The synthesis of isoxazolyl- and isothiazolylcarbamides exhibiting antitumor activity

Article abstract of DOI:10.1134/S1070428014110219

Accessible 5-phenyl(p-tolyl)isoxazol-3-carboxylic, 4,5-dichlorothiazol-3-carboxylic and 5-(benzylsulfanyl)-4-chlorothiazol-3-carboxylic acids were converted via a series of cascade transformations into the corresponding (1,2-azolyl)-3-carbonyl azides whose reaction with slightly basic aryl(heteryl)amines led to generation of 1-(1,2-azolyl)-3-aryl(heteryl)carbamides. To obtain isoxazolyl(isothiazolyl)carbamides containing the residues of highly basic amines, (1,2-azolyl)-3-carbonyl azides were preliminary transformed into aryl (1,2-azol-3-yl)carbamates by the action of phenol or 4-fluorophenol. Carbamates then were introduced into reaction with aliphatic or heterocyclic amines. Some of the obtained compounds and their precursors show high antitumor activity and are capable to increase the effect of cytostatic drugs applied in the medical practice.

Full text of DOI:10.1134/S1070428014110219

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 11, pp. 1667–1676. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.I. Potkin, S.K. Petkevich, А.V. Kletskov, Yu.S. Zubenko, P.V. Kurman, S.G. Pashkevich, Т.А. Gurinovich, V.А. Kulchitskiy, 2014,
published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 11, pp. 1680–1688.
The Synthesis of Isoxazolyl- and Isothiazolylcarbamides
Exhibiting Antitumor Activity
a
a
a
a
b
V. I. Potkin , S. K. Petkevich , А. V. Kletskov , Yu. S. Zubenko , P. V. Kurman ,
c
c
c
S. G. Pashkevich , Т. А. Gurinovich , and V. А. Kulchitskiy
a
Institute of Physical Organics Chemistry of National Academy of Sciences of Belarus,
ul. Surganovа 13, Minsk, 220072 Belarus
e-mail: potkin@ifoch.bas-net.by
b
Institute of Bioorganic Chemistry of National Academy of Sciences of Belarus, Minsk, Belarus
c
Institute of Physiology of National Academy of Sciences of Belarus, Minsk, Belarus
Received 16 May, 2014
Abstract—Accessible 5-phenyl(p-tolyl)isoxazol-3-carboxylic, 4,5-dichlorothiazol-3-carboxylic and 5-(benzyl-
sulfanyl)-4-chlorothiazol-3-carboxylic acids were converted via a series of cascade transformations into the
corresponding (1,2-azolyl)-3-carbonyl azides whose reaction with slightly basic aryl(heteryl)amines led to
generation of 1-(1,2-azolyl)-3-aryl(heteryl)carbamides. To obtain isoxazolyl(isothiazolyl)carbamides contai-
ning the residues of highly basic amines, (1,2-azolyl)-3-carbonyl azides were preliminary transformed into aryl
(
1,2-azol-3-yl)carbamates by the action of phenol or 4-fluorophenol. Carbamates then were introduced into
reaction with aliphatic or heterоcyclic amines. Some of the obtained compounds and their precursors show high
antitumor activity and are capable to increase the effect of cytostatic drugs applied in the medical practice.
DOI: 10.1134/S1070428014110219
Isoxazoles and isothiazoles are the molecular frag-
ments of a wide spectrum of bioactive compounds,
among them the ureas with 1,2-azole groups also
belong to new promising antitumor agents [1]. For
instance, one of (5-benzyloxy-4-carbamoylisothiazol-
Basing on 5-phenyl(p-tolyl)isoxazole- and 4,5-
dichlorothiazole-3-carboxylic acids I–III we worked
out convenient procedures of synthesis of carbamides
substituted with isoxazole or isothiazole rings, aiming
to obtain compounds that were isosteres of antitumor
agents and promising for biotesting. The initial 5-
phenyl(p-tolyl)isoxazole- and 4,5-dichlorothiazole-3-
carboxylic acids are easily obtained as a result of suc-
cessive transformations of trichloroethylene dimer [7–9].
Along with 4,5-dichlorothiazole-3-carboxylic acid
(III) as a starting compound 5-(benzylsulfanyl)-4-
chlorothiazole-3-carboxylic acid (IV) was also used,
which we had obtained earlier [10, 11]. Adding the
acid IV to insecticides leads to increasing their
bioactivity [11]. Besides, the presence of benzylsul-
fanyl group in the position 5 makes it possible to hope
on obtaining the isosteric carbamide analog struc-
turally closer to the substance СР-547.632.
3
-yl)carbamides is an inhibitor of tyrosine kinase and
is nowadays extensively tested in USA as antitumor
substance СР-547.632 [2]. Among the isoxazolyl-
carbamides an effective inhibitor of Raf kinase was
also discovered, which regulates the processes of
cellular onkogenesis and apoptosis [3]. Hence the
synthesis of new derivatives of urea, substituted by
isoxazol or isothiazol heterоcycle is still relevant.
There are quite a number of synthesis variations of
substituted carbamides; from the ones recently
published the carbonylation of aliphatic amines with
S,S-dimethyldithiocarbonate and also with the carbon
oxide should be mentioned [4, 5]. One of the general
methods is the reaction of amines with acyl
carbamates, which in turn are obtained from acyl
azides. Various modifications of this method are
known, differing in steps of preparating azides, acyl
carbamates, and the participating reagents.
The chosen approach to the synthesis of N-
isoxazolyl(isothiazolyl)carbamides included the initial
preparation of the corresponding 1,2-azolylcarbonyl
azides V–VIII. The azides of 5-(p-tolyl)isoxazole- and
4,5-dichlorothiazole-3-carboxylic acids VI and VII
1
667

1
668
POTKIN et al.
Scheme 1.
O
O
O
OH
Cl
N3
SOCl2
NaN3
N
N
O
N
_
O
O
Me CO H O
O
2
2
R
R
I, II
IX, X
R
V, VI
O
O
Cl
Cl
Cl
OH
Cl
SOCl2
NaN
3
N3
_
N
N
S
Me CO H O
N
S
Cl
2
2
Cl
Cl
Cl
S
III
XI
VII
O
O
O
Cl
Cl
OMe
NHNH2
OMe
BnSH
NH NH2
2
_
MeONa MeOH
N
MeOH
N
N
Cl
BnS
BnS
S
S
S
XV
O
XIV
XIII
H
,
H
O
K
.
_
.
Et O H O
NaNO , HCl
1
2
2
2
H
2
O
O
O
Cl
Cl
Cl
OH
Cl
SOCl2
NaN3
N3
_
Me CO H O
2
2
N
N
N
BnS
BnS
BnS
S
IV
S
S
VIII
XII
R = H (I, V, IX), 4-Me (II, VI, X).
were synthesized earlier by the reaction of 5-(p-tolyl)-
isoxazole- and 4,5-dichlorothiazole-3-carbonyl chlo-
rides X and XI with sodium azide [12, 13]. The azide
of 5-phenylisoxazole-3-carboxylic acid (V) was
synthesized in the same way from 5-phenylisoxazole-
thiol in the step of nucleophilic substitution and
boiling the mixture allows decreasing the time of the
reaction from 8 to 2 h and increasing the yield of acid
IV from 85 to 95%. The intermediate ether may be
isolated in 97% yield by excluding the step of hydro-
lysis.
3
-carbonyl chloride (IX). To obtain 5-(benzylsul-
fanyl)-4-chlorothiazole-3-carbonyl azide (VIII) acid
chloride XII and hydrazide of 5-(benzylsulfanyl)-4-
chlorothiazole-3-carboxylic acid (XIII) were used;
their precursor was the methyl ester of that acid XIV.
The hydrazide XIII was obtained in 95% yield by
the action of hydrazine hydrate on ether XIV in
methanol. The subsequent treatment of hydrazide XIII
with nitrous acid (mixture of NaNO and HCl) led to
2
We optimized the recently published method of
synthesis of the initial acid IV, including the primary
preparation of methyl dichlorothiazole-3-carboxylate
the target azide of 5-(benzylsulfanyl)-4-chlorothiazole-
3-carboxylic acid (VIII). However as a result of low
solubility of hydrazide XIII in acid medium the
reaction proceeds slowly and the yield of azide VIII
did not exceed 65%, whereas in the reaction of 5-(ben-
zylsulfanyl)-4-chlorothiazolecarbonyl chloride (XII)
(XV), the selective substitution of the chlorine atom in
the position 5 of the heterоcycle by treating with
sodium benzylthiolate at 20°C, and the hydrolysis of
methyl 5-(benzylsulfanyl)-4-chlorothiazole-3-carboxy-
late (XIV) [11]. Applying the double excess of benzyl-
with NaN the target azide VIII was obtained in 82%
3
yield (Scheme 1).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

THE SYNTHESIS OF ISOXAZOLYL- AND ISOTHIAZOLYLCARBAMIDES
1669
Scheme 2.
O
2
3
R R NH
C H
N3
6
6
2
3
NR R
N
R1
HN
N
O
O
V, VI
O
C H
6
PhOH
6
R1
_
_
O
Ph
XVI XX, XXIII XXVIII
HN
N
O
2
3
R R NH
O
C H
6 6
R1
XXI, XXII
1
2
3
R = H (V, XVI–XIX, XXI, XXIII–XXVII), 4-Me (VI, XX, XXII, XXVIII); R = H, R = 4-BrC
6
H
4
6
(XVI), C H
4
-4-COOH
2
3
(
6
XVII), C H
4
-4-COOEt (XVIII), hexyl (XXIII), 6-hydroxyhexyl (XXIV), Bn (XXV); R R N = 3,5-dimethylpyrazol-1-yl
XIX), benzotriazol-1-yl (XX), piperazin-1-yl (XXVI), morpholin-4-yl (XXVII, XXVIII).
(
The azides V–VIII were used in syntheses of the
corresponding (1,2-azol-3-yl)ureas. By the example of
-aryl(p-tolyl)isoxazole-3-carbonyl azides V and VI
tuted isothiazolylureas with aliphatic residue in the
carbamide fragment. From the compounds we obtained
these are the benzylsulfanylisothiazolylcarbamides.
Taking into consideration the experimental data the
isoxazolylureas were obtained through isothiazolyl-
carbamates. Some preparatively important features for
obtaining the derivatives of 4,5-dichloronitroazole and
5-(benzylsulfanyl)-4-chlorothiazole series were found.
Whereas phenyl (4,5-dichlorothiazol-3-yl)carbamate
(XXIX) was obtained in similar way to compounds
XXI and XXII by treating dichloroisothiazolyl azide
VII with phenol in benzene, p-fluorophenol was
applied to the synthesis of the carbamate from azide
VIII, for phenylcarbamate possessed low solubility in
benzene that prevented its further application in
obtaining the carbamides, because the reaction procee-
ded too slow and with low conversion, and the formed
compounds required additional purification. Moreover,
p-fluorphenol has higher reactivity toward azides
comparing to phenol and the formation of 5-(benzyl-
sulfanyl)-4-chloroisothiazolylcarbamate (XXX) was fi-
nished in 30 min, while the reaction with phenol took 4 h.
5
we demonstrated that under the effect of weakly basic
aromatic and heterоcyclic amines (p-bromoaniline, p-
aminоbenzoic acid, its ethyl ether, 3,5-dimethyl-
pyrazole, and benzotriazole) at boiling the mixture in
benzene (5-aryl-isoxazol-3-yl)carbamides XVI–XX
formed (yields 63–91%), containing the residues of the
corresponding amines. However at the treatment with
more basic amines of aliphatic, alkylaromatic, and
heterоcyclic series (hexylamine, 6-aminоhexanol, ben-
zylamine, piperazine, and morpholine) this way of
synthesis of substitued isoxazolylureas is not realized
since the corresponding amides are obtained as predo-
minant products of the reaction. Therefore first the
urethane derivatives of 5-arylisoxazol-3-ylcarbamates
XXI and XXII [14] were synthesized. Phenyl [5-(p-
tolyl)isoxazol-3-yl]carbamate (XXII) was obtained by
reacting azide VI with phenol and used in the synthesis
of a palladium complex [12]. Phenyl (5-phenylisoxa-
zol-3-yl)carbamate (XXI) was obtained in the similar
way from azide V (Scheme 2).
Isothiazolylcarbamates XXIX and XXX were
brought into reaction with aliphatic amines (hexyl-
amine, 6-aminоhexanol, 2-aminоethoxyethanol, N',N'-
dimethylpropane-1,3-diamine). Considering higher
solubility of carbamate XXX in chloroform than in
benzene, the reaction with amines was performed in
boiling chloroform, and the excess of amine was used
Isoxazolylcarbamates were introduced in the
reaction with amines to obtain 5-arylisoxazolylureas
XXIII–XXVIII in 61–82% yields.
The closest analogs of the tyrosine kinase inhibitor,
the antitumor agent СР-547.632, are arylalkyl-substi-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

1
670
POTKIN et al.
Scheme 3.
O
Cl
H
H
H
R
OH
Cl
Cl
N
O
N
N3
N
R'NH2
HCCl3
R'
N
C
6
H
6
O
O
X
N
N
X
X
S
R
S
S
_
VII, VIII
XXIX, XXX
XXXI XXXV
X = Cl (VII, XXIX, XXXI), BnS (VIII, XXX, XXXII–XXXV); R = H (XXIX), F (XXX); R' = hexyl (XXXI, XXXII), 6-
hydroxyhexyl (XXXIII), 2-(2-hydroxyethoxy)ethyl (XXXIV), 3-(dimethylaminо)propyl (XXXV).
to compensate its binding in salt with liberating p-
fluorphenol, possessing higher acidity compared to
phenol. In the optimal conditions the reaction was
complete within 1 h (Scheme 3).
tives of heterоcyclic amines, a singlet at δ 9.37–9.86 ppm
corresponds to NH group of carbamide fragment.The
C=О group of the carbamide residue in IR spectra of
1,2-azolylurea is characterized by a pair of strong
–
1
13
absorption bands in the area 1547–1739 cm .
С
As a result functionalized carbamides with different
end groups were obtained, including the polar ones
important for biotesting, since the latter increased the
solubility of compounds in water.
NMR spectra confirm the number of carbon atoms in
the molecules of all synthesized compounds.
By the example of 1-[5-(benzylsulfanyl)-4-chloro-
isothiazol-3-yl]-3-hexylurea (XXXII) we carried out
the computer simulation of the possibility of em-
bedding this compound into the sites of cyclin-
dependent protein kinase 2 (Cdk2) and tyrosine kinase
VEGFR-2, for the conjugation with them regulates the
cytostatic effect of the drugs. For optimization of the
protein geometry the force field AMBER [15] was
applied, charges of aminoacids were obtained from
AMBER ff99SB and AM1-BCC [16]. The optimi-
zation of the ligand XXXII geometry was fulfilled
within the framework of the method of molecular
mechanics with application of the force field
MMFF94 [17]. The distribution of charges for the
optimized structure was obtained by the DFT method,
theoretic level B3LYP1/6-311++G. The ligand was
prepared using the program Avogadro [18], docking
results were visualized within the program UCSF
Chimera [19]. Calculations ab initio were made in the
program package Firefly [20], partly basing on
GAMESS (US) [21]. As graphic covering for
preparing the input files program Gabedit [22] was
applied. Docking was carried out in program complex
UCSF Dock 6.4 [23].
The composition and structure of the obtained
substances were determined basing on the elemental
analysis data, IR, Н and С NMR spectroscopy and
1
13
mass spectrometry.
The presence of the N fragment in molecules of
3
azides V and VIII is confirmed by the strong characte-
ristic absorption bands in the IR spectrum of these com-
–
1
pounds in the region 2146–2214 cm . In the mass
+
spectra of azides V and VIII ion peaks [M − N2]
possess the maximal intensity, no peaks of molecular
ions are detected.
In IR spectrum of isothiazolylhydrazide XIII NH2
and NH groups appear as broadened absorption bands
–
1
1
in the interval 3202–3337 cm , and in Н NMR spec-
trum they give rise to broadened singlets, δ 3.59 (NH2)
and 9.87 (NH) ppm.
Generation of carbamates XXI, XXIX, and XXX
from the corresponding azides is confirmed by the
absence of the absorption bands of the azide group in
–
1
the region 2146–2214 cm in their IR spectra and the
appearance of stretching vibration bands of N−H in the
–
1
1
interval 3198–3467 cm . In Н NMR spectra of
carbamates XXI, XXIX, and XXX the singlets at δ
In the course of the docking it was determined that
the molecule of 1-[5-(benzylsulfanyl)-4-chlorothiazol-
7
.60–9.21 ppm correspond to the NH groups.
3
-yl]-3-hexylurea (XXXII) is able to be embedded in
1
In Н NMR spectra of 1,2-azolylureas XVI–XVIII,
kinase sites, while the aminо groups of the carbamide
fragment form bonds with the oxygen atoms of the
aminоacid parts of kinase that facilitates stronger
conjugation of the isothiazole agent and the kinase
molecule.
XXIII–XXVI, and XXXI–XXXV the groups of NH
carbamide fragment appear as two singlets in the
1
interval 6.51–9.88 ppm. In Н NMR spectra of
isoxazolylureas XIX, XX, and XXVI–XXVIII, deriva-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

THE SYNTHESIS OF ISOXAZOLYL- AND ISOTHIAZOLYLCARBAMIDES
1671
The docking data fully correlated with the results of
biotesting, carried out in the Institute of Physiology of
National Academy of Sciences of Belarus. The
research on isoxazole and isothiazole derivatives was
carried out on various species of neuroepithelial primar
tumors (medulloblastoma, glioblastoma). It was
determined that the specimens of the synthesized
compounds and their precursors (1,2-azolylcar-
bamates) demonstrate antitumor activity and, which is
the most important point, can intensify the effect of
practically applied protocol cytostatics: cisplatine,
carboplatine, and citarabine. For the structure
cytostatic–azolylureaderivative 1 : 1, at 10 grade dilu-
tion (in some cases at even higher) the efficiency of
antitumor effect remains at the level of protocolly re-
commended doze of the individual drug. Hence a new
way opens to reduction of the side effects and toxicity
of chemical drugs at developing similar compositions.
added. The precipitate was filtered off, washed with
water, hexane, and recrystallized from chloroform.
Yield 6.38 g (95%). Physicochemical constants and IR
and NMR spectra were consistent with the published
data [11].
5
-Phenylisoxazole-3-carbonyl azide (V). To solu-
tion of 8.62 g (41.52 mmol) of chloride of 5-phe-
nylisoxazole-3-carboxylic acid (IX) in 40 mL of
anhydrous acetone was added 3 g of sodium azide and
the mixture was stirred for 3 h at 20°C, then it was
poured into water, the precipitate was filtered off,
washed with water, and dried in a vacuum over P O .
2
5
Yield 8.45 g (95%), mp 105–106°C (decomp.). IR
–
1
spectrum, cm : 3147, 3129, 3062, 2214, 2165, 1693,
1
9
612, 1592, 1573, 1497, 1438, 1229, 1172, 962, 946,
41, 856, 825, 762, 684, 673. H NMR spectrum, δ,
1
ppm: 6.94 s (1Н
), 7.48 m (3H ), 7.79 m (2Н ).
isoxazole
Ar Ar
1
3
С NMR spectrum, δ, ppm: 99.61 (CНisoxazole), 126.10
2CH ), 129.32 (2CH ), 131.19 (CH ), 126.43,
(
Ar
Ar
Ar
EXPERIMENTAL
1
57.45, 165.90 (3Cquat.), 172.57 (C=O). Found, %: C
+
IR spectra were registered on Fourier-
spectrophotometer Protege-460 Nicolet in tablets of
56.18; H 3.04; N 26.15. [M – N
2
] 186 (Irel 100%).
C H N O
10 6 4 2
. Calculated, %: C 56.08; H 2.82; N 26.16.
1
13
KBr. Н and С NMR spectra were recorded on a
M 214.18.
spectrometer Bruker Avance-500 in CDCl (V, VIII,
3
Methyl 5-(benzylsulfanyl)-4-chlorothiazole-3-
carboxylate (XIV). In 50 mL of anhydrous methanol
was dissolved 0.57 g (25 mmol) of metallic sodium,
XIV, XIX, XXI, XXIII, XXVI, and XXIX–XXXII),
in (CD ) CO (XXV), in (CD ) SO (IV, XIII, XVI–
3
2
3 2
XVIII, XX, XXIV, XXVII, XXVIII, and XXXIII–
XXXV). Chemical shifts were measured with respect
to the residual proton and to carbon signals of
deuterated solvents [CDCl , δ 7.26, δ 77.2 ppm;
5
.85 g (47 mmol) of benzylthiol was added, the
mixture was stirred for 15 min and a solution of 5 g
23 mmol) of methyl 4,5-dichlorothiazole-3-carboxyla-
(
3
Н
С
te (XV) in 30 mL of anhydrous methanol was added.
The reaction mixture was boiled for 2 h, cooled to
room temperature, and poured on ice. The solid
reaction product was filtered off, washed with water,
hexane, and dried in a vacuum. Yield 6.68 g (97%),
(
CD ) CO, δ 2.05, δ 30.2 ppm; (CD ) SO, δ 2.50,
3 2 Н С 3 2 Н
δС 40.1 ppm]. Mass-spectra were obtained on aGC-MS
instrument Hewlett Packard 5890/5972 (electron
impact with electron energy 70 eV; capillary column
НР-5MS 30 m × 0.25 mm, phase (5% PhMe Silicone)
–1
mp 103–103.5°C. IR spectrum, cm : 2951, 1724,
0
.25 µm, evaporator temperature 250°C).
-benzylsulfanyl-4-chloroisothiazol-3-carboxylic
acid chloride (XII) was obtained by the method [11].
-Benzylsulfanyl-4-chlorothiazole-3-carboxylic
1
1
439, 1345, 1230, 1200, 1083, 735, 717, 708. H NMR
5
spectrum, δ, ppm: 3.93 s (3Н, СН
3
), 4.19 s (2H,
S), 7.29 m (5HAr). С NMR spectrum, δ, ppm:
2.93 (ОСН ), 39.30 (CH S), 128.37 (СН ), 128.99
1
3
CH
2
5
3
2
Ar
5
(
2СН ), 129.04 (2СН ), 125.34, 135.00, 154.10,
Ar Ar
acid (IV). In 50 mL of anhydrous methanol was dis-
solved 0.57 g (25 mmol) of metallic sodium, 5.85 g
1
3
58.41 (4Cquat), 160.07 (C=O). Found, %: C 48.14; H
+
.28; Cl 11.88; N 4.65; S 21.46. [M] 299 (I 100%).
rel
(
47 mmol) of benzylthiol was added, the mixture was
C H ClNO S . Calculated, %: C 48.08; H 3.36; Cl
1
2
10
2 2
stirred for 15 min and a solution of 5 g (23 mmol) of
methyl 4,5-dichlorothiazole-3-carboxylate (XV) in 30 mL
anhydrous methanol was added. The reaction mixture
was boiled for 2 h, solution of 5 g of KОН in 10 mL of
water was added and the boiling was continued for 5
min more, then the solution was cooled to room
temperature and 15 mL of concentrated HCl was
1
1.83; N 4.67; S 21.39. M 299.80.
5-(Benzylsulfanyl)-4-chlorothiazole-3-carbonyl
azide (VIII). To cooled to 0°C solution of 1 g
(3.3 mmol) of acid chloride XII in 30 mL of acetone
was added dropwise while stirring the solution of 0.23 g
of sodium azide in 5 mL of water, then the mixture
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

1
672
POTKIN et al.
was stirred at this temperature for 30 min and poured
on ice. Solid reaction product was filtered off, washed
with water, and dried in a vacuum above Р О . Yield
138.26, 151.17, 159.06 (5Cquat), 168.42 (S=О). Found,
%: C 61.83; H 5.79; Br 22.42; N 15.34. C H BrN O .
1
6
12
3
2
2
5
1
Calculated, %: C 61.53; H 5.53; Br 22.31; N 15.38.
-[3-(5-Phenylisoxazol-3-yl)ureido]benzoic acid
XVII). Yield 91%, mp 237–240°C (decomp.). IR
–
0
3
1
7
.98 g (82%), mp 36–38°C. IR spectrum, cm : 3086,
064, 3031, 3007, 2923, 2854, 2146, 1683, 1494,
453, 1405, 1344, 1244, 1190, 1031, 946, 869, 744,
4
(
–1
spectrum, cm : 3334, 3280, 3253, 3118, 3089, 3029,
1
07, 695. H NMR spectrum, δ, ppm: 4.21 s (2H,
2
1
1
7
907, 2669, 2549, 1685, 1623, 1597, 1577, 1540,
520, 1450, 1430, 1416, 1379, 1317, 1290, 1260,
1
3
CН S), 7.31 m (5H ). С NMR spectrum, δ, ppm:
2
Ar
3
1
%
9.33 (CH S), 128.50 (CH ), 129.07 (4CH ), 125.64,
1
2
Ar
Ar
180, 946, 858, 763, 690. Н NMR spectrum, δ, ppm:
34.87, 153.69, 159.45 (4Cquat), 165.50 (C=O). Found,
: C 42.42; H 2.33; Cl 11.35; N 18.12; S 20.57. [M –
3
.35 s (1H, CH
), 7.52 d (2Н , J 6.8 Hz), 7.60 d
isoxazol
Ar
3
3
(
2Н , J 8.5 Hz), 7.88 d (2Н , J 6.8 Hz), 7.91 d
+
Ar Ar
N ] 310 (I 100%). C H ClN OS . Calculated, %: C
3
2
rel
11
7
4
2
(
2Н , J 8.5 Hz), 7.97 m (1Н ), 9.22 s (1H, NH), 9.79
Ar
Ar
4
2.51; H 2.27; Cl 11.41; N 18.03; S 20.64. M 310.78.
13
s (1H, NH), 12.75 br.s (1H, СООH). С NMR spec-
trum, δ, ppm: 99.84 (CHisoxazole), 117.61 (2СНAr), 125.46
(2СН ), 129.21 (2СН ), 130.29 (СН ), 130.58 (2СН ),
5
-(Benzylsulfanyl)-4-chlorothiazole-3-carbonyl
hydrazide (XIII). To 1 g (3.3 mmol) of methyl 5-ben-
zylsulfanyl-4-chlorothiazole-3-carboxylate (XIV) in
Ar
Ar
Ar
Ar
124.38, 126.87, 143.15, 151.13, 159.05 (5Cquat), 166.95
(S=О), 168.57 (S=О). Found, %: C 63.38; H 3.89; N
13.08. C H N O . Calculated, %: C 63.16; H 4.05; N
1
0 mL of methanol was added 0.165 mL of (3.3 mmol)
of hydrazine hydrate, and the mixture was stirred at
room temperature for 30 min. The formed precipitate
was filtered off, washed with methanol, and dried in a
vacuum over Р О . Yield 0.94 g (95%), mp 135–137°C.
1
7
13
3
4
13.00.
Ethyl 4-[3-(5-phenylisoxazol-3-yl)ureido]-
2
5
–
benzoate (XVIII). Yield 84%, mp 208–211°C. IR
1
IR spectrum, cm : 3337, 3275, 3202, 3031, 2922,
–1
spectrum, cm : 3370, 3321, 3300, 3274, 3132, 3068,
2
1
853, 1657, 1634, 1515, 1495, 1464, 1454, 1353,
340, 1274, 1248, 1144, 1083, 874, 698, 653. H NMR
3
1
1
034, 2996, 2959, 2857, 1734, 1679, 1627, 1595,
580, 1562, 1536, 1495, 1481, 1421, 1372, 1309,
1
spectrum, δ, ppm: 3.59 br.s (2H, NH ), 4.44 s (2H,
1
2
291, 1200, 1177, 1139, 850, 769, 690, 666. Н NMR
3
3
CН S), 7.30 t (1H , J 7.1 Hz), 7.35 t (2H , J
.1 Hz), 7.43 d (2Н , J 7.1 Hz), 9.87 br.s (1Н, NH).
С NMR spectrum, δ, ppm: 38.44 (CH S), 128.60
3
2
Ar
Ar
spectrum, δ, ppm: 1.30 t (3Н, СН , J 7 Hz), 4.27 q
3
3
7
3
Ar
(
2Н, СН , J 7 Hz), 7.31 s (1H, CH
), 7.51 m (3Н ),
1
3
2
isoxazol Ar
2
3
3
7
.62 d (2Н , J 8.5 Hz), 7.87 d (2Н , J 6.5 Hz), 7.92
Ar Ar
(
CH ), 129.34 (2CH ), 129.72 (2CH ), 120.66,
3
Ar
Ar
Ar
d (2Н , J 8.5 Hz), 9.24 s (1H, NH), 9.79 s (1H, NH).
Ar
1
36.35, 158.28, 158.92 (4Cquat), 160.16 (C=O). Found,
: C 43.90; H 3.51; Cl 11.80; N 14.05; S 21.44.
C H ClN OS . Calculated, %: C 44.07; H 3.36; Cl
13
С NMR spectrum, δ, ppm: 14.15 (CH ), 60.31 (CH ),
3
2
%
9
1
1
3.79 (CHisoxazole), 117.62 (2СН ), 125.42 (2СН ),
Ar Ar
1
1
10
3
2
28.25 (СН ), 129.15 (2СН ), 130.35 (2СН ),
Ar
Ar
Ar
1
1.83; N 14.02; S 21.39.
23.44, 126.86, 143.43, 151.05, 159.00 (5Cquat),
Isoxazolylureas XVI–XX. General method. A
165.29 (S=О), 168.54 (S=О). Found, %: C 65.21; H
solution of 20 mmol of amine and 20 mmol of the
corresponding azide V and VI in 50 mL of anhydrous
benzene was boiled for 4–10 h. The obtained preci-
pitate was filtered off, washed with benzene, and dried
in a vacuum.
4.55; N 11.89. C H N O . Calculated, %: C 64.95; H
1
9
17
3
4
4.88; N 11.96.
,5-Dimethyl-N-(5-phenylisoxazol-3-yl)-1H-py-
razole-1-carboxamide (XIX). Yield 63%, mp 155–
3
–1
1
58°C (decomp.). IR spectrum, cm : 3363, 3178,
1
-(4-Bromophenyl)-3-(5-phenylisoxazol-3-yl)urea
3059, 3046, 2996, 2927, 2853, 1739, 1621, 1595,
1577, 1541, 1494, 1442, 1426, 1339, 1249, 1092,
1029, 967, 947, 884, 803, 792, 765, 737, 686, 606. Н
–
1
(
XVI). Yield 78%, mp 238–239°C. IR spectrum, cm :
358, 3276, 3150, 3089, 3036, 2976, 2924, 2853,
704, 1634, 1610, 1585, 1558, 1534, 1497, 1485,
1
3
1
1
NMR spectrum, δ, ppm: 2.22 s (3Н, СН ), 2.59 s (3Н,
3
1
425, 1310, 1220, 1070, 764, 685, 500. Н NMR
СН ), 5.97 c (1H, CH
), 7.23 s (1H, CHisoxazole),
3
pyrazole
3
spectrum, δ, ppm: 7.27 s (1H, CHisoxazol), 7.51 m
7Н ), 7.87 m (2Н ), 8.99 s (1H, NH), 9.71 s (1H,
7.45 m (3Н ), 7.79 d (2Н , J 7.8 Hz), 9.86 s (1H,
Ar Ar
1
3
(
NH). С NMR spectrum, δ, ppm: 13.59 (CH ), 13.89
Ar
Ar
3
1
3
NH). С NMR spectrum, δ, ppm: 93.76 (CHisoxazol),
(CH ), 93.21 (CHisoxazole), 110.99 (CHpyrazole), 125.69
3
1
1
20.45 (2СН ), 125.38 (2СН ), 129.14 (2СН ),
(2СН ), 128.95 (2СН ), 130.35 (СН ), 127.36,
143.95, 148.01, 151.37, 157.78 (5Cquat), 170.21 (S=О).
Ar
Ar
Ar
Ar
Ar
Ar
30.39 (СН ), 131.54 (2СН ), 113.99, 126.82,
Ar
Ar
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

THE SYNTHESIS OF ISOXAZOLYL- AND ISOTHIAZOLYLCARBAMIDES
1673
Found, %: C 63.66; H 5.23; N 19.79. C H N O .
Calculated, %: C 63.82; H 5.00; N 19.85.
Calculated, %: C 41.54; H 2.09; Cl 24.52; N 9.69; S
11.09.
1
5
14
4
2
N-[5-(4-Methylphenyl)isoxazol-3-yl]-1H-benzo-
d][1,2,3]triazole-1-carboxamide (XX). Yield 85%,
mp 226–227°C (decomp.). IR spectrum, cm : 3185,
4-Fluorphenyl (5-benzylsulfanyl-4-chloroiso-
thiazol-3-yl)carbamate (XXX) was obtained in the
similar way as carbamates XXI and XXIX from 4-
fluorphenol and azide VIII, but the reaction mixture
was boiled for 30 min. Yield 98%, mp 133–137°C. IR
[
–
1
3
1
1
147, 3079, 3057, 3034, 2920, 2853, 1733, 1618,
607, 1592, 1571, 1548, 1501, 1477, 1449, 1433,
363, 1058, 1041, 1011, 923, 831, 791, 752, 745, 707.
–
1
spectrum, cm : 3467, 3417, 3263, 3061, 3032, 2924,
1736, 1597, 1536, 1496, 1455, 1435, 1402, 1227,
1189, 1152, 1113, 1026, 1003, 892, 851, 826, 770,
1
Н NMR spectrum, δ, ppm: 2.34 s (3Н, СН ), 7.22 s
3
3
(
(
(
1H, CHisoxazole), 7.32 d (2Н , J 7.6 Hz), 7.43 m
Ar
3
1
2Н ), 7.75 d (2Н , J 7.6 Hz), 7.91 m (2Н ), 9.79 s
709, 696, 633, 513, 486. Н NMR spectrum, δ, ppm:
Ar
Ar
Ar
1
3
3
1H, NH). С NMR spectrum, δ, ppm: 20.96 (СН3),
4.19 s (2H, CH S), 7.06 t (2H , J 8.5 Hz), 7.17 m
2
Ar
1
3
9
1
1
3.05 (CHisoxazole), 125.14 (2СН ), 125.40 (2СН ),
(2H ), 7.31 m (5H ), 7.60 s (1H, NH). C NMR
Ar
Ar
Ar Ar
29.50 (2СН ), 129.74 (2СН ), 124.16, 139.52,
spectrum, δ, ppm: 39.24 (CH S), 116.11 (CH ),
2 Ar
Ar
Ar
40.43, 150.40, 158.72, 164.51 (6Cquat), 169.95 (S=О).
116.29 (CH ), 122.94 (CH ), 123.01 (CH ), 128.37
Ar Ar Ar
Found, %: C 64.12; H 4.22; N 21.79. C H N O .
(CH ), 129.00 (2CH ), 129.12 (2CH ), 135.17,
Ar Ar Ar
1
7
13
5
2
Calculated, %: C 63.94; H 4.10; N 21.93.
146.18, 149.96, 151.43, 155.64, 159.41 (6Cquat),
1
7
5
61.36 (C=O). Found, %: C 51.92; H 3.28; Cl 8.77; N
.12; S 16.38. C H ClFN O S . Calculated, %: C
1.71; H 3.06; Cl 8.98; N 7.09; S 16.24.
Phenyl (1,2-azol-3-yl)carbamates (XXI and
XXIX). General method. The solution of 20 mmol of
phenol and 20 mmol of azide V and VII in 70 mL of
anhydrous benzene was boiled for 4 h. Then the
solvent was removed at a reduced pressure, solid
precipitate was washed with 5% solution of sodium
hydrogen carbonate, with water, dried in a vacuum,
and crystallized from 70% methanol.
17
12
2
2 2
(1,2-Azol-3-yl)ureas XXIII–XXVIII and XXXI.
General method. The solution of 20 mmol of amine
and 20 mmol of phenyl (1,2-azol-3-yl)carbamate XXI,
XXII, and XXIX in 50 mL of benzene was boiled for 7 h.
The precipitate of the obtained carbamide was filtered
off, washed with benzene, and dried in a vacuum.
Phenyl (5-phenylisoxazol-3-yl)carbamate (XXI).
Yield 79%, mp 176–178°C (decomp.). IR spectrum,
cm : 3264, 3218, 3087, 3033, 2966, 2867, 2799, 1748,
1-Hexyl-3-(5-phenylisoxazol-3-yl)urea (XXIII).
Yield 74%, mp 92–95°C. IR spectrum, cm : 3324,
–
1
–1
1
1
636, 1596, 1582, 1558, 1485, 1429, 1267, 1240,
209, 1165, 1070, 985, 793, 762, 727, 685. H NMR
3257, 3137, 3068, 3015, 2955, 2925, 2855, 1682, 1623,
1598, 1578, 1517, 1500, 1469, 1450, 1375, 1315,
1
1
spectrum, δ, ppm: 7.16 s (1Нisoxazole), 7.25 m (3H ),
7
NMR spectrum, δ, ppm: 93.27 (CНisoxazole), 121.56
1265, 1233, 1204, 1068, 945, 761, 685. Н NMR spec-
Ar
1
3
3
.43 m (5H ), 7.76 m (2Н ), 9.21 b.s (1H, NH). С
trum, δ, ppm: 0.88 t (3Н, СН , J 7.1 Hz), 1.32 m (4Н,
Ar
Ar
3
3
2СН ), 1.40 quintet (2Н, СН , J 7.1 Hz), 1.61 quintet
2
2
3
3
(
2CH ), 125.80 (2CH ), 126.07 (CH ), 128.99
(2Н, СН , J 7.1 Hz), 3.37 q (2Н, СН , J 6.6 Hz), 6.57
Ar
Ar
Ar
2
2
(
1
2CH ), 129.50 (2CH ), 130.50 (CH ), 127.21,
50.43, 151.55, 158.81 (5Cquat), 170.31 (C=O). Found,
s (1H, CHisoxazole), 7.23 b.s (1H, NH), 7.43 m (3Н ),
Ar
Ar
Ar
Ar
1
3
7.74 m (2Н ), 9.88 s (1H, NH). С NMR spectrum, δ,
Ar
%
: C 68.89; H 4.67; N 9.85. C H N O . Calculated,
ppm: 14.16 (CH ), 22.70 (CH ), 22.75 (CH ), 29.96
16
12
2
3
3
2
2
%
: C 68.56; H 4.32; N 9.99.
Phenyl (4,5-dichlorothiazol-3-yl)carbamate
(CH
2
), 31.65 (CH
2
), 40.61 (CH
2
N), 92.94 (CHisoxazole),
1
25.92 (2СН ), 129.06 (2СН ), 130.55 (СН ),
Ar Ar Ar
–1
127.23, 155.63, 159.77 (3Cquat), 169.10 (S=О). Found,
(
XXIX). Yield 80%, mp 125–127°C. IR spectrum, cm :
%: S 67.03; H 7.09; N 14.44. C H N O . Calculated,
16 21 3 2
3
1
1
7
7
198, 3080, 3044, 3032, 2979, 2924, 1746, 1717,
553, 1520, 1494, 1483, 1456, 1433, 1293, 1233,
198, 1167, 1124, 1074, 1032, 995, 896, 780, 7561,
40, 687, 647, 519, 501. Н NMR spectrum, δ, ppm:
.22 m (3Н ), 7.38 m (2Н ), 7.66 s (1Н, NH).
%
: S 66.88; H 7.37; N 14.62.
1-(6-Hydroxyhexyl)-3-(5-phenylisoxazol-3-yl)urea
1
–1
(XXIV). Yield 89%, mp 126–128°C. IR spectrum, cm :
3438, 3325, 3240, 3133, 3066, 3014, 2939, 2878,
2858, 1683, 1622, 1597, 1576, 1540, 1516, 1478,
1
3
С
Ar
Ar
NMR spectrum, δ, ppm: 121.46 (2CН ), 126.24
Ar
(
1
2
CН ), 129.62 (2CН ), 114.11, 148.28, 149.81,
50.28 (4Сquat), 151.24 (S=O). Found, %: C 41.72; H
1449, 1373, 1317, 1303, 1261, 1205, 1066, 945, 766,
Ar
Ar
1
689. Н NMR spectrum, δ, ppm: 1.28 m (4Н, 2СН ),
2
.17; Cl 24.70; N 9.59; S 11.17. C H Cl N O S.
1.43 m (4Н, 2СН ), 3.12 m (2Н, СН ), 3.38 m (2Н,
1
0
6
2
2
2
2
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

1
674
POTKIN et al.
СН ), 4.36 br.s (1Н, ОН), 6.51 br.s (1H, NH), 7.13 s
%: S 61.70; H 5.41; N 15.35. C H N O . Calculated,
2
14 15
3
3
(
(
2
6
(
1H, CH
), 7.50 m (3Н ), 7.83 m (2Н ), 9.42 s
%: S 61.53; H 5.53; N 15.38.
isoxazole
Ar
Ar
1
3
1H, NH). С NMR spectrum, δ, ppm: 25.85 (CH2),
6.85 (CH ), 30.23 (CH ), 33.10 (CH ), 39.83 (CH N),
1.27 (CH О), 94.26 (CH
N-[5-(4-Methylphenyl)isoxazol-3-yl]morpholine-
2 2 2 2
4
-carboxamide (XXVIII). Yield 61%, mp 242–245°C.
), 126.02 (2СН ), 129.79
–1
2
isoxazole
Ar
IR spectrum, cm : 3251, 3212, 3157, 3096, 3070,
2СН ), 130.95 (СН ), 127.61, 154.36, 160.34 (3Cquat),
Ar Ar
3
1
1
039, 2956, 2926, 2860, 1676, 1625, 1616, 1573,
556, 1509, 1428, 1366, 1305, 1267, 1247, 1218,
185, 1117, 990, 945, 878, 807, 569. Н NMR spec-
1
68.58 (S=О). Found, %: S 63.47; H 7.05; N 13.79.
C H N O . Calculated, %: S 63.35; H 6.98; N 13.85.
1
1
6
21
3
3
1
-Benzyl-3-(5-phenylisoxazol-3-yl)urea (XXV).
trum, δ, ppm: 2.35 s (3Н, СН
3
), 3.47 t (4Н, СН
2
NСН
J 4.4 Hz), 3.59 t (4Н, СН OСН , J 4.4 Hz), 7.14 s
2 2
2
,
–
1
3
3
Yield 82%, mp 187–189°C. IR spectrum, cm : 3284,
226, 3178, 3088, 3065, 3034, 2920, 2852, 1686,
659, 1630, 1604, 1585, 1566, 1514, 1496, 1453,
280, 1259, 1051, 1027, 762, 749, 698, 688. Н NMR
spectrum, δ, ppm: 4.50 d (2Н, СН , J 5.8 Hz), 7.06 s
3
3
1
1
(1H, CHisoxazole), 7.31 d (2НAr, J 8 Hz), 7.72 d (2НAr,
3
13
J 8 Hz), 9.81 s (1H, NH). С NMR spectrum, δ, ppm:
21.58 (СН ), 44.78 (2CH N), 66.53 (2CH O), 95.04
1
3
2
2
3
(CHisoxazole), 125.90 (2СНAr), 130.34 (2СНAr), 125.05,
140.73, 154.43, 161.12 (4Cquat), 168.59 (S=О). Found,
%: S 62.87; H 5.64; N 14.72. C15
%: S 62.71; H 5.96; N 14.63.
2
3
(
(
1H, CH
), 7.26 t (1H, NH, J 7.2 Hz), 7.34 t
isoxazole
3
3
3Н , J 7.4 Hz), 7.38 d (2Н , J 7.4 Hz), 7.52 m
H N O . Calculated,
17 3 3
Ar
Ar
3
(
3Н ), 7.86 d.d (2Н , J 7.4 Hz), 8.87 b.s (1H, NH).
Ar Ar
1
3
С NMR spectrum, δ, ppm: 45.36 (CH ), 95.16
CHisoxazole), 127.39 (2СН ), 128.82 (СН ), 129.21
2СН ), 130.27 (2СН ), 130.97 (2СН ), 132.16
2
1
-(4,5-Dichlorothiazol-3-yl)-3-hexylurea (XXXI).
(
(
(
(
–1
Ar
Ar
Yield 83%, mp 64–72°C. IR spectrum, ν, cm : 3312,
Ar Ar Ar
3
1
1
236, 3146, 3114, 2989, 2958, 2932, 2855, 1682,
547, 1528, 1509, 1478, 1457, 1373, 1345, 1321,
298, 1261, 1230, 1132, 1102, 1028, 701, 681, 555. Н
СН ), 129.42, 141.78, 155.73, 161.84 (4Cquat), 170.56
Ar
S=О). Found, %: S 69.79; H 5.02; N 14.35. C H ·
1
1
7
15
N O . Calculated, %: S 69.61; H 5.15; N 14.33.
3
3
2
NMR spectrum, δ, ppm: 0.84 m (3H, CH , J 6.8 Hz),
3
3
1
3
.29 m (6H, 3CH ), 1.54 quintet (2Н, СН , J 7.0 Hz),
2
2
N-(5-Phenylisoxazol-3-yl)piperazine-1-carboxa-
mide (XXVI). Yield 78%, mp 238–241°C (decomp.).
IR spectrum, cm : 3257, 3192, 3091, 3000, 2923,
865, 1673, 1626, 1598, 1579, 1549, 1500, 1471,
426, 1382, 1264, 1234, 995, 947, 875, 765, 686, 642.
Н NMR spectrum, δ, ppm: 3.00 t (4Н, СН NСН , J
Hz), 3.66 t (4Н, СН NНСН , J 5 Hz), 4.40 b.s (1H,
NH), 7.36 s (1H, CH
3
.31 q (2Н, СН N, J 6.5 Hz), 8.04 s (1Н, NH), 8.19 s
2
1
3
–
1
(
1Н, NH). С NMR spectrum, δ, ppm: 14.04 (CН3),
2
4
1
1
4
2.59 (CH ), 26.63 (CH ), 29.73 (CH ), 31.50 (CH ),
2
2 2 2 2
0.36 (CH ), 111.69, 147.04, 153.61 (3Cisothiazole),
1
2
1
3
53.91 (C=O). Found, %: S 40.37; H 5.51; Cl 24.11; N
2
2
3
4.22; S 10.93. C H Cl N OS. Calculated, %: S
5
10 15
2
3
2
2
0.55; H 5.10; Cl 23.94; N 14.19; S 10.82.
), 7.43 m (3Н ), 7.71 m
isoxazole
Ar
1
3
(
2Н ), 9.37 b.s (1H, NH). С NMR spectrum, δ, ppm:
Ar
1-[5-(Benzylsulfanyl)-4-chlorothiazol-3-yl]ureas
4
1
1
6
6
5.07 (2CH N), 45.71 (2CH NH), 94.73 (CHisoxazole),
2 2
25.61 (2СН ), 129.05 (2СН ), 130.39 (СН ), 127.35,
53.89, 160.71 (3Cquat), 169.26 (S=О). Found, %: S
1.98; H 5.85; N 20.51. C H N O . Calculated, %: S
1.75; H 5.92; N 20.58.
XXXII–XXXV. General method. The solution of
0.94 g (2.3 mmol) of 4-fluorphenyl (5-benzyl-sulfanyl-
4-chlorothiazol-3-yl)carbamate (XXX) and 4.6 mmol
of amine in 10 mL of chloroform was boiled for 1 h.
The solvent was removed at a reduced pressure, the
precipitate was recrystallized from chloroform and
dried in a vacuum.
Ar
Ar
Ar
1
4
16
4
2
N-(5-Phenylisoxazol-3-yl)morpholine-4-carboxa-
mide (XXVII). Yield 64%, mp 225–227°C. IR spec-
trum, cm : 3257, 3217, 3201, 3176, 3095, 3068, 3040,
–
1
1-[5-(Benzylsulfanyl)-4-chlorothiazol-3-yl]-3-he-
2
1
7
976, 2958, 2922, 2866, 1682, 1628, 1601, 1581,
553, 1501, 1431, 1279, 1267, 1251, 1120, 988, 875,
xylurea (XXXII). Yield 95%, mp 44–46°C. IR spec-
–
1
trum, cm : 3262, 2925, 1663, 1572, 1519, 1506, 1322,
1
1
63, 683, 576. Н NMR spectrum, δ, ppm: 3.47 t (4Н,
1101, 713, 694. Н NMR spectrum, δ, ppm: 0.87 t (3H,
3
3
3
СН NСН , J 4.3 Hz), 3.60 t (4Н, СН OСН , J 4.3 Hz),
CH , J 6.8 Hz), 1.31 m (6H, 3CH ), 1.57 m (2H,
2
2
2
2
3
2
3
3
7
6
4
1
1
.21 s (1H, CHisoxazole), 7.51 m (3Н ), 7.85 d (2Н , J
CH ), 3.33 q (2H, CH , J 6.6 Hz), 4.17 s (2H, CH S),
Ar
Ar
2 2 2
1
3
13
.6 Hz), 9.84 s (1H, NH). Spectrum NMR С, δ, ppm:
7.24 s (1H, NH), 7.32 m (5H ), 8.26 s (1H, NH). С
Ar
4.10 (2CH N), 65.85 (2CH O), 95.00 (CHisoxazole),
NMR spectrum, δ, ppm: 14.16 (CH ), 22.69 (CH ),
2
2
3
2
25.28 (2СН ), 129.13 (2СН ), 130.22 (СН ),
26.73 (CH ), 29.84 (CH ), 31.61 (CH ), 39.21 (CH S),
Ar
Ar
Ar
2 2 2 2
27.00, 153.73, 160.48 (3Cquat), 167.73 (S=О). Found,
40.43 (CH N), 128.39 (CH ), 129.02 (2CH ), 129.12
2 Ar Ar
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

THE SYNTHESIS OF ISOXAZOLYL- AND ISOTHIAZOLYLCARBAMIDES
1675
(
2CH ), 110.51, 135.33, 153.62, 154.08 (4Cquat),
Ar
spectrum, δ, ppm: 45.76 (2CH ), 27.76 (CH ), 38.05
3
2
1
1
5
54.20 (C=O). Found, %: C 53.41; H 5.99; Cl 8.97; N
0.98; S 16.85. C H ClN OS . Calculated, %: C
3.18; H 5.78; Cl 9.23; N 10.94; S 16.70.
(CH ), 38.46 (CH S), 57.36 (CH N), 128.44 (CH ),
2 2 2 Ar
129.20 (2CH ), 129.62 (2CH ), 111.12, 136.49,
1
7
22
3
2
Ar
Ar
153.87, 154.87 (4Cquat), 155.23 (C=O). Found, %: C
9.87; H 5.61; Cl 9.14; N 14.58; S 16.59.
C H ClN OS . Calculated, %: C 49.92; H 5.50; Cl
4
1
-[5-(Benzylsulfanyl)-4-chlorothiazol-3-yl]-3-(5-
1
6
21
4
2
hydroxyhexyl)urea (XXXIII). Yield 95%, mp 122–
9
.21; N 14.55; S 16.66.
REFERENCES
. Clerici, F., Gelmi, M.L., Pellegrino, S., and Pocar, D.,
–
1
1
2
1
25°C. IR spectrum, cm : 3281, 3167, 3058, 2955,
926, 2848, 1675, 1566, 1525, 1455, 1425, 1393,
1
323, 1106, 1058, 715, 697. Н NMR spectrum, δ,
3
ppm: 1.27 m (4H, 2CH ), 1.41 q (4H, 2CH , J 6.5 Hz),
2
2
1
3
3
3
6
7
7
.13 d (2H, CH , J 6.0 Hz), 3.37 t (2H, CH N, J
2
2
Bioactive Heterocycles III, Berlin–Heidelberg: Springer,
2007, vol. 9.
3
.2 Hz), 4.36 br.s (3H, CH + OH), 7.29 t (1H , J
.1 Hz), 7.34 t (2H , J 7.1 Hz), 7.41 d (2H , J
.1 Hz), 7.68 s (1H, NH), 8.88 s (1H, NH). C NMR
2
Ar
3
3
Ar
Ar
2. Beebe, J.S., Jani, J.P., Knauth, E., Goodwin, P, Higdon, C.,
Rossi, A.M., Emerson, E., Finkelstein, M., Floyd, E.,
Harriman, S., Atherton, J., Hillerman, S., Soderstrom, C.,
Kou, K., Gant, T., Noe, M.C., Foster, B., Rastinejad, F.,
Marx, M.A., Schaeffer, T., Whalen, P.M., and Ro-
berts, W.G., Cancer Res., 2003, vol. 63, p. 7301.
1
3
spectrum, δ, ppm: 25.85 (CH ), 26.91 (CH ), 30.12
2
2
(CH ), 33.12 (CH ), 38.07 (CH ), 39.93 (CH S), 61.27
2 2 2 2
(CH N), 128.48 (CH ), 129.24 (2CH ), 129.65 (2CH ),
2 Ar Ar Ar
1
11.21, 136.54, 153.87, 154.89 (4Cquat), 155.25 (C=O).
3
. Smith, R.A., Barbosa, J., Blum, C.L., Bobko, M.A.,
Caringal, Y.V, Dally, R., Johnson, J.S., Katz, M.E.,
Kennure, N., Kingery-Wood, J., Lee, W., Lowinger, T.B.,
Lyons, J., Marsh, V., Rogers, D.H., Swartz, S., Walling, T.,
and Wild, H., Bioorg. Med. Chem. Lett., 2001, vol. 11,
p. 2775.
Found, %: C 51.20; H 5.47; Cl 8.78; N 10.58; S 16.00.
C H ClN O S . Calculated, %: C 51.05; H 5.54; Cl
8
1
7
22
3
2 2
.86; N 10.51; S 16.03.
1
-[5-(Benzylsulfanyl)-4-chlorothiazol-3-yl]-3-[2-
(
2-hydroxyethoxy)ethyl]urea (XXXIV). Yield 89%,
–
1
4
5
6
. Artuso, E., Degani, I., Fochi, R., and Magistris, C.,
Synthesis, 2007, vol. 22, p. 3497.
. Mizuno, T., Nakai, T., and Mihara, M., Synthesis, 2009,
vol. 15, p. 2492.
. Scriven, E.F.V. and Turnbull, K., Chem. Rev., 1988,
vol. 88, p. 297; Laszlo, P. and Polla, E., Tetrahedron
Lett., 1984, vol. 25, p. 3701; Hemantha, H., Chenna-
krishnareddy, G., Vishwanatha, T., and Sureshbabu, V.,
Synlett., 2009, vol. 3, p. 407; Lebel, H. and Leogane, O.,
Org. Lett., 2006, vol. 8, p. 5717; Marinescu, L.,
Thinggaard, J., Thomsen, I.B., and Bols, M., J. Org.
Chem., 2003, vol. 68, p. 9453.
mp 99–100°C. IR spectrum, cm : 3482, 3343, 3253,
3
1
1
135, 3095, 3068, 2987, 2923, 2892, 2862, 1664,
568, 1520, 1508, 1454, 1454, 1413, 1324, 1279,
1
105, 1083, 1073, 1049, 886, 779, 720, 693, 619. Н
3
NMR spectrum, δ, ppm: 3.31 q (2H, CH , J 5.2 Hz),
3
2
3
.43 t (2H, CH , J 5.2 Hz), 3.48 m (4H, 2CH ), 4.37 s
2
2
3
(
2H, CH S), 4.60 t (1H, OH, J 5.4 Hz), 7.30 t (1H ,
2
A
r
3
3
3
J 7.3 Hz), 7.35 t (2H , J 7.3 Hz), 7.42 d (2H , J
Ar
Ar
1
3
7
.3 Hz), 7.73 b.s (1H, NH), 9.14 s (1H, NH). C NMR
spectrum, δ, ppm: 38.07 (CH ), 39.93 (CH S), 60.82
2
2
(CH N), 69.88 (CH ), 72.73 (CH ), 128.48 (CH ),
2 2 2 Ar
1
1
4
29.25 (2CH ), 129.65 (2CH ), 111.38, 136.54,
Ar Ar
53.92, 154.94 (4Cquat), 155.14 (C=O). Found, %: C
7
. Petkevich, S.К., Potkin, V.I., and Kaberdin, R.V., Russ.
J. Org. Chem., 2004, vol. 40, p. 1146; Shakirova, О.G.,
Kuratieva, N.V., Lavrenova, L.G., Bogomyakov, А.S.,
Petkevich, S.К., and Potkin, V.I., J. Struct. Chem.,
2010, vol. 51, p. 703.
6.35; H 4.77; Cl 9.07; N 10.88; S 16.48. C H Cl·
1
5
18
N O S . Calculated, %: C 46.44; H 4.68; Cl 9.14; N
1
3
3 2
0.83; S 16.53.
8
. Potkin, V.I., Gadzhily, R.А., Dikusar, Е.А., Petkevich, S.К.,
Zhukovskaya, N.А., Aliev, А.G., and Nagieva, Sh.F.,
Russ. J. Org. Chem., 2012, vol. 48, p. 127.
. Kaberdin, Р.В., Potkin, V.I., and Oldekop, Yu.А., Zh.
Org. Khim., 1990, vol. 26, p. 1560.
1
-[5-(Benzylsulfanyl)-4-chlorothiazol-3-yl]-3-[3-
(
dimethylaminо)propyl]urea (XXXV). Yield 92%,
mp 95–96°C. IR spectrum, cm : 3254, 3221, 3133,
093, 3061, 2987, 2937, 2860, 2819, 2772, 1662,
566, 1518, 1497, 1454, 1321, 1278, 1247, 1101, 716,
94. Н NMR spectrum, δ, ppm: 1.56 t (2H, J 6.8 Hz),
.10 s (6H, NМе ), 2.22 t (2H, CH , J 6.8 Hz), 3.17 q
2H, CH , J 6.3 Hz), 4.38 s (2H, CH S), 7.30 t (1H ,
J 7.3 Hz), 7.35 t (2H , J 7.3 Hz), 7.41 d (2H , J
.3 Hz), 7.79 s (1H, NH), 9.04 s (1H, NH). C NMR
–
1
9
3
1
6
2
1
1
0. Potkin, V.I., Nechai, N.I., and Kaberdin, R.V., Russ.
J. Org. Chem., 2007, vol. 43, p. 587.
1. Potkin, V.I., Kleckov, А.V., Zubenko, Yu.S., Diku-
sar, Е.А., Petkevich, S.К., Zvereva, Т.D., Zolotar, R.M.,
and Chepik, О.P., Dokl. Nats. Akad. Nauk Belarusi,
2013, vol. 3, p. 76.
1
3
3
2
2
3
(
2 2 Ar
3
3
3
Ar
Ar
1
3
7
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

1
676
POTKIN et al.
1
2. Potkin, V., Bumagin, N., Petkevich, S., Lyakhov, A.,
Rudakov, D., Livantsov, M., and Golantsov, N.,
Synthesis, 2011, vol. 44, p. 151.
18. Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vander-
meersch, T., Zurek, E., and Hutchison, G.R.,
J. Cheminform., 2012, vol. 4, p. 17.
1
1
1
3. Potkin, V.I. and Zubenko, Yu.S., Russ. J. Org. Chem.,
19. Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S.,
Greenblatt, D.M., Meng, E.C., and Ferrin, T.E.,
J. Comput. Chem., 2004, vol. 25, p. 1605.
20. Nemuchin, А.V., Grigorenko, B.L., and Granovsky, А.А.,
Vestn. MGU, Ser. Khim., 2004, vol. 45, p. 75.
21. Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, S.T.,
Gordon, M.S., Jensen, J.H., Koseki, S., Matsunaga, N., Ngu-
yen, K.A., Su, S., Windus, T.L., Dupuis, M., and Mont-
gomery, J.A., J. Comput. Chem., 1993, vol. 14, p. 1347.
2
009, vol. 45, p. 555.
4. Scriven, E.F.V. and Turnbull K., Chem. Rev., 1988, vol. 88,
p. 297.
5. Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R.,
Merz, K.M., Ferguson, D.M., Spellmeyer, D.C.,
Fox, T., Caldwell, J.W., and Kollman, P.A.,
J. Am. Chem. Soc., 1995, vol. 117, p. 5179.
6. Jakalian, A., Jack, D.B., and Bayly, C.I., J. Comput.
Chem., 2002, vol. 23, p. 1623.
1
1
22. Allouche, A.-R., J. Comput. Chem., 2011, vol. 32, p. 174.
23. Ewing, T.A., Makino, S., Skillman, A.G., and Kuntz, I.,
7. Halgren, T.A., J. Comput. Chem., 1996, vol. 17,
p. 490.
J. Comput.-Aided Molec. Des., 2001, vol. 15, p. 411.
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