Organocatalyzed enantioselective synthesis of 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2009.02.210

The first enantioselective synthesis of biologically active 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles has been achieved through a cinchona alkaloid-catalyzed tandem Michael addition and Thorpe-Ziegler type reaction between 2-pyrazolin-5-ones and benzyl

Full text of DOI:10.1016/j.tetlet.2009.02.210

Tetrahedron Letters 50 (2009) 2252–2255
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalyzed enantioselective synthesis of
6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles
*
Sanjib Gogoi, Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first enantioselective synthesis of biologically active 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles
has been achieved through a cinchona alkaloid-catalyzed tandem Michael addition and Thorpe-Ziegler
type reaction between 2-pyrazolin-5-ones and benzylidenemalononitriles. The reaction may also be car-
ried out in a three-component or a four-component fashion via the in situ formation of these two com-
ponents from simple and readily available starting materials. The desired products were obtained in
excellent yields with mediocre to excellent enantioselectivities (up to >99% ee).
Received 13 January 2009
Revised 23 February 2009
Accepted 26 February 2009
Available online 4 March 2009
Keywords:
Dihydropyrano[2,3-c]pyrazole
Pyrazole
Ó 2009 Elsevier Ltd. All rights reserved.
Dihydropyrane
Cinchona alkaloid
Organocatalysis
Multi-component reaction
Tandem reaction
Dihydropyrano[2,3-c]pyrazole derivatives have very important
biological activities, such as anticancer,1a antimicrobial,1b anti-
inflammatory,1c insecticidal,1d and molluscicidal activities.1e,f They
are also potential inhibitors of human Chk1 kinase (Fig. 1).1g Due to
their biological significance,1 there has been considerable interest
in developing synthetic methods for 6-amino-5-cyanodihydro-pyr-
ano[2,3-c]pyrazoles.2–6 These compounds may be readily obtained
from the reaction of 4-arylmethylene-5-pyrazolone and malono-
nitrile,2,3 or 2-pyrazolin-5-ones and benzylidenemalononitriles.3
The overall reaction is a tandem Michael addition and a Thorpe-
Ziegler type reaction (an enol addition to a cyano group) followed
by tautomerization.3 It should be pointed out that these com-
pounds may exist in the 1,4-dihydro or 2,4-dihydro tautomeric
forms when the N1 position is unsubstituted. Although most stud-
ies assigned the 1,4-dihydro structure to these derivatives,2–4 re-
cent X-ray crystallographic data prefer the 2,4-dihydro
tautomer.5,6
Since benzylidenemalononitriles may be synthesized in situ
from aromatic aldehydes and malononitrile under the reaction
conditions, these compounds may also be synthesized through a
three-component reaction of 2-pyrazolin-5-ones, malononitrile,
and aromatic aldehydes.4,5 Most recently, a four-component syn-
thesis by using hydrazine hydrate, acetoacetate, malononitrile,
and aromatic aldehydes has also been demonstrated.6 Neverthe-
less, to our knowledge, an enantioselective synthesis of these inter-
esting compounds has not yet been realized.7
During our ongoing research in developing novel organocatalyt-
ic enantioselective methods for the synthesis of biologically active
compounds,8 we became interested in the asymmetric synthesis of
6-amino-5-cyanodihydro-pyrano[2,3-c]pyrazoles. Herein we wish
to report the first enantioselective synthesis of these derivatives
through a tandem Michael addition-Thorpe-Ziegler reaction, using
some readily available cinchona derivatives as the catalyst.9
Initially we studied the synthesis with 3-methyl-2-pyrazolin-5-
one (10a) and benzylidenemalononitrile (11a) as the model sub-
strates. Several readily available cinchona alkaloid derivatives
(Scheme 1) were screened as the catalysts. The results are summa-
rized in Table 1.
OH
OH
CN
NH2
HN
N
O
an inhibitor of human Chk1 kinase
* Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (C.-G. Zhao).
Figure 1. A biologically active 6-amino-5-cyanodihydropyrano[2,3-c]-pyrazole.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.210

S. Gogoi, C.-G. Zhao / Tetrahedron Letters 50 (2009) 2252–2255
2253
enantiomer of cupreine (2), also leads to poor enantioselectivity
of the other enantiomer (6%, entry 9). Thus, this screening identi-
fied cupreine (2) as the best catalyst for the reaction. The results
also suggest that the reaction is very sensitive to the subtle
changes in the catalyst structure. Further screening of the reaction
conditions revealed that chloroform is also a good solvent for this
reaction (entry 10), while THF, ether, benzene, and acetonitrile are
worse ones (entries 11–14). Lowering the reaction temperature to
0 °C shows no improvement in the enantioselectivity (data not
shown). Furthermore, control experiments also indicate that the
product does not racemize under the reaction conditions (data
not shown).
OH
R1
N
N
H
N
H
N
RO
R2O
1: R = Me
2: R = H
3: R1 = OH, R2 = H
4: R1 = NH2, R2 = Me
CF3
S
OH
N
The absolute configuration of the major enantiomer obtained in
Table 1, entry 2 was determined to be R according to the X-ray
crystallographic analysis of the product 12a (Fig. 2).10 Our data also
indicate that the product exists in the 2,4-dihydro tautomer
form5,6 in the solid state.
N
CF3
HN
H
N
R1
N
H
N
The scope and limitation of this enantioselective synthesis were
next examined under the optimized conditions (with 5 mol % cat-
alyst 2 in CH2Cl2 at rt).10 The results are listed in Table 2. As shown
by the results in Table 2, besides 11a (entry 1), other benzylidene-
malononitriles also participate in this reaction. However, the
enantioselectivity of the reaction drops considerably if there is a
substituent on the phenyl ring of the benzylidenemalononitrile.
For example, the reaction of para-halogen-substituted benzylid-
enemalononitriles produces the expected products in high yields,
but the ee values of the obtained products are only mediocre
(48–62% ee, entries 2–5). Other electron-withdrawing groups at
the para-position, such as, cyano and nitro groups, also lead to
low ee values of the products (entries 6 and 7). Electron-donating
groups (Me and MeO) at para-position also diminish the enantiose-
lectivity of this reaction (entries 8 and 9). By comparing the results
in entry 4 and entry 10, it is evident that moving the substituent to
the meta-position leads to even worse enantioselectivity of the
product. These results hint that the enantioselectivity of this reac-
tion is most likely governed by steric factors instead of electronic
factors. Moreover, replacing the methyl group in 3-methyl-2-pyr-
azolin-5-one (10a) with a larger ethyl group (10b) also leads to
much poorer ee value of the product 12k (38% ee vs 96% ee, entries
OR
R2
5: R1 = -CH=CH2, R2 = OMe
6: R1 = -CH2CH3, R2 = OMe
7: R1 = -CH=CH2, R2 = H
8: R = Me
9: R = H
Scheme 1. Structure of the screened catalysts.
Table 1
Catalyst screening and reaction condition optimization for the two-component
reactiona
Ph
CN
Catalyst
CN
O
+
Ph
N
HN
N
H
Solvent, rt
CN
N
O
12a
Yieldb (%)
NH2
10a
11a
Entry
Catalyst
Solvent
Time (h)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
2
3
4
5
6
7
8
9
2
2
2
2
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
27
24
24
27
27
24
27
27
24
20
20
20
20
20
80
92
91
80
88
79
96
92
83
87
74
94
79
91
23
96
65
0
14
11
10
22d
6d
92
60
62
82
24
THF
Et2O
Benzene
CH3CN
a
All reactions were carried out with 10a (0.10 mmol), 11a (0.10 mmol), and the
catalyst (5 mol %) in the indicated solvent (2.0 mL) at rt.
b
Yield of isolated product after chromatography.
Determined by HPLC analysis on a ChiralPak AS column.
The S enantiomer was obtained as the major product.
c
d
As shown in Table 1, when quinine (1) was used as the catalyst
in CH2Cl2 at rt, a yield of 80% of the product 12a was obtained with
a low ee value of 23% (entry 1). In contrast, when cupreine (2) was
used as the catalyst, product 12a was obtained in high yield of 92%
with an excellent ee value of 96% (entry 2). Nevertheless, 9-epi-
cupreine (3) leads to a lower ee value of 65% (entry 3). When
9-epi-amino-9-deoxyquinine (4) was applied as the catalyst, a
racemic product was obtained (entry 4). Similarly, poor enantiose-
lectivities were achieved with quinine-derived thiourea catalysts
5–7 (entries 5–7). A low ee value of 22% for the opposite enantio-
mer was also obtained when quinidine (8) was used as the catalyst
(entry 8). It is most surprising that cupreidine (9), the pseudo-
Figure 2. ORTEP drawing of the product 12a.

2254
S. Gogoi, C.-G. Zhao / Tetrahedron Letters 50 (2009) 2252–2255
Table 2
Enantioselective two-component reaction for the synthesis of pyranopyrazoles with catalyst 2a
R2
R3
CN
R1
2
CN
+
O
R1
HN
N
CH2Cl2
rt
N
H
CN
R2
R3
11
N
O
12
NH2
10
Entry
Compound
R1
R2
R3
Time (h)
Yieldb (%)
eec (%)
1
2
12a
12b
12c
12d
12e
12f
12g
12h
12i
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
F
Cl
Br
I
CN
NO2
Me
OMe
H
H
H
H
H
H
H
H
H
H
Br
H
H
27
7.5
11
8
11
15
14
15
20
14
12
17
19
92
96
95
89
94
92
88
96
96
92
84
89
79
96
58
62
50
48
40
36
20
36
26
38
48
28
3d
4
5d
6
7
8
9
10
11
12
13e
12j
12k
12l
H
H
Ph
Me
12m
CN
CN
n-C5H11
a
Unless otherwise indicated, all reactions were carried out with 10a (0.10 mmol), 11a (0.10 mmol), and the catalyst (5 mol %) in CH2Cl2 (2.0 mL) at rt.
b
c
Yield of isolated product after chromatography.
Determined by HPLC analysis on a ChiralPak AS column.
Carried out at 0 °C.
d
e
Determined by HPLC analysis on a ChiralPak AD-H column.
1 and 11). Similar results were obtained with the product 12l of 3-
the reaction without these additives (entry 7). Under these individ-
ually optimized conditions, higher ee values of the products may
be obtained by using the three-component reaction than by using
phenyl-2-pyrazolin-5-one (10c, entry 12). The use of hexylidene-
malononitrile (entry 13) instead of benzylidenemalononitriles also
led to a poor ee value (28%) of the product 12m.
Multi-component reactions involving domino processes allow
molecular complexity and diversity to be created by the formation
of several new covalent bonds in a one-pot transformation. This
methodology has emerged as a powerful synthetic strategy.12 Most
recently, this approach also found many applications in organoca-
talysis.13 Since benzylidenemalononitriles (11) may be formed
in situ from aromatic aldehydes and malononitrile under the reac-
tion conditions,4,5 we also studied the three-component reaction of
10a, an aromatic aldehyde (13), and malononitrile (14). The results
are listed in Table 3.11
As shown by the results in Table 3, indeed, when cupreine (2)
was used as the catalyst, the desired product 12a may be obtained
in 80% yield and 96% ee by using 10a, 14, and benzaldehyde (13a)
as the substrates (entry 1). Since 1 equiv of water was formed un-
der the three-component reaction conditions, some drying agents
were intentionally added to the reaction mixture to evaluate their
effects on the enantioselectivity of this reaction. When 1 equiv of
Na2SO4 was used, the ee value of the product was improved to
99% ee (entry 2). However, adding 4 Å molecular sieves as the dry-
ing agent led to slightly inferior ee value of 94% (entry 3). The
yields were also slightly lower in both cases as compared to the
reaction without drying agents. Nonetheless, the effects of these
additives are more complicated. For example, with p-chlorobenzal-
dehyde (13c), molecular sieves prove to give the highest ee value
(70%, entry 6) of the product 12c, which is much higher than those
obtained without the additive or with Na2SO4 (entries 4 and 5).
However, with p-bromobenzaldehyde (13d), both additives give
worse enantioselectivities of the product 12d (entries 8 and 9) than
Table 3
Enantioselective three-component reaction for the synthesis of pyranopyrazoles with
catalyst 2a
R2
CHO
CN
CN
2, additive
10a +
+
CH2Cl2, rt
CN
R2
13
HN
N
O
NH2
14
12
Entry
12
Additive
—
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
12a
12a
12a
12c
12c
12c
12d
12d
12d
18
25
21
6
6
6
6.5
23
22
80
69
72
54
50
50
74
88
89
96
99
94
42
34
70
66
25
58
d
Na2SO4
MS(4 Å)e
—
d
Na2SO4
MS(4 Å)e
—
d
Na2SO4
MS(4 Å)e
a
All reactions were carried out with 10a (0.10 mmol), 13 (0.10 mmol), 14
(0.10 mmol), and the catalyst (5 mol %) in CH2Cl2 (2.0 mL) at rt.
b
Yield of isolated product after chromatography.
Determined by HPLC analysis on a ChiralPak AS column.
Na2SO4 (0.10 mmol) was added.
Molecular sieves (40 mg) were added.
c
d
e

S. Gogoi, C.-G. Zhao / Tetrahedron Letters 50 (2009) 2252–2255
2255
Table 4
Acknowledgments
Enantioselective four-component reaction for the synthesis of pyranopyrazoles with
catalyst 2a
This research is financially supported by the Welch Foundation
(Grant No. AX-1593) and partly by the National Institute of General
Medical Sciences (Grant No. 1SC1GM082718-01A1), for which the
authors are most grateful. The authors also thank Dr. Hadi Arman
for the help with the X-ray analysis.
O
2, additive
NH2
NH2
H2O
13 + 14 +
+
12
solvent, rt
O
EtO
16
15
Supplementary data
Entry
12
Additive (equiv)
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
12a
12a
12a
12a
12a
12a
12a
12a
12a
12c
12d
12g
12i
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
23
27
27
27
28
24
24
24
24
17
21
17
18
28
21
25
20
43
28
24
30
<5
75
73
80
82
16
89
96
90
>99
>99
>99
98
nd
23
58
2
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.210.
MgSO4 (1)
Na2SO4 (1)
MS(4 Å)d
Na2SO4 (2)e
Na2SO4 (2)
Na2SO4 (2)
Na2SO4 (2)
Na2SO4 (2)
Na2SO4 (2)
—
References and notes
MeCN
THF
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34
a
Unless otherwise indicated, all reactions were carried out with 13 (0.10 mmol),
14 (0.10 mmol), 15 (0.10 mmol), 16 (0.10 mmol), and the catalyst (5 mol %) in the
indicated solvent (2.0 mL) at rt.
b
Yield of isolated product after chromatography.
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c
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Next the four-component reaction was studied with cupreine
(2) by using hydrazine hydrate (15) and acetoacetate (16) as the
precursors for the in situ formation of compound 10a. The results
are listed in Table 4. Benzaldehyde (13a) leads to formation of ex-
pected 12a in 28% yield and 16% ee (entry 1). Again various drying
agents were evaluated for their effects on the stereoselectivity.
Much improved ee values were obtained after adding 1 equiv of
MgSO4 or Na2SO4, or molecular sieves (entries 2–4) to the reaction
mixture, with Na2SO4 giving the best results (entry 3). By adding
2 equiv of Na2SO4 and carrying out the reaction at 0 °C, a single
enantiomer of 12a may be obtained (entry 5). Similar results
may also be achieved in other solvents, such as chloroform (entry
6), acetonitrile (entry 7), and THF (entry 8), except for benzene (en-
try 9). Whereas this four-component reaction leads to the highest
ee value of product 12a, the yield is considerably lower than the
two-component or the three-component reaction. Higher yields
may be achieved for other aldehyde substrates, such as p-chloro
(13c), p-bromo (13d), p-nitro (13g), and p-methoxybenzaldehyde
(13i), but the enantioselectivities obtained were only low to medi-
ocre (entries 10–13).
In summary, we have developed the first enantioselective
method for the synthesis of 6-amino-5-cyanodihydropyrano[2,3-
c]pyrazoles via a two-component, a three-component, or a four-
component reaction using cupreine as the catalyst. The enantiose-
lectivity of this reaction was found to be highly dependent on the
reaction conditions and on the structure of the catalysts and the
substrates.