4-Bromo-3-methyl-1-phenylpyrazole in heterocyclic synthesis: Unexpected polysubstituted pyrazole derivatives

Article abstract of DOI:10.1002/jccs.200400119

Unexpected 4,4′-dipyrazolomethylidene (7), 4-amino-3a-bromo-3-methyl- 1-phenylpyrazolo[3,4-b]pyridin-6-thione (9), 4,4′-dipyrazolyl (18), ethyl 4-(3-methyl-1-phenylpyrazole-4-yl)fuoro[2,3-c]pyrazole-4-carboxylate (25), as well as the expected fuoro[2,3-c]pyrazole derivatives (15), (20) and (28) were isolated from a one-pot reaction of 4-bromo-3-methyl-1-phenylpyrazole (1) with some readily available reagents.

Full text of DOI:10.1002/jccs.200400119

Journal of the Chinese Chemical Society, 2004, 51, 785-790
785
4-Bromo-3-methyl-1-phenylpyrazole in Heterocyclic Synthesis:
Unexpected Polysubstituted Pyrazole Derivatives
Eman A. El-Rady* and Fawi M. Abd El Latif
Chemistry Department, Faculty of Science, South Valley University, Aswan, Egypt
Unexpected 4,4¢-dipyrazolomethylidene (7), 4-amino-3a-bromo-3-methyl-1-phenylpyrazolo[3,4-b]pyr-
idin-6-thione (9), 4,4¢-dipyrazolyl (18), ethyl 4-(3-methyl-1-phenylpyrazole-4-yl)fuoro[2,3-c]pyrazole-4-
carboxylate (25), as well as the expected fuoro[2,3-c]pyrazole derivatives (15), (20) and (28) were isolated
from a one-pot reaction of 4-bromo-3-methyl-1-phenylpyrazole (1) with some readily available reagents.
Keywords: 4-Bromopyrazole; Dipyrazolyly; Fuoro[2,3-c]pyrazole and dipyrazolomethylidene.
INTRODUCTION
The synthesis of pyrazole derivatives which may have
4,4¢-dipyrazolylmethylidene isomer.13 Two possible path-
ways may account for the formation of the unexpected com-
pound 7. Elimination of HBr yielded the intermediate 3,
which may split into thioformamide anion and 4-pyrazolyl
cation 4. Reaction with a second mole of 1 via elimination of
HBr yielded the intermediate 5, which loses HCN to give fi-
nally the methylidene compound 7. Or, it may have formed
via reaction of two molecules of 1 with one molecule of 2a
via elimination of two moles of hydrogen bromide to form the
intermediate 6, which may have undergone hydrolysis to
yield 7. However, the mass spectrum of the soluble product
revealed m/e at 337 (M+2, 100) showing an isotopic pattern
of bromine. Its ir spectrum showed an absorption band at v
3426 cm-1 due to amine function with lack of cyano absorp-
tion at 2220 cm-1. Formation of product 9 may have pro-
ceeded via elimination of water from the reactants forming
the intermediate 8, followed by cycloaddiation into the cyano
function to yield 9 rather than elimination of HBr to give 10.
Both of pyrrolo[2,3-c]pyrazole 11 and fuoro[2,3-c]pyrazole
13 were ruled out (Scheme II).
medicinal applications is of interest. Pyrazoles have been
used as antipyretic, analgesic drugs,1-3 bactericides, fungi-
cides,4 and as potential hypoglycemic agents.5 These consid-
erable biological and medicinal activities are responsible for
the interest in the synthesis of pyrazoles.6-12 In conjunction
with our previous interest in preparing pyrazole deriva-
tives13-16 which might have bioactive properties, we report
herein the results of the reaction of 4-bromo-3-methyl-1-
phenylpyrazole (1) with different readily available reagents.
RESULTS AND DISCUSSION
The reaction of 4-bromo-3-methyl-1-phenylpyrazol-
5-one 1 with cyanothioacetamide 2a was proceeded in
ethanolic piperidine at reflux for five hours. Colourless crys-
tals were formed during reflux, and the mother liquor con-
tained another soluble product. The mass spectrum of the in-
soluble product showed m/e at 358 (M+, 20), 357 (M-1, 48),
315 (100). The ir spectrum revealed the presence of absorp-
tion bands at v 1710 and 3480 cm-1 assigned for C=O and OH
groups, respectively, with lack of absorption band due to
cyano group. The 1H NMR spectrum (DMSO-d6) also showed
signals at 1.9, 2.1 and 7.1-7.8 ppm assigned for two methyl
and aromatic protons, respectively. It seems that the product
is 3,3¢-dimethyl-1,1¢-diphenyl-4,4¢-dipyrazolylmethylidene
7 (Scheme I). Previously, we reported 1,1¢,3,3¢-tetraphenyl-
Contrarily, compound 1 reacted with cyanoacetamide
2b under the same reaction conditions to form fuoro[2,3-
c]pyrazole 15 rather than pyrrolo[2,3-c]pyrazole 16 con-
firmed from spectroscopic data (Scheme II). The mass spec-
trum of 15 showed m/e at 256 (25). The ir spectrum of 15 re-
vealed the absence of a band corresponding to CN group and
showed bands at 1680 and 3345-3425 cm-1 due to C=O and
NH2 groups, respectively. The obtained product is assumed to
be formed via elimination of HBr to give the intermediate 14
followed by cycloaddition into cyano function rather than
Dedicated to Professor Dr. Dietrich Döpp on the occasion of his 65th birthday.
* Corresponding author. E-mail: emanelradi@hotmail.com

786 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
El-Rady and Abd El Latif
Scheme I
Me
Br
CN
EtOH/ pip./
reflux
+
N
O
7
S
on heat
N
H2N
Ph
2a
1
NH
2
CN
S
Me
N
Me
Hydrolysis
N
O
HO
N
N
Ph
Ph
6
Me
Br
Me
Me
1
HBr
N
N
N
O
O
N
N
HO
N
CN
Ph
Ph
Ph
7
CN
1
Me
NH2
S
H2N
2a
HBr
HCN
S
N
OH
N
Me
CN
Br
Ph
Me
Me
N
3
OH
N
N
N
O
HO
N
N
Ph
Ph
Ph
5
CN
+
Me
H N
2
H
HBr
-
+
N
O
S
N
+ 1
Ph
4
elimination of water leading to 16 (Scheme III).
ture yielded the expected fuoro[2,3-c]pyrazole 20. The MS of
1
On the other hand, the reaction of 1 with malononitrile
17 in ethanolic piperidine at reflux gave a colourless com-
pound on heat. The mass spectrum of the product showed m/e
at 346 (80), and the ir spectrum revealed a lack of absorption
band due to cyano function. The spectral data were in accord
with formation of unexpected 4,4¢-dipyrazolyl compound 18
which may form via free radical combination of pyrazolyl
radical (Scheme III). However, the reaction at room tempera-
20 showed m/e at 238 (M-2, 40). The H NMR spectrum
(DMSO-d6) revealed signals at 1.9, 3.5, 7.2-7.9 and 8.1 ppm
assigned for methyl, 4H-furan, aryl and imino protons, re-
spectively (Scheme III).
Also, it has been found that compound 1 reacting with
cyano acid hydrazid 21 and acetylacetone 22 under the same
reaction conditions afforded each of the unexpected products
7 and 18. However, ethyl cyanoacetate 23 reacted with 1 to

Synthesis of Unexpected Polysubstituted Pyrazole Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 787
Scheme II
yield a mixture of three products separated by fractional crys-
tallization. A minor amount was proved to be identical with 7
(IR, MS, 1H NMR, m.p, m.x). The 1H NMR spectrum of the
major product showed a pattern assigned to protons of ester
group at 1.1 (3H) and 3.9 ppm (2H), respectively. The mass
spectrum showed m/e at 457 (M+, 46), 429 (M-C2H4, 10), 384
(429-CO2, 9), 357 (10), 295 (16); and the ir spectrum showed
absorption bands at 3359, 3258, 1689 and 1641 cm-1 assigned
for OH, NH, C=O and C=C, respectively, showing the ab-
sence of absorption band at 2200-2220 cm-1 corresponding to
CN group. The product yielded was ethyl 4-(3-methyl-1-
phenylpyrazole-4-yl)fuoro[2,3-c]pyrazole-4-carboxylate 25
which may be formed via the intermediate 24. Probability of
formation of the spiro compound 26 was not observed.
Fuoro[2,3-c]pyrazole 28 was isolated in 10% yield, and its
structure is based on spectral and elemental analysis (Scheme
IV).
EXPERIMENTAL
Melting points are uncorrected. The IR spectra (potas-

788 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
El-Rady and Abd El Latif
Scheme III
sium bromide, n in cm-1) were recorded on a Pye-Unicam
9.
1
SP-1100 Spectrophotometer. H NMR spectra (DMSO, d =
ppm) were run on a Varian EM-390 Spectrometer using TMS
as internal standard. Mass spectra were recorded on a Varian
MAT 311 A spectrometer at 70 eV, and the elemental analy-
sis were determined at the Microanalytical Center, Cairo
University, Egypt.
3,3¢-Dimethyl-1,1¢-diphenyl-4,4¢-dipyrazolylmethylidene 7
This compound was isolated as colourless crystals, mp.
320-322 °C; IR: 1710 (CO), 3480 (OH); 1H nmr (DMSO-d6):
d 1.9 (s, 3H, CH3), 2.1 (s, 3H, CH3), 7.1-7.8 (m, 12H, aryl-H +
OH); MS, m/e (%): 358 (M+, 20). Anal. Calcd. for
C21H18N4O2 (358.40): C, 70.38; H, 5.06; N, 15.63. Found: C,
70.20; H, 5.16; N, 15.51.
Reaction of 4-bromo-3-methyl-1-phenylpyrazole (1) with
cyanothioacetamide 2a
A solution of 1 (1 mol), cyanothioacetamide 2a (1 mol),
and 0.1 mL of piperidine in 30 mL of dry ethanol was warmed
to reflux for five hours; the colourless product collected by
filtration and washed well with methanol was identified as 7.
The residue solution was concentrated under vacuum; the
solid formed after addition of 20 mL of cold water and 1 mL
of diluted HCl was collected by filtration, washed well with
100 mL of cold water and crystallised from methanol to give
4-Amino-3a-bromo-3-methyl-1-phenylpyrazolo[3,4-b]pyr-
idin-6-thione 9
This compound was isolated as yellow powder, mp.
1
187-189 °C; IR: 3426 (NH2); H nmr (DMSO-d6): d 1.9 (s,
3H, CH3), 7.3-7.9 (m, 6H, aryl-H), 8.2 (s, 2H, NH2); MS, m/e
(%): 337 (M+2, 100). Anal. Calcd. for C13H11N4SBr (335.22):
C, 46.58; H, 3.31; N, 16.71. Found: C, 46.48; H, 3.39; N,
16.65.

Synthesis of Unexpected Polysubstituted Pyrazole Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 789
Scheme IV
Reaction of 4-bromo-3-methyl-1-phenylpyrazole (1) with
cyanoacetamide 2b
5-Amino-4-carboxamido-3-methyl-1-phenylfuoro[2,3-c]-
pyrazole 15
To ethanol solution (30 mL ) of 1 (1 mol) an equimolar
amount of cyanoacetamide 2b (1 mol) was added. The mix-
ture was refluxed in the presence of 0.1 mL of piperidine for
six hours. A colourless product which formed during reflux
was collected by filtration and washed well with methanol to
give 15.
This compound was isolated as colourless crystals, mp.
170-172 °C; IR: 1680 (CO), 3345-3425 (NH2). 1H nmr
(DMSO-d6): d 1.8 (s, 3H, CH3), 5.6 (s, 2H, NH2), 7.3-7.9 (m,
5H, aryl-H), 8.6 (s, 2H, NH2); MS, m/e (%): 256 (M-2, 25).
Anal. Calcd. for C13H12N4O2 (256.27): C, 60.93; H, 5.72; N,
21.86. Found: C, 60.87; H, 5.65; N, 21.69.

790 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
El-Rady and Abd El Latif
Reaction of 4-bromo-3-methyl-1-phenylpyrazole (1) with
malononitrile 17
aryl-H + OH), 8.4 (s, 1H, NH); MS, m/e (%): 457 (M+, 46).
Anal. Calcd. for C25H23N5O4 (457.49): C, 65.67; H, 5.07; N,
15.31. Found: C, 65.52; H, 5.14; N, 15.20.
A solution of 1 (1 mol), malononitrile 17 (1 mol), and
0.1 mL of piperidine in 30 mL of dry ethanol was refluxed for
four hours. The solution was concentrated under vacuum and
the residue was triturated with methanol. The resulting
colourless product was collected by filtration and washed
well with methanol to give 18. The same reaction at room
temperature yielded a colourless product which was identi-
fied as 20.
4-Cyano-3-methyl-5-oxo-1-phenylfuoro[2,3-c]pyrazole 28
This compound was isolated as buff powder, mp. 180-
182 °C; IR: 1690 (CO), 2220 (CN); 1H nmr (DMSO-d6): d 1.7
(s, 1H, furyl-H), 3.2 (s, 3H, CH3), 7.2-8.0 (m, 5H, aryl-H);
MS, m/e (%): 239 (M+, 30). Anal. Calcd. for C13H9N3O2
(239.23): C, 65.27; H, 3.79; N, 17.57. Found: C, 65.42; H,
4.00; N, 17.39.
3,3¢-Dimethyl-1,1¢-diphenyl-4,4¢-dipyrazoylyl 18
This compound was isolated as colourless crystals, mp.
210-212 °C; IR: 1690 (CO), 3345 (OH); 1H nmr (DMSO-d6):
d 1.8 (s, 3H, CH3), 2.1 (s, 3H, CH3), 7.0-7.9 (m, 12H, aryl-H +
OH); MS, m/e (%): 346 (M+, 80). Anal. Calcd. for C20H18N4O2
(346.39): C, 69.35; H, 5.24; N, 16.17. Found: C, 69.15; H,
5.14; N, 16.37.
Received August 14, 2003.
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4-Cyano-5-imino-3-methyl-1-phenylfuoro[2,3-c]pyrazole
20
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A solution of 1 (1 mol), ethyl cyanoacetate 23 (1 mol),
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to reflux for five hours. The colourless product which formed
during reflux was collected by filtration and washed well
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Ethyl 4-(3-methyl-1-phenylpyrazole-4-yl)fuoro[2,3-c]pyr-
azole-4-carboxylate 25
This compound was isolated as colourless crystals, mp.
279-281 °C; IR: 1641 (C=C), 1689 (CO), 3258 (NH), 3359
1
(OH); H nmr (DMSO-d6): d 1.1 (t, 3H, CH3), 1.9 (s, 3H,
CH3), 2.0 (s, 3H, CH3), 3.9 (q, 2H, CH2), 7.2-7.9 (m, 11H,