Highly enantioselective Michael addition of pyrazolin-5-ones to nitroolefins catalyzed by cinchona alkaloid derived 4-methylbenzoylthioureas

Article abstract of DOI:10.1002/chir.23003

Cinchona alkaloid-derived 4-methyl/nitro benzoylthioureas were synthesized, which smoothly catalyzed the asymmetric Michael addition of pyrazolin-5-ones to nitroolefins. The results showed that electronic effects of substituents in the benzene ring of benzoylthioureas have subtle influences on their catalytic abilities and electron donating methyl group is favored than electron withdrawing nitro group. Preliminary Hartree-Fock calculations revealed that in the catalytic cycle, hydrogen bond energies of the complex formed with 4-methylbenzoylthioureas are about 0.19 to 1.56?kcal/mol higher than with the corresponding 4-nitrobenzoylthioureas. 4-Methylbenzoylthioureas were identified as the most effective catalysts that promoted asymmetric Michael addition of pyrazolin-5-ones to nitroolefins to give the S- or R-products with high enantioselectivities.

Full text of DOI:10.1002/chir.23003

Received: 16 April 2018
DOI: 10.1002/chir.23003
Revised: 19 June 2018
Accepted: 23 June 2018
R E G U L A R A R T I C L E
Highly enantioselective Michael addition of pyrazolin‐5‐
ones to nitroolefins catalyzed by cinchona alkaloid derived
4‐methylbenzoylthioureas
Mengchen Yang1 | Min Zhang1 | Zhenyu Wang1 | Li Tang1 | Wenbin Chen3 |
Shurong Ban1,2
| Qingshan Li1,2
1 School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, PR China
2 School of Chinese Materia Medica, Shanxi University of Chinese Medicine, Jinzhong, PR China
3 Institute of Elemento‐Organic Chemistry, Nankai University, Tianjin, PR China
Correspondence
Shurong Ban and Qingshan Li, School of
Abstract
Cinchona alkaloid‐derived 4‐methyl/nitro benzoylthioureas were synthesized,
Pharmaceutical Science, Shanxi Medical
University, 56 Xinjian South Road,
Taiyuan 030001, PR China.
which smoothly catalyzed the asymmetric Michael addition of pyrazolin‐5‐
ones to nitroolefins. The results showed that electronic effects of substituents
in the benzene ring of benzoylthioureas have subtle influences on their cata-
lytic abilities and electron donating methyl group is favored than electron with-
drawing nitro group. Preliminary Hartree‐Fock calculations revealed that in
the catalytic cycle, hydrogen bond energies of the complex formed with 4‐
methylbenzoylthioureas are about 0.19 to 1.56 kcal/mol higher than with the
corresponding 4‐nitrobenzoylthioureas. 4‐Methylbenzoylthioureas were identi-
fied as the most effective catalysts that promoted asymmetric Michael addition
of pyrazolin‐5‐ones to nitroolefins to give the S‐ or R‐products with high
enantioselectivities.
Email: shurongban@sxmu.edu.cn;
qingshanl@yahoo.com
Wenbin Chen, Institute of Elemento‐
Organic Chemistry, Nankai University,
94 Weijin Road, Tianjin 300071, PR China.
Email: wbchen@nankai.edu.cn
Funding information
Science and Technology Innovation
Foundation of Shanxi Medical University,
Grant/Award Number: C01201009; Tech-
nology Innovation Team of Shanxi Prov-
ince; Program for the Top Science and
Technology Innovation Teams of Higher
Learning Institutions of Shanxi province;
Fund for Shanxi Key Subjects Construc-
tion; Research Project Supported by
Shanxi Scholarship Council of China,
Grant/Award Number: 2017‐061; Fund
Program for the Scientific Activities of
Selected Returned Overseas Professionals
in Shanxi Province, Grant/Award Num-
ber: 2016; Natural Science Foundation of
Shanxi Province, Grant/Award Number:
2015011104; National Natural Science
Foundation of China, Grant/Award
Number: 81473100
KEYWORDS
4‐methylbenzoylthioureas, asymmetric Michael addition, Hartree‐Fock calculations, nitroolefins,
pyrazolin‐5‐ones
1 | INTRODUCTION
example, the novel pyrazolone derivatives were devel-
oped as small molecule inhibitors of sirtuins for potential
Pyrazolone, an important five‐membered ring heterocy-
clic motif, is found in many natural and synthetic prod-
ucts with a wide range of pharmacological activities. For
use as chemotherapeutics as well as tools to modulate
sirtuin activity.1 Norman and his co‐workers described a
potent class of pyrazolone c‐Met inhibitors with good
Chirality. 2018;1–9.
wileyonlinelibrary.com/journal/chir
© 2018 Wiley Periodicals, Inc.
1

2
YANG ET AL.
in vivo activity.2
A
series of 1,3,4‐trisubstituted‐
high enantio‐ and diastereoselectivities.21 In the context
of the above chemistry, we designed and synthesized cin-
chona alkaloid‐derived 4‐methyl/nitro benzoylthioureas
I‐VIII (Scheme 1) to find more competent catalysts and
study the electronic effects of substituents in the benzene
ring of benzoylthioureas on their catalytic performances
using both experimental and theoretical (Hartree‐Fock
calculation) methods.
pyrazolone derivatives were demonstrated as potent and
nonsteroidal farnesoid X receptor selective antagonists
by Huang et al.3 Hadi et al have exploited SAR studies
of pyrazolone scaffold for HIV‐1 integrase and discovered
a potent compound that exhibited single‐digit micromo-
lar activity against IN strand transfer process.4 Amata
et al reported the synthesis and assessment of a series of
pyrazolone derivatives of human phosphodiesterase 4
(hPDE4) inhibitors for the assessment of their activity
against the trypanosomal phosphodiesterase TbrPDEB1.5
Further, pyrazolone is a constituent structural feature of
many nonsteroidal anti‐inflammatory drugs clinically
useful in the treatment of arthritis and other musculo
skeletal and joint disorders.6 Therefore, the broad spec-
trum of biological activities of pyrazolone derivatives
have resulted in considerable interest in investigation on
the chemistry of pyrazolones especially the development
of asymmetric methods for building of pyrazolone‐based
chiral compounds.7-14
Pyrazolin‐5‐ones are widely used pyrazolone deriva-
tives and have active property, especially at the C‐4 loca-
tion, where nucleophilic reactions can easily occur.7 It
has been used as Michael donors in the asymmetric
additions to react with 1,4‐dicarbonyl but‐2‐enes,8
azodicarboxylates,9 alkynones,10 α,β‐unsaturated alde-
hydes,11 nitroolefins,7,12-14 etc.
Recent efforts toward the development of chiral dual
hydrogen bonding catalysts have produced outstanding
efficiency in a wide variety of asymmetric transforma-
tions.15-20 The two donor hydrogens in these scaffolds
serve to organize and activate the reaction substrates.
And the acidity of the N–H bonds is sensitive and critical
for these bifunctional organocatalysts (Figure 1).20
In our previous work, we have designed and synthe-
sized cinchona‐based benzoylthioureas that can catalyze
Michael addition of pyrazolin‐5‐ones to nitroolefins with
2 | MATERIALS AND METHODS
2.1 | General
9‐Amino‐9‐deoxyepicinchona alkaloids were synthesized
according to literature methods.22,23 Commercially
available compounds were used without further
purification. Solvents were dried according to standard pro-
cedures. Column chromatography was carried out using sil-
ica gel (200‐300 mesh). Melting points were measured on an
XT‐4 melting point apparatus without correction. The 1H‐
NMR spectra were recorded on BRUKER AVANCE II
400 MHz and 600 MHz spectrometer, while the 13CNMR
spectra were recorded at 100 and 150 MHz. Infrared spectra
were obtained on Thermo Scientific Nicolet iS5. The high
resolution electrospray ionization mass spectrometry (ESI‐
HRMS) spectra were obtained on Bruker APEX IV mass
spectrometer. Optical rotations were measured on Rudolph
Research Analytical Autopol III. The enatiomeric excesses
of the products were determined by chiral high‐performance
liquid chromatography (HPLC) analysis using a Lumtech
instrument on chiralpak AS‐H, IC (n‐hexane/2‐propanol as
eluent). The absolute configuration of the products were
determined by comparing HPLC data and specific rotation
ratio with data in literatures.7,24 All calculations were
performed with Gaussian 03. Molecular geometries were
fully optimized with the HF/sto‐3g method.
FIGURE 1 Development of relevant
chiral organocatalysts bearing two NH‐
donor hydrogen atoms

YANG ET AL.
3
SCHEME 1 Synthesis of 4‐methyl/nitro
benzoylthioureas I‐VIII
2.2 | Synthesis of organocatalysts I‐VIII
2.2.2 | N‐(((S)‐(6‐methoxyquinolin‐4‐yl)
((1S,2S,4S,5R)‐5‐vinylquinuclidin‐2‐yl)
methyl)carbamothioyl)‐4‐nitrobenzamide
(II):
9‐Amino‐9‐deoxyepicinchona alkaloid (1 mmol) was
dissolved in CH2Cl2 (5 mL) and cooled to 0°C, then
followed by addition of Et3N and the solution of
isothiocyanate (1.5 mmol) in CH2Cl2. After stirred at
room temperature for 20 hours (monitored by TLC), the
reaction mixture was concentrated and purified by silica
gel column chromatography (ethyl acetate–petroleum as
the eluent) to give the organocatalysts I‐VIII.
30
yellow solid; 61.2% yield; m.p. 131.7‐134.4°C; [α]D
=
1
−309.60 (c = 0.2, CH2Cl2); H NMR (400 MHz, CDCl3)
δ 11.32 (s, 1H), 9.03 (s, 1H), 8.77 (d, J = 4.6 Hz, 1H),
8.26‐8.42 (m, 2H), 8.08‐7.95 (m, 3H), 7.71 (br. s, 1H),
7.40 (d, J = 5.9 Hz, 2H), 5.70‐5.79 (m, 1H), 4.96‐5.03 (m,
2H), 4.00 (s, 3H), 3.27‐3.37 (m, 3H), 2.80‐2.87 (m, 2H),
2.31‐2.36 (m, 1H), 1.77‐1.90 (m, 2H), 1.64‐1.71 (m, 3H),
1.41‐1.47 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 178.76,
164.96, 158.03, 150.62, 147.66, 144.88, 141.34, 137.47,
131.95, 128.98, 124.26, 122.09, 114.83, 102.10, 56.04,
55.84, 41.58, 39.55, 28.03, 27.41, 26.09; IR (ATR): ν
2928.98, 2862.47, 1675.43, 1620.46, 1522.71, 1506.15,
1473.73, 1344.19, 1298.87, 1257.99, 1226.89, 1154.74,
2.2.1 | N‐(((S)‐(6‐methoxyquinolin‐4‐yl)
((1S,2S,4S,5R)‐5‐vinylquinuclidin‐2‐yl)
methyl)carbamothioyl)‐4‐
methylbenzamide (I):
white
solid;
72.6%
yield;
m.p.
87.5‐90.4°C;
[α]D = −302.40 (c = 0.2, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 11.54 (s, 1H), 8.91 (s, 1H), 8.77 (d, J = 4.5 Hz,
1H), 8.03 (d, J = 9.2 Hz, 1H), 7.77 (s, 1H), 7.71
(d, J = 8.2 Hz, 2H), 7.38–7.42 (m, 2H), 7.29 (s, 1H), 6.01
(br. s, 1H), 5.70‐5.79 (m, 1H), 4.98‐5.04 (m, 2H), 4.02
(s, 3H), 3.35‐3.41 (m, 2H), 2.85‐2.87 (m, 2H), 2.41
(s, 3H), 2.31‐2.37 (m, 1H), 1.68‐1.72 (m, 3H), 1.43‐1.49
(m, 2H), 0.86‐1.00 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 179.45, 166.77, 158.01, 147.68, 144.94, 144.64, 141.45,
131.90, 129.88, 128.98, 127.64, 122.16, 114.73, 102.16,
56.05, 55.89, 41.61, 39.57, 28.04, 27.48, 26.14, 21.76; IR
(ATR): ν 3221.52, 2922.56, 2858.24, 1668.30, 1620.67,
1505.10, 1473.64, 1342.65, 1258.06, 1156.43, 1028.32,
829.11, 747.41, 668.15, 609.41 cm−1; HRMS m/z calcd
for C29H33N4O2S [M + H]+ 501.2319, found 501.2329.
1027.83, 849.97, 790.69, 716.08, 701.76, 606.15 cm−1
;
30
1
HRMS m/z calcd for C28H30N5O4S [M + H]+532.2013,
found 532.2017.
2.2.3 | 4‐Methyl‐N‐(((S)‐quinolin‐4‐
yl((1S,2S,4S,5R)‐5‐vinylquinuclidin‐2‐yl)
methyl)carbamothioyl) benzamide (III):
white
solid;
84.5%
yield;
m.p.
103.2‐105°C;
30
1
[α]D = −219.68 (c = 0.2, CH2Cl2); H NMR (600 MHz,
CDCl3) δ 11.49 (s, 1H), 8.84 (d, J = 5.8 Hz, 2H), 8.40
(s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.73‐7.61 (m, 3H), 7.58
(s, 1H), 7.39 (s, 1H), 7.19 (d, J = 5.5 Hz, 2H), 5.89 (s,
1H), 5.70‐5.58 (m, 1H), 4.89 (dd, J = 21.5, 13.8 Hz, 2H),
3.43‐3.04 (m, 3H), 2.77 (s, 2H), 2.33 (s, 3H), 2.23 (s, 1H),

4
YANG ET AL.
1.61 (s, 2H), 1.22 (d, J = 49.1 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 179.54, 166.70, 150.26, 148.63,
144.59, 141.36, 130.57, 129.85, 129.34, 129.02, 127.67,
126.92, 123.91, 114.75, 55.93, 41.46, 39.52, 29.80, 27.91,
27.48, 25.83, 21.74; IR (ATR): ν 3225.31, 2922.11,
2859.25, 1667.72, 1610.08, 1589.67, 1495.11, 1342.02,
1256.43, 1184.26, 1155.36, 1116.91, 1074.95, 1018.65,
912.29, 833.45, 818.85, 747.79, 694.99, 668.37,
825.93, 747.34, 611.17 cm−1; HRMS m/z calcd for
C29H33N4O2S [M + H]+501.2319, found 501.2339.
2.2.6 | N‐(((1R)‐(6‐methoxyquinolin‐4‐yl)
((1S,2R,4S)‐5‐vinylquinuclidin‐2‐yl)methyl)
carbamothioyl)‐4‐nitrobenzamide (VI):
30
yellow solid; 64.4% yield; m.p. 72.9‐73.5 °C; [α]D
=
1
606.16 cm−1
;
HRMS m/z calcd for C28H31N4OS
+281.00 (c = 0.2, CH2Cl2); H NMR (600 MHz, CDCl3)
δ11.30 (s, 1H), 9.05 (s, 1H), 8.76 (d, J = 4.5 Hz, 1H),
8.33 (d, J = 8.8 Hz, 2H), 7.99‐8.03 (m, 3H), 7.69 (br. s,
1H), 7.39–7.42 (m, 2H), 5.90‐5.97 (m, 1H), 5.15‐5.20
(m, 2H), 4.01 (s, 3H), 3.33 (s, 1H), 3.03‐3.13 (m, 4H),
2.33‐2.38 (m, 1H), 2.20‐2.23 (m, 1H), 2.00‐2.04 (m, 2H),
1.56‐1.71 (m, 3H); 13C NMR (150 MHz, CDCl3) δ
178.98, 175.79, 164.99, 158.12, 150.63, 147.60, 144.85,
140.38, 137.51, 130.01, 129.02, 128.70, 124.23, 123.97,
122.53, 115.10, 101.76, 55.78, 49.40, 47.59, 39.10, 36.04,
27.38, 27.34, 26.59; IR (ATR): ν 3353.73, 3180.09,
2919.96, 2849.86, 1719.66, 1660.08, 1631.45, 1603.71,
1522.44, 1469.83, 1429.58, 1344.11, 1260.18, 1174.03,
1028.33, 850.14, 826.01, 717.17, 701.62 cm−1; HRMS m/z
[M + H]+471.2213, found 471.2212.
2.2.4 | 4‐Nitro‐N‐(((S)‐quinolin‐4‐
yl((1S,2S,4S,5R)‐5‐vinylquinuclidin‐2‐yl)
methyl)carbamothioyl) benzamide (IV):
yellow solid; 79.4% yield; m.p. 108.3‐111°C;
30
1
[α]D = −219.60 (c = 0.2, CH2Cl2); H NMR (600 MHz,
CDCl3) δ11.40 (s, 1H), 9.08 (s, 1H), 8.91 (d, J = 4.3 Hz,
1H), 8.43 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.15
(d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.75
(t, J = 7.5 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.46 (s, 1H),
5.68‐5.74 (m, 1H), 4.94‐5.00 (m, 2H), 2.84‐3.36 (m, 3H),
2.84‐2.86 (m, 2H), 2.17‐2.32 (m, 2H), 1.64‐1.84 (m, 5H);
13C NMR (150 MHz, CDCl3) δ 178.82, 164.91, 150.66,
150.24, 148.64, 141.30, 137.54, 130.66, 129.45, 129.01,
126.99, 124.26, 123.72, 114.86, 55.98, 41.44, 39.56, 29.83,
27.95, 27.43; IR (ATR): ν 3170.69, 3073.63, 2922.62,
2854.28, 1675.86, 1636.25, 1602.97, 1589.62, 1520.36,
1343.00, 1255.87, 1155.35, 1109.35, 1074.64, 1012.78,
calcd for C28H30N5O4S [M
532.1998.
+
H]+532.2013, found
2.2.7 | 4‐Methyl‐N‐(((1R)‐quinolin‐4‐
yl((1S,2R,4S)‐5‐vinylquinuclidin‐2‐yl)
methyl)carbamothioyl) benzamide (VII):
851.45, 794.79, 754.76, 718.74, 701.59, 668.30 cm−1
;
white solid; 73.2% yield; m.p. 61‐62.1°C; [α]D30 = +174.00
HRMS m/z calcd for C27H28N5O3S [M + H]+502.1907,
found 502.1914.
(c = 0.2, CH2Cl2); H NMR (600 MHz, CDCl3) δ11.52
1
(s, 1H), 8.83‐8.94 (m, 2H), 8.44 (s, 1H), 8.14 (d, J = 8.3 Hz,
1H), 7.72 (d, J = 8.1 Hz, 2H), 7.66 (dd, J = 16.2, 8.2 Hz,
1H), 7.46 (d, J = 4.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H),
5.90‐6.00 (m, 2H), 5.09‐5.30 (m, 2H), 3.01‐3.10 (m, 3H),
2.42 (s, 3H), 2.32 (d, J = 6.9 Hz, 1H), 2.22 (t, J = 7.7 Hz,
1H), 2.01 (s, 2H), 1.45‐1.66 (m, 5H); 13C NMR
(150 MHz, CDCl3) δ 179.64, 166.76, 150.18, 148.55,
144.61, 140.34, 132.26, 129.89, 129.42, 129.09, 127.68,
127.52, 126.89, 123.95, 123.78, 115.10, 49.33, 47.55,
39.37, 32.06, 29.83, 27.53, 27.34, 26.63, 21.76; IR (ATR):
ν 3357.22, 3180.63, 2919.84, 2850.42, 1660.50, 1632.21,
1610.28, 1589.80, 1504.14, 1468.80, 1424.64, 1338.63,
1257.95, 1168.09, 1117.84, 1018.93, 912.60, 844.78,
748.38, 720.30, 697.26, 600.09 cm−1; HRMS m/z calcd
for C28H31N4OS [M + H]+471.2213, found 471.2234.
2.2.5 | N‐(((1R)‐(6‐methoxyquinolin‐4‐yl)
((1S,2R,4S)‐5‐vinylquinuclidin‐2‐yl)methyl)
carbamothioyl)‐4‐methylbenzamide (V):
white
solid;
75.3%
yield;
m.p.
175‐176.8°C;
30
1
[α]D = +352.95 (c = 0.2, CH2Cl2); H NMR (400 MHz,
CDCl3) δ11.50 (s, 1H), 8.90 (s, 1H), 8.75 (s, 1H), 8.02
(d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 3H), 7.37‐7.41
(m, 2H), 7.27‐7.29 (m, 2H), 5.90‐5.98 (m, 1H), 5.12‐5.19
(m, 2H), 4.01 (s, 3H), 3.25 (s, 1H), 2.98‐3.08 (m, 4H),
2.41 (s, 3H), 2.31‐2.35 (m, 1H), 1.83 (s, 1H), 1.51‐1.59
(m, 2H), 1.251.34 (m, 2H), 0.96‐1.03 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 179.49, 166.79, 157.99, 147.63,
144.87, 144.61, 140.64, 132.25, 132.15, 131.79, 129.87,
129.03, 128.67, 128.55, 127.64, 122.47, 114.88, 101.81,
77.48, 77.16, 76.84, 55.78, 49.44, 47.64, 39.29, 27.47,
26.75, 25.52, 21.75; IR (ATR): ν 3347.97, 3179.08,
3079.36, 3025.97, 2922.57, 2850.87, 1676.90, 1611.77,
1587.86, 1512.27, 1464.04, 1307.55, 1342.95, 1269.10,
1218.43, 1176.85, 1155.75, 1037.35, 921.05, 844.62,
2.2.8 | 4‐Nitro‐N‐(((1R)‐quinolin‐4‐
yl((1S,2R,4S)‐5‐vinylquinuclidin‐2‐yl)
methyl)carbamothioyl) benzamide (VIII):
yellow
solid;
51.2%
yield;
m.p.
76.5‐80.2°C;
20
[α]D = +360.73 (c = 0.275,CH2Cl2); IR (ATR): ν

YANG ET AL.
5
3353.98, 3176.08, 3072.35, 2920.14, 2849.91, 1732.70,
1675.34, 1603.31, 1522.19, 1424.77, 1344.87, 1254.34,
1167.98, 1109.24, 1081.01, 1013.12, 914.53, 849.79,
Hydrogen bond energy of complex of III + 2a:
−17.25 kcal/mol.
Hydrogen bond energy of complex of IV + 2a:
−16.13 kcal/mol.
1
754.95, 718.42, 701.71, 604.40 cm−1; H NMR (600 MHz,
CDCl3) δ 11.36 (s, 1H), 9.19 (s, 1H), 8.89 (d, J = 3.9 Hz,
1H), 8.38 (s, 1H), 8.29 (d, J = 8.4 Hz, 2H), 8.14
(d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.74
(t, J = 7.3 Hz, 1H), 7.67‐7.61 (m, 1H), 7.43 (d, J = 3.4 Hz,
1H), 5.93 (ddd, J = 16.9, 10.2, 6.6 Hz, 1H), 5.17
(dd, J = 22.6, 13.9 Hz, 2H), 3.20 (s, 1H), 3.11‐3.01
(m, 3H), 2.95 (s, 1H), 2.33 (d, J = 6.2 Hz, 1H), 2.08‐1.87
(m, 2H), 1.56 (ddd, J = 32.2, 28.3, 21.7 Hz, 4H); 13C
NMR (150 MHz, CDCl3) δ 178.75, 164.86, 150.53,
150.06, 148.48, 140.22, 137.47, 130.48, 129.34, 128.89,
126.78, 124.13, 123.60, 114.99, 60.41, 49.30, 47.48, 39.26,
29.33, 27.37, 26.58; HRMS m/z calcd for C27H28N5O3S
[M + H]+502.1907, found 502.1913.
Energy of V: −1859.2058 Hartree.
Energy of VI: −2021.3316 Hartree.
Energy of complex of
V
+
nitrostyrene 2a:
nitrostyrene 2a:
−2363.7656 Hartree.
Energy of complex of VI
−2525.8911 Hartree.
+
Hydrogen bond energy of complex of V + 2a:
−9.54 kcal/mol.
Hydrogen bond energy of complex of VI + 2a:
−9.35 kcal/mol.
Energy of VII: −1746.7867 Hartree.
Energy of VIII: −1908.9072 Hartree.
Energy of complex of VII + nitrostyrene 2a:
−2251.3469 Hartree.
Energy of complex of VIII + nitrostyrene 2a:
−2413.4716 Hartree.
Hydrogen bond energy of complex of VII + 2a:
−9.85 kcal/mol.
Hydrogen bond energy of complex of VIII + 2a:
−12.42 kcal/mol.
2.3 | General procedure of asymmetric
Michael addition
To a stirred solution of catalyst (III or V, 0.02 mmol) and
nitroolefin (0.15 mmol) in CHCl3 (1.0 ml) was added
pyrazolone 1 (0.1 mmol). The reaction mixture was
stirred at −30°C (monitored by TLC). After the reaction
is completed, the mixture was concentrated and purified
by silica gel column chromatography (ethyl acetate‐
petroleum as the eluent) to give the products 3.7,24 The
ee values were determined by chiral HPLC analysis.
3 | RESULTS AND DISCUSSION
To study the catalytic activities of I‐VIII, the Michael
addition of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one (1a)
with β‐nitrostyrene (2a) was used as a model reaction.
The direct product of this reaction would be a 4‐
substituted pyrazolinone bearing 2 stereocenters, but
prompt aromatization occurs to give the observed aroma-
tized products.7 The reactions were performed in CH2Cl2
with 10 mol% catalysts at the room temperature for
3 hours, and isolated yields and enantioselectivities of
3a were showed in the Table 1. To our delight, all of cat-
alysts I‐VIII could promote the reaction smoothly and
gave the desired product 3a with good to and moderate
enantioselectivities (Table 1). Importantly, both enantio-
mers of 3a can be accessed by using either of the
pseudoenantiomeric cinchona alkaloids derivatives. The
catalysts I, II, III, and IV gave the S‐enantiomers prefer-
entially, whereas the catalysts V, VI, VII, and VIII
afforded the R‐enantiomers predominantly. Moreover,
the results showed that electronic effects of substituents
in the benzene ring of benzoylthioureas have the subtle
influences on their catalytic abilities and electron donat-
ing methyl group is favored than withdrawing groups
nitro group (except for VII and VIII, entries 7 and 8,
Table 1). 4‐Methyl benzoylthioureas I, III, and V could
2.4 | HF calculations
All calculations were performed with Gaussian 03.
Molecular geometries were fully optimized with the HF/
sto‐3g method.
Energy of nitrostyrene 2a: −504.5446 Hartree.
Energy of I: −1859.1948 Hartree.
Energy of II: −2021.3227 Hartree.
Energy of complex of I + nitrostyrene 2a: −2363.7672
Hartree.
Energy of complex of II
−2525.8926 Hartree.
Hydrogen bond energy of complex of I + 2a:
−17.44 kcal/mol.
Hydrogen bond energy of complex of II + 2a:
−15.88 kcal/mol.
Energy of III: −1746.7766 Hartree.
Energy of IV: −1908.9036 Hartree.
Energy of complex of III + nitrostyrene 2a:
−2251.3487 Hartree.
+ nitrostyrene 2a:
Energy of complex of IV + nitrostyrene 2a:
−2413.4739 Hartree.

6
YANG ET AL.
TABLE 1 Screening of organocatalysts for the enantioselective
Michael addition of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one to
β‐nitrostyrenea
electron‐donating group (OCH3, CH3) have better
catalytical abilities (excellent yields and better ee values)
and higher hydrogen bond energies. However, there is
no completely consistent relationship between hydrogen
bond energy and catalytical ability. The above theoretical
calculations method could be of interest for predicting the
behavior of the catalysts, but the results are too limited to
provide a general method.
Entry
Cat.
Yield, %b
ee, %c
Based on the above results, the III was used to further
screen the optimal reaction conditions including solvent,
catalyst loading, and temperature (Table 2). Almost each
tested solvent gave excellent yields and good
enantioselectivities except methanol and DMSO (entries
1‐7, Table 2). The best solvent was CHCl3 (94.9% yield
and 85% ee, entry 5, Table 2). Then the reaction
temperature was investigated, and the results proved that
lowering the temperature to −30°C in CHCl3 led to an
excellent yield (94.6%) and grateful enantioselectivity
1
2
3
4
5
6
7
8
I
92
78
95
91
94
90
91
92
77(S)
71(S)
79(S)
73(S)
79(R)
65(R)
67(R)
70(R)
II
III
IV
V
VI
VII
VIII
TABLE 2 Screening of the optimum reaction conditions for the
enantioselective Michael addition of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐
5‐one to β‐nitrostyrenea
aAll reactions were carried out with 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one 1a
(0.1 mmol,17.4 mg), β‐nitrostyrene 2a (22 mg, 0.15 mmol) and the catalyst
(10 mol%) in 1.0‐mL DCM at room temperature for 3 h.
bIsolated yield after column chromatography on silica gel.
cDetermined by chiral HPLC on Chiralpak AS‐H column with n‐hexane and
2‐propanol.
all gave the excellent yields and better ee values (entries
1, 3, and 5, Table 1). In the postulated dual H‐bonding
enhanced catalytic cycle, the first step is the formation
of the complex of nitrostyrene and dual H‐donor through
hydrogen bonding.12,14 Then the hydrogen bond energies
of complexes the formed with catalysts and nitrostyrene
were preliminarily calculated and analyzed by
Hartree‐Fock method. The results of theoretical
calculations demonstrated that the above complexes
could be formed through hydrogen bonding between
N–H of catalysts and nitro group of nitrostyrene. And
the hydrogen bond energies of the complexes are ranged
from 9.35 to 17.44 kcal/mol. Moreover, the hydrogen
bond energies of the complexes with 4‐methyl
benzoylthioureas are about 0.19 to 1.56 kcal/mol higher
than with the corresponding 4‐nitro benzoylthioureas
(I > II, III > IV, V > VI). However, an inverse
relationship was observed for VII and VIII both in
theoretical calculation and experimental research. The
reason need to be further studied. To discuss about the
electronic effects of these substituents on the benzene
ring, we synthesized quinin‐benzoylthioureas with other
substituents such as methoxy, CF3, and H groups. Their
catalytical abilities were examined under conditions in
Table 1, and hydrogen bond energies were also calculated
using Hartree‐Fock method. The results (see Supporting
Information) indicate that benzoylthioureas with H and
Cat. Loading,
mol%
Time,
h
Yield,
%
ee,
%
b
c
Entry
Solvent
1
DCM
10
10
10
10
10
10
10
10
10
10
5
3
3
95
83
92
87
95
90
62
92
91
95
93
97
93
79
25
69
69
85
81
1
2
MeOH
THF
3
3
4
EtOAc
CHCl3
Toluene
DMSO
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
3
5
3
6
3
7
3
8d
9e
10f
11
12
13
8
91
63
94
91
97
96
3
12
12
12
12
20
30
aAll reactions were carried out at 25°C with 3‐methyl‐1‐phenyl‐2‐pyrazolin‐
5‐one 1a (0.1 mmol, 17.4 mg), β‐nitrostyrene 2a (22 mg, 0.15 mmol) and
the catalyst III in 1.0‐mL solvent.
bIsolated yield after column chromatography on silica gel.
cDetermined by chiral HPLC on Chiralpak AS‐H column with n‐hexane and
2‐propanol.
dThe reaction was carried out at 0°C.
eThe reaction was carried out at 60°C.
fThe reactions were carried out at −30°C.

YANG ET AL.
7
(94% ee) within 12 hours (entry 10, Table 2). Further
investigation showed that the catalyst loading had an
influence on the enantioselectivity of the product. When
increased from 5 to 20 mol%, the ee value of the product
improved from 91% to 97% (entries 10‐12, Table 2).
However, there is a slight decrease in enantioselectivity
when using 30 mol% catalyst III (entry 13, Table 2). At
last, 20 mol% catalyst III in CHCl3 at −30°C was
identified as the optimized reaction conditions.
Under the optimized experimental conditions, the
scope of the Michael addition was further studied using
a variety of substituents nitroolefins and pyrazolin‐5‐
ones, and the results were summarized in Table 3. To
our delight, the most reactions were occurred smoothly
with excellent yields and good to excellent
enantioselectivities (77 to >99% ee). The overall perfor-
mances of III were better than our previous
benzoylthiourea organocatalyst (In previous work,
benzoylthiourea organocatalyst gave the ee value ranged
from 52‐91%).21 The III‐promoted processes were suc-
cessful with all kinds of nitroalkenes which possessing
electron‐withdrawing, electron‐donating and heterocyclic
functionalities (entries 1‐14, Table 3). In addition, when
3‐Methyl‐1‐(4‐chlorophenyl)‐2‐pyrazolin‐5‐one (1c) was
used as Michael donor the yield and ee values were also
satisfied (entry 16, Table 3), whereas 3‐Methyl‐1‐(2‐
chlorophenyl)‐2‐pyrazolin‐5‐one (1b) gave the corre-
sponding product with 77% ee (entry 15, Table 3).
To prepare target products with the R and S enantio-
mers is very important for asymmetric synthesis. Data
from Table 1 have shown that using V as the catalyst
the model reaction occurred to give the R‐configuration
product with excellent yield and good enantioselctivity.
Then the organocatalyst V was examined in the
Michael reaction of pyrazolin‐5‐ones to nitroalkenes,
and the results are summarized in Table 4. To our
TABLE 3 Organocatalytic asymmetric Michael reaction of
pyrazolin‐5‐ones to nitroalkenes with catalyst IIIa
TABLE 4 Organocatalytic asymmetric Michael reaction of
pyrazolin‐5‐ones to nitroalkenes with catalyst Va
Time, Yield, ee,
Time, Yield, ee,
b
c
b
c
Entry R1
R2
h
%
%
Entry R1
R2
h
%
%
1
C6H5
C6H5
12
12
12
12
12
12
12
12
18
97
97
93
>99
95
96
95
95
91
95
91
79
98
87
85
77
93
1
C6H5
C6H5
12
12
12
12
12
12
12
12
18
95.3
96.4
95.2
93.7
94.5
95.6
94.3
94.9
93.2
93.1
91.7
94.6
92.8
96.2
92.8
93.5
>99
>99
97
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4‐CH3C6H4
2‐ClC6H4
4‐ClC6H4
2,4‐(Cl)2C6H3
4‐FC6H4
93
91
89
91
93
90
89
87
87
85
90
88
88
83
84
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4‐CH3C6H4
2‐ClC6H4
4‐ClC6H4
2,4‐(cl)2C6H3
4‐FC6H4
3
3
4
4
>99
95
5
5
6
6
>99
>99
97
7
4‐BrC6H4
2‐NO2C6H4
3‐NO2C6H4
7
4‐BrC6H4
2‐NO2C6H4
3‐NO2C6H4
8
8
9
9
95
10
11
12
13
14
15
16
3,4‐(OCH3)2C6H3 15
2,4‐(OCH3)2C6H3 15
10
11
12
13
14
15
16
3,4‐(OCH3)2C6H3 15
2,4‐(OCH3)2C6H3 15
93
95
4‐CF3C6H4
2‐thienyl
2‐furyl
12
12
12
12
12
4‐CF3C6H4
2‐thienyl
2‐furyl
12
12
12
12
12
97
>99
>99
65
2‐ClC6H4 C6H5
4‐ClC6H4 C6H5
2‐ClC6H4 C6H5
4‐ClC6H4 C6H5
>99
aAll reactions were carried out with pyrazolin‐5‐one
1
(0.1 mmol),
aAll reactions were carried out with pyrazolin‐5‐one
1
(0.1 mmol),
nitroalkene 2 (0.15 mmol), and the catalyst III (10 mg, 20 mol%) in 1.0‐mL
CHCl3 at −30°C.
nitroalkene 2 (0.15 mmol), and the catalyst V (10 mg, 20 mol%) in 1.0‐mL
CHCl3 at −30°C.
bIsolated yield after column chromatography on silica gel.
bIsolated yield after column chromatography on silica gel.
cDetermined by chiral HPLC on Chiralpak AS‐H, or IC column with n‐hex-
ane and 2‐propanol.
cDetermined by chiral HPLC on Chiralpak AS‐H, or IC column with n‐hex-
ane and 2‐propanol.

8
YANG ET AL.
3. Huang H, Yu Y, Gao Z, et al. Discovery and optimization of
1,3,4‐trisubstituted‐pyrazolone derivatives as novel, potent, and
nonsteroidal farnesoid X receptor (FXR) selective antagonists. J
Med Chem. 2012;55(16):7037‐7053.
exciting, the reactions gave satisfied yields and
enantioselectivities for most of the substrates. Both of
the electron‐withdrawing and electron‐donating substitu-
ents on the benzene ring of nitroalkenes react smoothly
with pyrazolone to provide the corresponding product
3‐R in excellent yields and enantioselectivities (entries
1‐14, Table 4). When other Michael donors such as 1b
and 1c were used to react with nitroalkene (2a), the good
results were also observed (entries 15 and 16, Table 4).
4. Hadi V, Koh Y‐H, Sanchez TW, Barrios D, Neamati N, Jung
KW. Development of the next generation of HIV‐1 integrase
inhibitors: pyrazolone as a novel inhibitor scaffold. Bioorg Med
Chem Lett. 2010;20(22):6854‐6857.
5. Amata E, Bland ND, Campbell RK, Pollastri MP. Evaluation of
pyrrolidine and pyrazolone derivatives as inhibitors of
trypanosomal phosphodiesterase B1 (TbrPDEB1). Tetrahedron
Lett. 2015;56(21):2832‐2835.
4 | CONCLUSION
6. Patel CK, Rami CS, Panigrahi B, Patel CN. Synthesis and
biological evaluation of (4‐substituted benzylidene)‐3‐methyl‐1‐
(substituted phenyl sulfonyl and substituted benzoyl)‐
1Hpyrazol‐5 (4H)‐one as anti‐inflammatory agent. J Chem
Pharm Res. 2010;2:73‐78.
In conclusion, we have developed highly efficient
cinchona
alkaloid‐derived
4‐methylbenzoylthiourea
organocatalysts that were successfully used to catalyze
the asymmetric Michael addition of pyrazolones to
nitroolefins. Not only the high reaction activities and
stereoselectivities were obtained, but also both R‐ and
S‐enantiomers were got, respectively. The hydrogen bond
energies of the complexes formed with I‐VIII and
β‐nitrostyrene were preliminarily calculated and analyzed
by Hartree‐Fock method. Applications of these
organocatalysts in other asymmetric reactions are
underway in our laboratory.
7. Li J‐H, Du D‐M. Squaramide‐catalysed enantioselective Michael
addition of pyrazolin‐5‐ones to nitroalkenes. Org Biomol Chem.
2013;11(36):6215‐6223.
8. Wang Z, Yang Z, Chen D, Liu X, Lin L, Feng X. Highly
enantioselective Michael addition of pyrazolin‐5‐ones catalyzed
by chiral metal/N,N'‐dioxide complexes: metal‐directed switch
in
Enantioselectivity.
Angew
Chem
Int
Ed.
2011;123(21):5030‐5034.
9. Yang Z, Wang Z, Bai S, Liu X, Lin L, Feng X. Asymmetric
α‐amination of 4‐substituted Pyrazolones catalyzed by a chiral
Gd (OTf)3/N,N'‐dioxide complex: highly enantioselective
synthesis of 4‐Amino‐5‐pyrazolone derivatives. Org Lett.
2011;13(4):596‐599.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the financial support
of the National Natural Science Foundation of China
(81473100), Natural Science Foundation of Shanxi
Province (2015011104), Fund Program for the Scientific
Activities of Selected Returned Overseas Professionals in
Shanxi Province (2016), Research Project Supported by
Shanxi Scholarship Council of China (2017‐061), Fund
for Shanxi Key Subjects Construction, Program for the
Top Science and Technology Innovation Teams of Higher
Learning Institutions of Shanxi province, Technology
Innovation Team of Shanxi Province, and Science and
Technology Innovation Foundation of Shanxi Medical
University (C01201009).
10. Wang Z, Chen Z, Bai S, et al. Highly Z‐selective asymmetric
conjugate addition of Alkynones with Pyrazol‐5‐ones promoted
by
2012;124(11):2830‐2833.
11. Alba A‐NR, Zea A, Valero G, et al. Highly stereoselective
synthesis of spiropyrazolones. Eur Org Chem.
2011;2011(7):1318‐1325.
N,N′‐dioxide–metal
complexes.
Angew
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J
12. Li F, Sun L, Teng Y, Yu P, Zhao JC‐G, Ma J‐A. Highly Diastereo‐
and enantioselective Organocatalytic one‐pot sequential
1,4‐addition/dearomative‐fluorination transformation. Chem A
Eur J. 2012;18(45):14255‐14260.
13. Wang H, Wang Y, Song H, Zhou Z, Tang C. Bifunctional
squaramide‐catalyzed one‐pot sequential Michael addition/
dearomative bromination: convenient access to optically active
brominated Pyrazol‐5(4H)‐ones with adjacent quaternary and
tertiary stereocenters. Eur J Org Chem. 2013;2013(22):4844‐4851.
ORCID
Shurong Ban http://orcid.org/0000-0001-9782-4310
14. Liao Y‐H, Chen W‐B, Wu Z‐J, et al. Organocatalytic asymmetric
Michael addition of Pyrazolin‐5‐ones to nitroolefins with
bifunctional thiourea: stereocontrolled construction of
contiguous quaternary and tertiary stereocenters. Adv Synth
Catal. 2010;352(5):827‐832.
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