Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea

Article abstract of DOI:10.1016/j.cclet.2014.01.034

Enantioselective synthesis of functionalized fluorinated dihydropyrano[2,3-c]pyrazoles has been achieved via a diaminocyclohexane- thiourea catalyzed cascade Michael addition and Thorpe-Ziegler type cyclization in high yields (up to 98%) with moderate to good enantioselectivity (up to 90% ee).

Full text of DOI:10.1016/j.cclet.2014.01.034

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Chinese Chemical Letters xxx (2014) xxx–xxx
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Chinese Chemical Letters
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Original article
Enantioselective synthesis of functionalized fluorinated
dihydropyrano [2,3-c]pyrazoles catalyzed by a simple
bifunctional diaminocyclohexane-thiourea
*
Hong-Fei Zhang, Zheng-Qing Ye, Gang Zhao
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Enantioselective synthesis of functionalized fluorinated dihydropyrano[2,3-c]pyrazoles has been
achieved via a diaminocyclohexane-thiourea catalyzed cascade Michael addition and Thorpe-Ziegler
type cyclization in high yields (up to 98%) with moderate to good enantioselectivity (up to 90% ee).
ß 2014 Gang Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Received 29 November 2013
Received in revised form 12 January 2014
Accepted 14 January 2014
Available online xxx
Keywords:
Trifluoromethyl
Pyrazoles
Cyclization
Organocatalysis
1. Introduction
enantioselective method for the synthesis of these compounds
using the cinchona alkaloid as the catalyst [6]. However, to the best
The incorporation of fluorine atom(s) or fluorine-containing
moieties into organic molecules would affect their lipophilicity
and spatial structure, thus emanating unique physical, chemical
and biological properties, which can lead to potential applications
in materials, medicinal, pharmaceutical and agrochemical sciences
[1]. In particular, the replacement of metabolically active hydrogen
atoms with fluorine atoms (or CF3) is commonly used in
contemporary medicinal chemistry to improve metabolic stability,
bioavailability and protein–drug interactions [2]. This strategy has
been illuminated in the organocatalytic asymmetric synthesis of
fluorinated molecules and several important methods have been
developed in the last decade [3].
of our knowledge, no chiral fluorinated dihydropyrano[2,3-
c]pyrazoles have been reported up to date [7]. Herein, based on
some previous studies in our group [8], we would like to present
an efficient catalyst system for the cascade Michael addition–
cyclization using diaminocyclohexane-thioureas [9] as a bifunc-
tional catalyst providing a series of novel chiral fluorinated
dihydropyrano[2,3-c]pyrazoles.
2. Experimental
1H NMR and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively, with TMS as an internal standard. 19F NMR
spectra were recorded at 282 MHz with CFCl3 as an external
standard. IR spectra were recorded in cmꢀ1. Melting points were
determined on an apparatus, which was not corrected. All solvents
were distilled prior to use unless otherwise noted. All reactions
sensitive to moisture or oxygen were conducted under an
atmosphere of nitrogen or argon.
To a mixture of 1 (0.1 mmol, 1.0 equiv.) and catalyst 3c
(0.01 mmol, 0.1 equiv.) in CHCl3 (2 mL) was added 2 (0.12 mmol,
1.2 equiv.). Then the reaction solution was vigorously stirred at
0 8C and monitored by TLC analysis. After the reaction was
complete, the mixture was concentrated and purified by flash
column chromatography on silica gel (petroleum ether/EtOAc as
Pyrano[2,3-c]pyrazoles are
a large class of heterocyclic
compounds possessing many important biological activities, such
as analgesic, anti-inflammatory, anti-tumor, insecticidal activities
and so on [4]. Since the first reaction for the synthesis of
pyrano[2,3-c]pyrazole derivatives from 3-methyl-1-phenylpyra-
zolin-5-one and tetracyanoethylene was reported by Junek in 1973
[5a], a large number of efficient synthetic methods to construct
dihydropyrano[2,3-c]pyrazole derivatives have been developed
[5]. Very recently, Zhao has reported the first organocatalyzed
*
Corresponding author.
E-mail address: zhaog@mail.sioc.ac.cn (G. Zhao).
1001-8417/$ – see front matter ß 2014 Gang Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2014.01.034
Please cite this article in press as: H.-F. Zhang, et al., Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-
c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.01.034

G Model
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2
H.-F. Zhang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Fig. 1. Thiourea catalysts evaluated in this study.
the eluent) to furnish the corresponding product 4. The data of
compounds 4a–p can be found in Supporting information.
catalysts but higher enantioselectity could be obtained with
catalysts 3b–f (entries 2–7). With the c-hexyl substituted catalyst
3h, a lower ee value was obtained (entry 8). Encouraged by the
above improvement made with the modified diaminocyclohex-
ane-thiourea catalysts, additional catalysts 3h–m derived from
amino acids and the cinchona alkaloid were also synthesized and
evaluated in this reaction. We found that the cinchona alkaloid-
derived bifunctional thiourea catalysts 3i and 3j both gave poor
enantioselectivity (entries 9 and 10) probably due to their strong
base effect and with the amino acid-based catalysts 3k, 3l and 3m;
similar inferior results were also obtained. For all of the reactions,
the desired products could be obtained in high yields (>90%) in no
more than 50 min.
3. Results and discussion
Initially, the Takemoto’s catalyst 3a (Fig. 1) was investigated in
the model reaction between (Z)-4-benzylidene-1-phenyl-3-(tri-
fluoromethyl)-1H-pyrazol-5(4H)-one (1a) and malononitrile (2) in
dichloromethane (DCM) at room temperature. The reaction gave
the desired cyclic product 4a in an excellent yield; however, a poor
enantioselectivity (57% ee) was also observed (Table 1, entry 1). In
order to enhance the enantioselectivity, several other diaminocy-
clohexane-thiourea catalysts with weaker H-bond donating ability
on the thiourea were screened. As expected, the yields that were
more correlative with the tertiary amine altered little with these
Then the reactions in various solvents were screened. The
results were summarized in Table 2. Generally, the reactions
Table 1
Screening of the catalysts.a
Ph
Ph
N
N
N
N
Cat. 3
CN
O
O
+
F3C
NH2
DCM, RT
CN
F3C
Ph
Ph
CN
1a
2
4a
Entry
Cat.
Time (min)
Yield (%)b
ee (%)c
1
2
3a
3b
3c
3d
3e
3f
40
40
30
30
50
40
20
20
50
40
30
40
40
95
94
95
94
93
94
93
90
93
92
90
91
90
57
71
72
70
70
64
53
46
14
33
5
3
4
5
6
7
3g
3h
3i
8
9
10
11
12
13
3j
3k
3l
8
3m
15
a
All the reactions were carried out with 1a (0.1 mmol) and 2 (0.12 mmol) in the presence of 3 (0.01 mmol) in CH2Cl2 (2.0 mL) at room temperature.
b
c
Yields of isolated products.
Determined by chiral HPLC analysis.
Please cite this article in press as: H.-F. Zhang, et al., Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-
c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.01.034

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3
Table 2
Optimization of the reactions in various solvents under different temperatures.a
Ph
Ph
N
N
N
CN
O
N
Cat. 3c
O
+
F3C
NH2
solvent
CN
F3C
Ph
4a
Ph
CN
1a
2
Entry
Solvent
Time (h)
Yield (%)b
ee (%)c
1
2
Et2O
1
1.5
1
90
92
95
–
53
67
75
–
Toluene
CHCl3
3
4
n-Hexane
THF
3
5
3.5
3.5
0.5
0.5
3.5
0.5
6
93
60
92
90
57
95
95
94
93
30
53
67
63
55
67
81
79
80
6
Xylenes
PhCl
7
8
ClCH2CH2Cl
CCl4
9
10
11d
12e
13f
Cl2CHCHCl2
CHCl3
CHCl3
12
24
CHCl3
a
Unless otherwise specified, all the reactions were carried out with 1a (0.1 mmol) and 2 (0.12 mmol) in the presence of 3c (0.01 mmol) in solvent (2.0 mL) at room
temperature.
b
c
d
e
f
Yields of isolated products.
Determined by chiral HPLC analysis.
The reaction was carried out at 0 8C.
The reaction was carried out at ꢀ5 8C.
The reaction was carried out at ꢀ10 8C.
proceeded smoothly in most solvents providing 4a in excellent
yields except in those that the substrates have poor solubility in
such as n-hexane, xylenes and CCl4 (entries 4, 6, 9). Further
investigation showed that the reaction worked the best in
chloroform, which gave the desired product in 95% yield and
75% ee (entry 3). Lowering the reaction temperature from room
temperature to 0 8C increased the ee value to 81% while the
excellent yield was maintained (entry 11). However, even lower
Table 3
Investigation of reaction scope.a
R2
R2
N
N
N
Cat. 3c
N
CN
O
O
+
F3C
NH2
CHCl3, 0 oC
F3C
CN
R1
R1
CN
1
2
4
Entry
R1, R2 (1)
Time (h)
Product
Yield (%)b
ee (%)c
1
2
4-OMe-C6H4, Ph
4-Me-C6H4, Ph
4-F-C6H4, Ph
10
8
4b
4c
4d
4e
4f
93
92
92
92
89
86
90
98
88
90
82
90
93
93
92
90
88
80
79
71
47
75
60
77
78
76
65
63
67
35
3
6.5
6.5
12
4
4-Cl-C6H4, Ph
4-Br-C6H4, Ph
4-NO2-C6H4, Ph
3-Br-C6H4, Ph
2-Br-C6H4, Ph
2-Furyl, Ph
5
6
8
8
4g
4h
4i
7
8
8
9
10
8
4j
10
11
12
13
14
15
Ph, 4-Me-C6H4
Ph, 4-OMe-C6H4
Ph, 4-Br-C6H4
Ph, 4-Cl-C6H4
Ph, 3-Cl-C6H4
Ph, 2-Cl-C6H4
4k
4l
8
12
8
4m
4n
4o
4p
7.5
8.5
a
Unless otherwise specified, all the reactions were carried out with 1 (0.1 mmol) and 2 (0.12 mmol) in the presence of 3c (0.01 mmol) in CHCl3 (2.0 mL) at 0 8C.
Yields of isolated products.
b
c
Determined by chiral HPLC analysis.
Please cite this article in press as: H.-F. Zhang, et al., Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-
c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.01.034

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tolerant with a heteroaromatic ring by giving the product 4g in
good yield and enantioselectivity (entry 9). A similar substituent
effect was observed while changing the substituents on R2.
Although slightly lower ee values were obtained with this type
of substrates, good enantioselectivity could also be obtained with
electro-donating substituents (entries 10–15).
Notably, although in a prolonged reaction time, the non-
fluorinated substrate 1q also proceeded efficiently to give the
desired product 4q in excellent yields with slightly lower ee values
(Scheme 1), which provides an easy access to this kind of important
intermediates.
Scheme 1. Reaction of the non-fluorinated substrate 1q.
temperatures brought no improvement in enantioselectivity but
led to a prolonged reaction time (entry 13). As a consequence, the
optimal condition for this Michael addition–cyclization was
obtained with 10 mol % of 3c in CHCl3 at 0 8C.
Having established the optimal conditions for the cascade
Michael addition–cyclization, we next explored the scope of the
reaction and the representative results are listed in Table 3. For
pyrazoles with different R1 substituents, excellent yields and good
ee values could be generally obtained regardless of the electronic
nature or positions of the substituents on the phenyl group of R1
except the substrates with a strong electron-withdrawing nitro
group or ortho-substituents (entries 1–8). This reaction was also
In an effort to realize the goal of generating biologically
interesting products, further transformations of the chiral pyr-
ano[2,3-c]pyrazole products 4 obtained above were then investi-
gated (Scheme 2). With aluminum chloride as a catalyst [10], the
Friedla¨nder reaction of the pyrano[2,3-c]pyrazole 4f with cyclo-
hexanone afforded the heterocyclic product 5 in 70% yield without
sacrificing the stereo-integrity. The absolute configuration of 5 was
then confirmed by X-ray crystallography to be S [11] and the
absolute configuration of product 4 was determined in the same
manner (Scheme 2). It should be noted that these types of
heterocyclic compounds with pyranopyridine scaffold are known
to possess potential biological activities, such as antiallergic, anti-
Scheme 2. Transformation of the product 4f.
Scheme 3. Proposed catalytic mechanism of the asymmetric Michael addition–cyclization reaction.
Please cite this article in press as: H.-F. Zhang, et al., Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-
c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.01.034

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5
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the carbonyl group of 4-aryliden-5-pyrazolones by forming two
hydrogen bonds using the N–Hs. When R1 or R2 contained
electron-donating groups, more powerful hydrogen bonds were
formed and herein high ee values were achieved. The mechanism
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In summary, we have developed an asymmetric organocatalytic
cascade Michael addition–cyclization reaction using bifunctional
diaminocyclohexane-thiourea catalysts. The reactions gave the
attractive products in excellent yields and good enantioselectivity
under mild reaction conditions, making it a novel and valuable
method for the construction of potential biologically active
functionalized fluorinated dihydropyano[2,3-c]pyrazoles, which
are also important intermediates in medicinal chemistry and can
be valuable for the pharmaceutical industry.
Acknowledgments
This work was supported by National Basic Research Program of
China (973 Program, No. 2010CB833200), the National Natural
Science Foundation of China (Nos. 21032006, 203900502,
20532040, 21290180), Science and Technology Commission of
Shanghai Municipality (No. 11XD1406400).
Appendix A. Supplementary data
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organocatalysts (mdos): enantioselective synthesis of dihydropyrano[2,3-c]pyr-
azoles, Tetrahedron Lett. 52 (2011) 3905–3908.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.01.034.
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c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.01.034

G Model
CCLET-2860; No. of Pages 6
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[R(int) = 0.0219]; date/restraints/parameters: 5448/0/316. X-ray analysis of
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[11] X-ray crystal: Triclinic, space group: P-1, Final
R indices [I>2sigma(I)]:
˚
R1 = 0.0537, wR2 = 0.1763; unit cell dimensions: a = 7.6593(12) A, b = 13.191(2)
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of NAD+-dependent DNA ligase by pyridochromanones, J. Biol. Chem. 278 (2003)
39435–39442.
˚
˚
A, c = 13.678 (2) A, a = 67.787(2)8, b = 82.977(3)8, g = 86.498(2)8; volume:
3
˚
1269.7(3) A ; crystal size: 0.39 mm ꢂ 0.30 mm ꢂ 0.28 mm; T = 173(2) K; Z,
calculated density: 2, 1.416 mg/m3; reflections collected/unique: 9139/5448
Please cite this article in press as: H.-F. Zhang, et al., Enantioselective synthesis of functionalized fluorinated dihydropyrano [2,3-
c]pyrazoles catalyzed by a simple bifunctional diaminocyclohexane-thiourea, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.01.034