Practical synthesis of S-alkyl thiocarbamate herbicides by carbonylation of amines with carbon monoxide and sulfur

Article abstract of DOI:10.1016/j.tet.2004.01.060

An industrial and economic carbonylation of amines with carbon monoxide and sulfur has been developed for the synthesis of S-alkyl thiocarbamate herbicides. In the presence of potassium carbonate and solvent DMSO, S-alkyl thiocarbamates, such as thiobencarb and orbencarb (herbicides) are synthesized in excellent yields from amines, carbon monoxide, sulfur, and alkyl halides under mild conditions (1atm, 20°C).

Full text of DOI:10.1016/j.tet.2004.01.060

Tetrahedron 60 (2004) 2869–2873
Practical synthesis of S-alkyl thiocarbamate herbicides by
carbonylation of amines with carbon monoxide and sulfur
*
Takumi Mizuno, Toshiyuki Iwai and Takatoshi Ito
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Received 10 December 2003; accepted 15 January 2004
Dedicated to Professor Noboru Sonoda on the occasion of his 70th birthday
Abstract—An industrial and economic carbonylation of amines with carbon monoxide and sulfur has been developed for the synthesis of S-
alkyl thiocarbamate herbicides. In the presence of potassium carbonate and solvent DMSO, S-alkyl thiocarbamates, such as thiobencarb and
orbencarb (herbicides) are synthesized in excellent yields from amines, carbon monoxide, sulfur, and alkyl halides under mild conditions
(1 atm, 20 8C).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Also, direct carbonylation of amines (2) with carbon
monoxide and sulfur for the synthesis of S-alkyl thio-
carbamate herbicides (1) has been developed. It seems to
be a straightforward and useful method of herbicide
synthesis.
A series of S-alkyl thiocarbamates (1) is well known as
useful herbicides, and these herbicides (1) (e.g., thiobencarb
(1a) and orbencarb (1b)) have been produced in an
industrial large-scale.1 – 3 Therefore, development of
synthetic methods of S-alkyl thiocarbamates (1) is of an
importance.
Grisley and Stephens reported S-alkyl thiocarbamate (1)
synthesis from secondary amines (2), carbon monoxide,
sulfur, and alkyl halides.8 However, this reaction requires
high temperature and pressurized carbon monoxide.
In 1989, our research group found that selenium exhibits
excellent catalytic activity toward the carbonylation of
amines (2) with carbon monoxide and sulfur. This selenium-
catalyzed carbonylation of amines (2) with carbon
monoxide and sulfur smoothly proceeds under mild
conditions to give thiocarbamate salts (3), the alkylation
of which leads to the formation of S-alkyl thiocarbamates
(1) in excellent yields.9,10 Owing to the toxicity of selenium,
however, use of this preparative method is considerably
limited for industrial production of herbicides.
Many methods for the synthesis of S-alkyl thiocarbamates
(1) have been reported. Among them, the reaction of amines
(2) with thiols and phosgene or with carbonyl sulfide,
followed by alkylation with alkyl halides has been known as
the general routes.4 – 6 Indeed, S-alkyl thiocarbamate
herbicides (1) are industrially produced by a two-step
reaction, which includes the generation of carbonyl sulfide
from carbon monoxide and sulfur under high temperature,
and the reaction of carbonyl sulfide with amines (2) and
alkyl halides.2
Next, we also found a high-yield synthesis of S-alkyl
thiocarbamate (1) by the reaction of carbamoyl lithiums
which were prepared in situ from lithium amides and carbon
monoxide (1 atm) at low temperature (278 8C), with
elemental sulfur and alkyl halides, or disulfides.11–13
However, this synthetic method may be not suitable for
industrial production of S-alkyl thiocarbamate herbicides
(1), because of the need for expensive lithium amides and
low temperature reaction conditions (278 8C).
Keywords: S-Alkyl thiocarbamates; Herbicide; Carbon monoxide; Sulfur;
Carbonylation.
Furthermore, we very recently reported the carbonylation of
amines (2) with carbon monoxide and sulfur, assisted by
*
Corresponding author. Tel.: þ81-6-6963-8051; fax: þ81-6-6963-8049;
e-mail address: tmizuno@omtri.city.osaka.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.060

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T. Mizuno et al. / Tetrahedron 60 (2004) 2869–2873
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to provide
S-alkyl thiocarbamates (1) in excellent yields under mild
conditions (1 atm, 20 8C).14 However, this method seems to
be not attractive for industrial production of S-alkyl
thiocarbamate herbicides (1), because of the price of DBU
compared with inorganic bases.
from diethylamine, carbon monoxide, sulfur, and 4-chloro-
benzyl chloride was examined (Table 1).
S-4-Chlorobenzyl N,N-diethylthiocarbamate (Thio-
bencarb,3 1a) are prepared in excellent yields in the
presence of 1.5 equiv. of K2CO3 and DMSO as a solvent
under 1 atm of carbon monoxide at 20 8C for 6 h (entry 1).
When using 10 mmol of Et2NH (2a), yield of 1a was much
lowered (29%) (entry 2). Thus, the need of 2 equiv. of
diethylamine (2a) may be suggested for the formation of
N,N-diethyl-ammonium salt of N,N-diethylthiocarbamate
(3a) as an intermediate.
Therefore, in our strategy, we explored an industrial and
economic route to the S-alkyl thiocarbamates herbicides (1)
under mild conditions (1 atm, 20 8C) using an inorganic
base.
Use of 1.0 or 0.5 equiv. of K2CO3 lowered the yields of
S-4-chlorobenzyl N,N-diethylthiocarbamate (Thio-
bencarb,3 1a) (entries 3 and 4). Also, synthesis of 1a in
DMF resulted in moderate yield (entry 5). NMP,
sulfolane, and THF as solvents were not effective for
the preparation of 1a (entries 6–8). The reaction in the
presence of other bases (Na2CO3, KHCO3, NaHCO3,
KOH, NaOH, AcONa) or in the absence of a base,
resulted in the formation of the desired 1a in moderate
yields (43–70%) (entries 9–15).
2. Results and discussion
Our trial employing K2CO3 as a base and DMSO as a
solvent, which are cheap and commercially available, leads
to successful carbonylation of diethylamine (2a) with
carbon monoxide and sulfur. Diethylamine (2.07 mL,
20 mmol) (2a) easily reacted with carbon monoxide
(1 atm) and sulfur (321 mg, 10 mmol) at 20 8C for 5 h in
the presence of K2CO3 (2.07 g, 15 mmol) using DMSO
(20 mL) as a solvent. The resulting thiocarbamate salt (3a)
in DMSO was esterified by 4-chlorobenzyl chloride
(1.39 mL, 11 mmol) under an ambient pressure, at 20 8C
for 1 h to give S-4-chlorobenzyl N,N-diethylthiocarbamate
(Thiobencarb,3 1a) in quantitative yield (Eq. 1).
In the presence of 1.5 equiv. of K2CO3 and DMSO as a
solvent under 1 atm of carbon monoxide at 20 8C for 6 h,
S-alkyl thiocarbamate herbicides (1a-i) were synthesized
from the corresponding amines (2a-d) and alkyl halides
(Eq. 2, Table 2).
ð1Þ
ð2Þ
The influence of bases and solvents on the synthesis of 1a
Table 1. Influence of bases (15 mmol) and solvents (20 mL) on the
synthesis of Thiobencarb (1a)
Entry
Base
Solvent
Yield (%)a
S-Alkyl thiocarbamates (1a-i) from secondary amines
(2a-d) were prepared in excellent yields under mild
conditions (1 atm, 20 8C) (entries 1–9). General names of
herbicides are as follows: Thiobencarb: 1a, Orbencarb: 1b,
Prosulfocarb: 1c, Methiobencarb: 1d, Molinate: 1e, NTN-
7072: 1f, Ethiolate: 1g, EPTC: 1h, Cycloate: 1i.3 Even in
considerably large scale, S-alkyl thiocarbamates (1g,h) were
given in good yields (entries 7 and 8), although long
reaction time was required (22 h for carbonylation and 2 h
for alkylation).
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KHCO3
NaHCO3
KOH
DMSO
DMSO
DMSO
DMSO
DMF
NMP
Sulfolane
THF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
99
29b
69
66
68
48
18
10
60
50
43
54
47
70
39
c
d
9
10
11
12
13
14
15
NaOH
AcONa
none
Based on our finding on the smooth reaction of salts of
thiolates 4 with carbon monoxide to convert into salts of
thiocarbamates 3,15 we suggest a plausible pathway for this
carbonylation of amines (2) with carbon monoxide and
sulfur using K2CO3 and DMSO as follows (Scheme 1).
Elemental sulfur is readily subjected to S–S bond fission by
the reaction with secondary amines (2) strongly assisted by
K2CO3 and DMSO as a solvent, to form ammonium salts of
thiolate anions 4.16,17 The reaction of 4 with carbon
a
Reaction conditions: diethylamine (2.07 mL, 20 mmol), sulfur (321 mg,
10 mmol), K2CO3 (2.07 g, 15 mmol), 4-chlorobenzyl chloride (1.39 mL,
11 mmol), DMSO (20 mL), CO (1 atm), 20 8C, 5 h for carbonylation and
1 h for alkylation.
Et2NH (10 mmol) was used.
K2CO3 (10 mmol) was used.
K2CO3 (5 mmol) was used.
b
c
d

T. Mizuno et al. / Tetrahedron 60 (2004) 2869–2873
Table 2. Synthesis of S-alkyl thiocarbamate herbicides (1a-i)
2871
Entry
1
R1R2NH
Et2NH
R3X
Yield (%)a
2a
2a
1ab
1bc
99
2
Et2NH
98
3
4
5
n-Pr2NH
2b
2a
2c
1cd
1de
1ef
99
98
94
Et2NH
EtI
6
2c
1fg
96
7
8
9
Et2NH
n-Pr2NH
c-HexEtNH
2a
2b
2d
EtI
EtI
EtI
1gh
1hj
1ik
88(94)i
94(85)i
98
a
Reaction conditions: amine (20 mmol), sulfur (321 mg, 10 mmol), K2CO3 (2.07 g, 15 mmol), alkyl halide (11 mmol), DMSO (20 mL), CO (1 atm), 20 8C,
5 h for carbonylation and 1 h for alkylation.
b
c
d
e
f
Thiobencarb.3
Orbencarb.3
Prosulfocarb.3
Methiobencarb.3
Molinate.3
NTN-7072.3
Ethiolate.
g
h
i
Reaction conditions: amine (200 mmol), sulfur (3.21 g, 100 mmol), K2CO3 (20.7 g, 150 mmol), ethyl iodide (8.80 mL, 110 mmol), DMSO (50 mL), CO
(1 atm), 20 8C, 22 h for carbonylation and 2 h for alkylation.
j
EPTC.3
Cycloate.3
k
monoxide gives the carbonylated species 5. Through an
elimination of carbonyl sulfide from 5, ammonium salts of
thiocarbamates 3 are generated.
4. Experimental
4.1. General
It seems that the main role of K2CO3 and DMSO as a
solvent in this carbonylation is the acceleration of the
formation of thiolates 4.
Melting points were determined on a Mettler FP 5
instrument and were uncorrected. FT-IR spectra were
recorded on a Nicolet Magna-IR 550 instrument. H and
1
13C NMR spectra were obtained on a JEOL JNM-AL300
(300, 75 MHz) instrument. Chemical shifts were reported in
ppm relative to tetramethylsilane (d-units). Mass and exact
mass spectra were recorded on a JEOL JMS-600 spec-
trometer. Amines (2a-d), alkyl halides, solvents, inorganic
bases, sulfur (99.5%), and carbon monoxide (99.9%) were
used as purchased.
3. Conclusion
A practical synthetic method for S-alkyl thiocarbamate
herbicides (1) has been developed under mild conditions
(1 atm, 20 8C), in which the carbonylation of amines (2)
with carbon monoxide and sulfur is powerfully assisted by
K2CO3 and DMSO as a solvent.
4.2. Typical procedure for the synthesis of S-4-
chlorobenzyl N,N-diethylthiocarbamate (Thiobencarb,3
1a) from diethylamine (2a), 4-chlorobenzyl chloride,
carbon monoxide, and sulfur
From the viewpoint of application to actual industrial
production of S-alkyl thiocarbamate herbicides (1), the
present reaction is very significant, in terms of the use of
easily available and cheap carbon monoxide, sulfur, K2CO3,
and DMSO as a solvent, and mild reaction conditions
(1 atm, 20 8C).
A DMSO (20 mL) solution containing diethylamine (2a)
(2.07 mL, 20 mmol), powdered sulfur (321 mg, 10 mmol)
and K2CO3 (2.07 g, 15 mmol) was vigorously stirred under
carbon monoxide (1 atm) at 20 8C for 5 h. Into the DMSO

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T. Mizuno et al. / Tetrahedron 60 (2004) 2869–2873
Scheme 1.
solution of thiocarbamate salt (3a), 4-chlorobenzyl chloride
(1.39 mL, 11 mmol) was added slowly at 0 8C under argon
atmosphere. The reaction mixture was stirred for additional
1 h at 20 8C. The resulting mixture was then poured into 1 N
HCl (100 mL), and extracted with t-butyl methyl ether (100,
50 mL£2). After evaporation of solvents and purification by
short-column chromatography (silica gel, toluene/AcOEt,
1:1), S-4-chlorobenzyl N,N-diethylthiocarbamate (Thio-
bencarb,3 1a) was obtained in a 99% yield (2.54 g) as a
pure form. S-4-Chlorobenzyl N,N-diethylthiocarbamate
(Thiobencarb,3 1a): oil; IR (neat) 2975, 1650, 1410, 1250,
1115 cm21; 1H NMR (300 MHz, CDCl3) d 1.16 (t, J¼7 Hz,
6H), 3.37 (br s, 4H), 4.11 (s, 2H), 7.23–7.30 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 13.2, 33.8, 42.1, 128.6, 130.3,
132.8, 137.2, 166.3; MS (m/z, %) 257 (Mþ, 45), 125 (28),
100 (100), 72 (38). Exact MS calcd for C12H16ClNOS:
257.0641. Found: 257.0630.
6.83 (d, J¼8 Hz, 2H), 7.27 (d, J¼8 Hz, 2H); 13C NMR
(75 MHz CDCl3) d 13.3, 34.0, 41.9, 55.2, 113.9, 130.0,
130.2, 158.6, 166.8; MS (m/z, %) 253 (Mþ, 98), 121 (100),
100 (60), 72 (29). Exact MS calcd for C13H19NO2S:
253.1137. Found: 253.1141.
4.2.4. S-Ethyl perhydroazepin-1-carbothioate
(Molinate,3 1e). Oil; IR (neat) 2930, 1650, 1405,
1155 cm21
;
1H NMR (300 MHz, CDCl3) d 1.29 (t,
J¼7 Hz, 3H), 1.54–1.60 (m, 4H), 1.73 (br s, 4H), 2.91 (q,
J¼7 Hz, 2H), 3.45 (t, J¼6 Hz, 2H), 3.56 (t, J¼6 Hz, 2H);
13C NMR (75 MHz, CDCl3) d 15.4, 24.5, 26.9, 27.2, 27.9,
28.4, 47.3, 47.6, 167.8; MS (m/z, %) 187 (Mþ, 73), 126
(100), 83 (24), 55 (36). Exact MS calcd for C9H17NOS:
187.1031. Found: 187.1021.
4.2.5. S-4-Chlorobenzyl perhydroazepin-1-carbothioate
(NTN-7072,3 1f). Mp 58.0 8C (60–62 8C4); IR (melt) 2930,
;
1635, 1405, 850 cm21 1H NMR (300 MHz, CDCl3) d
1.54–1.57 (m, 4H), 1.73 (br s, 4H), 3.42 (q, J¼6 Hz, 2H),
3.56 (t, J¼6 Hz, 2H), 4.11 (s, 2H), 7.23–7.30 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 26.9, 27.2, 27.8, 28.4, 33.9, 47.6,
47.7, 128.6, 130.3, 132.8, 137.2, 166.9; MS (m/z, %) 283
(Mþ, 63), 126 (100), 125 (36), 55 (17). Exact MS calcd for
C14H18ClNOS: 283.0798. Found: 283.0795.
4.2.1. S-2-Chlorobenzyl N,N-diethylthiocarbamate
(Orbencarb,3 1b). Oil; IR (neat) 2975, 1650, 1410, 1250,
1115 cm21; 1H NMR (300 MHz, CDCl3) d 1.16 (t, J¼7 Hz,
6H), 3.37 (br s, 4H), 4.28 (s, 2H), 7.15–7.22 (m, 2H), 7.33–
7.36 (m, 1H), 7.49–7.52 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 13.5, 32.3, 42.1, 126.9, 128.5, 129.4, 131.3, 134.2,
136.3, 166.5; MS (m/z, %) 257 (Mþ, 16), 222 (55), 125 (31),
100 (100), 89 (10), 72 (35). Exact MS calcd for C12H16-
ClNOS: 257.0641. Found: 257.0633.
4.2.6. S-Ethyl N,N-diethylthiocarbamate (Ethiolate,3 1g).
Oil; IR (neat) 2975, 2935, 1650, 1405, 1250, 1115 cm21; 1H
NMR (300 MHz, CDCl3) d 1.17 (t, J¼7 Hz, 6H), 1.29 (t,
J¼7 Hz, 3H), 2.90 (q, J¼7 Hz, 2H), 3.38 (br s, 4H); 13C
NMR (75 MHz, CDCl3) d 13.4, 15.4, 24.5, 41.8, 167.2; MS
(m/z, %) 161 (Mþ, 26), 100 (100), 72 (83). Exact MS calcd
for C7H15NOS: 161.0874. Found: 161.0859.
4.2.2. S-Benzyl N,N-di-n-propylthiocarbamate (Pro-
sulfocarb,3 1c). Oil; IR (neat) 2965, 1650, 1405, 1220,
1125 cm21; 1H NMR (300 MHz, CDCl3) d 0.89 (t, J¼7 Hz,
6H), 1.60 (q, J¼7 Hz, 4H), 3.22 (br s, 2H), 3.32 (br s, 2H),
4.15 (s, 2H), 7.22–7.36 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 11.2, 21.6, 34.7, 49.3, 127.0, 128.5, 128.9, 138.3,
167.2; MS (m/z, %) 251 (Mþ, 50), 128 (100), 92 (21), 91
(97), 86 (51). Exact MS calcd for C14H21NOS: 251.1344.
Found: 251.1328.
4.2.7. S-Ethyl N,N-di-n-propylthiocarbamate (EPTC,3
1h). Oil; IR (neat) 2965, 1650, 1405, 1220, 1125 cm21; 1H
NMR (300 MHz, CDCl3) d 0.90 (t, J¼7 Hz, 6H), 1.28 (t,
J¼7 Hz, 3H), 1.60 (br s, 4H), 2.90 (q, J¼7 Hz, 2H), 3.27 (br
s, 4H); 13C NMR (75 MHz, CDCl3) d 11.2, 15.3, 21.2, 24.6,
49.1, 167.7; MS (m/z, %) 189 (Mþ, 28), 132 (24), 128 (100),
89 (20), 86 (80). Exact MS calcd for C9H19NOS: 189.1187.
Found: 189.1185.
4.2.3. S-4-Methoxybenzyl N,N-diethylthiocarbamate
(Methiobencarb,3 1d). Oil; IR (neat) 2975, 1650, 1515,
1405, 1250, 1115 cm21; 1H NMR (300 MHz, CDCl3) d 1.16
(t, J¼7 Hz, 6H), 3.37 (br s, 4H), 3.78 (s, 3H), 4.11 (s, 2H),

T. Mizuno et al. / Tetrahedron 60 (2004) 2869–2873
2873
3. Uesugi, Y.; Ueji, M.; Koshioka, M. Pesticide data book; 3rd
ed. Soft Science: Tokyo, 1997.
4.2.8. S-Ethyl N-cyclohexyl-N-ethylthiocarbamate
(Cycloate,3 1i). Oil; IR (neat) 2935, 1650, 1405, 1230,
1
1095 cm21; H NMR (300 MHz, CDCl3) d 1.03–1.80 (m,
4. Tilles, H. J. Am. Chem. Soc. 1959, 81, 714–727.
5. Chin-Hsien, W. Synthesis 1981, 622–623.
6. Very recently, S-alkyl thiocarbamtes (1) were synthesized by
the reaction of trichloroacetyl chloride with amines (2) and
thiols7.
16H), 2.90 (q, J¼7 Hz, 2H), 3.31 (q, J¼7 Hz, 2H), 3.65 (br
s, 0.5H), 4.17 (br s, 0.5H); 13C NMR (75 MHz, CDCl3) d
15.2, 15.6, 24.3, 25.3, 25.7, 30.7, 38.2, 56.8, 167.1; MS (m/z,
%) 215 (Mþ, 38), 154 (100), 83 (98), 55 (31). Exact MS
calcd for C11H21NOS: 215.1344. Found: 215.1331.
7. Wynne, J. H.; Jensen, S. D.; Snow, A. W. J. Org. Chem. 2003,
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4.3. General procedure for the synthesis of ethyl N,N-
diethylthiocarbamate (Ethiolate,3 1g) in large scale
8. Grisley, D. W., Jr.; Stephens, J. A. J. Org. Chem. 1961, 26,
3568.
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452–453.
A solution of diethylamine (2a) (20.7 mL, 200 mmol),
powdered sulfur (3.21 g, 100 mmol) and K2CO3 (20.7 g,
150 mmol) in DMSO (50 mL) was very vigorously stirred
under carbon monoxide (1 atm) at 20 8C for 22 h. Ethyl
iodide (8.80 mL, 110 mmol) was added carefully at 0 8C
under argon atmosphere into the DMSO solution of
thiocarbamate salt (3a). The solution was stirred for
additional 2 h at 20 8C. The resulting mixture was then
poured slowly into 1 N HCl (100 mL), and extracted with
t-butyl methyl ether (100, 50 mL£2). After evaporation of
solvents and purification by vacuum distillation, S-ethyl
N,N-diethylthiocarbamate (Ethiolate,3 1g) was obtained in
94% yield (15.2 g).
10. Mizuno, T.; Nishiguchi, I.; Sonoda, N. Tetrahedron 1994, 50,
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