Ambident properties of 4-substituted thiosemicarbazides in condensations with fluoroacetic acids

Article abstract of DOI:10.1007/s11178-005-0376-7

4-Substituted thiosemicarbazides react with di- and trifluoroacetic acids to give the corresponding 3-fluoroalkyl-4,5-dihydro-1,2,4-triazole-5(1II)- thiones. Condensation of 4,4-disubstituted thiosemicarbazides with trifluoroacetic acid leads to formation of 2-amino-5-trifluoromethyl-1,3,4- thiadiazoles.

Full text of DOI:10.1007/s11178-005-0376-7

Russian Journal of Organic Chemistry, Vol. 41, No. 10, 2005, pp. 1522–1525. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 10, 2005,
pp. 1553–1556.
Original Russian Text Copyright © 2005 by Vasil’eva, Filyakova, Sidorova, Filatov, Charushin.
Dedicated to Full Member of the Russian Academy of Sciences
N.S. Zefirov on His 70th Anniversary
Ambident Properties of 4-Substituted Thiosemicarbazides
in Condensations with Fluoroacetic Acids
E. B. Vasil’eva1, V. I. Filyakova1, L. P. Sidorova2, I. E. Filatov3, and V. N. Charushin1
1 Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 22, Yekaterinburg, 620219 Russia
e-mail: cec@ios.uran.ru
2 Ural State Technical University, ul. Mira 19, Yekaterinburg, Russia
3 Institute of Electrophysics, Ural Division, Russian Academy of Sciences,
ul. Amundsena 106, Yekaterinburg, 620016 Russia
Received June 8, 2005
Abstract—4-Substituted thiosemicarbazides react with di- and trifluoroacetic acids to give the corresponding
3-fluoroalkyl-4,5-dihydro-1,2,4-triazole-5(1H)-thiones. Condensation of 4,4-disubstituted thiosemicarbazides
with trifluoroacetic acid leads to formation of 2-amino-5-trifluoromethyl-1,3,4-thiadiazoles.
Ambident properties of thioamides, thiohydrazides,
and thiosemicarbazides as N,S-difunctional nucleo-
philes have been well documented and utilized in the
synthesis of various heterocyclic compounds, such as
thiazoles, pyrazoles, thiadiazoles, triazoles, thiadi-
azines, triazines, etc. [1–5]. Condensation of thiosemi-
carbazides with carboxylic acids could lead to forma-
tion of both thiadiazoles III and dihydrotriazolethiones
IV [6–8]. Interest in these compounds originates from
the fact that 1,3,4-thiadiazole and 1,2,4-triazole deriva-
tives exhibit various kinds of biological activity, in-
cluding antiphlogistic, analgetic, antiviral, and antibac-
terial [8]. One of the most effective ways of enhancing
biological activity of chemical compounds and/or ex-
tending its range is introduction of di- or trifluoro-
methyl substituents into their molecules, for fluorine
atoms and fluoroalkyl groups are characterized by
an unusual combination of electronic and steric prop-
erties. In addition, the presence of fluorine atoms
increases the ability of compounds to penetrate cell
membranes due to improved solubility in lipids [9–11].
assigned the structure of polyfluorinated 4,5-dihydro-
1,2,4-triazole-5(1H)-thiones. However, no rigorous
proofs for the assumed structures were given. Ashton
et al. [7, 8] described reactions of 2-methyl-, 4-(2-pyr-
idyl)-, and 4-(4-nitrobenzyl)thiosemicarbazides with
trifluoroacetic acid. The authors believed that the prod-
ucts were the corresponding dihydrotriazolethiones IV,
but the H NMR and mass spectra given therein could
equally belong to dihydrotriazolethiones IV and thiadi-
azoles III.
1
In the present work we examined reactions of di-
and trifluoroacetic acids with morpholine-4-carbothio-
hydrazide (Ia), piperidine-1-carbothiohydrazide (Ib),
pyrrolidine-1-carbothiohydrazide (Ic), 4-arylthiosemi-
carbazides Id–Ig, and 4-piperidinothiosemicarbazide
(Ih). Hydrazides Ia–Ic may be regarded as 4,4-disub-
stituted thiosemicarbazides. The reactions successfully
occurred in excess difluoro- or trifluoroacetic acid. The
condensation of thiosemicarbazides Ia–Ic with tri-
fluoroacetic acid afforded exclusively thiadiazoles
IIIa–IIIc (Scheme 1) whose structure was confirmed
by the data of elemental analysis, gas chromatog-
There are very limited published data on fluorine-
containing thiadiazoles and dihydrotriazolethiones. For
example, condensation products of nonfluorinated
thiosemicarbazides with a series of polyfluorinated
acid fluorides [12] and of 2,4-disubstituted thiosemi-
carbazides with trifluoroacetic anhydride [13] were
1
raphy–mass spectrometry, and H, 19F, and 13C NMR
spectroscopy. Compounds IIIa–IIIc characteristically
showed in the 19F NMR spectra a singlet at įF 102 ppm
from the trifluoromethyl group. Thiadiazoles IIIa–IIIc
can be used as model compounds to distinguish be-
1070-4280/05/4110-1522 © 2005 Pleiades Publishing, Inc.

AMBIDENT PROPERTIES OF 4-SUBSTITUTED THIOSEMICARBAZIDES
1523
Scheme 1.
O
H
H
N
N
CF3COOH
R2N
N
R2N
N
NH2
N
CF3
H
F3C
NR2
S
S
S
Ia–Ic
IIIa–IIIc
R2N = morpholino (a), piperidino (b), 1-pyrrolidinyl (c).
Scheme 2.
O
H
N
NH
RNH
N
RF
S
N
H
RF
N
R
S
H
N
RFCOOH
IIa, IIb
RNH
NH2
IVa–IVf
S
O
H
N
N
N
Id–Ih
RNH
N
H
RF
RF
NHR
S
S
IIId–IIIf
Id, IIIe, IVa, IVe, R = Ph; Ie, IVc, R = 4-MeC6H4; If, IIIf, IVb, R = 3,4-(MeO)2C6H3; Ig, IIIe, IVd, R = 4-FC6H4;
Ih, IVf, R = piperidino; IIa, IIIf, IVa, IVb, RF = HCF2; IIb, IIId, IIIe, IVc–IVf, RF = CF3.
rise to much more abundant fragment ion with m/z 150
(Irel 42% against 3% for IVe); this ion is likely to
be formed by elimination of CF3 and CN from the
molecular ion.
tween dihydrotriazolethione and thiadiazole structures
III and IV of the products obtained by condensation of
4-substituted thiosemicarbazides Id–Ih with fluorocar-
boxylic acids.
Thus 4-substituted thiosemicarbazides exhibit am-
bident properties in the condensation with di- and tri-
fluoroacetic acids. The described reactions provide
a convenient synthetic route to 3-difluoromethyl- and
3-trifluoromethyl-4,5-dihydro-1,2,4-triazole-5(1H)-
thiones IV. Isomeric heterocyclic systems, thiadiazoles
III, are formed as by-products (3–9%).
Under analogous conditions, from thiosemicarba-
zides Id–Ih and fluoroacetic acid IIa and IIb we
obtained the corresponding 4,5-dihydro-1,2,4-triazole-
5(1H)-thiones IVa–IVf as the major products. Thiadi-
azoles IIId–IIIf were formed as by-products (3 to 9%)
in the condensations of thiosemicarbazides Id–If with
difluoro- and trifluoroacetic acids (Scheme 2). Com-
pounds IIId and IIIe were identified by the 19F NMR
spectra which contained a singlet at įF 102 ppm in
addition to the signal at įF ~98 ppm from the CF3
group of dihydrotriazolethiones IVd and IVe. Com-
pound IVb showed in the 19F NMR spectrum a doublet
at įF 44.49 ppm from the HCF2 group and a doublet at
įF 47.10 ppm, the latter belonging to thiadiazole IIIf.
EXPERIMENTAL
1
The H, 19F, and 13C NMR spectra were recorded
from solutions in CDCl3 on Tesla BS-567A (80 MHz
1
for H and 75 Hz for 19F) and Bruker DRX-400 spec-
1
trometers (400 MHz for H, 376 MHz for 19F, and
100 MHz for 13C); the chemical shifts were measured
relative to tetramethylsilane (1H and 13C) and hexa-
fluorobenzene (19F) as internal references. The IR
spectra were obtained on a Perkin–Elmer Spectrum I
instrument from samples dispersed in mineral oil. Gas
chromatography–mass spectrometry was performed on
a Varian Saturn 2100T GC/MS system (GC 3900);
VF-5ms capillary column, 30 m×0.25 mm; carrier gas
helium, flow rate 1 ml/min; oven temperature prog-
ramming from 40°C (3 min) to 200°C at a rate of
According to the GC–MS data, the condensation of
thiosemicarbazide Id with trifluoroacetic acid gives
two products, dihydrotriazolethione IVe (major peak
with a retention time of 15.00 min) and thiadiazole
IIIe (minor peak; retention time 15.14 min). The mass
spectra of both products contain ion peaks with
m/z 246 [M + H]+, 245 [M]+, and 244 [M – H]+, as well
as fragment ion peaks with m/z 176 [M – CF3]+, 168
[M – Ph]+, 150 [M – CF3 – CN]+, 77 [Ph]+, and 69
[CF3]. Unlike compound IVe, thiadiazole IIIe gives
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

VASIL’EVA et al.
1524
2
ppm: 6.53 t (1H, HCF2, JCF = 51.5 Hz), 7.39–7.61 m
20 deg/min. Thiosemicarbazides Ia–Ih were synthe-
sized by the procedure reported in [14].
(5H, C6H5), 11.96 br.s (1H, NH). 19F NMR spectrum:
įF 44.76 ppm, d (HCF2, JFH = 51.5 Hz). Found,
%: C 47.30; H 2.88; F 16.72; N 18.61; S 14.08.
C9H7F2N3S. Calculated, %: C 47.57; H 3.11; F 16.72;
N 18.49; S 14.11.
2
General procedure for condensation of thiosemi-
carbazides with di- and trifluoroacetic acids. Di- or
trifluoroacetic acid, 0.04 mol, was added dropwise
under stirring to 0.02 mol of thiosemicarbazide Ia–Ih,
and the mixture was heated for 8 h under reflux. The
mixture was poured into water, and the precipitate was
filtered off and recrystallized from water or hexane–
chloroform (3:1).
3-Difluoromethyl-4-(3,4-dimethoxyphenyl)-4,5-
dihydro-1,2,4-triazole-5(1H)-thione (IVb) and
5-difluoromethyl-2-(3,4-dimethoxyphenylamino)-
1,3,4-thiadiazole (IIIf). Yield 35%. Yellow crystals,
mp 215–216°C (from hexane–chloroform, 1:3). IR
spectrum, Ȟ, cm–1: 3090, 3040, 2750 (NH); 1590
2-Morpholino-5-trifluoromethyl-1,3,4-thiadi-
azole (IIIa). Yield 84%. Colorless crystals, mp 94–
95°C (from water). IR spectrum, Ȟ, cm–1: 1464 (C=N);
1
(C=N); 1170, 1130, 1050 (C–F). H NMR spectrum
1
(DMSO-d6), į, ppm: 3.90 s (3H, OCH3), 3.95 s (3H,
1135, 1114, 1026 (C–F). H NMR spectrum, į, ppm:
2
2
OCH3), 6.51 t (1H, HCF2, JCF = 51 Hz), 6.68–7.26 m
3.61 t (4H, CH2O, JCH = 5.1 Hz), 3.85 t (4H, CH2N,
(3H, C6H3), 11.54 br.s (1H, NH). 19F NMR spectrum,
2JCH = 5.1 Hz). 19F NMR spectrum: įF 102.23 ppm, s
2
(CF3). 13C NMR spectrum, įC, ppm: 49.88 s (CNC),
įF, ppm: IVb: 44.09 d (HCF2, JFH = 51.3 Hz); IIIf:
47.09 d (HCF2, JFH = 51.9 Hz); signal intensity ratio
IVb:IIIf § 10:1. Found, %: C 45.64; H 3.64; F 12.72;
N 14.25; S 11.28. C11H11F2N3O2S. Calculated, %:
C 45.99; H 3.86; F 13.23; N 14.63; S 11.16.
2
1
65.80 s (COC), 119.38 q (CF3, JCF = 271.8 Hz),
2
146.36 q (C5, JCF = 39.2 Hz), 174.13 s (C2). Mass
spectrum, m/z (Irel, %): 240 (100) [M]+, 86 (11), 84
(14), 69 (36). Found, %: C 35.17; H 3.34; F 23.80;
N 17.78; S 13.56. C7H8F3N3SO. Calculated, %:
C 35.15; H 3.37; F 23.83; N 17.57; S 13.40.
4-(4-Methylphenyl)-3-trifluoromethyl-4,5-di-
hydro-1,2,4-triazole-5(1H)-thione (IVc). Yield 55%.
Yellow crystals, mp 141–143°C (from hexane–chloro-
form, 1:3). IR spectrum, Ȟ, cm–1: 3034, 2742 (NH);
2-Piperidino-5-trifluoromethyl-1,3,4-thiadiazole
(IIIb). Yield 32.8%. Yellow crystals, mp 37–38°C
(from hexane–chloroform, 3:1). IR spectrum, Ȟ, cm–1:
1
1606 (C=N); 1220, 1179, 1156 (C–F). H NMR spec-
1
trum (DMSO-d6), į, ppm: 2.65 s (3H, CH3), 7.09–
7.48 m (4H, C6H4), 10.53 br.s (1H, NH). 19F NMR
spectrum (CDCl3–C6F6): įF 99.91 ppm, s (CF3). Found,
%: C 46.50; H 3.20; F 21.54; N 16.11; S 12.30.
C10H8F3N3S. Calculated, %: C 46.33; H 3.11; F 21.98;
N 16.21; S 12.37.
1464 (C=N); 1182, 1139, 1030 (C–F). H NMR spec-
trum, į, ppm: 1.73 m (6H, CH2), 3.58 m (4H, NCH2).
19F NMR spectrum: įF 102.21 ppm, s (CF3). 13C NMR
spectrum, įC, ppm: 23.90 s, 24.99 s, 51.42 s (CH2);
1
2
119.60 q (CF3, JCF = 271.4 Hz); 145.37 q (C5, JCF
=
38.8 Hz), 174.01 s (C2). Found, %: C 40.54; H 3.34;
F 23.92; N 17.75. C8H10F3N3S. Calculated, %: C 40.50;
H 4.25; F 24.02; N 17.71.
4-(4-Fluorophenyl)-3-trifluoromethyl-4,5-di-
hydro-1,2,4-triazole-5(1H)-thione (IVd) and
2-(4-fluorophenylamino)-5-trifluoromethyl-1,3,4-
thiadiazole (IIId). Yield 88%. Colorless crystals,
mp 139–140°C (from water). IR spectrum, Ȟ, cm–1:
3083, 3039, 2747 (NH); 1599 (C=N); 1276, 1197,
2-(1-Pyrrolidinyl)-5-trifluoromethyl-1,3,4-thiadi-
azole (IIIc). Yield 35.8%. Yellow crystals, mp 68–
69°C (from hexane–chloroform, 3:1). IR spectrum, Ȟ,
cm–1: 1478 (C=N); 1182, 1134, 1094, 1030 (C–F).
1H NMR spectrum, į, ppm: 2.12 m (4H, CH2), 3.56 m
(4H, NCH2). 19F NMR spectrum: įF 102.40 ppm, s
(CF3). 13C NMR spectrum, įC, ppm: 25.72 s, 51.02 s
1
1164 (C–F). H NMR spectrum, į, ppm: 7.26–7.38 m
(4H, C6H4F), 12.50 br.s (1H, NH). 19F NMR spectrum,
įF, ppm: IVd: 53.61 s (1F, 4-FC6H4), 98.31 s (3F, CF3);
IIId: 102.14 s (3F, CF3), 47.04 s (1F, 4-FC6H4); signal
intensity ratio IVd:IIId § 10:1. Found, %: C 41.10;
H 2.00; N 16.01; S 12.25. C9H5F4N3S. Calculated, %:
C 41.07; H 1.91; N 15.96; S 12.18.
1
(CH2); 119.56 q (CF3, JCF = 271.2 Hz); 144.48 q (C5,
2JCF = 38.9 Hz); 169.91 s (C2). Found, %: C 37.55;
H 3.80; N 18.75; S 14.32. C7H8F3N3S. Calculated, %:
C 37.67; H 3.61; N 18.82, S 14.36.
3-Difluoromethyl-4-phenyl-4,5-dihydro-1,2,4-tri-
azole-5(1H)-thione (IVa). Yield 45%. Yellow crystals,
mp 198–199°C (from hexane–chloroform, 1 : 3). IR
spectrum, Ȟ, cm–1: 3088, 3039, 2744 (NH); 1594
(C=N); 1126, 1077, 1056 (C–F). 1H NMR spectrum, į,
4-Phenyl-3-trifluoromethyl-4,5-dihydro-1,2,4-tri-
azole-5(1H)-thione (IVe) and 2-phenylamino-5-tri-
fluoromethyl-1,3,4-thiadiazole (IIIe). Yield 70%.
Yellow crystals, mp 153–154°C (from chloroform). IR
spectrum, Ȟ, cm–1: 3071, 3032, 2743 (N–H); 1618
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

AMBIDENT PROPERTIES OF 4-SUBSTITUTED THIOSEMICARBAZIDES
1525
(C=N); 1251, 1176, 1150 (C–F). 1H NMR spectrum, į,
ppm: 7.25–7.61 m (5H, C6H5), 11.00 br.s (1H, NH).
19F NMR spectrum, įF, ppm: IVe: 98.34 s (CF3); IIIe:
3. Klayman, D.L., Bartosevich, J.F., Griffin, T.S.,
Mason, C.J., and Scovill, J.P., J. Med. Chem., 1979,
vol. 22, p. 855.
4. Novikova, A.P., Petrova, N.M., and Chupakhin, O.N.,
102.17 s (CF3); signal intensity ratio IVe:IIIe § 30:1.
1
13C NMR spectrum, įC, ppm: 116.52 q (CF3, JCF
=
Khim. Geterotsikl. Soedin., 1991, no. 11, p. 1443.
5. Denisova, A.V., Glukhareva, T.V., Andronnikova, G.P.,
Mokrushin, V.S., Dehaen, W., Luyten, I., Sosnov-
skikh, V.Ya., Meervelt, L., and Bakulev, V.A., J. Chem.
Res., 2001, p. 12.
6. Golovlyova, S.M., Moskvichev, Yu.A., Aliv, E.M.,
Kobylinsky, O.B., and Ermolaeva, V.V., Chem. Hetero-
cycl. Comp., 2001, vol. 37, p. 1102.
7. Ashton, W.T., Cantone, C.L., Chang, L.L., Hut-
chins, S.M., Strelitz, R.A., MacCoss, M., Chang, R.S.L.,
Lotti, V.J., Faust, K.A., Tsing-Bau Chen, Bunting, P.,
Schorn, T.W., Kivlighn, S.D., and Siegl, P.K.S., J. Med.
Chem., 1993, vol. 36, p. 591.
8. Ashton, W.T., Cantone, C.L., Meurer, L.C., Tol-
man, R.L., Greenlee, W.J., Patchett, A.A., Lynch, R.J.,
Schorn, T.W., Strouse, J.F., and Siegl, P.K.S., J. Med.
Chem., 1992, vol. 35, p. 2103.
271.8 Hz); 127.83 s, 130.04 s, 130.98 s, 131.92 s
(Carom); 141.67 q (C3, JCF = 41.4 Hz); 171.28 s (C5).
2
Mass spectrum, m/z (Irel, %): IVe: 246 (100) [M + H]+,
245 (36) [M]+, 244 (64), 150 (3), 77 (16), 69 (13); IIIe:
246 (41) [M + H]+, 245 (100) [M]+, 244 (69), 150 (42),
92 (4), 77 (38), 69 (31). Found, %: C 44.08; H 2.25;
F 23.19; N 17.23; S 13.12. C9H6F3N3S. Calculated, %:
C 44.08; H 2.47; F 23.24; N 17.14; S 13.07.
4-Piperidino-3-trifluoromethyl-4,5-dihydro-
1,2,4-triazole-5(1H)-thione (IVf). Yield 50%. Yellow
crystals, mp 155–156°C (from hexane–chloroform,
1:3). IR spectrum, Ȟ, cm–1: 3060, 3100, 2740 (NH);
1
1598 (C=N); 1219, 1160, 1155 (C–F). H NMR spec-
trum, į, ppm: 1.48–1.74 m (10H, CH2), 8.25 br.s (1H,
NH). 19F NMR spectrum: įF 101.88 ppm, s (CF3).
Found, %: C 38.56; H 4.01; F 22.62; N 22.23.
C8H11F3N4S. Calculated, %: C 38.09; H 4.40; F 22.59;
N 22.21.
9. Fluorine Compounds. Modern Technology and Applica-
tions, Ishikawa, N., Ed. Translated under the title Novoe
v tekhnologii soedinenii ftora, Moscow: Mir, 1984,
p. 500.
10. Welch, J.T. and Eshwaraksrishnan, S.J., Fluorine in Bio-
organic Chemistry, New York: Wiley, 1991.
This study was performed under financial support
by the State Program “Leading Scientific Schools”
(project no. NSh 1766.2003.03).
11. Organofluorine Compounds in Medicinal Chemistry
and Biomedical Applications, Filler, R., Kobayashi, Y.,
and Yagupolskii, L.M., Eds., Amsterdam: Elsevier, 1993.
12. Vershilov, S.V., Popova, L.M., Mungalov, V.E., and
Ryabinin, N.A., Zh. Prikl. Khim., 1994, vol. 67, p. 1124.
REFERENCES
1. Shawali, A.S., Abclallah, M.A., and Zayed, M.M.,
J. Heterocycl. Chem., 2002, vol. 39, p. 45.
13. Organofluorine Chemistry – Principles and Commercial
Applications, Banks, R.E., Smart, B.E., and Tatlow, J.C.,
Eds., New York: Plenum, 1994.
14. Kazakov, V.Ya. and Postovskii, I.Ya., Dokl. Akad. Nauk
SSSR, 1960, vol. 134, p. 824.
2. Izbrannye metody sinteza i modifikatsii geterotsiklov
(Selected Methods of Synthesis and Modification of
Heterocycles), Kartsev, V.G., Ed., Moscow: IBS, 2003,
vol. 2, p. 327.
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