Cyanoacetophenone as a synthon for 1,4,5-substituted pyrazoles

Article abstract of DOI:10.1007/PL00010132

An improved synthesis of cyanoacetophenone is described. Cyanoacetophenone was reacted with dimethylformamide-dimethylacetal and diphenylformamidine to give 1-dimethylamino-3-oxo-3-phenyl-1-propene-2-carbonitrile and 1-anilinomethylene-3-oxo-3-phenyl-1-propene-2-carbonitrile. Reaction of 1-dimethylamino-3-oxo-3-phenyl-1-propene-2-carbonitrile with hydrazines gave either 1-substituted 5-amino-4-benzoylpyrazoles or (1-substituted) 4-cyano-5-phenylpyrazoles. Treatment of 1-anilinomethylene-3-oxo-3-phenyl-1-propene-2-carbonitrile with phenylhydrazine also yielded 5-amino-4-benzoyl-1-phenylpyrazole, whereas reaction with unsubstituted hydrazine afforded 4-cyano-5-phenylpyrazole.

Full text of DOI:10.1007/PL00010132

Monatshefte fuÈr Chemie 129, 1207±1211 (1998)
Cyanoacetophenone as a Synthon for
1,4,5-Substituted Pyrazoles
Ã
Claudia Reidlinger , Renate Dworczak, and Hans Junek
Institute of Organic Chemistry, Karl Franzens University Graz, A-8010 Graz, Austria
Summary. An improved synthesis of cyanoacetophenone is described. Cyanoacetophenone was
reacted with dimethylformamide-dimethylacetal and diphenylformamidine to give 1-dimethylamino-
3-oxo-3-phenyl-1-propene-2-carbonitrile and 1-anilinomethylene-3-oxo-3-phenyl-1-propene-2-car-
bonitrile. Reaction of 1-dimethylamino-3-oxo-3-phenyl-1-propene-2-carbonitrile with hydrazines
gave either 1-substituted 5-amino-4-benzoylpyrazoles or (1-substituted) 4-cyano-5-phenylpyrazoles.
Treatment of 1-anilinomethylene-3-oxo-3-phenyl-1-propene-2-carbonitrile with phenylhydrazine
also yielded 5-amino-4-benzoyl-1-phenylpyrazole, whereas reaction with unsubstituted hydrazine
afforded 4-cyano-5-phenylpyrazole.
Keywords. Cyanoacetophenone; 1-, 4-, 5-Substituted pyrazoles; Ring closure reaction.
Cyanacetophenon, ein Synthon fuÈr 1,4,5-substituierte Pyrazole
Zusammenfassung. Eine verbesserte Darstellung von Cyanacetophenon wird beschrieben.
Cyanacetophenon reagierte mit Dimethylformamid-dimethylacetal bzw. Diphenylformamidin zu
1-Dimethylamino-3-oxo-3-phenyl-1-propen-2-carbonitril und 1-Anilinomethylen-3-oxo-3-phenyl-1-
propen-2-carbonitril. Durch Umsetzung von 1-Dimethylamino-3-oxo-3-phenyl-1-propen-2-carboni-
tril mit Hydrazinen wurden entweder 1-substituierte 5-Amino-4-benzoylpyrazole oder (1-
substituierte) 4-Cyano-5-phenylpyrazole erhalten. Reaktion von 1-Anilinomethylen-3-oxo-3-phe-
nyl-1-propen-2-carbonitril mit Phenylhydrazin ergab ebenfalls 5-Amino-4-benzoyl-1-phenylpyrazol,
È
wahrend unsubstituiertes Hydrazin zu 4-Cyan-5-phenylpyrazol reagierte.
Introduction
Introduction of substituents into the pyrazole system is easy in position 4. Other
ring positions are less accessible for electrophilic substitutions. Thus, in many
cases substituted pyrazoles have been obtained by ring closure reactions of already
substituted starting materials. In classical syntheses, 1,3-dioxo compounds were
cyclized with monosubstituted hydrazines to yield 3,5-di- or 1,3,5-trisubstituted
pyrazoles. Hydrazines and substituted hydrazines were cyclized with 1,3-dipoles
like e.g. ethoxymethylene-malononitrile [1±4] or 2-cyano-3-dimethylaminopro-
penal [5]. In some cases, also rearrangements of substituents have been observed
Ã
Corresponding author

1208
C. Reidlinger et al.
[6]. In this paper we report on a two step procedure for the synthesis of substituted
pyrazoles from easily accessible starting materials. The synthesis of cyanoaceto-
phenone 1 has been reported earlier [7±9], however, with poor yields; therefore, we
developed an alternative synthesis which gave 70±74% of products.
Results and Discussion
Cyanoacetophenone (1) was reacted with dimethylformamide-dimethylacetal
(DMFDMA) at room temperature to yield the (E)- and (Z)-isomers of the
aminomethylene derivative 2 (Scheme 1). Typically, 80 to 100% of the product had
(E)-con®guration. The ratio of (E)- and (Z)-isomers had no in¯uence on the
following condensations of 2 with different hydrazines which were performed
either in ethanol or in mixtures of ethanol and hydrochloric acid. In the ®rst step of
the reaction, the dimethylamino group was substituted by hydrazines to give
intermediate A (Scheme 2). The imino form gave compounds 4a, b and 5a±f by
ring closure to the carbon atoms of the carbonyl and nitrile groups. Structures of
4a, b and 5a±f were con®rmed by spectroscopical data (see Experimental).
Scheme 1

1,4,5-Substituted Pyrazoles
1209
Scheme 2
Scheme 3
5-Amino-4-benzoyl-1-phenylpyrazole (4b) was also obtained by condensation
of 3 [10] with phenylhydrazine. This was somewhat surprising as we had expected
to obtain 1,5-diphenyl-4-cyano-pyrazole which has been described earlier [10].
Other pathways to obtain 5a were either to condensate 2 with hydrazinoformic
methylester or to react 3 with hydrazine hydrate.
1H NMR spectroscopic data showed that 5a was the only structure present at
room temperature (singulet of the CH-proton at 8.7 ppm). At lower temperatures,
e.g. at 235 K, also 5a0 [10, 11] (Scheme 3) could be observed (additional singulet at
6.8 ppm). According to the experiments described above, 1 proved to be a valuable
synthon on the way to 1,4,5-substituted pyrazoles.
Experimental
All melting points are uncorrected (BuÈchi 500). Spectroscopic data were recorded with the following
instruments: IR spectra: Perkin-Elmer-Spectrophotometer 500 (KBr), 1H NMR spectra: Gemini 200
(referenced to internal TMS). Elemental analyses were performed on a C,H,N-Automat Carlo Erba
1106; the results were in accordance with the calculated values.
Cyanoacetophenone (1; C9H7NO)
In an improved synthesis, 45.50 g (300 mmol) !-chloroacetophenone were dissolved in 240 ml
ethanol and stirred together with a solution of 29.41 g (600 mmol) NaCN in 120 ml H2O at room
temperature for 1 h. The brownish solution was ®ltered and the solvent evaporated in vacuo to give a
precipitate. The residue was poured into 1000 ml ice/water and stirred for 3 h at room temperature.
The mixture was ®ltered, and the ®ltrate was acidi®ed with conc. HCl to give 1.
Colourless platelets; 32.00 g (74%); m.p.: 79±80ꢀC (H2O; Refs. [7±9]: 80±81ꢀC); IR (KBr):
ꢀ ˆ 1690, 2220, 2920 cmꢁ1; 1H NMR (200 MHz, ꢁ, DMSO-d6): 4.78 (s, 2H, CH2), 7.55±7.78 (m, 3H,
m-, p-aromatic protons), 7.94±8.00 (d, 2H, o-aromatic protons) ppm.

1210
C. Reidlinger et al.
1-Dimethylamino-3-oxo-3-phenyl-1-propene-2-carbonitrile (2; C12H12N2O)
4.35 g (30 mmol) 1 and 7.14 g (60 mmol) N,N-dimethylformamide-dimethylacetal were stirred at
room temperature. Compound 2 precipitated immediately. After 1 h, petroleum ether was added, and
the mixture was ®ltered giving yellowish crystals.
4.50 g (67%); m.p.: 106±108ꢀC (ethanol); IR (KBr): ꢀ ˆ 2200, 1650, 1600 cmꢁ1
;
1H NMR
(200 MHz, ꢁ, DMSO-d6): 3.40 (s, 6H, N-CH3), 7.45±7.69 (m, 5H, aromatic protons, 7.93 (s, 1H, CH)
ppm.
5-Amino-4-benzoylpyrazole (4a; C10H9N3O)
A mixture of 5.00 g (25 mmol) 2, 1.00 g (20 mmol) hydrazine hydrate, and 105 ml ethanol was
re¯uxed for 2 h. After evaporation of the yellow reaction mixture, yellow crystals were ®ltered and
washed with cold methanol and petroleum ether.
Colourless crystals; 1.14 g (30%); m.p.: 160±162ꢀC (acetonitrile); IR (KBr): ꢀ ˆ 3380, 3150,
2960, 1610, 1580 cmꢁ1; 1H NMR (200 MHz, ꢁ, DMSO-d6): 6.79 (s, 2H, NH2), 7.47±7.57 (m, 3H, p-
aromatic protons), 7.60 (s, 1H, CH), 7.71±7.73 (m, 2H, o-aromatic protons), 12.05 (s, 1H, NH) ppm.
5-Amino-4-benzoyl-1-phenylpyrazole (4b; C16H13N3O)
Method A: A mixture of 2.00 g (10 mmol) 2, 15 ml ethanol, 1.2 ml conc. HCl, and 1.08 g (10 mmol)
phenylhydrazine was re¯uxed for 1 h. After cooling to room temperature, the precipitate was ®ltered
and washed with ethanol to afford 1.96 g (74%) colourless crystals.
Method B: 1.48 g (10 mmol) 3 and 7.56 g (70 mmol) phenylhydrazine were re¯uxed in 50 ml
ethanol for 2 h. The precipitate was ®ltered after cooling to room temperature and washed with
ethanol.
Colourless crystals; 0.65 g (27%); m.p.: 183ꢀC; IR (KBr): ꢀ ˆ 3370, 3260, 3180, 1760,
1
1620 cmꢁ1; H NMR (200 MHz, ꢁ, DMSO-d6): 7.19 (s, 2H, NH2), 7.43±7.62 (m, 8H, aromatic
protons), 7.77±7.80 (m, 2H, o-aromatic protons), 7.82 (s, 1H, CH) ppm.
4-Cyano-5-phenylpyrazole (5a; C10H7N3)
Method A: A mixture of 2.00 g (10 mmol) 2, 0.50 g (10 mmol) hydrazine hydrate, 20 ml ethanol, and
0.2 ml conc. HCl was re¯uxed for 3 h. After evaporation of the solvent, the residue was diluted with
water and evaporated again. The precipitate was ®ltered to give 1.50 g (89%) of yellowish needles.
Method B: 2.00 g (10 mmol) 2, 0.90 g (10 mmol) hydrazinoformic acid methylester, 15 ml
ethanol, and 0.2 ml conc. HCl were re¯uxed for 6 h. After cooling to room temperature, the solution
was evaporated in vacuo. The residue was diluted with water and evaporated again. Yellowish
crystals were ®ltered off by suction and washed with a small amount of methanol to afford 1.36 g
(80%) of 5a.
Method C: 2.48 g (10 mmol) 3 and 0.40 g (10 mmol) hydrazine hydrate were re¯uxed in 50 ml
ethanol for 2 h. The solution was evaporated and the precipitate diluted with petroleum ether and
®ltered to give colourless platelets.
Yield: 1.11 g (82%); m.p.: 130ꢀC (methanol/H2O); IR (KBr): ꢀ ˆ 3320, 3120, 2960, 2230,
1660 cmꢁ1; 1H NMR (200 MHz, ꢁ, DMSO-d6): 7.30±7.60 (m, 3H, aromatic protons), 7.82±7.97 (m,
2H, aromatic protons), 8.70 (s, 1H, CH), 13.90 (br s, 1H, NH) ppm.
4-Cyano-1,5-diphenylpyrazole (5b; C16H11N3)
2.00 g (10 mmol) 2, 1.00 g (10 mmol) phenylhydrazine, and 15 ml ethanol were re¯uxed for 3 h.
After cooling to room temperature, 5b was ®ltered and washed with ethanol.

1,4,5-Substituted Pyrazoles
1211
1
Colourless needles; 0.93 g (38%); m.p.: 100ꢀC (ethanol); IR (KBr): ꢀ ˆ 2220, 1595 cmꢁ1; H
NMR (200 MHz, ꢁ, DMSO-d6): 7.30±7.50 (m, 10H, aromatic protons), 8.45 (s, 1H, CH) ppm.
4-Cyano-5-phenyl-1-p-tolylpyrazole (5c; C17H13N3)
A mixture of 2.00 g (10 mmol) 2, 1.60 g (10 mmol) 4-tolylhydrazine, 1.2 ml conc. HCl, and 15 ml
ethanol was re¯uxed for 1 h. The solvent was evaporated, the residue diluted with water and
evaporated again. The precipitate was ®ltered after addition of a small amount of methanol.
Yellow platelets; 0.37 g (14%); m.p.: 127±129ꢀC (methanol); IR (KBr): ꢀ ˆ 2220, 1620 cmꢁ1; 1H
NMR (200 MHz, ꢁ, DMSO-d6): 2.31 (s, 3H, CH3), 7.11±7.55 (m, 9H, aromatic protons), 8.40 (s, 1H,
CH) ppm.
1-(4-Chlorophenyl)-4-cyano-5-phenylpyrazole (5d; C16H10N3Cl)
3.00 g (15 mmol) 2, 2.70 g (15 mmol) 4-chlorophenylhydrazine, 0.3 ml conc. HCl, and 50 ml ethanol
were re¯uxed for 3 h. After cooling to room temperature, the solid was ®ltered giving yellow needles.
1
Yield: 1.97 g (47%); m.p.: 149ꢀC (ethanol); IR (KBr): ꢀ ˆ 2240, 1540, 1505 cmꢁ1; H NMR
(200 MHz, ꢁ, DMSO-d6): 7.32±7.41 (m, 4H, aromatic protons), 7.47±7.55 (m, 5H, aromatic protons),
8.45 (s, 1H, CH) ppm.
4-Cyano-1-(4-nitrophenyl)-5-phenylpyrazole (5e; C16H10N4O2)
3.00 g (15 mmol) 2, 2.30 g (15 mmol) 4-nitrophenylhydrazine, 0.3 ml conc. HCl, and 50 ml ethanol
were re¯uxed for 3.5 h. 5e precipitated from the boiling red solution; it was ®ltered after cooling to
room temperature and washed with ethanol to give yellow crystals.
Yield: 2.92 g (67%); m.p.: 171±172ꢀC (ethanol); IR (KBr): ꢀ ˆ 3080, 2240, 1600 cmꢁ1; 1H NMR
(200 MHz, ꢁ, DMSO-d6): 7.40±7.55 (m, 5H, aromatic protons), 7.55±7.64 (m, 2H, aromatic protons
of the nitrophenyl group), 8.25±8.34 (m, 2H, aromatic protons of the nitrophenyl group), 8.54 (s, 1H,
CH) ppm.
4-Cyano-1-(4-methoxyphenyl)-5-phenylpyrazole (5f; C17H13N3O)
A mixture of 2.00 g (10 mmol) 2, 1.38 g (10 mmol) 4-methoxyphenylhydrazine, 0.3 ml conc. HCl,
and 15 ml ethanol was re¯uxed for 1 h. The solution was evaporated and the precipitate was ®ltered.
Yield: 2.06 g (75%); m.p.: 125ꢀC (ethanol); IR (KBr): ꢀ ˆ 2228, 1510 cmꢁ1; 1H NMR (200 MHz,
ꢁ, DMSO-d6): 3.75 (s, 3H, OCH3), 6.90±7.55 (m, 9H, aromatic protons), 8.37 (s, 1H, CH) ppm.
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Received May 8, 1998. Accepted (revised) May 28, 1998