Synthesis of 1,2,5-thiadiazole-3(2H)-thiones and 1,2,5-thiadiazol-3(2H)-ones from 1,2,3-dithiazoles

Article abstract of DOI:10.1016/j.mencom.2009.03.010

5H-1,2,3-Dithiazole-5-thiones and 5H-1,2,3-dithiazol-5-ones undergo a new transformation into 1,2,5-thiadiazole-3(2H)-thiones and 1,2,5-thiadiazol-3(2H)-ones, respectively, upon treatment with primary amines; the structure of thiadiazolethione was confirm

Full text of DOI:10.1016/j.mencom.2009.03.010

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 84–86
Synthesis of 1,2,5-thiadiazole-3(2H)-thiones
and 1,2,5-thiadiazol-3(2H)-ones from 1,2,3-dithiazoles
Lidia S. Konstantinova,a Oleg A. Bol’shakov,a Natalia V. Obruchnikova,a Svetlana P. Golova,a
Yulia V. Nelyubina,b Konstantin A. Lyssenkob and Oleg A. Rakitin*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: orakitin@ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2009.03.010
5H-1,2,3-Dithiazole-5-thiones and 5H-1,2,3-dithiazol-5-ones undergo a new transformation into 1,2,5-thiadiazole-3(2H)-thiones
and 1,2,5-thiadiazol-3(2H)-ones, respectively, upon treatment with primary amines; the structure of thiadiazolethione was confirmed
by X-ray diffraction.
During the last two decades, much attention in the chemistry of
1,2,3-dithiazol-5-ones and their derivatives has been focused
on exploring reactions with nucleophiles (most frequently, alkyl-
amines). Nucleophilic attack can proceed at the ring carbon
atom C-2 with extrusion of diatomic sulfur, S2, and a chloride
anion, destruction of the heterocyclic ring and formation of
various functionalized derivatives such as N'-aryl-N-alkylcyano-
formamidines,1 N-alkyl- and N,N-dialkylcyanothioformamides,2
N,N'-disubstituted ureas3 and (alkylamino)cyanomethylidenes.4
But surprisingly other than 4-chloro-1,2,3-dithiazoles are hardly
available.5 Recently, we have found that 4-substituted 1,2,3-di-
thiazol-5-ones and 1,2,3-dithiazole-5-thiones can be selectively
obtained in a one-pot reaction of various ethanoneoximes with
S2Cl2 and pyridine in MeCN with subsequent addition of the
corresponding reagent (formic acid or thioacetamide) in the last
stage of the reaction.6 In search of new materials, we studied
the reaction of these 1,2,3-dithiazoles with primary alkylamines.
4-Phenyl-5H-1,2,3-dithiazole-5-thione 1a was found inert
towards primary arylamines (aniline). Treatment of thione 1a
with 4 equiv. of more basic benzylamine in chloroform by
reflux for 2 h afforded new product 2a.† Compound 2a (56%
yield), a yellow solid with C15H12N2S2 according to its mass
spectra, elemental analysis and 1H and 13C NMR spectra is
formally a product of addition of benzylamine and extrusion
of H2S the formation of which was confirmed by isolation of
benzylammonium hydrogen sulfide from the reaction mixture
in practically quantitative yield (Scheme 1).
Three isomeric structures can be proposed for this product:
1,2,5-thiadiazolone 2a, imino-1,2,3-dithiazole 3, and 1,2,3-thia-
diazole 4. Analysis of the spectral data obtained and calculated
NMR spectra of these structures did not give a strong preference
†
General procedure for the preparation of 1,2,5-thiadiazole-3(2H)-thiones
2 and 1,2,5-thiadiazol-3(2H)-ones 8. A mixture of primary amine
(1.8 mmol) and 1 or 7 (1 mmol) in acetonitrile (10 ml) or THF (10 ml)
was stirred at room temperature up to disappearance of 1 or 7. Solvents
were evaporated, and the residue was dissolved in DCM, washed with
H2O, dried with MgSO4 and evaporated. The residue was separated by
column chromatography (Silica gel Merck 60, light petroleum–CH2Cl2
mixtures) or crystallized from hot hexane.
New compounds were characterised by elemental analysis, 1H and
13C NMR, and mass spectra. The spectral data of selected thiadiazole-
thiones and thiadiazolones are given below.
2a: yield 56%, yellow crystals, mp 95–97 °C. 1H NMR (300 MHz,
CDCl3) d: 5.31 (s, 2H, CH2), 7.49 (m, 8H, Ar), 8.42 (m, 2H, Ar).
13C NMR (75.5 MHz, CDCl3) d: 53.8 (CH2), 128.1, 129.1, 129.5, 129.86,
129.92, 130.5 (10CH, Ar), 133.0, 133.2 , 160.5, 177.45 (4sp2 tertiary C).
Found (%): C, 63.45; H, 4.39; N, 10.05. Calc. for C15H12N2S2 (%): C,
63.35; H, 4.25; N, 9.85. MS (EI, 70 eV) m/z (%): 284 (M+, 25), 251 (13).
1
2b: yield 58%, yellow crystals, mp 140–143 °C. H NMR (300 MHz,
CDCl3) d: 5.30 (s, 2H, CH2), 7.17 (d, 2H, Ar, J 8.80 Hz), 7.48 (m, 5H,
Ar), 8.49 (d, 2H, Ar, J 8.80 Hz). 13C NMR (75.5 MHz, CDCl3) d: 53.8
(CH2), 115.2, 129.6, 130.0, 131.2, 131.3 (9CH, Ar), 129.2, 133.0, 160.9,
165.7, 177.2 (5sp2 tertiary C). Found (%): C, 59.70; H, 3.92; N, 9.32.
Calc. for C15H11FN2S2 (%): C, 59.58; H, 3.67; N, 9.26. MS (EI, 70 eV)
m/z (%): 302 (M+, 17), 269 (7), 121 (22).
S
S
R
R
CHCl3
+
PhCH2NH2
S
N CH2Ph
Δ = 3 h
N
N
S
S
2a R = Ph, 56%
1
2c: yield 54%, yellow crystals, mp 86–88 °C. 1H NMR (300 MHz,
CDCl3) d: 3.87 (s, 3H, Me), 5.29 (s, 2H, CH2), 6.97 (d, 2H, Ar, J 8.80 Hz),
7.46 (s, 5H, Ar), 8.48 (d, 2H, Ar, J 8.80 Hz). 13C NMR (75.5 MHz,
CDCl3) d: 53.6 (CH2), 55.4 (OMe), 113.4, 129.4, 129.8, 129.9, 130.7
(9CH, Ar), 125.8, 133.2, 159.9, 161.3, 177.2 (5sp2 tertiary C). Found
(%): C, 61.20; H, 4.63; N, 8.97. Calc. for C16H14N2OS2 (%): C, 61.12;
H, 4.49; N, 8.91. MS (EI, 70 eV) m/z (%): 314 (M+, 8), 133 (15).
2b R = 4-FC6H4, 58%
2c R = 4-MeOC6H4, 54%
2d R = 4-NO2C6H4, 43%
2e R = Me, 62%
2f R = 2-thienyl, 65%
2g R = 2-benzofuryl, 49%
CH2Ph
N
S
1
Ph
Ph
8a: yield 94%, colourless crystals, mp 87–90 °C. H NMR (300 MHz,
CDCl3) d: 5.05 (s, 2H, CH2), 7.40 (m, 5H, Ph), 7.48 (m, 3H, Ph), 8.48
(m, 2H, Ph). 13C NMR (75.5 MHz, CDCl3) d: 47.9 (CH2), 126.9, 128.0,
128.6, 128.7, 129.22, 130.5 (10CH, Ar), 128.8, 137.2, 149.6, 161.3
(4sp2 tertiary C). MS (EI, 70 eV) m/z (%): 268 (M+, 12), 135 (10). Found
(%): C, 67.28; H, 4.39; N, 10.50. Calc. for C15H12N2OS (%): C, 67.14;
H, 4.51; N, 10.44.
S
+ PhCH2NH2·H2S
S
N
N
N
S
CH2Ph
3
4
Scheme 1
– 84 –
© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 84–86
for one of them. The structure of 2a was finally proved by
S(2)
X-ray analysis of closely related analogue 2f (see below).
We extended the reaction with benzylamine to other 1,2,3-di-
thiazole-5-thiones 1. 1,2,5-Thiadiazolothiones 2 were obtained
in all reactions in moderate yields† (Scheme 1).
S(3)
C(1)
C(4)
C(5)
C(13')
N(2)
C(3)
C(6) C(7)
C(8)
C(12)
C(11)
C(2)
C(13)
The structure of thieno derivative 2f was confirmed by X-ray
diffraction analysis‡ (Figure 1). The bond lengths and angles of
the thiadiazole ring, except for S(1)–N(1) and N(1)–C(2)
bonds, fall into the range typical of such a type of heterocyclic
compounds. Close investigation of the molecular geometry of 2f
revealed the significant contribution of a betaine-like resonance
form with formal single N(1)–C(2) and double N(1)–S(1)
bonds. Moreover, when the standard dataset with 2q below 60°
was used, in the crystal of 2f the unexpected elongation [up to
1.543(4) Å] of presumably double C(3)–C(13) bond was
observed. The addition of high-angle data (2q < 90°) resulted in
the molecule of 2f being the superposition (80:20) of two
isomers with cisoid and transoid dispositions of S(2) and S(3)
atoms (Figure 1). The cis form (cis-2f) appears to be stabilized
by the extremely short intermolecular contact between sulfur of
the C=S group and one of the thiophene ring [S···S 3.1812(7) Å,
C(4)–S(3)–S(2) 171.33(6)°], accompanied by charge transfer
from the lone pair (Lp) of the S(2) atom to the σ* orbital of the
C–S bond. In turn, S(3') of the minor component (trans-2f)
presumably binds to the N(1) thiadiazole atom [S···N 2.9342(8) Å,
S(1)–N(1)–S(4) 175.95(6) Å] through charge transfer from one
of the sulfur Lps to the σ* orbital of S(1)–N(1) bond. Quantum
chemical calculations (B3LYP/6-311+G*)§ and subsequent topo-
logical analysis of theoretical electron density functions7 for
two isomers have shown that the cisoid-form is stabilized by the
S···S interaction, which contributes 2.9 kcal mol–1, as estimated by
Espinosa’s correlation scheme.8,9 In the second isomer instead
of S···N–C interaction the weaker (1.8 kcal mol–1) C(13')–H···S(2)
binding is observed. On the other hand, trans-2f was found to be
C(9)
N(1)
S(3')
C(10)
S(1)
A
C(4)
C(5)
C(3)
C(4)
C(5)
C(13)
S(3)
S(2)
S(2)
C(13')
C(3)
C(2)
N(1)
C(2)
S(3')
C(1)
C(1)
N(2)
N(2)
S(1)
N(1)
C(6)
C(6)
C(7)
C(7)
S(1)
C(8)
C(9)
C(12)
C(12)
C(11)
C(8)
C(9)
C(11)
C(10)
C(10)
B
C
Figure 1 General view of compound 2f (A), which is a superposition of
two isomers: cis-2f (B) and trans-2f (C) in a ratio of 4:1, with representa-
tion of atoms via thermal ellipsoids at 50% probability level. Selected bond
lengths (Å): C(1)–S(2) 1.6799(7), S(1)–N(1) 1.6222(6), S(1)–N(2) 1.6887(6),
N(1)–C(2) 1.3228(9), C(1)–C(2) 1.4614(10), C(1)–N(2) 1.3526(9), C(2)–C(3)
1.4521(10), N(2)–C(6) 1.4675(9); selected bond angles (°): C(2)–C(1)–N(2)
106.73(6), C(1)–C(2)–N(1) 114.65(6), C(2)–N(1)–S(1) 112.07(5), N(1)–S(1)–
N(2) 93.14(3), C(1)–N(2)–S(1) 113.36(5), C(1)–C(2)–C(3) 126.23(6).
a little more stable (0.63 kcal mol–1) than cis-2f, apparently,
owing to conjugation between thiadiazole and thiophene cycles
that is more pronounced in the case of the transoid-form.
The N(1) atom of both isomers participates in the formation
of the N···S–N interaction [S···N 2.9045(8) Å, N(1')–S(1)–N(2)
168.56(7) Å] with the charge being transferred from the nitrogen
Lp to the σ* orbital of the latter bond that leads to the dimeriza-
tion of the neighbouring molecules. These supramolecular asso-
ciates are assembled into a 3D framework by a number of weak
S···H, π···π and S···S contacts.
It was envisaged that 1,2,3-dithiazole-5-thiones 7 on reaction
with primary amines should give ketones 8. We checked this
possibility by treatment of dithiazolone 7a with benzylamine,
but it turned out that the formation of 1,2,5-dithiazolone 8a is
complicated by formation of a by-product, N-substituted 2-oxo-
acetamide 9a (Scheme 2).
To obtain thiadiazolone 8a selectively, the reaction between
7a (R = Ph) and benzylamine was investigated in detail; the
nature of the solvent appeared crucial for successful reaction. If
the reaction was carried out in an inert solvent such as chloro-
form, starting dithiazolone 7a was isolated in a practically
quantitative yield. Attempts to employ strong aprotic dipolar
solvents such as DMF or acetonitrile at room temperature led to
formation of the mixtures of 8 and 9 in a ratio of 1:1 or 1:2,
respectively. Treatment of benzylamine with 7a in absolute THF
gave selectively 1,2,5-thiadiazolone 8a in quantitative yield. We
then extended these conditions to other ketones 7. 1,2,5-Thia-
diazolones 8 were obtained in high yields in practically all
8b: yield 100%, colourless crystals, mp 72–74 °C. 1H NMR (300 MHz,
CDCl3) d: 5.03 (s, 2H, CH2), 6.99 (d, 2H, Ar, J 8.80 Hz), 7.39 (m, 5H,
Ar), 8.46 (d, 2H, Ar, J 8.80 Hz). 13C NMR (75.5 MHz, CDCl3) d: 47.8
(CH2), 115.4, 115.7, 126.7, 128.7, 129.1 (9CH, Ar), 125.8, 134.7, 148.4,
161.1, 165.7 (5sp2 tertiary C). MS (EI, 70 eV) m/z (%): 286 (M+, 100),
256 (20), 173 (5), 121 (87). Found (%): C, 63.08; H, 3.92; N, 9.55. Calc.
for C15H11FN2OS (%): C, 62.92; H, 3.87; N, 9.78.
8c: yield 100%, colourless crystals, mp 68–72 °C. 1H NMR (300 MHz,
CDCl3) d: 3.87 (s, 3H, Me), 5.03 (s, 2H, CH2), 7.14 (m, 2H, Ar), 7.39
(m, 5H, Ar), 8.49 (m, 2H, Ar). 13C NMR (75.5 MHz, CDCl3) d: 47.9
(CH2), 113.9, 128.6, 128.7, 128.9, 129.2 (9CH, Ar), 125.2, 134.9, 149.2,
161.3, 161.4 (5sp2 tertiary C). MS (EI, 70 eV) m/z (%): 298 (M+, 43),
256 (– S, 12), 160 (5), 133 (45). Found (%): C, 64.65; H, 4.92; N, 9.55.
Calc. for C16H14N2O2S (%): C, 64.41; H, 4.73; N, 9.39.
‡
Crystallographic data. Crystals of 2f (C13H10N2S3, M = 290.41) are
monoclinic, space group P21/c, at 100 K: a = 12.6684(3), b = 13.9186(7)
and c = 7.4243(5) Å, b = 104.972(5)°, V = 1264.66(11) Å3, Z = 4 (Z' = 1),
dcalc = 1.525 g cm–3, m(MoKα) = 5.66 cm–1, F(000) = 600. Intensities of
50901 reflections were measured with a Bruker SMART APEX2 CCD
diffractometer [l(MoKα) = 0.71072 Å, w-scans, 2q < 90°] and 10363
independent reflections [Rint = 0.0458] were used in further refinement.
The structure was solved by direct method and refined by the full-matrix
least-squares technique against F2 in the anisotropic-isotropic approxi-
mation. The positions of hydrogen atoms were calculated, and they were
refined in an isotropic approximation in riding model. The molecule is
disordered by two positions with the 80:20 ratio. For 2f, the refinement
converged to wR2 = 0.0927 and GOF = 1.003 for all independent reflec-
tions [R1 = 0.0355 was calculated against F for 7426 observed reflec-
tions with I > 2s(I)]. All calculations were performed using SHELXTL
PLUS 5.0.
§
DFT calculations of the isolated cis-2f and trans-2f were performed
with the Gaussian0310 program package using the B3LYP functional.
Full optimization of the molecules was carried out with the 6-311+G*
basis set starting from the X-ray structural data. As convergence criteria,
the standard threshold limits of 4.5×10–4 and 1.8×10–3 a.u. were applied
for the maximum force and displacement, respectively. The topological
analysis of computed electron densities was performed using the AIM2000
program packages.11
CCDC 723464 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
– 85 –

Mendeleev Commun., 2009, 19, 84–86
the heterocyclic ring and the formation of key intermediate 10.
O
The formation of the 1,2,5-dithiazole ring occurs probably
through an intramolecular attack of amide (thioamide) nitrogen
onto the S-2 sulfur atom with extrusion of hydrogen sulfide. The
formation of oxamide 9 could be suggested via the hydrolysis
of intermediate 10 with extrusion of S2 and NH3.
R
THF
+
PhCH2NH2
S
room
temperature
N
S
7
O
O
R
This work was supported by the Russian Foundation for
Basic Research (grant no. 08-03-00003a).
CH2Ph
R
N
N
CH2Ph
+
H
N
S
O
References
9e R = Me, 87%
8a R = Ph, 94%
8b R = 4-FC6H4, 100%
1
2
3
4
5
H. Lee and K. Kim, J. Org. Chem., 1993, 58, 7001.
H.-S. Lee and K. Kim, Tetrahedron Lett., 1996, 37, 3709.
Y.-G. Chang, H.-S. Lee and K. Kim, Tetrahedron Lett., 2001, 42, 8197.
M.-K. Jeon and K. Kim, J. Chem. Soc., Perkin Trans. 1, 2000, 3107.
(a) M. A. Gray, C. W. Rees and D. J. Williams, Heterocycles, 1994, 37,
1827; (b) K. Emayan and C. W. Rees, Bull. Soc. Chim. Belg., 1997,
106, 605.
8c R = 4-MeOC6H4, 100%
8d R = 4-NO2C6H4, 90%
8f R = 2-thienyl, 95%
8g R = 2-benzofuryl, 96%
Scheme 2
cases except for the methyl derivative where oxoacetamide 9e
was formed selectively in a yield of 87% (Scheme 2).
6
L. S. Konstantinova, O. I. Bol’shakov, N. V. Obruchnikova, H. Laborie,
A. Tanga, V. Sopéna, I. Lanneluc, L. Picot, S. Sablé, V. Thiéry and
O. A. Rakitin, Bioorg. Med. Chem. Lett., 2009, 19, 136.
R. F. W. Bader, Atoms in Molecules. A Quantum Theory, Clarendon
Press, Oxford, 1990.
E. Espinosa, E. Molins and C. Lecomte, Chem. Phys. Lett., 1998, 285,
170.
E. Espinosa, I. Alkorta, I. Rozas, J. Elguero and E. Molins, Chem.
Phys. Lett., 2001, 336, 457.
The reactions described are the conversions of 1,2,3-dithiazole
to 1,2,5-thiadiazole ring systems through insertion of nucleophilic
amine and elimination of H2S. The most plausible pathway
(Scheme 3) includes a nucleophilic attack of amine onto the
C-5 position of the dithiazole ring followed by opening of
7
8
9
10 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery, R. E. Stratmann,
J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin,
M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi,
B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A.
Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, A. G. Baboul,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts,
R. L. Martin, D. J. Fox, T. A. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S. Replogle
and J. A. Pople, Gaussian 98, Revision A.9, 1998, Gaussian, Inc.,
Pittsburgh PA.
X
HX
X
NH2R2
NHR2
R1
R1
R1
R2NH2
S
S
S
N
N
N
S
S
S
X = S, O
R1
N
X
X
R1
R2
NR2
H
N
N
– H2S
S
S
HS
2 X = S
8 X = O
10
11 AIM2000 designed by Friedrich Biegler-König, University of Applied
Sciences, Bielefeld, Germany.
9
H2O
– NH3
OH
R1
OH2 X
X
R1
OH
X
NHR2
N
NHR2
R1
HN
S
– S2
NHR2
NH2
S
HS
HS
Scheme 3
Received: 15th September 2008; Com. 08/3216
– 86 –