The reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with DMSO: an improved synthesis of 4-chloro-1,2,3-dithiazol-5H-one

Article abstract of DOI:10.1016/j.tet.2009.06.075

4,5-Dichloro-1,2,3-dithiazolium chloride 2 (Appel salt) reacts with either DMSO, diphenylsulfoxide 11 or methylphenylsulfoxide 12 to give 4-chloro-5H-1,2,3-dithiazol-5-one 1 in excellent yields. The use of catalytic amounts of DMSO (1 mol %) in MeCN in th

Full text of DOI:10.1016/j.tet.2009.06.075

Tetrahedron 65 (2009) 6855–6858
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The reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with DMSO:
an improved synthesis of 4-chloro-1,2,3-dithiazol-5H-one
*
Andreas S. Kalogirou, Panayiotis A. Koutentis
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2009
Received in revised form 2 June 2009
Accepted 19 June 2009
Available online 24 June 2009
4,5-Dichloro-1,2,3-dithiazolium chloride 2 (Appel salt) reacts with either DMSO, diphenylsulfoxide 11 or
methylphenylsulfoxide 12 to give 4-chloro-5H-1,2,3-dithiazol-5-one 1 in excellent yields. The use of
catalytic amounts of DMSO (1 mol %) in MeCN in the presence of water (1 equiv) transforms Appel salt 2
into dithiazolone 1 in near quantitative yields (92%). Rational mechanisms are proposed to explain the
catalytic nature of these reactions.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Reactions of dimethylsulfoxide (DMSO) with Appel salt 2
4-Chloro-1,2,3-dithiazol-5H-one 1 has good antimicrobial ac-
tivity,1 and reacts with 1ꢀ and 2ꢀ alkylamines to afford N-alkyl- and
The reaction of Appel salt 2 with DMSO (1 equiv) in dry DCM at
ca. 20 ꢀC gave the dithiazolone 1 rapidly (3–4 h) in high yield (83%).
The reaction worked equally well in dry or wet DCM, however, in
dry MeCN or THF the consumption of Appel salt 2 was faster,1.5 and
1 h respectively. What was more suprising was that the conversion
of Appel salt 2 into dithiazolone 1 could be achieved with only
N,N-dialkylcyanothioformamides.2 Furthermore dithiazolone
1
was a good
a-thiocyanating agent for a,b-unsaturated b-amino
esters,3 and a useful reagent for the synthesis of symmetrical N,N0-
dialkylureas.4
O
S
Cl
Cl
Cl
Table 1
Reaction of Appel salt 2 with dry DMSO and water (0–1 equiv), in dry solvent at
20 ꢀC, protected with a CaCl2 drying tube
N
+ S
N
Cl _
S
S
O
Cl
Cl
Cl
1
2
DMSO
H2O
+
+S
_
N
S
N
Dithiazolone 1 can be prepared by reacting 4,5-dichloro-1,2,3-
dithiazolium chloride 2 (Appel salt)5 with either NaNO3 in DCM at ca.
39 ꢀC for 16 h,5 or with ortho-trimethylsilylbenzamidoxime and
pyridine in DCM at ca. 20 ꢀC for 34 h6 which give the dithiazolone 1 in
73 and 70% yields respectively. The chemistry of Appel salt 2, an
important reagent for the preparation of neutral 1,2,3-dithiazoles,
has been reviewed.2,7 While Appel salt 2 condenses with either active
methylenes, 1ꢀ anilines or H2S to afford 4-chloro-5H-1,2,3-dithiazol-
ylidenes, dithiazolimines or dithiazole-5-thione respectively in good
yields, treating Appel salt 2 with water surprisingly does not give
a good recovery of the expected 4-chloro-1,2,3-dithiazol-5H-one 1.
During ongoing studies of the chemistry of Appel salt 2 we
discovered a new rapid and near quantitative synthesis of dithia-
zol-5-one 1 which required water and catalytic quantities of DMSO.
An account of our findings is outlined below.
S
S
Cl
2
1
2 (mmol) Solvent (mL) DMSO (equiv) H2O (equiv) Time (h) Yield of 1a (%)
0.96
0.96
0.96
2.40
2.40
2.40
2.40
2.40
2.40
2.40
2.40
2.40
82.60
82.60
DCM (10)
MeCN (10)
THF (10)
1
1
1
1
0.5
0.1
0.01
0
0.01
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
4
1.5
1
3.5
3
3
4.5
8.5
1
6
2
83
83
83
77
84
DCM (25)
DCM (25)
DCM (25)
DCM (25)
DCM (25)
MeCN (25)
MeCN (25)
THF (25)
86
88
59b
86
54b
44
19b
91c
77c
0.01
0
THF (25)
MeCN (200) 0.01
MeCN (200) 0.001
2.5
2
6
a
Isolated by chromatography unless otherwise stated.
Sulfur, dithiazolethione 3 and the thiazolone 4 byproducts observed.
Isolated by distillation (92 ꢀC, 23 mbar).
b
c
* Corresponding author. Tel.: þ357 22 892783; fax: þ357 22 892809.
E-mail address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.075

6856
A.S. Kalogirou, P.A. Koutentis / Tetrahedron 65 (2009) 6855–6858
catalytic quantities of DMSO, when water (1 equiv) was added to
the reaction mixture (Table 1).
reductive dechlorination to give dimethylsulfide 8.14 In light of this
complexity there could be difficulties to get a clear picture of the
reaction mechanism.
In an attempt to identify the formation of any byproducts, the
reaction between Appel salt 2 (0.036 mmol) and dry DMSO (2.6 mL,
When only 1 mol % of DMSO was used the reaction in THF gave
a complex mixture and dithiazolone 1 in moderate yield (44%). Re-
peating the reactions in either DCM, MeCN or THF in the absence of
DMSO (0 mol %) also led to low recoveries of dithiazolone 1 and
complex reaction mixtures fromwhich 4-chloro-1,2,3-dithiazole-5H-
thione 3 and the thiazol-5-one 4 could be identified by TLC. Since the
use of MeCN rapidly provided good yields of dithiazolone 1, the re-
action was scaled up. As such reacting a suspension of Appel salt 2
(82.60 mmol) in dry MeCN with DMSO (1 mol %) and water (1 equiv)
gave rapidly (2 h) dithiazolone 1, isolated by distillation (bp 92 ꢀC at
23 mbar) directly from the reaction mixture, in very high yield (91%).
At this scale reducing the amount of DMSO to 0.1 mol % led to a longer
reaction time (6 h) and lower yield of dithiazolone 1 (77%) although
still higher than the reaction performed in the absence of DMSO
(0 mol %) (54%) which was complex (by TLC).
1 equiv) was repeated in DCM-d2 (0.75 mL) in an NMR tube. Ini-
tially 13C NMR (75 MHz) spectroscopy showed the presence of the
dithiazolone 1 C-5 and C-4 carbon resonances at 183.3 and
146.95 ppm respectively together with three additional resonances
at 52.7, 38.2 and 15.3 ppm. DEPT-180 13C NMR studies supported
the resonance at 52.7 ppm to be a CH2 while those at 38.2 and 15.3
were both CH3 resonances. 1H NMR spectroscopy showed three
single resonances at 4.75, 2.87 and 2.29 ppm. After 24 h only the
dithiazolone C-5 and C-4 and the 52.7 and 15.3 ppm resonances
remained in the 13C spectra while only the 4.75 and 2.29 ppm
resonances, integrating 2:3, were visible in the 1H NMR spectra.
These figures corresponded closely to the reported 13C and 1H NMR
resonances for (chloromethyl)(methyl)sulfane 9 (dC 52.0, 15.0 and
dH 4.65, 2.25 ppm),15 strongly supporting the transformation of
DMSO into this molecule on treatment with Appel salt 1 under
anhydrous conditions. DMSO can be transformed into (chloro-
methyl)(methyl)sulfane 9 on treatment with either acid chlorides,
chloroiminium salts or chlorine,15 and the mechanism involved
A reaction mechanism that supported the catalytic behaviour of
DMSO was proposed and some preliminary studies helped identify
some important byproducts. The nucleophilic oxygen of the DMSO8
can attack the highly electrophilic dithiazolium C-5 position to af-
ford a new oxosulfonium dithiazole intermediate 5, from which
a number of possible senarios can be postulated (Scheme 1).
O
Cl
Cl_
Me
Cl
S+
O
S
H2O
HCl
A
S
N
+
+
+
Me
Me
Me
Me
Me
Me
S
Me
Me
1
6
HCl
Cl_ or H2O
B
S
S
O
HCl
Cl_
Me
8
H
Cl
Cl
Cl
Cl
H2O
O
Cl_
+
S+
B
C
S
Cl
S
1
H2C
+S
Cl_
N
S
N
Cl_
Me
A
S
S
9
7
H2O
2
5
S
OH
H2O
Me
H
Me
Me S+
Cl
S
Cl
HCl
10
O
S
O
C
Intramolecular Path B
S
N
1
Me
Scheme 1.
In scenario A, chloride attacks the oxosulfonium intermediate 5 at
sulfur9,10 to eliminate dithiazolone 1 and chlorodimethylsulfonium
chloride 6. In scenario B, water or chloride deprotonates the a-proton
Pummerer rearrangement of the unstable chlorodimethyl-
sulfonium chloride 6.15 The identity of the species displaying dC
38.2 and dH 2.87 ppm resonances was more tentative, and the
NMR resonances closely matched those reported for hydroxyl-
dimethylsulfonium chloride (dC 37.2 and dH 2.87 ppm).15 When the
NMR study was repeated using CDCl3 instead of DCM-d2 a new
resonance was observed in both the 13C and 1H NMR spectra which
was tentatively assigned to dimethylsulfide 8 (dC 37.2 and dH
2.87 ppm). These peaks were avoided when the CDCl3 was passed
through a column of basic alumina prior to its use indicating pos-
sibly that HCl was responsible for reductive dechlorination of the
intermediate chlorodimethylsulfonium chloride 6. None of these
species were actually isolated and these assignments remain
tentative.
Examining the reaction of Appel salt 2 with diphenylsulfoxide
11 and methylphenylsulfoxide 12 respectively was also instructive
(Table 2).
In dry MeCN the reaction of Appel salt 2 with either diphenyl or
methylphenylsulfoxide 11 or 12 (1 equiv) gave dithiazolone 1 in 69
and 84% respectively together with a moderate recovery of the
from the oxosulfonium intermediate 5 to release dithiazolone 1 and
also methyl(methylene)sulfonium chloride 7. Finaly in scenario C
water could directly attack the sulfonium intermediate 5 to release
dithiazolone 1 and regenerate DMSO. Scenario B could also proceed
via an intramolecular pathway that may be favoured. Interestingly in
the presence of HCl and/or water the chemistry of DMSO, chloro-
dimethylsulfonium chloride 6 and methyl(methylene)sulfonium
chloride 7 became more complex. In the presence of HCl, DMSO can
convert to the chlorodimethylsulfonium chloride 6, which can
hydrolyse back to DMSO in the presence of water,11 or eliminate
HCl to form methyl(methylene)sulfonium chloride 7.12 Methyl-
(methylene)sulfonium chloride 7 reportedly reacts with water to
afford methylthiomethanol 10 and not DMSO while reaction with
chloride gave (chloromethyl)(methyl)sulfane 9 and not chloro-
dimethylsulfonium chloride 6.9 Furthermore methylthiomethanol 10
in the presence of HCl was in equilibrium with DMSO.13 Lastly
chlorodimethylsulfonium chloride 6 can suffer chloride assisted

A.S. Kalogirou, P.A. Koutentis / Tetrahedron 65 (2009) 6855–6858
6857
Table 2
Reaction of Appel salt 2 (2.40 mmol) with sulfoxides 11 or 12, in dry MeCN (25 mL) with water (0–1 equiv) at ca. 20 ꢀC
CN
S
N
S
S
Cl
Cl
Cl
+S
Cl_
Cl
O
O
S
11 R = Ph
12 R = Me
+
+
+
1
+
+
S
N
N
S
N
Ph
R
Ph
R
S
S
S
2
11 R = Ph
13
3
4
12 R = Me
PhSO$R (equiv)
H2O (equiv)
Time (h)
13
3
Yields (%) 1
4
11 or 12
11 (1)
11 (1)
11 (0.10)
11 (0.01)
12 (1)
0
1
1
1
0
1
1
1
1
1
1
2
6
1
1
2
4
7
52
11
0
0
4
13
0
0
0
4
13
69
76
70
59
84
84
81
74
55
2
2
8
7
11 (48)
11 (88)
(0)
99
98
da
da
da
da
d
(0)
Traces
12 (22)
12 (91)
12 (71)
(0)
12 (1)
1
3
6
6
12 (0.1)
12 (0.01)
d (0)
d
a
Unresolved and unidentified mixture of organic sulfides.
respective starting sulfoxides 11 (48%) and 12 (22%). Under these
conditions the reaction with diphenylsulfoxide 11 also gave
diphenylsulfide 13 (R¼Ph) (52%), while that with methyl-
phenylsulfoxide 12 gave a mixture of unidentified sulfides. The
reduction of sulfoxides into sulfides can occur in the presence
of chloride, via the chlorosulfonium species14 and in the ab-
sence of sufficient water in the reaction mixture these chlor-
osulfonium species cannot hydrolyse back to the starting
sulfoxides (Scheme 2). Adding water (1 equiv) to both of these
reactions gave higher yields of diphenyl and methylphenylsulf-
oxides 11 (88%) and 12 (91%) respectively.
3. Summary
A simple and convenient high yielding synthesis of 4-chloro-
5H-1,2,3-dithiazol-5-one 1 has been achieved by treating 4,5-
dichloro-1,2,3-dithiazolium chloride 2 with catalytic amounts of
DMSO (1 mol %) in MeCN in the presence of water (1 equiv). Fur-
thermore, a mechanistic study identified several byproducts
originating from the DMSO and supported its catalytic role in the
above transformation.
4. Experimental
4.1. General
Cl_
HCl
Cl_
O
S
OH
S+
Cl
S+
HCl
S
_
H2O
Cl2
H2O
R
R
R
R
R
R
R
R
Solvents DCM, MeCN and THF were freshly distilled from CaH2
under argon. DMSO was dried with neutral alumina, refluxed with
CaH2 and then redistilled under vacuum and stored over 4 Å mo-
lecular sieves under argon. Reactions were protected from atmo-
spheric moisture by CaCl2 drying tubes. Anhydrous Na2SO4 was
used for drying organic extracts, and all volatiles were removed
under reduced pressure. All reaction mixtures and column eluents
were monitored by TLC using commercial glass backed thin layer
chromatography (TLC) plates (Merck Kieselgel 60 F254). The plates
were observed under UV light at 254 and 365 nm. The technique of
dry flash chromatography was used throughout for all non-TLC
scale chromatographic separations using Merck Silica Gel 60 (less
than 0.063 mm). Melting points were determined using a Poly-
Therm-A, Wagner & Munz, Koefler-Hotstage Microscope apparatus.
Decomposition points (decomp.) and mp >250 ꢀC were determined
using a TA Instruments DSC Q1000 with samples hermetically
sealed in aluminium pans under an argon atmosphere; using
heating rates of 5 ꢀC/min. Solvents used for recrystallization are
indicated after the melting point. UV spectra were obtained using
a Perkin-Elmer Lambda-25 UV/vis spectrophotometer and in-
flections are identified by the abbreviation ‘inf’. IR spectra were
recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer with
a Pike Miracle Ge ATR accessory and strong, medium and weak
peaks are represented by s, m and w respectively. 1H and 13C NMR
spectra were recorded on a Bruker Avance 300 machine (at 300 and
75 MHz, respectively). Deuterated solvents were used for
Scheme 2.
When Appel salt 2 was treated with only catalytic quantities of
either sulfoxide the reaction mixtures gave interesting results. The
use of diphenylsulfoxide 11 (10 mol %) gave no recovery of sulfoxide,
but afforded the diphenylsulfide 13 (R¼Ph) in 98% and the dithia-
zolone 1 in 70% yield. The use of less diphenylsulfoxide 11 (1 mol %)
gave yields of dithiazolone 1 (56%) and thiazol-5-one 4 (8%) similar
to the control experiment which had only water (1 equiv) and no
sulfoxide. By comparison the use of methylphenylsulfoxide
(10 mol %) led to a good yield of dithiazolone 1 (80%) and a good
recovery of methylphenylsulfoxide 12 (70%) indicating that the
catalytic cycle was still active. With methylphenylsulfoxide 12
(1 mol %) no sulfoxide was recovered despite the reasonable re-
covery of dithiazolone 1 (70%). Since the formation of sulfides 13 in
the reaction mixture can be considered byproducts originating from
side reactions competing with the catalytic cycle, it can be deduced
that the catalytic cycle involving the diphenylsulfoxide 11 was less
efficient than that of the methylphenylsulfoxide 12 which inturn
was less efficient than that of DMSO. Presumably the phenyl groups
introduce steric crowding around the sulfur atom which favours the
chloride promoted dechlorination of the chlorosulfonium to afford
the sterically less demanding sulfide. Furthermore, the reaction of
the diphenylsulfoxide 11 showed that the
methyl sulfoxides were not necessary for the reaction to occur.
a-hydrogens in the

6858
A.S. Kalogirou, P.A. Koutentis / Tetrahedron 65 (2009) 6855–6858
homonuclear lock and the signals are referenced to the deuterated
solvent peaks. Low resolution (EI) mass spectra were recorded on
a Shimadzu Q2010 GCMS with direct inlet probe. 4,5-Dichloro-
1,2,3-dithiazolium chloride 2,5 was prepared according to the lit-
erature procedure.
sample. A final elution (DCM–tBuOMe, 4:1) gave recovered diphe-
nylsulfoxide 11 (421.8 mg, 87%) as a colourless solid, mp 67–68 ꢀC
(lit.,17 70.5 ꢀC) (hexane) identical to an authentic sample.
Acknowledgements
4.2. Reactions of Appel salt 2 with DMSO: typical procedure
(see Table 1)
The authors wish to thank the Cyprus Research Promotion
Foundation [Grant No. NEAYPODOMH/NEKYP/0308/02] and the
following organisations in Cyprus for generous donations of
chemicals and glassware: the State General Laboratory, the Agri-
cultural Research Institute and the Ministry of Agriculture. Fur-
thermore we thank the A.G. Leventis Foundation for helping to
establish the NMR facility in the University of Cyprus.
To a stirred solution of 4,5-dichloro-1,2,3-dithiazolium chloride
2 (500 mg, 2.40 mmol) in dry DCM (25 mL) at ca. 20 ꢀC, H2O (43
m
L,
2.40 mmol) and then DMSO (1.7
mL, 2.40 mmol) were added. After
4.5 h no 4,5-dichloro-1,2,3-dithiazolium chloride 2 remained. The
reaction mixture was adsorbed onto silica and chromatography
(hexane–DCM, 2:1) gave 4-chloro-5H-1,2,3-dithiazol-5-one
1
(319.5 mg, 87%) as pale yellow plates, mp 35–36 ꢀC (lit.,5 39 ꢀC)
(from pentane) identical to an authentic sample.
References and notes
1. Joseph, R. W.; Antes, D. L.; Osei-Gyimah, P. U.S. Patent 5,688,744, 1997.
2. Kim, K. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120, 229.
3. Park, Y. S.; Kim, K. Tetrahedron Lett. 1999, 40, 6439.
4. Chang, Y.-G.; Lee, H.-S.; Kim, K. Tetrahedron Lett. 2001, 42, 8197.
5. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118, 1632.
6. Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W.; Torroba, T.; White, A. J. P.;
Williams, D. J. J. Chem. Soc., Perkin Trans. 1 1999, 2243.
7. Rakitin, O. A. (eds. in Chief: Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor,
R. J. K.). In Comprehensive Heterocyclic Chemistry III; Zhdankin, V. V., Ed.; Elsevier:
Oxford, 2008; Vol. 6, chapter 6.01, p 1; Konstantinova, L. S.; Rakitin, O. A. Russ.
Chem. Rev. 2008, 77, 521; Kim, K. Sulfur Rep. 1998, 21, 147.
8. Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 2000, 1081.
9. Findlay, J. B. C.; Fickwick, C. W. G.; Kersey, I. D.; Ward, P. Tetrahedron Lett. 1995,
36, 2299.
10. Fenselau, A.; Moffatt, J. J. Am. Chem. Soc. 1966, 88, 1762.
11. Warthmann, W.; Schmidt, A. Chem. Ber. 1975, 108, 520.
12. Bordwell, F. G.; Pitt, B. M. J. Am. Chem. Soc. 1955, 77, 572.
13. Smythe, J. J. Chem. Soc. 1909, 349.
14. Chasar, D. W.; Pratt, T. M.; Shockcor, J. P. Phosphorus, Sulfur Silicon Relat. Elem.
1980, 8, 183; Madesclaire, M. Tetrahedron 1988, 44, 6537.
15. Gauvreau, J. R.; Poignant, S.; Martin, G. J. Tetrahedron Lett. 1980, 21, 1319.
16. Rees, C. W.; Sivadasan, S.; White, A. J. P.; Williams, D. J. J. Chem. Soc., Perkin Trans.
1 2002, 1535.
4.3. Reactions of Appel salt 2 with diphenyl or
methylphenylsulfoxides 11 and 12: typical
procedure (see Table 2)
To a stirred solution of 4,5-dichloro-1,2,3-dithiazolium chloride
2 (500 mg, 2.40 mmol) in dry MeCN (25 mL) at ca. 20 ꢀC, H2O
(43 mL, 2.40 mmol) and then diphenylsulfoxide 11 (484.8 mg,
2.40 mmol) were added. After 1 h no 4,5-dichloro-1,2,3-dithiazo-
lium chloride 2 remained. The reaction mixture was adsorbed onto
silica and chromatography (hexane–DCM, 8:1) gave diphenyl-
sulfide (49.1 mg, 11%) as an oil identical with an authentic sample,
and further elution (hexane–DCM, 2:1) gave 4-chloro-5H-1,2,3-
dithiazol-5-one 1 (319.5 mg, 87%) as pale yellow plates, mp 35–
36 ꢀC (lit.,5 39 ꢀC) (from pentane) identical to that reported above.
Further elution (hexane–DCM, 2:3) gave (4E)-4-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-4,5-dihydro-5-oxothiazole-2-carbonitrile
(3.1 mg, 2%) as dark red crystals, mp (DSC onset) 220 ꢀC (decomp.)
[lit.,16 252–254 ꢀC (from cyclohexane)] identical to an authentic
4
17. Colby, C. E.; McLoughlin, C. S. Chem. Ber. 1887, 20, 195.