Synthesis of 4-thioacetyl-1,2,3-thiadiazoles. Reversible rearrangement of N-substituted 5-methyl-1,2,3-thiadiazole-4-carbothioamides

Article abstract of DOI:10.1134/S1070428012100132

The equilibrium in the reversible rearrangement of 5-methyl-1,2,3- thiadiazole-4-carbothioamides into 5-amino-4-thioacetyl-1,2,3-thiadiazoles is displaced toward the former, and polar solvents favor increased fraction of the thioketone. Pleiades Publishin

Full text of DOI:10.1134/S1070428012100132

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 10, pp. 1333–1336. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © P.E. Prokhorova, T.A. Kalinina, T.V. Glukhareva, Yu.Yu. Morzherin, 2012, published in Zhurnal Organicheskoi Khimii, 2012,
Vol. 48, No. 10, pp. 1338–1341.
Synthesis of 4-Thioacetyl-1,2,3-thiadiazoles.
Reversible Rearrangement of N-Substituted 5-Methyl-
1,2,3-thiadiazole-4-carbothioamides
P. E. Prokhorova, T. A. Kalinina, T. V. Glukhareva, and Yu. Yu. Morzherin
Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: yu.yu.morzherin@ustu.ru
Received September 20, 2011
Abstract—The equilibrium in the reversible rearrangement of 5-methyl-1,2,3-thiadiazole-4-carbothioamides
into 5-amino-4-thioacetyl-1,2,3-thiadiazoles is displaced toward the former, and polar solvents favor increased
fraction of the thioketone.
DOI: 10.1134/S1070428012100132
1,2,3-Thiadiazoles containing an acetyl group in the
4-position have been poorly studied [1]. Such com-
pounds are generally synthesized according to Wolff
[2], which determines a limited set of substituents and
hence a limited number of available 4-acetyl-1,2,3-
thiadiazole derivatives. With a view to synthesize new
derivatives of 4-acyl-1,2,3-thiadiazoles I we propose
a retrosynthetic scheme based on transformations of
5-methyl-1,2,3-thiadiazole-4-carboxamides IV. The
scheme includes rearrangement of 1,2,3-thiadiazole-4-
carbothioamides III into isomeric 4-thioacetyl-1,2,3-
tiadiazoles II and subsequent hydrolysis of the thio-
ketone group (Scheme 1).
thionation of N-substituted 5-methyl-1,2,3-thiadiazole-
4-carboxamides IV gave individual thioamides IIIa–
IIId rather than isomer mixtures (Scheme 2), and the
structure of IIIa–IIId was determined by spectral
methods and X-ray analysis of a single crystal of IIIa
(see figure). Isomers II were detected only by TLC,
but we failed to isolate them.
In order to identify isomeric thioketones II we
examined effects of the solvent and temperature on the
isomer ratio. The ratio of isomers II and III depended
on the solvent (Table 1), but did not depend on the
temperature or reaction time. We therefore concluded
that the formation of 4-thioacetyl-1,2,3-thiadiazole II
is an equilibrium process; the fraction of II increased
with rise in the polarity of the medium.
Analogous reversible rearrangement was reported
by us previously [3]. Unlike the results obtained in [3],
Scheme 1.
O
S
S
O
Me
Me
NR1R2
NR1R2
N
N
N
N
N
N
N
N
NR1R2
NR1R2
Me
Me
S
S
S
S
I
II
III
IV
Scheme 2.
O
S
S
NR1R2
NR1R2
Me
P4S10, 1,4-dioxane
N
N
N
N
N
S
N
Me
IVa–IVd
Me
IIIa–IIId
NR1R2
IIa–IId
S
S
R1 = H, R2 = 4-MeC6H4 (a), Ph (b); R1R2 = (CH2)5 (c), R1R2N = morpholin-4-yl (d).
1333

PROKHOROVA et al.
1334
Table 1. Solvent effect on the ratio of isomers IIa and IIIa
δ(Harom), ppm
δ(CH3), ppm
Mole fraction, %
Dipole moment
Solvent
µ , D [4]
IIa
IIIa
IIa
IIIa
IIa
IIIa
C6D6
0.0
3.8
7.35, 6.96
–
7.63, 6.90
7.71, 7.27
7.74, 7.25
7.89, 7.29
7.77, 7.21
2.34, 2.05
–
2.45, 2.02
3.09, 2.39
2.93, 2.37
2.99, 2.37
2.87, 2.37
2.4
2.9
3.4
3.5
4.4
97.6
97.1
96.6
96.5
95.6
CDCl3
CD3OD
Acetone-d6
DMSO-d6
5.7
7.01, 6.72
7.04, 6.83
6.95, 6.67
2.95, 2.33
3.00, 2.33
2.94, 2.23
9.0
13.50
We have found a good correlation between the
composition of equilibrium mixture IIa/IIIa and
dipole moment of the solvent: ν = (0.142±0.015)μ +
(2.4±0.1), r = 0.98, s = 0.14, n = 5; ν is the mole
fraction of II (%), and μ is the dipole moment of the
solvent (D). However, solvent effect on the equi-
librium is insignificant: considerable increase of the
dipole moment is accompanied by change of the
fraction of II from 2.4 to 4.6%.
ΔHf values for thioamide IIIg and amine IIg is as
small as 0.6 kcal/mol. Thus the results of quantum-
chemical calculations suggest that the proposed
scheme for the preparation of 5-amino-4-acetyl-1,2,3-
thiadiazoles is applicable only to derivatives contain-
ing electron-withdrawing groups in the carbothioamide
fragment.
To conclude, we have shown that thiadiazoles III
are formed as equilibrium mixtures with isomeric thio-
ketones II, the former prevailing. The fraction of thio-
ketones II in a polar solvent (DMSO) is higher than in
weakly polar chloroform. Thioamides III turned out to
be stable on heating in boiling water, and we failed to
isolate targeted 4-acetyl-1,2,3-thiadiazoles I.
We estimated the stabilities of isomeric thiadiazoles
II and III by quantum-chemical calculations. As
subjects for the study we selected 5-methyl-1,2,3-thia-
diazole-4-carbothioamides having different substit-
uents on the amide nitrogen atom. The calculations
were performed in terms of AM1 and PM3 semiem-
pirical approximations, as well as at the DFT level
[B3LYP/6-31G(d)], using GAUSSIAN 03W software
package [5]; the results are collected in Table 2. It is
seen that electron-donor substituents in the aromatic
ring on the amide nitrogen atom stabilize thioamide
structure III and that electron-withdrawing groups
favor thioketone isomer II. Aliphatic substituents on
the nitrogen stabilize carbothioamide III. For instance,
the enthalpy of formation of thiadiazole IIIc con-
siderably exceeds that found for the corresponding
thioketone IIc. On the other hand, the difference in
EXPERIMENTAL
The progress of reactions and the purity of products
were monitored by TLC on Kieselgel 60 F254 plates.
The IR spectra were recorded on a Bruker Alpha-E
1
spectrometer. The H and 13C NMR spectra were run
on a Bruker DRX-400 instrument at 400 and 100 MHz,
respectively, using TMS as internal reference.
The X-ray diffraction data for compound IIIa were
acquired at 295 K on an Xcalibur 3 diffractometer
[CCD detector, MoKα irradiation, λ = 0.71073, ω/θ-
scanning, 2θmax = 143.0°, μ(CuKα) = 0.424 mm–1] from
a 0.50×0.34×0.11-mm single crystal (orange plate).
Monoclinic crystal system, space group P21/n;
C11H11N3S2; unit cell parameters: a = 7.2598(10), b =
23.649(4), c = 7.4688(6) Å; β = 112.299(11)°; V =
1186.4(3) Å3; Z = 4; dcalc = 1.396 g/cm3. Total of
6318 reflection intensities were measured (2798 inde-
pendent reflections); R1 = 0.0389 [for 1230 reflections
with I > 2σ(I)], wR2 = 0.0843.
5-Methyl-1,2,3-thiadiazole-4-carbothioamides
III and 1-(5-arylamino-1,2,3-thiadiazol-4-yl)ethane-
thiones II (general procedure). 5-Methyl-1,2,3-thiadi-
azole-4-carboxamide IVa–IVd, 1.0 g (3.6 mmol), was
Structure of the molecule of 5-methyl-N-(4-methylphenyl)-
1,2,3-thiadiazole-4-carbothioamide (IIIa) according to the
X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 10 2012

SYNTHESIS OF 4-THIOACETYL-1,2,3-THIADIAZOLES.
1335
Table 2. Calculated enthalpies of formation of compounds
II and III
dissolved in 10 ml of anhydrous 1,4-dioxane,
0.5 mmol of P4S10 was added at a temperature not
exceeding 60°C, and the mixture was heated for 2 h
under reflux. The mixture was evaporated, the residue
was treated with water, the mixture was heated to the
boiling point and left to stand for crystallization, and
the precipitate was filtered off, washed with water, and
dried. The product was a mixture of compounds III
and II, the former prevailing.
ΔHf, kcal/mol
Compound
no.
AM1
1.88
0.00
16.790
0.00
1.50
0.00
0.91
0.00
8.55
0.00
PM3
0.38
0.00
3.73
0.00
0.15
0.00
–0.21–
0.00
0.01
0.00
B3LYP/6-31G(d)
4.00
IIb
IIIb
IIc
0.00
13.830
0.00
IIIc
IIea
IIIea
IIfa
IIIfa
IIga
IIIga
5-Methyl-N-(4-methylphenyl)-1,2,3-thiadiazole-
4-carbothioamide (IIIa). Yield 0.705 g (63%),
mp 80°C, Rf 0.58 (chloroform–hexane, 9:1). IR spec-
20.160
0.00
1
trum, ν, cm–1: 3258 (N–H), 1110 (C=S). H NMR
–4.49–
0.00
spectrum, δ, ppm (s, 1H, NH): 11.08 (CDCl3), 12.10
(DMSO-d6), 10.95 (C6D6), 11.50 (acetone-d6), 11.62
(CD3OD). 13C NMR spectrum (CDCl3), δC, ppm:
21.18, 119.91, 123.68, 129.55, 135.48, 137.05, 154.30,
158.72, 183.61. Found, %: C 53.12; H 4.40; N 16.57;
S 25.95. C11H11N3S2. Calculated, %: C 52.98; H 4.45;
N 16.85; S 25.72.
0.64
0.00
a
R1 = H, R2 = 4-MeOC6H4 (e), 4-MeOC(O)C6H4 (f), Me (g).
1.52–1.63 m (2H, CH2), 1.76–1.84 m (4H, CH2), 2.83 s
(3H, CH3), 3.54–3.60 m (2H, NCH2), 4.20–4.10 m
(2H, NCH2).
1-[5-(4-Methylphenylamino)-1,2,3-thiadiazol-4-
yl]ethanethione (IIa). Rf 0.56 (chloroform–hexane,
1
9:1). H NMR spectrum, δ, ppm (s, 1H, NH): 9.39
(DMSO-d6), 9.22 (C6D6), 9.92 (acetone-d6), 9.69
(CD3OD) (for other signals, see Table 1).
(5-Methyl-1,2,3-thiadiazol-4-yl)(morpholin-4-yl)-
methanethione (IIId). Yield 0.45 g (56%), mp 85°C,
Rf 0.44 (ethyl acetate–hexane, 1:2). IR spectrum:
5-Methyl-N-phenyl-1,2,3-thiadiazole-4-carbo-
thioamide (IIIb). Yield 0.6 g (53%), mp 62°C, Rf 0.58
(chloroform–hexane, 9 : 1). 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.94 s (3H, CH3), 7.06 t (1H,
1
ν 1107 cm–1 (C=S). H NMR spectrum (DMSO-d6–
CCl4), δ, ppm: 2.63 s (3H, CH3), 3.46–3.49 m (2H,
OCH2), 3.62–3.65 m (2H, OCH2), 3.83–3.86 m (2H,
NCH2), 4.38–4.41 m (2H, NCH2). 13C NMR spectrum
(DMSO-d6–CCl4), δC, ppm: 9.81, 48.72, 52.18, 65.65,
66.26, 150.08, 158.62, 186.31. Found, %: C 41.97;
H 4.83; N 18.25; S 27.91. C8H11N3OS2. Calculated, %:
C 41.90; H 4.83; N 18.32; S 27.96.
Harom, J = 8.4 Hz), 7.20 t (2H, Harom, J = 8.4 Hz), 7.77 d
(2H, Harom, J = 8.4 Hz), 12.10 s (1H, NH). Found, %:
C 50.95; H 3.67; N 17.98; S 27.49. C10H9N3S2. Cal-
culated, %: C 51.04; H 3.85; N 17.86; S 27.25.
1-(5-Phenylamino-1,2,3-thiadiazol-4-yl)ethane-
thione (IIb). Rf 0.57 (chloroform–hexane, 9:1).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.87 s (3H,
1-[5-(Morpholin-4-yl)-1,2,3-thiadiazol-4-yl]-
ethanethione (IId). Rf 0.43 (ethyl acetate–hexane,
1
CH3), 7.04 t (1H, Harom, J = 8.4 Hz), 7.11 t (2H, Harom
,
1:2). H NMR spectrum (DMSO-d6–CCl4), δ, ppm:
J = 8.4 Hz), 7.71 d (2H, Harom, J = 8.4 Hz), 10.50 s
(1H, NH).
2.88 s (3H, CH3), 3.60–3.65 m (4H, OCH2), 4.10–
4.20 m (4H, NCH2).
(5-Methyl-1,2,3-thiadiazol-4-yl)(piperidin-1-yl)-
5-Methyl-1,2,3-thiadiazole-4-carboxamides IVa–
IVd (general procedure). 5-Methyl-1,2,3-thiadiazole-
4-carboxylic acid, 2.0 g (10 mmol), was dissolved in
15 ml of toluene, 1 mol of phosphorus(V) chloride was
added, and the mixture was heated for 3 h under reflux.
The corresponding amine, 10 mmol, was then added,
the mixture was heated for 2 h under reflux and
washed with three portions of water, the organic phase
was separated, dried over Na2SO4, and evaporated
under reduced pressure, and the residue was recrys-
tallized from ethanol.
methanethione (IIIc). Yield 0.46 g (56%), mp 73°C,
1
Rf 0.47 (ethyl acetate–hexane, 1:1). H NMR spectrum
(DMSO-d6–CCl4), δ, ppm: 1.52–1.63 m (2H, CH2),
1.76–1.84 m (4H, CH2), 2.53 s (3H, CH3), 3.35–3.43 m
(2H, NCH2), 4.30–4.40 m (2H, NCH2). Found, %:
C 47.67; H 5.93; N 18.29; S 28.11. C9H13N3S2. Calcu-
lated, %: C 47.55; H 5.76; N 18.48; S 28.21.
1-[5-(Piperidin-1-yl)-1,2,3-thiadiazol-4-yl]-
ethanethione (IIc). Rf 0.46 (ethyl acetate–hexane,
1
1:1). H NMR spectrum (DMSO-d6–CCl4), δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 10 2012

PROKHOROVA et al.
1336
(2H, OCH2), 3.67–3.74 m (4H, NCH2, OCH2). Found,
5-Methyl-N-(4-methylphenyl)-1,2,3-thiadiazole-
%: C 44.87; H 5.13; N 19.96; S 15.21. C8H11N3O2S.
Calculated, %: C 45.06; H 5.20; N 19.70; S 15.04.
4-carboxamide (IVa). Yield 1.51 g (65%), mp 143°C,
Rf 0.65 (chloroform). IR spectrum, ν, cm–1: 3344
(N–H), 1677 (C=O). H NMR spectrum (CDCl3), δ,
ppm: 2.35 s (3H, 5-CH3), 3.01 s (3H, 4′-CH3), 7.19 d
(2H, Harom, J = 8.4 Hz), 7.59 d (2H, Harom, J = 8.4 Hz),
9.39 s (1H, NH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 10.60, 20.43, 120.58, 129.06, 129.83, 158.6.
Found, %: N 18.09; S 13.81. C11H11N3OS. Calculated,
%: N 18.01; S 13.74.
1
REFERENCES
1. Bakulev, V.A. and Dehaen, W., The Chemistry of
1,2,3-Thiadiazoles, Hoboken, NJ: Wiley, 2004.
2. Regitz, M. and Liedhegener, A., Justus Liebigs Ann.
Chem., 1967, vol. 710, p. 118.
3. Morzherin, Yu.Yu., Bakulev, V.A., Dankova, E.F., and
Mokrushin, V.S., Khim. Geterotsikl. Soedin., 1994, p. 548.
4. Reichardt, C., Solvents and Solvent Effects in Organic
Chemistry, Weinheim: VCH, 1988, 2nd ed.
5-Methyl-N-phenyl-1,2,3-thiadiazole-4-carbox-
amide (IVb). Yield 1.38 g (63%), mp 147°C, Rf 0.65
(chloroform). IR spectrum, ν, cm–1: 3390 (N–H), 1655
1
5. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Jr.,,
Vreven, T., Kudin, K.N., Burant, J.C., Millam, J.M.,
Iyengar, S.S., Tomasi, J., Barone, V., Mennucci, B.,
Cossi, M., Scalmani, G., Rega, N., Petersson, G.A.,
Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fuku-
da, R., Hasegawa, J., Ishida, M., Nakajima, T.,
Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X.,
Knox, J.E., Hratchian, H.P., Cross, J.B., Bakken, V.,
Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E.,
Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C.,
Ochterski, J.W., Ayala, P.Y., Morokuma, K., Voth, G.A.,
Salvador, P., Dannenberg, J.J., Zakrzewski, V.G.,
Dapprich, S., Daniels, A.D., Strain, M.C., Farkas, O.,
Malick, D.K., Rabuck, A.D., Raghavachari, K., Fores-
man, J.B., Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford, S.,
Cioslowski, J., Stefanov, B.B., Liu, G., Liashenko, A.,
Piskorz, P., Komaromi, I., Martin, R.L., Fox, D.J.,
Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A.,
Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W.,
Wong, M.W., Gonzalez, C., and Pople, J.A., Gaussian
03, Revision A.1, Wallingford CT: Gaussian, 2004.
(C=O). H NMR spectrum (CDCl3), δ, ppm: 3.02 s
(3H, CH3), 7.18 t (1H, Harom, J = 7.4 Hz), 7.42–7.36 m
(2H, Harom), 7.71 d (2H, Harom, J = 7.6 Hz), 9.64 s (1H,
NH). Found, %: C 53.55; H 4.20; N 20.47; S 13.98.
C10H9N3OS. Calculated, %: C 54.78; H 4.14; N 19.16;
S 14.62.
(5-Methyl-1,2,3-thiadiazol-4-yl)(piperidin-1-yl)-
methanone (IVc). Yield 0.85 (43%), mp 107°C,
Rf 0.68 (chloroform–ethanol, 9:1). IR spectrum (KBr):
ν 1675 cm–1 (C=O). 1H NMR spectrum (DMSO-d6), δ,
ppm: 1.45–1.68 m (6H, CH2), 2.66 s (3H, CH3), 3.34–
3.39 m (2H, NCH2), 3.68–3.73 m (2H, NCH2). Found,
%: C 50.92; H 6.16; N 19.99; S 15.32. C9H13N3OS.
Calculated, %: C 51.16; H 6.20; N 19.89; S 15.18.
(5-Methyl-1,2,3-thiadiazol-4-yl)(morpholin-4-yl)-
methanone (IVd). Yield 0.64 (35%), mp 75°C, Rf 0.69
(chloroform–ethanol, 30:1). IR spectrum: ν 1625 cm–1
1
(C=O). H NMR spectrum (DMSO-d6), δ, ppm: 2.66 s
(3H, CH3), 3.39–3.43 m (2H, NCH2), 3.56–3.60 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 10 2012