Synthesis of S -(2-thioxo-1,3-dithiolan-4-yl)methyl dialkylcarbamothioate and S -thiiran-2-ylmethyl dialkylcarbamothioate via intermolecular O-S rearrangement in water

Article abstract of DOI:10.1021/ol2005825

Chemical equations presented. A facile synthesis of S-(2-thioxo-1,3- dithiolan-4-yl)methyl dialkylcarbamothioates (3) and S-thiiran-2-ylmethyl dialkylcarbamothioate (5) has been reported by the reaction of 5-(chloromethyl)-1,3-oxathiolane-2-thione (1) wit

Full text of DOI:10.1021/ol2005825

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2330–2333
Synthesis of S-(2-Thioxo-1,3-dithiolan-4-yl)-
methyl Dialkylcarbamothioate and
S-Thiiran-2-ylmethyl Dialkylcarbamothioate
via Intermolecular OꢀS Rearrangement in
Water†,‡
Nand Lal, Lalit Kumar, Amit Sarswat, Santosh Jangir, and Vishnu Lal Sharma*
Medicinal & Process Chemistry Division, Central Drug Research Institute (CSIR),
Lucknow-226001, India
vlscdri@gmail.com
Received March 4, 2011
ABSTRACT
A facile synthesis of S-(2-thioxo-1,3-dithiolan-4-yl)methyl dialkylcarbamothioates (3) and S-thiiran-2-ylmethyl dialkylcarbamothioate (5) has been
reported by the reaction of 5-(chloromethyl)-1,3-oxathiolane-2-thione (1) with sodium dialkylcarbamodithioate (2) and dialkylamine (4),
respectively, through intermolecular OꢀS rearrangement in water. A plausible mechanism of formation of the title compounds has also been
proposed.
Organosulfur compounds are important intermediates
for the synthesis of various biologically active molecules.1
Thiocarbamates, a class of organosulfur compounds are of
great interest as these exhibit anesthetic,2 fungicidal,3
spermicidal,4 pesticidal,5 and anti-HIV activities.6 In addi-
tion, these compounds are well-known for their use as
commercial herbicides.7 Organic trithiocarbonates have
receivedmuchattentionbecauseof their various industrial,
synthetic, and medicinal applications.8
(6) (a) Spallarossa, A.; Cesarini, S.; Ranise, A.; Bruno, O.; Schenone,
S.; La Colla, P.; Collu, G.; Sanna, G.; Secci, B.; Loddo., R. Eur. J. Med.
Chem. 2009, 44, 2190–2201. (b) Ranise, A.; Spallarossa, A.; Cesarini, S.;
Bondavalli, F.; La Colla, P.; Loddo, R. J. Med. Chem. 2005, 48, 3858–
3873.
† CDRI Communication no. 8039.
‡ Dedicated to the International Year of Chemistry 2011.
(7) Chen, Y. S.; Schuphan, I.; Casida, J. E. J. Agric. Food Chem. 1979,
27, 709–712.
(1) (a) Brooks, G. T. Sulphur Containing Drugs and Related Organic
Compounds: Chemistry, Biochemistry, and Toxicology; Damani, L. A.,
Ed.; Chichester: Ellis Horwood, 1989; Vol. 1, Part A, p 62. (b) Brillon, D.
Sulfur Rep. 1992, 12, 297–332.
(2) Wood, T. F.; Gardner, J. H. J. Am. Chem. Soc. 1941, 63, 2741–
2742.
(3) Erian, A. W.; Sherif, S. M. Tetrahedron 1999, 55, 7957–8024.
(4) (a) Kumar, L.; Sarswat, A.; Lal, N.; Jain, A.; Maikhuri, J. P.;
Shukla, P. K.; Gupta, G.; Sharma, V. L. Eur. J. Med. Chem. 2010, 45,
817–824. (b) Kiran Kumar, S. T. V. S.; Kumar, L; Sharma, V. L.; Jain,
A.; Jain, R. K; Maikhuri, J. P.; Kumar, M.; Shukla, P. K.; Gupta, G.
Eur. J. Med. Chem. 2008, 43, 2247–2256. (c) Dwivedi, A. K.; Sharma,
V. L.; Kumaria, N.; Kiran Kumar, S. T. V. S.; Srivastava, P. K.; Ansari,
A. H.; Maikhuri, J. P.; Gupta, G. Bioorg. Med. Chem. 2007, 15, 6642–
6648.
(8) (a) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 252, 201–
236. (b) Ishii, A.; Nakayama, J. Top. Curr. Chem. 2005, 251, 181–225.
(c) Miller, J. D.; Li, J.; Davidtz, J. C.; Vos, F. Miner. Eng. 2005, 18, 855–865.
(d) Gulea, M.; Masson, S. Top. Curr. Chem. 2004,250, 257–293. (e) Chander,
S. Int. J. Min. Process 2003, 72, 141–150. (f) Jesberger, M.; Davis, T. P.;
Barner, L. Synthesis 2003, 1929–1958. (g) Chirumamilla, R. R.; Marchant,
R.; Nigam, P. J. Chem. Technol. Biotechnol. 2001, 76, 123–127. (h) Zhang,
Y.; Talalay, P. Cancer Res. 1994, 54, 1976–1981.
(9) (a) Dehmel, F.; Ciossek, T.; Maier, T.; Weinbrenner, S.; Schmidt,
B.; Zoche, M.; Beckers, T. Bioorg. Med. Chem. Lett. 2007, 17, 4746–
4752. (b) Wegener, D.; Wirsching, F.; Riester, D.; Schwienhorst, A.
Chem. Biol. 2003, 10, 61–70.
(10) Amarnath, J. V.; Amarnath, K.; Valentine, H.; Valentine, W. M.
Toxicol. Sci. 2003, 76, 65–74.
(5) (a) Chen-Hsien, W. Synthesis 1981, 622–623. (b) Spallarossa, A.;
Cesarini, S.; Ranise, A.; Bruno, O.; Schenone, S.; La Colla, P.; Collu, G.;
Sanna, G.; Secci, B.; Loddo., R. Eur. J. Med. Chem. 2009, 44, 1650–1663.
(11) (a) Metzer, P. Pure Appl. Chem. 1996, 68, 863–868. (b) Anisuzzaman,
A. K. M.; Owen, L. N. Chem. Commun. 1996, 16–17. (c) Erima, S.; Pradhan,
N. Compt. Rend. Chem. 2003, 6, 1035–1045.
r
10.1021/ol2005825
Published on Web 04/01/2011
2011 American Chemical Society

These compounds have extensively been used as
pharmaceuticals,9 agrochemicals,10 and intermediates8a,11
forthepreparation of acyclicand cycliccompoundshaving
two sulfur-containing functional groups on adjacent car-
bon atoms.12 There are several publications illustrating
intramolecular or intermolecular oxygen sulfur exchange.13
In our ongoing efforts4 to develop dually active vaginal
microbicides, we attempted to hybridize a spermicidal
pharmacophore dithiocarbamate4,14 and microbicidal moiety
thiocarbonates.15
pursue the rearrangement chemistry illustrated in scheme 1.
In this paper, a new route toward the synthesis of S-(2-
thioxo-1,3-dithiolan-4-yl)methyl dialkylcarbamothioates (3)
and S-thiiran-2-ylmethyl-dialkylcarbamothioate (5) utilizing
5-(chloromethyl)-1,3-oxathiolane-2-thione (1)18 is reported
where 1 has been used for the first time as the starting
material.
To explore the versality of the reaction (Scheme 1), the
reaction of 1 with various sodium dialkylcarbamodithio-
ates (2) was studied. The reaction of sodium 4-methylpi-
perazine-1-carbodithioate (2a) with 1 was chosen as model
reaction for optimization (Table 1). This model reaction
was carried out in different solvents at room temperature
as well as at reflux temperature. The duration of reaction
and the isolated yields were observed. There was no
progress in the reactions after hours at room temperature,
while at reflux the reactions were completed at different
time periods. Significant rate enhancement was observed
in water compared to organic solvents (Table 1). This
acceleration is probably due to factors such as hydropho-
bic effect,19 enhanced hydrogen bonding in the transition
state,20 etc.
Scheme 1. Reactions of 5-(chloromethyl)-1,3-oxathiolane-2-
thione (1) with (2a) and (4a)
In a logical extension of our initial study, it was envi-
saged that the reaction of sodium 4-methylpiperazine-1-
carbodithioate (2a) with 5-(chloromethyl)-1,3-oxathio-
lane-2-thione (1) would give rise to S-(2-thioxo-1,3-ox-
athiolan-5-yl)methyl 4-methylpiperazine-1-carbodithioate
(6, Scheme 1). However, contrary to our expectation, the
desired compound 6 was not obtained, and surprisingly,
the major product was found to be S-(2-thioxo-1,3-dithio-
lan-4-yl)methyl 4-methylpiperazine-1-carbothioate (3b),
isolated in 96% yield. The structural elucidation of com-
pound 3b revealed that oxygenꢀsulfur exchange between
dithiocarbamate (2a) and cyclic dithiocarbonate (1) had
occurred. Moreover, to study the course of the reaction,
efforts were made to replace the chlorine atom of 1 with N-
methylpiperazine (4a). The results obtained were again
unusual as S-thiiran-2-ylmethyl 4-methylpiperazine-1-car-
bothioate (5b) was formed instead of 7 (Scheme 1). How-
ever, it is interesting to note that an alkyl (other than
chloromethyl)-substituted 1,3-oxathiolane-2-thione re-
acted with amines to undergo ring-opening reaction and
to obtain thiourethanes having thiol moiety.16 There seems
to be no direct precedent for this rearrangement, although
there is some resemblance17 provided the motivation to
Table 1. Reaction of 1 with Sodium 4-Methylpiperazine-1-
Carbodithioate (2a)a
entry
solventb
time (h)
yieldc (%) of 3b
1
2
3
4
5
6
7
methanol
THF
2
8
70
67
62
72
80
77
96
ethyl acetate
acetonitrile
chloroform
DCM
9
6.5
7
10
1
water
a 1.2 equiv. b Reaction carried out at reflux temperatures. c Isolated
yields.
The structure of 3b was elucidated by IR, 1H NMR, and
13C NMR spectra. In the IR spectrum, a strong peak was
observed at 1650 cmꢀ1 for CdO, while in the 13C NMR
spectrum, there was no chemical shift for Nꢀ(CdS)ꢀS (δ
192ꢀ195)4 and Oꢀ(CdS)ꢀS (δ 210)16 while there were
chemical shifts at δ 165.2 [Nꢀ(CdO)ꢀS] and δ 226.6
[Sꢀ(CdS)ꢀS]21 that justified the presence of thiocarba-
mate and trithiocarbonate groups in 3b. Thus, the unusual
product was presumably formed via oxygen sulfur swap
over between 1 and 2a. In addition, the aliquots obtained
during the reaction exhibited m/z 185 (Mþ þ 1) in the
ESIꢀMS spectrum, which revealed the intermittent for-
mation of intermediate IV (Scheme 2).
(12) Corey, E. J.; Mitra, R. B. J. Am. Chem. Soc. 1962, 84, 2938.
(13) (a) Burns, M.; Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. J.
Org. Chem. 2010, 75, 6347–6353. (b) Kalicki, P.; Karchier, M.; Michalak,
K.; Wicha, J. J. Org. Chem. 2010, 75, 5388–5391. (c) Doyle, W. C., Jr. US
Patent 3 728 371, 1973; Chem. Abstr. 1973, 79, 5246. (d) Rollin, P.
Tetrahedron Lett. 1986, 27, 4169.
(18) Halimehjani, A. Z.; Ebrahimi, F.; Azizi, N.; Saidi, M. R. J.
Heterocycl. Chem. 2009, 46, 347–350.
(14) Tripathi, R. P.; Khan, A. R.; Setty, B. S.; Bhaduri, A. P. Acta
Pharm. 1996, 46, 169–176.
(19) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159–164. (b) Otto, S.;
Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 1, 2809–2820.
(20) Chandrasekhar, J.; Shariffskul, S.; Jorgensen, W. L. J. Phys.
Chem. B 2002, 106, 8078–8085.
(21) Clegg, W.; Harrington, R. W.; North, M.; Villuendas, P. J. Org.
Chem. 2010, 75, 6201–6207.
(15) (a) Overberger, C. G.; Drucker, A. J. Org. Chem. 1964, 29, 360.
(b) Yasuda, N.; Yatami, T.; Ohnuki, T.; Okutsu, M. J. Heterocycl.
Chem. 1984, 21, 1845.
(16) (a) Choi, W.; Sanda, F.; Endo, T. J. Polym. Sci., Part A: Polym.
Chem. 1998, 36, 1189–1195. (b) Choi, W.; Nakajima, M.; Sanda, F.;
Endo, T. Macromol. Chem. Phys. 1998, 199, 1909–1915.
(17) Kiran Kumar, S. T. V. S; Sharma, V. L.; Dwivedi, A. K. J.
Heterocycl. Chem. 2006, 43, 001–005.
(22) Guseinova, A. T.; Rzaeva, I. A.; Alieva, K. I.; Aliev, I. A.;
Allakhverdiev, M. A. Russ. J. Appl. Chem. 2009, 82, 2151–2155.
Org. Lett., Vol. 13, No. 9, 2011
2331

Scheme 2. Plausible Mechanism of the Reaction of 1 with 2
Figure 1. 1H NMR (in parentheses) and 13C NMR values (A)
and 13C to 1H HMBC (B) of 3c in CDCl3.
correlated with protons at δ 3.41 and 4.50, respectively (B,
Figure 1).The generality and scope of this rearrangement
was established by several additional examples (Table 2).
The plausible mechanism (Scheme 2) was proposed on
the basis of previous analogy17 and the detection of the
formation of intermediate IV and a peak at m/z 16 more
than the molecular weight of 3b in ESI-MS. It involves the
initial nucleophilic attack of dithiocarbamates ion (2a) on
CdS of 1 resulting in the intermediate IV via IIꢀIIc, which
finally gave rearranged product (3b) by straightforward
nucleophilic substittution of chloride ion from IV with
thiocarbamate ion (V).
It was further supported by the observation of molecular
ion peak at m/z 325 (Mþ þ 16), when 2a was taken in
excess.
The structure of the products (Table 2) was confirmed
by2DNMR (COSY, HMBC, and HSQC) spectroscopy of
1
3c. In the 1Hꢀ H COSY spectrum, there was a correlation
between C-4 proton at δ 4.50 and the protons at C-3 (δ 3.87,
4.13) as well as with protons at C-6 (δ 3.41) (A, Figure 1). In
the HMBC spectrum, C-1 (δ 226.5) correlated with pro-
tons present at δ 3.87, 4.13, and 4.50. In addition, C-8 (δ
165.8) associated with the protons at δ 3.41 and 3.68. C-4
(δ 59.7) was found to correlate with the protons having
chemical shifts δ 3.41, 3.87, and 4.13 while C-3 (δ 33.0)
To further extend this rearrangement, 1 was reacted with
secondary amine (2a without SdCꢀSꢀ). Thus, treatment
of N-methylpiperazine (4a, 1.2 equiv) with 1 unexpectedly
gave 5b in quantitative yield instead of the usual chlorine-
substituted product 7 apparently via the oxygenꢀsulfur
exchange (Scheme 1). The reaction occurred in ethyl
acetate and methanol as well. All of the synthesized
compounds through this route (Table 3) have been struc-
Table 2. Synthesis of S-(2-Thioxo-1,3-dithiolan-4-yl)methyl
Dialkylcarbamothioatesa
1
turally confirmed by H NMR, 13C NMR, MS, and IR
spectroscopy. The results are also reported in our previous
publication17 to synthesize S-thiiran-2-ylmethyl dialkyl-
carbamothioate by means of a different course (Scheme 3).
Scheme 3. Synthesis of S-Thiiran-2-ylmethyl-4-methylpipera-
zine-1-carbothioate (5b)
As shown in Scheme 4, the mechanism may be proposed
on the basis of product obtained. The dialkyl amine (4)
participates in nucleophilic attack to open the 1,3-oxathio-
lane-2-thione ring (1) and to give the intermediate (IIIb),
which further cleaves in to IVa and IVb by means of
oxygen sulfur rearrangement. Finally, S-thiiran-2-yl-
methyl-dialkylcarbamothioate (5) yields by way of simple
nucleophilic substitution.
a All reactions were carried out at 100 °C in water. b Isolated yields.
Conclusively, two new routes (Scheme 1) for the synthesis of
S-(2-thioxo-1,3-dithiolan-4-yl)methyl dialkylcarbamothioate
2332
Org. Lett., Vol. 13, No. 9, 2011

Table 3. Synthesis of S-Thiiran-2-ylmethyl Dialkylcarba-
mothioate
Scheme 4. Mechanistic Pathway of the Reaction of 1 with 4
for the first time, are described as passing through a remark-
able rearrangement. To the best of our knowledge, the so-
called products derived from Scheme 1 (Table 2) have not
been documented in the literature to date. The study may
facilitate the synthesis of structural analogues of 3 and 5 and
further biological evaluation.
Acknowledgment. We gratefully acknowledge the tech-
nical assistance received from Mrs. Tara Rawat, Technical
Officer, CDRI, Lucknow and Research Fellowships from
the University Grants Commission (N.L. and L.K.) and
Council of Scientific and Industrial Research (A.S. and S.J.).
Staff members of SAIF Division, CDRI, Lucknow, are
acknowledged for providing the spectral data. This study
was partly supported by a grant from the Ministry of
Health and Family Welfare, Government of India.
a Isolated yield. b Values in parentheses indicate reported % yield.
Supporting Information Available. Spectral data of all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(3) and S-thiiran-2-ylmethyl dialkylcarbamothioate (5) using
5-(chloromethyl)-1,3-oxathiolane-2-thione (1) as a reactant
Org. Lett., Vol. 13, No. 9, 2011
2333