Acylation and carbamoylation of 2-hydrazinothiazole derivatives. Identification of isomeric structures

Article abstract of DOI:10.1007/s11178-005-0208-9

Acylation and carbamoylation of 2-(arylmethylidenehydrazino)- and 2-(aroylhydrazino)thiazoles was performed, and structure of the products was established.

Full text of DOI:10.1007/s11178-005-0208-9

Russian Journal of Organic Chemistry, Vol. 41, No. 4, 2005, pp. 584–590. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005,
pp. 594–600.
Original Russian Text Copyright © 2005 by Denisova, Bakulev, Dehaen, Toppet, Van Meervelt, Kodess.
Acylation and Carbamoylation of 2-Hydrazinothiazole
Derivatives. Identification of Isomeric Structures
A. B. Denisova1, V. A. Bakulev1, W. Dehaen2, S. Toppet2, L. Van Meervelt2, and M. I. Kodess3
1 Ural State Technical University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: diman@internethome.ru
2 Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200 F, B-3001 Leuven (Heverlee), Belgium
3 Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 20, Yekaterinburg, 620219 Russia
Received March 9, 2004
Abstract—Acylation and carbamoylation of 2-(arylmethylidenehydrazino)- and 2-(aroylhydrazino)thiazoles
was performed, and structure of the products was established.
2-Hydrazinothiazole derivatives exhibit various
kinds of biological activity, in particular antibacterial,
antiviral, and antitumor [1]. According to the results of
biological studies, compounds having a substituent in
the hydrazino group possess stronger biological ac-
tivity and lower toxicity, as compared to their unsub-
stituted analogs. Of specific interest are semi- and
thiosemicarbazido derivatives, for they are structural
analogs of 2-ureidothiazoles some of which exhibit
antileukemic activity [2].
The amidrazone fragment in 2-arylmethylidene-
and 2-(aroylhydrazino)thiazoles contains two potential
nucleophilic centers: the ring and side-chain nitrogen
atoms. Therefore, their reactions with electrophiles
E could result in formation of isomeric structures A
and/or B (Scheme 1).
it was shown that carbamoylation and thiocarbamoyla-
tion of these compounds occurs at the ring nitrogen
atom. However, the data of elemental analysis, IR and
1H NMR spectroscopy, and mass spectrometry are
insufficient to rigorously assign isomeric structures A
and B; these data indicate only the presence of an acyl
(or carbamoyl) moiety in the product.
In order to examine the relative reactivity of the
nitrogen atoms in the thiazole ring and side chain in
2-hydrazinothiazole derivatives having a substituent at
the terminal hydrazine nitrogen atom, we performed
chloroacetylation and carbamoylation of 2-aryl-
methylidenehydrazino- and 2-(aroylhydrazino)thia-
zoles Ia–Ic and IIa–IIc (Schemes 2, 3). The structure
of products III–V thus obtained was determined using
13C NMR spectroscopy, and the structure of Va was
proved by the X-ray diffraction data. In addition, we
synthesized model compounds VI–VIII (Schemes 4, 5)
already containing substituent at the ring nitrogen atom
(VI) or in the side chain (VII, VIII) [5–8] and
examined their spectral parameters.
The reactivity of monosubstituted hydrazinothia-
zoles toward electrophiles was studied in [3, 4] where
Scheme 1.
R
N
N
N
S
E
The reactions of 2-arylmethylidenethiazoles Ia–Ic
and 2-(aroylhydrazino)thiazoles IIa–IId with chloro-
acetyl chloride at room temperature gave the corre-
sponding N-chloroacetyl derivatives IIIa–IIIc and
IVa–IVd as individual products. Under analogous con-
ditions, carbamoylation of 2-aroylhydrazinothiazoles
IIa–IId with phenyl and p-chlorophenyl isocyanates
afforded N-arylcarbamoylhydrazides Va–Vc as the
only products.
R
N
E
A
N
N
E
R
S
H
N
N
N
S
B
E = ArNCO, RCOCl.
1070-4280/05/4104-0584 © 2005 Pleiades Publishing, Inc.

ACYLATION AND CARBAMOYLATION OF 2-HYDRAZINOTHIAZOLE DERIVATIVES.
585
Scheme 2.
R
R
ClCH2COCl
MeCN
N
N
Ar
Ar
N
N
N
H
N
S
S
O
Cl
Ia–Ic
IIIa–IIIc
Ar = p-O2NC6H4, R = Ph (a); Ar = 3,4,5-(MeO)3C6H2, R = p-MeC6H4 (b), CO2Et (c).
Scheme 3.
R
R
R
ClCH2COCl
MeCN
N
N
N
H
H
H
Ar
Ar
Ar
Ar'NCO, MeCN
N
N
N
N
N
N
S
S
S
H
O
O
O
O
O
Cl
NHAr'
Va–Vc
IIa–IId
IVa–IVd
II, IV, Ar = Ph, R = CO2Et (a), p-ClC6H4 (b), p-MeC6H4 (c); Ar = 3,4,5-(MeO)3C6H2, R = p-MeC6H4 (d); V, Ar = Ar' = Ph,
R = H (a); Ar = Ph, Ar' = p-ClC6H4 (b); R = p-ClC6H4, p-MeC6H4 (c).
The presence of a chloroacetyl or arylcarbamoyl
are also the most sensitive to introduction of a car-
bonyl-contaning group into the initial structure. As
a result, the C2 signal was displaced upfield by 12.70–
15.00 ppm, and the C5 signal suffered a downfield shift
by 6.51–7.42 ppm. The chemical shifts of C4 and
carbon atoms of the two carbonyl groups (at C4 in the
thiazole ring and in the benzoylhydrazide fragment)
remained almost unchanged. The observed variations
are similar to those found for Ic/IIIc; therefore, we
presumed that both acylation and carbamoylation of
monosubstituted 2-hydrazinothiazole derivatives Ic
and IIa involves electrophilic attack at the same
nitrogen atom.
Signals in the 13C NMR spectra of compounds IIa
and Va were assigned using HETCOR and HMBC
two-dimensional correlation techniques. Initial ben-
zoylhydrazine IIa showed an interaction between the
C2 atom and NH proton, which is rarely observed in
13C NMR spectra; as a result, the C2 signal appears as
a doublet of doublets. The C2 signal in the spectra of
IVa and Va is a doublet, presumably due to the lack of
interaction between C2 and NH proton (for the latter is
replaced by acyl group).
moiety in compounds III–V was confirmed by their
1
analytical data and H NMR and mass spectra (see
Experimental). However, rigorous identification of
possible isomeric structures cannot be performed on
the basis of these data. It should also be noted that the
1H NMR spectra of III–V are characterized by an ap-
preciable downfield shift of signals from the thiazole
ring proton (∆δ = 0.7–0.9 ppm), proton of the CH=N
fragment (∆δ = 0.8–1.2 ppm), and carboxamide NH
proton (∆δ = 0.78–0.97 ppm) relative to the cor-
responding signals of the initial compounds (see
Experimental). These data may be treated only as
an indirect evidence that the reaction occurred at the
exocyclic nitrogen atom (N'), and additional proofs are
necessary.
Therefore, we examined the 13C NMR spectra of
the following pairs: Ic, IIIc; Ia, IVa; and IIa, Va.
Specific attention was given to variation of chemical
shifts of the carbon atoms in the thiazole ring of prod-
ucts III–V relative to the corresponding parameters of
initial compounds I and II. The 13C NMR spectra of
the above compounds are given in Experimental. The
following variations in the 13C chemical shifts were
observed for chloroacetylation product IIIc relative
to initial compound Ic: C5, 7.4 ppm downfield; C2,
13.3 ppm upfield; C4, unchanged.
To estimate the effect of substituent on the ring
nitrogen atom on the chemical shifts of carbon atoms
in the thiazole ring, we synthesized 3-phenyl- and 3-
methyldihydrothiazoles VIa and VIb according to the
procedure described in [5] and recorded their 13C NMR
spectra (see Experimental; no relevant data were given
in [5]). It is seen that the C4 and C5 signals of com-
pounds VIa and VIb appear in a stronger field relative
Analysis of the 13C NMR spectra of ethyl 2-ben-
zoylhydrazino-4-thiazolecarboxylate (IIa) and its
chloroacetyl and carbamoyl derivatives IVa and Va
showed that the C2 and C5 atoms in the thiazole ring
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

DENISOVA et al.
586
Scheme 4.
R
R
R
CO2Et
NH
NH
ArCHO
BrCH2COCO2Et
N
Ar
Ar
N
H2N
N
N
H
S
N
S
N
S
H
VIa, VIb
Ar = 3,4,5-(MeO)3C6H2, R = Ph (a), Me (b).
Scheme 5.
CO2Et
CO2Et
F3C
EtO
N
N
N
N
AcOH, AcONa
F3C
N
H
N
S
S
O
OH
VIII
VII
to those of thiazole Ic having no substituent on the
ring nitrogen atom. The largest shift is observed or C4
(∆δC = 11.50–12.00 ppm), while the shift of the
C5 signal is smaller in absolute value, ∆δC = 2.91–
3.62 ppm. An upfield shift was also observed for
the ester carbonyl carbon signal. Attachment of both
phenyl and methyl groups (which possess different
electronic properties) to the thiazole nitrogen atom did
not change the position of the C2 signal located at
δC 169 ppm in the spectra of the three compounds
(Ic, VIa, and VIb).
fluorobutane-1,3-dione (an analog of VIII) to the
corresponding 3-trifluoromethyl-substituted pyrazole
(an analog of VII) revealed the same trends in varia-
tion of the carbon chemical shifts [6].
As follows from analysis of our results and
published data [9, 10], substituents at the endo- and
exocyclic nitrogen atoms produce different (in both
absolute value and sign) changes of the chemical shifts
of the thiazole carbon atoms. The presence of a sub-
stituent on N3 induces upfield shifts of the C4 and C5
signals, the effect on C4 being stronger, while the
chemical shift of C2 remains unchanged. Attachment of
an electron-acceptor group to the exocyclic nitrogen
atom leads to an upfield shift of the C2 signal and
a downfield shift of the C5 signal, whereas the position
of the C4 signal does not change. These relations could
help us to identify acyl, alkyl, and carbamoyl deriva-
tives of monosubstituted hydrazinothiazoles. The ob-
served chemical shifts of the thiazole carbon atoms in
the 13C NMR spectra of IIIc, IVa, and Va are similar
to those found for model structure VII (in comparison
with the initial compounds) and strongly different from
the corresponding parameters of 3-substituted dihydro-
thiazoles VIa and VIb. Therefore, compounds III–V
are products of electrophilic attack at the exocyclic
nitrogen atom.
As model compound having a substituent at the
side-chain nitrogen atom we selected ethyl 2-(5-hy-
droxy-3-trifluoromethyl-1-pyrazolyl)thiazole-4-car-
boxylate (VII), which is the product of intramolecular
acylation (cyclization) of ethyl 4,4,4-trifluoro-3-(4-
ethoxycarbonylthiazol-2-ylhydrazono)butanoate (VIII)
(Scheme 5). The chemical shifts of the carbon atoms
in the thiazole ring of compound VIII were almost
identical to those found for structurally similar thia-
zolylhydrazone Ic (see Experimental). Comparison of
the 13C NMR spectra of model compounds VII and
VIII shows that the intramolecular cyclization is
accompanied by an appreciable (∆δC = 11.50 ppm)
upfield shift of the C2 signal and slightly smaller
downfield shift (∆δC = 7.10 ppm) of the C5 signal,
while the position of the C4 signal does not change.
The chemical shifts of carbon atoms in the pyrazole
ring coincided with those found for 5-substituted
3-trifluoromethyl-1-(2-thiazolyl)pyrazoles whose 13C
NMR spectra characteristically contain a quartet at
δC 143.1 ppm due to the C3 atom [6, 7]. It should be
added that the intramolecular cyclization of 2-thia-
zolylhydrazone derived from 1-(2-thienyl)-4,4,4-tri-
Our conclusions were confirmed by the X-ray
diffraction data obtained for ester Va [11] (see figure).
Colorless monoclinic crystals of Va were isolated from
an oversaturated solution in chloroform; the following
unit cell parameters were found: a = 13.618(2), b =
11.870(2), c = 24.588(4) Å; α = 90, β = 95.546, γ =
90°; V = 3955.9(11) Å3; Z = 8; space group P21/n
(no. 14). The molecule of Va is not planar. There are
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

ACYLATION AND CARBAMOYLATION OF 2-HYDRAZINOTHIAZOLE DERIVATIVES.
587
two conformations differing by arrangement of the
mean plane of the thiazole ring and benzene ring in the
C22
C23
C21
C20
phenylcarbamoyl group with respect to the benzoyl-
hydrazine fragment. One of these conformations is
characterized by coplanar arrangement of the thiazole
ring and benzene ring of the phenylcarbamoyl frag-
ment, while in the other conformation the thiazole and
benzene ring planes form a dihedral angle of 24.8°.
The benzene ring in the benzoylhydrazine fragment is
almost orthogonal to the mean plane of the thiazole
and phenylcarbamoyl rings. No hydrogen bond is
formed between the carbonyl group and NH proton,
for these groups are located in different planes. The
thiazole ring approaches a regular pentagon. The bond
lengths and bond angles therein are typical of five-
membered aromatic heterocycles: the C–C and C–N
bond lengths range from 1.30 to 1.39 Å. The bond
angles in the thiazole ring range from 88° (C2SC5)
to 116° (SC2N3). The benzene rings deviate from
planarity by no more than 2°. The complete set of
crystallographic parameters, including bond lengths
and bond and dihedral angles, is available from the
authors (see also [11]).
C24
C19
C17
O26
O18
N16 N3
C2
C25
C28
O27
C29
N9
C4
C5
C11
N6
C7
O8
C10
C15
C12
C13
S1
C14
Structure of the molecule of ethyl 2-(N'-benzoyl-N-phenyl-
carbamoylhydrazino)thiazole-4-carboxylate (Va).
3
7.87 d and 8.27 d (4H, AA'BB' system, J = 8.7 Hz),
8.13 s (1H, CH=N), 12.54 s (1H, NH). Found, %:
N 17.21; S 9.54. C16H12N4O2S. Calculated, %: N 17.28;
S 9.89.
4-(4-Methylphenyl)-2-[N'-(3,4,5-trimethoxyben-
zylidene)hydrazino]thiazole (Ib). Yield 82%, color-
EXPERIMENTAL
1
less crystals, mp 255–257°C. H NMR spectrum, δ,
1
The H and 13C NMR spectra were measured on
ppm: 2.32 s (3H, Me), 3.70 s (3H, 4-OMe), 3.84 s (6H,
3-OMe, 5-OMe), 6.97 s (2H, 2-H, 6-H), 7.20 s (1H,
Bruker WM-250 (1H, 250.13 MHz), Bruker DRX-400
3
1
(13C, 100.61 MHz; H, 400.13 MHz), and Bruker
5-H), 7.21 d and 7.74 d (4H, AA'XX' system, J =
1
AMX-400 spectrometers (13C, 100.61 MHz; H,
7.9 Hz), 7.96 s (1H, CH=N), 12.07 s (1H, NH). Found,
%: N 11.26; S 7.97. C20H21N3O3S. Calculated, %:
N 10.96; S 8.36.
400.13 MHz) using CDCl3 and DMSO-d6 as solvents
and tetramethylsilane as internal reference. The mass
spectra (electron impact, 70 eV) were recorded on
a Varian MAT-311A spectrometer (accelerating voltage
3 kV). The progress of reactions and the purity of
products were monitored by TLC on Sorbfil UV-254
and Silufol UV-254 plates using chloroform–ethanol
(15:1 and 9:1) as eluent. The melting points were not
corrected.
Ethyl 2-[N'-(3,4,5-trimethoxybenzylidene)hydra-
zino]thiazole-4-carboxylate (Ic). Yield 78%, colorless
1
crystals, mp 209–211°C. H NMR spectrum, δ, ppm:
3
1.34 t (3H, Me, J = 7.1 Hz), 3.71 s (3H, 4-OMe),
3
3.84 s (6H, 3-OMe, 5-OMe), 4.25 q (2H, CH2, J =
7.1 Hz), 6.91 s (2H, C6H2), 7.59 s (1H, 5-H), 7.85 s
(1H, CH=N), 12.25 s (1H, NH). 13C NMR spectrum,
1
2
δC, ppm: 118.5 d (C5, J = 192 Hz), 143.0 d (C4, J =
4-Substituted 2-(N'-arylmethylidenehydrazino)-
thiazoles Ia–Ic (general procedure). Appropriate
aromatic aldehyde, 2.70 mmol, was added to a solution
of 2.66 mmol of the corresponding 4-substituted
2-hydrazinothiazole in 30 ml of ethanol, and the mix-
ture was heated for 15 min under reflux. The mixture
was cooled, and the precipitate was filtered off, dried,
and recrystallized from ethanol.
1
3
4.0 Hz), 143.2 d.t (HC=N, J = 161, J = 5.5 Hz),
161.6 t.d (4-CO, J = 3.3, J = 1.8 Hz), 169.2 d (C2,
3J = 10 Hz). Found, %: N 11.73; S 8.56. C16H19N3O5S.
Calculated, %: N 11.50; S 8.77.
3
3
4-Substituted 2-(N'-aroylhydrazino)thiazoles
IIa–IId (general procedure). Substituted benzoyl
chloride, 2.70 mmol, and triethylamine, 2.70 mmol,
were added dropwise under stirring to a solution of
2.66 mmol of 4-substituted 2-hydrazinothiazole in
15 ml of dioxane. The solvent was removed, the
residue was treated with water, and the precipitate was
2-[N'-(4-Nitrobenzylidene)hydrazino]-4-phenyl-
thiazole (Ia). Yield 95%, yellow crystals, mp 249–
1
251°C. H NMR spectrum, δ, ppm: 7.27–7.45 m (3H,
C6H5), 7.39 s (1H, 5-H), 7.90–7.92 m (2H, C6H5),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

DENISOVA et al.
588
1
filtered off, dried, and recrystallized from ethanol–
water (4:1).
less crystals, mp 132–135°C. H NMR spectrum, δ,
ppm: 5.16 s (2H, CH2), 7.35–7.50 m (3H, C6H5), 7.90–
8.02 m (2H, C6H5), 8.12 d and 8.32 d (4H, AA'BB', 3J =
8.9 Hz), 8.25 s (1H, 5-H), 7.83 s (1H, CH=N). Mass
spectrum, m/z (Irel, %): 399/401 (47/18) [M]+, 323 (91)
[M – 76], 323 (91), 322 (17), 248 (17), 202 (49), 201
(18), 175 (48), 174 (18), 161 (19), 133 (100), 128 (14).
Found, %: Cl 8.96; N 13.95; S 7.88. C18H13ClN4O3S.
Calculated, %: Cl 8.88; N 14.04; S 8.03.
Ethyl 2-(N'-benzoylhydrazino)thiazole-4-carbox-
ylate (IIa). Yield 75%, colorless crystals, mp 194–
1
196°C. H NMR spectrum, δ, ppm: 1.26 t (3H, Me,
3
3J = 7.1 Hz), 4.25 q (2H, OCH2, J = 7.1 Hz), 7.30–
7.75 m (3H, C6H5), 7.70 s (1H, 5-H), 7.80–8.10 m (2H,
C6H5), 9.80 s (1H, NH), 10.90 s (1H, NH). 13C NMR
1
spectrum, δC, ppm: 118.4 d (C5, J = 194 Hz), 142.8 d
2
3
3
(C4, J = 4.3 Hz), 160.9 t.d (4-CO, J = 3.2, J =
2-[N-Chloroacetyl-N'-(3,4,5-trimethoxybenzyli-
dene)hydrazino]-4-(4-methylphenyl)thiazole (IIIb).
Yield 84%, colorless crystals, mp 188–190°C.
1H NMR spectrum, δ, ppm: 2.33 s (3H, Me), 3.73 s
(3H, 4-OMe), 3.83 s (6H, 3-OMe, 5-OMe), 5.09 s (2H,
CH2), 7.19 s (2H, C6H2), 7.26 d and 7.82 d (4H,
3
3
1.8 Hz), 166.4 d.t (PhCON, J = 10.6, J = 3.8 Hz),
172.5 d.d (C2, J = 9.2, J = 5.1 Hz). Found, %:
N 14.21; S 10.88. C13H13N3O3S. Calculated, %:
N 14.43; S 11.01.
3
3
2-(N'-Benzoylhydrazino)-4-(4-chlorophenyl)-
thiazole (IIb). Yield 77%, colorless crystals, mp 215–
3
AA'XX', J = 8.1 Hz), 8.12 s (1H, 5-H) 8.48 s (1H,
1
217°C. H NMR spectrum, δ, ppm: 7.28 s (1H, 5-H),
CH=N). Mass spectrum, m/z (Irel, %): 459/461 (3/1)
[M]+, 383 (10) [M – 76], 266/268 (23/9), 218 (14), 217
(100), 190 (56), 178 (11), 150 (10), 148 (27), 147 (17).
Found, %: Cl 7.54; N 9.35; S 7.35. C22H22ClN3O4S.
Calculated, %: Cl 7.71; N 9.14; S 6.97.
3
7.40 d and 7.78 d (4H, AA'BB', J = 8.5 Hz), 7.45–
7.75 m (3H, C6H5), 7.87–8.13 m (2H, C6H5), 9.56 s
(1H, NH), 10.77 s (1H, NH). Found, %: Cl 10.86;
N 12.56; S 9.61. C16H12ClN3OS. Calculated, %:
Cl 10.75, N 12.74; S 9.72.
Ethyl 2-[N-chloroacetyl-N'-(3,4,5-trimethoxy-
benzylidene)hydrazino]thiazole-4-carboxylate
(IIIc). Yield 85%, colorless crystals, mp 147–149°C.
2-(N'-Benzoylhydrazino)-4-(4-methylphenyl)-
thiazole (IIc). Yield 75%, colorless crystals, mp 238–
1
1H NMR spectrum, δ, ppm: 1.31 t (3H, Me, J =
3
240°C. H NMR spectrum, δ, ppm: 2.30 s (3H, Me),
3
7.18 d and 7.75 d (4H, AA'XX', J = 8.2 Hz), 7.25 s
7.1 Hz), 3.73 s (3H, 4-OMe), 3.84 s (6H, 3-OMe,
3
(1H, 5-H), 7.40–7.70 m (3H, C6H5), 7.85–8.10 m
(2H, C6H5), 9.50 s (1H, NH), 10.75 s (1H, NH).
Found, %: N 13.42; S 10.25. C17H15N3OS. Calculated,
%: N 13.58; S 10.36.
5-OMe), 4.31 q (2H, OCH2, J = 7.0 Hz), 5.05 s (2H,
CH2), 7.16 s (2H, C6H2), 8.52 s (1H, CH=N), 8.55 s
(1H, 5-H). 13C NMR spectrum, δC, ppm: 125.9 d (C5,
1J = 191 Hz), 142.7 d (C4, J = 3.0 Hz), 154.3 d.t
2
(HC=N, J = 169, J = 5.5 Hz), 155.9 d (C2, J =
1
3
3
4-(4-Methylphenyl)-2-[N'-(3,4,5-trimethoxyben-
zoyl)hydrazino]thiazole (IId). Yield 74%, colorless
3
3
10 Hz), 161.0 t.d (4-CO, J = 3.3, J = 2.0 Hz). Mass
spectrum, m/z (Irel, %): 441/443 (16/6) [M]+, 365 (67)
[M – 76], 366/364 (31/18), 320/318 (21/8), 248 (11),
208 (14), 201 (13), 200 (24), 199 (74), 195 (12), 194
(62), 193 (100), 180 (53), 173 (15), 172 (68), 167 (14),
165 (62), 153 (62), 152 (16), 150 (44), 137 (29).
Found, %: Cl 8.24; N 9.35; S 7.41. C18H20ClN3O6S.
Calculated, %: Cl 8.02; N 9.51; S 7.26.
1
crystals, mp 186–188°C. H NMR spectrum, δ, ppm:
2.32 s (3H, Me), 3.74 s (3H, 4-OMe), 3.85 s (6H,
3-OMe, 5-OMe), 7.17 s (1H, 5-H), 7.20 d and 7.72 d
3
(4H, AA'XX', J = 8.2 Hz), 7.28 s (2H, C6H2), 10.89 s
(1H, NH). Found, %: N 10.68; S 7.89. C20H21N3O4S.
Calculated, %: N 10.52; S 8.03.
4-Substituted 2-(N'-arylmethylidene)- and 2-[N'-
aroyl-N-(chloroacetyl)hydrazino]thiazoles IIIa–IIIc
and IVa–IVd (general procedure). Triethylamine,
2.80 mmol, was added to a mixture of 2.66 mmol of
thiazole Ia–Ic or IIa–IId and 2.75 mmol of chloro-
acetyl chloride in 30 ml of anhydrous acetonitrile (or
ethyl acetate), and the mixture was heated for 15 min
under reflux. The solvent was distilled off, the residue
was treated with water, and the precipitate was filtered
off and dried.
Ethyl 2-(N'-benzoyl-N-chloroacetylhydrazino)-
thiazole-4-carboxylate (IVa). Yield 82%, colorless
1
crystals, mp 169–171°C. H NMR spectrum, δ, ppm:
3
3
1.29 t (3H, Me, J = 7.2 Hz), 4.24 q (2H, OCH2, J =
2
7.1 Hz), 4.48 d and 4.76 d (2H, CH2, J = 15.6 Hz),
3
3
3
7.56 d (2H, J = 7.2 Hz), 7.65 d.d (1H, J = 7.2, J =
3
4
7.6 Hz), 7.99 d.d (2H, C6H5, J = 7.2, J = 1.2 Hz),
8.13 s (1H, 5-H), 11.83 (1H, NH). 13C NMR spectrum,
δC, ppm: 125.8 d (C5, J = 193 Hz), 140.6 d (C4, J =
1
2
4.3 Hz), 157.5 d (C2, J = 6.6 Hz), 160.5 t.d (4-CO,
3
2-[N-Chloroacetyl-N'-(4-nitrobenzylidene)hy-
drazino]-4-phenylthiazole (IIIa). Yield 85%, color-
3J = 3.2, J = 1.5 Hz), 167.0 d.t (PhCO, J = 8.7, J =
3
3
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

ACYLATION AND CARBAMOYLATION OF 2-HYDRAZINOTHIAZOLE DERIVATIVES.
589
3.8 Hz). Mass spectrum, m/z (Irel, %): 368/370 (47/22)
[M]+, 332 (38), 323/325 (19/8) [M – 45], 294 (14), 293
(20), 292 (100) [M – 75], 260 (31), 246 (12), 245 (12),
186 (51), 142 (14). Found, %: N 11.73; S 8.54.
C15H14ClN3O4S. Calculated, %: N 11.43; S 8.72.
Ethyl 2-(N'-benzoyl-N-phenylcarbamoylhydra-
zino)thiazole-4-carboxylate (Va). Yield 88%, color-
1
less crystals, mp 188–190°C. H NMR spectrum, δ,
ppm: 1.22 t (3H, Me, 3J = 7.0 Hz), 4.20 q (2H, OCH2,
3J = 7.0 Hz), 7.00–7.80 m (8H, C6H5), 7.85–8.40 m
(2H, C6H5), 8.12 s (1H, 5-H), 9.95 s (1H, NH), 11.43 s
(1H, NH). 13C NMR spectrum, δC, ppm: 124.9 d (C5,
2-(N'-Benzoyl-N-chloroacetylhydrazino)-4-
(4-chlorophenyl)thiazole (IVb). Yield 81%, colorless
2
1J = 192 Hz), 140.6 d (C4, J = 3.8 Hz), 159.8 d (C2,
1
crystals, mp 179–181°C. H NMR spectrum, δ, ppm:
3
3
3J = 9.2 Hz), 160.7 t.d (4-CO, J = 3.2, J = 1.7 Hz),
167.0–167.2 m (PhCO). Mass spectrum, m/z (Irel, %):
[M]+ absent, 291 (15), 186 (9), 140 (8), 120 (6), 119
(80), 106 (7), 91 (23), 77 (29). Found, %: N 13.74;
S 7.85. C20H18N4O4S. Calculated, %: N 13.65; S 7.81.
7.42 d and 7.81 d (4H, AA'BB', 3J = 8.5 Hz), 4.70 d and
2
4.90 d (2H, CH2, J = 15.6 Hz), 7.59–7.80 m (3H,
C6H5), 7.79–8.12 m (2H, C6H5), 7.90 s (1H, 5-H),
11.74 (1H, NH). Mass spectrum, m/z (Irel, %): 405/407
(2/1.4) [M]+, 369/371 (11/4), 329/331 (5/2) [M – 76],
208/210 (5/3), 105 (100). Found, %: Cl 17.65; N 10.25;
S 7.76. C18H19Cl2N3O2S. Calculated, %: Cl 17.45;
N 10.34; S 7.89.
2-[N'-Benzoyl-N-(4-chlorophenylcarbamoyl)-
hydrazino]-4-(4-chlorophenyl)thiazole (Vb). Yield
1
90%, colorless crystals, mp 232–234°C. H NMR
3
2-(N'-Benzoyl-N-chloroacetylhydrazino)-4-
(4-methylphenyl)thiazole (IVc). Yield 79%, colorless
spectrum, δ, ppm: 7.39 d and 7.78 d (8H, AA'BB', J =
8.6 Hz), 7.50–7.80 m (3H, C6H5), 7.61 s (1H, 5-H),
8.00–8.25 m (2H, C6H5), 9.99 s (1H, NH), 11.30 s
(1H, NH). Mass spectrum, m/z (Irel, %): [M]+ absent,
329/331 (14/6), 224/226 (7/3), 153/155 (28/9),
125/127 (9/3), 106 (8), 105 (100), 77 (27). Found, %:
Cl 14.53; N 11.74; S 6.44. C23H16Cl2N4O2S. Calcu-
lated, %: Cl 14.67; N 11.59; S 6.63.
1
crystals, mp 180–182°C. H NMR spectrum, δ, ppm:
2
2.28 s (3H, Me), 4.70 d and 4.78 d (2H, CH2, J =
15.6 Hz), 7.17 d and 7.68 d (4H, AA'BB', 3J = 8.1 Hz),
7.60–7.76 m (3H, C6H5), 7.75 s (1H, 5-H), 7.96–
8.13 m (2H, C6H5), 11.70 (1H, NH). Mass spectrum,
m/z (Irel, %): 385/387 (5/2) [M]+, 309 (7) [M – 76], 349
(8), 204 (7), 188 (5), 116 (3), 106 (8). Found, %:
Cl 9.02; N 10.77; S 8.03. C19H16ClN3O2S. Calculated,
%: Cl 9.19; N 10.89; S 8.31.
2-[N'-Benzoyl-N-(4-chlorophenylcarbamoyl)-
hydrazino]-4-(4-methylphenyl)thiazole (Vc). Yield
1
84%, colorless crystals, mp 229–231°C. H NMR
3
2-[N-Chloroacetyl-N'-(3,4,5-trimethoxybenzoyl)-
hydrazino]-4-(4-methylphenyl)thiazole (IVd). Yield
spectrum, δ, ppm: 7.13 d and 7.70 d (4H, AA'XX', J =
3
8.6 Hz), 7.39 d and 7.79 d (4H, AA'BB', J = 8.8 Hz),
1
81%, colorless crystals, mp 220–222°C. H NMR
7.50–7.80 m (3H, C6H5), 7.61 s (1H, 5-H), 8.00–
8.27 m (2H, C6H5), 10.07 s (1H, NH), 11.28 s (1H,
NH). Mass spectrum, m/z (Irel, %): [M]+ absent, 310
(13), 311 (8), 153/155 (35/10), 205 (8), 189 (10), 143
(6), 105 (100), 77 (25). Found, %: Cl 7.73; N 12.34;
S 6.82. C24H19ClN4O2S. Calculated, %: Cl 7.66;
N 12.10; S 6.93.
spectrum, δ, ppm: 2.29 s (3H, Me), 3.79 s (3H,
4-OMe), 3.89 s (6H, 3-OMe, 5-OMe), 4.59 d and
2
4.87 d (2H, CH2, J = 15.6 Hz), 7.39 s (2H, C6H2),
3
7.18 d and 7.72 d (4H, AA'XX', J = 8.3 Hz), 7.77 s
(1H, 5-H), 11.67 (1H, NH). Mass spectrum, m/z (Irel,
%): 475/477 (12/5) [M]+, 441 (44), 440/442 (55/9),
424/426 (20/2), 400 (3) [M –76], 381 (14), 366 (26),
229 (10), 225 (10), 220 (17), 219 (48), 217 (27), 216
(18), 196 (51), 195 (100), 194 (30), 193 (51), 188 (21).
Found, %: Cl 7.31; N 8.97; S 6.68. C22H22ClN3O5S.
Calculated, %: Cl 7.45; N 8.83; S 6.74.
4-Substituted 2-(N'-aroyl-N-arylcarbamoylhy-
drazino)thiazoles Va–Vc (general procedure). To
a suspension of 2.66 mmol of 2-aroylhydrazinothiazole
IIa–IIc in 25 ml of anhydrous acetonitrile or ethyl
acetate we added under stirring at room temperature
2.72 mmol of phenyl isocyanate (dropwise) or
4-chlorophenyl isocyanate (in portions). The mixture
was stirred for 1 h (TLC), and the precipitate was
filtered off, washed with anhydrous acetonitrile, and
dried.
3-Substituted 2-(N'-arylmethylidenehydrazono)-
2,3-dihydrothiazoles VIa and VIb were synthesized
according to the procedure reported in [5].
Ethyl 3-phenyl-2-[N'-(3,4,5-trimethoxybenzyli-
dene)hydrazono]-2,3-dihydrothiazole-4-carboxylate
(VIa). Yield 78%, light yellow crystals, mp 136–
1
137°C. H NMR spectrum, δ, ppm: 1.09 t (3H, Me,
3J = 7.3 Hz), 3.72 s (3H, 4-OMe), 3.82 s (6H, 3-OMe,
3
5-OMe), 4.05 q (2H, OCH2, J = 7.3 Hz), 6.94 s (2H,
2'-H, 6'-H), 7.25–7.35 m (3H, C6H5), 7.40–7.55 m (2H,
C6H5), 7.49 s (1H, 5-H), 8.07 s (1H, CH=N). 13C NMR
1
spectrum, δC, ppm: 115.6 d (C5, J = 195 Hz), 131.5 d
2
1
3
(C4, J = 5.0 Hz), 153.2 d.t (HC=N, J = 163, J =
5.1 Hz), 158.0 t.d (4-CO, 3J = 3.0, 3J = 2.8 Hz), 169.2 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

DENISOVA et al.
590
(C2, 3J = 6 Hz). Mass spectrum, m/z (Irel, %): 441 (100)
[M]+, 442 (26), 235 (12), 234 (83), 206 (13), 180 (20),
165 (39), 150 (14). Found, %: N 9.36; S 7.02.
C22H23N3O5S. Calculated, %: N 9.52; S 7.26.
thiazole-4-carboxylate and 30 ml of ethanol, and the
mixture was heated for 30–40 min under reflux. A part
of the solvent was distilled off, and the precipitate was
filtered off and recrystallized from ethanol–water
(5:1). Yield 87%, light yellow crystals, mp 96–97°C.
Ethyl 3-methyl-2-[N'-(3,4,5-trimethoxybenzyli-
dene)hydrazono]-2,3-dihydrothiazole-4-carboxylate
(VIb). Yield 81%, light yellow crystals, mp 135–
3
1H NMR spectrum, δ, ppm: 1.28 t (3H, Me, J =
3
7.0 Hz), 1.39 t (3H, Me, J = 7.0 Hz), 3.52 s (2H,
3
1
CH2), 4.22 q (2H, OCH2, J = 7.0 Hz), 4.38 q (3H,
137°C. H NMR spectrum, δ, ppm: 1.30 t (3H, Me,
OCH2, 3J = 7.0 Hz), 7.26 s (1H, 5-H), 7.64 s (1H, NH).
13C NMR spectrum, δC, ppm: 119.8 d (C5), 120.8 q
3J = 7.3 Hz), 3.62 s (1H, 3-Me), 3.70 s (3H, 4-OMe),
3
3.82 s (6H, 3-OMe, 5-OMe), 4.27 q (2H, OCH2, J =
1
2
(CF3, J = 273.0 Hz), 129.5 q (F3CC, J = 33.5 Hz),
142.8 d (C4), 160.0–161.5 m (4-CO), 168.1 (C2). Mass
spectrum, m/z (Irel, %): 353 (15) [M]+, 308 (12), 307
(20), 288 (10), 284 (55), 262 (27), 261 (100), 259
(11), 235 (17), 234 (13), 210 (10), 206 (15). Found, %:
N 11.26; S 9.55. C12H14F3N3O4S. Calculated, %:
N 11.89; S 9.08.
7.3 Hz), 7.04 s (2H, 2-H, 6-H), 7.44 s (1H, 5-H), 8.24 s
(1H, CH=N). 13C NMR spectrum, δC, ppm: 115.0 d
1
(C5, J = 196 Hz), 130–132 m (C4), 151.7 d.t (HC=N,
3
3
3
1J = 163, J = 5.1 Hz), 158.5 t.d (4-CO, J = 3.1, J =
2.8 Hz), 169.5 d.q (C2, J = 5.8, J = 3.0 Hz). Mass
spectrum, m/z (Irel, %): 379 (100) [M]+, 380 (22), 194
(5), 190 (6), 180 (20), 172 (51), 165 (41), 160 (9), 150
(15), 144 (11). Found, %: N 11.30; S 8.35.
C17H18N3O5S. Calculated, %: N 11.07; S 8.45.
3
3
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 01-03-33173).
Ethyl 2-(5-hydroxy-3-trifluoromethylpyrazol-1-
yl)thiazole-4-carboxylate (VII). A mixture of 3 mmol
of compound VIII, 3 mmol of sodium acetate, and
30 ml of glacial acetic acid was heated for 40 min
under reflux. A part of the solvent was distilled off, the
precipitate of compound VII sodium salt was filtered
off and dispersed in water, and the mixture was
acidified to pH 3–4 with hydrochloric acid and stirred
for 3 h. The precipitate was filtered off, washed with
water, and dried. Yield 75%, colorless crystals,
REFERENCES
1. Andronnikova, G.P., Usol’tseva, S.V., Nikolaeva, S.V.,
Anoshina, G.M., Nifontov, V.I., and Emelina, E.M.,
Khim.-Farm. Zh., 1988, vol. 11, p. 1326.
2. Lee-Cheng, R.K.Y. and Cheng, C.C., J. Med. Chem.,
1979, vol. 22, p. 28.
3. Usol’tseva, S.V., Denisova, A.B., and Andronniko-
va, G.P., Zh. Org. Khim., 1992, vol. 28, p. 2182.
4. Berg, S.S., Peart, B.J., and Toft, M.F., J. Chem Soc.,
Perkin Trans. 1, 1975, p. 1040.
5. Hildegard, J., Seifert, K., John, S., and Bulka, S.,
Pharmazie, 1978, vol. 33, p. 259.
6. Denisova, A.B., Sosnovskikh, V.Ya., Dehaen, W., Top-
pet, S., Van Meervelt, L., and Bakulev, V.A., J. Fluorine
Chem., 2002, vol. 115, p. 183.
7. Singh, S.P. and Kumar, D.S., Indian J. Chem., Sect. B,
1992, vol. 31, p. 233.
8. Saloutin, V.I., Fomin, A.N., and Pashkevich, K.I., Izv.
Akad. Nauk SSSR, Ser. Khim., 1985, no. 1, p. 144.
9. Abbotto, A., Bradamante, S., and Pagani, G., J. Org.
Chem., 1996, vol. 61, p. 1761.
10. Utinan, M.F., Gulbis, Yu.V., Valter, R.E., and Lie-
pin’sh, E.E., Khim. Geterotsikl. Soedin., 1991, p. 410.
11. Cambridge Crystallographic Data Center. Entry
1
mp 145–146°C. H NMR spectrum, δ, ppm: 1.32 t
(3H, Me, 3J = 7.0 Hz), 4.35 q (2H, OCH2, 3J = 7.0 Hz),
5.81 s (1H, 4-H, pyrazole), 8.28 s (1H, 5-H, thiazole).
1
13C NMR spectrum, δC, ppm: 120.8 q (CF3, J =
269.3 Hz), 126.9 d (C5, thiazole, 1J = 195.3 Hz), 142.7 d
2
2
(C4, thiazole, J = 5.6 Hz), 143.1 q (C3, pyrazole, J =
37.5 Hz), 156.6 d (C2, thiazole, 3J = 10.1 Hz), 160.4 t.d
3
2
(4-CO, J = 3.4, J = 1.5 Hz). Mass spectrum, m/z
(Irel, %): 307 (26) [M]+, 263 (6), 262 (18), 261 (100),
108 (8). Found, %: N 13.62; S 10.73. C10H8F3N3O3S.
Calculated, %: N 13.67; S 10.43.
Ethyl 2-[N'-(2-ethoxycarbonyl-1-trifluoro-
methylethylidene)hydrazino]thiazole-4-carboxylate
(VIII). Ethyl 4,4,4-trifluoro-3-oxobutanoate, 3.3 mmol,
and concentrated hydrochloric acid, 0.5 mmol, were
added to a mixture of 3 mmol of ethyl 2-hydrazino-
no. CCDC 161525.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005