On the reaction of 3-cyanochromones with phenyl- and methylhydrazines: Structural revision and a simple synthesis of chromeno[4,3-c]pyrazol-4-ones

Article abstract of DOI:10.1002/jhet.370

(Chemical Equation Presented) Reactions of 3-cyanochromones with phenylhydrazine gave the corresponding 5-amino-4-salicyloyl-1-phenylpyrazoles, 2-aminochromone-3-carbaldehyde N-phenylhydrazones, and 1-phenylchromeno[4,3-c] pyrazol-4(1H)-one, depending on

Full text of DOI:10.1002/jhet.370

May 2010
On the Reaction of 3-Cyanochromones with Phenyl- and
Methylhydrazines: Structural Revision and a Simple Synthesis of
Chromeno[4,3-c]pyrazol-4-Ones
629
Vyacheslav Ya. Sosnovskikh,a* Vladimir S. Moshkin,a and Mikhail I. Kodessb
aDepartment of Chemistry, Ural State University, 620083 Ekaterinburg, Russia
bInstitute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620041 Ekaterinburg, Russia
*E-mail: vyacheslav.sosnovskikh@usu.ru
Received October 1, 2009
DOI 10.1002/jhet.370
Published online 3 May 2010 in Wiley InterScience (www.interscience.wiley.com).
Reactions of 3-cyanochromones with phenylhydrazine gave the corresponding 5-amino-4-salicyloyl-1-
phenylpyrazoles, 2-aminochromone-3-carbaldehyde N-phenylhydrazones, and 1-phenylchromeno[4,3-
c]pyrazol-4(1H)-one, depending on the reaction conditions. With methylhydrazine, 3-(2-hydroxyaryl)-1-
methylpyrazole-4-carbonitriles and 2-methylchromeno[4,3-c]pyrazol-4(2H)-ones were obtained in
moderate to high yields.
J. Heterocyclic Chem., 47, 629 (2010).
INTRODUCTION
ether), they acquire the ability to undergo a nucleophilic
1,4-attack followed by additional transformations related
to c-pyrone ring opening and heterocyclizations at the
C-4 atom and/or at the cyano group. However, although
nucleophilic 1,4-addition occurs easily, which is clearly
demonstrated by the transformation of 3-cyanochro-
mones 1 into 2-amino-3-formylchromones under basic
conditions [3,7], the reactions of 1 with dinucleophiles
were further interpreted from both the viewpoint of 1,4-
addition at the C-2 atom (this direction is equivalent to
the 1,2-attack at the CHO group of 2-amino-3-formyl-
chromone) and 1,2-addition to the cyano group, which
inevitably led to contradictory results [6,8,9].
The chemistry of 3-cyanochromones has been
developed since the mid-1970s after the simple and con-
venient Vilsmeier-Haack method was proposed for the
synthesis of 3-formylchromones from 2-hydroxyaceto-
phenones, DMF, and POCl3 [1]. Treatment of 3-formyl-
chromones with hydroxylamine via 3-formylchromone-
3-oximes leads to 3-cyanochromones 1 [2,3]. In addi-
tion, 1 can be synthesized directly from 2-hydroxyaceto-
phenones and hydroxylamine under the Vilsmeier-Haack
conditions [4] and from O-methylated chromone-3-
oximes [5].
The introduction of the electron-withdrawing CN
group at the 3-position of the chromone system changes
crucially the reactivity of the pyrone ring with respect
to nucleophiles, and provides a broad synthetic potential
of 3-cyanochromones 1 [6]. The diversity of properties
of these compounds is due to the fact that, being highly
reactive geminally activated push–pull alkenes (a,b-un-
saturated ketones and nitriles simultaneously) with a
good leaving group at the b-carbon atom, whose role is
played by the phenolate anion (a fragment of the enol
RESULTS AND DISCUSSION
Recently [10], we reported on the ring transformations
of the chromones 1 to 2-aminochromone-3-carboxamide,
3-amino-4H-chromeno[3,4-d]isoxazol-4-one, and 3-(dia-
minomethylene)chroman-2,4-dione under the action of
hydroxylamine in alkaline medium, some of which were
previously incorrectly formulated [6]. Now we were
C
V
2010 HeteroCorporation

630
V. Y. Sosnovskikh, V. S. Moshkin, and M. I. Kodess
Vol 47
Scheme 1
1
interested in the course of the reactions of 3-cyanochro-
mones 1 with phenyl- and methylhydrazines. The reac-
tion with phenylhydrazine has already been the subject
of investigations and to the intermediate was assigned
the structure 5 without NMR spectral data [9]. The
authors believed that the reaction occurred via 1,2-addi-
tion of phenylhydrazine to the cyano group of 1a–c to
give amidohydrazones 5a–c, which on prolonged reflux-
ing in ethanol afforded 3-aminopyrazoles 6a–c [6,9]. On
the other hand, it was claimed that refluxing benzene
induces the initial 1,4-addition of phenylhydrazine pro-
ducing ultimately the phenylhydrazone derivatives 7 [8].
It should be noted that the pyrazole structure 6 was not
established with certainly and in the light of our previ-
ous results [10] it seemed more logical to us that the
more nucleophilic nitrogen atom of the phenylhydrazine
would attack at the 2-position of the chromone rather
than at the CN group.
On the basis of H and 13H NMR spectroscopy and
using 2D HSQC, HMBC, and NOESY experiments we
found that the reaction products of 1a,b and phenylhy-
drazine were, in fact, 5-amino-1-phenyl-4-salicyloylpyr-
azoles 8a,b (Scheme 1). The structural assignment for
these compounds as the 5-aminopyrazoles was based on
the presence of a NOESY cross-peak from the ortho
protons of the phenyl (d 7.55–7.60 ppm, H-200, H-600)
onto the NH2 group and the absence of cross-peak
between pyrazole H-3 proton and ipso-C of N–Ph in the
HMBC spectrum (for 8a). In addition, all the signals in
the 1H and 13C NMR spectra of compound 8a were
assigned on the basis of 2D H–13C HSQC and HMBC
1
experiments. Besides the signals expected for the aro-
1
matic protons, the H NMR spectra of 8a,b in DMSO-
d6 showed three singlets due to the NH2 group (d 7.1
ppm), pyrazole H-3 proton (d 7.7 ppm) and phenolic
hydroxyl (d 10.5–10.8 ppm). It is concluded that the se-
ries of the reported products such as 5, was not in fact
obtained. Moreover, based on the similarities between
We studied repeatedly the reactions of chromones 1
with phenylhydrazine under the conditions described in
refs. 8 and 9 and confirmed the structure of compounds
7a–c, which can easily be prepared in refluxing benzene
in the presence of Et3N for 0.5 h (for 1c this reaction
occurs both in benzene and ethanol without Et3N,
whereas for 1b the reaction in benzene without Et3N
gives a complex mixture of isomeric open-chain inter-
mediates and 7b). However, we were unable to repro-
duce the claimed synthesis of 6a–c; instead, 5-amino-
pyrazoles 8a,b as mixtures with 7a,b were obtained in
refluxing ethanol (8a:7a ¼ 82:18 and 8b:7b ¼ 76:26).
When these mixtures were treated with 20% sulfuric
acid in ethanol [9], 5-aminopyrazoles 8a,b were isolated
as pure compounds in 44–49% yields. Refluxing an
ethanolic solution of 1c with phenylhydrazine afforded
only the hydrazone 7c with no traces of 8c.
1
the H NMR spectral data of 8 with those reported for 6
in CDCl3 [9], it is clearly evident that the structure 6
should be revised to 8.
We also found that chromone 1a, when treated with
phenylhydrazine in refluxing AcOH, underwent transfor-
mation into 1-phenylchromeno[4,3-c]pyrazol-4(1H)-one
9 (55% yield). This observation is in line with other
report on the condensation of 3-cyano-2-methylchro-
mone with arylhydrazines, which leads to 1-aryl-3-meth-
ylchromeno[4,3-c]pyrazol-4(1H)-ones [11], and not to
the claimed earlier 4-methyl-2-phenylchromeno[4,3-
c]pyrazol-3(2H)-one [12]. Previously, compound 9 was
obtained by the reactions of phenylhydrazine with chro-
mone-3-carboxylic acid [13], 4-chloro-3-coumarincarbal-
dehyde [14], and 4-azido-3-coumarincarbaldehydes [15].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
On the Reaction of 3-Cyanochromones with Phenyl- and Methylhydrazines:
Structural Revision and a Simple Synthesis of Chromeno[4,3-c]pyrazol-4-ones
631
Scheme 2
Products 7–9 can result from the initial nucleophilic
1,4-addition of phenylhydrazine to the C-2 atom of 1 to
give, as a mixture of isomers, the open chain intermedi-
ate A, further transformation of which is controlled by
the nucleophilicity of the OH and NH groups and
depends on the reaction conditions. Two different reac-
tion paths for A may be envisaged. In refluxing ethanol,
intramolecular addition of the NHPh function to the CN
group with subsequent hydrogen shift leads to 5-amino-
pyrazole 8 as a major product. The alternative cycliza-
tion of A involving the phenolic hydroxyl and the cyano
group to form hydrazone 7 occurs in refluxing benzene
in the presence of Et3N. When 1 was allowed to react
with phenylhydrazine in refluxing acetic acid, the ini-
tially formed hydrazone 7 could not be isolated and
underwent intramolecular cyclization at the keto group
to give chromeno[4,3-c]pyrazol-4(1H)-one 9. Thus, the
initial Michael addition of phenylhydrazine to 1 leads to
three different types of products and the 1,2-addition at
the CN group was not observed at all (Scheme 1). This
clearly indicates that the C-2 atom of 3-cyanochromone
is more susceptible to nucleophilic attack than the CN
group. Note that in its reaction with sodium azide, it
behaves as a simple arylnitrile to form 3-(1H-tetrazol-5-
yl)chromone [2a,16].
It is of interest that chromones 1 react in different
manner with methylhydrazine to provide a completely
different regiochemistry pattern. When an equimolar
mixture of 1a–c and methylhydrazine was refluxed in
benzene for 0.5 h, 3-arylpyrazoles 10a–c were obtained
in 40–46% yields (Scheme 2). This reaction exhibits
high regioselectivity and pyrazole 10c was isolated as
the single product. However, in the case of 10a,b, some
amount of 5-arylpyrazoles 11a,b was observed (7 and
25%, respectively). The determination of the isomers ra-
from 1a–c and methylhydrazine under the same reaction
conditions, however, better yields were achieved if the
transformation was performed in a two-step approach.
The regioisomeric compounds 13 were not detected,
except for the reactions of 1b, in which case the 1H
NMR spectra of the products showed the presence of
13b (25–28%) along with compound 12b as the major
product (Scheme 2).
1
tio can easily be performed by H NMR spectroscopic
1
analysis. The H NMR spectra of compounds 10a–c in
DMSO-d6 consisted of a characteristic singlet due to the
phenolic hydroxyl in the region of d 9.8–10.4 ppm and
two singlets due to the resonances of the pyrazole pro-
ton and the MeN group at d 8.56–8.58 and 3.94 ppm.
The IR spectra are also of diagnostic value in this 4-cya-
nopyrazole series (mCN ¼ 2230 cmꢀ1).
Spectral data and melting point of 12a were consist-
ent with previous reported [17], this confirms the regio-
chemistry of the reaction with methylhydrazine. Interest-
ingly, although the chemistry of the tricyclic chro-
meno[4,3-c]pyrazol-4-one system has been well docu-
mented [11–15], we have found that compound 12a has
been obtained only very recently from chromeno[4,3-
b][1,5]benzodiazepin-7(8H)-one and methylhydrazine
[17], while derivatives 12b,c are hitherto unreported. In
conjunction with the pharmaceutical importance known
for the fused heterocycles incorporating a coumarin moi-
ety [18], this simple synthesis of chromeno[4,3-c]pyra-
zol-4-ones from readily available 3-cyanochromones is
noteworthy and will complement the published synthetic
methods.
The formation of these pyrazoles may be rationalized
by initial 1,4-addition of the more nucleophilic second-
ary nitrogen atom of methylhydrazine on the C-2 atom
of 1 with concomitant opening of the pyrone ring to
give intermediate B. Further, the intramolecular hetero-
cyclization occurs between the NH2 group and the car-
bonyl, which seems more reactive than the cyano group.
Compounds 10a–c, so obtained, were then allowed to
react under more vigorous conditions (boiling acetic
acid for 5 h). This afforded coumarins 12a–c in high
yields (70–92%), which were also obtained directly
In conclusion, 3-cyanochromone represents a very re-
active system and its reactions with phenyl- and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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V. Y. Sosnovskikh, V. S. Moshkin, and M. I. Kodess
Vol 47
7.51 (d, 1H, H-8, J ¼ 8.8 Hz), 7.71 (dd, 1H, H-7, J ¼ 8.8, 2.7
Hz), 7.94 (d, 1H, H-5, J ¼ 2.7 Hz), 8.42 (s, 1H, HC¼¼N), 9.07
(br s, 2H, NH2), 10.14 (s, 1H, NH). Anal. Calcd for
C16H12ClN3O2: C, 61.25; H, 3.86; N, 13.39. Found: C, 60.91;
H, 3.88; N, 13.01.
methylhydrazines give a variety of products. As the
identity of some of these products was in doubt, we
have reinvestigated the reaction with phenylhydrazine
and found that by varying the conditions, 5-amino-4-sal-
isyloyl-1-phenylpyrazoles, 2-aminochromone-3-carbalde-
hyde N-phenylhydrazones, and 1-phenylchromeno[4,3-
c]pyrazol-4(1H)-one could be prepared in moderate to
good yields. With methylhydrazine, 3-(2-hydroxyaryl)-1-
methylpyrazole-4-carbonitriles and 2-methylchromeno
[4,3-c]pyrazol-4(2H)-ones were obtained. A simple and
convenient synthesis of chromeno[4,3-c]pyrazol-4-ones
was developed and the generality of this method is
being investigated further.
5-Amino-4-salicyloyl-1-phenylpyrazole (8a). This compound
was prepared from chromone 1a and phenylhydrazine accord-
ing to the procedure described previously for 6a [9]. Yield
44%, mp 143–144ꢁC (lit. [9] mp 144ꢁC); 1H NMR (DMSO-
d6): d 6.94 (ddd, 1H, H-50, J ¼ 7.7, 7.3, 0.9 Hz), 6.97 (dd, 1H,
H-30, J ¼ 8.4, 0.9 Hz), 7.15 (s, 2H, NH2), 7.40 (ddd, 1H, H-40,
J ¼ 8.4, 7.3, 1.6 Hz), 7.45 (m, 1H, H-400), 7.55–7.61 (m, 5H,
H-60, H-200, H-300, H-500, H-600), 7.74 (s, 1H, H-3), 10.79 (s, 1H,
1
OH); H NMR (CDCl3): d 6.08 (s, 2H, NH2), 6.97 (td, 1H, H-
50, J ¼ 7.5, 1.0 Hz), 7.04 (dd, 1H, H-30, J ¼ 8.4, 0.9 Hz),
7.43–7.49 (m, 2H, H-40, H-400), 7.55–7.58 (m, 4H, H-200, H-300,
H-500, H-600), 7.90 (dd, 1H, H-60, J ¼ 7.9, 1.6 Hz), 7.97 (s, 1H,
H-3), 11.84 (s, 1H, OH); 13C NMR (DMSO-d6): d 104.35
(C4), 116.94 (C30), 119.02 (C50), 123.75 (C200, C600), 124.81
(C10), 127.72 (C400), 129.44 (C60), 129.53 (C300, C500), 132.61
(C40), 137.39 (C100), 141.89 (C3), 150.65 (C5), 157.04 (C20),
189.03 (C¼¼O); MS (EI): m/z (%) 279 [M]þ (45), 159
[Mþ1AHOC6H4CO]þ (100), 158 [MAHOC6H4CO]þ (29),
121 [HOC6H4CO]þ (27), 93 [HOC6H4]þ (15), 77 [Ph]þ (34),
69 (30). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N,
15.05. Found: C, 68.51; H, 4.86; N, 15.01.
EXPERIMENTAL
1H (400 MHz) and 13C (100 MHz) NMR spectra were
recorded on a Bruker DRX-400 spectrometer in DMSO-d6
with TMS as the internal standard. IR spectra were recorded
on Perkin–Elmer Spectrum BX-II instrument (KBr) and Bruker
Alpha instrument (ATR, ZnSe). Elemental analyses were per-
formed at the Microanalysis Services of the Institute of Or-
ganic Synthesis, Ural Branch, Russian Academy of Sciences.
Melting points are uncorrected. All solvents used were dried
and distilled per standard procedures. The starting 3-cyano-
chromones 1a–c were prepared according to described proce-
dures [16].
General procedure for the preparation of 2-aminochro-
mone-3-carbaldehyde N-phenylhydrazones (7a–c). A solu-
tion of chromone 1 (1.2 mmol), phenylhydrazine (130 mg, 1.2
mmol) and two drops of Et3N in benzene (5 mL) was refluxed
for 0.5 h and the reaction mixture cooled. The deposited phe-
nylhydrazone 7 was filtetred and washed with benzene. For 1c
this reaction occurs both in benzene and ethanol without Et3N.
5-Amino-4-(2-hydroxy-5-methylbenzoyl)-1-phenylpyrazole
(8b). This compound was prepared from chromone 1b and
phenylhydrazine according to the procedure described previ-
ously for 6b [9]. Yield 49%, mp 148–149ꢁC ꢀ(1lit. [9] mp
151ꢁC); IR (ATR, ZnSe): 1597, 1573, 1531 cm
;
1H NMR
(DMSO-d6): d 2.28 (s, 3H, Me), 6.86 (d, 1H, H-30, J ¼ 8.2
Hz), 7.11 (s, 2H, NH2), 7.20 (dd, 1H, H-40, J ¼ 8.2, 2.0 Hz),
7.36 (d, 1H, H-60, J ¼ 2.0 Hz), 7.43–7.47 (m, 1H, H-400),
7.55–7.60 (m, 4H, H-200, H-300, H-500, H-600), 7.75 (s, 1H, H-3),
10.53 (s, 1H, OH). Anal. Calcd for C17H15N3O2: C, 69.61; H,
5.15; N, 14.33. Found: C, 69.74; H, 5.36; N, 14.26.
2-Aminochromone-3-carbaldehyde
(7a).Yield 46%, mp 274–275ꢁC (lit. [8a] mp 270ꢁC); IR
(KBr): 3317, 3256, 3109, 1646, 1600, 1532 cmꢀ1 1H NMR
N-phenylhydrazone
1-Phenylchromeno[4,3-c]pyrazol-4(1H)-one (9). A solution
of chromone 1a (250 mg, 1.46 mmol) and phenylhydrazine
(160 mg, 1.48 mmol) in 5 mL of glacial acetic acid was
heated at reflux for 4 h. The resulting reaction mixture was
then diluted with water (15 mL) and the solid that formed was
filtered, washed with water, dried, and recrystallized from ace-
tonitrile to give 9 as colorless needles in 55% yield (210 mg),
mp 192–193ꢁC (lit. [13] mp 191ꢁC, lit. [14] mp 183–185ꢁC,
lit. [15] mp 209–210ꢁC). 1H NMR (DMSO-d6): d 7.07 (dd,
1H, H-9, J ¼ 8.0, 1.8 Hz), 7.11 (ddd, 1H, H-8, J ¼ 8.0, 6.8,
1.0 Hz), 7.47 (dd, 1H, H-6, J ¼ 8.4, 1.0 Hz), 7.54 (ddd, 1H,
H-7, J ¼ 8.4, 6.8, 1.8 Hz), 7.59–7.62 (m, 2H, Ph), 7.68–7.71
(m, 3H, Ph), 8.35 (s, 1H, H-3).
General procedure for the preparation of 3-(2-hydrox-
yaryl)-1-methylpyrazole-4-carbonitriles (10a–c). A solution
of chromone 1 (1.0 mmol) and methylhydrazine (55 mg, 1.2
mmol) in 4 mL of benzene was refluxed for 0.5 h. The result-
ing reaction mixture was then diluted with hexane (5 mL) and
the solid that formed was filtered and washed with benzene/
hexane mixture (1:1) to give 10 as yellow crystals.
;
(DMSO-d6): d 6.71 (tt, 1H, H-40, J ¼ 7.3, 1.0 Hz), 6.85–6.89
(m, 2H, H-20, H-60), 7.19–7.24 (m, 2H, H-30, H-50), 7.41 (ddd,
1H, H-6, J ¼ 7.8, 7.2, 1.0 Hz), 7.45 (dd, 1H, H-8, J ¼ 8.4, 1.0
Hz), 7.68 (ddd, 1H, H-7, J ¼ 8.4, 7.2, 1.7 Hz), 8.02 (dd, 1H,
H-5, J ¼ 7.8, 1.7 Hz), 8.45 (s, 1H, HC¼¼N), 8.98 (br s, 2H,
NH2), 10.10 (s, 1H, NH). Anal. Calcd for C16H13N3O2: C,
68.81; H, 4.69; N, 15.05. Found: C, 68.83; H, 4.72; N, 15.06.
2-Amino-6-methylchromone-3-carbaldehyde N-phenylhy-
drazone (7b). Yield 79%, mp 298–300ꢁC (lit. [8a] mp 275ꢁC);
IR (ATR, ZnSe): 3243, 1640, 1604, 1594, 1549, 1520 cmꢀ1
;
1H NMR (DMSO-d6): d 2.40 (s, 3H, Me), 6.71 (tt, 1H, H-40, J
¼ 7.4. 1.0 Hz), 6.85–6.89 (m, 2H, H-20, H-60), 7.19–7.23 (m,
2H, H-30, H-50), 7.34 (d, 1H, H-8, J ¼ 8.4 Hz), 7.48 (ddq, 1H,
H-7, J ¼ 8.4, 2.3, 0.6 Hz), 7.82 (br d, 1H, H-5, J ¼ 2.0 Hz),
8.45 (s, 1H, HC¼¼N), 8.93 (br s, 2H, NH2), 10.07 (s, 1H, NH).
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33.
Found: C, 69.53; H, 5.06; N, 14.41.
2-Amino-6-chlorochromone-3-carbaldehyde
N-phenylhy-
drazone (7c). Yield 71%, mp 308–310ꢁC (lit. [8a] mp 290ꢁC);
IR (ATR, ZnSe): 3375, 3245, 1610, 1600, 1579, 1529 cmꢀ1
;
3-(2-Hydroxyphenyl)-1-methylpyrazole-4-carbonitrile (10a). Yield
40%, mp 155–156ꢁC; IR (KBr): 3130, 2229, 1621, 1586,
;
1542, 1506, 1462 cmꢀ1 1H NMR (DMSO-d6): (10a, 93%) d
1H NMR (DMSO-d6): d 6.72 (tt, 1H, H-40, J ¼ 7.4, 1.2 Hz),
6.86–6.89 (m, 2H, H-20, H-60), 7.19–7.24 (m, 2H, H-30, H-50),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
On the Reaction of 3-Cyanochromones with Phenyl- and Methylhydrazines:
Structural Revision and a Simple Synthesis of Chromeno[4,3-c]pyrazol-4-ones
633
3.94 (s, 3H, MeN), 6.91 (td, 1H, H-50, J ¼ 7.5, 1.1 Hz), 6.97
(dd, 1H, H-30, J ¼ 8.2, 1.1 Hz), 7.29 (ddd, 1H, H-40, J ¼ 8.2,
7.3, 1.7 Hz), 7.50 (dd, 1H, H-60, J ¼ 7.7, 1.7 Hz), 8.57 (s, 1H,
H-5), 10.05 (s, 1H, OH); 5-(2-hydroxyphenyl)-1-methylpyra-
zole-4-carbonitrile (11a, 7%) d 3.72 (s, 3H, Me), 6.98 (td, 1H,
H-50, J ¼ 7.5, 1.0 Hz), 7.06 (dd, 1H, H-30, J ¼ 8.2, 1.0 Hz),
7.30 (dd, 1H, H-60, J ¼ 7.7, 1.7 Hz), 7.41 (ddd, 1H, H-40, J ¼
8.2, 7.3, 1.7 Hz), 8.09 (s, 1H, H-3), 10.05 (br s, 1H, OH); MS
(EI): m/z (%) 199 [M]þ (100), 171 (20), 156 (22), 42 (27).
Anal. Calcd for C11H9N3O: C, 66.32; H, 4.55; N, 21.09.
Found: C, 65.96; H, 4.58; N, 20.74.
C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 66.96; H,
4.81; N, 13.06.
8-Chloro-2-methylchromeno[4,3-c]pyrazol-4(2H)-one (12c). Yield
92%, mp 228–230ꢁC; IR (ATR, ZnSe): 1747, 1736, 1589,
1554, 1511 cmꢀ1 1H NMR (DMSO-d6): d 4.10 (s, 3H, Me),
;
7.38 (d, 1H, H-6, J ¼ 8.8 Hz), 7.47 (dd, 1H, H-7, J ¼ 8.8, 2.5
Hz), 7.91 (d, 1H, H-9, J ¼ 2.5 Hz), 8.74 (s, 1H, H-3). Anal.
Calcd for C11H7ClN2O2: C, 56.31; H, 3.01; N, 11.04. Found:
C, 55.96; H, 2.88; N, 11.42.
Acknowledgment. This work was financially supported by the
RFBR (Grant 06-03-32388).
3-(2-Hydroxy-5-methylphenyl)-1-methylpyrazole-4-carboni-
trile (10b). Yield 42%, mp 150–151ꢁC; IR (KBr): 3176, 3120,
1
2230, 1621, 1591, 1543, 1503, 1467 cmꢀ1; H NMR (DMSO-
REFERENCES AND NOTES
d6): (10b, 75%) d 2.24 (s, 3H, Me), 3.94 (s, 3H, MeN), 6.86
(d, 1H, H-30, J ¼ 8.3 Hz), 7.08 (dd, 1H, H-40, J ¼ 8.3, 2.0
Hz), 7.30 (d, 1H, H-60, J ¼ 2.0 Hz), 8.56 (s, 1H, H-5), 9.79
(br s, 1H, OH); 5-(2-hydroxy-5-methylphenyl)-1-methylpyra-
zole-4-carbonitrile (11b, 25%) d 2.26 (s, 3H, Me), 3.70 (s, 3H,
MeN), 6.95 (d, 1H, H-30, J ¼ 8.3 Hz), 7.10 (d, 1H, H-60, J ¼
2.0 Hz), 7.21 (dd, 1H, H-40, J ¼ 8.3, 2.0 Hz), 8.08 (s, 1H, H-
3), 10.07 (br s, 1H, OH). Anal. Calcd for C12H11N3O: C,
67.59; H, 5.20; N, 19.71. Found: C, 67.18; H, 5.15; N, 19.42.
3-(5-Chloro-2-hydroxyphenyl)-1-methylpyrazole-4-carboni-
trile (10c). Yield 46%, mp 213–214ꢁC; IR (KBr): 3122, 2231,
[1] (a) Harnisch, H. Justus Liebigs Ann Chem 1972, 765, 8;
(b) Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron Lett 1973, 1995;
(c) Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron 1974, 30, 3553.
[2] (a) Nohara, A. Tetrahedron Lett 1974, 1187; (b) Klutchko,
S.; Cohen, M. P.; Shavel, J.; von Strandtmann, M. J Heterocycl Chem
1974, 11, 183.
[3] (a) Petersen, U.; Heitzer, H. Justus Liebigs Ann Chem
1976, 1659; (b) Hagen, H.; Nilz, G.; Walter, H.; Landes, A.; Freund,
W. D.E. Pat. 4,039,281, (1992); Chem Abstr 1992, 117, 111473.
[4] Reddy, G. J.; Latha, D.; Thirupathaiah, C.; Rao, K. S. Tet-
rahedron Lett 2004, 45, 847.
1
1621, 1580, 1541, 1498, 1461 cmꢀ1; H NMR (DMSO-d6): d
[5] Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Zehnder, L. R.;
Park, F.; Kim, M.; Tran, T.-T. T. J Org Chem 1999, 64, 8736.
[6] Ghosh, C. K.; Karak, S. K. J Heterocycl Chem 2005, 42, 1035.
[7] Nohara, A.; Ishiguro, T.; Ukawa, K.; Sugihara, H.; Maki,
Y.; Sanno, Y. J Med Chem 1985, 28, 559.
3.94 (s, 3H, MeN), 6.98 (d, 1H, H-30, J ¼ 8.7 Hz), 7.33 (dd,
1H, H-40, J ¼ 8.7, 2.7 Hz), 7.43 (d, 1H, H-60, J ¼ 2.7 Hz),
8.58 (s, 1H, H-5), 10.37 (br s, 1H, OH). Anal. Calcd for
C11H8ClN3O: C, 56.54; H, 3.45; N, 17.98. Found: C, 56.54;
H, 3.64; N, 17.85.
General procedure for the preparation of 2-methylchro-
meno[4,3-c]pyrazol-4(2H)-ones (12a–c). A solution of pyraz-
ole 10 (1.0 mmol) in 3 mL of glacial acetic acid was refluxed
for 5 h. The resulting reaction mixture was then diluted with
water (10 mL) and the solid that formed was filtered, washed
with water, and dried to give 12 as colorless crystals.
[8] (a) Ghosh, C. K.; Tewari, N.; Bandyopadhyay, C. Indian J
Chem 1983, 22B, 1200; (b) Ghosh, C. K.; Ghosh, C.; Patra, A. Indian
J Chem 1998, 37B, 387.
[9] Ghosh, C. K.; SinhaRoy, D. K.; Mukhopadhyay, K. K.
J Chem Soc Perkin Trans 1 1979, 1964.
[10] Sosnovskikh, V. Ya.; Moshkin, V. S.; Kodess, M. I. Tetra-
hedron Lett 2008, 49, 6856.
[11] (a) Colotta, V.; Cecchi, L.; Melani, F.; Palazzino, G.; Filac-
chioni, G. Tetrahedron Lett 1987, 28, 5165.
2-Methylchromeno[4,3-c]pyrazol-4(2H)-one
(12a). Yield
1
92%, mp 209–210ꢁC (lit. [17] mp 210ꢁC); H NMR (DMSO-
d6): d 4.09 (d, 3H, Me, J ¼ 0.5 Hz), 7.38 (ddd, 1H, H-8, J ¼
7.7, 7.3, 1.2 Hz), 7.44 (ddd, 1H, H-6, J ¼ 8.4, 1.2, 0.4 Hz),
7.55 (ddd, 1H, H-7, J ¼ 8.4, 7.3, 1.7 Hz), 7.99 (ddd, 1H, H-9,
J ¼ 7.7, 1.7, 0.4 Hz), 8.79 (q, 1H, H-3, J ¼ 0.5 Hz). Anal.
Calcd for C11H8N2O2: C, 66.00; H, 4.03; N, 13.99. Found: C,
65.64; H, 4.08; N, 13.84.
[12] Ghosh, C. K.; Pal, C. Indian J Chem 1985, 24B, 1288.
[13] Chantegrel, B.; Nadi, A.-I.; Gelin, S. Tetrahedron Lett
1983, 24, 381.
[14] (a) Moorty, S. R.; Sundaramurthy, V.; Subba Rao, N. V. In-
dian J Chem 1973, 11, 854; (b) Strakova, I.; Petrova, M.; Belyakov,
S.; Strakovs, A. Chem Heterocycl Comp 2003, 39, 1608.
[15] Steinfu¨hrer, T.; Hantschmann, A.; Pietsch, M.; Weißenfels,
M. Justus Liebigs Ann Chem 1992, 23.
2,8-Dimethylchromeno[4,3-c]pyrazol-4(2H)-one (12b). Yield
70%, mp 158–160ꢁC; IR (ATR, ZnSe): 1743, 1591, 1557,
;
1524 cmꢀ1 1H NMR (DMSO-d6): (12b, 72%) d 2.43 (s, 3H,
[16] Nohara, A.; Kuriki, H.; Saijo, T.; Sugihara, H.; Kanno, M.;
Sanno, Y. J Med Chem 1977, 20, 141.
Me), 4.09 (s, 3H, NMe), 7.22 (d, 1H, H-6, J ¼ 8.5 Hz), 7.28
[17] Trimeche, B.; Gharbi, R.; Houla, S. E.; Martin, M.-T.;
Nuzillard, J. M.; Mighri, Z. J Chem Res 2004, 170.
(dd, 1H, H-7, J ¼ 8.5, 2.0 Hz), 7.76 (br s, 1H, H-9), 8.67 (s,
1H,
H-3);
1,8-dimethylchromeno[4,3-c]pyrazol-4(1H)-one
[18] (a) Darbarwar, M.; Sundaramurthy, V. Synthesis 1982, 337;
(b) Colotta, V.; Cecchi, L.; Filacchioni, G.; Melani, F.; Palazzino, G.;
Martini, C.; Giannaccini, G.; Lucacchini, A. J Med Chem 1988, 31, 1;
(c) Ibrahim, M. A.ARKIVOC 2008, xvii, 192.
(13b, 28%) d 2.49 (s, 3H, Me), 4.36 (s, 3H, NMe), 7.35 (d,
1H, H-6, J ¼ 8.5 Hz), 7.40 (dd, 1H, H-7, J ¼ 8.5, 2.0 Hz),
7.94 (br s, 1H, H-9), 8.07 (s, 1H, H-3). Anal. Calcd for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet