A New Cyclisation of Sulfenylated Dimethyl Sulfoxide and Thiosemicarbazone Adducts using Thionyl Chloride

Article abstract of DOI:10.1039/a605234g

Adducts (4a-d) obtained by nucleophilic addition of sulfenylated dimethyl sulfoxide derivatives (2a,b) to thiosemicarbazones (3a,b) undergo a new intramolecular cyclisation, involving deoxygenative demethylation, to yield 5-sulfenylated 4-aryl-2-thiocarbamoyl-1,2,3-thiadiazolidines (7a-d) on treatment with thionyl chloride.

Full text of DOI:10.1039/a605234g

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90 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 90–91†
A New Cyclisation of Sulfenylated Dimethyl Sulfoxide and
Thiosemicarbazone Adducts using Thionyl Chloride†
Lal Dhar S. Yadav* and Daya R. Pal
Department of Chemistry, University of Allahabad, Allahabad, 211002 India
Adducts (4a–d) obtained by nucleophilic addition of sulfenylated dimethyl sulfoxide derivatives (2a,b) to
thiosemicarbazones (3a,b) undergo a new intramolecular cyclisation, involving deoxygenative demethylation, to yield
5-sulfenylated 4-aryl-2-thiocarbamoyl-1,2,3-thiadiazolidines (7a–d) on treatment with thionyl chloride.
We recently published a convenient method for the synthesis
of 6-sulfenylated 2-amino-1,3,4-thiadiazines from sulfenyla-
ted dimethyl sulfoxide and thiosemicarbazone adducts
involving the acid-labile methylsulfinyl leaving group.1 We
now report a new, efficient and simple intramolecular cyclisa-
tion of the same adducts to 5-sulfenylated 4-aryl-2-thiocarba-
moyl-1,2,3-thiadiazolidines (7a–d) involving deoxygenative
demethylation on treatment with thionyl chloride. These sul-
fenylated heterocycles were required in connection with the
development of potential pharmacological agents and agro-
chemicals.1,2
treatment with thionyl chloride in pyridine, resulting in
60–69% yield of 7 with 93–96% diastereoselectivity. The
evolution of methanethiol on treatment of 7 with methyl
iodide in ethanol followed by alkaline hydrolysis with potas-
sium hydroxide provides chemical evidence for the presence
of the thiourea residue in 7. The easy and wide availability of
the requisite substrates and the simple operations under mild
conditions makes the present cyclisation a potential general
synthetic method for a variety of cyclic systems.
Experimental
The synthetic sequence leading to the formation of 7 is
depicted in Scheme 1. The formation of adducts 4 and their
cyclisation to 7 were highly diastereoselective. The crude
Mps were determined in open glass capillaries and are uncor-
rected. IR spectra were recorded in KBr on a Perkin-Elmer 993
1
spectrophotometer. H NMR spectra were recorded on a Perkin-
Elmer R-32 (90 MHz) spectrometer using [2H6]dimethyl sulfoxide
as solvent and SiMe4 as internal standard. Mass spectra were
recorded on a JEOL D-300 mass spectromter at 70 eV. Elemental
analyses were carried out in a Coleman automatic carbon, hydro-
gen and nitrogen analyser.
1
isolates were checked by H NMR for their diastereomeric
ratios to avoid inadvertent alteration of these ratios during
subsequent isolation and purification (see Experimental sec-
tion). The reaction of chloromethyl methyl sulfoxide and the
sodium salt of 5-aryl-2-sulfanyl-1,3,4-oxadiazoles 1 in reflux-
ing ethanol for 5 h furnished 2. Nucleophilic addition of sul-
fur-stabilised carbanions, generated in situ by the action of
sodium methoxide on 2 in methanol at room temperature, to
5-Aryl-2-methylsulfinylmethylsulfanyl-1,3,4-oxadiazoles 2 and 1-[1-
aryl-2-(5-aryl-1,3,4-oxadiazol-2-ylsulfanyl)-2-(methylsulfinyl)ethyl]-
thiosemicarbazides 4.sThese were prepared according to the
method described earlier1 and recrystallised from ethanol. The
i. NaOH–EtOH
i. NaOH–MeOH
Me
O
O
S
Ar
O
S
S
O
Ar
O
SH
Ar
O
S
S
ii. ClCH2SMe
ii. Ar'CH = NNHC—NH2
S
Me
3a Ar' = Ph
b Ar' = 4-ClC6H4
N
N
N
N
N
N
Ar'
N
H
N
H
NH2
1a Ar = Ph
b Ar = 2-ClC6H4
2a Ar = Ph
b Ar = 2-ClC6H4
4a Ar = Ph, Ar' = Ph
b Ar = 2-ClC6H4, Ar' = Ph
c Ar = Ph, Ar' = 4-ClC6H4
d Ar = 2-ClC6H4, Ar' = 4-ClC6H4
SOCl2 Pyridine
O
S
O
Cl
S
Cl–
Me
Cl–
S
C
S
S
S
Ar
O
S
Ar
O
S
S+
Ar
O
S
SOCl2
+
–HCl
NH2
–SO2
Me
N
C
N
NH2
Pyridine
N
N
Ar'
N
N
N
N
N
H
Ar'
N
H
N
H
NH2
Ar'
N
H
7
6a–d
5a–d
a Ar = Ph, Ar' = Ph
b Ar = 2-ClC6H4, Ar' = Ph
c Ar = Ph, Ar' = 4-ClC6H4
d Ar = 2-ClC6H4, Ar' = 4-ClC6H4
Scheme 1
the CtN of thiosemicarbazones 3 followed by quenching
with dilute hydrochloric acid afforded 4 in 65–72% yield with
high diastereoselectivity (92–96%). Adducts 4 underwent a
new cyclisation, involving deoxygenative demethylation, on
crude product 4 was recrystallised from ethanol to give a dia-
stereomeric mixture (ꢀ97:ꢁ3; in the crude isolates the ratio was
92–96:8–4, determined by 1H NMR spectroscopy) which was
again recrystallised from ethanol to obtain an analytical sample of
a single diastereomer 4 (Tables 1 and 2). On the basis of 1H NMR
and published data,5–7 compounds 4 were assigned erythro (syn)
1
*To receive any correspondence.
stereochemistry, as their H NMR spectra exhibit a coupling con-
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
stant, JSCH,NCH = 4 Hz, which is smaller than that of the very minor
(ꢁ3%) diastereomer (threo or anti), JSCH,NCH = 10 Hz.
5-Aryl-2-(4-thiocarbamoyl-1,2,3-thiadiazolidin-5-ylsulfanyl)-1,3,4-

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J. CHEM. RESEARCH (S), 1997 91
Table 1 Yields, mps, molecular formulae and elemental analyses of compounds 2, 4 and 7
Found (required) (%)
Yield
(%)
Mp
(T/°C)
Molecular
formula
Compd.
C
H
N
2a
2b
4a
4b
4c
4d
7a
7b
7c
7d
74
70
72
68
65
71
68
60
69
62
164–166
171–173
151
180–182
157–158
146
155–156
130
147–148
158–160
C10H10N2O2S2
C10H9ClN2O2S2
C18H19N5O2S3
C18H18ClN5O2S3
C18H18ClN5O2S3
C18H17Cl2N5O2S3
C17H15N5OS3
C17H14ClN5OS3
C17H14ClN5OS3
C17H13Cl2N5OS3
47.3 (47.2)
41.5 (41.6)
50.0 (49.9)
46.1 (46.2)
46.0 (46.2)
42.9 (43.0)
50.6 (50.9)
46.6 (46.8)
47.0 (46.8)
43.2 (43.4)
4.1 (4.0)
3.0 (3.1)
4.2 (4.4)
3.9 (3.9)
3.7 (3.9)
3.3 (3.4)
3.6 (3.8)
3.2 (3.0)
3.0 (3.2)
2.7 (2.8)
11.1 (11.0)
9.6 (9.7)
16.3 (16.2)
15.2 (15.0
15.1 (15.0)
13.8 (13.9)
17.6 (17.4)
15.9 (16.1)
16.0 (16.1)
15.0 (14.9)
Table 2 Spectral data for compounds 2, 4 and 7
Compd.
v
max/cmꢂ1
dH (J in Hz)
Mǹ
2a
2b
4a
1030 (StO)
1035 (StO)
1030 (StO)
2.59 (s, 3 H, Me), 4.25 (s, 2 H, CH2), 7.31–7.76 (m, 5 H, ArH)
2.62 (s, 3 H, Me), 4.28 (s, 2 H, CH2), 7.48–8.03 (m, 4 H, ArH)
2.56 (s, 3 H, Me), 3.72 (d, 1 H, J 4.0, SCH), 4.92 (d, 1 H, J 4.0, NCH), 7.32–7.82 (m, 10 H,
ArH), 8.40–9.22 (br, 4 H, NHNHCSNH2)
2.58 (s, 3 H, Me), 3.71 (d, 1 H, J 4.0, SCH), 4.92 (d, 1 H, J 4.0, NCH), 7.30–8.06 (m, 9 H,
ArH), 8.40–9.20 (br, 4 H, NHNHCSNH2)
2.52 (s, 3 H, Me), 3.74 (d, 1 H, J 4.0, SCH), 4.94 (d, 1 H, J 4.0, NCH), 7.34–8.09 (m, 9 H,
ArH), 8.44–9.18 (br, 4 H, NHNHCSNH2)
2.57 (s, 3 H, Me), 3.76 (d, 1 H, J 4.0, SCH), 4.96 (d, 1 H, J 4.0, NCH), 7.36–8.16 (m, 8 H,
ArH), 8.41–9.15 (br, 4 H, NHNHCSNH2)
4.20 (d,. 1 H, J 4.5, 5-H), 4.58–4.73 (br, 3 H, NH, NH2), 5.23 (d, 1 H, J 4.5, 4-H), 7.28–7.76
(m, 10 H, ArH)
4.10 (d, 1 H, J 4.5, 5-H), 4.62–4.82 (br, 3 H, NH, NH2), 5.26 (d, 1 H, J 4.5, 4-H), 7.31–7.93 (m,
9 H, ArH)
4.19 (d, 1 H, J 4.5, 5-H), 4.69–4.90 (br, 3 H, NH, NH2), 5.28 (d, 1 H, J 4.5, 4-H), 7.40–8.02 (m,
9 H, ArH)
254
288
433
4b
4c
4d
7a
7b
7c
7d
1035 (StO)
467
467
503
401
435
435
471
1030 (StO)
1035 (StO)
3310–3365 (NH, NH2)
3305–3370 (NH, NH2)
3315–3360 (NH, NH2)
3320–3375 (NH, NH2)
4.22 (d, 1 H, J 4.5, 5-H), 4.70–4.89 (br, 3 H, NH, NH2), 5.24 (d, 1 H, J 4.5, 4-H), 7.39–8.04 (m
8 H, ArH)
oxadiazoles 7. General Procedure.sA solution of 4 (20 mmol) and
thionyl chloride (2.0 ml, 25 mmol) in pyridine (50 ml) was refluxed
for 8 h. The pyridine was evaporated under reduced pressure at
40 °C and the residue obtained was washed with water and recrystal-
lised from ethanol to give a diastereomeric mixture (ꢀ97:ꢁ3%; in
the crude isolates the ratio was 93–96:7–4, determined by 1H NMR
spectroscopy) which on second recrystallisation from ethanol fur-
nished an analytical sample of a single diastereomer 7 (Tables 1 and
2). Compounds 7 were assigned cis stereochemistry, as the coupling
constant, J4,5 = 4.5 Hz, for 7 was lower than that for the very minor
(ꢁ3%) diastereomer (trans), J4.5 = 11 Hz.7–9
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Received, 26th July 1996; Accepted, 18th November 1996
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