Synthesis of 4-arylhydrazono-3-arylthiomethyl-4,5-dihydro-1H-1-R-5-pyrazolones

Article abstract of DOI:10.1023/B:COHC.0000003517.58980.76

It has been established that interacting ethyl 2-arylhydrazono-4-arylthio-3-oxobutyrates with hydrazine, methylhydrazine, and phenylhydrazine forms 4-arylhydrazono-3-arylthiomethyl-4,5-dihydro-1H-1-R-pyrazolones.

Full text of DOI:10.1023/B:COHC.0000003517.58980.76

Chemistry of Heterocyclic Compounds, Vol. 39, No. 8, 2003
SYNTHESIS OF 4-ARYLHYDRAZONO-
3-ARYLTHIOMETHYL-4,5-DIHYDRO-
1H-1-R-5-PYRAZOLONES
V. N. Bodnar, V. N. Britsun, and M. O. Lozinskii
It has been established that interacting ethyl 2-arylhydrazono-4-arylthio-3-oxobutyrates with hydrazine,
methylhydrazine, and phenylhydrazine forms 4-arylhydrazono-3-arylthiomethyl-4,5-dihydro-1H-1-R-
pyrazolones.
Keywords: 4-arylhydrazono-3-arylthiomethyl-4,5-dihydro-1H-1-R-5-pyrazolones, hydrazine, ethyl
2-arylhydrazono-4-arylthio-3-oxobutyrates, ethyl 2-arylhydrazono-4-bromo-3-oxobutyrates.
The interaction of β-keto esters with hydrazine is the classic method of synthesizing functionalized
pyrazolones [1]. Ethyl 2-arylhydrazono-3-oxobutyrate also reacts with hydrazine and its derivatives with the
formation of 4-arylhydrazono-3-methyl-5-pyrazolones which possess antimicrobial and fungicidal activity [2,3],
and also may be used as dyestuffs [4]. But the use of ethyl 2-arylhydrazono-3-oxobutyrate does not permit the
synthesis of 5-pyrazolones modified in position 3 of the pyrazolone ring.
Previously we proposed a convenient method for the synthesis of esters of 2-arylhydrazono-4-bromo-3-
oxobutyric acid and showed that they are highly reactive compounds and may be used for the synthesis of
nitrogen-containing heterocycles [5-8].
HS–Ar2
Ph3N
CO–CH2SAr2
CO2Ph
CO–CH2Br
CO2Ph
Ar1NH–N=C
Ar1NH–N=C
.
–Ph3N HBr
2
1
CH2SAr2
CH2SAr2
C
C=N–NH–R
N
C
N
H2N–NH–R
– H2O
Ar1NH–N=C
Ar1
N
N
C
– PhOH
R
C–OPh
O
H...O
3
A
1a–c, 2a–c, 3a–e Ar1 = Ph; 2d, 3f Ar1 = p-MeOC6H4; 2e, 3g Ar1 = p-NO2C6H4;
N
N
2a,d,e, 3a–c,f,g Ar2 = Ph; 2b, 3d Ar2 =
3 a R = H, b R = Me, c, d, e, f, g R = Ph
; 2c, 3e Ar2 =
;
S
N
H
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, Kiev 02094; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1169-1172,
August, 2003. Original article submitted May 10, 2002.
1018
0009-3122/03/3908-1018$25.00©2003 Plenum Publishing Corporation

While continuing these investigations we established that esters of 2-arylhydrazono-4-arylthio-3-
oxobutyric acid 2a-e, synthesized by the interaction of esters of 2-arylhydrazono-4-bromo-3-oxobutyric acid
1a-c with thiophenol, 2-mercaptobenzothiazole, and 2-mercaptobenzimidazole, are converted by the action of
hydrazine and its derivatives (methylhydrazine and phenylhydrazine) in acetic acid into 4-arylhydrazono-3-
arylthiomethyl-4,5-dihydro-1H-1-R-5-pyrazolones 3a-g.
1
The yields, H NMR and IR spectra, data of elemental analysis, and molecular ion peaks [M]+ of the
compounds synthesized are given in Tables 1 and 2. In the 1H NMR spectra of thioethers 2a-e the signals of the
CO–CH2S and NH groups (4.33-4.82 and 11.87-12.16 ppm respectively) are characteristic. In the IR spectra
there are absorption bands for the carbonyl group (1610-1710) and the NH group (3000-3100 cm-1). In the
1H NMR spectra of pyrazolones 3a-g signals were observed for the CH2S group (4.16-4.74 ppm) and in the IR
spectra there were absorption bands for the C=O (1660-1670) and NH (3000-3200 cm-1) groups.
The yields of the heterocyclization products 3a-g were 40-67%. In our view, the formation of
pyrazolones 3a-g from thioethers 2a-e proceeds through the intermediate hydrazones A [1].
It is known that due to sp2-hybridization of the imine nitrogen atom and restriction of rotation about the
=C–C= bond, the hydrazones of dicarbonyl compounds may exist in syn and anti forms, each of which may be
found in s-cis and s-trans conformations [9]. But the formation of only one conformation may be asserted for
the synthesized compounds from the data of 1H NMR spectroscopy. Consequently there is a basis for supposing
that compounds 3a-g are formed in the syn-s-cis form, which is the most stable since it is stabilized by an
intramolecular hydrogen bond N–H···O=C [9,10]. Indirect confirmation of the formation of a hydrogen bond is
the small reduction of the frequency of the carbonyl group absorption in the IR spectra of compounds 3a-g in
1
comparison with the initial thioethers 2a-e (by 10-40 cm-1), and in the H NMR spectra of compounds 3a-g
compared with 2a-e a reduction is observed in the chemical shift of the hydrazone fragment proton of
0.57-0.80 ppm towards low field, which is in agreement with the data of [11,12].
TABLE 1. Characteristics of Compounds 2a-e, 3a-g
Found, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
[М]+
Calculated, %
С
H
N
C18H18N2O3S
C19H17N3O3S2
C19H18N4O3S
C19H20N2O4S
C18H17N3O5S
C16H14N4OS
C17H16N4OS
C22H18N4OS
C23H17N5OS2
C22H18N6OS
C23H20N4O2S
C22H17N5O3S
63.34
63.16
5.11
5.26
8.41
8.19
97-99
47
59
61
69
55
44
61
50
42
40
41
67
342
399
382
372
387
310
324
386
443
426
416
431
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
57.37
4.41
10.48
112-114
119-121
69-70
57.14
4.26
10.53
59.35
59.69
4.50
4.71
14.34
14.66
61.35
5.51
7.30
61.29
5.38
7.53
55.69
55.81
4.22
4.39
10.56
10.85
117-119
133-134
131-132
126-127
173-175
219-221
121-123
152-153
61.60
4.63
18.31
61.94
4.52
18.06
62.71
62.96
4.78
4.94
17.42
17.28
68.17
4.39
14.41
68.39
4.66
14.51
62.51
62.30
3.79
3.84
15.57
15.80
65.01
4.13
19.48
64.79
4.23
19.72
66.55
66.35
4.69
4.80
13.55
13.46
61.35
3.79
16.45
3g
61.25
3.94
16.24
1019

TABLE 2. Spectral Characteristics of Compounds 2a-e, 3a-g
Com-
IR spectrum, ν, cm-1
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz)
pound
3000 (NH), 1700 (C=O), 1.28 (3H, t, J = 7.5, СH3CH2O); 4.30 (2Н, q, J = 7.5,
2a
1630, 1600, 1520, 1470
СH3CH2O); 4.35 (2Н, s, CO–CH2–S);
7.08-7.42 (10H, m, 2C6H5); 11.95 (1H, s, –NH–N=)
3000 (NH), 1710 (C=O), 1.30 (3H, t, J = 7.8, СH3CH2O); 4.29 (2Н, q, J = 7.8,
2b
2c
1600, 1530, 1470, 1430
СH3CH2O); 4.95 (2Н, s, CO–CH2–S); 7.16-7.56 (7H, m, Ar);
7.80 (1H, s, Ar); 8.02 (1H, s, Ar); 12.16 (1H, s, –NH–N=)
3100 (NH), 1670 (С=О), 1.28 (3H, t, J = 7.2, СH3CH2O); 4.30 (2Н, q, J = 7.2,
1600, 1530, 1480, 1400,
1350
СH3CH2O); 4.82 (2Н, s, CO–CH2–S); 7.13 (3Н, m, Ar);
7.41-7.56 (6H, m, Ar); 12.05 (1H, s, –NH–N=);
12.52 (1H, br. s, NH)
3000 (NH), 1700 (C=O), 1.25 (3H, t, J = 7.7, СH3CH2O); 3.79 (3H, s, CH3O);
2d
2e
1600, 1530, 1480, 1400
4.26 (2Н, q, J = 7.7, СH3CH2O ); 4.33 (2Н, s, CO–CH2–S);
6.97 (2H, d, J = 9.1, p-C6H4); 7.23-7.55 (7H, m, Ar);
12.16 (1H, s, –NH–N=)
3000 (NH), 1700 (C=O), 1.26 (3H, t, J = 7.8, СH3CH2O); 4.33 (2Н, q, J = 7.8,
1600, 1540, 1400, 1350
СH3CH2O); 4.41 (2Н, s, CO–CH2–S); 7.20-7.39 (5H, m,
C6H5); 7.61 (2H, d, J = 8.9, p-O2N–C6H4); 8.24 (2H, d,
J = 8.9, p-O2N–C6H4); 11.87 (1H, s, –NH–N=)
3100 (NH), 1670 (C=O), 4.16 (2Н, s, CН2–S); 7.21-7.46 (10H, m, 2C6H5);
3a
3b
3c
3d
3e
1600, 1550, 1490, 1400
3200 (NH), 3050, 1670
7.49 (1H, s, CO–NH); 12.44 (1H, br. s, –NH–N=)
3.28 (3H, s, CH3); 4.18 (2Н, s, CН2–S);
(C=O), 1580, 1500,1450 7.30-7.51 (10H, m, 2C6H5); 12.68 (1H, br. s, –NH–N=)
3100 (NH), 1670 (C=O), 4.29 (2Н, s, CН2–S); 7.16-7.85 (15H, m, 3C6H5);
1600, 1560, 1500, 1360
13.32 (1H, br. s, –NH–N=)
3100 (NH), 1670 (C=O), 4.82 (2Н, s, CН2–S); 7.11-7.35 (4H, m, Ar); 7.40-7.53 (6H,
1600, 1570, 1500, 1440 m, Ar); 7.89-8.03 (4H, m, Ar); 13.11 (1H, br. s, –NH–N=)
3050, 1670 (С=О), 1600, 4.74 (2Н, s, CН2–S); 7.16 (6H, m, Ar); 7.45 (6H, m, Ar);
1560, 1500, 1450, 1410
7.86 (2H, d, J = 9.1, Ar); 12.03 (1Н, br. s, –NH–);
13.19 (1H, br. s, –NH–N=)
3000 (NH), 1660 (C=O), 3.78 (3H, s, CH3O); 4.28 (2Н, s, CН2–S); 7.03 (2H, d,
3f
1600, 1570, 1500, 1450
J = 9.6, p-C6H4); 7.14-7.51 (10H, m, 2C6H5); 7.86 (2H, d,
J = 9.6, p-C6H4); 13.18 (1H, br. s, –NH–N=)
3100 (NH), 1670 (C=O), 4.30 (2Н, s, CН2–S); 7.24-7.78 (12H, m, Ar); 8.24 (2H, d,
1600, 1560, 1500, 1350 J = 9.9, p-O2N–C6H4); 13.17 (1H, br. s, –NH–N=)
3g
The given method of synthesis therefore enables the preparation of previously unknown
4-arylhydrazono-4,5-dihydro-1H-1-R-5-pyrazolones containing an arylthiomethyl or hetarylthiomethyl fragment
in position 3 of the pyrazolone ring.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian-300 (300 MHz) instrument, internal standard was
TMS. The IR spectra were recorded on a Specord IR-75 instrument in KBr disks. The mass spectra were taken
on a MX-1303 instrument.
Ethyl 2-Arylhydrazono-4-bromo-3-oxobutyrates (1a-c) were synthesized by the procedure of [5].
Ethyl 2-Arylhydrazono-4-arylthio-3-oxobutyrates (2a-e). A solution of thiophenol (10 mmol) and
triethylamine (10 mmol) in benzene (50 ml) was added with stirring to a solution of ethyl 2-arylhydrazono-4-
bromo-3-oxobutyrate (10 mmol) in benzene (40 ml). The reaction mixture was stirred at 20°C for 30 min, at
50°C for 10 min, and cooled. Triethylamine hydrochloride was filtered off, and the filtrate evaporated to
dryness. The residue was recrystallized from alcohol.
1020

4-Arylhydrazono-3-arylthiomethyl-4,5-dihydro-1H-1-R-5-pyrazolones (3a-g).
A
solution of
hydrazine (or methylhydrazine, phenylhydrazine) (10 mmol) in acetic acid (30 ml) was added dropwise with
stirring to a solution of 2-arylhydrazono-4-arylthio-3-oxobutyric acid ethyl ester (10 mmol) in acetic acid
(30 ml). The reaction mixture was boiled for 8 h, cooled to room temperature, the precipitated solid was filtered
off, washed with acetic acid (2 × 10 ml), and recrystallized from acetic acid.
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1021