Acylotropy in the cyclocondensation of acetothioacetanilide with benzhydrazide [2]

Full text of DOI:10.1023/A:1019581701478

Chemistry of Heterocyclic Compounds, Vol. 38, No. 5, 2002
ACYLOTROPY IN THE
CYCLOCONDENSATION OF
ACETOTHIOACETANILIDE
WITH BENZHYDRAZIDE
I. B. Dzvinchuk, S. A. Kartashov, A. V. Vypirailenko, and M. O. Lozinskii
Keywords: pyrazoles, acylotropy, isomerization, selectivity, cyclocondensation.
Borisevich and Pel'kis [1] found that acetothioacetanilide (1) reacts selectively with phenylhydrazine to
give 5-anilino-3-methyl-1-phenylpyrazole. On the other hand, this reaction with benzoylhydrazine (2) gives a
mixture of the expected 5-anilino-1-benzoyl-3-methylpyrazole (3) and its isomer, 3-anilino-1-benzoyl-5-
methylpyrazole (4). Upon prolonged heating of the reagents in benzene at reflux, pyrazole 3 was isolated in low
yield. Upon prolonged heating of the reagents in ethanol at reflux, pyrazole 4 was isolated in low yield [2].
NHPh
EtOH, ∆ 3.5 h
NH2NHCOPh
+
Me
S
14%
2
O
1
NHPh
C6H6, ∆ 6 h
200 oC, 2 h
47%
Me
3
N
31%
N
PhCO
4
NHPh
Me
N
N
3
COPh
200 oC, 2 h
3
4
1. 2-PrOH, 15 oC, 3.5 h
2. ∆ 15 min
34%
66%
84%
The reasons for the nonselective reaction of reagents 1 and 2 according to Borisevich et al. [2] have not
been examined. We offer the following explanation. Firstly, pyrazole 3 tends to rearrange to 4 due to migration
of the benzoyl group between the nitrogen atoms of the pyrazole ring. Stabilization of 3 by intramolecular
hydrogen bonding between the benzoyl group oxygen atom and the aniline fragment hydrogen atom does not
hinder the acylotropic isomerization upon prolonged heating. Secondly, the benzoylhydrazone of
acetothioacetanilide, which is initially formed in this reaction, has poor solubility. Hence, the cyclization of this
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02094 Kiev, Ukraine; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 703-705, May, 2002.
Original article submitted November 19, 2001.
618
0009-3122/02/3805-0618$27.00©2002 Plenum Publishing Corporation

initial product in benzene proceeds slowly. This behavior does not facilitate stopping of the reaction at the step
involving formation of 3. Thirdly, the formation of N-acylpyrazoles is complicated by their hydrazinolysis and,
in ethanol, also by their alcoholysis.
A stepwise procedure for these reactions was found to be necessary for the selective synthesis of
pyrazoles 3 and 4. The reaction of 1 and 2 in 2-propanol without heating leads to the predominant formation of
the benzoylhydrazone of 1. Subsequent brief heating at reflux leads selectively to pyrazole 3. At 200°C, 3
1
isomerizes to give 4. This isomerization is an equilibrium process. H NMR spectroscopy indicates that the
equilibrium mixture contains about 66% of 4. The same result was obtained in a separate experiment upon
heating 4. Isomer 4 was isolated predominantly upon crystallization of the melt from toluene. The yield can
probably be increased if the solvent is removed from the filtrate by distillation and the residue is again brought
to the equilibrium state by heating. Borisevich et al. [2] obtained 3 and 4 in yields of 31% and 14%,
respectively. Our procedure permitted an increase in the yields of these products to 84 and 47%, respectively.
These results hold significance for optimizing the conditions for the synthesis of 3- and 5-arylamino-N-
acylpyrazoles, which have been difficult to obtain.
5-Anilino-1-benzoyl-3-methylpyrazole (3). Samples of up to 5 mmoles of 1 and 2 in 2-propanol (5 ml)
were stirred until the solution was homogeneous and then maintained for 3.5 h at 15°C. The suspension obtained
was treated according to one of the procedures below.
A. The mixture was heated at reflux with shaking for about 15 min until homogeneous and then stirred
until the onset of crystallization. The mixture was slowly cooled to 5°C. The precipitate was filtered off and
washed with 2-propanol to give 1.17 g 3 (84%) as yellow crystals with mp 89-90.5°C (89-90°C [2]).
IR spectrum in KBr pellet, ν, cm-1: 1680 (C=O), 3370 (N–H). 1H NMR spectrum (300 MHz, DMSO-d6, TMS as
the internal standard), δ, ppm: 2.14 (3H, s, CH3); 6.08 (1H, s, 4-H); 7.00-7.38 (5H, m, C6H5N); 7.52-7.97 (5H,
m, C6H5C=O); 9.33 (1H, s, NH).
B. The precipitate was removed from the suspension by filtration and the benzoylhydrazone of
acetothioacetanilide (5) was obtained in 77% yield; mp 133-135°C (dec.). IR spectrum in KBr pellet, δ, cm-1:
1670 (C=O), 3205, 3250 (N–H). Found, %: C 65.66; H 5.55; N 13.39; S 10.32. C17H17N3OS. Calculated, %:
C 65.57; H 5.50; N 13.49; S 10.30. Fusion of hydrazone 5 led to its decomposition with the release of H2S and
cyclization to pyrazole 3, which was identical in melting point and thin-layer chromatographic behavior to the
sample obtained using procedure A.
3-Anilino-1-benzoyl-5-methylpyrazole (4). A sample of 3 or 4 (5 mmol) was maintained for 2 h at
200°C. The melt was dissolved in toluene (5 ml). After cooling, the mixture was maintained for 10 min at 0°C.
The precipitate was filtered off and washed with toluene to give 0.65 g 4 (47%) as yellow crystals with
1
mp 124-126°C (118-119°C [2]). IR spectrum in KBr pellet, δ, cm-1: 1670, 1680 (C=O), 3380 (N–H). H NMR
spectrum (300 MHz, DMSO-d6, TMS as the internal standard), δ, ppm: 2.61 (3H, s, CH3); 6.12 (1H, s, 4-H);
6.77-7.42 (5H, m, C6H5N); 7.52-7.99 (5H, m, C6H5C=O); 9.05 (1H, s, NH).
The authors express their gratitude to Aventis CropScience for financial support.
REFERENCES
1.
2.
A. N. Borisevich and P. S. Pel'kis, Khim. Geterotsikl. Soedin., 312 (1969).
A. N. Borisevich, A. Sh. Bragina, V. P. Forsyuk, and V. I. Dombrovskaya, Physiologically Active
Compounds [in Russian], Vol. 9, Naukova Dumka, Kiev (1977), p. 47.
619