An efficient four-component synthesis of multisubstituted pyrano[2,3-c]pyrazole

Article abstract of DOI:10.1080/00397911.2010.551169

A series of substituted pyrano[2,3-c]pyrazole derivatives were synthesized by a one-pot reaction of methyl 4-methyl-3-oxovalerate, phenylhydrazine, aromatic aldehyde, and malononitrile in ethanol with catalysis by triethylamine. The title compounds were o

Full text of DOI:10.1080/00397911.2010.551169

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An Efficient Four-Component Synthesis
of Multisubstituted Pyrano[2,3-
c]pyrazole
Keyume Ablajan a & Zulipiya Maimaiti a
a College of Chemistry and Chemical Enginnering, Xinjiang
University, Urumqi, China
Accepted author version posted online: 27 Oct 2011. Version of
record first published: 26 Mar 2012
To cite this article: Keyume Ablajan & Zulipiya Maimaiti (2012): An Efficient Four-Component
Synthesis of Multisubstituted Pyrano[2,3-c]pyrazole, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:13, 1959-1966
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Synthetic Communications1, 42: 1959–1966, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.551169
AN EFFICIENT FOUR-COMPONENT SYNTHESIS OF
MULTISUBSTITUTED PYRANO[2,3-c]PYRAZOLE
Keyume Ablajan and Zulipiya Maimaiti
College of Chemistry and Chemical Enginnering, Xinjiang University,
Urumqi, China
GRAPHICAL ABSTRACT
Abstract A series of substituted pyrano[2,3-c]pyrazole derivatives were synthesized by a
one-pot reaction of methyl 4-methyl-3-oxovalerate, phenylhydrazine, aromatic aldehyde,
and malononitrile in ethanol with catalysis by triethylamine. The title compounds were
obtained in good to excellent yields. A possible mechanism for this reaction was proposed.
Keywords Aldehyde; malononitrile; methyl methyl-3-oxovalerate; multicomponent
reaction; one-pot synthesis; pyrano[2,3-c]pyrazole
INTRODUCTION
Multicomponent reactions (MCRs) have been widely used in synthetic,
combinatorial, and medicinal chemistry as an effective method to construct multiple
bonds in a single operation.[1] These reactions are atom-efficient processes and incor-
porate the essential parts of the starting materials into the final product. MCRs are
powerful tools in the modern drug-discovery process and allow the fast, automated,
and high-throughput generation of organic compounds.[2] In the past decade, there
has been tremendous development in three- and four-component reaction, and much
effort has been devoted to the development of a new MCRs.[3] The application of
MCRs is increasing rapidly because of the simplicity of reaction, less pollution,
and short reaction times. The development of simple synthetic routes for widely used
organic compounds from readily available reagents is a challenging work in organic
synthesis.[4]
Received August 12, 2010.
Address correspondence to Keyume Ablajan, College of Chemistry and Chemical Engineering,
Xinjiang University, 830046 Urumqi, China. E-mail: ablajan209@hotmail.com
1959

1960
K. ABLAJAN AND Z. MAIMAITI
Scheme 1. One-pot synthesis of substituted pyrano[2,3-c]pyrazole derivatives (5a–5j).
Pyrano[2,3-c]pyrazoles have been used as intermediates in the synthesis of
heterocycles because of their important practical applicability.[5] Also, many
methods have been reported for the formation of pyrano[2,3-c]pyrazole, and this
moiety has been widely used in medicinal chemistry because of its diverse biological
activities and pharmacological properties,[6] such as anticancer,[7] anti-
inflammatory,[8] and antimicrobial properties.[9]
Therefore, new routes for the synthesis of these molecules have attracted con-
siderable attention in the search for a rapid entry to these heterocycles. Generally,
6-amino-4H-pyrano[2,3-c]pyrazoles were synthesized by the reaction of arylidene-
malononitriles with 3-methylpyrazol-5-one or condensation of 4-arylidenepyrazol-5-
ones with malononitrile via a two-step process.[5c] Recently, a few reports have
described the synthesis of substituted pyrano[2,3-c]pyrazole derivatives via MCRs
of aldehyde, malononitrile, and 3-methy-2-pyrazolin-5-one in the presence of
piperidine,[10] KF ꢀ 2H2O,[11] or D,L-proline.[12] In addition, a three-component
Table 1. Reaction times and yields of compounds 5a–5j
Entry
R
Ar
Product
Time (min)
Yield (%)a
1
2
CH3
CH3
C6H5
5a
5b
5c
5d
5e
5f
10
10
10
8
81
90
92
84
80
80
84
90
87
85
73
80
82
75
74
75
76
84
80
76
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-rC6H4
3
CH3
CH3
4
5
CH3
CH3
6
6
p-FC6H4
6
7
CH3
CH3
p-O2NC6H4
p-HOC6H4
3-Pyridyl
5g
5h
5i
8
8
8
9
CH3
CH3
6
10
11
12
13
14
15
16
17
18
19
20
1-Naphthyl
C6H5
5j
8
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
5a
5b
5c
5d
5e
5f
15
15
15
15
15
15
15
15
15
15
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-rC6H4
p-FC6H4
p-O2NC6H4
p-HOC6H4
3-Pyridyl
5g
5h
5i
1-Naphthyl
5j
aYields of the isolated products.

SYNTHESIS OF MULTISUBSTITUTED PYRANO[2,3-c]PYRAZOLE
1961
base[13] or electrocatalyzed[14] reaction of aldehydes, malonodinitrile, and pyrazolin-
5-one was a simple protocol for preparation of the diverse pyrano[2,3-c]pyrazoles.
Although there is a developed four-component synthetic method for some 6-amino-
2,4-dihydro-pyrano-[2,3-c]pyrazol-5-carbo-nitriles,[15] the method was unable to
extend it to phenyl hydrazine as a reactant. Therefore, improved and high-efficiency
syntheses for a novel multisubstituted pyrano[2,3-c]pyrazoles are in demand.
As part of our current study in the development of new synthetic methods in
heterocyclic chemistry and our interest in pyrazole-based MCRs, herein we describe
an efficient synthesis of substituted pyrano[2,3-c]pyrazols via a one-pot, four-
component reaction catalyzed by triethylamine (Scheme 1). The reaction has been
carried out by refluxing the mixture of four reactants at 80 ꢁC for 6–15 min. The
yields of products 5a–5j are presented in Table 1. The 1H NMR spectra of products
5a–5j clearly indicated the formation of pyrano[2,3-c]pyrazoles 5.
RESULTS AND DISCUSSION
The corresponding products 5 were obtained in good yields (73–92%) through
the reaction of 1, 2, 3, and 4. As shown in Table 1, the yields were slightly higher
when electron-withdrawing groups (such as NO2 and Cl group) exist in aromatic
aldehydes rather than electron-donating groups. It must be pointed out that the reac-
tion requires less reaction time (6–8 min) for formation of corresponding products
when electron-withdrawing groups exist in aromatic aldehydes.
Significant differences in yields of the same products were observed by using 1a
and 1b reactants, respectively. When methyl 4-methyl-3-oxovalerate 1a was used as a
reactant instead of ethyl 4-methyl-3-oxovalerate 1b, the yields of products 5a–5j
increased by 6–10% (Table 1).
The structures of products 5a–5j were deduced on the basis of infrared (IR),
1
mass (MS), H NMR, and elemental analyses. The identification of representative
compound 5i is discussed as an example. The mass spectrum of compound 5i dis-
played highly abundant m=z 358 and m=z 380 ions that correspond to adduct mol-
ecular ion peaks [M þ H]þ and [M þ Na]þ, respectively. Characteristic absorption
bands of CN group at 2189 cmꢂ1 and NH2 group at 3357, 3133 cmꢂ1 were observed
1
in the IR spectrum of 5i. The H NMR spectrum of compound 5i showed a broad
peak at 7.29 ppm, which belongs to two H’s of the NH2 group. A sharp singlet
appeared at 4.83 ppm assigned to one H of CH in pyrano ring. The H in two Me
of isoproply group appeared at 0.81 and 1.04 ppm, respectively, coupled with the
H of CH (2.43 ppm, septet), which was confirmed by coupling constant (J ¼ 7.2 Hz).
According to the structure of products, we assume that the different signals for Me
were related to the stereogenic center in products.
The formation of compounds 5a–5j is explained as follows (Scheme 2). At first,
intermediates 6 and 8 were formed by the condensation of phenylhydrazine (2) with
methyl 4-methyl-3-oxovalerate (1a) and arylaldehydes (3) with malononitrile (4),
respectively. Subsequent Michael reaction between intermediate 6 and intermediate
=
8 and intramolecular reaction between NH and C O occur simultaneously, leading
to intermediate 9. Furthermore, after the removal of methanol from 9, the sub-
sequent intramolecular cyclization in intermediate 10B by the nucleophilic attack
of OH group to the carbon of CN moiety affords the final product 5.

1962
K. ABLAJAN AND Z. MAIMAITI
Scheme 2. Proposed mechanism for the formation of 5a–5j.
In summary, we have developed a new, convenient, one-pot method for the syn-
thesis of 6-amino-4-aryl-3-isopropyl-1-phenyl-4H-pyrano[2,3-c]pyrazole-5-carbonitrile
via a four-component reaction using triethylamine as a catalyst. This method has
the advantages of good yields, easy workup, and short reaction times, which make it
a useful and attractive process for the synthesis of these types of compounds.
EXPERIMENTAL
The melting point was determined on a Buchi B2540 microscopic melting
1
apparatus. The H NMR spectrum was recorded on a Varian Inova 400 instrument
with dimethylsulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as
internal standard. Infrared (IR) spectrum was measured with a Bruker Equinox55
spectrometer as KBr pellets. The elemental analyses was performed with a Perkin-
Elmer EA-1110 elemental analyses instrument. Mass spectral (MS) data were
obtained on an MDS mass spectrometer. All chemicals were obtained from commer-
cial suppliers and used without further purification.
General Procedure for the Syntheses of 6-Amino-4-aryl-
3-isopropyl-1-phenyl-4H-pyrano[2,3-c]pyrazole-5-carbonitrile
A solution of methyl 4-methyl-3-oxovalerate 1a (0.300 g, 2 mmol) and phenyl-
hydrazine 2 (0.225 g, 2 mmol) was refluxed in absolute ethanol (20 ml) for 2 min.
Then, phenyl aldehyde 3 (0.221 g, 2 mmol), malononitrile 4 (0.138 g, 2 mmol), and
triethylamine (2–3 drops) were added to the mixture, and the heating continued

SYNTHESIS OF MULTISUBSTITUTED PYRANO[2,3-c]PYRAZOLE
1963
for 5 to 10 min. The reaction system was cooled to room temperature. The precipi-
tate that formed was filtered off, washed with ethanol, and recrystallized from
ethanol-DMF to afford the pure product.
Data
Compound 5a. White crystals; mp 234–236 ꢁC. IR (KBr, n=cmꢂ1): 3455, 3320
1
=
=
(NH2, br), 2200 (CꢃN), 1658, 1590, 1517 (C N, C C). H NMR (400 MHz, DMSO-
d6): d ¼ 0.82 (d, 3H, J ¼ 7.2 Hz, CH3), 1.03 (d, 3H, J ¼ 7.2 Hz, CH3), 2.46 (sep, 1H,
J ¼ 7.2 Hz, CH), 4.36 (s, 1H, CH), 7.18 (s, 2H, NH2), 7.18–7.82 (m, 10H, Ar-H).
MS, m=z (%): 357 ([M þ H]þ, 100), 379 ([M þ Na]þ, 38). Anal. calcd. for
C22H20N4O (356.43) C, 74.14; H, 5.66; N, 15.72. Found: C, 74.01; H, 5.46; N, 15.67.
Compound 5b. White crystals; mp 247–248 ꢁC. IR (KBr, n=cmꢂ1): 3466,
1
=
=
3321 (NH2, br), 2201 (CꢃN), 1661, 1593, 1515 (C N, C C). H NMR (400 MHz,
DMSO-d6): d ¼ 0.83 (d, 3 H, J ¼ 7.2 Hz, CH3), 1.03 (d, 3H, J ¼ 7.2 Hz, CH3), 2.50
(sep, 1H, J ¼ 7.2 Hz, CH), 2.29 (s, 3H, CH3), 4.66 (s, 1H, CH), 7.14 (s, 2H, NH2),
7.11 (d, J ¼ 8.8 Hz, 2H, p-H3C-C6H4), 7.12–7.50 (m, 5H, C6H5), 7.80 (d, J ¼ 8.8 Hz,
2H, p-H3C-C6H4). MS, m=z (%): 371 ([M þ H]þ, 100), 393 ([M þ Na]þ, 50). Anal.
calcd. for C23H22N4O (370.45): C, 74.57; H, 5.99; N, 15.12. Found: C, 74.44; H,
5.94; N, 15.02.
Compound 5c. White crystals; mp 270–272 ꢁC. IR (KBr, n=cmꢂ1): 3460, 3322
(NH2, br), 2201 (CꢃN), 1660, 1592, 1516 (C N, C C). 1H NMR (400 MHz,
DMSO-d6): d ¼ 0.84 (d, 3H, J ¼ 7.2 Hz, CH3), 1.01 (d, 3H, J ¼ 7.2 Hz, CH3), 2.46
(sep, 1H, J ¼ 7.2 Hz, CH), 3.74 (s, 3H, OCH3), 4.66 (s, 1H, CH), 7.13 (s, 2H,
NH2), 6.90 (d, J ¼ 8.4 Hz, 2H, p-H3CO-C6H4), 7.16 (d, J ¼ 8.4 Hz, 2H, p-H3CO-C6-
H4), 7.32–7.80 (m, 5H, C6H5). MS, m=z (%): 387 ([M þ H]þ, 50), 409 ([M þ Na]þ,
100). Anal. calcd. for C23H22N4O2(386.45): C, 71.48; H, 5.74; N, 14.50. Found: C,
71.28; H, 5.69; N, 14.43.
=
=
Compound 5d. White crystals; mp 268–270 ꢁC. IR (KBr, n=cmꢂ1): 3456,
1
=
=
3324 (NH2, br), 2200 (CꢃN), 1661, 1591, 1517 (C N, C C). H NMR (400 MHz,
DMSO-d6): d ¼ 0.84 (d, 3H, J ¼ 6.8 Hz, CH3), 1.04 (d, 3H, J ¼ 6.8 Hz, CH3), 2.49
(sep, 1H, J ¼ 6.8 Hz, CH), 4.77 (s, 1H, CH), 7.23 (s, 2H, NH2), 7.30 (d, J ¼ 8.4 Hz,
2H, p-Cl-C6H4), 7.33–7.80 (m, 5H, C6H5), 7.39 (d, J ¼ 8.4 Hz, 2H, p-Cl-C6H4).
MS, m=z (%): 413 ([M þ Na]þ, 60), 391 ([M þ H]þ, 80). Anal. calcd. for
C22H19ClN4O (390.87): C, 67.60; H, 4.90; N, 14.33. Found: C, 67.34; H, 4.79, N,
14.10.
Compound 5e. White crystals; mp 262–264 ꢁC; IR (KBr, n=cmꢂ1): 3452, 3324
(NH2, br), 2197 (CꢃN), 1660, 1591, 1517 (C N, C C). 1H NMR (400 MHz,
DMSO-d6): d ¼ 0.86 (d, 3H, J ¼ 7.2 Hz, CH3), 1.04 (d, 3H, J ¼ 7.2 Hz, CH3), 2.45
(sep, 1H, J ¼ 7.2 Hz, CH), 4.75 (s, 1H, CH), 7.23 (s, 2H, NH2), 7.26 (d, J ¼ 8.8 Hz,
2H, p-Br-C6H4), 7.33–7.53 (m, 5H, C6H5), 7.81 (d, J ¼ 8.8 Hz, 2H, p-Br-C6H4).
MS, m=z (%): 459 ([M þ 2 þ Na]þ, 40), 457 ([M þ Na]þ, 36), 437 ([M þ 2 þ H]þ,
100), 435 ([M þ H]þ, 80). Anal. calcd. for C22H19BrN4O (435.32): C, 60.70; H,
4.40; N, 12.87. Found: C, 60.47; H, 4.32, N, 13.04.
=
=

1964
K. ABLAJAN AND Z. MAIMAITI
Compound 5f. White crystals; mp 262–263 ꢁC. IR (KBr, n=cmꢂ1): 3471, 3358
(NH2, br), 2198 (CꢃN), 1681, 1601, 1591 (C N, C C). 1H NMR (400 MHz,
DMSO-d6): d ¼ 0.84 (d, 3H, J ¼ 7.2 Hz, CH3), 1.04 (d, 3H, J ¼ 7.2 Hz, CH3), 2.45
(sep, 1H, J ¼ 7.2 Hz, CH), 4.76 (s, 1H, CH), 7.17 (s, 2H, NH2), 7.15 (d, J ¼ 8.4 Hz,
2H, p-F-C6H4), 7.31–7.80 (m, 5H, C6H5), 7.31 (d, J ¼ 8.4 Hz, 2H, p-F-C6H4). MS,
m=z (%): 398 ([M þ 2 þ Na]þ, 10), 397 ([M þ Na)þ, 20), 376 ([M þ 1 þ H]þ, 38),
375 ([M þ H]þ, 100). Anal. calcd. for C22H19FN4O (374.42): C, 70.57; H, 5.11; N,
14.96. Found: C, 70.38; H, 5.08; N, 14.87.
=
=
Compound 5g. Yellow crystals; mp 281–283 ꢁC. IR (KBr, n=cmꢂ1): 3425,
1
=
=
3331 (NH2, br), 2200 (CꢃN), 1684, 1600, 1517 (C N, C C). H NMR (400 MHz,
DMSO-d6): d ¼ 0.85 (d, 3H, J ¼ 7.2 Hz, CH3), 1.05 (d, 3H, J ¼ 7.2 Hz, CH3), 2.43
(sep, 1H, J ¼ 7.2 Hz CH), 4.97 (s, 1H, CH), 7.32–7.61 (m, 5H, C6H5), 7.35 (s, 2H,
NH2), 7.80 (d, J ¼ 8.8 Hz, 2H, p-O2N-C6H4), 8.23 (d, J ¼ 8.8 Hz, 2H, p-
O2N-C6H4). MS, m=z (%): 424 ([M þ Na]þ, 100), 402 ([M þ H]þ, 25). Anal. calcd.
for C22H19N5O3(401.42): C, 65.83; H, 4.77; N, 17.45. Found: C, 65.68; H, 4.70; N,
17.32.
Compound 5h. White crystals; mp 261–263 ꢁC. IR (KBr, n=cmꢂ1): 3398
(OH), 3325, 3214 (NH2, br), 2177 (CꢃN), 1658, 1594, 1515 (C N, C C). 1H
NMR (400 MHz, DMSO-d6): d ¼ 0.85 (d, 3H, J ¼ 6.8 Hz, CH3), 1.02 (d, 3H,
J ¼ 6.8 Hz, CH3), 2.47 (sep, 1H, J ¼ 7.2 Hz, CH), 4.59 (s, 1 H, CH), 6.70 (d, 2H,
J ¼ 8.4 Hz, p-HO-C6H4), 7.03 (d, 2H, J ¼ 8.4 Hz, p-HO-C6H4), 7.09 (s, 2H, NH2),
7.31–7.79 (m, 5H, C6H5), 9.33 (s, 1 H, OH). MS, m=z (%): 395 ([M þ Na]þ), 373
([M þ H]þ). Anal. calcd. for C22H20N4O2 (372.43): C, 70.95; H, 5.41; N, 15.04.
Found: C, 70.78; H, 5.37; N, 14.98.
=
=
Compound 5i. White crystals; mp 250–252 ꢁC. IR (KBr, n=cmꢂ1): 3357, 3133
1
=
=
(NH2, br), 2189 (CꢃN), 1660, 1582, 1515 (C N, C C). H NMR (400 MHz, DMSO-
d6): d ¼ 0.81 (d, 3H, J ¼ 6.8 Hz, CH3), 1.04 (d, 3H, J ¼ 6.8 Hz, CH3), 2.43 (sep, 1H,
J ¼ 6.8 Hz, CH), 4.83 (s, 1H, CH), 7.29 (s, 2H, NH2), 7.32–7.80 (m, 5H, C6H5),
7.38 (t, 1H, J ¼ 8.0 Hz, 4.0 Hz, pyridyl-H), 7.74 (dd, 1H, J ¼ 8.0 Hz, 2 Hz, pyridyl-H),
8.49 (dd, 1H, J ¼ 1.6 Hz, 4.8 Hz, pyridyl-H), 8.55 (d, 1H, J ¼ 1.6 Hz, pyridyl-H). MS,
m=z (%): 380 ([M þ Na]þ, 50), 358 ([M þ H]þ, 100). Anal. calcd. for C21H19N5O
(357.41): C, 70.57; H, 5.36; N, 19.59. Found: C, 70.42; H, 5.29; N, 19.49.
Compound 5j. White crystals; mp 204–206 ꢁC. IR (KBr, n=cmꢂ1): 3373, 3175
(NH2, br), 2182 (CꢃN), 1658, 1594, 1515 (C N, C C). 1H NMR (400 MHz,
DMSO-d6): d ¼ 0.91 (d, 3H, J ¼ 7.2 Hz, CH3), 1.06 (d, 3H, J ¼ 7.2 Hz, CH3), 2.21
(sep, 1H, J ¼ 7.2 Hz, CH), 4.36 (s, 1H, J ¼ 7.2 Hz, CH), 7.20 (s, 2H, NH2),
7.33–798 (m, 12H, Ar-H). MS, m=z (%): 429 ([M þ Na]þ, 50), 407 ([M þ H]þ,
100). Anal. calcd. for C26H22N4O (406.49): C, 76.83; H, 5.46; N, 13.78. Found: C,
76.76; H, 5.39; N, 13.61.
=
=
ACKNOWLEDGMENT
We thank the Natural Science Foundation of Xinjiang Science Technology
Agency (No. 2009 211A02) for the financial support.

SYNTHESIS OF MULTISUBSTITUTED PYRANO[2,3-c]PYRAZOLE
1965
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