Syntheses based on 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide and azide

Article abstract of DOI:10.1007/s10593-006-0096-0

Treatment of 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide with NH₄SCN and PhCONCS gave the corresponding thiosemicarbazides, arylsulfochlorides yielded the arylsulfonylhydrazides, and diazotization conditions gave the correspondi

Full text of DOI:10.1007/s10593-006-0096-0

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
SYNTHESES BASED ON 3,4-DIMETHYL-
2-THIOXOTHIAZOLINE-5-CARBOXYLIC
ACID HYDRAZIDE AND AZIDE
V. V. Dovlatyan, K. A. Eliazyan, V. A. Pivazyan, and A. P. Yengoyan
Treatment of 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide with NH4SCN and PhCONCS
gave the corresponding thiosemicarbazides, arylsulfochlorides yielded the arylsulfonylhydrazides, and
diazotization conditions gave the corresponding azide. The interactions of the latter with different
nucleophiles have been studied and a series of novel carbamic acid, urea, and semicarbazide derivatives
containing a thiazoline fragment have been prepared.
Keywords: arylsulfohydrazide, hydrazide, carbamic acid, semicarbazide, thiazolineisocyanate,
thiosemicarbazide.
In continuation of our search for a novel series of biologically active substances based on the previously
reported 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide (1) [1] we now report the preparation of its
arylsulfonyl and thiocarbamoyl derivatives 2a-e and 3, 4 respectively as well as the azide product of its
diazotization 5. Compounds 2a-e are related in structure to known sulfonylamides [2] or thiourea derivatives [3]
and hence attract particular interest as potential medicinal agents and pesticides. The azide 5, being a
thiazolineisocyanate donor under Curtius reaction conditions can serve as a valuable starting compound for the
development of novel routes to functionalize a thiazoline system and this has been demonstrated in a series of
examples.
When treated with arylsulfochlorides in pyridine medium at 20°C the hydrazide 1 gave high yields
(80-90%) of the arylsulfonylhydrazides 2a-e and when refluxed with ammonium thiocyanate in ethanol or with
benzoylisothiocyanate in dioxane the thiosemicarbazide 3 (yield 61%) or benzoylthiosemicarbazide 4
(yield 78%) respectively (Scheme 1).
A single unsuccessful attempt to carry out the reaction of thiazolecarboxylic acid hydrazides to the
corresponding azide has been reported in the literature. In [3] it was shown that 2-substituted
5-phenylthiazolecarboxylic acid hydrazides in excess acetic acid and the presence of NaNO2 underwent a more
extensive reaction and, in place of the expected azides, gave the N,N'-bis(2-substituted-5-phenyl)thiazolylureas.
Despite this data we have found in our work that hydrazide 1 readily forms the azide 5 when treated with
an equimolar amount of HNO2 in aqueous medium in 91% yield. The reactions of the azide with various
nucleophiles have been studied. It was found that, at 100-120°C in absolute toluene, the azide indicated
underwent a Curtius rearrangement reaction to the corresponding isocyanate which reacts with alcohols, amines,
and hydrazides to form novel derivatives of carbamic acid 6a-g, urea 7a-k, and semicarbazide 8a-d containing a
thiazoline fragment.
__________________________________________________________________________________________
Armenian Agricultural Academy, Yerevan 375009; e-mail: vdovlat@netsys.am. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 430-436, March, 2006. Original article submitted
February 13, 2003; revision submitted December 15, 2003.
0009-3122/06/4203-0383©2006 Springer Science+Business Media, Inc.
383

Scheme 1
O
O
O
S
Me
Me
C–NHNHSO2Ar
Me
Me
C–NHNH–C–NH–C–Ph
Ph–CO–N=C=S
N
S
O
N
S
ArSO2Cl
NH4SCN
Me
Me
C–NHNH2
S
S
2a–e
4
N
S
O
NaNO2
AcOH
S
O
S
CN3
Me
1
Me
C–NHNH–C–NH2
N
S
Me
N
S
S
Me
S
5
3
2 a Ar = Ph, b Ar = C6H4Me-4, c Ar = C6H4Cl-2, d Ar = C6H3Me2-2,3,
e Ar = C6H4NHCOMe-4
The composition and structure of the synthesized compounds were confirmed by elemental analytical
1
data and by H NMR spectroscopy (Tables 1 and 2). The structure of azide 5 agrees also with the IR data
(Table 1).
Me
Me
NHCONHR
NHCOOR
Me
Me
RNH2
ROH
5
N
S
N
S
RNHNH2
S
S
7a–k
6a–g
Me
NHCONHNHR
N
S
Me
S
8a–d
6 a R = Et; b R = Pr-i; c R = Ph; d R = (CH2)2Cl; e R = (CH2)2NMe2;
NMe2
N
NMe2
N
N
N
N
N
f R =
g R =
CH2CH2O
CH2CH2S
,
NMe2
NMe2
7 a R = Bu-t; b R = Ph; c R = C6H4Cl-2; d R = C6H4Cl-4; e R = C6H3Cl2-2,4;
f R = (CH2)2OPh; g R = (CH2)2OC6H4Me-4; h R = (CH2)2OC6H3Cl2-2,4;
Me
,
Me
Me
N
N
N
S
N
S
i R =
j R =
k R =
,
,
CONHPh
COOEt
OMe
8 a R = SO2Ph; b R = SO2C6H4Me-4; c R = SO2C6H4NHAc-4; d R = Ac
384

385

386

387

EXPERIMENTAL
1H NMR spectra were taken on a Mercury-300 (300 MHz) instrument using DMSO-d6 and with TMS as
internal standard. IR spectra were recorded on a UR-20 instrument (vaseline oil paste). Monitoring of the course
of the reaction and the purity of the compounds obtained was carried out by TLC using Silufol UV-254 plates
and eluent acetone–hexane (2:1).
3,4-Dimethyl-2-thioxothiazoline-5-carboxylic Acid Arylsulfonylhydrazides 2a-e. Hydrazide 1
(2.03 g, 10 mmol) was added in small portions with stirring to a solution of the arylsulfochloride (10 mmol) in
pyridine (5 ml) at 0°C. The mixture was held for 2 days at 20-25°C, diluted with iced water (20 ml), and the
separated crystals of compounds 2a-e were filtered off and recrystallized from 25% EtOH.
3,4-Dimethyl-2-thioxothiazoline-5-carboxylic Acid Thiosemicarbazide (3). A mixture of the
hydrazide 1 (2.03 g, 10 mmol), NH4SCN (1.25 g, 15 mmol), and 36% HCl (1.2 ml, 15 mmol) was refluxed in
EtOH (10 ml) for 1 h. The EtOH was distilled off and the residue was treated with H2O (10 ml). The precipitated
crystals were filtered off to give compound 3 (1.6 g).
3,4-Dimethyl-2-thioxothiazoline-5-carboxylic Acid Benzoylthiosemicarbazide (4). PhCOCl (1.4 g,
10 mmol) was added portionwise to a solution of NH4SCN (0.84 g, 11 mmol) in dry dioxane (10 ml). The
mixture obtained was refluxed for 15 min and the hydrazide 1 (2.03 g, 10 mmol) was added to it at such a rate
that gentle refluxing continued. After cooling, the reaction product was treated with water (20 ml) and the
precipitate was filtered off to give compound 4 (2.88 g).
3,4-Dimethyl-2-thioxothiazoline-5-carboxylic Acid Azide (5). NaNO2 (1.75 g, 25 mmol) was added to
a suspension of the hydrazide 1 (2.03 g, 10 mmol) in water (30 ml) and AcOH (1.50 g, 25 mmol) was added
portionwise slowly at 0°C. The mixture was stirred for 3 h at 20-25°C. The precipitate was filtered off, washed
on the filter with water (30 ml), and dried in air to give the azide 5 (1.95 g).
Esters of 3,4-Dimethyl-2-thioxothiazoline-5-carbamic Acid (6a-g), N-Alkyl(aryl, heteryl)-N'-
(3,4-dimethyl-2-thioxothiazolin-5-yl)ureas
(7a-k),
and
4-Acetyl-(arylsulfonyl)-1-(3,4-dimethyl-2-
thioxothiazolin-5-yl)semicarbazides (8a-d). A suspension of azide 5 (2.14 g, 10 mmol) and the nucleophile
(alcohol, amine, or substituted hydrazine) (10 mmol) in absolute toluene (10 ml) (in the case of aliphatic
alcohols the latter are the solvent) was held in the presence of a catalytic amount of pyridine at 100-120°C for
2 h. After cooling the reaction mixture the precipitated product was filtered off and washed with petroleum ether.
Most of the products 7 were additionally purified by recrystallization (solvent given in Table 2).
REFERENCES
1.
V. V. Dovlatyan, K. A. Eliazyan, V. A Pivazyan, and A. P. Engoyan, Khim. Geterotsikl. Soedin., 1409
(2003).
2.
3.
4.
M. D. Mashkovskii, Drugs [in Russian], Vol. 2, Novaya Volna, Moscow (1996), p. 319.
N. N. Mel'nikov, Pesticides [in Russian], Khimiya, Moscow (1987), p. 326.
V. A. Mamedov, I. Kh. Rizvanov, I. A. Nuretdinov, and Yu. Ya. Efremov, Khim. Geterotsikl. Soedin.,
987 (1994).
388