A novel one-pot solvent-free, triethylamine-assisted, selenium-catalyzed synthesis of thiocarbamates from nitroarenes, carbon monoxide, and thiols

Article abstract of DOI:10.1055/s-2005-869839

A novel one-pot solvent-free synthesis of a series of thiocarbamates is reported. Nitroarenes, carbon monoxide, and thiols are the starting materials, with cheap element selenium as catalyst; this method offers a simple access to thiocarbamates mostly in moderate to good yields. The selenium catalyst can be easily recovered and recycled. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869839

LETTER
1535
A Novel One-Pot Solvent-Free, Triethylamine-Assisted, Selenium-Catalyzed
Synthesis of Thiocarbamates from Nitroarenes, Carbon Monoxide, and Thiols
A
Novel
One-Pot
S
i
olvent
a
-Free
S
ynth
o
esis of Thio
p
carbamates eng Zhang,a,b Shiwei Lu*a,b
c
National Engineering Research Center for Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 161 Zhongshan
Road, Dalian 116011, Liaoning, P. R. China
d
Graduate School of Chinese Academy of Sciences, Beijing, P. R. China
Fax +86(411)83698749; E-mail: lusw@dicp.ac.cn
Received 15 March 2005
of them need complex and/or expensive starting materials.
Despite the above intensive efforts, there is still room for
improvement. Very recently, we reported a new and facile
route for the synthesis of thiocarbamates from aniline,
Abstract: A novel one-pot solvent-free synthesis of a series of thio-
carbamates is reported. Nitroarenes, carbon monoxide, and thiols
are the starting materials, with cheap element selenium as catalyst;
this method offers a simple access to thiocarbamates mostly in mod-
erate to good yields. The selenium catalyst can be easily recovered carbon monoxide, and thiols mediate by stoichiometric
selenium in two steps.18
and recycled.
Key words: thiocarbamates, carbon monoxide, selenium, thiols,
carbonylation, nitroarenes
It is evident that nitroarenes are cheaper than aromatic
amines in terms of cost; moreover, nitroarenes are an ox-
idant per se. Thus, in using them instead of aniline as start-
ing materials, there is no need for an additional oxidant to
Thiocarbamates are compounds of growing interest be-
cause of their medicinal effects including bactericidal,1
antiviral,2 and their applications in agriculture as fungi-
cides,3 pesticides,4 and herbicides.5 There are numerous
methods for the synthesis of thiocarbamates. One of the
most common approaches makes use of amine, carbon
monoxide, and element sulfur as starting materials, fol-
lowed by alkylation with alkyl halides,5c,6 or gaseous car-
bonyl sulfide5d,7 is employed instead of carbon monoxide
and sulfur; however, this method suffers from drawbacks
such as multi-step synthesis, a large amount of solvent re-
quired, a great excess of one or two starting materials,
and/or low yield. Intramolecular rearrangements of vari-
ous derivatives are frequently employed for this purpose;
however, these methods are extremely limited by starting
material.8 Although addition of thiols to isocyanates can
offer the corresponding thiocarbamates in good yield; del-
eterious, expensive and low available isocyanates and cat-
alysts are limitations associated with these methods.5d,9
Oxidative coupling of aryl thiols with amines and carbon
monoxide is an approach to thiocarbmates, but this meth-
od usually requires complex and expensive catalysts.10
Thiocarbamate synthesis has also been accomplished by
methods such as treating carbamoyl chlorides with thiols
and their derivatives,11 condensation of chlorothiofor-
mates with amines,12 hydrolysis of thiocyanates,13 seleni-
um or palladium-catalyzed carbonylation of amine and
disulfide14 and the reaction of trichloroacetyl chloride
with thiols and amines.15 Cyclic thiocarbamates can be
obtained from the reaction of amino thiols with carbon
monoxide in the presence of selenium.16 There are still
other ways to access these compounds;17 however, most
carry out the selenium-catalyzed carbonylation with thiols
to thiocarbamates. Therefore, herein we describe a novel
one-pot solvent-free approach to thiocarbamates. Using
nitroarenes, carbon monoxide, and thiols as starting mate-
rials, with cheap, easily available selenium as catalyst, the
reaction can proceed well in the presence of triethylamine
under mild conditions.
In order to find the optimal experimental conditions, the
reaction of nitrobenzene with propanethiol was examined
(Table 1, entry 2). All reagents were used directly without
further purification. In the absence of selenium or triethyl-
amine, the reaction failed. The minimum amount of sele-
nium and triethylamine required was 5 mol% and 0.5
equivalent of the substrate. The reaction was conducted at
60 °C, below this temperature the reaction proceeded too
slowly, and at temperatures higher than this, more side
product (diphenylurea) was formed. The reaction pro-
ceeded well without solvent, reaching completion within
ten hours. The desired product phenyl-thiocarbamic acid
(S)-propyl ester (2b) was obtained in high yield in addi-
tion to a little side product diphenylurea. The catalyst se-
lenium can be easily recovered from the reaction mixture
by simple filtration. The product 2b was purified either by
column chromatography or by recrystallization from light
petroleum ether.
To demonstrate the scope and efficiency of the present
method, we applied the triethylamine-assisted selenium-
catalyzed system to a variety of thiols under the optimal
conditions (Table 1). As shown in Table 1, the reaction is
amenable to a range of thiols. For straight chain thiols, the
reaction proceeded well to the corresponding thiocarbam-
ates in good yields (Table 1, entries 1, 2, 4, 6, 7). Steric
factors seemed to explain the lower yields of thiocarbam-
ates with branch components (Table 1, entries 3, 5, 8).
Competitive formation of diphenylurea accounted for
SYNLETT 2005, No. 10, pp 1535–1538
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7
.0
6
.2
0
0
5
Advanced online publication: 12.05.2005
DOI: 10.1055/s-2005-869839; Art ID: U07205ST
© Georg Thieme Verlag Stuttgart · New York

1536
X. Zhang, S. Lu
LETTER
Table 1 Isolated Yields of Thiocarbamate Using Nitrobenzene as One of the Reactantsa
Et3N
NO2
+
RSH
+
3 CO
NHCOSR
+
2 CO2
cat. Se
1
2
Entry
Thiol
1a
R
Product
Yield (%)
Entry
8
Thiol
1h
1i
R
Product
2h
Yield (%)
1
2
3
4
5
6
7
Ethyl
2a
2b
2c
2d
2e
2f
80
84
57
80
8
Cyclohexyl
Benzyl
67
62
15
18
38
41
1b
1c
Propyl
i-Propyl
Butyl
9
2i
10
11
12
13
1j
Phenyl
2j
1d
1e
1k
1l
4-Chlorophenyl
4-Methylphenyl
4-Methoxyphenyl
2k
t-Butyl
Pentyl
Hexyl
2l
1f
79
75
1m
2m
1g
2g
a Reaction conditions: nitrobenzene (10 mmol), thiol (10 mmol), Se (0.5 mmol), Et3N (5 mmol), CO (0.8 MPa), 60 °C, 10 h.
more of the nitrobenzene consumption, resulting in a low According to above, the reaction can proceed well when
yield of phenyl-thiocarbamic acid (S)-benzyl ester alkyl thiols with straight chain or with less hindered
(Table 1, entry 9). When aryl thiols were used instead of branch chain are used.
alkyl thiols in the reactions, poor yields were obtained
To extend further the utility of this reaction, a range of ni-
(Table 1, entries 10–13). This is mostly due to the weak
troarenes with different substituents were investigated us-
nucleophilicity of aryl thiols. Competitive oxidation of
ing propanethiol as the thiol reactant (Table 2). As shown
benzenethiol to the corresponding disulfide consumed
in Table 2, the reaction system can tolerate many func-
most of the thiol, resulting in the lower yield of phenyl-
tional groups. With the majority of substrates, the reaction
thiocarbamic acid (S)-phenyl ester (Table 1, entry 10).
proceeded well to the desired thiocarbamates in moderate
to good yields. In addition to nitroarenes, nitroheteroaro-
matics can also function in the reaction. For example,
Electronic effect seemed to explain the lower yield of
phenyl-thiocarbamic acid (S)-4-chlorophenyl ester (2k).
Table 2 Isolated Yields of Thiocarbamate Using Propanethiol as One of the Reactantsa
Et3N
ArNO2
+
CH3CH2CH2SH
+
3 CO
ArNHCOSCH2CH2CH3
+ 2 CO2
cat. Se
3
Entry
1
Substrate
Product
Yield (%)
0
Entry
8
Substrate
Product
Yield (%)
81
3a
3h
Cl
H3C
NO2
NO2
NO2
2
3b
59
9
3i
69
Cl
H3C
NO2
3
4
5
3c
3d
3e
49
63
52
10
11
12
3j
3k
3l
81
79
79
H3CH2C
NO2
Cl
NO2
Br
NO2
(H3C)2HC
NO2
OCH3
NO2
H3COC
NO2
6
7
3f
83
61
13
14
3m
3n
84
84
Cl
H3CO
H3CO
NO2
H3C
NO2
3g
CH3
NO2
NO2
N
a Reaction conditions: nitrobenzene (1 equiv), thiol (1 equiv), Se (5 mol%), Et3N (0.5 equiv), CO stoichiometric, 60 °C, 10 h.
Synlett 2005, No. 10, 1535–1538 © Thieme Stuttgart · New York

LETTER
A Novel One-Pot Solvent-Free Synthesis of Thiocarbamates
1537
Se
NHCOSeH
Et3N
CO
R
H2O
6
NO2
R
[SeCO]
H2Se
4
Et3N
RSH
1
NH2
R
[SeCO]
Et3N
O
1
RSCSR
CO2
Et3N
3
O
RSH
O
RSH
NHCSR
H2Se
[RSCSeH]
R
4
5
2
Scheme 1 A possible reaction pathway to thiocarbamates 5
using 2-methoxy-5-nitro-pyridine as starting material, the 1) Reaction with thiol
desired thiocarbamate was obtained in 84% yield (entry
To be specific, 1 first underwent nucleophilic addition of
one thiol molecule to form monoselenothiocarbonate 2,
which then underwent nucleophilic attack by another thiol
molecule, generating dithiocarbonate 3 and 4. Take phe-
nyl methanethiol for example, we succeeded in proving
this by obtaining dithiocarbonic acid S,S¢-dibenzyl ester in
excellent yield under the same reaction conditions except
that a stoichiometric amount of selenium was used.21
14). Both electronic and steric factors seem to affect the
reaction. On the whole, the electron-rich substrates are
more reactive than the electron-deficient ones, resulting in
higher product yields than the former (Table 2, entries 6–
14) compared to the latter (Table 2, entries 1–5). As for
the steric factor, the substrates with substituents at the
ortho-position of nitroarenes are less reactive than those
that are para-substituted, resulting in lower product yields
of the former (Table 2, entries 1, 7, 12) than the latter
(Table 2, entries 3, 9, 13). 2-Chloronitrobenzene failed to
undergo this reaction (Table 2, entry 1) mostly due to the
combination of the two factors.
2) Reaction with water.
Alternately, 4 may also originate by the reaction of 1 with
small amounts of water present as impurities in the re-
agents. Nitroarene can then be reduced to the correspond-
ing amine by the resulting 4.23 Accordingly, 4 was
oxidized to selenium for the next catalytic cycle. The nu-
cleophilic attack of amine on 3 led to the formation of the
desired thiocarbamate 5, accompanied by the release of
one thiol molecule. We proved this by treating aniline
with dithiocarbonic acid S,S¢-dibenzyl ester under our re-
One remarkable advantage of the present catalytic system
is that of the selenium acts as a phase-transfer catalyst.19
Before the reaction, the selenium catalyst is a solid; during
the reaction process, solid selenium reacts with carbon
monoxide to form SeCO, which can dissolve in the reac-
tion mixture to form a homogeneous catalytic system.
Then SeCO reacts with thiol, affording the corresponding
thiocarbonate and hydrogen selenide. The resulting hy-
drogen selenide is then oxidized to solid selenium by ni-
troarenes. So after the reaction, the catalyst selenium can
easily be separated from the reaction mixtures by simple
phase separation. The recovered selenium can be recy-
cled. Recycling of catalyst was carried out by filtration of
catalyst from the crude reaction mixture followed by
drying it. Using the reaction of nitrobenzene with pro-
panethiol as an example, the reusability of the catalyst was
tested and the product yield only dropped from 84% to
79% after five cycles.
action conditions.24 In addition, according to Sonoda,16
5
may also be obtained by the reaction of thiol with seleno-
carbamic acid salts 6 (which is generated from 1 and
amine). According to the above, we suggested the follow-
ing reaction path depicted in Scheme 1.
In summary, we have developed a novel one-pot solvent-
free approach to thiocarbamates. Using straight-chain or
less hindered alkyl thiols as thiol reactant, this reaction
can proceed well with electro-rich or electro-neutral ni-
troarenes (including nitroheteroarenes) in high yields.
Simple starting materials, cheap and recyclable catalyst,
one-pot synthesis, solvent-free condition, simple opera-
tion of the reaction and simple purification of the products
make the present method very significant from the view
point of application.
Although a detailed study of the mechanism has not been
accomplished, our preliminary experimental findings on
the selenium-catalyzed carbonylation suggested that the
reaction process involved the formation of carbonyl se-
lenide 1,20 generated in situ from carbon monoxide and se-
lenium under basic conditions. The resulting 1 then
formed hydrogen selenide 4, most likely via two ap-
proaches: 1) reaction with thiol or 2) reaction with water.
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Synlett 2005, No. 10, 1535–1538 © Thieme Stuttgart · New York

1538
X. Zhang, S. Lu
LETTER
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was then sealed, flushed three times with carbon monoxide.
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recrystallization from light petroleum ether in 72% yield as
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Synlett 2005, No. 10, 1535–1538 © Thieme Stuttgart · New York