Synthesis of substituted pyranopyrazoles under neat conditions via a multicomponent reaction

Article abstract of DOI:10.1055/s-0029-1217526

A simple and efficient synthesis of pyranopyrazoles in good yields via a four-component reaction between an aromatic aldehyde, hydrazine hydrate, ethyl acetoacetate and malononitrile under neat conditions is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217526

LETTER
2002
Synthesis of Substituted Pyranopyrazoles under Neat Conditions via a
Multicomponent Reaction
S
ynthesis of Subst
r
itute
d
Py
a
ranopyrazo
s
les ampattu S. Nagarajan, Boreddy S. R. Reddy*
Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600020, India
Fax +91(44)24911589; E-mail: induchem2000@yahoo.com
Received 23 April 2009
ferent from reactions in organic solvents. In particular, re-
actions with negative activation volume are reported to
occur faster in water than in organic solvents.11 MCRs are
suggested to have a negative activation volume.12 The re-
cently reported preparation of pyranopyrazoles13 in a wa-
ter-mediated reaction requires water and a base. Here, we
report a mild and efficient multicomponent reaction for
the synthesis of pyranopyrazole derivatives under neat
conditions (solvent- and catalyst-free) at room tempera-
ture as described in Scheme 1.
Abstract: A simple and efficient synthesis of pyranopyrazoles in
good yields via a four-component reaction between an aromatic al-
dehyde, hydrazine hydrate, ethyl acetoacetate and malononitrile un-
der neat conditions is described.
Key words: neat conditions, hydrazine hydrate, acetoacetate, pyra-
nopyrazole
Multicomponent reactions (MCRs) are processes in
which three or more reactants are combined in a single
chemical step to produce products that incorporate sub-
stantial portions of all the reactants. These reactions are
effective in building highly functionalized small organic
molecules from readily available starting materials in a
single step with inherent flexibility for creating molecular
complexity and diversity coupled with minimization of
time, labor, cost and waste production.1 Organic reactions
in aqueous media is another attractive area in green chem-
istry.2 Water as a reaction medium offers several benefits
including control over exothermic reactions, and workup
and purification can be carried out by simple phase-sepa-
ration techniques. On the other hand, pyranopyrazoles are
an important class of heterocyclic compounds. They find
applications as pharmaceutical ingredients3,4 including
antifungal and antimicrobial activities.5 The first reported
pyranopyrazole was synthesized from the reaction be-
tween 3-methyl-1-phenylpyrazolin-5-one and tetracyano-
O
R
H2N NH2
R
H
CN
2
1
HN
3–11 min
N
O
O
O
NH2
CN
5
O
NC
4
3
Scheme 1 Synthesis of pyranopyrazole
The reaction between hydrazine hydrate, ethyl acetoace-
tate, benzaldehyde and malononitrile resulted in pyran-
opyrazole without catalyst and solvent. The products were
obtained in good yield without a base and water. These re-
actions were completed in 3–11 minutes and the products
were obtained by extraction with ethyl acetate. The for-
mation of the pyranopyrazole product of Table 1, entry 19
ethylene.6
Various
6-amino-5-cyano-4-aryl-4H-
pyrazolo[3,4-b]pyrans were synthesized by the reaction of
arylidene malononitrile with 3-methyl pyrazolin-5-one or
by the condensation of 4-arylidene pyrazolin-5-one with
malononitrile.7 Sharanin et al.8 have developed a three-
component reaction between pyrazolone, an aldehyde and
malononitrile in ethanol using triethylamine as the cata-
lyst. Shestopalov and co-workers9 reported the synthesis
of pyrazolopyran via a three-component condensation be-
tween N-methylpiperidone, pyrazolin-5-one and malono-
nitrile in absolute ethanol. However, this reaction
occurred only on heating or when induced by electro-
chemical methods under an inert atmosphere. Peng and
1
was ascertained by the appearance of a low-intensity H
NMR signal at d = 12.05 ppm indicating the presence of a
secondary amine proton. Moreover, tertiary carbon signal
appeared in 13C NMR at d = 35.9 ppm.
To examine the efficiency of this new multicomponent re-
action, a series of different aldehydes were employed. As
shown in Table 1, this protocol can be applied to aromatic
aldehydes either with electron-withdrawing groups (nitro
or halide groups) or electron-donating groups (hydroxyl
or alkoxy group). Furthermore, a series of different substi-
tuted aldehydes gave excellent yields.
co-workers10 have developed a two-component reaction The formation of the product is proposed to involve the
involving pyran derivatives and hydrazine hydrate to ob- following tandem reaction steps: pyrazolone (6) forma-
tain pyranopyrazoles in water. Also, organic reactions in tion by reaction between hydrazine hydrate and ethyl ace-
water exhibit unique reactivity and selectivity that are dif- toacetate. Knoevenagal condensation between aldehyde
and malononitrile to give 7 and Michael addition of 6 and
7 to give 8, followed by cyclization and tautomerization to
give substituted pyranopyrazoles as shown in Scheme 2.
SYNLETT 2009, No. 12, pp 2002–2004
Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1217526; Art ID: G10409ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Substituted Pyranopyrazoles
2003
Table 1 Synthesis of Pyranopyrazoles 5 via the Four-Component
The substituents on the aldehyde moiety play a significant
role in the MCR process. The presence of an electron-re-
leasing group, such as methyl and methoxy in the para po-
sition relative to the aldehyde group enhanced the product
formation as indicated by short reaction time and higher
yield (Table 1, entries 15 and 19). Similarly, a strong elec-
tron-withdrawing group, such as cyano and nitro group
para to the aldehyde group led to lower yields (Table 1,
entries 11 and 12). The nature of disubstituted aromatic al-
dehyde also affects the product time and yield. The disub-
stituted aldehyde with electron-donating groups in para
and meta positions required shorter reaction time and gave
higher yield (entries 13, 22 and 23).
Reaction14–16
Entry Aldehyde
Yield (%)Time (min)
1
2
benzaldehyde
53
62
74
70
64
56
48
58
66
71
40
37
82
49
82
62
66
60
65
80
64
66
88
62
64
5–6
5–8
7–10
5–7
6–8
5–7
7–9
6–8
8–10
5–7
7–9
6–8
5–7
5–11
3–5
6–7
8–11
7–9
3–5
9–10
8–10
5–7
4–6
7–10
6–9
3-bromobenzaldehyde
4-bromo-3-methylbenzaldehyde
3-methyl-4-flurobenzaldehyde
2-bromobenzaldehyde
2-fluorobenzaldehyde
4-hydroxybenzaldehyde
4-bromobenzaldehyde
2-chlorobenzaldehyde
4-fluorobenzaldehyde
4-nitrobenzaldehyde
3
4
5
6
7
Also, trisubstituted aldehyde in ortho and para positions
with respect to the aldehyde group affects reaction time
and yield. Entry 14 gave a low yield and required a longer
reaction time.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
In summary, one-step multicomponent reactions of struc-
turally diverse aldehydes with hydrazine hydrate, ethyl
acetoacetate and malononitrile resulted in the formation
of substituted pyranopyrazoles. This is a very useful tech-
nique for the preparation of substituted pyranopyrazoles.
The biological studies of all the pyranopyrazole deriva-
tives are in progress.
4-cyanobenzaldehyde
2,6-diisopropylbenzaldehyde
2,4,6-trimethylbenzaldehyde
4-methylbenzaldehyde
salicylaldehyde
Acknowledgment
A. S. Nagarajan thanks the DST (SR/S1/PC-33/2006) for financial
assistance.
4-quinolinealdehyde
4-antharacenealdehyde
4-methoxybenzaldehyde
2,6-dichlorobenzaldehyde
3-chlorobenzaldehyde
2-methyl-4-methoxybenzaldehyde
3,5-dimethylbenzaldehyde
furfuraldehyde
References and Notes
(1) (a) Zhu, J.; Bienayme, H. In Multicomponent Reactions;
Zhu, J.; Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005,
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Tellado, F. Chem. Soc. Rev. 2007, 36, 484. (c) Ugi, I. Pure
Appl. Chem. 2001, 73, 187. For MCR-based heterocyclic
libraries see: (d) Lie’by-Muller, F.; Simon, C.;
Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006, 25,
432. (e) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J.
Org. Chem. 2004, 4957. (f) Evdokimov, N. M.; Kireev,
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Kornienko, A. J. Org. Chem. 2007, 72, 3443. For drug
isobutyraldehyde
O
NH2
H2N
O
N
N
1
EtO
O
H
3
6
R
CN
CN
R
H
O
CN
CN
2
7
4
R
R
H
R
CN
H
N
CN
6
7
HN
N
HN
CN
N
N
O
NH
O
NH2
C
O
N
9
5
8
Scheme 2
Synlett 2009, No. 12, 2002–2004 © Thieme Stuttgart · New York

2004
A. S. Nagarajan, B. S. R. Reddy
LETTER
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(14) General Procedure for Pyranopyrazoles: To a stirred
mixture of hydrazine hydrate 1 (2 mmol) and ethyl
acetoacetate 3 (2 mmol), aldehyde 2 (2 mmol) and
malononitrile 4 (2 mmol) were added successively at r.t.
with vigorous stirring for 3–11 min. The precipitated solid
was filtered, and washed with a mixture of EtOAc–hexane
(20:80). The product obtained was pure as found in TLC and
1H NMR and 13C NMR spectroscopy. However, the products
were further purified by recrystallization from EtOAc.
Table 1, entry 4: yellow solid; mp 158–161 °C. 1H NMR
(500 MHz, DMSO-d6): d = 1.75 (s, 3 H), 2.16 (s, 3 H), 2.46
(s, 2 H), 4.53 (s, 1 H), 6.85 (s, 1 H), 7.01 (d, 1 H, J = 12.0
Hz), 7.03 (d, 1 H, J = 8.4 Hz), 12.09 (br s, 1 H). 13C NMR
(125 MHz, DMSO-d6): d = 10.3, 14.8, 39.8, 57.7, 98.1,
115.2, 121.3, 127.2, 130.9, 136.2, 140.9, 155.2, 159.0,
161.3. IR (KBr): 3484.5, 3239.7, 2195.3, 1638.0, 1597.6,
1493.4, 1399.4, 1116.5, 1057.3, 822.1, 749.0, 549.6 cm–1.
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284.3. Anal. Calcd for C15H13FN4O: C, 63.37; H, 4.61; N,
19.71. Found: C, 6 3.29; H, 4.52; N, 19.63.
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(500 MHz, DMSO-d6): d = 1.76 (s, 3 H), 2.47 (s, 2 H), 4.58
(s, 1 H), 7.10 (d, 2 H, J = 10.0 Hz), 7.47 (d, 2 H, J = 10.0 Hz),
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(s, 3 H), 4.50 (s, 1 H), 6.83 (d, 2 H, J = 8.4 Hz), 7.04 (d, 2 H,
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d6): d = 10.3, 35.9, 55.5, 58.1, 98.4, 114.3, 121.4, 129.0,
136.1, 136.9, 155.3, 158.5, 161.2. IR (KBr): 3481.4, 3253.2,
2925.3, 2191.1, 1642.5, 1600.8, 1492.0, 1392.8, 1258.4,
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for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C,
63.71; H, 5.15; N, 19.94.
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Synlett 2009, No. 12, 2002–2004 © Thieme Stuttgart · New York

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