Synthesis of oxamic acids thiohydrazides and carbamoyl-1,3,4-thiadiazoles

Article abstract of DOI:10.1023/B:RUJO.0000010181.01921.77

A convenient preparation method was developed for oxamic acids thiohydrazides by reaction of α-chloroacetamides with a preliminary prepared solution of elemental sulfur and hydrazines. A series of carbamoyl-1,3,4-thiadiazole derivatives was obtained.

Full text of DOI:10.1023/B:RUJO.0000010181.01921.77

Russian Journal of Organic Chemistry, Vol. 39, No. 8, 2003, pp. 1133 1139. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 8, 2003,
pp. 1204 1210.
Original Russian Text Copyright
2003 by Yarovenko, Shirokov, Krupinova, Zavarzin, Krayushkin.
Synthesis of Oxamic Acids Thiohydrazides
and Carbamoyl-1,3,4-thiadiazoles
V. N. Yarovenko, A. V. Shirokov, O. N. Krupinova, I. V. Zavarzin,
and M. M. Krayushkin
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia
Received September 27, 2002
Abstract A convenient preparation method was developed for oxamic acids thiohydrazides by reaction of
-chloroacetamides with a preliminary prepared solution of elemental sulfur and hydrazines. A series of
carbamoyl-1,3,4-thiadiazole derivatives was obtained.
We formerly developed a convenient general
method of monothiooxamides synthesis by reaction
of available chloroacetamides with a preliminary
prepared solution of elemental sulfur in amines [1].
Synthetic approaches basing on modifications of
amide and thioamide groups in the monothiooxamides
are promising for building up a wide range of
various compounds. For instance, we showed that
modification of the thioamide group in the monothio-
oxamides effected with N-nucleophiles provided
versatile hetarenecarboxamides [2 7].
solution of -chloroacetamide in DMF gave rise to
the corresponding oxamic acids thiohydrazides. The
yields of products IId, e were no more than 20 30%.
In the present study in extension of our research
concerning the use of the products of S-functionaliza-
tion of organic compounds in the synthesis of
S,N-heterocyclic substances we investigated the
possibility of preparation of oxamic acids thio-
hydrazides. The oxamic acids thiohydrazides having
in a single molecule thiohydrazide and amide groups
possess great synthetic potential and are very interest-
ing for preparation of complexing structures and
biologically active compounds [8 10].
We investigated the effect of storage time in DMF
of a preliminary prepared solution containing ele-
mental sulfur, mono- and disubstituted hydrazines,
and triethylamine on the yield of oxamic acids thio-
hydrazides. We succeeded in increasing the yield of
oxamic acids thiohydrazides (II) to 60 70% using a
sulfur solution obtained by mixing the components
for 20 30 min.
However the known preparation methods for
oxamic acids hydrazides with substituents at the
terminal nitrogen of the thiohydrazide moiety are
laborious [11], and the unsubstituted derivatives are
synthesized in three stages starting with chloroacet-
amides [12].
I, R = H (a), 4-Cl (b); II, X = NMe2: R = H (a),
4-Cl (b); X= NHPh, R= H (c); X= N(CH2CH2)2N
CH3: R = H (d), 4-Cl (e).
We studied the possibility to prepare oxamic acids
thiohydrazides in one stage by reaction of available
-chloroacetamides with the elemental sulfur and
hydrazides.
The method is of general character and provides a
possibility to prepare among others oxamic acids
thiohydrazides containing an -amino acid fragment.
The procedure we proposed was not formerly used
for the synthesis of oxamic acids thiohydrazides.
However we failed to obtain oxamic acids thio-
hydrazides with unsubstituted thiohydrazide moiety
Actually it turned out that simultaneous addition of
hydrazines, elemental sulfur, and triethylamine to a
1070-4280/03/3908-1133$25.00 2003 MAIK Nauka/Interperiodica

1134
YAROVENKO et al.
by reaction of -chloroacetamides with hydrazine
hydrate. Apparently hydrazine readily reacted with
the elemental sulfur and also reduced the polysulfide
bonds in anions arising in the system sulfur
hydrazine decomposing therewith to gaseous nitrogen.
atives that can be interesting for the synthesis of
pharmaceuticals and pesticides [13 15]. For instance,
in the reaction of thiahydrazides IV with haloacetyl
chlorides were cleanly obtained carbamoyl-1,3,4-
thiadiazoles with halomethyl groups.
With greater success we applied to the synthesis of
unsubstituted thiohydrazides the approach we had
developed for preparation of monothiooxamides. It
was shown earlier that monothiooxamides cleanly
formed in reaction of easily accessible N(S)-morpho-
lino-N(O)-R-thiooxamides with various amines [5].
The application of hydrazine instead of amine in this
procedure made possible the preparation of unsub-
stituted thiohydrazides of oxamic acids (IV).
However our attempts to perform heterocyclization
by treating with substituted benzoyl chlorides were
unsuccessful. Thiadiazoles VI with aryl groups were
synthesized by oxidation of the corresponding hydra-
zones with FeCl3.
I, III, IV, R = H (a), 4-Cl (b), 4-MeO (c), 4-Br (d),
4-F (e), 2,3-Me2 (f), 3-Me (g).
VI, R = H: R = H (a), 4-NO2 (b); R = 4-MeO,
The oxamic acids thiohydrazides obtained are
valuable synthons for preparation of versatile hetero-
cyclic products. We obtained therefrom in particular
quite a number of carbamoyl-1,3,4-thiadiazole deriv-
R
= H (c).
Reactions of thiohydrazides with alkyl oxalyl
chlorides furnished the corresponding alkoxycarbonyl
derivatives of substituted thiadiazoles VII.
V, R = CF3: R = H (a), 4-Cl (b), 4-MeO (c), 4-Br
(d); R = CCl3: R = H (e), 4-Cl (f), 4-MeO (g),
2,3-Me2 (h); R = CHCl2, R = 4-MeO (i); R =
CH2Cl, R = 4-MeO (j).
VII, R = 4-MeO: R = Et (a), t-Bu (b).
Thus we developed a new preparation method
for oxamic acids thiohydrazides and synthesized
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003

SYNTHESIS OF OXAMIC ACIDS THIOHYDRAZIDES
1135
therefrom derivatives of carbamoyl-1,3,4-thiadi-
azoles.
The anions originate from the cleavage by amines of
the eight-membered cycle of the elemental sulfur
molecule [16]. Apparently at a sufficiently high con-
centration just polysulfide anins and not hydrazines
predominantly react with the chloroacetamides. From
the nucleophilic substitution of chlorine results the
corresponding polysulfide where the hydrazine
molecules effect simultaneous proton abstraction
and sulfide bond cleavage to furnish a thioaldehyde
fragment. The thioaldehyde reacts with hydrazine
yielding a hydrazone which further suffers oxidation
by sulfur into the corresponding thiohydrazide
moiety.
We believe that increased yield of oxamic acids
thiohydrazides at application of the preliminary pre-
pared solutions of elemental sulfur and hydrazines as
compared to the mode of simultaneous addition of
reagents is presumably due to reduced possibility of
the side reaction (alkylation of hydrazines with
chloroacetamides) under these conditions.
It is known that at sufficiently long interaction
between amines and elemental sulfur a considerable
amount of polysulfide anions accumulates in solution.
Hence at sufficiently high concentration of poly-
sulfide anions generated in the system sulfur hydr-
azines apparently a pattern may be realized with
participation of intermediate structures which sig-
nificantly facilitate the thiolation process of the
methylene fragment. The monothiooxamides arise
from chloroacetamides also along a similar scheme.
Synthesis of chloroacetanilides Ia h. Chloro-
acetanilides were synthesized from appropriate aryl-
amines and chloroacetyl chloride by a known
procedure [17].
Simultaneous addition of 1-amino-4-methyl-
piperazine, elemental sulfur, and triethylamine to
-chloroacetanilide. To 6 mmol of chloroacetanilide
Ia, b in 5 ml of DMF was added 18 mmol of sulfur,
12 mmol of 1-amino-4-methylpiperazine, and 2 ml of
triethylamine. The reaction mixture was stirred at
room temperature for 3 h and was left standing for
12 h. Then the mixture was poured into water, the
separated precipitate was filtered off and dried. To
remove the unreacted sulfur the product was dissolv-
ed in acetone, the acetone solution was separated,
and the solvent was evaporated in a vacuum. The
solid residue was recrystallized from ethanol.
Thus we demonstrated that the application of a
preliminary prepared sulfur solution in amines or
hydrazines is a convenient way of S-functionalization
of -chloroacetamides.
EXPERIMENTAL
1H NMR spectra were registered on spectrometers
Bruker WM-200 (200 MHz) and Bruker WM-250
(250 MHz) in DMSO-d6. Mass spectra were measur-
ed on Varian MAT CH-6 instrument with direct
admission of a sample into the ion source, ionizing
electrons energy 70 eV, and control voltage 1.75 kV.
Melting points were measured on Boetius heating
block and were reported uncorrected. The analysis of
reaction mixtures and checking of the products purity
was carried out by TLC on Silufol UV-254 plates,
eluent ethyl acetate hexane, 1: 1 by volume.
N(1)-Phenyl-2-(2-amino-4-methylpiperazino)-2-
thiooxacetamide (IId). Yield 24%, mp 132 135 C.
1H NMR spectrum, , ppm (J, Hz): 2.25 s (3H,
CH3); 3.65 t (2 H, CH2); 4.1 t (2H, CH2); 7.1 t (1H,
Harom, J 7.37 ); 7.3 t (2H, H arom, J 7.61); 7.6 d
(2H, Harom, J 7.92); 10.55 s (1H, NH). Mass spec-
trum, m/z: 278 [M]+ . Found, %: C 56.20; H 6.42;
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1136
YAROVENKO et al.
N 20.16; S 11.45. C13H18N4OS. Calculated, %:
C 56.09; H 6.52; N 20.13; S 11.52.
1H NMR spectrum, , ppm (J, Hz): 2.25 s (3 H,
CH3); 3.65 t (2 H, CH2); 4.1 t (2H, CH2); 7.1 t (1H,
Harom, J 7.37); 7.3 t (2H, Harom, J 7.61); 7.6 d
(2H, Harom, J 7.92); 10.55 s (1H, NH). Mass spec-
trum, m/z: 278 [M]+ .
N(1)-(4-Chlorophenyl)-2-(2-amino-4-methyl-
piperazino)-2-thiooxacetamide (IIe). Yield 36%,
1
mp 128 130 C. H NMR spectrum, , ppm (J, Hz):
N(1)-(4-Chlorophenyl)-2-(2-amino-4-methyl-
piperazino)-2-thiooxacetamide (IIe). Yield 57%, mp
128 130 C. 1H NMR spectrum, , ppm (J, Hz):
2.25 s (3H, CH3); 3.65 t (1H, CH2); 4.1 t (1H,
CH2); 7.3 d (2H, Harom, J 8.73); 7.65 d (2H,
Harom, J 8.72); 10.7 s (1H, NH). Mass spectrum,
m/z: 312 [M]+ .
2.25 s (3H, CH3); 3.65 t (1H, CH2); 4.1 t (1H,
CH2); 7.3 d (2H, H arom, J 8.73 ); 7.65 d (2H,
Harom, J 8.72); 10.7 s (1H, NH). Mass spectrum,
m/z: 312 [M]+ . Found, %: C 50.02; H 5.39; Cl
11.40; N 18.03; S 10.34. C13H17ClN4OS. Calculated,
%: C 49.91; H 5.48; Cl 11.33; N 17.91; S 10.25.
Synthesis of oxamic acids thiohydrazides IIa f.
A mixture of 18 mmol of sulfur, 12 mmol of hydr-
azine, and 2 ml of triethylamine in 5 ml of DMF was
stirred for 30 min, then a solution of 6 mmol of
chloroacetanilide Ia c in 3 ml of DMF was poured
thereto. The reaction mixture was stirred at room
temperature for 3 h and then was left overnight. Then
the mixture was poured into water, the separated
precipitate was filtered off and dried. To remove the
unreacted sulfur the product was dissolved in acetone,
the acetone solution was separated, and the solvent
was evaporated in a vacuum. The solid residue was
recrystallized from ethanol.
Methyl-2-{[(4-methylpiperazin-1-amino)(thio-
oxo)acetyl]amino}-3-phenylpropanoate (IIf). Yield
1
68%, mp 168 170 C. H NMR spectrum, , ppm (J,
Hz): 2.5 m (3H, CH3); 3.00 3.5 m (8H, CH2);
3.65 m (3H, CH3); 4.0 m (2H, CH2); 4.65 m (1H,
CH); 7.3 m (5H, Harom); 9.00 d (1H, NH). Mass
spectrum, m/z: 302 [M 62]+ . Found, %: C 56.12;
H 6.71; N 15.25; S 8.91. C17H24N4O3S. Calculated,
%: C 56.02; H 6.64; N 15.37; S 8.80.
Synthesis of monothiooxamides IIIa g. N(1)-
Aryl-2-morpholino-2-thiooxacetamides were prepared
by a published procedure [8]. To a suspension of
3 mmol of sulfur in 30 ml of morpholine was added
at stirring a solution of 1 mmol of chloroacetanilide
Ia g in 5 ml of DMF. The reaction mixture was stir-
red for 1 h at room temperature. Then the mixture
was poured into water, the separated precipitate was
filtered off and dried. To remove the unreacted sulfur
the product was dissolved in acetone, the acetone
solution was separated, and the solvent was evaporat-
ed in a vacuum. The solid residue was recrystallized
from ethanol.
N(1)-Phenyl-2-(N,N-dimethylhydrazino)-2-thio-
oxacetamide (IIa). Yield 51%, mp 135 137 C.
1H NMR spectrum, , ppm (J, Hz): 3.25 d (6H,
HNMe2); ); 7.1 t (1H, Harom, J 7.37); 7.3 t (2H,
Harom, J 7.61); 7.6 d (2H, Harom, J 7.92); 10.40 s
(1H, NH). Mass spectrum, m/z: 208[M 15]+ . Found,
%: C 53.86; H 5.92; N 18.78; S 14.32. C10H13N3OS.
Calculated, %: C 53.79; H 5.87; N 18.82; S 14.36.
N(1)-(4-Chlorophenyl)-2-(N,N-dimethylhydr-
azino)-2-thiooxacetamide (IIb). Yield 62%, mp
174 176 C. 1H NMR spectrum, , ppm (J, Hz):
3.25 s (6 H, HNMe2); 7.4 d (2H, Harom, J 8.73 );
7.6 d (2H, Harom, J 8.72); 10.65 s (1H, NH). Mass
spectrum, m/z: 242 [M 15]+ . Found, %: C 46.55;
H 4.64; Cl 13.81; N 16.20; S 12.40. C10H12ClN3OS.
Calculated, %: C 46.60; H 4.69; Cl 13.76; N 16.30;
S 12.44.
Synthesis of unsubstituted thiohydrazides of
oxamic acids IVa g. To a solution of 0.8 mmol of
monothiooxamide IIIa g in 2 ml of DMF was added
30 mmol of hydrazine hydrate, and the mixture was
left standing at room temperature. On completion of
reaction (TLC monitoring) the reaction mixture was
poured into 50 ml of water, the solution was acidified
by hydrochloric acid to pH 5. The separated pre-
cipitate was filtered off and recrystallized from
ethanol.
N(1)-Phenyl-2-phenylhydrazino-2-thiooxacet-
1
amide (IIc). Yield 62%, mp 148 150 C. H NMR
spectrum, , ppm (J, Hz): 7.2 m (3H, Harom);
7.25 m (2H, Harom); 7.35 m (2H, H arom); 7.75 d
(2H, Harom); 10.25 s (1H, NH). Mass spectrum,
m/z: 271 [M]+ . Found, %: C 62.06; H4.79; N15.37;
S 11.98. C14H13N3OS. Calculated, %: C 61.97;
H 4.83; N 15.49; S 11.82.
N(1)-Phenyl-2-hydrazino-2-thiooxacetamide
(IVa). Yield 83%, mp 144 147 C. H NMR spect-
1
rum, , ppm (J, Hz); 7.15 t (1H, Harom, J 7.37 );
7.4 t (2H, Harom, J 7.61); 7.6 d (2H, Harom,
J 7.92); 10.20 s (1H, NH). Mass spectrum, m/z:
195 [M]+ . Found, %: C 49.34; H 4.50; N 21.63;
S 16.33. C8H9N3OS. Calculated, %: C 49.21;
H 4.65; N 21.52; S 16.42.
N(1)-Phenyl-2-(2-amino-4-methylpiperazino)-2-
thiooxacetamide (IId). Yield 64%, mp 132 135 C.
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SYNTHESIS OF OXAMIC ACIDS THIOHYDRAZIDES
1137
N(1)-(4-Chlorophenyl)-2-hydrazino-2-thioox-
acetamide (IVb). Yield 84.5%, mp 172 174 C.
1H NMR spectrum, , ppm (J, Hz): 7.4 d (2H,
Harom, J 8.73 ); 7.8 d (2H, Harom, J 8.72); 10.30 s
(1H, NH). Mass spectrum, m/z: 229 [M]+ . Found,
%: C 41.94; H 3.42; Cl 15.51; N 18.23; S 14.01.
C8H8ClN3OS. Calculated, %: C 41.83; H 3.51; Cl
15.44; N 18.29; S 13.96.
by volume) the reaction mixture was poured into
water, the separated precipitate was filtered off and
recrystallized from ethanol.
N-Phenyl-5-(trifluoromethyl)-1,3,4-thiadiazole-
2-carboxamide (Va). Yield 89%, mp 177 180 C.
1H NMR spectrum, , ppm (J, Hz): 7.1 t (1H,
Harom, J 7.37); 7.3 t (2H, Harom, J 7.61); 7.6 d
(2H, Harom, J 7.92); 11.40 s (1H, NH). Mass spec-
trum, m/z: 273 [M]+ . Found, %: C 44.05; H 2.14;
N 15.42; S 11.81. C10H6F3N3OS. Calculated, %:
C 43.96; H 2.21; N 15.38; S 11.73
N(1)-(4-Methoxyphenyl)-2-hydrazino-2-thio-
oxacetamide (IVc). Yield 62%, mp 161 163 C.
1H NMR spectrum, , ppm (J, Hz): 3.75 s (3H,
Harom, J 8.83); 7.7 d (2H, Harom, J 8.83); 10.1 s
(1H, NH). Mass spectrum, m/z: 225 [M]+ . Found,
%: C 47.85; H 4.84; N 18.77; S 14.12. C9H11N3O2S.
Calculated, %: C 47.99; H 4.92; N 18.65; S 14.23.
N-(4-Chlorophenyl)-5-trifluoromethyl-1,3,4-
thiadiazole-2-carboxamide (Vb). Yield 51.5%, mp
181 183 C. 1H NMR spectrum, , ppm (J, Hz):
7.5 d (2H, Harom, J 8.73); 7.9 d (2H, Harom, J8.72);
11.50 11.60 s (1H, NH). Mass spectrum, m/z: 307
[M]+ . Found, %: C 39.12; H 1.51; Cl 11.63;
N 13.60; S 10.33. C10H5ClF3N3OS. Calculated, %:
C 39.04; H 1.64; Cl 11.52; N 13.66; S 10.42.
N(1)-(4-Bromophenyl)-2-hydrazino-2-thioox-
acetamide (IVd). Yield 60%, mp 164 166 C.
1H NMR spectrum, , ppm (J, Hz): 7.50 d (2H,
Harom, J 8.86, J 8.85); 7.75 d (2H, Harom); 10.30 s
(1H, NH). Mass spectrum, m/z: 274 [M]+ . Found,
%: C 34.93; H 2.82; Br 29.26; N 15.47; S 11.81.
C8HBrN3OS. Calculated, %: C 35.05; H 2.94; Br
29.15; N 15.33; S 11.70.
N-(4-Methoxyphenyl)-5-(trifluoromethyl)-1,3,4-
thiadiazole-2-carboxamide (Vc). Yield 75%, mp
1
157 158 C. H NMR spectrum, , ppm (J, Hz): 4.7 s
(3H, CH3); 6.9 d (2H, Harom, J 8.83); 7.80 d (2H,
Harom, J 8.84); 11.20 s (1H, NH). Mass spectrum,
m/z: 303 [M]+ . Found, %: C 43.49; H 2.74;
N 13.95; S 10.44. C11H8F3N3O2S. Calculated, %:
C 43.57; H 2.66; N 13.86; S 10.57.
N(1)-(4-Fluorophenyl)-2-hydrazino-2-thioox-
acetamide (IVe). Yield 75%, mp 157 160 C.
1H NMR spectrum, , ppm (J, Hz): 7.2 m (2H,
Harom); 7.80 t (2H, Harom); 10.20 s (1 H, NH).
Mass spectrum, m/z: 213 [M]+ . Found, %: C 45.16;
H 3.85; N 19.62; S 15.12. C8H8FN3OS. Calculated,
%: C 45.06; H 3.78; N 19.71; S 15.04.
N-(4-Bromophenyl)-5-(trifluoromethyl)-1,3,4-
thiadiazole-2-carboxamide (Vd). Yield 45.2%, mp
183 186 C. 1H NMR spectrum, , ppm (J, Hz):
7.5 7.6 d (2H, Harom); 7.80 7.90 d (2H, Harom);
11.50 s (1H, NH). Mass spectrum, m/z: 352 [M]+ .
Found, %: C 34.01; H 1.52; Br 22.56; N 12.01;
S 9.05. C10H5BrF3N3OS. Calculated, %: C 34.11;
H 1.43; Br 22.69; N 11.93; S 9.11.
N(1)-(2,3-Dimethylphenyl)-2-hydrazino-2-thio-
oxacetamide (IVf). Yield 68%, mp 150 153 C.
1H NMR spectrum, , ppm (J, Hz): 2.3 s (6H, CH3);
7.25 m (1H, Harom); 7.50 m (1H, Harom); 10.10 s
(1H, NH). Mass spectrum, m/z: 223 [M]+ . Found,
%: C 53.88; H 5.97; N 18.74; S 14.29. C10H13N3OS.
Calculated, %: C 53.79; H 5.87; N 18.82; S 14.36.
Synthesis of 5-(trichloromethyl)-1,3,4-thiadi-
azole-2-carboxamides Ve h. To 10 mmol of oxamic
acid thiohydraside IVe h in 5 ml of DMF was added
20 ml of trichloroacetyl chloride. After 4 h the reac-
tion mixture was poured into water, the separated
precipitate was filtered off and recrystallized from
ethanol.
N(1)-(3-Methylphenyl)-2-hydrazino-2-thioox-
acetamide (IVg). Yield 71%, mp 156 158 C.
1H NMR spectrum, , ppm (J, Hz): 2.2 s (3 H, CH3);
6.95 d (1H, Harom, J 7.4); 7.25 t (1H, Harom,
J 7.74); 7.25 d (1H, Harom, J 8.14); 7.50 s (2H,
Harom); 10.05 s (1H, NH). Mass spectrum, m/z: 209
[M]+ . Found, %: C 51.53; H 5.29; N 20.16; S15.20.
C9H11N3OS. Calculated, %: C 51.66; H 5.30;
N 20.08; S 15.32.
N-Phenyl-5-(trichloromethyl)-1,3,4-thiadiazole-
2-carboxamide (Ve). Yield 64%, mp 152 153 C.
1HNMR spectrum, , ppm (J, Hz): 7.1 t (1H, Harom,
J 7.37 ); 7.3 t (2H, Harom, J 7.61); 7.6 d (2H,
Harom, J 7.92); 11.40 s (1H, NH). Mass spectrum,
m/z: 322 [M]+ . Found, %: C 37.14; H 1.75; Cl 33.05;
N 13.12; S 9.90. C10H6Cl3N3OS. Calculated, %:
C 37.23; H 1.87; Cl 32.97; N 13.03; S 9.94.
Synthesis of 5-(trifluoromethyl)-1,3,4-thiadi-
azole-2-carboxamides Va d. To 10 mmol of oxamic
acid thiohydraside IVa d in 5 ml of DMF was added
20 ml of trifluoroacetic anhydride. After 15 min
(TLC monitoring, eluent ethyl acetate hexane, 1: 2
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YAROVENKO et al.
N-(4-Chlorophenyl)-5-(trichloromethyl)-1,3,4-
Synthesis of 5-aryl-1,3,4-thiadiazole-2-carb-
oxamides VIa c. A mixture of 1 mmol of thiohydr-
azide IVa, c and 1.1 mmol of aldehyde in 6 ml of
ethanol was boiled for 15 min. To the reaction mix-
ture obtained a solution was added of 2 mmol of
iron(III) chloride hexahydrate in 5 ml of ethanol, and
the mixture was heated for 1.5 h more. Then the reac-
tion mixture was cooled to room temperature, the
separated precipitate was filtered off, twice washed
with 3 ml of ethanol, with 5 ml of water, and dried in
air.
thiadiazole-2-carboxamide (Vf). Yield 62%, mp
165 167 C. 1H NMR spectrum, , ppm (J, Hz):
7.4 d (2H, Harom, J 8.73); 7.9 d (2H, Harom,
J 8.72); 11.40 s (1H, NH). Mass spectrum, m/z: 357
[M]+ . Found, %: C 33.72; H 1.53; Cl 39.64;
N 11.85; S 9.05. C10H5Cl4N3OS. Calculated, %:
C 33.64; H 1.41; Cl 39.72; N 11.77; S 8.98.
N-(4-Methoxyphenyl)-5-(trichloromethyl)-1,3,4-
thiadiazole-2-carboxamide (Vg). Yield 75%, mp
1
157 158 C. H NMR spectrum, , ppm (J, Hz): 4.7 s
(3H, CH3); 6.9 d (2H, Harom, J 8.83); 7.80 d (2H,
Harom, J 8.84); 11.20 s (1H, NH). Mass spectrum,
m/z: 352 [M]+ . Found, %: C 37.34; H 2.20;
Cl 30.29; N 12.04; S 9.15. C11H8Cl3N3O2S. Cal-
culated, %: C 37.47; H 2.29; Cl 30.16; N 11.92;
S 9.09.
N-Phenyl-5-phenyl-1,3,4-thiadiazole-2-carb-
oxamide (VIa). Yield 70%, mp 228 230 C.
1H NMR spectrum, , ppm (J, Hz): 7.1 t (1H,
Harom, J 7.37); 7.25 t (1H, Harom, J 7.38); 7.6 m
(4 H, Harom); 7.8 d (2 H, Harom, J 7.92); 8.1 d
(2H, Harom, J 7.92); 11.0 s (1H, NH). Mass spec-
trum, m/z: 281 [M]+ . Found, %: C 63.92; H 4.01;
N 15.09; S 11.32. C15H11N3OS. Calculated, %: C
64.04; H 3.94; N 14.94; S 11.40.
N-(2,3-Dimethylphenyl)-5-(trichloromethyl)-
1,3,4-thiadiazole-2-carboxamide (Vh). Yield 52%,
1
mp 138 140 C. H NMR spectrum, , ppm (J, Hz):
2.1 s (3H, CH3); 2.2 s (3H, CH3); 7.10 7.20 m (3H,
Harom); 10.85 s (1H, NH). Mass spectrum, m/z: 349
[M]+ . Found, %: C 41.21; H 2.95; Cl 30.36;
N 11.86; S 9.03. C12H10Cl3N3OS. Calculated, %:
C 41.10; H 2.87; Cl 30.33; N 11.98; S 9.14.
N-Phenyl-5-(4-nitrophenyl)-1,3,4-thiadiazole-2-
carboxamide (VIb). Yield 72%, mp 248 250 C.
1H NMR spectrum, , ppm (J, Hz): 7.1 t (1H,
Harom, J 7.92); 7.35 t (2H, Harom, J 7.38); 7.65 m
(4H, Harom); 8.4 d (2H, Harom, J 7.92); 11.0 s
(1H, NH). Mass spectrum, m/z: 326 [M]+ . Found,
%: C 55.11; H 3.03; N 17.12; S 9.95. C15H10N4O3S.
Calculated, %: C 55.21; H 3.09; N 17.17; S 9.83.
5-(Dichloromethyl)-1,3,4-thiadiazole-2-carbox-
amide Vi. To 10 mmol of oxamic acid thiohydraside
IVi in 5 ml of DMF was added 20 ml of dichloro-
acetyl chloride. After 4 h the reaction mixture was
poured into water, the separated precipitate was
filtered off and recrystallized from ethanol. Yield
N-(4-Methoxyphenyl)-5-phenyl-1,3,4-thiadiazole-
2-carboxamide (VIc). Yield 67%, mp 225 226 C.
1H NMR spectrum, , ppm (J, Hz): 3.8 s (3H, CH3);
7.0 d (2H, Harom, J 8.83); 7.6 m (3H, Harom);
7.8 m (2H, Harom); 8.1 d (2H, Harom, J 7.92);
11.0 s (1H, NH). Mass spectrum, m/z: 311 [M]+ .
Found, %: C 61.64; H 4.33; N 13.39; S 10.43.
C16H13N3O2S. Calculated, %: C 61.72; H 4.21;
N 13.50; S 10.30.
1
78%, mp 133 135 C. H NMR spectrum, , ppm (J,
Hz): 4.7 s (3H, CH3); 6.4 s (1H, CH3); 6.9 d (2H,
Harom, J 8.83); 7.80 d (2H, Harom, J 8.84); 11.20 s
(1H, NH). Mass spectrum, m/z: 318 [M]+ . Found,
%: C 41.65; H 2.73; Cl 22.32; N 13.19; S 10.01.
C11H9Cl2N3O2S. Calculated, %: C 41.52; H 2.85;
Cl 22.28; N 13.21; S 10.08.
Ethyl 5-{[(4-methoxyphenyl)amino]carbonyl}-
1,3,4-thiadiazole-2-carboxylate (VIIa). To 10 mmol
of oxamic acid thiohydrazide IVc in 5 ml of DMF
was added 20 mmol of methyl oxalyl chloride. In 4 h
the separated precipitate was filtered off and recrystal-
lyzed from methanol. Yield 72%, mp 135 138 C.
1H NMR spectrum, , ppm (J, Hz): 2.5 t (3H, CH3);
4.5 d (2H, CH2); 3.8 s (3H, CH3); 6.9 d (2H, Harom,
J 8.83); 7.80 d (2H, Harom, J 8.84); 11.20 s (1H,
NH). Mass spectrum, m/z: 307 [M]+ . Found, %:
C 50.92; H 4.14; N 13.73; S 10.55. C13H13N3O4S.
Calculated, %: C 50.81; H 4.26; N 13.67; S 10.43.
5-(Chloromethyl)-1,3,4-thiadiazole-2-carbox-
amide Vj. To 10 mmol of oxamic acid thiohydraside
IVc in 5 ml of DMF was added 20 ml of monochloro-
acetyl chloride. After 4 h the reaction mixture was
poured into water, the separated precipitate was
filtered off and recrystallized from ethanol. Yield
1
51%, mp 146 148 C. H NMR spectrum, , ppm (J,
Hz): 4.7 s (3H, CH3); 6.9 d (2H, Harom, J 8.83);
7.80 d (2H, Harom, J 8.84); 11.20 s (1H, NH). Mass
spectrum, m/z: 283 [M]+ . Found, %: C 46.44;
H 3.46; Cl 12.61; N 14.74; S 11.45. C11H10ClN3O2S.
Calculated, %: C 46.56; H 3.55; Cl 12.49; N 14.81;
S 11.30.
tert-Butyl
5-{[(4-methoxyphenyl)amino]carb-
onyl}-1,3,4-thiadiazole-2-carboxylate (VIIb). To
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003

SYNTHESIS OF OXAMIC ACIDS THIOHYDRAZIDES
10 mmol of oxamic acid thiohydrazide IVc in 5 ml 1999, p. 753.
1139
of DMF was added 20 mmol of tert-butyl oxalyl
chloride. In 4 h the separated precipitate was filtered
off and recrystallyzed from t-BuOH. Yield 65%,
6. Yarovenko, V.N., Kosarev, S.A., Shirokov, A.V.,
Zavarzin, I.V., and Krayushkin, M.M., Izv. Akad.
Nauk, Ser. Khim., 2000, p. 1487.
7. Yarovenko, V.N., Ctoyanovich, F.M., Zolotar-
skaya, O.Yu., Chernoburova, E.I., Zavarzin, I.V.,
and Krayushkin, M.M., Izv. Akad. Nauk, Ser. Khim.,
2002, p. 136.
8. German Patent 229409, 1985; Chem. Abstr., 1987,
vol. 106, 8566.
9. German Patent 292253, 1991; Chem. Abstr., 1991,
vol. 115, 280036
1
mp 151 152 C. H NMR spectrum, , ppm (J, Hz):
1.3 s (9H, CH3); 3.8 s (3H, CH3); 6.9 d (2H,
Harom, J 8.83); 7.80 d (2H, Harom, J 8.84);
11.20 s (1H, NH). Mass spectrum, m/z: 335 [M]+.
Found, %: C 53.86; H 5.02; N 13.07; S 10.04.
C15H17N3O4S. Calculated, %: C 53.72; H 5.11;
N 12.53; S 9.56.
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