An efficient, one-pot synthesis of trithiocarbonates from the corresponding thiols using the Mitsunobu reagent

Article abstract of DOI:10.1016/j.tetlet.2008.06.001

A novel Mitsunobu-based protocol has been developed for the synthesis of a variety of symmetrical and unsymmetrical trithiocarbonates from primary, secondary and tertiary thiols using carbon disulfide, in good to excellent yields. This protocol is mild and efficient compared to other reported methods.

Full text of DOI:10.1016/j.tetlet.2008.06.001

Tetrahedron Letters 49 (2008) 4886–4888
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An efficient, one-pot synthesis of trithiocarbonates from the corresponding
thiols using the Mitsunobu reagent
b
b
b
Devdutt Chaturvedi a, , Amit K. Chaturvedi , Nisha Mishra , Virendra Mishra
*
a Bio-Organic Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi 180 001, J&K, India
b Synthetic Research Laboratory, Department of Chemistry, B.S.A.P.G. College, Mathura 281 004, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel Mitsunobu-based protocol has been developed for the synthesis of a variety of symmetrical and
unsymmetrical trithiocarbonates from primary, secondary and tertiary thiols using carbon disulfide, in
good to excellent yields. This protocol is mild and efficient compared to other reported methods.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 April 2008
Revised 28 May 2008
Accepted 2 June 2008
Available online 5 June 2008
Keywords:
Mitsunobu reagent
Carbon disulfide
Thiols
Trithiocarbonates
Organic trithiocarbonates have received much attention due to
their numerous industrial, synthetic and medicinal applications.1
They have been used extensively as pharmaceuticals,2 agrochemi-
cals,3 intermediates in organic synthesis,4 for protection of thiol
functionality,5 in free radical polymerization reactions,6 as lubri-
cating additives,7 in material science,8 in froth flotation9 for the
recovery of minerals from their ores and for their absorption prop-
erties of the metals.10 Moreover, they are useful synthons for the
preparation of various compounds such as sulfines,11 ketenes,12 tri-
thiocarbonate-S-oxides,13 thiols,14 dithiocarboxylate derivatives,15
thioacetates,16 olefins,17 nitro 1,3-benzodithiole-2-thiones,18 phos-
phite ylides19 and in various C–C bond forming reactions20 which
necessitates their preparation through convenient and safe
methods.
The classical synthesis of trithiocarbonates involves reaction of
thiols with thiophosgene21 or its derivatives.22 These methods
have several drawbacks such as the use of costly, toxic and corro-
sive reagents. Alternative routes for their synthesis involve reac-
tion of metal xanthates with epoxides,23 or episulfides,24 the
reaction of sodium trithiocarbonates with organic dihalides,25 or
epoxides,26 reaction of CS2 with alkyl halides using KOH,27 reaction
of alkyl halides with the hydroxide form of an anion exchange
resin,28 and by S-arylation of potassium carbonotrithiolates with
diaryliodonium salts.29 The application of a phase transfer catalyst
has had an enormous impact on the synthesis of this class of
compounds30 but the method requires strongly basic conditions.
Recently, a method for the synthesis of trithiocarbonates was
reported using a Cs2CO3/CS2 system.31 Most of these methods
suffer from limitations such as long reaction times, use of
expensive strongly basic reagents, tedious work-up and low yields.
Consequently, there is continued interest in developing new and
convenient methods for the synthesis of trithiocarbonates under
mild reaction conditions.
Our group32 has been engaged over several years on the devel-
opment of new, efficient and safer protocols for the synthesis of
carbamates, dithiocarbamates and dithiocarbonates (xanthates)
using cheap and readily available reagents such as CO2 and CS2.
Recently, we reported33 the synthesis of carbamates, dithiocarba-
mates, carbonates, O,S-dialkyl dithiocarbonates (xanthates) and
S-alkyl carbamates from a variety of starting materials using the
Mitsunobu reagent. We report herein a chemoselective, highly
efficient and mild synthesis of symmetrical and unsymmetrical
trithiocarbonates from various primary, secondary and tertiary
thiols using the Mitsunobu reagent. Thus, we carried out34 the syn-
thesis of trithiocarbonates by mild thiocarbonation of thiols with
carbon disulfide using the Mitsunobu reagent at room tempera-
ture. To the best of our knowledge, this is the first report on an effi-
cient and mild synthesis of symmetrical and unsymmetrical
trithiocarbonates from the corresponding thiols using Mitsunobu’s
reagent (Table 1).
We assume that the unstable thiocarbonic acid 1 generated
from the reaction of a thiol with carbon disulfide, reacts with the
Mitsunobu zwitterion 2 formed from reaction of Ph3P and diethyl
azadicarboxylate, to furnish the unstable ionic species 3 which in
turn undergoes rearrangement to form a more stabilized ionic
* Corresponding author. Tel.: +91 191 2569000–10x210.
E-mail address: ddchaturvedi002@yahoo.co.in (D. Chaturvedi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.001

D. Chaturvedi et al. / Tetrahedron Letters 49 (2008) 4886–4888
4887
Table 1
Conversion of various thiols into trithiocarbonates of general formula Ia
Entry
R1
R2
R3
R4
R5
R6
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Phenyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Phenyl
n-Hexyl
n-Propyl
n-Octyl
Cyclohexyl
n-Butyl
Phenyl
4-Methoxyphenyl
n-Octyl
n-Dodecyl
Phenyl
Benzyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3
3
4
2
3
3
3
3
2
3
3
2
2
2
3
3
2
82
93
85
91
84
82
80
83
81
83
78
82
88
98
90
80
90
2-Phenethyl
2-Phenethyl
n-Propyl
i-Amyl
n-Butyl
2-Naphthyloxyethyl
2-Naphthyloxyethyl
n-Butyl
n-Butyl
n-Hexyl
n-Heptyl
n-Octyl
n-Heptyl
n-Pentyl
2-Naphthyloxyethyl
3-(2-Naphthyloxy)prop-1-yl
n-Propyl
H
H
H
H
H
H
H
H
H
H
H
n-Butyl
n-Butyl
H
H
H
H
Methyl
H
H
H
n-Butyl
H
H
H
H
H
H
H
3-Methoxybenzyl
n-Dodecyl
Cyclohexyl
n-Butyl
H
n-Butyl
H
n-Butyl
H
n-Octyl
a
All the products were characterized from IR, NMR and mass spectral data.
Wirsching, F.; Riester, D.; Schwienhorst, A. Chem. Biol. 2003, 10, 61–70; (e)
O’Brian, J.; Wilson, I.; Orton, T.; Pognan, F. Eur. J. Biochem. 2000, 267, 5421–
5429.
S
R1
R4
R6
R1
R3
R4
R6
a
3. (a) Leysen, M.; Roybrouck, G.; Voorde, H. V. D. Allergy 1974, 29, 455–461; (b)
Knowels, C. O. Environ. Health Perspect. 1976, 14, 93–102; (c) Johnson, D.;
Amarnath, J. V.; Amarnath, K.; Valentine, H.; Valentine, W. M. Toxicol. Sci. 2003,
76, 65–74.
4. (a) Metzer, P. Pure Appl. Chem. 1996, 68, 863–868; (b) Quiclet-Sire, B.; Zard, S. Z.
Top. Curr. Chem. 2006, 252, 201–236; (c) Anisuzzaman, A. K. M.; Owen, L. N.
Chem. Commun. 1996, 16–17; (d) Erima, S.; Pradhan, N. Compt. Rend. Chem.
2003, 6, 1035–1045.
R2
S
R2
R5
SH
R5
S
SH
+
R3
I
Scheme 1. Reagents and conditions: (a) dry DMSO, DEAD/Ph3P, CS2, rt, 2–4 h.
5. Wuts, P. G. M.; Greene, T. W. Protecting Groups in Organic Synthesis; John Wiley
& Sons, 2006.
species 4. Nucleophilic attack of the sulfur atom of the other thiol
followed by intramolecular electronic rearrangement leads to the
formation of the trithiocarbonate of general formula I.
6. (a) Mayadunne, R. T. A.; Rizzardo, E.; Chiefari, J.; Kristina, J.; Moad, G.; Postama,
A.; Thang, S. H. Macromolecules 2000, 33, 243–245; (b) Lai, J. T.; Filla, D.; Shea, R.
Macromolecules 2002, 35, 6754–6756; (c) Duwez, A. S.; Guillet, P.; Colard, C.;
Gohy, J. F.; Fustin, C. A. Macromolecules 2006, 39, 2729–2731; (d) Wang, R.;
McCormick, C. L.; Lowe, A. B. Macromolecules 2005, 38, 9518–9525; (e)
Postama, A.; Davis, T. P.; Li, G.; Moad, G.; O’Shea, M. S. Macromolecules 2006,
39, 5307–5318.
7. (a) Ali, M. F.; Abbas, S. Fuel Process. Technol. 2006, 87, 573–584; (b) Anand, O. N.;
Kumar, V.; Singh, A. K.; Bist, R. P. S. Lubrication Sci. 2007, 19, 159–167; (c)
Degani, L.; Fochi, R.; Gatti, A.; Regondi, V. Synthesis 1986, 894–895.
8. (a) Choi, W.; Sanda, F.; Endo, T. Macromolecules 1998, 31, 2454; (b) Choi, W.;
Sanda, F.; Endo, T. Macromolecules 1998, 31, 9093; (c) Choi, W.; Sanda, F.; Endo,
T. Heterocycles 2000, 52, 125–132; (d) Nemoto, N.; Sanda, F.; Endo, T.
Macromolecules 2000, 33, 1737–7229.
Thus, various primary, secondary and tertiary thiols were
reacted with the Mitsunobu reagent/CS2 system to affords trithio-
carbonates in very good to excellent yields (78–98%) at room
temperature in 2–4 h. We have used solvents including DMSO,
DMF, benzene, acetonitrile, dichloromethane, hexane, heptane,
methanol, chloroform and acetone with dry DMSO proving to be
the most suitable for carrying out this transformation. The overall
reaction is shown in Scheme 1.
In conclusion, we have developed a convenient and efficient
protocol for the one-pot, three-component coupling of various
thiols with primary, secondary and tertiary thiols using the
Mitsunobu reagent/CS2 system. This reaction generates the corres-
ponding, trithiocarbonates in good to excellent yields at room
temperature. Furthermore, this method exhibits substrate versa-
tility, mild reaction conditions and experimental convenience.
9. (a) Harris, G. H. Kirk-Othmer Encyclopedia of Chem. Technol., 2000.; (b)
Yekeler, H.; Yekeler, M. Appl. Surf. Sci. 2004, 236, 435–443.
10. (a) Porento, M.; Hirra, P. Theor. Chim. Acta 2002, 107, 200–205; (b) Guo, Y. R.;
Pan, Q. J.; Fang, G. Z.; Liu, Z. M. Chem. Phys. Lett. 2005, 413, 59–64; (c)
Kipershlak, E. Z.; Pakshwer, A. B.; Kostikobe, E. B. Fibre Chem. 1978, 10, 156–
168; (d) Foye, W. O.; Marshall, J. R.; Mickles, J. J. Pharm. Sci. 2006, 52, 406–407;
(e) El-khateeb, M.; Roller, A. Polyhedron 2007, 26, 3920–3924.
11. Metzner, P. Pure Appl. Chem. 1996, 68, 863–868.
12. Leriverend, C.; Metzner, P.; Capperucci, A.; Degl’lnnocenti, A. Tetrahedron 1997,
53, 1323–1342.
13. El-Sayed, I.; Hilmy, K. M. H.; El-Kousy, S. M.; Fischer, A.; Slem, H. S. Phosphorus,
Sulfur Silicon 2003, 178, 2403–2413.
Acknowledgements
14. Martin, D. J.; Greco, C. C. J. Org. Chem. 1968, 33, 1275–1280.
15. Oliva, A.; Molinari, A.; Sanchez, L. Synth. Commun. 1998, 28, 3381–3386.
16. Jordis, U.; Rudolf, M. Phosphorus, Sulfur Silicon 1984, 19, 279–283.
17. Corey, E. J.; Carey, F. A.; Winter, R. A. E. J. Am. Chem. Soc. 1965, 87, 934–935.
18. Rasheed, K.; Warkentin, J. D. J. Org. Chem. 1980, 45, 4041–4044.
19. Corey, E. J.; Markl, G. Tetrahedron Lett. 1967, 8, 3201–3204.
20. Chandrasekharan, M.; Bhat, L.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1993, 34,
6439–6442.
The authors thank Dr. Nitya Anand for his fruitful suggestions
and the SIAF division of CDRI for providing spectroscopic and ana-
lytical data.
References and notes
1. (a) Gulea, M.; Masson, S. Top. Curr. Chem. 2004, 250, 257–293; (b) Ishii, A.;
Nakayama, J. Top. Curr. Chem. 2005, 251, 181–225; (c) Quiclet-Sire, B.; Zard, S. Z.
Top. Curr. Chem. 2006, 252, 201–236; (d) Chander, S. Int. J. Min. Process. 2003, 72,
141–150; (e) Miller, J. D.; Li, J.; Davidtz, J. C.; Vos, F. Miner. Eng. 2005, 18, 855–
865; (f) Zhang, Y.; Talalay, P. Cancer Res. 1994, 54, 1976–1981; (g)
Chirumamilla, R. R.; Marchant, R.; Nigam, P. J. Chem. Technol. Biotechnol.
2001, 76, 123–127; (h) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003,
1929–1958.
21. Duus, F. In Comprehensive Organic Chemistry; Barton, D., Ollis, W. D., Eds.;
Pergamon: New York, 1979; Vol. 3, p 432.
22. (a) Goldt, H. C.; Wanns, A. E. J. Org. Chem. 1961, 26, 4047–4052; (b) Blackman, L.
C. F.; Dewar, M. J. S. J. Chem. Soc. 1957, 157–165; (c) Runge, F.; El-Hewchi, Z.;
Renner, H. J.; Taeger, E. J. Prakt. Chem. 1959, 7, 279–283; (d) El-Hewchi, Z. J.
Prakt. Chem. 1962, 16, 201–206.
23. McCasland, G. E.; Zanglungo, A. B.; Durham, L. J. J. Org. Chem. 1976, 41, 1125–
1130.
2. (a) Foye, W. O.; Mickles, J.; Duvall, R. N.; Marshall, J. R. J. Med. Chem. 1963, 6,
509–512; (b) Kawamoto, I.; Endo, R.; Sugahara, S. J. Antibiot. 1986, 39, 1551–
1556; (c) Dehmel, F.; Ciossek, T.; Maier, T.; Weinbrenner, S.; Schmidt, B.; Zoche,
M.; Beckers, T. Bioorg. Med. Chem. Lett. 2007, 17, 4746–4752; (d) Wegener, D.;
24. Craighton, A. M.; Owen, L. N. J. Chem. Soc. 1960, 1024–1030.
25. (a) Frank, R. L.; Drake, S. S.; Smith, P. V.; Stevens, C. J. Polym. Sci. 1948, 2, 50–61;
(b) Reid, E. E. Organic Chemistry of Bivalent Sulfur; Chemical Publishing
Company: New York, 1958.

4888
D. Chaturvedi et al. / Tetrahedron Letters 49 (2008) 4886–4888
26. Saeed, M.; Abbas, M.; Abdel-Jalil, R. J.; Zahid, M.; Voelter, W. Tetrahedron Lett.
2003, 44, 315–317.
27. Leung, M. K.; Hsieh, D. T.; Lee, K. H.; Liou, J. C. J. Chem. Res. 1995, 478–480.
28. Tamami, B.; Kiasat, A. R. Iran. Polym. J. 1999, 8, 17–23.
29. Wang, F. Y.; Chen, Z. C.; Zheng, Q. G. J. Chem. Res. (S) 2003, 12, 810–811.
30. (a) Lee, A. W. M.; Chan, W.; Wong, H. C. Synth. Commun. 1988, 18, 1531–1535;
(b) Sugawara, A.; Shirahata, M.; Sato, S.; Sato, R. Bull. Chem. Soc. Jpn. 1984, 57,
3353–3358; (c) Sugawara, A.; Husegawa, K.; Suzuki, K. J.; Takahash, Y.; Saito, R.
Bull. Chem. Soc. Jpn. 1987, 60, 435–440; (d) Hurges, R.; Hoock, C. Angew. Chem.,
Int. Ed. 1992, 31, 1611–1616.
Chaturvedi, D.; Mishra, N.; Mishra, V. J. Sulfur Chem. 2007, 28, 607–612; (p)
Chaturvedi, D.; Mishra, N.; Mishra, V. Monatsh. Chem. 2008, 139, 267–270.
33. (a) Chaturvedi, D.; Kumar, A.; Ray, S. Tetrahedron Lett. 2003, 44, 7637–7639; (b)
Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2006, 47, 1307–1309; (c) Chaturvedi,
D.; Ray, S. Tetrahedron Lett. 2007, 48, 149–151; (d) Chaturvedi, D.; Mishra, N.;
Mishra, V. Tetrahedron Lett. 2007, 48, 5043–5045; (e) Chaturvedi, D.; Mishra,
N.; Mishra, V. Synthesis 2008, 355–357.
34. General experimental procedure:
Thiol (7.56 mmol) was taken in dry DMSO (25 ml) and CS2 (11.5 mmol) was
added and the reaction mixture was stirred at room temperature for 30 min.
31. Aoyagi, N.; Ochiai, B.; Mori, H.; Endo, T. Synlett 2006, 636–638.
32. For reviews see: (a) Chaturvedi, D.; Ray, S. Curr. Org. Chem. 2007, 11, 987–998;
(b) Chaturvedi, D.; Mishra, N.; Mishra, V. Curr. Org. Synth. 2007, 3, 308–320. For
our research work see: (c) Chaturvedi, D.; Kumar, A.; Ray, S. Synth. Commun.
2002, 32, 2651–2656; (d) Chaturvedi, D.; Ray, S. Lett. Org. Chem. 2005, 2, 742–
744; (e) Chaturvedi, D.; Ray, S. J. Sulfur Chem. 2005, 26, 365–371; (f) Chaturvedi,
D.; Ray, S. Monatsh. Chem. 2006, 137, 201–206; (g) Chaturvedi, D.; Ray, S.
Monatsh. Chem. 2006, 137, 311–317; (h) Chaturvedi, D.; Ray, S. Monatsh. Chem.
2006, 137, 459–463; (i) Chaturvedi, D.; Ray, S. Monatsh. Chem. 2006, 137, 465–
469; (j) Chaturvedi, D.; Ray, S. J. Sulfur Chem. 2006, 27, 265–271; (k)
Chaturvedi, D.; Ray, S. Monatsh. Chem. 2006, 137, 1219–1223; (l) Chaturvedi,
D.; Mishra, N.; Mishra, V. Chin. Chem. Lett. 2006, 17, 1309–1312; (m)
Chaturvedi, D.; Mishra, N.; Mishra, V. J. Sulfur Chem. 2007, 28, 39–44; (n)
Chaturvedi, D.; Mishra, N.; Mishra, V. Monatsh. Chem. 2007, 138, 57–60; (o)
To this,
a
mixture of triphenylphosphine (7.56 mmol) and diethyl
azodicarboxylate (7.56 mmol) was added slowly in 2–3 small portions. Next,
the corresponding thiol (7.56 mmol) was added with constant stirring at rt.
The reaction was continued until completion (cf. Table 1) as confirmed by TLC.
The reaction mixture was then poured into distilled water (50 ml) and
extracted with ethyl acetate thrice. The combined organic layer dried over
anhydrous sodium sulfate and then concentrated to afford the desired
trithiocarbonate.
Trithiocarbonic ester dibenzyl ester (entry 1)IR (neat): 1205 (C@S) cmÀ1 1H NMR
;
(400 MHz, CDCl3): d 4.62 (s, 4H, J = 7.2 Hz, PhCH2S), 7.24–7.35 (m, 10H, Ar-H)
ppm; 13C NMR (100 MHz, CDCl3): d 41.52 (Ph.CH2S), 127.51, 128.53, 129.62,
131.50, 140.10, 142.20 (aromatic region), 222.72 (C@S) ppm; Mass (EI): m/e (%)
290 (89); Anal. Calcd for C15H14S3: C, 62.02; H, 4.86; S, 33.12. Found: C, 62.34;
H, 5.02; S, 32.89.