Enantioselective synthesis of N-phenyl-dihydropyrano[2,3-c]pyrazoles via cascade Michael addition/Thorpe-Ziegler type cyclization catalyzed by a chiral squaramide

Article abstract of DOI:10.1002/cjoc.201400829

Abstract Enantioselective synthesis of biologically active dihydropyrano[2,3-c]pyrazoles has been achieved through a squaramide-catalysed Michael addition/Thorpe-Ziegler type cyclization cascade reaction between arylidenepyrazolones and malononitrile. A series of optically active dihydropyano[2,3-c]pyrazoles were obtained in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 79% ee) under mild reaction conditions. Enantioselective synthesis of biologically active dihydropyrano[2,3-c]pyrazoles has been achieved through a squaramide-catalysed Michael addition/Thorpe-Ziegler type cyclization cascade reaction between arylidenepyrazolones and malononitrile. A series of optically active dihydropyano[2,3-c]pyrazoles were obtained in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 79% ee) under mild reaction conditions.

Full text of DOI:10.1002/cjoc.201400829

FULL PAPER
DOI: 10.1002/cjoc.201400829
Enantioselective Synthesis of N-Phenyl-dihydropyrano[2,3-c]-
pyrazoles via Cascade Michael Addition/Thorpe-Ziegler Type
Cyclization Catalyzed by a Chiral Squaramide
Junhua Li and Daming Du*
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, China
Enantioselective synthesis of biologically active dihydropyrano[2,3-c]pyrazoles has been achieved through a
squaramide-catalysed Michael addition/Thorpe-Ziegler type cyclization cascade reaction between arylidenepyra-
zolones and malononitrile. A series of optically active dihydropyano[2,3-c]pyrazoles were obtained in excellent
yields (up to 99%) and moderate to good enantioselectivities (up to 79% ee) under mild reaction conditions.
Keywords organocatalysis, squaramide, heterocycles, Michael addition, cyclization
Introduction
provide an easy access to the chiral pyrano[2,3-c]-
pyrazole derivatives. In 2009, Zhao's group reported the
first organocatalysed enantioselective synthesis of
N-Phenyl-3-substituted 5-pyrazolone derivatives,
which have been known since 1883, are very useful as
intermediates for pharmaceuticals and are used as
anti-inflammatory agents and allergy inhibitors.[1] On
the other hand, due to various pharmacological proper-
ties such as anticoagulant, anticancer, antianaphylactic,
and fungicidal activities, 2-amino-4H-pyrans or
2-amino-4H-chromenes are rather unusual among the
pyran or chromene family members.[2] Therefore, great
efforts have been devoted to synthesize pyrazolone,
2-amino pyran or 2-amino-4H-chromene derivatives to
find more useful compounds, and significant achieve-
ments have been achieved, especially in asymmetric
synthesis.[3] Pyrazolones fused to pyran rings constitute
a very important class of compounds in the heterocyclic
area, and were widely used as important precursors in
the field of medicinal chemistry because of their useful
biological and pharmacological properties such as anti-
bacterial, anticoagulant, anticancer, spasmolytic, hyp-
notic, diuretic, and insecticide.[4] Consequently, it at-
tracted us to explore a new method to construct highly
functionalized chiral dihydropyrano[2,3-c]pyrazole de-
rivatives through organocatalysed Michael addition/
cyclization cascade reaction.
6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles
from
2-pyrazolin-5-ones and benzylidenemalononitriles or
multi-component reaction system using the cinchona
alkaloid as the catalyst.[8a] In 2011 the same group
reported the modularly designed organocatalysis model
for the synthesis of 6-amino-5-cyanodihydropyrano-
[2,3-c]pyrazoles from 3-methyl-2-pyrazolin-5-one and
benzylidenemalononitriles.[8b] Since these catalytic
systems were not useful for the enantioselective synthe-
sis of N-phenyldihydropyrano[2,3-c]pyrazoles by using
2-pyrazolin-5-ones and benzylidenemalononitriles or
multi-component reaction system according to our ex-
periments, new catalytic system should be explored.
Most recently, Zhao's group reported the enantioselec-
tive synthesis of fluorinated N-phenyl-dihydropyrano-
[2,3-c]pyrazoles from 3-trifluoromethyl arylidene pyra-
zolones and malononitrile using a diaminocyclohexane-
thiourea catalyst.[9] However, we are not aware of any
reports about the asymmetric synthesis of N-phenyl-di-
hydropyrano[2,3-c]pyrazoles catalysed by squaramide.
Squaramides as efficient organocatalysts have been
widely used in the asymmetric catalysis.[10] Herein, we
would like to present an efficient squaramide-catalysed
enantioselective Michael addition/Thorpe-Ziegler type
cyclization cascade reaction between arylidene pyrazo-
lones and malononitrile. The desired N-phenyldihydro-
pyrano[2,3-c]pyrazoles were obtained in excellent yields
and moderate to good enantioselectivities, and most of
the substrates were first reported by organocatalysed
enantioselective synthesis.
Junek et al. reported the first reaction for the synthe-
sis of racemic pyrano[2,3-c]pyrazole derivatives from
3-methyl-1-phenylpyrazolin-5-one and tetracyanoethyl-
ene in 1973.[5] Then a number of methods were devel-
oped for the synthesis of the racemic pyrano[2,3-c]-
pyrazole derivatives.[6] In recent years, organocatalysed
asymmetric reactions have made great progress,[7] which
*
E-mail: dudm@bit.edu.cn; Tel.: 0086-010-68914985
Received December 4, 2014; accepted January 12, 2015; published online February 3, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400829 or from the author.
418
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 418—424

Enantioselective Synthesis of N-Phenyl-dihydropyrano[2,3-c]pyrazoles
Results and Discussion
O
O
O
O
The initial investigation of the reaction between un-
saturated pyrazolone 1a and the malononitrile 2 was
performed in CH2Cl2 at room temperature in the pres-
ence of an organocatalyst at 5 mol% loading, and the
screening results are given in Table 1. The quinine-de-
rived squaramide I and II were first screened, and the
product 3a was obtained in excellent yields with good
enantioselectivities (70% ee and 79% ee) (Table 1, En-
tries 1 and 2). Inspired by the results, other squaramide
catalysts were explored, as shown in Figure 1.
All these organocatalysts could effectively catalyze
this model reaction and afforded the product 3a in ex-
cellent yields, but the organocatalysts including quini-
dine-derived squaramide III and IV, chiral 1,2-diamino-
cyclohexane-derived squaramides VI and VII, C2-sym-
metric squaramide VIII, L-phenylalanine and quinine-
derived squaramide IX, L-valine and quinine-derived
squaramide X, and one kind of thiourea bifunctional
catalyst V afforded no better results in terms of enanti-
oselectivity for this asymmetric reaction (Table 1,
Entries 3－10). In comparison with other catalysts, qui-
nine-derived squaramide II obtained a better yield and
enantioselectivity, and was selected as the best catalyst
for further optimization.
H
N
N
Ar
N
H
HN
N
Ar
N
H
HN
H
OMe
OMe
N
I Ar = 3,5-(CF3)2C6H3
II Ar = 4-CF3C6H4
III Ar = 3,5-(CF3)2C6H3
IV Ar = 4-CF3C6H4
O
O
CF3
Ar
S
N
H
N
H
N
N
N
N
F3C
H
H
H
VI Ar = 3,5-(CF3)2C6H3
VII Ar = 4-CF3C6H4
N
V
O
O
N
H
N
N
NH
HN
H
OMe
MeO
N
VIII
CF3
With the optimal catalyst established, further reac-
tion parameters were explored. The screening of the
solvents revealed that CH2Cl2 was still the best solvent
for this reaction (Table 2, Entry 1). Compared with
CH2Cl2, the reaction performed in ClCH2CH2Cl, CHCl3,
PhCH3, CH3CN, THF or Et2O also afforded the product
O
O
Bn
H
H
N
N
F3C
N
H
N
H
OMe
O
N
H
IX
Table 1 Screening of the organocatalysta
CF3
O
O
i-Pr
H
N
H3C
Ph
+ NC
Ph
O
H3C
N
N
F3C
N
H
N
H
CN
5 mol% catalyst
N
CN
OMe
O
O
N
CH2Cl2, r.t., 40 min
N
NH2
2
Ph
Ph
N
1a
X
3a
Figure 1 The structures of screened organocatalysts.
Entry
Catalyst
I
Yieldb/%
98
eec/%
70
1
2
in good yields but with lower enantioselectivities (Table
2, Entries 2－5, 7 and 8). When the reaction was carried
out in xylene, the similar enantioselectivity was ob-
tained but with lower yield (Table 2, Entry 6). Using
CH2Cl2 as the solvent, we further reduce the reaction
temperature to 0 ℃ or −15 ℃, the excellent yields
were still obtained but the enantioselectivities were
slightly lower than that at room temperature (Table 2,
Entries 9 and 10). Next, the effects of catalyst loadings
and the amount of solvents were also investigated, but
no better results were obtained. Consequently, the opti-
mal reaction condition for this Michael addition/cycli-
zation was obtained: with 5 mol% of catalyst II in
CH2Cl2 at room temperature.
II
99
79
3
III
IV
82
63d
54d
39d
39
4
91
5
V
94
6
VI
98
7
VII
VIII
IX
93
28
8
99
43
9
89
18
10
X
98
30
a
Reactions were carried out with 1a (0.1 mmol) and 2 (0.15
mmol) in CH2Cl2 (0.5 mL) at room temperature for 40 min.
b Isolated yield after column chromatography purification. c De-
termined by chiral HPLC analysis. d The opposite enantiomer.
With the optimal reaction conditions established, a
Chin. J. Chem. 2015, 33, 418—424
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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419

Li & Du
FULL PAPER
Table 2 Optimization of reaction conditions for the enantiose-
lective Michael addition/cyclization cascade reactiona
signed by analogy.
Encouraged by the above results, alternative Michael
addition/cyclization cascade reaction system was also
explored for synthesis of dihydropyrano[2,3-c]pyrazoles
under the optimal conditions (Scheme 1). When
3-methyl-1-phenylpyrazolin-5-one (4) and benzylidene
malononitrile 5 were used as reactants, the product 3a
was obtained in good yield and moderate enantioselec-
tivity.
Ph
H3C
H3C
N
Ph
CN
catalyst II
+
N
NC
CN
O
solvent
N
N
2
O
NH2
Ph
Ph
3a
1a
Loading/
mol%
Entry
Solvent
CH2Cl2
T/℃
r.t.
Yieldb/%
eec/%
Scheme 1 The alternative method for synthesis of 3a
1
2
5
5
99
98
99
83
72
84
73
96
99
96
93
99
94
98
79
52
58
57
30
77
63
56
76
75
63
54
51
53
ClCH2CH2Cl r.t.
H3C
CN
3
CHCl3
PhCH3
CH3CN
Xylene
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
5
5 mol% catalyst II
N
+
O
N
Ph
4
4
5
CN
CH2Cl2, r.t., 1 h
5
5
5
6
5
Ph
H3C
N
CN
7
5
8
Et2O
5
N
O
NH2
9d
10e
11f
12
13g
14h
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
Ph
3a
−15
r.t.
r.t.
r.t.
r.t.
5
80% yield, 57% ee
2
Based on the previous study on the mechanism of
bifunctional squaramide-catalyzed organocatalytic
Michael addition[11] and the absolute configuration of
the product assigned by comparison with literature,[9]
10
5
5
a
a Unless otherwise specified, all reactions were carried out with
1a (0.10 mmol) and 2a (0.15 mmol) in solvent (1.0 mL) for 40
min. b Isolated yield after column chromatography purification.
Determined by chiral HPLC analysis. Reaction for 2 h.
e Reaction for 3 h. f Reaction for 1 h. Reaction for 80 min, and 1
possible transition state model is proposed and shown in
Figure 2. We envision that the chiral squaramide acts as
a bifunctional catalyst. The malononitrile is deproto-
nated by the basic nitrogen atom of the tertiary amine.
Meanwhile, the arylidenepyrazolone is activated by the
squaramide moiety through forming two hydrogen
bonds. The deprotonated malononitrile attacks the aryli-
denepyrazolone from the Si-face to afford the S-con-
figured stereocenter and the final product is formed after
the following cyclization step, which is consistent with
the observed results.
c
d
g
mL solvent was used. h 0.25 mL solvent was used.
diverse array of substituted substrates was evaluated.
The results are summarized in Table 3. The electronic
properties of the substituent on the phenyl ring have a
significant influence on the enantioselectivities.
Generally, good to excellent yields were obtained with
different substrates, and moderate to good enantioselec-
tivities were obtained. Various unsaturated pyrazolones
bearing either electron-withdrawing or electron-do-
nating groups (F, Cl, Br, Me, OMe, and NO2) on R1
groups were investigated. The enantioselectivities of
products with electron-donating group (3b, 3c, 3d, 3e,
3f) on the para position were superior to that of product
with electron-withdrawing group (3g). However the
enantioselectivity of product with electron-donating
group on the meta position (3k) was better than that of
any other substituted substrates. The enantioselectivities
of products with ortho substituent (3h, 3i, 3j) were
lower than those of products with para substituent (3b,
3c, 3d, 3e, 3f). In addition, the substituents on the R2
and R3 groups were also investigated (3l－3o), but only
moderate enantioselectivities were obtained for this
Michael addition/cyclization cascade system. The con-
figurations of product 3o was assigned according to the
comparison of optical rotation with literature report,[9]
and the configurations of other compounds were as-
N
CF3
O
O
OMe
H
F3C
N
H
N
H
Ph
O
H3C
N
CN
N
O
Ph
N
NH2
H
Ph
Ph
N
H
N
N
C
CH3
Si-face attack
N
Figure 2 The proposed transition state for enantioselective
Michael addition/cyclization cascade reaction.
Conclusions
In summary, we have successfully developed a
squaramide-catalysed enantioselective Michael addi-
tion/cyclization cascade reaction of arylidenepyrazolone
with malononitrile, and a series of potential biologically
420
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 418—424

Enantioselective Synthesis of N-Phenyl-dihydropyrano[2,3-c]pyrazoles
Table 3 Substrate scope of the Michael addition/cyclization cascade reactiona
R1
R3
R1
R3
CN
5 mol% catalyst II
N
+
N
NC
CN
O
N
N
CH2Cl2, r.t.
O
NH2
R2
R2
2
3
1
F
Br
Cl
Me
Ph
O
H3C
N
H3C
N
H3C
N
H3C
N
H3C
N
CN
CN
CN
NH2
CN
CN
N
N
NH2
N
O
NH2
N
N
O
O
NH2
O
NH2
Ph
Ph
Ph
Ph
Ph
3a 40 min, 99% yieldb
79% eec
3b 40 min, 97% yield
66% ee
3d 40 min, 98% yield
58% ee
3c 40 min, 99% yield
60% ee
3e 40 min, 97% yield
63% ee
OMe
NO2
OMe
CN
NO2
H3C
Br
H3C
H3C
H3C
H3C
CN
NH2
CN
CN
CN
N
N
Ph
N
N
N
N
N
Ph
N
N
O
O
NH2
O
NH2
N
O
NH2
O
NH2
Ph
Ph
Ph
3j 100 min, 96% yield
50% ee
3h 40 min, 98% yield
48% ee
3i 40 min, 90% yield
53% ee
3g 40 min, 99% yield
55% ee
3f 100 min, 98% yield
61% ee
Ph
Ph
H3C
H3C
NO2
CN
NH2
CN
Ph
F3C
Ph
Ph
N
N
N
CN
NH2
CN
H3C
N
O
O
NH2
N
CN
NH2
N
N
N
O
N
N
Ph
O
NH2
Ph
Ph
O
Cl
Me
3od 120 min, 77% yield
52% ee
3k 40 min, 99% yield
73% ee
3l 40 min, 98% yield
50% ee
3m 40 min, 97% yield
54% ee
3n 40 min, 98% yield
41% ee
a Unless noted otherwise, reactions were carried out with arylidene pyrazolone 1 (0.1 mmol), malononitrile 2 (0.15 mmol) and catalyst II
b
c
(5 mol%) in CH2Cl2 (0.5 mL) at room temperature. Isolated yield after column chromatography purification. Determined by chiral
HPLC analysis using a Daicel Chiralpak AD-H or IB column. d The configuration of the known product was determined according to ref.
9, the configurations of other products were assigned by analogy.
spectra were recorded at 100 MHz. Infrared spectra
were obtained with a Perkin Elmer Spectrum One FT-IR
spectrometer. The ESI-HRMS spectra were obtained
with a Bruker APEX IV FTMS spectrometer. Optical
rotations were measured with a Krüss P8000 polarime-
ter at the indicated concentration with unit g per 100 mL.
The enantiomeric excesses of the products were deter-
mined by chiral HPLC using Agilent 1200 LC instru-
ment using Daicel Chiralpak AD-H or IB columns.
The squaramide organocatalysts were prepared fol-
lowing the reported procedures.[10f,10g,10l]
active dihydropyano[2,3-c]pyrazoles were first con-
structed by organocatalysed asymmetric synthesis. The
corresponding products were obtained in excellent
yields (up to 99%) and with moderate to good enanti-
oselectivities (up to 79% ee) under mild reaction condi-
tions. Further studies on chiral squaramides are under-
way in our group to broaden their applications in
asymmetric catalysis.
Experimental
Commercially available compounds were used with-
out further purification. Column chromatography was
carried out using silica gel (200－300 mesh). Melting
points were measured with an XT-4 melting point appa-
General procedure for the enantioselective Michael
addition/cyclization reaction
To a mixture of arylidenepyrazolone 1 (0.1 mmol),
and catalyst II (2.8 mg, 0.005 mmol) in CH2Cl2 (0.5 mL)
was added malononitrile 2 (0.15 mmol). The mixture
was vigorously stirred at room-temperature for indicated
1
ratus without correction. The H NMR spectra were re-
corded with a Varian Mercury-plus 400 MHz or a
Bruker AVIII 400 MHz spectrometer, while 13C NMR
Chin. J. Chem. 2015, 33, 418—424
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421

Li & Du
FULL PAPER
time until the reaction was completed (monitored by
TLC). The reaction mixture was then concentrated and
the resulting residue was purified by silica gel column
chromatography with the eluent (ethyl acetate-petro-
leum ether 1∶2) to afford the desired products.
Compound 3e was obtained according to the general
procedure as a white solid (33.1 mg, 97% yield). m.p.
145－148 ℃; HPLC (Daicel Chiralpak AD-H column,
n-hexane-isopropanol 85∶15, flow rate 1.0 mL•min−1,
detection at 254 nm): minor enantiomer tR＝6.7 min,
major enantiomer tR＝5.5 min, 63% ee; [α]2D5 ＝−26.7
(S)-6-Amino-3-methyl-1,4-diphenyl-1,4-dihydro-
1
pyrano[2,3-c]pyrazole-5-carbonitrile
(3a)[6b,9]
(c＝0.42, acetone); H NMR (400 MHz, DMSO-d6) δ:
Compound 3a was obtained according to the general
procedure as a white solid (32.7 mg, 99% yield). m.p.
86－89 ℃; HPLC (Daicel Chiralpak AD-H column,
n-hexane-isopropanol 85∶15, flow rate 1.0 mL•min−1;
detection at 254 nm): minor enantiomer tR＝7.1 min,
major enantiomer tR＝6.1 min, 79% ee; [α]2D5 ＝−14.0
7.79 (dd, J1＝1.2 Hz, J2＝8.8 Hz, 2H, ArH), 7.49 (t, J＝
8.0 Hz, 2H, ArH), 7.32 (t, J＝7.4 Hz, 1H, ArH), 7.18－
7.12 (m, 6H, ArH＋NH2), 4.63 (s, 1H, CH), 2.29 (s, 3H,
CH3), 1.79 (s, 3H, CH3).
(S)-6-Amino-4-(4-methoxyphenyl)-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3f)[6b] Compound 3f was obtained according to
the general procedure as a white solid (35.0 mg, 98%
yield). m.p. 159－162 ℃; HPLC (Daicel Chiralpak
AD-H column, n-hexane-isopropanol 85∶15, flow rate
1.0 mL•min−1, detection at 254 nm): minor enantiomer
tR＝9.2 min, major enantiomer tR1＝7.2 min, 61% ee;
[α]2D5 ＝＋9.9 (c＝0.42, acetone); H NMR (400 MHz,
DMSO-d6) δ: 7.79－7.76 (dd, J1＝1.0 Hz, J2＝8.6 Hz,
2H, ArH), 7.50 (t, J＝8.0 Hz, 2H, ArH), 7.34－7.30 (m,
1H, ArH), 7.18－7.16 (m, 4H, ArH＋NH2), 6.90 (d, J＝
8.8 Hz, 2H, ArH), 4.63 (s, 1H, CH), 3.75 (s, 3H, OCH3),
1.79 (s, 3H, CH3).
1
(c＝0.62, acetone); H NMR (400 MHz, acetone-d6) δ:
7.85－7.83 (m, 2H, ArH), 7.48 (t, J＝8.0 Hz, 2H, ArH),
7.38－7.25 (m, 6H, ArH), 6.48 (s, 2H, NH2), 4.72 (s, 1H,
CH), 1.84 (s, 3H, CH3).
(S)-6-Amino-4-(4-fluorophenyl)-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3b)[6j] Compound 3b was obtained according to
the general procedure as a white solid (33.7 mg, 97%
yield). m.p. 164－166 ℃; HPLC (Daicel Chiralpak
AD-H column; n-hexane-isopropanol 85∶15, flow rate
1.0 mL•min−1, detection at 254 nm): minor enantiomer
tR＝7.5 min, major enantiomer tR1＝6.1 min, 66% ee;
[α]2D5 ＝−13.2 (c＝0.53, acetone); H NMR (400 MHz,
acetone-d6) δ: 7.85－7.82 (m, 2H, ArH), 7.48 (d, J＝8.0
Hz, 2H, ArH), 7.40－7.36 (m, 2H, ArH), 7.31 (t, J＝7.4
Hz, 1H, ArH), 7.13 (t, J＝8.8 Hz, 2H, ArH), 6.51 (s, 2H,
NH2), 4.76 (s, 1H, CH), 1.85 (s, 3H, CH3).
(S)-6-Amino-4-(4-chlorophenyl)-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3c)[6b] Compound 3c was obtained according to
the general procedure as a white solid (36.1 mg, 99%
yield). m.p. 160－164 ℃; HPLC (Daicel Chiralpak
AD-H column, n-hexane-isopropanol 85∶15, flow rate
1.0 mL•min−1, detection at 254 nm): minor enantiomer
tR＝7.6 min, major enantiomer tR1＝6.1 min, 60% ee;
[α]2D5 ＝−28.4 (c＝0.53, acetone); H NMR (400 MHz,
DMSO-d6) δ: 7.80－7.77 (m, 2H, ArH), 7.50 (t, J＝8.0
Hz, 2H, ArH), 7.41 (d, J＝8.4 Hz, 2H, ArH), 7.35－
7.29 (m, 3H, ArH), 7.27 (s, 2H, NH2), 4.73 (s, 1H, CH),
1.80 (s, 3H, CH3).
(S)-6-Amino-4-(4-bromophenyl)-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3d)[6b] Compound 3d was obtained according to
the general procedure as a white solid (40.0 mg, 98%
yield). m.p. 173－177 ℃; HPLC (Daicel Chiralpak
AD-H column, n-hexane-isopropanol 85∶15, flow rate
1.0 mL•min−1, detection at 254 nm): minor enantiomer
tR＝7.8 min, major enantiomer tR1＝6.2 min, 58% ee;
[α]2D5 ＝−25.4 (c＝0.52, acetone); H NMR (400 MHz,
acetone-d6) δ: 7.79 (d, J＝8.0 Hz, 2H, ArH), 7.55 (d,
J＝8.0 Hz, 2H, ArH), 7.50 (t, J＝8.0 Hz, 2H, ArH),
7.32 (t, J＝7.4 Hz, 1H, ArH), 7.27－7.23 (m, 4H,
ArH＋NH2), 4.72 (s, 1H, CH), 1.80 (s, 3H, CH3).
(S)-6-Amino-3-methyl-1-phenyl-4-(p-tolyl)-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3e)[6j]
(S)-6-Amino-3-methyl-4-(4-nitrophenyl)-1-phenyl-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3g)[6j]
Compound 3g was obtained according to the general
procedure as a white solid (37.0 mg, 99% yield). m.p.
177－181 ℃; HPLC (Daicel Chiralpak AD-H column,
n-hexane-isopropanol 85∶15, flow rate 1.0 mL•min−1,
detection at 254 nm): minor enantiomer tR＝14.7 min,
major enantiomer tR＝10.5 min, 55% ee; [α]2D5 ＝−18.0
1
(c＝0.49, acetone); H NMR (400 MHz, DMSO-d6) δ:
8.24 (d, J＝8.8 Hz, 2H, ArH), 7.80 (d, J＝7.6 Hz, 2H,
ArH), 7.59 (d, J＝8.8 Hz, 2H, ArH), 7.51 (t, J＝8.0 Hz,
ArH), 7.38 (s, 2H, NH2), 7.34 (t, J＝7.4 Hz, ArH), 4.93
(s, 1H, CH), 1.80 (s, 3H, CH3).
(S)-6-Amino-4-(2-bromophenyl)-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3h)[12] Compound 3h was obtained according to
the general procedure as a white solid (39.9 mg, 98%
yield). m.p. 139－142 ℃; HPLC (Daicel Chiralpak
AD-H column, n-hexane-isopropanol 85∶15, flow rate
1.0 mL•min−1, detection at 254 nm): minor enantiomer
tR＝7.0 min, major enantiomer tR1＝6.4 min, 48% ee;
[α]2D5 ＝−23.8 (c＝0.63, acetone); H NMR (400 MHz,
acetone-d6) δ: 7.84－7.81 (m, 2H, ArH), 7.62 (d, J＝8.8
Hz, 1H, ArH), 7.49－7.44 (m, 2H, ArH), 7.37－7.28 (m,
3H, ArH), 7.23－7.18 (m, 1H, ArH), 6.58 (s, 2H, NH2),
5.27 (s, 1H, CH), 1.82 (s, 3H, CH3).
(S)-6-Amino-3-methyl-4-(2-nitrophenyl)-1-phenyl-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3i)[6l]
Compound 3i was obtained according to the general
procedure as a white solid (33.5 mg, 90% yield). m.p.
152－155 ℃; HPLC (Daicel Chiralpak IB column,
n-hexane-isopropanol 85∶15, flow rate 1.0 mL•min−1,
detection at 254 nm): minor enantiomer tR＝13.9 min,
422
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 418—424

Enantioselective Synthesis of N-Phenyl-dihydropyrano[2,3-c]pyrazoles
major enantiomer tR ＝16.8 min, 53% ee; [α]D25
＝
procedure as a white solid (33.9 mg, 97% yield). m.p.
174－177 ℃; HPLC (Daicel Chiralpak IB column,
n-hexane-isopropanol 85∶15, flow rate 0.5 mL•min−1,
detection at 254 nm): minor enantiomer tR＝13.5 min,
major enantiomer tR＝14.2 min, 54% ee; [α]2D5 ＝−20.2
＋ 15.3 (c ＝ 1.7, acetone); 1H NMR (400 MHz,
DMSO-d6) δ: 7.90 (dd, J1＝1.0 Hz, J2＝8.2 Hz, 1H,
ArH), 7.80 (dd, J1＝1.0 Hz, J2＝8.6 Hz, 2H, ArH), 7.70
(dt, J1＝1.2 Hz, J2＝7.6 Hz, 1H, ArH), 7.56－7.49 (m,
4H, ArH), 7.38 (s, 2H, NH2), 7.36－7.32 (m, 1H, ArH),
5.21 (s, 1H, CH), 1.76 (s, 3H, CH3).
1
(c＝0.53, acetone); H NMR (400 MHz, DMSO-d6) δ:
7.66 (d, J＝8.4 Hz, 2H, ArH), 7.35 (t, J＝7.6 Hz, 2H,
ArH), 7.29 (d, J＝8.4 Hz, 2H, ArH), 7.25 (d, J＝8.0 Hz,
3H, ArH), 7.19 (s, 2H, NH2), 4.67 (s, 1H, CH), 2.35 (s,
3H, CH3), 1.77 (s, 3H, CH3).
(S)-6-Amino-4-(2-methoxyphenyl)-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3j)[6l] Compound 3j was obtained according to
the general procedure as white solid (34.3 mg, 96%
yield). m.p. 87－90 ℃; HPLC (Daicel Chiralpak IB
column, n-hexane−isopropanol 85∶15, flow rate 1.0
mL•min−1, detection at 254 nm): minor enantiomer tR＝
8.6 min, major enantiomer tR＝9.6 min, 50% ee; [α]D25
(S)-6-Amino-1,3,4-triphenyl-1,4-dihydropyrano-
[2,3-c]pyrazole-5-carbonitrile (3n)[6m] Compound 3n
was obtained according to the general procedure as a
white solid (38.3 mg, 98% yield). m.p. 159－163 ℃;
HPLC (Daicel Chiralpak AD-H column, n-hexane-iso-
propanol 85∶15, flow rate 1.0 mL•min−1, detection at
254 nm): minor enantiomer tR＝6.9 min, major enanti-
omer tR＝8.6 min, 41% ee; [α]2D5 ＝＋43.0 (c＝0.53,
acetone); 1H NMR (400 MHz, DMSO-d6) δ: 7.95－7.93
(m, 2H, ArH), 7.63－7.55 (m, 4H, ArH), 7.43－7.39 (m,
1H, ArH), 7.30－7.21 (m, 9H, ArH＋NH2), 7.16－7.12
(m, 1H, ArH), 5.10 (s, 1H, CH).
1
＝−28.1 (c＝1.7, acetone); H NMR (400 MHz, ace-
tone-d6) δ: 7.84－7.81 (m, 2H, ArH), 7.49－7.44 (m,
2H, ArH), 7.31－7.22 (m, 2H, ArH), 7.16 (dd, J1＝1.6
Hz, J2＝7.6 Hz, 1H, ArH), 7.03 (dd, J1＝0.8 Hz, J2＝
8.4 Hz, 1H, ArH), 6.93 (dt, J1＝0.8 Hz, J2＝7.4 Hz, 1H,
ArH), 6.40 (s, 1H, NH2), 5.15 (s, 1H, CH), 3.87 (s, 3H,
OCH3), 1.85 (s, 3H, CH3).
(S)-6-Amino-3-methyl-4-(3-nitrophenyl)-1-phenyl-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3k)[6e]
Compound 3k was obtained according to the general
procedure as a white solid (37.1 mg, 99% yield). m.p.
183－186 ℃; HPLC (Daicel Chiralpak AD-H column,
n-hexane-isopropanol 85∶15, flow rate 1.0 mL min−1,
detection at 254 nm): minor enantiomer tR＝13.5 min,
major enantiomer tR＝9.9 min, 73% ee; [α]2D5 ＝−12.8
(S)-6-Amino-1,4-diphenyl-3-(trifluoromethyl)-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(3o)
Compound 3o was obtained according to the general
procedure as a white solid (29.4 mg, 77% yield). m.p.
170－173 ℃; HPLC (Daicel Chiralpak IB column,
n-hexane-isopropanol 85∶15, flow rate 1.0 mL•min−1,
detection at 254 nm): minor enantiomer tR＝9.0 min,
major enantiomer tR1＝12.7 min, 52% ee; [α]2D5 ＝＋4.8
(c＝1.45, CH2Cl2); H NMR (400 MHz, acetone-d6) δ:
7.91－7.88 (m, 2H, ArH), 7.60－7.56 (m, 2H, ArH),
7.50－7.45 (m, 1H, ArH), 7.36－7.30 (m, 4H, ArH),
7.29－7.24 (m, 1H, ArH), 6.61 (s, 0.3H, NH2), 4.85 (s,
1H, CH). Lit.[9] (R)-enantiomer: m.p. 185－187 ℃;
[α]2D5 ＝−12.3 (c＝1.39 in CH2Cl2), 80% ee.
1
(c＝0.53, acetone); H NMR (400 MHz, DMSO-d6) δ:
8.18－8.15 (m, 2H, ArH), 7.82－7.78 (m, 3H, ArH),
7.70－7.66 (m, 1H, ArH), 7.51 (t, J＝8.0 Hz, 2H, ArH),
7.39 (s, 2H, NH2), 7.36－7.32 (m, 1H, ArH), 4.98 (s,
1H, CH), 1.81 (s, 3H, CH3).
(S)-6-Amino-1-(4-chlorophenyl)-3-methyl-4-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (3l) Compound 3l was obtained according to the
general procedure as a white solid (36 mg, 98% yield).
m.p. 178－181 ℃; HPLC (Daicel Chiralpak IB column,
n-hexan-isopropanol 85∶15, flow rate 1.0 mL•min−1,
detection at 254 nm): minor enantiomer tR＝8.1 min,
major enantiomer tR＝9.5 min, 50% ee; [α]2D5 ＝−21.9
The reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one
with 2-benzylidenemalononitrile for synthesis of 3a
To a mixture of 3-methyl-1-phenyl-2-pyrazolin-5-
one 4 (17.4 mg, 0.1 mmol), and catalyst II (2.8 mg,
0.005 mmol) in CH2Cl2 (0.5 mL) was added
2-benzylidenemalononitrile 5 (18.5 mg, 0.12 mmol).
The mixture was vigorously stirred at room temperature
for 1 h. The reaction mixture was then concentrated and
the resulting residue was purified by silica gel column
chromatography with the eluent (ethyl acetate-
petroleum ether 1∶2) to afford the desired product 3a
(26.4 mg, 80% yield).
1
(c＝0.54, acetone); H NMR (400 MHz, DMSO-d6) δ:
7.83 (d, J＝9.2 Hz, 2H, ArH), 7.53 (d, J＝8.8 Hz, 2H,
ArH), 7.35 (t, J＝7.6 Hz, 2H, ArH), 7.28－7.24 (m, 5H,
ArH＋NH2), 4.68 (s, 1H, CH), 1.78 (s, 3H, CH3); 13C
NMR (400 MHz, DMSO-d6) δ: 159.2, 145.6, 143.8,
143.4, 136.3, 130.1, 129.1, 128.4, 127.7, 127.0, 121.3,
119.8, 98.8, 58.1, 36.6, 12.5; IR (KBr) ν: 3469, 3360,
3323, 3195, 2922, 2198, 2189, 1659, 1588, 1514, 1489,
1458, 1411, 1381, 1264, 1177, 1129, 1095, 1061, 1011,
Acknowledgement
We are grateful for financial support from the Na-
tional Natural Science Foundation of China (Grant No.
21272024).
828, 754, 701, 659, 522, 507 cm−1. HRMS (ESI) calcd
＋
for C20H16ClN4O [M ＋ H]
363.10072, found
363.10142.
(S)-6-Amino-3-methyl-4-phenyl-1-(p-tolyl)-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3m)[6k]
Compound 3m was obtained according to the general
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