) found: m/z 357.0883 M+;
calcd. for C18H16ClN3O3 357.0880.
4-Chloro-4-(1-(4-methoxyphenyl)-2-nitroethyl)-3-methyl-1-
phenyl-1H-pyrazol-5-one (4b)
35.7 mg, 92% yield, 93% ee, 98:2 dr, []2D0 = 72.7° (c =
1-Benzyl-3-methyl-4-(2-nitro-1-phenylethyl)-1H-pyrazol-5-
ol (3r)
33.1 mg, 98% yield, 89% ee, []2D0 = 66.6° (c = 1.0,
1.0, CH2Cl2), [determined by HPLC analysis Daicel Chi-
ralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 8.488 min (minor) and tR =
10.218 min (major)]; 1H NMR (400 MHz, CDCl3)  2.23 (s,
3H), 3.71 (s, 3H), 4.13 (dd, J = 8.4 Hz, 5.6 Hz, 1H),
5.405.42 (m, 2H), 6.76 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8
Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H),
7.71 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) 
168.2, 160.3, 156.9, 136.7, 129.1, 128.9, 126.1, 123.3,
119.2, 114.8, 74.7, 65.4, 55.1, 48.4, 13.1; IR (KBr) ν 2964,
2925, 1719, 1685, 1655, 1610, 1570, 1509, 1399, 1255, 757
cm1; HRMS (ESI) found: m/z 387.0984 M+; calcd. for
C19H18ClN3O4 387.0986.
CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm, 1.0
1
mL/min, tR = 32.289 min (minor), 34.494 min (major)]; H
NMR (400 MHz, CDCl3)  1.78 (s, 3H), 4.44 (t, J = 6.8 Hz,
1H), 4.64 (dd, J = 26.4 Hz, 16.0 Hz, 2H), 4.78 (dd, J = 12.4
Hz, 6.4 Hz, 1H), 5.24 (dd, J = 12.4 Hz, 9.6 Hz, 1H),
6.906.93 (m, 2H), 7.127.13 (m, 3H), 7.197.24 (m, 3H),
7.317.33 (m, 2H); 13C NMR (100 MHz, CDCl3)  144.7,
139.5, 135.9, 128.8, 128.6, 127.7, 127.5, 127.4, 127.0,
101.6, 122.7, 77.1, 47.0, 39.7, 10.6; IR (KBr) ν 3063, 2921,
1550, 1453, 1377, 1275, 1076, 1030, 699 cm1; MS (ESI)
m/z 338.0 [M+H]+.

270
Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
4-Chloro-3-methyl-4-(2-nitro-1-(p-tolyl)ethyl)-1-phenyl-1H-
pyrazol-5-one (4c)
34.2 mg, 92% yield, 97% ee, 95:5 dr, []2D0 = 82.3° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IA, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 6.846 min (minor) and tR = 8.360
1
min (major)]; H NMR (400 MHz, CDCl3)  2.22 (s, 3H),
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IC, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 0.8 mL/min, tR = 9.120 min (major) and tR =
15.019 min (minor)]; 1H NMR (400 MHz, CDCl3)  2.23 (s,
3H), 2.26 (s, 3H), 4.15 (dd, J = 8.4 Hz, 6.4 Hz, 1H),
5.425.44 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0
Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H),
7.71 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) 
168.2, 156.9, 139.7, 136.8, 130.1, 129.0, 128.7, 127.7,
126.1, 119.3, 74.7, 65.4, 48.8, 21.0, 13.2; IR (KBr) ν 2965,
2925, 1718, 1656, 1630, 1401, 1372, 1286, 780 cm1;
HRMS (ESI) found: m/z 371.1034 M+; calcd. for
C19H18ClN3O3 371.1037.
4.15 (t, J = 8.0 Hz, 1H), 5.405.42 (m, 2H), 7.11 (d, J = 8.4
Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.407.44 (m, 4H), 7.70
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)  167.9,
156.5, 136.5, 132.7, 130.9, 129.5, 129.0, 126.3, 124.0,
119.2, 74.3, 65.0, 48.5, 13.0; IR (KBr) ν 2965, 2926, 2854,
1717, 1656, 1629, 1620, 1560, 1401, 757 cm1; HRMS (ESI)
found: m/z 434.9988 M+; calcd. for C18H15BrClN3O3
434.9985.
4-Chloro-3-methyl-4-(2-nitro-1-(4-nitrophenyl)ethyl)-1-
phenyl-1H-pyrazol-5-one (4g)
37.4 mg, 93% yield, 90% ee, 99:1 dr, []2D0 = 86.1° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IA, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 11.806 min (minor) and tR =
16.212 min (major)]; 1H NMR (400 MHz, CDCl3)  2.24 (s,
3H), 4.31 (t, J = 7.2 Hz, 1H), 5.47 (d, J = 7.2 Hz, 2H), 7.25
(t, J = 7.6 Hz, 1H), 7.387.46 (m, 4H), 7.67 (d, J = 7.6 Hz,
2H), 8.12 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
 167.5, 156.2, 148.4, 139.1, 136.3, 129.2, 129.1, 126.4,
124.4, 119.0, 73.9, 64.9, 48.4, 13.1; IR (KBr) ν 2965, 2927,
2855, 1719, 1656, 1630, 1499, 1401, 697 cm1; HRMS (ESI)
found: m/z 402.0726 M+; calcd. for C18H15ClN4O5
402.0731.
4-Chloro-4-(1-(4-fluorophenyl)-2-nitroethyl)-3-methyl-1-
phenyl-1H-pyrazol-5-one (4d)
34.9 mg, 93% yield, 89% ee, 96:4 dr, []2D0 = 129.9° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IA, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 6.959 min (minor) and tR = 7.811
1
min (major)]; H NMR (400 MHz, CDCl3) 2.22 (s, 3H),
4.19 (t, J = 7.2 Hz, 1H), 5.43 (d, J = 7.2 Hz, 2H), 6.96 (t, J
= 8.4 Hz, 2H), 7.227.27 (m, 3H), 7.41 (t, J = 8.0 Hz, 2H),
7.71 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) 
1
167.9, 163.1 (d, JC-F = 248.7 Hz), 156.7, 136.5, 129.8 (d,
3JC-F = 8.3 Hz), 129.0, 127.7, 126.2, 119.1, 116.5 (d, 2JC-F =
21.7 Hz), 74.4, 65.3, 48.2, 13.1; IR (KBr) ν 2964, 2925,
1719, 1647, 1637, 1560, 1509, 1449, 1389, 1287, 828, 757
cm1; HRMS (ESI) found: m/z 375.0781 M+; calcd. for
C18H15ClFN3O3 375.0786.
4-Chloro-4-(1-(2-chlorophenyl)-2-nitroethyl)-3-methyl-1-
phenyl-1H-pyrazol-5-one (4h)
36.1 mg, 92% yield, 92% ee, 98:2 dr, []2D0 = 167.3° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IA, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 7.149 min (major) and tR = 8.497
4-Chloro-4-(1-(4-chlorophenyl)-2-nitroethyl)-3-methyl-1-
phenyl-1H-pyrazol-5-one (4e)
35.3 mg, 90% yield, 96% ee, 95:5 dr, []2D0 = 57.8° (c =
1
min (minor)]; H NMR (400 MHz, CDCl3)  2.32 (s, 3H),
5.00 (dd, J = 10.8 Hz, 3.6 Hz, 1H), 5.29 (dd, J = 13.6 Hz,
10.8 Hz, 1H), 5.52 (dd, J = 13.6 Hz, 3.6 Hz, 1H), 7.127.14
(m, 2H), 7.227.27 (m, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.60 (t,
J = 5.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H); 13C NMR (100
MHz, CDCl3)  168.0, 157.2, 136.6, 134.3, 132.5, 130.9,
129.0, 128.6, 127.1, 126.2, 125.3, 119.1, 75.0, 65.5, 46.9,
13.7; IR (KBr) ν 2963, 2922, 2850, 1718, 1637, 1595, 1491,
1399, 1375, 1284, 756 cm1; HRMS (ESI) found: m/z
391.0493 M+; calcd. for C18H15Cl2N3O3 391.0490.
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IA, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 6.730 min (minor) and tR = 8.065
1
min (major)]; H NMR (400 MHz, CDCl3)  2.22 (s, 3H),
4.17 (t, J = 7.2 Hz, 1H), 5.43 (d, J = 7.2 Hz, 2H), 7.18 (d,
J = 8.4 Hz, 2H), 7.247.28 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H),
7.71 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) 
167.9, 156.6, 136.5, 135.8, 130.4, 129.7, 129.2, 129.0,
126.3, 119.2, 74.4, 65.1, 48.4, 13.1; IR (KBr) ν 2964, 2926,
2855, 1717, 1630, 1553, 1491, 1401, 757 cm1; HRMS (ESI)
found: m/z 391.0491 M+; calcd. for C18H15Cl2N3O3
391.0490.
4-(1-(2-Bromophenyl)-2-nitroethyl)-4-chloro-3-methyl-1-
phenyl-1H-pyrazol-5-one (4i)
40.6 mg, 93% yield, 96% ee, 83:17 dr, []2D0 = 193.2° (c =
4-(1-(4-Bromophenyl)-2-nitroethyl)-4-chloro-3-methyl-1-
phenyl-1H-pyrazol-5-one (4f)
39.7 mg, 91% yield, 94% ee, 99:1 dr, []2D0 = 138.6° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IC, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 7.476 min (major) and tR =

Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
271
12.235 min (minor)]; 1H NMR (400 MHz, CDCl3)  2.33 (s,
3H), 5.01 (dd, J = 10.4 Hz, 3.2 Hz, 1H), 5.30 (dd, J = 13.6
Hz, 10.4 Hz, 1H), 5.53 (dd, J = 13.6 Hz, 3.2 Hz, 1H),
7.137.15 (m, 2H), 7.237.28 (m, 2H), 7.43 (t, J = 8.0 Hz,
2H), 7.607.62 (m, 1H), 7.74 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3)  168.1, 157.2, 136.6, 134.4, 132.6,
130.9, 129.0, 128.6, 127.2, 126.2, 125.3, 119.1, 75.1, 65.5,
47.0, 13.7; IR (KBr) ν 2964, 2925, 2854, 1717, 1595, 1557,
1498, 1399, 1372, 1287, 756 cm1; HRMS (ESI) found: m/z
434.9990 M+; calcd. for C18H15BrClN3O3 434.9985.
(s, 3H), 3.133.18 (m, 1H), 4.59 (dd, J = 14.8 Hz, 5.2 Hz,
1H), 5.49 (dd, J = 14.8 Hz, 4.4 Hz, 1H), 7.26 (t, J = 7.6 Hz,
1H), 7.45 (t, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3)  168.0, 157.4, 137.0, 129.0,
126.0, 118.8, 74.4, 65.8, 39.4, 25.4, 23.7, 21.2, 12.8; IR
(KBr) ν 2966, 2928, 1720, 1596, 1559, 1500, 1399, 1364,
1291, 756, 691 cm1; HRMS (ESI) found: m/z 323.1035 M+;
calcd. for C15H18ClN3O3 323.1037.
4-Chloro-4-(2-nitro-1-phenylethyl)-1,3-diphenyl-1H-pyrazol-
5-one (4m)
38.6 mg, 92% yield, 90% ee, 97:3 dr, []2D0 = 57.4° (c =
4-Chloro-3-methyl-4-(2-nitro-1-(3-phenoxyphenyl)ethyl)-1-
phenyl-1H-pyrazol-5-one (4j)
41.4 mg, 92% yield, 88% ee, 81:19 dr, []2D0 = 129.1° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 0.8 mL/min, tR = 9.195 min (major) and tR =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IC, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 7.434 min (major) and tR = 9.807
1
10.651 min (minor)]; H NMR (400 MHz, CDCl3)  4.63
(dd, J = 10.4 Hz, 4.0 Hz, 1H), 5.54 (dd, J = 14.0 Hz, 10.4
Hz, 1H), 5.64 (dd, J = 14.0 Hz, 4.0 Hz, 1H), 6.87 (d, J = 7.2
Hz, 2H), 7.08 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H),
7.29 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.527.59
(m, 3H), 7.78 (d, J = 7.6 Hz, 2H), 8.00 (d, J = 7.2 Hz, 2H);
13C NMR (100 MHz, CDCl3)  168.4, 154.5, 136.6, 131.4,
131.2, 129.4, 129.3, 129.1, 128.9, 128.8, 128.2, 126.8,
126.4, 119.5, 74.1, 64.3, 49.3; IR (KBr) ν 2963, 2924, 2853,
1719, 1655, 1553, 1491, 1399, 1321, 1289, 759, 690 cm1;
HRMS (ESI) found: m/z 419.1041 M+; calcd. for
C23H18ClN3O3 419.1037.
1
min (minor)]; H NMR (400 MHz, CDCl3)  2.22 (s, 3H),
4.15 (dd, J = 8.0 Hz, 6.0 Hz, 1H), 5.415.43 (m, 2H),
6.856.89 (m, 3H), 6.95 (t, J = 8.0 Hz, 2H), 7.11 (t, J = 7.2
Hz, 1H), 7.217.29 (m, 4H), 7.41 (t, J = 7.6 Hz, 2H), 7.70
(d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) 167.9,
158.2, 156.7, 156.1, 136.7, 133.7, 130.8, 129.9, 129.0,
126.1, 123.9, 122.2, 119.7, 119.3, 119.2, 118.0, 74.3, 65.3,
48.8, 13.2; IR (KBr) ν 2965, 2926, 2853, 1719, 1663, 1637,
1560, 1399, 730 cm1; HRMS (ESI) found: m/z 472.1038
[M+Na]+; calcd. for C24H20ClN3O4+Na 472.1040.
4-Chloro-3-(4-methoxyphenyl)-4-(2-nitro-1-phenylethyl)-1-
phenyl-1H-pyrazol-5-one (4n)
40.5 mg, 90% yield, 92% ee, 99:1 dr, []2D0 = 43.7° (c =
4-Chloro-4-(1-(furan-2-yl)-2-nitroethyl)-3-methyl-1-phenyl-
1H-pyrazol-5-one (4k)
31.3 mg, 90% yield, 94% ee, 80:20 dr, []2D0 = 22.7° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 0.8 mL/min, tR = 13.792 min (major) and tR =
19.529 min (minor)]; 1H NMR (400 MHz, CDCl3)  3.92 (s,
3H), 4.60 (dd, J = 10.4 Hz, 4.0 Hz, 1H), 5.52 (dd, J = 14.4
Hz, 10.4 Hz, 1H), 5.64 (dd, J = 14.4 Hz, 4.0 Hz, 1H), 6.89
(d, J = 7.6 Hz, 2H), 7.047.11 (m, 4H), 7.18 (t, J = 7.6 Hz,
1H), 7.27 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.77
(d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H); 13C NMR (100
MHz, CDCl3)  168.3, 162.0, 154.3, 136.7, 131.3, 129.3,
128.9, 128.8, 128.5, 128.3, 126.2, 121.3, 119.5, 114.5, 74.1,
64.5, 55.4, 49.5; IR (KBr) ν 2964, 2924, 2852, 1719, 1655,
1560, 1509, 1399, 160, 702 cm1; HRMS (ESI) found: m/z
449.1141 M+; calcd. for C24H20ClN3O4 449.1142.
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak IB, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 6.649 min (major) and tR = 8.647
1
min (minor)]; H NMR (400 MHz, CDCl3)  2.29 (s, 3H),
4.39 (dd, J = 10.4 Hz, 3.6 Hz, 1H), 5.355.41 (m, 2H), 6.26
(t, J = 3.2 Hz, 1H), 6.31 (d, J = 3.2 Hz, 1H), 7.257.27 (m,
2H), 7.41 (t, J = 7.6 Hz, 2H), 7.72 (d, J = 7.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3)  167.6, 156.7, 145.5, 143.8,
136.8, 129.0, 126.1, 119.2, 111.0, 110.0, 72.7, 63.8, 42.8,
12.9; IR (KBr) ν 2963, 2925, 1719, 1655, 1596, 1560, 1499,
1399, 1368, 1292, 755 cm1; HRMS (ESI) found: m/z
347.0675 M+; calcd. for C16H14ClN3O4 347.0673.
4-Chloro-3-methyl-4-(3-methyl-1-nitrobutan-2-yl)-1-phenyl-
1H-pyrazol-5-one (4l)
23.6 mg, 73% yield, 88% ee, 99:1 dr, []2D0 = +19.9° (c =
1-Benzyl-4-chloro-3-methyl-4-(2-nitro-1-phenylethyl)-1H-
pyrazol-5-one (4o)
35.3 mg, 95% yield, 91% ee, 99:1 dr, []2D0 = 30.3° (c =
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 1.0 mL/min, tR = 5.618 min (minor) and tR = 6.406
min (major)]; 1H NMR (400 MHz, CDCl3)  0.90 (d, J = 6.4
Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 1.571.64 (m, 1H), 2.29
1.0, CH2Cl2), [determined by HPLC analysis with Daicel
Chiralpak AD-H, i-PrOH/hexane (v/v = 10/90), 254 nm UV
detector, 0.8 mL/min, tR = 13.092 min (major) and tR =
18.729 min (minor)]; 1H NMR (400 MHz, CDCl3)  2.10 (s,

272
Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
Table 1 Optimization of the reaction conditions a)
3H), 4.11 (dd, J = 10.0 Hz, 4.4 Hz, 1H), 4.67 (d, J = 15.2
Hz, 1H), 4.79 (d, J = 15.2 Hz, 1H), 5.355.46 (m, 2H),
7.117.13 (m, 4H), 7.16 (t, J = 3.6 Hz, 2H), 7.237.25 (m,
1H), 7.317.33 (m, 3H); 13C NMR (100 MHz, CDCl3) 
169.6, 156.1, 135.0, 131.7, 129.3, 129.2, 128.6, 128.2,
128.0, 127.9, 74.5, 64.1, 48.5, 48.3, 13.0; IR (KBr) ν 2962,
2922, 2852, 1714, 1629, 1554, 1404, 1379, 702 cm1;
HRMS (ESI) found: m/z 394.0929 [M+Na]+; calcd. for
C19H18ClN3O3+Na 394.0934.
3 Results and discussion
The conjugate addition reaction between 3-methyl-1-pheny-
lpyrazolone (1a) with trans-β-nitrostyrene (2a) was selected
as a model reaction, and a series of chiral thiourea deriva-
tives that had been previously developed and studied in our
laboratory, as well as several different organic acids, were
evaluated as catalysts for this transformation. The results
are given in Table 1. The use of saccharide-derived amine-
thioureas A–C gave the adduct 3a in high yield with mod-
erate enantioselectivity (entries 1–3). Notably, chiral cata-
lyst D exhibited a good level of stereoselectivity with an
opposite sense of asymmetric induction (Entry 4). This in-
dicates that the (S,S)configuration of 1,2-diphenylethane-1,
2-diamine matched the -D-glucopyranose to enhance ste-
reochemical control. Subsequently, we found that the com-
bination of the bifunctional amine-thiourea D and organic
acids catalyzed the model reaction with high enantioselec-
tivity and up to 91% ee was obtained (entries 5–8). Howev-
er, the use of catalysts E and F, which contain the bulkier
groups in the saccharide moiety, resulted in a dramatic de-
crease in enantioselectivity (entries 9 and 10). Further opti-
mization of the enantioselectivity was achieved with the
combination of catalyst D and benzoic acid by changing
solvents, catalyst, and acid loading (entries 11–22). It was
found that in the presence of 10 mol% amine-thiourea D
and 20 mol% benzoic acid, the conjugate addition reaction
of 3-methyl-1-phenylpyrazolone 1a to trans-β-nitrostyrene
2a could be efficiently performed in toluene at room tem-
perature, providing the desired product 3a at a 99% yield
with 96% ee.
Catalyst
(X mol%)
A (10)
Acid
(Y mol%)
Yield
ee
Entry
Solvent
(%) b) (%) c)
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
96
97
99
99
99
99
99




30
28
45
80
B (10)
C (10)
D (10)
D (10)
D (10)
D (10)
CH3CO2H (20)
PhCO2H (20)
89
91
4-MeC6H4CO2H (20) CH2Cl2
4-NO2C6H4CO2H
89
8
D (10)
CH2Cl2
99
90
(20)
9
E (10)
F (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (5)
PhCO2H (20)
PhCO2H (20)
PhCO2H (10)
PhCO2H (40)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
99
99
99
99
99
99
99
98
99
99
99
92
99
95
74
66
89
92
94
94
96
96
96
89
87
5
10
11
12
13
14
15
16
17
18
19
20
21
22
toluene
xylene
Et2O
THF
CH3CN
DMF
EtOH
73
93
toluene
a) Mixtures of 1a (0.1 mmol), 2a (0.15 mmol), catalyst (10 mol% or
5 mol%), and PhCO2H (20 mol% or 5 mol%) in solvent (1.0 mL) were
stirred at room temperature for 48 h (entries 1–4), 12 h (entries 5–21), and
60 h (entry 22); b) isolated yields; c) the ee value was determined by HPLC
in a chiral stationary phase.
With an effective combination thus in hand, we next in-
vestigated the scope of the conjugate addition reaction by
employing different nucleophiles and a wide variety of ni-
troolefins (the results are summarized in Table 2). The ni-
troolefins with different substitution patterns on the aro-
matic ring all gave the expected products 3a–3j in high
yields and with excellent enantioselectivities (entries 1–10).
The reaction with 2-naphthyl- and 9-anthracenyl-substituted
olefins also worked well to afford the adducts 3k and 3l in
high yields and with high enantioselectivities (entries 11
and 12). Heteroaromatic nitroalkene 2m is also a viable
substrate, affording the desired product 3m in 95% yield
with 93% ee (Entry 13). Notably, alkyl-substituted nitroole-
fins may also be used as reaction partners; the desired
products 3n and 3o, which were respectively derived from
linear and branched substrates were obtained in good yields
with high enantioselectivities (entries 14 and 15). Finally,
other nucleophilic donors were tested for the conjugate ad-
dition reaction. To our delight, similarly high levels of

Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
273
Table 2 Scope of organocatalytic asymmetric addition of pyrazolin-5-
ones 1 to nitroolefins 2 a)
reactivity and enantiocontrol were observed for the adducts
3p–3r (entries 16–18). Configurations of the known produc-
ts 3f and 3l were determined by comparing the optical rota-
tion value with the literature data [2e], and the configurati-
ons of other products were tentatively assigned by analogy.
We noted that the pyrazol-5-ol adducts 3 can tautomerize
at room temperature; as the concentration becomes higher,
the tautomerization becomes easier [9]. Therefore, we fur-
ther investigated the one-pot subsequent conjugate addi-
tion/dearomative chlorination of pyrazol-5-ones by using
the co-catalyst of amine-thiourea D and benzoic acid to
generate optically active chlorinated pyrazol-5(4H)-ones-
with adjacent quaternary and tertiary stereocenters. As sho-
wn in Scheme 2, this asymmetric one-pot multistep is com-
patible with a wide range of nitroolefin substrates: a series
of chlorinated pyrazol-5-ones 4a–o were generated in
73%–95% yields with 88%–97% ee and good to excellent
diastereoselectivities. The electronic properties of the sub-
stituents on the aromatic rings of nitroolefins did not have a
significant effect on the stereoselectivities of the reactions.
Substrates with electron-neutral, electron-withdrawing,
and electron-donating groups efficiently participated in this
reaction to deliver the chlorinated pyrazolin-5-ones 4a–h
with uniformly high diastereo- and enantioselectivities re-
gardless of the substitution pattern. However, 2-bromo and
Entry
1
2
3
4
5
6
7
8
Product 3 (R1, R2, R)
Me, Ph, Ph
Yield (%) b) EE (%) c)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
99
96
98
98
99
98
95
96
94
96
98
96
95
74
78
95
96
98
96
96
97
95
94
95 (R)
95
97
97
96
96
90 (R)
93
90
88
98
92
89
Me, Ph, 4-MeOC6H4
Me, Ph, 4-MeC6H4
Me, Ph, 4-FC6H4
Me, Ph, 4-ClC6H4
Me, Ph, 4-BrC6H4
Me, Ph, 4-NO2C6H4
Me, Ph, 2-ClC6H4
Me, Ph, 2-BrC6H4
Me, Ph, 3-PhOC6H4
Me, Ph, 2-naphthyl
Me,Ph, 9-anthracenyl
Me, Ph, 2-furyl
Me, Ph, propyl
Me, Ph, isobutyl
Ph, Ph, Ph
4-MeOC6H4, Ph, Ph
Me, Bn, Ph
9
10
11
12
13
14 d)
15 d)
16
17
18
a) General conditions: 1 (0.1 mmol), 2 (0.15 mmol), catalyst D
(10 mol%), PhCO2H (20 mol%), and toluene (1.0 mL); b) isolated yields;
c) the ee value was determined by HPLC in a chiral stationary phase; d)
reaction time: 72 h.
Scheme 2 One-pot asymmetric conjugate addition/dearomative chlorination.

274
Zhang KF, et al. Sci China Chem February (2014) Vol.57 No.2
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3-phenoxy-substituted nitrostyrenes and furyl-substituted
nitroolefin provided the subsequent products 4i–k with
lower diastereoselectivity. In addition, less reactive aliphatic
nitroolefin was also tolerated in this reaction, and the de-
sired product 4l was obtained at a 73% yield with 99:1 dr
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donors to give the corresponding products 4m–o in high
yields and stereoselectivities.
3
4 Conclusions
In summary, we have identified an efficient, cooperative
catalyst system for the conjugate addition of 4-nonsubsti-
tuted pyrazolones to nitroolefins and subsequent dearoma-
tive chloroination. The corresponding adducts and subse-
quent products were obtained in high to excellent yields (up
to > 99%) and high stereoselectivities (up to 99/1 dr, 98% ee)
under mild reaction conditions. Other, ongoing investiga-
tions are focusing upon further bioactive assays of these
small molecules, mechanistic studies into the origin of the
catalyst cooperativity, and extension of the underlying prin-
ciples to other multifunctional thiourea-catalyzed transfor-
mations.
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China (21172170 and 21225208) and the National Basic Research Pro-
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7
8
9
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The pyrazol-5-ol adducts are stable at 40 °C for one month, and no-
tautomerization can be detected by TLC and 1H NMR analysis.