4-Functionally substituted 3-hetarylpyrazoles: VI. 1,3-diaryl-4-isocyanatopyrazoles

Article abstract of DOI:10.1023/A:1013982203774

1,3-Diaryl-4-isocyanatopyrazoles were obtained by reaction of 1,3-diarylpyrazole-4-carboxylic acids with ethyl chloroformate and sodium azide or by reaction of 1,3-diarylpyrazole-4-carbonyl chloride with trimethylsilyl azide. The title compounds react with amines, hydrazine hydrate, alcohols, phenols, and monochloroacetic acid to afford 4-pyrazolyl-substituted ureas, semicarbazides, urethanes, and amides respectively.

Full text of DOI:10.1023/A:1013982203774

Russian Journal of Organic Chemistry, Vol. 37, No. 12, 2001, pp. 1747 1752. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 12, 2001,
pp. 1828 1833.
Original Russian Text Copyright
,
2001 by Vovk, Mel nichenko, Chornous, Bratenko.
4-Functionally Substituted 3-Hetarylpyrazoles: VI.*
1,3-Diaryl-4-isocyanatopyrazoles
M. V. Vovk, N. V. Mel,nichenko, V. A. Chornous, and M. K. Bratenko
Institute of Organic Chemistry, Ukrainian Academy of Sciences,
Bukovinskaya State Medical Academy, Chernovtsy, 58000 Ukraine
Received May 3, 2000
Abstract 1,3-Diaryl-4-isocyanatopyrazoles were obtained by reaction of 1,3-diarylpyrazole-4-carboxylic
acids with ethyl chloroformate and sodium azide or by reaction of 1,3-diarylpyrazole-4-carbonyl chloride
with trimethylsilyl azide. The title compounds react with amines, hydrazine hydrate, alcohols, phenols, and
monochloroacetic acid to afford 4-pyrazolyl-substituted ureas, semicarbazides, urethanes, and amides
respectively.
1,3-Diarylpyrazole-4-carboxylic acids that we have
formerly synthesized [2] can be applied as convenient
precursors to preparation of new derivatives with a
highly electrophilic isocyanate group. Note that pyr-
azolyl isocyanates up till now remain a poorly studied
heterocumulene type. The only such compounds
described in the literature are 5-pyrazolyl isocyanates
[3], and 4-pyrazolyl isocyanates are unknown. Yet
taking into account the high pharmacological [4 7]
and physiological [8, 9] activity of a number of
4-substituted pyrazoles the synthesis of 4-isocyanato-
pyrazoles as initial compounds for preparation of
versatile derivatives presents an important task.
provides a possibility to use directly acids IIa e
(Scheme 1). Under mild conditions of the reaction
between the acids and ethyl chloroformate and
sodium azide we were able to isolate and characterize
by IR spectra 4-pyrazoyl azides IIIa e that were
solid compound stable to prolonged storage in a
refrigerator but decomposing at melting. The target
isocyanates were obtained by decomposing the azides
by heating for 4 h in toluene or dioxane.
In the second, organosilicon , procedure [11] (b)
into the reaction with pyrazole-4-carbonyl chlorides
IVa e [2] was brought trimethylsilyl azide instead of
sodium azide. The heating of the reagents for 4 h in
boiling toluene furnished isocyanates Ia e in 46 59%
yield (Scheme 1).
We tried two approaches to the synthesis of
1,3-diaryl-4-isocyanatopyrazoles Ia e which were
both improved preparative modifications of Curtius
reaction. The formate method [10] (procedure a)
Isocyanatopyrazoles Ia e (Table 1) are crystalline
solids stable to prolonged storage protected from
Scheme 1.
I IV, Ar = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 4-BrC6H4 (d), 4-EtC6H4 (e).
For communication V see [1].
*
1070-4280/01/3712-1747$25.00 2001 MAIK Nauka/Interperiodica

1748
VOVK et al.
solution are monomeric. The lack in the IR spectrum
Scheme 2.
of compound Ie taken in a KBr pellet of an absorption
1
band in 2250 2300 cm region and the presence of a
1
band at 1730 cm suggests that it probably has
dimerized during distillation into urethinedione V
with a melting point of 152 C. Yet in solution
(independent of the solvent nature) compound V
occurs exclusively as monomeric isocyanate Ie.
Special spectral investigation showed that the dis-
sociation of urethinedione V to isocyanate Ie can
proceed also without solvent. Thus after 6 months of
storage compound V completely converted into
isocyanate Ie with
a
melting point 50 51 C
(Scheme 2).
It should be noted that the chemical shift of the
signal from the proton in the 5 position of the pyr-
1
azole ring in the H NMR spectra of isocyanates I
depends considerably on the solvent character. In
particular, in polar solvents of DMSO type this
proton gives rise to a signal at 8.90 8.75 ppm. At
the same time in deuterobenzene the signal shifts
upfield by 2 ppm to the region 6.72 6.85 ppm.
moisture. The best way to purify compounds Ia, b, e
is by vacuum distillation, compounds Ic, d by re-
crystallization. The analysis of the IR spectra revealed
that isocyanates Ia d both in the solid state and in
Table 1. Yields, constants, spectra, and elemental analyses of 1,3-diaryl-4-isocyanatopyrazoles Ia e
Compd. Yield, %
no.
bp,
C
mp,
(solvent for
crystallization)
C
IR spectrum
(CH2Cl2),
(N=C = O), cm
(p, mm Hg)
1H NMR spectrum (C6D6), , ppm
1
a
b
Ia
Ib
Ic
45
47
52
52 195 198 (0.04)
55 199 200 (0.04)
59
92
2270
2280
2275
8.06 d, 7.41 d (4H arom), 7.26 6.93 m
(6H arom), 6.79 s (1H, CH=)
8.07 7.89 m (4H arom), 7.57 7.21 m
(5H arom), 6.73 s (1H, CH=)
7.79 d, 7.38 d (4H arom), 7.22 6.92 m
(5H arom), 6.75 s (1H, CH=)
105
105 106
(hexane benzene,
10:1)
Id
Ie
46
44
53
121 122
(hexane benzene,
5: 1)
2280
2270
7.74 d, 7.37 d (4H arom), 7.34 6.91 m
(5H arom), 6.72 s (1H, CH=)
46 194 195 (0.04)
50 51
8.03 d, 7.43 d (4H arom), 7.13 6.91 m
(5H arom), 6.85 s (1H, CH=), 2.46 q
(2H, CH2), 1.03 t (3H, CH3)
Compd.
no.
Found, %
Calculated, %
Formula
C
H
N
C
H
N
Ia
Ib
Ic
Id
Ie
73.82
68.99
65.22
56.07
74.95
4.08
3.53
3.20
3.19
4.97
15.81
15.17
14.33
12.42
14.29
C16H11N3O
73.75
68.81
64.98
56.49
74.72
4.24
3.61
3.41
2.96
5.22
16.08
15.05
14.21
12.35
14.52
C16H10FN3O
C16H10ClN3O
C16H10BrN3O
C18H15N3O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

4-FUNCTIONALLY SUBSTITUTED 3-HETARYLPYRAZOLES: VI.
1749
Table 2. Yields, constants, spectra and elemental analyses of N-(1,3-diaryl-4-pyrazolyl)ureas IXa g
1
Compd. Yield,
mp,
C
IR spectrum (KBr), , cm
no.
IXa
IXb
IXc
IXd
IXe
IXf
IXg
%
(solvent for
crystallization)
1H NMR spectrum [(CD3)2SO], , ppm
C = O
1710
N H
3310
55
57
78
74
77
55
58
253 255
(dioxane ethanol,
1: 10)
260 262
(dioxane ethanol,
3: 2)
137 138
(benzene hexane,
5: 1)
205 207
(dioxane water,
3: 1)
229 231
(dioxane ethanol,
1: 6)
243 245
(ethanol water,
5: 1)
130 131
(benzene hexane,
5: 1)
8.74 s (1H, CH=), 8.03 s (1H, NH), 7.88 d, 7.79 d
(4H arom), 7.53 7.31 m (8H arom), 6.89 d
(2H arom), 3.72 t (4H, CH2O), 3.01 t (4H, CH2N)
9.71 s (1H, NH), 8.73 s (1H, CH=), 8.43 s (1H,
NH), 8.12 d, 7.90 d, 7.80 d, 7.69 d (8H arom),
7.56 7.29 m (6H arom)
1705
1720
1720
1715
1710
1715
3300
3290
3315
3280
3330
3315
8.52 s (1H, CH=), 7.22 7.05 m (14H arom), 6.30 s
(1H, NH), 4.56 s (2H, CH2), 3.07 s (3H, CH3)
8.55 s (1H, CH=), 8.28 c (1H, NH), 7.87 6.81 m
(14H arom), 3.61 m (4H, CH2N), 3.16 m (4H,
CH2N)
8.58 s (1H, CH=), 7.82 7.29 m (10H arom, NH),
6.38 s (1H, NH), 3.46 m (1H, CH), 1.79 1.66 m
(8H, CH2)
9.12 s (1H, NH), 8.93 s (1H, NH), 8.74 s (1H,
CH=), 8.69
(10H arom)
s
(1H arom), 7.91 7.32
m
8.57 s (1H, CH=), 7.83 7.34 m (10H arom, NH),
6.45 t (1H, NH), 3.55 t (4H, CH2O), 3.09 q (2H,
CH2), 2.67 q (2H, CH2), 2.32 2.28 m (2H, CH2),
1.56 q (2H, CH2), 1.23 s (3H, CH3)
Compd.
Found, %
Calculated, %
no.
Formula
C
H
N
C
H
N
IXa
IXb
IXc
IXd
IXe
IXf
IXg
70.77
66.31
71.54
70.87
66.71
56.03
69.46
5.77
4.40
5.41
5.70
5.59
3.34
7.50
16.10
17.32
13.62
15.67
14.07
11.47
16.31
C26H25N5O2
C22H17N5O3
C24H21FN4O
C26H24FN5O
C22H23ClN4O
C23H15Cl2F3N4O
C25H31N5O2
71.05
66.15
71.99
70.73
66.91
56.25
69.26
5.73
4.29
5.28
5.48
5.87
3.08
7.21
15.93
17.53
13.99
15.86
14.19
11.40
16.05
In order to prepare from the isocyanatopyrazoles I
potential bioactive compounds we carried out their
reaction with amines VIa g, alcohols VIIa c,
phenols VIId, e, and acids VIIIa, b. The heating of
isocyanates Ia c, e in benzene with amines VIa g
affords in high yield N -alkyl(aryl)-N-pyrazolylureas
IXa g (Table 2). The reaction of the isocyanates with
alcohols VIIa c and phenols VIId, e requires pro-
longed heating in benzene (4 5 h) in the presence of
catalytic quantity of triethylamine. As a result form
urethanes Xa e (Scheme 3).
Some derivatives of 4-isocyanatopyrazole can be
prepared without isolation of the isocyanates in pure
state since the isolation process is accompanied with
significant decrease in the yield. In particular, ureas
IXh,i and semicarbazides IXj, k were obtained in
high yield by treating with aqueous ammonia and
hydrazine hydrate crude isocyanates Ia, c prepared
by decomposition of the corresponding 4-pyrazolyl
azides in dioxane (Scheme 4).
Isocyanate Ia with acids exhibits peculiar behavior.
For instance, when treated with glacial acetic acid it
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1750
VOVK et al.
is hydrolyzed to afford sym-dipyrazolylurea XI. Yet
Scheme 3.
the monochloroacetic acid with this compound affords
amide XII (Scheme 5).
EXPERIMENTAL
IR spectra of compounds obtained were registered
1
on spectrophotometer UR-20. H NMR spectra were
measured on spectrometer Varian Gemini (300 MHz).
1,3-Diaryl-4-isocyanatopyrazoles Ia e (Table 1).
(a). To a dispersion of 0.01 mol of acid IIa e in 30 ml
of anhydrous acetone was added at stirring and cool-
ing to 0 C 0.011 mol of triethylamine, and after
15 min 0.011 mol of ethyl chloroformate in 5 ml of
acetone. The stirring was continued for 1 h more, and
at the same temperature was added 0.011 mol of
sodium azide in 15 ml of water. The reaction mixture
was stirred for 4 h at 0 C and then poured into
100 ml of ice water. The product was filtered off and
dried in a vacuum desiccator over P2O5. Thus were
obtained pyrazole-4-carbonyl azides IIIa e. Yields,
melting points, and IR spectra of the crude com-
VI, R1 = H, R2 = cyclo-C6H11 (a), 3-morpholino-
propyl (b), 4-morpholinophenyl (c), 4-NO2C6H4 (d),
2-Cl-5-CF3C6H3 (e); R1 = Me, R2 = Bn (f); R1R2 =
(CH2)2NPh(CH2)2 (g); VII, R3 = 2-morpholinoethyl
(` ), (2-chlorophenyl)methyl (b), 2-furylmethyl (c),
4-FC6H4 (d), 3-CH3C6H4 (e); IX, Ar = Ph, R1 = H,
R2 = 4-morpholinophenyl (` ), 4-NO2C6H4 (b); Ar =
4-FC6H4, R1
=
Me, R2
=
Ph (c); R1R2
=
1
(CH2)2NPh(CH2)2 (d); Ar = 4-ClC6H4, R1 = H, R2 =
cyclo-C6H11 (e), 2-Cl-5-CF3C6H3 (f); Ar = 4-EtC6H4,
R1 = H, R2 = 3-morpholinopropyl (g); X, Ar = Ph,
pounds are as follows: 92%, 72 74 C, 2140 cm
1
(IIIa), 88%, 89 92 C, 2145 cm (IIIb), 91%,
1
102 103 C, 2150 cm
(IIIc), 86%, 91 95 C,
1
1
R3
=
2-morpholinoethyl (` ), (2-chlorophenyl)-
2155 cm (IIId), 76%, 73 76 C, 2145 cm (IIIe).
Azides IIIa e in 50 ml of toluene were heated to
boiling for 4 h till the liberation of nitrogen stopped.
The solvent was removed at reduced pressure, the
residue was purified by distillation or recrystalliz-
ation.
methyl (b); Ar = 4-ClC6H4, R3 = 2-furylmethyl (c),
4-FC6H4 (d); Ar = 4-EtC6H4, R3 = 3-CH3C6H4 (e).
Scheme 4.
(b) To a solution of 0.01 mol of pyrazole-4-carb-
onyl chloride was added at stirring within 0.5 h
0.012 mol of trimethylsilyl azide in 10 ml of toluene.
The mixture was heated for 4 5 h till the liberation
of nitrogen stopped. The solvent was removed at
reduced pressure, the residue was purified by distill-
ation or recrystallization.
IX, Ar = Ph, R = H (h), NH2 (j); Ar = 4-ClC6H4,
R = H (i), NH2 (k).
N -Alkyl(aryl)-N-(4-pyrazolyl)ureas IXa g
(Table 2). To a solution of 4 mmol of isocyanate
Ia c, e in 30 ml of benzene was added 4 mmol of
amine VIa g, and the mixture was heated to boiling
for 2 h. Then the solvent was evaporated, and the
residue was purified by recrystallization.
Scheme 5.
N-(4-Pyrazolyl)ureas IXh, i, and 1-[N-(4-pyr-
azolyl)]semicarbazides IXj, k. In 10 ml of dioxane
was heated to boiling 2 mmol of pyrazolyl azide Ia, c
for 3 h till the liberation of nitrogen stopped. The
solution was cooled, and thereto was added 4 ml of
25% aqueous ammonia (hydrazine hydrate) in 10 ml
of dioxane. The mixture was stirred for 1 h at room
temperature and 1 h at boiling. Then the reaction
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

4-FUNCTIONALLY SUBSTITUTED 3-HETARYLPYRAZOLES: VI.
1751
Table 3. Yields, constants, spectra, and elemental analyses of N-(1,3-diaryl-4-pyrazolyl)urethanes Xa e
1
Compd. Yield,
mp,
C
IR spectrum (KBr), , cm
%
(solvent
for
1H NMR spectrum [(CD3)2SO], , ppm
no.
crystallization)
C = O
1740
N H
3245
Xa
82
120 122
(benzene hexane,
4: 1)
8.51 s (1H, CH=), 8.16 s (1H, NH), 7.93 7.83 m
(4H arom), 7.56 7.31 m (6H arom), 4.25 m
(2H, CH2O), 3.59 m (2H, CH2O), 2.61 m (2H,
CH2N), 2.47 m (4H, CH2N)
Xb
Xc
60
53
125 127
(ethanol water, 5: 1)
132 133
(benzene hexane,
4: 1)
1735
1735
3260
3250
8.34 s (1H, CH=), 7.81 7.35 m (15H arom, NH),
5.26 s (2H, CH2O)
9.13 s (1H, NH), 8.61 s (1H, CH=), 7.87 7.36 m
(10H arom), 6.47 m (2H arom), 5.09 m (2H,
CH2O)
Xd
Xe
62
53
144 145
(benzene hexane,
3: 1)
1740
1735
3245
3260
8.66 s (1H, CH=), 8.39 s (1H, NH), 7.88 7.30 m
(13H arom)
165 166
(ethanol water,
6: 1)
8.45 s (1H, CH=), 7.72 7.01 m (13H arom),
2.71 q (2H, CH2), 2.37 s (3H, CH3), 1.28 t (3H,
CH3)
Compd.
Found, %
Calculated, %
no.
Formula
C
H
N
C
H
N
Xa
Xb
Xc
Xd
Xe
67.48
68.58
64.45
67.14
75.75
6.01
4.57
4.29
4.04
5.54
14.20
10.03
10.42
10.67
10.28
C22H24N4O3
C23H18ClN3O2
C21H16ClN3O3
C22H15ClFN3O
C25H23N3O2
67.33
68.40
64.04
67.44
75.54
6.16
4.49
4.09
3.86
5.83
14.28
10.40
10.67
10.72
10.57
mixture was cooled and poured into ice water, the
precipitate was filtered off, dried, and crystallized.
1-[1-phenyl-3-(4-chlorophenyl)]-4-pyrazolyl-
semicarbazide (IXk). Yield 67%, mp 182 183 C
1
(ethanol dioxane, 10:1). IR spectrum (KBr), cm :
N - ( 1 , 3 - D i p h e n y l ) - 4 - p y r a z o l y l u r e a
1690 (C=O), 3290 3350 (N H). Found, %: C
58.96; H 4.11; N 21.59. ¢16H14ClN5O. Calculated,
%: C 58.70; H 4.30; N 21.33.
(IXh). Yield 68%, mp 152 153 C (ethanol
1
dioxane, 2:1). IR
spectrum (KBr), cm : 1695
(C=O), 3300 3350 (N H). Found, %: C 69.34;
H 4.86; N 20.27. C16H14N4O. Calculated, %:
C 69.05; H 5.07; N 20.13.
N-(4-Pyrazolyl)-O-alkyl(aryl)urethanes
Xa e
(Table 3). To a solution of 4 mmol of isocyanate
Ia, c, e in 30 ml of benzene was added 0.04 mol of
alcohol VIIa c or phenol VIId, e, and 5 drops of
triethylamine. The mixture was heated to boiling for
4 5 h, then the solvent was evaporated, and the
residue recrystallized.
N-[1-Phenyl-3-(4-chlorophenyl)]-4-pyrazolylurea
(IXi). Yield 72%, mp 208 209 C (ethanol dioxane,
1
1: 1). IR spectrum (KBr), cm : 1690 (C=O), 3280
3300 (N H). Found, %: C 61.62; H 3.99; N 17.74.
C16H13ClN4O. Calculated, %: C 61.44; H 4.19; N
17.91.
N,N -Bis[1,3-diphenyl-4-pyrazolyl]urea (XI) and
(1,3-diphenyl-4-pyrazolyl)chloroacetamide (XII).
To a solution of isocyanate Ia in 15 ml of toluene was
added 2 mmol of acetic or monochloroacetic acid, and
the mixture was boiled for 3 h. The solvent was
evaporated, and the residue recrystallized.
1-(1,3-Diphenyl-4-pyrazolyl)semicarbazide (IXj).
Yield 64%, mp 169 170 C (ethanol). IR spectrum
1
(KBr), cm : 1700 (C=O), 3300 3370 (N H). Found,
%: C 65.62; H 5.21; N 23.61. C16H15N5O. Calculat-
ed, %: C 65.58; H 5.14; N 23.83.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1752
VOVK et al.
Compound XI. Yield 65%, mp 242 243 C. IR
Zh. Org. Khim., 2001, vol. 37, no. 4, pp. 587 590.
3. Butler, D.E. and Alexander, S.M., J. Heterocyclic
Chem., 1982, vol. 19, no. 5, pp. 1173 1177.
4. Makhsumov, A.G., Atakhodzhaeva, M.A., Talipo-
va, M.A., and Dzhuraev, A.D., Khim.-Farm. Zh.,
1988, vol. 24, no. 4, pp. 431 433.
5. Zagorevskii, V.A., Vlasova, H.V., Zykov, D.A., and
Kirsanov, Z.D., Khim.-Farm. Zh., 1989, vol. 23,
no. 8, pp. 966 971.
6. Morozov, I.S., Klimova, H.V., Bykov, H.V., and
Zaitseva, N.M., Khim.-Farm. Zh., 1991, vol. 25,
no. 3, pp. 29 31.
7. Neyal, S.S. and Singh, C.P., Asian J. Chem.,
1999, vol. 11, no. 2, pp. 523 527.
1
spectrum (KBr), cm : 1685 (C=O), 3215 3280
(N H). 1H NMR spectrum [(CD3)2SO], , ppm:
8.68 s (2H, CH=), 8.46 s (2H, NH), 7.92 s, 7.81 d
(8H arom), 7.58 7.31 m (12H arom). Found, %:
79.20; H 5.33; N 12.11. C31H24N4O. Calculated, %:
C 79.46; H 5.16; N 11.96.
Compound XI. Yield 58%, mp 113 114 C. IR
1
spectrum (KBr), cm : 1705 (C=O), 3280 (N H).
1H NMR spectrum [(CD3)2SO], , ppm: 9.94 s (1H,
NH), 8.74 s (1H, CH=), 7.87 d, 7.79 d (4H arom),
7.53 7.31 m (6H arom). Found, %: C 65.74; H
4.71; N 13.16. C17H14ClN3O. Calculated, %: C
65.49; H 4.53; N 13.48.
8. US Patent, 5807806, 1998; Chem. Abstr., 1998,
vol. 129, 245145.
9. Japan Patent, 09301974, 1997; Chem. Abstr., 1998,
vol. 128, 22908r.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001