Synthesis of 1,3,4-thiadiazolines from 1,2-dithiole-3-thiones

Article abstract of DOI:10.1070/MC2005v015n02ABEH002086

The thiocarbonyl group of 4,5-dichloro-1,2-dithiole-3-thione reacts as a 1,3-dipolarophile towards diaryl nitrile imines by 1,3-dipolar cycloaddition followed by opening of the dithiole ring with loss of sulfur to give 5-methylene-1,3,4-thiadiazolines; th

Full text of DOI:10.1070/MC2005v015n02ABEH002086

,
2005, 15(2), 55–56
Synthesis of 1,3,4-thiadiazolines from 1,2-dithiole-3-thiones
a
a
b
a
Vladimir A. Ogurtsov, Oleg A. Rakitin,* Charles W. Rees* and Alexey A. Smolentsev
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: orakitin@ioc.ac.ru
b
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AZ.
E-mail: c.rees@imperial.ac.uk
DOI: 10.1070/MC2005v015n02ABEH002086
The thiocarbonyl group of 4,5-dichloro-1,2-dithiole-3-thione reacts as a 1,3-dipolarophile towards diaryl nitrile imines by 1,3-
dipolar cycloaddition followed by opening of the dithiole ring with loss of sulfur to give 5-methylene-1,3,4-thiadiazolines; this
reaction together with nucleophilic displacement (before or after cycloaddition) of the selectively reactive 5-chlorine atom
provides a rapid access to stable 5-methylene-1,3,4-thiadiazolines.
1
,3,4-Thiadiazoles and thiadiazolines are of great pharma-
Table 1 Yields of 1,3,4-thiadiazoles 5 in the reaction of substituted
4-chloro-1,2-dithiole-3-thiones 1b,c with various diaryl nitrile imines.
1
ceutical and industrial importance. Technological uses include
dyes, optically active liquid crystals and photographic materials;
large numbers have been patented as herbicides, insecticides,
fungicides, bactericides, and anthelmintics, and in medicine
derivatives were found to have antihypertensive, anticonvulsive
S
Cl
Cl
H
Et3N
N
Ar1
Ar2
S
C
N
N
Ar1
Ar2
N
S
1
,2
PhX
and other activities.
Many methods are available for the synthesis of these com-
pounds, and 1,3-dipolar cycloaddition showed early promise.1
Such a reaction was the addition of nitrile imines, from the
2
3
1b,c
Ar2
N
N
Ar1
corresponding hydrazonyl chlorides to the C=S group of thio-
Cl
PhX
amides and thioketones,1 and these included two isolated
S
3,4
reactions between nitrile imines and 1,2-dithiole-3-thiones.
Recently, we found that this reaction can be extended to fused
,2-dithiole-3-thiones such as bis[1,2]dithiolo[1,4]thiazines.5
,5-Dichloro-1,2-dithiole-3-thione 1a is readily available and
S
1
5
4
6
has useful functionality and reactivity; it seemed to us that if
a reacted similarly with nitrile imines it could provide a ready
1
2
2
Ar , Ar
1b X = O
1c X = S
1
1
2
a Ar = Ar = Ph
5ab 59%
5bb 65%
5cb 59%
5db 61%
5ac 55%
5bc 62%
5cc 57%
5dc 59%
route to a range of unusual 1,3,4-thiadiazolines suitable for
biological testing and further elaboration. However, the addition
of diphenyl nitrile imine 3a to 1a gives unstable products,
which could not be isolated from the reaction mixture. The only
substance obtained, in boiling benzene, was dihydrotetrazine 4,
the known product of dimerization of 3a (Scheme 1).
1
2
b Ar = 4-NO C H , Ar = Ph
2
2
6
4
1
c Ar = Ph, Ar = 4-NO C H
2
6
4
1
2
d Ar = 4-MeC H , Ar = Ph
6
4
8
tives. Indeed, the reaction of 1a and 2a with triethylamine in
benzene at room temperature followed by addition of phenol or
thiophenol led to thiadiazolines 5, X = O and S, though in low
yields (Scheme 2).
Cl
H
N
Alternatively, the reactive 5-chlorine in 1a could first be dis-
placed by the nucleophile to give stable products (1b,c), which
underwent cycloaddition with diphenyl nitrile imine 3a to give
Ph
N
Ph
S
Ph
N
Ph
2
a
Cl
Cl
N
S
†
∆
, Et3N
N
thiadiazolines 5 in much better yields (Scheme 3). The ejected
S
Ph
N
Ph
sulfur could be isolated by column chromatography in an almost
quantitative yield.
Ph
C
N
N
Ph
1
a
4
3
a
S
Scheme 1
Cl
Cl
H
Et N
3
It seems likely that the expected 1:1 adduct 5aa was formed
N
S
Ph
C
N
N
Ph
5
Ph
N
Ph
by 1,3-dipolar cycloaddition followed by loss of sulfur but, as
an aliphatic thioacyl chloride, it was too unstable to be readily
isolated. If so, it might be intercepted by nucleophiles at the
thioacyl group to give more stable thiocarboxylic acid deriva-
S
PhX
7
2
a
3a
1b,c
Ph
N
N
Ph
S
Cl
S
Cl
Cl
Cl
H
Et N
3
N
S
Ph
C
N
N
Ph
Ph
PhX
S
Ph
N
S
5
5
ab X = O (59%)
ac X = S (55%)
2
a
3a
1a
Scheme 3
Ph
Ph
N
S
N
N
N
S
Ph
Ph
To confirm the stability of 1,3,4-thiadiazolines and to broaden
the scope of this reaction, we also investigated the reactions of
-phenoxy- 1b and 5-phenylthio-1,2-dithiole-3-thione 1c with
substituted nitrile imines 3 (Table 1). In all cases, 1,3,4-thiadiazo-
lines 5 were obtained under the same conditions as for 5ab,ac
in comparable yields (55–65%) (Table 1) and were stable to
column chromatography and in storage at room temperature.
Cl
Cl
PhXH
Cl
S
5
S
PhX
5
aa
5ab X = O (29%)
ac X = S (25%)
5
Scheme 2
Mendeleev Commun. 2005 55

,
2005, 15(2), 55–56
Thus, nucleophilic displacement of the reactive 5-chlorine in
,5-dichloro-1,2-dithiole-3-thione 1 and cycloaddition of diaryl
nitrile imines provides a short and ready access to 5-methylene-
This work was supported by the Royal Society, MDL Infor-
mation Systems (UK) Ltd and the Wolfson Foundation (the
Wolfson Centre for Organic Chemistry in Medical Science at
Imperial College).
4
1
,3,4-thiadiazolines capable of further elaboration.
References
†
General procedure for the preparation of 5. Triethylamine (1.7 mmol)
1
(a) G. Kornis, in Comprehensive Heterocyclic Chemistry I, eds. A. R.
Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol. 4, Ch. 4.27,
p. 545; (b) G. I. Kornis, in Comprehensive Heterocyclic Chemistry II,
ed. R. C. Storr, Pergamon, Oxford, 1996, vol. 4, Ch. 4.10, p. 379.
C. B. Chapleo, P. L. Myers, A. C. B. Smith, M. R. Stillings, I. F. Tulloch
and D. C. Walter, J. Med. Chem., 1988, 31, 7.
was added to a stirred solution of N-aryl-α-chloroarylhydrazone 2
1.5 mmol) in benzene (15 ml). Then, a solution of 5-substituted 4-chloro-
,2-dithiole-3-thiones 1a–c (1 mmol) in benzene (10 ml) was added
(
1
dropwise, and stirring was continued for 1 h. Triethylamine hydrochloride
was filtered off, the filtrate was evaporated under reduced pressure, and
final products and sulfur were separated by column chromatography
2
3
4
5
Y. Poirier, Bull. Soc. Chim. Fr., 1968, 1203.
(
Silica gel Merck 60).
All new compounds were characterised by elemental analysis, H NMR,
IR and mass spectra and for some of them by HMRS.
M. Maguet, Y. Poirier and J. Teste, Bull. Soc. Chim. Fr., 1970, 1503.
S. Barriga, P. Fuertes, C. F. Marcos, D. Miguel, O. A. Rakitin, C. W. Rees
and T. Torroba, J. Org. Chem., 2001, 66, 5766.
1
1
5
ab: yellow crystals, mp 181–182 °C. H NMR (CDCl ) d: 7.10 (d,
3
6
7
8
V. A. Ogurtsov, O. A. Rakitin, C. W. Rees and A. A. Smolentsev, Mendeleev
Commun., 2003, 50.
A. D. Williams, in Comprehensive Organic Functional Group Trans-
formations, ed. C. J. Moody, Pergamon, Oxford, 1995, vol. 5, Ch. 5.11.
G.-J. Wentrup, M. Koepke and F. Boberg, Synthesis, 1975, 525.
2
H, ArH, J 8.1 Hz), 7.28 (m, 1H, ArH), 7.50 (m, 10H, ArH), 7.87
–1
(
d, 2H, ArH, J 6.8 Hz). IR (KBr, n/cm ): 1592 (Ph), 1488, 1440,
+
320, 1200, 1164, 1128, 920, 764. MS, m/z (%): 422 (M , 8), 329
+
22 15 2 2
requires 422.0314. Found (%): C, 62.33; H, 3.68; N, 6.54. Calc. for
C H ClN OS (%): C, 62.48; H, 3.57; N, 6.62.
2
5
2
15
2
2
1
bb: red crystals, mp 185–186 °C. H NMR (CDCl ) d: 7.10 (m, 2H,
3
ArH), 7.30 (m, 1H, ArH), 7.52 (m, 7H, ArH), 8.06 (d, 2H, ArH, J 6.9 Hz),
–
1
8
1
9
.34 (d, 2H, ArH, J 8.6 Hz). IR (KBr, n/cm ): 3064 (C–H), 1616, 1588,
536, 1520 (NO ), 1488, 1444, 1344 (NO ), 1316, 1196, 1176 (C=S),
2
2
+
20, 852, 760. MS, m/z (%): 467 (M , 7), 374 (M – PhO, 39), 358
(
M – PhS, 100), 328 (M – PhS, NO, 85), 312 (M – PhS, NO , 30).
2
+
Found M , 467.0174; C H ClN O S requires 467.0165. Found (%):
22
14
3
3 2
C, 56.23; H, 3.15; N, 8.56. Calc. for C H ClN O S (%): C, 56.47;
22
14
3
3 2
H, 3.02; N, 8.98.
1
5cb: bright yellow crystals, mp 187–189 °C. H NMR (CDCl ) d: 7.12
3
(
m, 2H, ArH), 7.30 (m, 1, ArH), 7.47 (m, 5H, ArH), 7.70 (m, 2H, ArH),
7
1
1
(
1
.85 (m, 2H, ArH), 8.37 (m, 2H, ArH). 13C NMR (CDCl ) d: 97.21,
3
2
28.52, 145.95, 146.81, 153.80, 154.74, 157.63, (7sp -tertiary C), 122.69,
24.18, 126.23, 126.38, 127.32, 129.37, 129.51, 131.80 (8C–H), 195.76
–
1
C=S). IR (KBr, n/cm ): 1608, 1592, 1520 (NO ), 1460, 1348 (NO ),
2
2
+
304, 1196, 1176 (C=S), 920, 760. MS, m/z (%): 467 (M , 7), 374
(
(
M – PhO, 41), 358 (M – PhS, 100), 328 (M – PhS, NO, 98), 312
+
M – PhS, NO , 43). Found M , 467.0171; C H ClN O S requires
2
22 14
3
3 2
4
67.0165. Found (%): C, 55.94; H, 3.19; N, 8.89. Calc. for C H ClN O S
22 14 3 3 2
(
%): C, 56.47; H, 3.02; N, 8.98.
db: yellow crystals, mp 186–188 °C. H NMR (CDCl ) d: 2.42 (s,
1
5
3
3
7
1
H, Me), 7.12 (m, 2H, ArH), 7.29 (s, 2H, ArH), 7.51 (m, 8H, ArH),
–1
.74 (d, 2H, ArH, J 7.9 Hz). IR (KBr, n/cm ): 1592, 1492, 1448, 1360,
+
324, 1200, 1164, 1132, 920, 760. MS, m/z (%): 436 (M , 10), 343
+
(
M – PhO, 61), 327 (M – PhS, 100). Found M , 436.0466; C H ClN OS
23
17
2
2
requires 436.0471. Found (%): C, 63.22; H, 3.92; N, 6.41. Calc. for
C H ClN OS (%): C, 62.96; H, 4.00; N, 6.38.
2
5
3
17
2
2
1
ac: dark red crystals, mp 197–200 °C. H NMR (CDCl ) d: 7.48 (m,
3
–1
1
1
1
3H, ArH), 7.82 (m, 2H, ArH). IR (KBr, n/cm ): 1592, 1488, 1440,
404, 1276, 1148, 968, 768. MS, m/z (%): 438 (M , 5), 329 (M – PhS,
00). Found M , 438.0083; C H ClN S requires 438.0086. Found
+
+
22
15
2 3
(
%): C, 59.58; H, 3.75; N, 6.14. Calc. for C H ClN S (%): C, 60.19;
22 15 2 3
1
3
1
0H, ArH), 8.00 (d, 2H, ArH, J 8.8 Hz), 8.30 (d, 2H, ArH, J 8.8 Hz). IR
–
1
(KBr, n/cm ): 1592, 1540, 1520 (NO ), 1492, 1420, 1344 (NO ), 1276,
2
2
9
76, 852. MS, m/z (%): 374 (M – PhS, 37), 328 (M – PhS, NO , 35).
2
Found (%): C, 54.37; H, 2.83; N, 8.78. Calc. for C H ClN O S (%):
22
14
3
2 3
C, 54.59; H, 2.92; N, 8.68.
cc: deep red crystals, mp 183–185 °C. H NMR (CDCl ) d: 7.49 (m,
1
5
3
8
H, ArH), 7.66 (m, 2H, ArH), 7.81 (m, 2H, ArH), 8.38 (m, 2H, ArH).
–
1
IR (KBr, n/cm ): 1612, 1592, 1520 (NO ), 1412, 1348 (NO ), 1268,
2
2
+
1148, 1108, 972, 880. MS, m/z (%): 483 (M , 4), 374 (M – PhS, 13), 329
(
59). Found (%): C, 54.34; H, 2.91; N, 8.55. Calc. for C H ClN O S
22
14
3
2 3
(
%): C, 54.59; H, 2.92; N, 8.68.
dc: orange crystals, mp 211–215 °C. H NMR (CDCl ) d: 2.41 (s,
1
5
3
3
H, Me), 7.25 (d, 2H, ArH, J 8.5 Hz), 7.51 (t, 10H, ArH, J 4.6 Hz), 7.70
–1
(
d, 2H, ArH, J 8.5 Hz). IR (KBr, n/cm ): 1704, 1592, 1416, 1288, 968,
+
+
8
4
3
76. MS, m/z (%): 452 (M , 9), 343 (M – PhS, 100). Found M ,
52.0243; C H ClN S requires 452.0242. Found (%): C, 60.75; H,
2
3
17
2 3
.84; N, 5.90. Calc. for C H ClN S (%): C, 60.98; H, 3.78; N, 6.18.
2
3
17
2
3
Received: 12th November 2004; Com. 04/2411
5
6
Mendeleev Commun. 2005