A facile, safe and inexpensive preparation of S -methyl arylcarbamothioates by methylthiocarbonylation of primary arylamines with O, S -dimethyl carbonodithioate

Article abstract of DOI:10.1055/s-0029-1219226

O,S-Dimethyl carbonodithioate is proposed as a suitable and safely handled reagent that can be used in the methylthiocarbonylation of primary arylamines to give S-methyl arylcarbamothioates. Optimal conditions involved a one-step procedure that was carried out at 45C in a solvent-free system, in the presence of triethyl(methyl)ammonium S-methyl carbonodithioate as a reaction promoter. The title products were obtained pure in yields that, with one exception, varied between 72 and 91% (average yield of the 12 considered examples was 83%). The by-product S,S-dimethyl carbonodithioate is also a valuable reagent. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1219226

PAPER
1113
A Facile, Safe and Inexpensive Preparation of S-Methyl Arylcarbamothioates
by Methylthiocarbonylation of Primary Arylamines with O,S-Dimethyl
Carbonodithioate
P
reparati
a
onof
S
-M
e
c
thyl
A
rylca
o
rbamothioate
p
s
o Degani,1 Rita Fochi,* Claudio Magistris
Dipartimento di Chimica Generale e Chimica Organica, Università degli Studi di Torino, C.so M. D'Azeglio 48, 10125 Torino, Italy
E-mail: rita.fochi@unito.it
Received 19 November 2009; revised 24 November 2009
presence of methanethiol and a catalytic system (H2S,
Abstract: O,S-Dimethyl carbonodithioate is proposed as a suitable
Et3N, and NH4VO3).10 The direct conversion of aryl-
and safely handled reagent that can be used in the methylthiocarbo-
amines into S-methyl arylcarbamothioates employ the fol-
lowing reactions: (i) reaction, under pressure, of primary
nylation of primary arylamines to give S-methyl arylcarbamothio-
ates. Optimal conditions involved a one-step procedure that was
carried out at 45 °C in a solvent-free system, in the presence of tri- arylamines with carbon monoxide and dimethyl disulfide,
catalyzed by elemental selenium11a or a metal selenide,11b
in the presence of a tertiary amine; (ii) reaction of aryl-
ethyl(methyl)ammonium S-methyl carbonodithioate as a reaction
promoter. The title products were obtained pure in yields that, with
one exception, varied between 72 and 91% (average yield of the 12
amines with carbon monoxide and elemental sulfur in the
considered examples was 83%). The by-product S,S-dimethyl car-
presence of a tertiary amine and selenium as catalyst, fol-
bonodithioate is also a valuable reagent.
lowed by methylation with methyl iodide;9c,h,11c (iii) reac-
Key words: O,S-dimethyl carbonodithioate, arylcarbamothioates,
tion of arylamines with carbon monoxide and
thiocarbonylation, S,S-dimethyl carbonodithioate, toluene-2,4-
dithiocarbamic acid S,S-dimethyl ester
methanethiol in the presence of an organic base and sele-
nium as catalyst;9p and (iv) reaction of arylamines with S-
methyl chlorothioformate.12 For the preparation of the S-
methyl arylcarbamothioates based on the use of arylamine
S-Methyl arylcarbamothioates 4 are part of an important
derivatives, the procedures are: (i) reaction of aryl isocy-
class of compounds, the carbamothioates (or thiocarbam-
anates with LiAlHSH9g followed by methylation with
ates), which are of notable interest in various fields of
methyl iodide;5,6,9g (ii) reaction of aryl isocyanates with
‘fine chemicals’ (especially agrochemicals and pharma-
dimethyl disulfide in the presence of Zn/AlCl3;9j (iii) reac-
ceuticals), and as starting and intermediate materials in or-
tion of aryl isocyanates with methanethiol in the presence
ganic synthesis.2,3 Indeed, with regard to S-methyl
of triethylamine;4a (iv) reaction of aryl isothiocyanates
arylcarbamothioates 4, it has been highlighted that some
with 3-(aminomethyl)pyridine followed by treatment of
can act as herbicides and parasiticides4a or are effective in
the N-aryl N¢-(3-pyridylmethyl)thioureas obtained with
inhibiting germination of barnyard grass seeds,4c are
methyl iodide;4c and (v) isomerization of O-methyl aryl-
acaricides4b or can increase the selectivity of important
carbamothioates promoted by Br2, MeI or BF3/Et2O.13 All
carbamothioate herbicides.4d,e Furthermore, some of the
these procedures are relatively difficult, especially if they
compounds of type 4 exhibit potent inhibitory effects on
are to be applied on a large scale, in that they are very la-
the dopa oxidase activity of mushroom tyrosinase5 or
borious and/or start from reagents that are hazardous and/
show superoxide anion-scavenging activity.6 In the field
or expensive, and use costly catalysts.
of organic synthesis, they have been proposed as interme-
diates for the production of carbamates,7 ureas,7 and iso-
cyanates.8 In scientific and patent literature, also in the
most recent publications, a great variety of procedures
have been proposed for the preparation of S-alkyl
arylcarbamothioates2,4e,5,9 and, especially, of S-methyl
arylcarbamothioates 4. With regard to the synthesis of the
latter, nearly all the procedures reported to date start with
primary arylamines or their synthetic derivatives (aryl iso-
cyanates and aryl isothiocyanates), the exception being
one procedure that uses aromatic nitroderivatives as start-
ing material. In this latter case, S-methyl arylcarbamothio-
ates 4 were prepared by reductive carbonylation of
aromatic nitro-derivatives with carbon monoxide in the
The present research is aimed at the preparation of S-methyl
arylcarbamothioates 4 by reaction of O,S-dimethyl car-
bonodithioate (1) with primary arylamines 2 in the pres-
ence of the promoter triethyl(methyl)ammonium S-
methyl carbonodithioate (3; Scheme 1).
_
Et3MeN MeSC(S)O (3)
S
O
45 °C
ArNH2
_
MeS
OMe
ArNH
SMe
MeSH ( MeSNa)
1
2
4
Scheme 1 Synthesis of S-methyl arylcarbamothioates 4a–l by reac-
tion of arylamines 2 with O,S-dimethyl carbonodithioate (1)
The study forms part of a wide ranging project that ad-
dresses the development of new, safe, and soft synthetic
methodologies, based on the use of S,S-dimethyl carbon-
odithioate [5; (MeS2)CO] and O,S-dimethyl carbon-
SYNTHESIS 2010, No. 7, pp 1113–1122
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219226; Art ID: Z24809SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

1114
I. Degani et al.
PAPER
odithioate (1). The early research in this work addressed diphenylurea (V) was collected by filtration in 21% yield.
the use of S,S-dimethyl carbonodithioate (5), which is a The organic solution contained the above products in the
safe and easily handled carbonylating agent that can be following percentages (by gas-chromatography): the
used as a phosgene14 substitute for the production of vari- starting aniline (11%), I (22%), II (36%), III (11%), IV
ous classes of compounds; specifically S-methyl car- (5%), and V (11%). Note that the expected simple substi-
bamothioates,3 carbamates,15 and mono-, di- and tri- tution product, O-methyl phenylcarbamothioate (IV), was
substituted ureas.16 Following this, the most recent work present as only 5%. Furthermore, the limited amount of
was devoted to studying the synthetic potential of O,S- residue remaining after solvent evaporation indicated that
dimethyl carbonodithioate (1) as a substitute for S,S-di- significant reagent loss had occurred.
methyl carbonodithioate (5), of which it is the precursor,17
as a substitute for phosgene. This latest research has, in
S
particular, been concerned with setting up new synthetic
PhNH2
MeS
OMe
sequences that use reagent 1 as the starting material to pre-
pare S-methyl alkylcarbamothioates and S-methyl
dialkylcarbamothioates18 (which, in turn, are useful as
precursors of carbamates and ureas), as an alternative to
the well-known synthetic sequence: O,S-dimethyl car-
bonodithioate (1) → S,S-dimethyl carbonodithioate (5) →
S-methyl carbamothioates → carbamates or ureas.3,15,18
1
– MeSH
– H2S
100 °C
PhNHMe
PhNMe2
I (22%)
II (36%)
S
S
Achieving the objective of the present research – setting
up new procedures for the synthesis of S-methyl arylcar-
bamothioates 4 based on the use of O,S-dimethyl car-
Ph(Me)N
OMe
PhNH
OMe
III (11%)
IV (5%)
O
O
bonodithioate (1)
–
called for the preliminary
PhNH
N(Me)Ph
PhNH
NHPh
consideration of two important experimental data report-
ed in the literature.19,20 One19 concerns the impossibility of
obtaining the S-methyl phenylcarbamothioate (4a) by re-
acting aniline with S,S-dimethyl carbonodithioate (5).
This result, which was also confirmed in the present
study, led us to exclude the use of reagent 5 for the syn-
thesis of S-methyl arylcarbamothioates 4, and prompted
us to evaluate the exclusive use of O,S-dimethyl car-
bonodithioate (1). Nevertheless, this second option was
counteracted by the second set of literature data20 that es-
tablished the impossibility of stopping the reaction of
aniline with 1 at the O-methyl phenylcarbamothioate sub-
stitution product [which is useful for the conversion into
its isomer S-methyl phenylcarbamothioate (4a)]. Indeed,
it has been reported that this reaction proceeds until the
N,N¢-diphenylurea formed. In the present study we only
partially confirmed this result, and found the cited reac-
tion to be quite complex and not suitable from the prepar-
ative point of view. In fact, when aniline was reacted with
O,S-dimethyl carbonodithioate (1) at 100 °C (Scheme 2),
there was, from the very beginning of the reaction, a plen-
tiful development of sulfur hydride and methanethiol, as
is also reported in the literature,20 together with the forma-
tion of a colorless solid consisting of N,N¢-diphenylurea,
which separated out from the oily reaction mixture. GC
and GC-MS analyses of the mixture revealed the presence
of a variety of products. The main constituents of the re-
action mixture were, in the following order from the gas
chromatograph: methylaniline (I), dimethylaniline (II),
O-methyl methyl(phenyl)carbamothioate (III), O-methyl
phenylcarbamothioate (IV), N-methyl-N,N¢-diphenylurea
(V) and N,N¢-diphenylurea (VI). After eight hours, re-
agent 1 disappeared, whilst a portion of the aniline re-
mained unchanged. After cooling, methylene chloride
was added to the reaction mixture and the solid N,N¢-
V (11%)
VI 21%
isolated
Scheme 2 Reaction of aniline with O,S-dimethyl carbonodithioate
(1) at 100 °C in the absence of the promoter triethyl(methyl)ammoni-
um S-methyl carbonodithioate (3); the percentages reported in
brackets were determined from GC analysis
On the other hand, in earlier research18 we demonstrated
the possibility of modifying the pathway followed by the
reaction of primary and secondary aliphatic amines with
O,S-dimethyl carbonodithioate (1), by working in the
presence of methylammonium salts. Under these condi-
tions, the reactions afforded directly, in a single prepara-
tive step, the S-methyl alkylcarbamothioates and
dialkylcarbamothioates instead of the corresponding iso-
meric O-methyl alkylcarbamothioates and dialkylcar-
bamothioates, which usually form in the absence of such
salts. On the basis of these results, we decided to apply our
acquired knowledge to the synthesis of S-methyl arylcar-
bamothioates 4. This led us to investigate the reactions of
primary arylamines with O,S-dimethyl carbonodithioate
(1) in the presence of an ammonium salt, namely anhy-
drous triethyl(methyl)ammonium carbonodithioate (3),
which was prepared in situ by reacting equimolar amounts
of the same carbonodithioate 1 with triethylamine, at
45 °C for two hours (Scheme 3).
S
_
45 °C
Et3N
Et3MeN MeSC(S)O
MeS
OMe
1
3
Scheme 3 Synthesis of triethyl(methyl)ammonium S-methyl carbo-
nodithioate (3) by reaction of O,S-dimethyl carbonodithioate (1) with
triethylamine
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

PAPER
Preparation of S-Methyl Arylcarbamothioates
Table 1 S-Methyl Arylcarbamothioates 4a–l
1115
As described previously,18 the salt 3 separated out from
the oily mixture as a colorless solid as soon as it formed.
1H NMR analysis of the whole mixture (both solid and oil)
showed the formation of the ammonium salt 3 (~17%) and
S,S-dimethyl carbonodithioate (5; ~5.5%). The ratio 1/5
was ~90:10 (1H NMR and GC analyses). In order to iden-
tify suitable conditions for the formation of S-methyl aryl-
carbamothioates 4, we first examined the reaction of O,S-
dimethyl carbonodithioate (1) and aniline in the presence
of the said salt 3, at 45 °C under various conditions
(Table 1, entries 1–3; Procedures A–C). Procedures A and
B were similar, differing only in the molar ratio of 1/tri-
ethylamine/aniline, (A, 1.5:0.5:1 and B, 1.7:0.5:1). In
these procedures, the aniline was added directly to the
mixture containing 3, which dissolved immediately. The
new, homogeneous oily mixture was then dripped slowly
into the O,S-dimethyl carbonodithioate (1), which was
maintained at 45 °C. The reactions were exothermic and
went to completion in one hour. During the course of the
reaction the disappearance of 1 was accompanied by par-
tial isomerization to S,S-dimethyl carbonodithioate (5). A
Entry Ar
Proce- Molar ratio Com- Yield
durea 2/1/Et3N
pd 4 (%)b
4a 83
4a 88
4a 86
4b 64
4b 72
1
Ph
A
B
C
A
B
A
A
A
A
A
B
D
B
B
A
B
A
D
1:1.5:0.5
1:1.7:0.5
1:1.5:0.5
1:1.5:0.5
1:1.7:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.7:0.5
1:1.7:0.5
1:1.7:0.5
1:1.7:0.5
1:1.5:0.5
1:1.7:0.5
1:1.7:0.5
1:5.0:1
2
Ph
3
Ph
4
2-MeC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeSC6H4
4-ClC6H4
5
6
4c
91
7
4d 87
8
4e
4f
90
88
9
10
11
4g 78
4g 88
4g 88
4h 88
4-ClC6H4
part of the aniline (~10–13%) remained unchanged. In 12
procedure C, the reagents were used in the same molar ra-
tio as in procedure A, but the order of their mixing was re-
4-ClC6H4
13
4-BrC6H4
3-CF3C6H4
2,6-Me2C6H3
2,6-Me2C6H3
3,5-Me2C6H3
2-Me-4-(MeSCONH)C6H3
versed. All three procedures supplied the desired product,
S-methyl phenylcarbamothioate (4a), in high yield (83–
88%). The isomer O-methyl phenylcarbamothioate was
present only in trace amounts and was, in any case, easily
eliminated. It was also possible to recover the unreacted
aniline (see the experimental section), as well as the co-
product S,S-dimethyl carbonodithioate (5), which formed
under all the reaction conditions. Procedure D was used
when the arylamine was solid and only partially soluble in
the mixture containing the ammonium salt 3 (Table 1; en-
try 12).
14
15
16
17
18
4i
4j
4j
76
46
48
4k 90
4l 85
a All the reactions were carried out at 45 °C.
b Yield of the pure product isolated by column chromatography (SiO2,
CH2Cl2).
As an example: the solid 4-chloroaniline was finely
ground and added, in one portion, to the said mixture con-
taining 3, maintained at 45 °C, then O,S-dimethyl car-
bonodithioate (1) was dripped slowly into it. The molar
ratio 4-chloroaniline/1/triethylamine was 1:1.7:0.5. Upon
addition of the first drops of 1, both the ammonium salt 3
and the aniline dissolved. In this case, the reaction reached
completion in one hour, and the S-methyl 4-chlorophenyl-
carbamothioate (4g) was obtained pure in 88% yield.
then the resultant methylaniline (path E). Alongside the
methylation products, i.e. methylaniline (I) and dimethyl-
aniline (II), in the last two reactions there was also release
of S-methyl carbonodithioic acid (VII), which was unsta-
ble and dissociated into methanethiol and carbon oxysul-
fide (path C). The carbon oxysulfide reacted with aniline
to form phenylthiocarbamic acid (VIII; path F) which, in
turn, gave rise to the phenyl isocyanate (IX; path G) by
elimination of sulfur hydride. Finally, IX reacted with
both aniline and N-methylaniline to supply N,N¢-diphenyl-
urea (VI; path H) and N-methyl-N,N¢-diphenylurea (V;
path I), respectively.
The results obtained in the above trials are fully consistent
with the reaction mechanisms already hypothesized18 for
the reactions of aliphatic amines with O,S-dimethyl car-
bonodithioate (1) in the absence or presence of the trieth-
yl(methyl)ammonium carbonodithioate (3). Thus, when
the reagents O,S-dimethyl carbonodithioate (1) and
aniline were heated to 100 °C in the absence of the meth-
ylammonium salt 3 (Scheme 4), formation of both O-
methyl phenylcarbamothioate (IV) (path A) and O-meth-
yl methyl(phenyl)carbamothioate (III) (path D) was ob-
served, together with the development of methanethiol,
through acylic nucleophilic substitution reactions pro-
ceeding by addition–elimination. At the same time, 1
acted as a methylating agent, first of aniline (path B) and
In contrast, when the reaction between O,S-dimethyl car-
bonothioate (1) and aniline was carried out in the presence
of triethyl(methyl)ammonium carbonodithioate (3;
Scheme 5), it promoted: (i) the formation of S-methyl
phenylcarbamothioate (4a; paths A and B), and (ii) the
isomerization of 1 to S,S-dimethyl carbonodithioate (5;
paths A and C).
In particular, it can be hypothesized that the reaction that
leads to the direct formation of S-methyl phenylcar-
bamothioate (4a; paths A and B) proceeds through a chain
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

1116
I. Degani et al.
PAPER
S
S
_
A
B
Et3MeN
MeSH
PhNH
OMe
MeS
O
S
_
IV
3
= Y
S
PhNH2
MeS
OMe
S
_
1
PhNH2Me
A
MeS
O
MeS
OMe
1
SH
SMe
OMe
_
Et3N
PhNHMe
Y
MeS
O
MeS
I
VII
6
PhNH2
B
1
C
C
*
COS
MeSH
SMe
SMe
MeS
NH2Ph
_
S
MeS
MeS
O
Y
OMe
D
E
5
MeSH
Ph(Me)N
OMe
7
S
III
SMe
– MeSH
_
PhNHMe
MeS
OMe
S
Y
_
MeS
MeO
OMe
1
PhMe2NH
NHPh
6
MeS
MeS
O
_
Y
1
8
SH
chain
reaction
1
PhMe2N
O
II
MeS
O
VII
NHPh
C
4a
*
MeSH
COS
H2S
SMe
OMe
_
Y
MeS
O
F
G
6
*
PhNH2
COS
PhNCO
PhNH
SH
PhNH2
VIII
IX
chain
reaction
O
PhNH2
Scheme 5 Mechanism of the reaction of aniline with O,S-dimethyl
carbonodithioate (1) at 45 °C in the presence of the promoter
triethyl(methyl)ammonium S-methyl carbonodithioate (3)
PhNH
NHPh
H
VI
PhNCO
O
IX
PhNHMe
PhNH
N(Me)Ph
I
to being determined by the presence or absence of the pro-
moter 3, is also drastically influenced by the reaction tem-
perature. On the basis of the hypothesized mechanism,
one can understand why the amount of reagent 1 required
by the reaction with aniline to give 4a (Table 1, entry 2;
molar ratio 1/aniline = 1.7:1) is greater than that required
by the reactions with aliphatic amines to give the S-methyl
alkylcarbamothioates (molar ratio 1/RNH2 = 1:1–1.2).18
In fact, because of the lower nucleophilicity of the aniline
compared to that of the aliphatic amines, the formation of
4a (path B), compared to that of the alkylcarbamothioates,
is more disadvantaged, thus favoring the isomerization of
1 to 5 (path C).
V
Scheme 4 Mechanism of the reaction of aniline with O,S-dimethyl
carbonodithioate (1) at 100 °C in the absence of the promoter
triethyl(methyl)ammonium S-methyl carbonodithioate (3)
reaction that is promoted by the ammonium cation of 3.
The latter can react with 1 to give the methoxybis(methyl-
sulfanyl)methylium cation 6, which is more prone than 1
to react with aniline (path B) to form the tetrahedral inter-
mediate 7. This intermediate then eliminates methanethiol
to form the intermediate 8, which transfers a methyl group
to reagent 1, thereby maintaining the chain reaction and
giving rise to the S-methyl phenylcarbamothioate (4a).
We hypothesize that path C, i.e. the isomerization of 1 to
S,S-dimethyl carbonodithioate (5), can also occur through
a chain reaction promoted by 3, via 6. In the presence of
the salt 3 at the reaction temperature (~45 °C), the two re-
actions B and C compete with each other, but both almost
exclusively prevail over other reactions that take place in
the absence of the salt 3 and at higher temperature
(100 °C). Evidently, the course of the reaction, in addition
The study was then developed further by reacting the O,S-
dimethyl carbonodithioate (1) with substituted anilines of
different nucleophilicity and steric hindrance. The consid-
ered examples show that the nucleophilicity of the
anilines, which is controlled by the electronic effects of
the substituents, has little influence (Table 1, entries 1–14
and 17), whereas steric hindrance has a much more
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

PAPER
Preparation of S-Methyl Arylcarbamothioates
1117
marked effect (compare: entries 2 and 3 with entries 6 and amine. The procedure is facile, safe and inexpensive and,
7; entries 15 and 16 with entry 17).
were it to be applied on a large scale, it would also have
the advantage of supplying the co-product S,S-dimethyl
carbonodithioate (5), which is a valuable reagent that is
industrially used in organic synthesis.
Our attention then turned to a case that could have inter-
esting implications in the field of applied chemistry: the
reaction of O,S-dimethyl carbonodithioate (1) with tolu-
ene-2,4-diamine, carried out in the presence of trieth-
yl(methyl)ammonium S-methyl carbonodithioate (3),
prepared in situ as described above, from 1 and triethyl-
amine (Table 1, entry 18). The reaction was performed ac-
cording to procedure D, and required a large excess of 1
(molar ratio of amine/1/triethylamine, 1:5:1) and longer
reaction times (2 h) to go to completion. Pure S,S-dimeth-
yl 4-methylphenylene-1,3-di(carbamothioate) (or tolu-
Column chromatography and TLC were performed on Merck silica
1
gel 60 (70–230 mesh ASTM) and GF 254, respectively. H (200
MHz) and 13C (50 MHz) NMR spectra of samples in CDCl3, unless
otherwise noted, were recorded on a Bruker Avance 200 spectrom-
eter. Mass spectra were recorded on an AT 5973N mass-selective
detector connected to an AT 6890N GC, cross-linked methyl sili-
cone capillary column. All the reactions were carried out in a sol-
vent-free system and were performed in oven-dried glassware. No
ene-2,4-dithiocarbamic acid S,S-dimethyl ester) (4l) was particular device was, however, adopted to exclude moisture or ox-
ygen. Details for the reactions and yields of the pure (GC, GC-MS,
easily obtained in 85% yield. Furthermore, the by-product
1H NMR) S-methyl arylcarbamothioates 4 are listed in Table 1. The
S,S-dimethyl carbonodithioate (5) was isolated in a yield
molecular structure of all the products were confirmed by compari-
of 90%, calculated on the overall amount of 1 that was
son of their physical (mp or bp) and spectral data (MS, 1H NMR, 13
C
added to the reaction (i.e. the amounts used both to pre-
pare the promoter 3 and for the methylthiocarbonylation
of the toluene-2,4-diamine) minus the amount of 1 con-
sumed in the reaction forming 41. Compound 4l has al-
ready been proposed in the literature for the synthesis of
polymers.7 In this case, it was prepared in an autoclave by
reaction of toluene-2,4-diamine with carbon monoxide,
dimethyl disulfide, triethylamine and elemental selenium
as catalyst, in acetonitrile. This procedure, which was de-
scribed in a patent,11a was not judged suitable for industri-
al applications. In contrast, we think that the procedure
proposed here for the preparation of 4l on a laboratory
scale also has the requisites necessary for large-scale pro-
duction; the current approach also makes 4l a promising
candidate for the production of polymers, especially poly-
urethanes [most likely proceeding through toluene diiso-
cyanate (TDI)]. In this perspective it is important to
highlight that the procedure is inexpensive and that, be-
sides the low cost of the reagent O,S-dimethyl carbono-
dithioate (1) and the simple reaction conditions, the cost-
effectiveness is also guaranteed by the production of
methanethiol, a well known commercial reagent and, es-
pecially, of S,S-dimethyl carbonodithioate (5). Indeed, the
latter compound is a valuable reagent that is used on both
laboratory and industrial scales for thiomethylation reac-
tions on heteroaromatic and aliphatic saturated and unsat-
urated substrates, with advantageous methanethiol
substitution,21 and for the production of mesyl chloride
and methanesulfonic acid.22 Furthermore, it is also used in
carbonylation reactions3,15,16 as a substitute to the ex-
tremely hazardous phosgene.14
NMR) with those reported in the literature; satisfactory microanal-
yses were obtained for all the new compounds. The arylamines 2
were purchased from Aldrich Chemical Co and used without further
purification. O,S-Dimethyl carbonodithioate (1) and S,S-dimethyl
carbonodithioate (5) were supplied by Oxon Italia S.p.A. (Italy)23 or
prepared as described in the literature.17
S-Methyl Arylcarbamothioates 4a–l; Typical Procedures
S-Methyl Phenylcarbamothioate (4a); Procedure A (Table 1,
Entry 1)
A mixture of O,S-dimethyl carbonodithioate (1; 1.22 g, 10 mmol)
and Et3N (1.01 g, 10 mmol) was heated to 45 °C in an oil bath, with
stirring. After 10–15 min, triethyl(methyl)ammonium S-methyl car-
bonodithioate (3) began to form and separate from the reaction mix-
ture as a colorless solid, according to the procedure previously
reported.18 The mixture was stirred for ~2 h. During this time the
1
amount of solid 3 increased rapidly. H NMR of a portion of the
mixture, dissolved in CHCl3, showed the presence of the starting re-
agents, namely 1 [d = 2.29 (s, 3 H, SCH3), 3.90 (s, 3 H, OCH3);
39%] and Et3N [d = 0.74 (t, J = 7.2 Hz, 9 H, 3 × CH2CH3), 2.24 (q,
J = 7.2 Hz, 6 H, 3 × CH2CH3); 39%], and the formed products S,S-
dimethyl carbonodithioate [5; d = 2.15 (s, 6 H, 2 × SCH3); 5%] and
the ammonium salt [3; d = 1.15 (t, J = 7.3 Hz, 9 × N+CH2CH3), 1.
88 (s, 3 H, SCH3), 2.93 (s, 3 H, N+CH3), 3.28 (q, J = 7.3 Hz, 6 H,
3 × N+CH2CH3); similar to that reported;18 17%]. GC analysis of the
supernatant liquid mixture, previously washed with H2O, showed
that the 1/5 ratio was ~90:10. After cooling to r.t., aniline (2;
R = Ph; 1.86 g, 20 mmol) was added in one portion, with stirring.
The salt 3 dissolved at once (the dissolution was endothermic), and
a homogeneous liquid mixture was obtained. This new mixture was
added dropwise over 6–7 min to O,S-dimethyl carbonodithioate (1;
2.44 g, 20 mmol), previously heated to 45 °C, with stirring (there
was an immediate exothermic reaction). After 30 min, GC analysis
of the oily reaction mixture showed the presence of the two starting
reagents, the formation of the title compound 4a (as the major prod-
uct), and an increase in the amount of S,S-dimethyl carbonodithio-
ate (5). Stirring and heating were maintained for 30 min, until the
starting reagent 1 disappeared, while unreacted aniline was still
present (~10–15%). MS analysis also showed traces of the follow-
ing byproducts: dimethyl disulfide (m/z = 94 [M+]), and the isomer
of 4a, i.e. O-methyl phenylcarbamothioate (IV; Scheme 4; m/z =
167 [M+], 135 [M+ – CH3OH]). MeSH formed during the reaction
was collected in aq NaOH (10–15%) and recovered as sodium
methanethiolate. The mixture was treated with CH2Cl2–H2O (2:1,
150 mL). The aqueous layer was separated and extracted with
CH2Cl2 (50 mL). The combined organic extracts were washed suc-
cessively with H2O (2 × 50 mL), aq 5% HCl (50 mL) and again with
In conclusion, the present research has led to the develop-
ment of a new procedure that is valid for lab-scale and, po-
tentially, large-scale syntheses of S-methyl aryl-
carbamothioates 4. These compounds, in turn, constitute a
class of starting materials that promise to be excellent for
the production of isocyanates, ureas and carbamates. The
procedure is based on methylthiocarbonylation of primary
arylamines with O,S-dimethyl carbonodithioate (1) in the
presence of triethyl(methyl)ammonium S-methyl carbono-
dithioate (3) prepared in situ by reacting 1 with triethyl-
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

1118
I. Degani et al.
PAPER
H2O (50 mL), dried (Na2SO4), and evaporated under reduced pres-
sure. The title compound 4a was obtained pure by column chroma-
tography (silica gel; CH2Cl2) of the crude residue. The byproduct O-
methyl phenylcarbamothioate (IV) was also isolated in <1% yield
(~0.02 g) as a colorless solid.
endothermic) and a homogeneous liquid mixture was obtained. This
mixture was added dropwise over 6–7 min to O,S-dimethyl carbono-
dithioate (1; 2.44 g, 20 mmol), previously heated to 45 °C, with stir-
ring. After 10–15 min, a solid substance began to separate from the
mixture, the amount of which increased rapidly in the time. After 1
h, GC analysis showed the disappearance of 1, while 4-bromophe-
nylaniline was still present (~20%). A second portion of O,S-di-
methyl carbonodithioate (1; 0.49 g, 4 mmol) was added dropwise
over 1–2 min and stirring and heating were maintained for 1 h. After
this time, GC analysis showed the disappearance of 1, and a further
decrease in the amount of unreacted aniline. As described in Proce-
dure A, the reaction mixture was treated with CH2Cl2–H2O (3:1,
200 mL). The aqueous solution was separated and extracted with
CH2Cl2 (50 mL). The combined organic extracts were washed with
H2O (2 × 50 mL), aq HCl (5%, 50 mL) and again with H2O (50 mL),
dried (Na2SO4), and evaporated under reduced pressure. The title
compound 4h was obtained pure by column chromatography (silica
gel; CH2Cl2) of the crude residue.
Yield: 2.77 g (83%, based on the aniline); colorless crystals; purity
100% (GC, MS, 1H NMR).
1H NMR: d = 4.07 (s, 3 H, OCH3), 6.85–7.38 (m, 5 H, ArH), 8.95
(br s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 167 (100) [M+], 166 (15), 152 (4) [M+ –
CH3], 151 (7), 136 (11) [M+ – CH3O], 135 [M+ – CH3OH], 134 (23),
123 (6), 119 (24), 110 (38), 109 (7), 107 (8), 106 (40), 92 (12), 91
(18), 77 (33), 75 (24), 65 (20), 51 (15).
The acidic aqueous solution was basified with aq NaOH (10%) and
extracted with CH2Cl2 (2 × 50 mL). The combined organic extracts
were repeatedly washed with H2O (5 × 50 mL), dried (Na2SO4), and
evaporated under reduced pressure to recover the pure unreacted
aniline (GC, GC-MS, 1H NMR). Yield: 0.30 g (11%).
Yield: 4.33 g (88%; based on 4-bromoaniline); colorless crystals;
purity 100% (GC, MS, 1H NMR).
Note: To recover the co-product S,S-dimethyl carbonodithioate (5),
in a collateral reaction the combined organic extracts were washed
and dried as above, and then slowly evaporated at atmospheric pres-
sure, maintaining the bath temperature at 40–45 °C. The residue
consisted mainly of 4a and 5 (1H NMR analysis). Column chroma-
tography as above gave compound 5 in the first solvent fractions,
which were carefully evaporated at atmospheric pressure to give a
yellowish oil (1.14 g, recovery: ~70%, calculated on the overall
amount of 1 that was available to react, i.e. the amounts used both
for the preparation of the promoter 3 and for the methylthiocarbon-
ylation of aniline, minus the amount of 1 consumed for the forma-
tion of 4a). As above, the title compound 4a was obtained in 83%
yield (2.77 g).
S-Methyl 4-Chlorophenylcarbamothioate (4g); Procedure D
(Table 1, Entry 12)
Finely ground 4-chloroaniline (2, R = 4-ClC6H4; 2.55 g, 20 mmol)
was directly added in one portion under stirring to a mixture con-
taining the solid triethyl(methyl)ammonium S-methyl carbono-
dithioate (3), prepared as described in Procedure A by heating O,S-
dimethyl carbonodithioate (1; 1.22 g, 10 mmol) and Et3N (1.01 g,
10 mmol) at 45 °C for 2 h. O,S-Dimethyl carbonodithioate (1; 2.44
g, 20 mmol) was then added dropwise over 6–7 min. The solid am-
monium salt 3 and 4-chloroaniline dissolved at once and an exother-
mic reaction occurred. After the addition, stirring and heating at
45 °C were maintained for 1 h. GC analysis showed the complete
disappearance of 1, while 4-chloroaniline (~20%) remained. A sec-
ond portion of O,S-dimethyl carbonodithioate (1; 0.49 g, 4 mmol)
was added dropwise over 1–2 min and stirring and heating were
maintained for 1 h. After this time, GC analysis showed the disap-
pearance of 1, and a further decrease in the amount of unreacted 4-
chloroaniline. Workup as above gave the pure title compound 4g.
Procedure B (Table 1, Entry 2)
The reaction was carried out according to Procedure A, with the fol-
lowing modification. After the reaction was stirred and heated at
45 °C for 1 h, a second portion of O,S-dimethyl carbonodithioate (1;
0.49 g, 4 mmol) was added dropwise over 1–2 min. After 1 h, GC
analysis showed the disappearance of 1, and a further decrease in
the amount of unreacted aniline, compared with the amount present
before the addition (subsequent additions of 1 were ineffective).
Workup as above gave the pure title compound 4a.
Yield: 3.54 g (88%, based on 4-chloroaniline); colorless crystals.
S,S-Dimethyl 4-Methylphenylene-1,3-di(carbamothioate)
[Toluene-2,4-dithiocarbamic Acid S,S-Dimethyl Ester] (4l);
Procedure D (Table 1, Entry 18)
Yield: 2.94 g (88%, based on aniline).
Finely ground toluene-2.4-diamine (1.22 g, 10 mmol) was directly
added in one portion under stirring to a mixture containing the solid
triethyl(methyl)ammonium S-methyl carbonodithioate (3), pre-
pared as described in Procedure A by heating O,S-dimethyl car-
bonodithioate (1; 1.22 g, 10 mmol) and Et3N (1.01 g, 10 mmol) at
45 °C for 2 h. O,S-Dimethyl carbonodithioate (1; 2.44 g, 20 mmol)
was then added dropwise to the mixture over 6–7 min (when the
first drops were added, an exothermic reaction occurred and the sol-
ids, i.e. salt 3 and toluene-2.4-diamine, disappeared, and a viscous
brown oil formed). After 15–20 min a colorless solid began to form.
During the reaction the amount of viscous brown oil decreased and,
simultaneously, the amount of solid increased. GC and GC-MS
analyses of the reaction mixture, carried out after 30 min, showed
the disappearance of the starting reagents, i.e. 1 and toluene-2.4-di-
amine, and the presence of three products: S,S-dimethyl carbono-
dithioate (5; m/z = 122 [M+], 75 [M+ – CH3S]), and toluene-2.4-di-
isocyanate (m/z = 174 [M+]), as major products, and 2-aminotolu-
ene-4-isocyanate {or 4-aminotoluene-2-isocyanate; m/z = 148
(100) [M+], 147 (62), 120 (6), 119 (13), 106 (16), 92 (7), 65 (6)}, as
a minor product. The diisocyanate and the isocyanate formed by
thermal decomposition of 4l and of the intermediate monocarbamo-
thioate, i.e. S-methyl 2-aminotolyl-4-carbamothioate (or 4-amino-
tolyl-2-carbamothioate), respectively, under the GC conditions.
Procedure C (Table 1, Entry 3)
The promoter triethyl(methyl)ammonium S-methyl carbonodithio-
ate (3) was prepared as described in Procedure A and maintained at
45 °C, with stirring. A mixture of O,S-dimethyl carbonodithioate
(1; 2.93 g, 24 mmol) and aniline (2, R = Ph; 1.86 g, 20 mmol) was
then added dropwise over 6–7 min. The solid salt 3 dissolved at
once and an exothermic reaction occurred. After the addition, stir-
ring and heating at 45 °C were maintained for 1 h. GC analysis
showed the complete disappearance of 1, while a small amount of
the unreacted aniline (8–10%, by GC analysis) was still present.
Workup as above gave the pure title compound 4a.
Yield: 2.87 g (86%, based on aniline).
S-Methyl 4-Bromophenylcarbamothioate (4h); Procedure B
(Table 1, Entry 13)
Finely ground 4-bromoaniline (2, R = 4-BrC6H4; 3.44 g, 20 mmol)
was added in one portion to a stirred mixture containing the solid tri-
ethyl(methyl)ammonium S-methyl carbonodithioate (3), prepared
as described in Procedure A by heating a mixture of O,S-dimethyl
carbonodithioate (1; 1.22 g, 10 mmol) and Et3N (1.01 g, 10 mmol)
at 45 °C for 2 h, and then cooling to r.t. Both the solids, i.e. 4-bro-
moaniline and the ammonium salt 3, dissolved (the dissolution was
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

PAPER
Preparation of S-Methyl Arylcarbamothioates
1119
The presence of 4l and the intermediate monocarbamothioate in the
reaction mixture was confirmed by 1H NMR and GC-MS analyses
(for 1H NMR and GC-MS data of 4l, see below).
1H NMR: d = 2.43 (s, 3 H, SCH3), 7.11 (app t, J = 7.5 Hz, 1 H, ArH),
7.32 (br s, 1 H, NH), 7.32 (app t, J = 7.5 Hz, 2 H, ArH), 7.43 (app
d, J = 7.5 Hz, 2 H, ArH). Identical to the reported spectrum.6a
13C NMR: d = 14.09 (CH3), 121.40, 125.90, 130.55 (CH), 139.24
Monocarbamothioate
(C), 168.15 (C=O). Similar to the reported spectrum.6a
1H NMR (DMSO-d6): d = 1.95 (s, 3 H, CH3), 2.25 (s, 3 H, SCH3),
4.75 (br s, 2 H, NH2; disappeared after treatment with D2O), 6.58
(dd, J = 8.1, 2.0 Hz, 1 H, ArH), 6.75 (d, J = 8.1 Hz, 1 H, ArH), 6.87
(d, J = 2.0 Hz, 1 H, ArH), 9.88 (br s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 167 (41) [M+], 120 (26) [M+ – CH3S],
119 (100) [M+ – CH3SH], 92 (26), 91 (19), 77 (27), 75 (9), 65 (15),
64 (8), 51 (6).
13C NMR (DMSO-d6): d = 11.93 (SCH3), 17.15 (CH3), 105.26,
S-Methyl 2-Tolylcarbamothioate (4b)
107.62, 116.73 (CH), 130.12, 137.73, 146.94 (C), 164.74 (C=O).
Colorless crystals; mp 78.3–79.5 °C (CH2Cl2–pentane) (Lit.24
70 °C). Spectral data are not reported.
MS: m/z (%) = 196 (83) [M+], 149 (20) [M+ – CH3S], 148 (100) [M+
– CH3SH], 147 (49), 121 (20), 119 (8), 106 (38), 94 (20), 93 (9), 79
(7), 77 (14).
1H NMR: d = 2.26 (s, 3 H, CH3), 2.40 (s, 3 H, SCH3), 7.07–7.27 (2
× m, partially overlapped, 4 H, ArH and NH; NH disappeared after
treatment with D2O), 7.58 (app d, J = 7.4 Hz, 1 H, ArH).
13C NMR: d = 14.09 (SCH3), 19.19 (CH3), 126.22, 127.62, 128.20,
131.59 (CH), 132.10, 136.79 (C), 169.16 (C=O).
MS (EI, 70 eV): m/z (%) = 181 (73) [M+], 134 (39) [M+ – CH3S],
133 (100) [M+ – CH3SH], 132 (11), 106 (38), 105 (28), 104 (37), 91
(56), 79 (8), 78 (15), 77 (23), 75 (12), 65 (10).
Two further portions (each addition 1.22 g, 10 mmol) of 1 were then
added after 30 and 60 min. About 30 min after each addition, GC
analysis showed the disappearance of 1 and a large increase of 5.
The reaction was complete after a total time of 2 h (disappearance
of the intermediate monocarbamothioate). The reaction mixture
was cooled, treated with CH2Cl2 (100 mL), and the solid was fil-
tered under suction on a Büchner funnel, and then was washed di-
rectly on the Büchner funnel with CH2Cl2 (80–100 mL). The title
compound 4l was pure by GC, GC-MS, 1H NMR.
S-Methyl 3-Tolylcarbamothioate (4c)
The compound is known, but physical and spectral data were not re-
ported.4c,d
Yield: 2.30 g (85%, based on toluene-2.4-aniline); colorless solid.
1H NMR of the collected organic extracts showed the presence of
S,S-dimethyl carbonodithioate (5), as the major product, Et3N
[d = 0.92 (t, 6 H, 3 × CH3), 2.46 (q, 4 H, 3 × CH2)], and the promot-
er triethyl(methyl)ammonium S-methyl carbonodithioate [3;
d = 1.19 (t, J = 7.3 Hz, 9 H, 3 × CH2CH3), 1.98 (s, 3 H, SCH3), 3.00
(s, 3 H, N+CH3), 3.30 (q, J = 7.3 Hz, 6 H, 3 × CH2); similar to that
reported18]. The organic solution was washed with H2O (2 × 80 mL;
to remove 3), aq HCl (5%, 50 mL; to remove Et3N), again with H2O
(50 mL), and then dried (Na2SO4). The mixture was distilled at at-
mospheric pressure with a Vigreux distillation apparatus until the
temperature of distillate was 39–40 °C (heating bath kept below
50 °C). The remaining residue was S,S-dimethyl carbonodithioate
(5; 4.72 g; recovery: ~90%, calculated on the overall amount of 1
that was available to react, i.e. the amounts used both for the prepa-
ration of the promoter 3 and for the methylthiocarbonylation of tol-
uene-2.4-aniline, minus the amount of 1 consumed for the
formation of 4l).
Colorless crystals; mp 68.6–69.7 °C (CH2Cl2–pentane).
1H NMR: d = 2.32 (s, 3 H, CH3), 2.43 (s, 3 H, SCH3), 6.95 (app d,
J = 5.4 Hz, 1 H, ArH), 7.13–7.24 (m, 2 H, ArH), 7.29 (br s, 1 H,
ArH), 7.45 (br s, 1 H, NH).
13C NMR: d = 14.10 (SCH3), 22.87 (CH3), 118.50, 122.08, 126.71,
130.34 (CH), 139.16, 140.50 (C), 168.06 (C=O).
MS (EI, 70 eV): m/z (%) = 181 (60) [M+], 134 (29) [M+ – CH3S],
133 (100) [M+ – CH3SH], 132 (15), 106 (25), 105 (7), 104 (20), 91
(42), 79 (9), 78 (10), 77 (18), 65 (8).
Anal. Calcd for C9H11NOS: C, 59.64; H, 6.12; N, 7.73; S, 17.69.
Found: C, 59.57; H, 6.14; N, 7.71; S, 17.68.
S-Methyl 4-Tolylcarbamothioate (4d)
Colorless crystals; mp 111–112 °C (CH2Cl2) (Lit.6a 102.1–
103.5 °C).
1H NMR: d = 2.22 (s, 3 H, CH3), 2.42 (s, 3 H, SCH3), 7.12 (app d,
J = 8.4 Hz, 2 H, ArH), 7.20 (br s, 1 H, NH; disappeared after treat-
ment with D2O), 7.27 (dt, J = 8.4, 2.4 Hz, 2 H, ArH). Similar to the
reported spectrum.6a
13C NMR: d = 14.05 (SCH3), 22.28 (CH3), 121.73, 131.04 (CH),
135.71, 136.58 (C), 167.94 (C=O). Similar to the reported spec-
trum.6a
MS (EI, 70 eV): m/z (%) = 181 (65) [M+], 134 (23) [M+ – CH3S],
133 (100) [M+ – CH3SH], 132 (22), 106 (53), 105 (9), 104 (21), 91
(24), 79 (10), 78 (11), 77 (20), 75 (8), 65 (7).
Note: In some cases, a very viscous colorless oil (instead of a solid
as above) began to separate during the reaction, and the whole reac-
tion mixture eventually became an emulsion. 1H NMR analysis of
the emulsion showed the presence of 4l and S,S-dimethyl carbono-
dithioate (5), as major products, and the intermediate S-methyl 2-
aminotolyl-4-carbamothioate (or 4-aminotolyl-2-carbamothioate),
Et3N and the promoter 3, as minor products. The reaction reached
completion with the disappearance of the intermediate monocar-
bamothioate. The emulsion was then allowed to cool to r.t., diluted
with MeOH (10 mL), and then allowed to stand until very small col-
orless crystals separated. The supernatant solvent was cautiously
1
decanted. H NMR showed that the solid was the pure title com-
pound 4l. 1H NMR of the liquid showed the presence of 5, Et3N and
a small amount of 4l.
S-Methyl 4-Methoxyphenylcarbamothioate (4e)
Colorless crystals; mp 102.1–102.8 °C (CH2Cl2).
1H NMR: d = 2.39 (s, 3 H, SCH3), 3.78 (s, 3 H, OCH3), 6.84 (dt,
J = 9.0, 2.7 Hz, and m, partially overlapped, 3 H, 2 × ArH and NH;
NH disappeared after treatment with D2O), 7.31 (dt, J = 9.0, 2.7 Hz,
2 H, ArH).
13C NMR: d = 12.41 (SCH3), 55.28 (OCH3), 114.05, 122.13 (CH),
130.41, 156.60 (C), 166.79 (C=O).
MS (EI, 70 eV): m/z (%) = 197 (66) [M+], 150 (13) [M+ – CH3S],
149 (100) [M+ – CH3SH], 134 (40), 123 (7), 122 (82), 106 (19), 95
(10), 78 (10), 75 (8), 52 (10).
S-Methyl Arylcarbamothioate 4a–l
Procedures and yields for S-methyl arylcarbamothioates 4a–l are
listed in Table 1; physical and spectral data, and elemental analyses
for the new compounds, are reported below.
S-Methyl Phenylcarbamothioate (4a)
Colorless crystals; mp 83.3–84.6 °C (CH2Cl2–pentane) (Lit.9h
84.6 °C; Lit.6a 71.2–72.8 °C).
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

1120
I. Degani et al.
PAPER
Anal. Calcd for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10; S, 16.26.
Found: C, 54.84; H, 5.65; N, 7.10; S, 16.29.
13C NMR (CDCl3): d = 12.23 (SCH3), 18.12 (CH3), 128.16, 132.57
(CH), 135.49, 138.01 (C), 171.73 (C=O).
MS (EI, 70 eV): m/z (%) = 195 (61) [M+], 148 (42) [M+ – CH3S],
147 (100) [M+ – CH3SH], 146 (7), 132 (12), 120 (36), 119 (32), 118
(21), 105 (54), 92 (8), 79 (8), 77 (20), 75 (9), 65 (7).
S-Methyl 4-Methylsulfanylphenylcarbamothioate (4f)
Colorless crystals; mp 123.1–123.7 °C (CH2Cl2).
1H NMR: d = 2.42 (s, 3 H, SCH3), 2.47 (s, 3 H, Ar-SCH3), 7.22 (dt,
J = 8.8, 2.3 Hz, 2 H, ArH), 7.27 (br s, 1 H, NH), 7.35 (dt, J = 8.8,
2.3 Hz, 2 H, ArH).
Anal. Calcd for C10H13NOS: C, 61.50; H, 6.71; N, 7.17; S, 16.42.
Found: C, 61.49; H, 6.65; N, 7.13; S, 16.49.
13C NMR: d = 12.45 (SCH3), 16.38 (C-SCH3), 120.40, 122.78 (CH),
133.74, 135.09 (C), 166.22 (C=O).
S-Methyl 3,5-Dimethylphenylcarbamothioate (4k)
Colorless crystals; mp 115.4–115.8 °C (CH2Cl2).
MS (EI, 70 eV): m/z (%) = 213 (72) [M+], 166 (12) [M+ – CH3S],
165 (100) [M+ – CH3SH], 150 (37), 139 (6), 138 (63), 106 (9), 96
(7), 75 (8).
1H NMR: d = 2.30 (s, 6 H, 2 × CH3), 2.43 (s, 3 H, SCH3), 6.77 (br
s, 1 H, ArH), 7.06 (br s, 2 H, ArH), 7.27 (br s, 1 H, NH).
13C NMR: d = 12.44 (SCH3), 21.12 (CH3), 117.48, 126.02 (CH),
137.38, 138.66 (C), 166.15 (C=O).
MS (EI, 70 eV): m/z (%) = 195 (65) [M+], 148 (29) [M+ – CH3S],
147 (100) [M+ – CH3SH], 146 (10), 132 (31), 120 (24), 118 (10),
105 (40), 91 (15), 79 (7), 77 (18).
Anal. Calcd for C9H11NOS2: C, 50.67; H, 5.20; N, 6.57; S, 30.06.
Found: C, 50.78; H, 5.19; N, 6.53; S, 30.09.
S-Methyl 4-Chlorophenylcarbamothioate (4g)
Colorless crystals; mp 132.5–133.6 °C (CH2Cl2) (Lit.6a 130.5–
131.5 °C).
1H NMR: d = 2.42 (s, 3 H, SCH3), 2.47 (s, 3 H, SCH3), 7.22 (dt,
J = 8.8, 2.3 Hz, 2 H, ArH), 7.27 (br s, 1 H, NH), 7.35 (dt, J = 8.8,
2.3 Hz, 2 H, ArH). Similar to the reported spectrum.6a
Anal. Calcd for C10H13NOS: C, 61.50; H, 6.71; N, 7.17; S, 16.42.
Found: C, 61.62; H, 6.65; N, 7.14; S, 16.45.
S,S-Dimethyl 4-Methylphenylene-1,3-di(carbamothioate)
[Toluene-2,4-dithiocarbamic Acid S,S-Dimethyl Ester] (4l)
Spectral data were not reported.
Colorless crystals; mp 195.2–196.3 °C (toluene) (Lit.7,11a mp
185 °C).
1H NMR (DMSO-d6): d = 2.11 (s, 3 H, CH3), 2.26 (s, 3 H, SCH3),
2.28 (s, 3 H, SCH3), 7.12 (d, J = 8.3 Hz, 1 H, ArH), 7.25 (dd,
J = 8.3, 2.1 Hz, 1 H, ArH), 7.51 (d, J = 2.1 Hz, 1 H, ArH), 9.69 (br
s, 1 H, NH), 10.27 (br s, 1 H, NH).
13C NMR: d = 12.45 (SCH3), 120.79, 128.95 (CH), 129.23, 136.10
(C), 166.33 (C=O). Similar to the reported spectrum.6a
MS (EI, 70 eV): m/z (%) = 201 (30) [M+], 155 (33), 154 (16) [M+ –
SCH3], 153 (100) [M+ – CH3SH], 128 (9), 127 (10), 126 (28), 125
(25), 99 (11), 90 (15), 75 (17), 63 (10).
S-Methyl 4-Bromophenylcarbamothioate (4h)
Colorless crystals; mp 145–146.2 °C (CH2Cl2).
1H NMR: d = 2.43 (s, 3 H, SCH3), 7.34 (dt, J = 9.0, 2.4 Hz, 2 H,
ArH), 7.42 (dt, J = 9.0, 2.4 Hz, 2 H, ArH).
13C NMR (DMSO-d6): d = 13.60 (SCH3), 19.09 (CH3), 118.41,
129.35 (CH), 132.44, 138.09, 138.95 (C), 167.00, 168.06 (C=O).
MS (EI, 70 eV): Under the GC-MS conditions, 4l decomposed and
three products were revealed, in the following order: (1) toluene-
2,4-diisocyanate: m/z (%) = 174 (100) [M+], 173 (26), 146 (28), 145
(62), 132 (16), 119 (8), 118 (10), 91 (11), 76 (6); (2) S-methyl 2-iso-
cyanatotolyl-4-carbamothioate [or 4-isocyanatotolyl-2-carbam-
othioate]: m/z (%) = 222 (65) [M+], 175 (25) [M+ – CH3S], 174
(100) [M+ – CH3SH], 173 (12), 147 (34), 146 (23), 145 (34), 132
(13), 119 (5), 118 (7), 104 (13), 92 (8), 91 (7), 77 (16), 75 (19), 65
(7); (3) S-methyl 4-isocyanatotolyl-2-carbamothioate [or 2-isocy-
anatotolyl-4-carbamothioate]: m/z (%) = 222 (55) [M+], 207 (6),
175 (34) [M+ – CH3S], 174 (100) [M+ – CH3SH], 173 (13), 147 (29),
146 (24), 145 (35), 132 (34), 119 (5), 118 (7), 104 (5), 92 (5), 91 (6),
77 (12), 75 (19), 65 (7).
13C NMR: d = 14.10 (SCH3), 118.43, 122.71 (CH), 133.52, 138.25
(C), 168.00 (C=O).
MS (EI, 70 eV): m/z (%) = 247 (36) [M+], 245 (34), 200 (16) [M+ –
CH3S], 199 (97) [M+ – CH3SH], 198 (17), 197 (100), 172 (29), 171
(17), 170 (309), 169 (14), 91 (18), 90 (24), 75 (23), 64 (11), 63 (18).
Anal. Calcd for C8H8BrNOS: C, 39.04; H, 3.28; N, 5.69; S, 13.03.
Found: C, 39.14; H, 3.30; N, 5.69; S, 13.04.
S-Methyl 3-Trifluoromethylphenylcarbamothioate (4i)
Colorless crystals; mp 101.4–102.8 °C (CH2Cl2).
1H NMR: d = 2.38 (s, 3 H, SCH3), 7.25–7.35 (m, 2 H, ArH), 7.38
(app d, J = 7.7 Hz, 1 H, ArH), 7.54 (dt, J = 7.7, 1.6 Hz, 1 H, ArH),
7.68 (br s, 1 H, NH).
Trial Reactions
13C NMR: d = 12.43 (SCH3), 115.07, 120.65, 126.24, 131.50 (q,
JC–F = 271.0 Hz, CF3), 120.72, 121.00, 129.48 (CH), 130.39,
131.04, 131.68, 132.33 (q, JC–F = 32.5 Hz, CCF3), 138.04 (C),
166.64 (C=O).
A) Reactions with Arylamines and S,S-Dimethyl Carbono-
dithioate (5)
1) A mixture of aniline (0.93 g, 10 mmol) and S,S-dimethyl car-
bonodithioate (5; 1.22 g, 10 mmol) was heated to 180 °C with an oil
bath for 10 h, with stirring. The reaction failed; GC and GC-MS
analyses of the mixture showed the presence of only unchanged
starting reagents.
MS (EI, 70 eV): m/z (%) = 235 (25) [M+], 188 (29) [M+ – CH3S],
187 (100) [M+ – CH3SH], 160 (22), 145 (20), 140 (7), 75 (16).
Anal. Calcd for C9H8F3NOS: C, 45.95; H, 3.43; N, 5.95; S, 13.63.
Found: C, 46.02; H, 3.39; N, 5.90; S, 13.68.
2) A mixture of 4-methoxyaniline (1.23 g, 10 mmol) and S,S-di-
methyl carbonodithioate (5; 1.22 g, 10 mmol) was heated to 185 °C
with an oil bath for 5 h, with stirring. The reaction failed (GC and
GC-MS analyses).
S-Methyl 2,6-Dimethylphenylcarbamothioate (4j)
Colorless crystals; mp 95.7–96.3 °C (EtOAc–pentane).
1H NMR (CDCl3): d = 2.23 (br s, 9 H, 2 × CH3 and SCH3), 6.83 (m,
1 H, ArNH; disappeared after treatment with D2O), 7.05 (m, 3 H,
ArH).
3) A mixture of 4-methoxyaniline (1.23 g, 10 mmol) and S,S-di-
methyl carbonodithioate (5; 1.22 g, 10 mmol) was dissolved in an-
hydrous toluene and the obtained solution was heated to reflux
(111 °C) for 8 h. The reaction failed (GC and GC-MS analyses).
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

PAPER
Preparation of S-Methyl Arylcarbamothioates
1121
B) Reaction of Aniline with O,S-Dimethyl Carbonodithioate (1)
in the Absence of Triethyl(methyl)ammonium S-Methyl Car-
bonodithioate (3)
(4) (a) Harris, G. H. Patent US 2863899, 1958; Chem. Abstr.
1959, 53, 50995. (b) Freud, H.; Jaeger, A. (Schering AG)
Patent DE 1139694, 1962; Chem. Abstr. 1963, 59, 1701.
(c) Sugiyama, H.; Okuda, I.; Kazumae, N.; Kimura, I.; Ito,
H. (Kumiai Chemical Industry Co., Ltd., Jpn) Patent JP
48008812, 1973; Chem. Abstr. 1973, 79, 28396.
1) A mixture of aniline (0.93 g, 10 mmol) and O,S-dimethyl car-
bonodithioate (1; 1.22 g, 10 mmol) was heated to 45 °C for 4 h, with
stirring. GC and GC-MS analyses showed the presence of traces of
N-methylaniline, in addition to the two unchanged reagents. When
the mixture was then heated to 60 °C for 2 h, the amount of N-
methylaniline increased (2–3%). After heating to 80 °C for 4 h, the
amount of N-methylaniline increased to 7–8% and N,N-dimethyl-
aniline and N,N¢-diphenylurea began to form.
(d) Czajkowski, A. J.; Schafer, D. E. (Monsanto Co.) Patent
US 4231786, 1980; Chem. Abstr. 1980, 94, 116011.
(e) Cui, D.; Li, Z.; Liu, R.; Song, G.; Qian, X. Org. Prep.
Proced. Int. 2003, 35, 223.
(5) Lee, K. H.; Koketsu, M.; Hcoi, S. Y.; Lee, K. J.; Lee, P.
Chem. Pharm. Bull. 2005, 53, 747.
2) The above mixture was directly heated to 100 °C, with stirring.
After 3 h, about 10% of the reagent 1 was still present and the fol-
lowing products were formed: N-methylaniline (I: m/z = 107 [M+])
and N,N-dimethylaniline (II: m/z = 121 [M+]), as major products,
and O-methyl N-methyl-N-phenylcarbamothioate (III: m/z = 181
[M+], 106 [M+ – CH3], 150 [M+ – CH3O]), O-methyl phenylcar-
bamothioate (IV: m/z = 167 [M+], 152 [M+ – CH3], 135 [M+ –
CH3OH]), N-methyl-N,N¢-diphenylurea (V: m/z = 226 [M+]) and
N,N¢-diphenylurea (VI: m/z = 212 [M+]). A colorless solid began to
separate from the reaction mixture, which increased over time to-
gether with plentiful gas evolution (MeSH and H2S) observed. After
8 h, the starting O,S-dimethyl carbonodithioate (1) disappeared,
while about 10% of aniline was still present. The mixture was dilut-
ed with CH2Cl2 (50 mL) and the solid was filtered under suction on
a Büchner funnel and then washed directly on the Büchner funnel
with further CH2Cl2 (10 mL). The colorless solid was pure (GC,
(6) (a) Takahashi, H.; Nishina, A.; Fukumoto, R.-h.; Kimura,
H.; Koketsu, M.; Ishihara, H. Eur. J. Pharm. Sci. 2005, 24,
291. (b) Takahashi, M.; Sekiguchi, A.; Nishina, A.; Kimura,
H.; Koketsu, M. (Gunma Prefecture, Jpn) Patent JP 195615,
2008; Chem. Abstr. 2008, 149, 299862.
(7) Koch, P.; Anfossi, B. (Anic S.p.A., Italy) Patent DE
2617918, 1976; Chem. Abstr. 1977, 86, 43427.
(8) Kim, S.-m.; Park, S.-e.; Kim, S.-j. (Korea Kumho
Petrochemical Co., Ltd., S. Korea) Patent KR 9704412,
1997; Chem. Abstr. 2000, 133, 192768.
(9) For syntheses and applications of S-alkyl arylcarbamo-
thioates, see: (a) Yoshida, K.; Isobe, M.; Yano, K.;
Nagamatsu, K. Bull. Chem. Soc. Jpn. 1985, 58, 2143.
(b) Sitzmann, M. E.; Gilligan, W. H. J. Org. Chem. 1985, 50,
5879. (c) Sonoda, N.; Mizuno, T.; Murakami, S.; Kondo, K.;
Ogawa, A.; Ryu, I.; Kambe, N. Angew. Chem., Int. Ed. Engl.
1989, 28, 452. (d) Klimochkin, Y. N.; Moiseev, I. K.;
Abramov, O. V.; Vladyko, G. V.; Korobchenko, L. V.;
Boreko, E. I. Khimiko-Farmatsevticheskii Zhurnal 1991, 25,
49; Chem. Abstr. 1991, 115, 207563. (e) Nagao, Y.; Abe,
Y.; Misono, T.; Ichizen, N.; Shima, Y.; Iesaki, H.;
Furushima, M. Nippon Kagaku Kaishi 1993, 719; Chem.
Abstr. 1994, 120, 106493. (f) Harayama, H.; Nagahama, T.;
Kozera, T.; Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y.
Bull. Chem. Soc. Jpn. 1997, 70, 445. (g) Koketsu, M.;
Kobayashi, C.; Ishihara, H. Heteroat. Chem. 2003, 14, 374.
(h) Mizuno, T.; Takahashi, J.; Ogawa, A. Tetrahedron 2003,
59, 1327. (i) Zhang, X.; Lu, S. Synlett 2005, 1535.
(j) Movassagh, B.; Zakinezhad, Y. Chem. Lett. 2005, 34,
1330. (k) Zhang, X.; Lu, S. Cuihua Xuebao 2005, 26, 453;
Chem. Abstr.; 2005, 143: 422104. (l) Su, W.; Zhang, J.
(Zhejiang University of Technology, CN) Patent CN
1785973, 2006; Chem. Abstr. 2006, 145, 145424.
(m) Zhang, X.; Lu, S.; Wang, S. (Dalian Institute of
Chemical Physics, CN) Patent CN 1721402, 2006; Chem.
Abstr. 2006, 145, 188564. (n) Zhang, X.; Lu, S. (Dalian
Institute of Chemical Physics, CN) Patent CN 1814588,
2006; Chem. Abstr. 2006, 145, 271467. (o) Zhang, X.;
Lu, S. (Dalian Institute of Chemical Physics, CN) Patent CN
1824651, 2006; Chem. Abstr. 2006, 145, 292701.
(p) Zhang, X.; Lu, S. (Dalian Institute of Chemical Physics,
CN) Patent CN 1847224, 2006; Chem. Abstr. 2006, 145,
471265. (q) Zhang, X.; Lu, S. Synth. Commun. 2007, 37,
3291. (r) Chaturvedi, D.; Mishra, N.; Mishra, V. Synthesis
2008, 355. (s) Zhang, X.; Lu, S.-W. Gaodeng Xuexiao
Huaxue Xuebao 2008, 29, 1137; Chem. Abstr. 2008, 150,
237190.
1
GC-MS, H NMR) N,N¢-diphenylurea (VI; 0.23 g, 21%). GC and
GC-MS analyses of the collected organic solutions revealed the
presence of unreacted aniline and the above products, in the follow-
ing GC order and percentage ratio: aniline (10%), I (22%), II
(36%), III (11%), IV (5%), V (11%). After evaporation of the sol-
vent under reduced pressure, 0.73 g of residue remained.
Acknowledgment
This work was supported by the Ministero dell’Università e della
Ricerca (MIUR) and the National Research Council (CNR), Italy,
National Project ‘New synthetic methodologies for industrial inter-
mediates and products’ and by the University of Turin.
References
(1) Professor Emeritus, University of Turin, Italy.
(2) For reviews on the synthesis and applications of
carbamothioates, see: (a) Rossi, L. In Science of Synthesis,
Vol. 18; Knight, J. G., Ed.; Thieme Verlag: Stuttgart, 2005,
599–648; and references cited therein. (b) Petersen, U. In
Houben-Weyl, 4th ed., Vol. E4; Hagemann, H., Ed.; Georg
Thieme Verlag: Stuttgart, 1983, 293–309; and references
cited therein. (c) Melnikov, N. N. In Chemistry of
Pesticides; Gunther, F. A.; Gunther, J. D., Eds.; Springer
Verlag: New York, 1971, 206–222; and references cited
therein.
(3) For recent references on the synthesis and applications of
carbamothioates, see: Artuso, E.; Carvoli, G.; Degani, I.;
Fochi, R.; Magistris, C. Synthesis 2007, 1096; and references
cited therein.
(10) (a) Macho, V.; Schmidtova, M.; Vojcek, L.
(Chemickotechnologicka Facultà Stu.) Patent SK 277855,
1995; Chem. Abstr. 1997, 126, 59754. (b) Macho, V.
Petrol. Coal 1996, 38, 29; Chem Abstr. 1997, 126, 13620.
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York

1122
I. Degani et al.
PAPER
S.p.A., Italy) Patent IT 2004MI2402, 2005; Chem. Abstr.
2009, 151, 123682. (b) Artuso, E.; Degani, I.; Fochi, R.;
Magistris, C. Synthesis 2007, 3497. (c) Degani, I.; Fochi,
R.; Magistris, C.; Migliaccio, M. Synthesis 2009, 801.
(17) Degani, I.; Fochi, R.; Regondi, V. Synthesis 1981, 149.
(18) Degani, I.; Fochi, R.; Magistris, C. Synthesis 2009, 3807.
(19) Leung, M.-k.; Lai, J.-L.; Lau, K.-H.; Yu, H.-h.; Hsiao, H.-J.
J. Org. Chem. 1996, 61, 4175.
(11) (a) Koch, P.; Anfossi, B. (Anic S.p.A., Italy) Patent DE
2617917, 1976; Chem. Abstr. 1977, 86, 43426.
(b) Giroldini, V.; Neri, C. (Anic S.p.A., Italy) Patent EP
86017, 1983; Chem. Abstr. 1982, 100, 5887. (c) Mizuno,
T.; Nishiguchi, I.; Sonoda, N. Tetrahedron 1994, 50, 5669.
(12) Schirmer, U.; Becker, R.; Wuerzer, B. (BASF A.G.) Patent
DE 2926049, 1981; Chem. Abstr. 1981, 95, 6871.
(13) Elderfield, R. C.; Short, F. W. J. Org. Chem. 1953, 18, 1092;
and references cited therein.
(20) Delepine, M. M.; Schving, P. Bull. Soc. Chim. Fr. 1910, 7,
(14) For more information on the toxicity of phosgene, see for
example: (a) Lewis, R. J. Sr. Sax’s Dangerous Properties of
Industrial Materials, 11th ed., Vol. 3; Wiley: Hoboken,
2004, 2944–2945. (b) Senet, J.-P. In Recent Advances in
Phosgene Chemistry, Vol. 1; Société Nationale des Poudres
et des Explosifs: Nanterre, 1997, 10–11. (c) Cotarca, L.;
Eckert, H. Phosgenations: A Handbook; Wiley-VCH:
Weinheim, 2003, 9.
(15) (a) Carvoli, G.; Degani, I.; Pallucca, E.; Fochi, R.; Gazzetto,
S.; Artuso, E.; Lazzaroni, M.; Cadamuro, S. (Oxon Italia
S.p.A., Italy) Patent IT MI 001284, 2005. (b) Artuso, E.;
Degani, I.; Fochi, R.; Magistris, C. Synthesis 2008, 1612.
(c) Degani, I.; Fochi, R.; Magistris, C. Synthesis 2008, 2919.
(16) (a) Carvoli, G.; Degani, I.; Pallucca, E.; Fochi, R.; Serri, A.
M.; Cadamuro, S.; Gazzetto, S.; Migliaccio, M. (Oxon Italia
898.
(21) (a) Degani, I.; Fochi, R.; Regondi, V. (CNR, Italy) Patent EP
63327, 1982; Chem. Abstr.; 1983, 98: 160238. (b) Degani,
I.; Fochi, R.; Regondi, V. Synthesis 1983, 630. (c) Degani,
I.; Fochi, R.; Regondi, V. Synthesis 1986, 1070.
(d) Cadamuro, S.; Degani, I.; Fochi, R.; Regondi, V. Chem.
Ind. (London) 1986, 671. (e) Degani, I.; Fochi, R.; Regondi,
V. (CNR, Italy) Patent IT 1173436, 1987.
(22) (a) Barbero, M.; Degani, I.; Fochi, R.; Regondi, V. (CNR,
Italy) Patent EP 234249, 1987; Chem. Abstr. 1988, 108,
23697. (b) Barbero, M.; Cadamuro, S.; Degani, I.; Fochi, R.;
Regondi, V. Synthesis 1989, 957.
(23) Oxon Italia S.p.A., 20016 Pero (Milano), Italy.
(24) Bielschowsky, W. Ber. Dtsch. Chem. Ges. 1882, 15, 1317.
Synthesis 2010, No. 7, 1113–1122 © Thieme Stuttgart · New York