An efficient, one-pot synthesis of S-alkyl thiocarbamates from the corresponding thiols using the Mitsunobu reagent

Article abstract of DOI:10.1055/s-2008-1032025

A novel Mitsunobu-based protocol has been developed for the synthesis of variety of S-alkyl thiocarbamates from the corresponding thiols and amines using gaseous carbon dioxide, in good to excellent yields. This protocol is mild and efficient compared to other reported methods. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032025

SHORT PAPER
355
An Efficient, One-Pot Synthesis of S-Alkyl Thiocarbamates from the
Corresponding Thiols Using the Mitsunobu Reagent
O
ne-PotSynthesis
e
of
S
-Alkyl
v
T
hiocarbam
d
a
tes utt Chaturvedi,*a Nisha Mishra,b Virendra Mishrab
a
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
E-mail: ddchaturvedi002@yahoo.co.in
b
Synthetic Research Lab, Department of Chemistry, B. S. A. P. G. College, Mathura 281 004, India
Received 20 September 2007; revised 1 November 2007
Our group19 has been engaged over several years in the
development of new and efficient protocols for the syn-
thesis of carbamates, dithiocarbamates and dithiocarbon-
ates (xanthates) using cheap and abundantly available
reagents such as carbon dioxide and carbon disulfide. Re-
cently, we reported20 the synthesis of carbamates, dithio-
carbamates, carbonates and O,S-dialkyl dithiocarbonates
(xanthates) from the corresponding alcohols using the
Mitsunobu reagent, diethyl azodicarboxylate (DEAD).
Based on our recent work,20 we report herein a chemose-
lective, highly efficient and mild synthesis of S-alkyl thio-
carbamates of primary, secondary and tertiary thiols using
the Mitsunobu reagent.
Abstract: A novel Mitsunobu-based protocol has been developed
for the synthesis of variety of S-alkyl thiocarbamates from the cor-
responding thiols and amines using gaseous carbon dioxide, in good
to excellent yields. This protocol is mild and efficient compared to
other reported methods.
Key words: thiols, carbon dioxide, Mitsunobu reagent, thiocar-
bamates
S-Alkyl thiocarbamates (S-alkylthiourethanes) constitute
an important and versatile class of compounds for a vari-
ety of industrial, synthetic and medicinal applications.1
They have been extensively used as pharmaceuticals,2
agrochemicals,3 intermediates in organic synthesis,4 for
the protection of amino groups in peptide chemistry5 and
as linkers in combinatorial chemistry.6 Despite the afore-
mentioned reasons, these compounds are most noted for
their use as commercial herbicides. Some of the potent
herbicides such as Thiobencarb,7 Orbencarb,8 EPTC9 and
Molinate10 are well-known examples. These compounds
require preparation by convenient and safe methodolo-
gies.
We carried out the synthesis of S-alkyl thiocarbamates by
mild thiocarbamation of amines with gaseous carbon di-
oxide using a variety of primary secondary and tertiary
thiols mediated by the Mitsunobu reagent at room temper-
ature. We assume that the unstable carbamic acid 1, gen-
erated from an amine with carbon dioxide, reacts with
zwitterion 2, formed from triphenylphosphine and
DEAD, to furnish the unstable ionic species 3 which, in
turn, would undergo a self rearrangement to form the
more stabilized ionic species 4. Nucleophilic attack of the
sulfur atom from the corresponding thiol, followed by in-
tramolecular electronic rearrangement leads to the forma-
tion of the thiocarbamate as shown in Scheme 1.
Classical synthesis of S-alkyl thiocarbamates involves a
two-step reaction using phosgene,11 its derivatives12 and
carbon monoxide.13 These methods are associated with
several drawbacks, such as the use of costly, toxic and
corrosive reagents. Many reports illustrate the intramolec-
ular rearrangement of various derivatives to afford S-alkyl
thiocarbamates, however, these rearrangements are ex-
tremely limited in starting substrates.14 Transition-metal
species containing elements such as palladium,15 nickel16
and rhodium17 have also been employed to promote rear-
rangement and product formation. There are a variety of
other methods, however, most require the preparation of
complex starting materials.18 Thus, 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 continuing interest in
the development of new and convenient methods for the
synthesis of S-alkyl thiocarbamates using mild reaction
conditions.
R1
O
C
R1
R2
R5
R5
R4
a
+
SH
HN
N
R4
S
R2
R3
R3
I
Scheme 1 Proposed mechanism of the formation of S-alkylthio-
carbamates
Thus, various primary and secondary amines were reacted
with a range of primary, secondary and teriary thiols using
the DEAD/CO2 system to afford the thiocarbamates in
very good to excellent yields (80–99%) at room tempera-
ture in two to four hours (Table 1). We examined many
solvents such as dimethyl sulfoxide, N,N-dimethylform-
amide, benzene, acetonitrile, dichloromethane, hexane,
heptane, methanol, chloroform and acetone, and found
that anhydrous dimethyl sulfoxide proved to be the most
suitable solvent for carrying out this transformation. The
overall reaction is shown in Scheme 2.
SYNTHESIS 2008, No. 3, pp 0355–0357
x
x
.
x
x
.2
0
0
8
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032025; Art ID: Z22607SS
© Georg Thieme Verlag Stuttgart · New York

356
D. Chaturvedi et al.
SHORT PAPER
O
R5
R4
R5
R4
CO2
1
+
NH
N
OH
COOEt
Ph3P
N
N
COOEt
2
3
Ph3P EtOOC N N COOEt
+
COOEt
H
Ph3P
N N COOEt
1 +
2
O
R5
R4
N
O
O
R1
COOEt
H
O
C
R5
R4
R5
R4
N
PPh3
N
N
COOEt
O
Ph3P=O
+
R2
R3
+
S
N
R1
4
SH
R2
S-alkyl
thiocarbamate
EtO2CNHNHCO2Et
R3
Scheme 2 Reagents and conditions: (a) DMSO (anhyd), DEAD, Ph3P, CO2, r.t., 2–4 h.
Table 1 Conversion of Thiols into S-Alkyl Thiocarbamates of General Formula Ia
Entry
1
R1
R2
H
R3
H
R4
R5
Time (h)
Isolated yield (%)
Ph
n-Pr
Et
n-Pr
3
96
99
98
99
99
94
96
85
80
94
85
96
98
90
86
92
93
99
2
4-MeOC6H4
4-ClC6H4
n-C5H11
n-C7H15
i-C5H11
H
H
Et
3
3
H
H
-(CH2)4-
n-Bu
Et
3
4
H
H
H
2.5
3
5
H
H
Et
6
H
H
-(CH2)5-
3
7
Ph
Me
n-Bu
n-Bu
H
H
-(CH2)2O(CH2)2-
4-MeOC6H4
n-C8H17
Bn
3.5
3.5
4
9
n-Bu
H
H
10
11
12
13
14
15
16
17
18
19
n-Bu
n-Bu
H
H
n-C6H13
n-C7H15
n-C8H17
n-C7H15
n-C5H11
(2-C10H7)OCH2CH2
(2-C10H7)OCH2CH2CH2
n-C6H13
n-C10H21
H
3
Me
H
H
n-C12H23
PhCH2CH2
n-Bu
H
3
H
H
2.5
2.5
4
H
H
n-Bu
H
Me
H
H
c-C6H11
n-C8H17
n-C12H23
Bn
H
H
3
H
H
H
2
Me
H
Me
H
H
4
c-C6H11
H
3
a All products were characterized by IR, NMR and mass spectral data.
In conclusion, we have developed a convenient and effi- more, this method exhibits substrate versatility, mild
cient protocol for one-pot, three-component coupling of a reaction conditions and experimental convenience. This
range of amines with primary, secondary and tertiary thi- synthetic protocol is believed to offer a more general
ols via a combination of DEAD and CO2. This reaction method for the formation of C–S and C–N bonds essential
generates the corresponding S-alkyl thiocarbonates in ex- to numerous organic syntheses.
cellent yields (80–99%) at room temperature. Further-
Synthesis 2008, No. 3, 355–357 © Thieme Stuttgart · New York

SHORT PAPER
One-Pot Synthesis of S-Alkyl Thiocarbamates
357
Chemicals were procured from Merck, Aldrich and Fluka chemical
companies. Reactions were carried out under an atmosphere of N2.
IR spectra were recorded on Bomem MB-104–FTIR spectropho-
tometer, and NMR spectra were obtained on an AC-300F instru-
ment [1H NMR (400 MHz), 13C NMR (100 MHz)], using CDCl3 as
solvent and TMS as internal standard. Mass spectra were recorded
using a Bruker Esquire 3000 spectrometer.
(2) (a) Goel, A.; Mazur, S. J.; Fattah, R. J.; Hartman, T. L.;
Turpin, J. A.; Huang, M.; Rice, W. G.; Appela, W.; Inman,
J. K. Bioorg. Med. Chem. Lett. 2002, 12, 767. (b) Wood, T.
F.; Gardner, J. H. J. Am. Chem. Soc. 1941, 63, 2741.
(3) Erian, A. W.; Sherif, S. M. Tetrahedron 1999, 55, 7957.
(4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(5) Benoiton, N. L. Chemistry of Peptide Synthesis; CRC Press:
Boca Raton, 2006.
General Procedure
Amine (7.56 mmol) was taken in anhydrous DMSO (25 mL) and
gaseous CO2 was bubbled through at r.t. for 30 min. To this, a mix-
ture of Ph3P (7.56 mmol) and DEAD (7.56 mmol) was added slowly
in 2–3 small portions. The corresponding thiol (7.56 mmol) was
then added at r.t. with constant stirring and the reaction was allowed
to continue until completion (Table 1; reaction monitored by TLC).
The reaction mixture was then poured into distilled H2O (50 mL)
and extracted with EtOAc (3 × 50 mL). The organic layer was sep-
arated and dried over anhydrous NaSO4 and then concentrated to af-
ford the desired S-alkylated thiocarbamate.
(6) Albericio, F. Peptide Science 2000, 55, 123.
(7) Sonoda, N.; Mizuno, T.; Murakami, S.; Kondo, K.; Ogawa,
A.; Ryu, I.; Kambe, N. Angew. Chem., Int. Ed. Engl. 1989,
28, 452.
(8) Mizuno, T.; Iwai, T.; Ito, T. Tetrahedron 2004, 60, 2869.
(9) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron 2005, 61, 9157.
(10) Uesugi, Y.; Ueji, M.; Koshioka, M. Pesticide Data Book, 3rd
ed.; Soft Science: Tokyo, 1997.
(11) Tilles, H. J. Am. Chem. Soc. 1959, 81, 714.
(12) Chin-Hsien, W. Synthesis 1981, 622.
(13) (a) Mizuno, T.; Nishiguchi, I.; Sonoda, N. Tetrahedron
1994, 50, 5669. (b) Mizuno, T.; Nishiguchi, I.; Okushi, T.;
Hirashima, T. Tetrahedron Lett. 1991, 32, 6867.
(14) (a) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410.
(b) Newmann, M. S.; Kareness, H. A. J. Org. Chem. 1966,
31, 3980. (c) Newmann, M. S.; Hetzel, F. W. J. Org. Chem.
1969, 34, 3604. (d) Hackler, R. E.; Balko, T. W. J. Org.
Chem. 1973, 38, 2106.
(15) Jones, W. D.; Reynolds, K. A.; Sperry, C. K.; Lachicotte, R.
J.; Godelski, S. A.; Valente, R. R. Organometallics 2000, 19,
1661.
(16) Jacob, J.; Reynolds, K. A.; Jones, W. D.; Goldeski, S. A.;
Valente, R. R. Organometallics 2001, 20, 1028.
(17) Kuniyashu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh,
K.; Kurosawa, H. J. Org. Chem. 1999, 64, 7305.
(18) (a) Ottmann, G.; Hooks, H. Jr. Angew. Chem. Int. Ed. 1966,
5, 250. (b) Batey, R. A.; Yoshina-Ishii, C.; Taylor, S. D.;
Santhkumar, V. Tetrahedron Lett. 1999, 40, 2669.
(c) Akiba, K. Y.; Inamoto, N. J. Chem. Soc., Chem.
Commun. 1973, 13.
(19) (a) Chaturvedi, D.; Kumar, A.; Ray, S. Synth. Commun.
2002, 32, 2651. (b) Chaturvedi, D.; Ray, S. Lett. Org. Chem.
2005, 2, 742. (c) Chaturvedi, D.; Ray, S. J. Sulfur Chem.
2005, 26, 365. (d) Chaturvedi, D.; Ray, S. Monatsh. Chem.
2006, 137, 201. (e) Chaturvedi, D.; Ray, S. Monatsh. Chem.
2006, 137, 311. (f) Chaturvedi, D.; Ray, S. Monatsh. Chem.
2006, 137, 459. (g) Chaturvedi, D.; Ray, S. Monatsh. Chem.
2006, 137, 465. (h) Chaturvedi, D.; Ray, S. J. Sulfur Chem.
2006, 27, 265. (i) Chaturvedi, D.; Ray, S. Monatsh. Chem.
2006, 137, 1219. (j) Chaturvedi, D.; Mishra, N.; Mishra, V.
Chin. Chem. Lett. 2006, 17, 1219. (k) Chaturvedi, D.;
Mishra, N.; Mishra, V. J. Sulfur Chem. 2007, 28, 39.
(l) Chaturvedi, D.; Mishra, N.; Mishra, V. Monatsh. Chem.
2007, 138, 57.
S-Benzyl N,N-Dipropylthiocarbamate (Entry 1)
Oil.
IR (neat): 2965, 1650, 1405, 1220, 1125 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7 Hz, 6 H), 1.60 (q,
J = 7 Hz, 4 H), 3.22 (br s, 2 H), 3.32 (br s, 2 H), 4.15 (s, 2 H), 7.22–
7.36 (m, 5 H, Ar-H).
13C NMR (100 MHz, CDCl3): d = 11.2, 21.6, 34.7, 49.3, 127.0,
128.5, 128.9, 138.3, 167.2.
MS (EI, 70 eV): m/z (%) = 251 (50), 128 (100), 92 (21), 91 (97), 86
(51).
HRMS (EI, 70 eV): m/z calcd for C14H21NOS: 251.1344; found:
251.1328.
S-(4-Methoxybenzyl) N,N-Diethylthiocarbamate (Entry 2)
Oil.
IR (neat): 2975, 1650, 1515, 1405, 1250, 1115 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.16 (t, J = 7 Hz, 6 H), 3.37 (br s,
4 H), 3.78 (s, 3 H), 4.11 (s, 2 H), 6.83 (d, J = 8 Hz, 2 H), 7.27 (d,
J = 8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.3, 34.0, 41.9, 55.2, 113.9,
130.0, 130.2, 158.6, 166.8.
MS (EI, 70 eV): m/z (%) = 253 (98), 121(100), 100 (60), 72 (29).
HRMS (EI, 70 eV): m/z calcd for C13H19NO2S: 253.1137; found:
253.1141.
Acknowledgment
The authors thank Dr. Suprabhat Ray for his fruitful suggestions
and the SIAF Division of CDRI for providing spectroscopic and
analytical data.
(20) (a) Chaturvedi, D.; Kumar, A.; Ray, S. Tetrahedron Lett.
2003, 44, 7637. (b) Chaturvedi, D.; Ray, S. Tetrahedron
Lett. 2006, 47, 1307. (c) Chaturvedi, D.; Ray, S.
Tetrahedron Lett. 2007, 48, 149. (d) Chaturvedi, D.;
Mishra, N.; Mishra, V. Tetrahedron Lett. 2007, 48, 5043.
References
(1) (a) Sanders, H. J. Chem. Eng. News 1981, 59 (45), 20.
(b) Sugiyama, H. J. Synth. Org. Chem., Jpn. 1980, 38, 555.
Synthesis 2008, No. 3, 355–357 © Thieme Stuttgart · New York