Metathetic sulfur transfer mediated by N-(2-aminophenyl)-4-methyl-thiazolin-2-thione derivatives: a route to diversely substituted S-alkylcarbamothioates

Article abstract of DOI:10.1016/j.tet.2010.01.020

A new route to S-alkylcarbamothioates is disclosed. In a first step, N-(2-aminophenyl)-4-methyl-thiazolin-2-thione is transformed into a mono- or disubstituted urea at nitrogen, and then in a second step, alkylated at sulfur. The resulting salts, after treatment with a base, gave S-alkylcarbamothioates in high isolated yields together with 3-methyl[1,3]thiazolo[3,2-a]benzimidazole under very mild conditions.

Full text of DOI:10.1016/j.tet.2010.01.020

Tetrahedron 66 (2010) 1852–1858
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Tetrahedron
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Metathetic sulfur transfer mediated by N-(2-aminophenyl)-4-methyl-thiazolin-
2-thione derivatives: a route to diversely substituted S-alkylcarbamothioates
Abdallah Larbi Doukara, Mohammed Amine Mehdid, Ayada Djafri, Federico Andreoli,
*
Nicolas Vanthuyne, Christian Roussel
´
´
Chirosciences, ISM2, Universite Paul Cezanne Aix-Marseille III, 13397 Marseille CEDEX 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route to S-alkylcarbamothioates is disclosed. In a first step, N-(2-aminophenyl)-4-methyl-thi-
azolin-2-thione is transformed into a mono- or disubstituted urea at nitrogen, and then in a second step,
alkylated at sulfur. The resulting salts, after treatment with a base, gave S-alkylcarbamothioates in high
isolated yields together with 3-methyl[1,3]thiazolo[3,2-a]benzimidazole under very mild conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 3 December 2009
Received in revised form 30 December 2009
Accepted 5 January 2010
Available online 11 January 2010
Keywords:
Sulfur transfer
Heterocycle
Thiazolin-2-thione
Alkylation
Urea
1. Introduction
Compound 1a conveys the appropriate molecular characteristics
to achieve this goal: an axial chirality, a urea in a suitable confor-
Compound 1a was designed to perform enantioselective ex-
traction of carboxylates of N-protected amino acids (Fig. 1).
mation for double hydrogen bonding with a carboxylate anion and
a positive charge to enhance the binding through electrostatic in-
teraction. X-ray of 1a showed that the iodide anion developed si-
multaneous H-bonding with the two parallel NH of the urea; it was
an encouraging hint to introduce 1a in the very active field of anion
selective receptors.1,2 To our surprise, 1a in the presence of a car-
boxylate anion, which acted as a base, was readily and quantitatively
transformed into 3-methyl[1,3]thiazolo[3,2-a]benzimidazole 7,
which was known from a previous study,3 and S-methyl phenyl-
carbamothioate 2a (Scheme 1). The reaction was particularly clean
and proceeded at room temperature in CD3CN during NMR analysis.
H3C
S
H
N
H3C
N
+
S
N
1a
O
7
2a
Figure 1. 4-Methyl-2-(methylthio)-3-(2-(3-phenylureido)phenyl)thiazol-3-ium iodide
(1a). X-ray of 1a including a CH2Cl2 molecule, iodine-violet, chlorine-green, nitrogen-
blue, oxygen-red, sulfur-yellow.
Scheme 1. Metathetic process leading to 7 and carbamothioate 2a from 1a.
The outcome of the new reaction depicted in Scheme 1 corre-
sponds to a metathetic process in which a carbamothioate frame-
work is obtained by connecting two molecular fragments bound to
a heterocyclic template, which concomitantly gives the highly
conjugated heterocycle 7.
* Corresponding author.
E-mail address: christian.roussel@univ-cezanne.fr (C. Roussel).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.020

A.L. Doukara et al. / Tetrahedron 66 (2010) 1852–1858
1853
S-Alkyl alkylcarbamothioates, S-alkyl dialkylcarbamothioates
and S-alkyl arylcarbamothioates constitute a highly valuable class
of compounds since they are active on diverse biological targets.
Synthesis and properties of carbamothioates have been recently
reviewed in 2005 by Rossi.4 S-alkylcarbamothioates such as Moli-
nate, Ethiolate or EPTC are produced at the multi-ton scale as ag-
rochemicals. Obviously, the reaction described in Scheme 1 cannot
be used for a large scale preparation of S-alkylcarbamothioates
since for each mole of 2a, a mole of 7 is produced in a very poor
atom economy. Nevertheless, we believe that there is room for
a safe, clean and flexible method to prepare libraries of very pure
S-alkylcarbamothioates for screening purposes. The main concern
in the previously reported synthesis of S-alkylcarbamothioates is
the occurrence of several sulfur containing by-products generated
by the sulfur source (S8,5 COS,6 thioureas,7 thiocyanates,8 alkyl-
mercaptans,6,9 alkyldisulfides,10 LiAlHSH11). These by-products and
the S-alkyl carbamothioate are formed during the same reaction
step and the isolation of the targeted compound requires extensive
purification. As said before the reaction described in Scheme 1 is
very efficient in term of sulfur atom: one of the sulfur atoms is
quantitatively transferred and the second sulfur atom is trapped
into an aromatic structure. Results using the unprecedented
methodology described in Scheme 1 are reported herein.
reacting the amino group of N-(2-aminophenyl)-4-methyl-thiazo-
lin-2-thione 4 with a series of commercially available isocyanates
(procedure A, Table 1) or by a triphosgene mediated coupling of the
amino group of 4 with the corresponding primary or secondary
amines (procedure B, Table 1). Ureas 3l–n were prepared to illus-
trate the preparation of the well known Molinate, Ethiolate and
EPTC, respectively.
Table 1
Isolated yields in carbamothioates 2 from compounds 1 (Y/1), compounds 2 (Y/2)
and N-(2-aminophenyl)-4-methyl-thiazolin-2-thione 4 (Y/4)
a
Cpd
R1
R2
R3
Y/1
Y/3
Y/4
2a
2b
2c
2d
2e
2f
2g
2h
2i
Phenyl
p-Tolyl
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Et
Et
Et
Et
Decyl
Decyl
Et
Et
Et
A
A
A
A
B
A
A
B
B
A
A
B
B
B
95
94
93
96
96
93
96
94
97
97
95
dg
dg
dg
92
91
90
94
95
91
90
90
96
93
92
95
96
96
86
87
87
91
60
85
87
57
72
87
88
64
66
61
3,5-Bis TFMPb
4-Nitrophenyl
3,5-Bis TFMBc
Phenyl
p-Tolyl
3,5-Bis TFMBc
i-Pr
2j
Phenyl
p-Tolyl
–(CH2)6–
Et
Pr
2k
2ld
2me
2nf
Et
Pr
a
Urea route: A: R1NCO, CH3CN; B: Triphosgene, NEt3, CH2Cl2 then R1R2NH.
2. Results and discussion
b
c
d
e
f
Bis TFMP¼3,5-bis(trifluoromethyl)phenyl.
bis TFMB¼3,5-bis(trifluoromethyl)benzyl.
Large libraries of thiazolium salts 1 can be selectively prepared in
high yield from urea derivatives 3 by alkylation at sulfur (Scheme 2).
Alkylation at sulfur in N-substituted thiazoline-2-thiones is a well
documented bimolecular reaction which can be performed with
various alkylating agents such as alkyltosylates or alkyl halides in
polar aprotic solvents.12 Alkyl iodides were chosen to exemplify the
reaction. The consumption of 3 was monitored by TLC. Salts 1a–n
were obtained in isolated yields greater than 96% from the corre-
sponding ureas 3a–n.
Molinate.
Ethiolate.
EPTC.
g
Thiazolium salts have not been isolated.
The key starting material N-(2-aminophenyl)-4-methyl-thiazo-
lin-2-thione 4 is readily available at a multigram scale from CS2,
1,2-diaminobenzene and 1-chloro-propan-2-one.13 It is worth
mentioning that all the by-product issues linked to the sulfur
source in classical carbamothioate syntheses are solved once and
for all during the preparation of 4 with no significant incidence on
the purity of 2, two steps later.
Under basic conditions, the mechanism of the metathetic re-
action leading to 2 from 1 probably involves the formation of
a neutral tetrahedral intermediate 5 by addition of the nitrogen of
the urea to the highly activated C-2 carbon in the thiazolium salt 1
(Scheme 3). The stable conformation observed by X-ray for 1a re-
veals that the nitrogen of the urea is situated in a plane perpen-
dicular to the heterocyclic framework, in an ideal situation for
a nucleophilic addition at the electrophilic C-2 position. The best
leaving group in the resulting tetrahedral intermediate 5 is obvi-
ously the R3Sꢀ group, which further attacks the highly activated
intermediate 6 to yield the final products.
S
S
S
S
H3C
N
R2
N
H3C
N
R3
step 2
X
(i) or (ii)
step 1
H
NH2
N
R1
O
4
3
R3
S
S
R3
R2
+
N
R2
N
H3C
NEt3
S
N
R1
7
+
H
N
R1
CH3CN
rt
O
2
O
-
1
X
R3
(i) R1-N=C=O (R2= H); (ii) triphosgene, R1NHR2
R3
-
H3C
H3C
S
S
S
Scheme 2. Two steps synthesis of 1a–n from N-(2-aminophenyl)-4-methyl-thiazolin-
2-thione 4.
S
Base
N
N
+
7
2
1
O
O
N
N+
R2
R2
1 N
1 N
5
6
Thiazolium salts 1a–n in the presence of a base such as
triethylamine in CH3CN were transformed in less than 15 min in
carbamothioates 2a–n and 3-methyl[1,3]thiazolo[3,2-a]benzimid-
azole 7 at room temperature. In all the reported examples the re-
action media were outstandingly clean. The substituent diversity
on the nitrogen is brought by the substituent(s) of the starting urea
formed in Step 1, while the substituent diversity at sulfur in car-
bamothioates 2 is brought by the alkylating agent (R3-X) in Step 2.
Selected examples are reported in Table 1. The isolated yields in
2a–n from 3a–n were greater than 90% for two combined steps
(Scheme 2). Diversely substituted ureas 3a–n were obtained by
R
R
Scheme 3. Proposed intermediates to obtain carbamothioates 2a–n from thiazolium
salts 1a–n.
The proposed intermediate 6 is so highly activated that one may
envision a concerted process within a tight ion pair consisting of
R3Sꢀ and 6. In order to address this issue experiments were per-
formed in which equimolecular amounts of the two salts 1k (R1¼p-
tolyl, R3¼n-decyl) and 1a (R1¼phenyl, R3¼methyl) were mixed and
simultaneously treated with triethylamine in methanol. The crude

1854
A.L. Doukara et al. / Tetrahedron 66 (2010) 1852–1858
reaction mixture was analysed by ESI-MS after evaporation of the
solvent. Compounds with masses (Mþ1 and MþNa) corresponding
to the four possible S-alkylcarbamothioates 2 were obtained in
similar amount. Thus, the two expected S-alkylcarbamothioates 2k
(R1¼p-tolyl, R3¼n-decyl) and 2a (R1¼phenyl, R3¼methyl) resulting
from the parent salts 1k and 1a and the two S-alkylcarbamo-
thioates resulting from cross-coupling 2b (R1¼p-tolyl, R3¼methyl)
and 2j (R1¼phenyl, R3¼n-decyl) were obtained. These experiments
ruled out any tight ion pair intramolecular mechanism in the for-
mation of the S-alkylthiocarbamates 2. They also ruled out the
formation of 7 and 2 from a concerted elimination occurring in 5.
136.76, 140.00, 152.28, 189.18; HRMS m/z calcd C18H18N3OS2
[MþH]þ: 356.0886; found: 356.0883.
4.2.3. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-(2-(4-methyl-2-thio-
xothiazol-3(2H)-yl)phenyl)urea (3c). Yield: 97% (2.08 g, colourless
crystals); mp 221–223 ꢁC; 1H NMR (300 MHz, CDCl3)
d 1.92 (d, 3H,
J¼0.8 Hz; CH3), 6.65 (q, 1H, J¼0.8 Hz; H5), 6.84–6.93 (m, 6H; Ar),
7.13–7.19 (m, 1H; Ar), 7.20–7.28 (m, 1H; Ar), 7.34 (s, 1H; NH), 7.46 (s,
1H; Ar), 7.72 (s, 2H; Ar), 8.11–8.19 (m, 1H; Ar), 8.31 (s, 1H; NH); 13C
NMR (75 MHz, CDCl3)
d
15.31, 110.12, 115.52(sept, 2C; J¼4 Hz),
118.07 (q, 2C; J¼3 Hz), 123.20 (q, 2C; J¼273 Hz), 123.53, 124.82,
126.94, 128.35, 131.29, 131.79 (q, 2C; J¼33 Hz), 135.38, 140.31,
141.42, 151.40, 189.87; C19H13F6N3OS2 requires: C, 47.80; H, 2.74; N,
8.80; S, 13.43. Found: C, 47.70; H, 2.46; N, 8.76; S, 13.32.
3. Conclusion
In summary carbamothioates 2 are prepared in high yield from
thiazolium salts 1, which are obtained in a two-step process from
4.2.4. 1-(2-(4-Methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-(4-nitro-
N-(2-aminophenyl)-4-methyl-thiazolin-2-thione
4
acting as
phenyl)urea (3d). Yield: 97% (1.69 g, yellow crystals); mp 249–
a clean sulfur transfer agent. In the present study, 3-methyl[1,3]-
thiazolo[3,2-a]benzimidazole 7 is a signature of the starting het-
erocycle 4. Obviously changed signatures would be obtained
starting from other frameworks presenting a thiocarbonyl group
and an aminophenyl group in a topological relationship similar to
the one encountered in 4. The design of analogues of N-(2-ami-
nophenyl)-4-methyl-thiazolin-2-thione 4, which can be conve-
niently attached to a Merrifield bead is underway to provide
a traceless solid-phase synthesis of S-alkylcarbamothioates 2.
251 ꢁC; 1H NMR (200 MHz, DMSO-d6)
d
1.85 (d, 3H, J¼1.1 Hz; CH3),
6.94 (q, 1H, J¼1.1 Hz; H5), 7.20–7.34 (m, 2H; Ar), 7.45–7.55 (m, 1H;
Ar), 7.58–7.70 (m, 2H; Ar), 7.93 (s, 1H; NH), 8.02–8.12 (m, 1H; Ar),
8.13–8.25 (m, 2H; Ar), 9.83 (s, 1H; NH); 13C NMR (75 MHz, DMSO-
d6)
d 15.00, 107.95, 117.54 (2C), 123.48, 124.64, 125.20 (2C), 128.40,
129.20, 130.12, 135.12, 139.98, 141.22, 145.90, 151.92, 189.11; HRMS
m/z calcd C17H14N4O3S2 [MþH]þ: 387.0580; found: 387.0579.
4.3. General procedure (B) for the preparation of ureas 3e–i
4. Experimental section
4.1. General information
A solution of 4 (300 mg, 1.35 mmol) and NEt3 (2 equiv,
2.70 mmol) in dry CH2Cl2 (10 mL) is added dropwise to a solution of
triphosgene (1 equiv, 0.45 mmol) in dry CH2Cl2 (5 mL). The solution
is stirred for 1 h at room temperature and then the corresponding
amine (1.1 equiv) is added. After 12 h dry CH2Cl2 is added and the
solution washed 3ꢂ25 mL of brine. The organic layer is dried over
MgSO4 and evaporated to dryness. The resulting solid is purified by
silica gel chromatography.
1H NMR spectra were recorded at 500, 400, 300 or 200 MHz and
13C NMR spectra at 125, 100, 75 or 50 MHz on Bruker Avance DRX-
500 or 400, DPX-300 or 200 instruments, respectively. Chemical
shifts are reported in ppm with the signal for residual solvent as
internal standard. J values are reported in Hertz. High resolution
mass spectra were performed on Q-STAR Elite spectrometer.
Melting points were measured using a Bu¨chi Melting Point B-545
apparatus or a Kofler hot stage apparatus and are not corrected.
Filtrations through silica gel were performed with silica gel 60
(230–400 mesh). TLCs were carried out on Merck 60F254 silica
plates.
Crystallographic data for 1a have been deposited at the Cam-
bridge Crystallographic Data Centre and allocated the deposition
number CCDC-756573. This data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax:044(1223)336-033; E-mail: deposit@ccdc.cam.ac.uk].
4.3.1. 1-(3,5-Bis(trifluoromethyl)benzyl)-3-(2-(4-methyl-2-thio-
xothiazol-3(2H)-yl)phenyl)urea 3e. Yield: 62% (411 mg, white
solid); mp 167–169 ꢁC; Rf¼0.50 (CH2Cl2/AcOEt, 9:1); 1H NMR
(300 MHz, DMSO-d6)
d
1.81 (d, 3H, J¼1.2 Hz; CH3), 4.35–4.55 (m,
2H; CH2), 6.87 (q,1H, J¼1.2 Hz; H5), 7.12–7.20 (m, 2H; Ar), 7.36–7.47
(m, 3H; Ar and NH), 7.71 (s, 1H; NH), 7.94 (s, 2H; Ar), 7.98 (s, 1H; Ar),
8.03–8.09 (m, 1H; Ar); 13C NMR (75 MHz, DMSO-d6)
d 14.80, 41.93,
107.64, 120.53 (sept, 1C, J¼4 Hz), 122.48, 123.21, 123.37 (q, 2C,
J¼273 Hz), 127.25, 127.82 (q, 2C, J¼3 Hz), 129.03, 129.88, 130.17 (q,
2C, J¼33 Hz), 136.34, 139.94, 144.06, 155.15, 189.17; HRMS m/z calcd
C20H16F6N3OS2 [MþH]þ: 492.0634; found: 492.0639.
4.3.2. 1-Isopropyl-3-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)
urea (3f). Yield: 75% (311 mg, white solid); mp 198–200 ꢁC;
Rf¼0.36 (CH2Cl2/AcOEt, 7.5/2.5); 1H NMR (300 MHz, DMSO-d6)
4.2. General procedure (A) for the preparation of ureas 3a–d
Compound 4 (1 g, 4.5 mmol) is solubilised in CH3CN (10 mL).
Then the corresponding isocyanate (1.05 equiv) was added and the
solution stirred at room temperature. After 24 h the solvent was
removed and the resulting solid recrystallized from CH2Cl2.
d
1.04 (d, 3H, J1¼6.5 Hz; CH3), 1.08 (d, 3H, J1¼6.5 Hz; CH3), 1.81 (d,
3H, J¼1.2 Hz; CH3), 3.60–3.78 (sept, d, 1H, J1¼6.5 Hz, J2¼7.0 Hz; CH),
6.72 (d, 1H, J2¼7.0; NH), 6.90 (q, 1H, J¼1.2 Hz; H5), 7.05–7.11 (m, 2H;
Ar), 7.33 (s, 1H; NH), 7.35–7.43 (m, 2H; Ar), 8.16–8.23 (m, 1H; Ar);
13C NMR (75 MHz, DMSO-d6)
d 14.89, 22.87, 22.91, 41.10, 107.73,
4.2.1. 1-(2-(4-Methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-phenyl-
121.36, 122.38, 126.30, 129.00, 129.84, 136.88, 140.05, 154.15,
189.22; HRMS m/z calcd C14H18N3OS2 [MþH]þ: 308.0886; found:
308.0890.
urea (3a). Compound 3a was available from a previous study.2
4.2.2. 1-(2-(4-Methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-p-tolyl-
urea (3b). Yield: 96% (1.55 g, colourless crystals); mp 206–208 ꢁC;
4.3.3. N-(2-(4-Methyl-2-thioxothiazol-3(2H)-yl)phenyl)azepane-1-
carboxamide (3g). Yield: 67% (312 mg, white solid); mp 133–
135 ꢁC; Rf¼0.39 (CH2Cl2/AcOEt, 7:3); 1H NMR (200 MHz, CDCl3)
1H NMR (300 MHz, DMSO-d6)
d
1.84 (d, 3H, J¼1.1 Hz; CH3), 2.23 (s,
3H; CH3), 6.93 (q,1H, J¼1.1 Hz; H5), 7.06–7.31 (m, 6H; Ar), 7.44–7.50
(m, 1H; Ar), 7.66 (s, 1H; NH), 8.11–8.14 (m, 1H; Ar), 9.07 (s, 1H; NH);
d
1.41–1.84 (m, 8H; (CH2)4), 1.93 (d, 3H, J¼1.2 Hz; CH3), 3.27–3.55
13C NMR (75 MHz, DMSO-d6)
d
14.95, 20.32, 107.85, 118.23 (2C),
(m, 4H; N(CH2)2), 6.36 (q, 1H, J¼1.2 Hz; H5), 6.73 (s, 1H; NH), 7.04–
122.63, 123.55, 127.50, 129.08, 129.25 (2C), 129.96, 130.90, 135.96,
7.16 (m, 1H; Ar), 7.18–7.32 (m, 1H; Ar), 7.42–7.57 (m, 1H; Ar), 7.91–

A.L. Doukara et al. / Tetrahedron 66 (2010) 1852–1858
1855
8.02 (m, 1H; Ar); 13C NMR (75 MHz, CDCl3)
d
16.06, 26.92 (2C),
J¼33 Hz), 132.67, 134.22, 141.05, 145.80, 152.10, 179.72; HRMS m/z
calcd C20H16F6N3OS2 [MꢀI]þ: 492.0634; found: 492.0629.
28.30 (2C), 46.88 (2C), 106.75, 124.84,126.23, 127.32, 129.56, 130.59,
136.02, 141.08, 154.81, 188.63; HRMS m/z calcd C17H22N3OS2
[MþH]þ: 348.1199; found: 348.1200.
4.4.4. 4-Methyl-2-(methylthio)-3-(2-(3-(4-nitrophenyl)ureido)-
phenyl)thiazol-3-ium iodide (1d). Yield: 98% (134 mg, white solid);
4.3.4. 1,1-Diethyl-3-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)
mp 183–185 ꢁC; 1H NMR (500 MHz, DMSO-d6)
d 2.21 (d, 3H,
urea (3h). Yield: 69% (299 mg, white solid); mp 129–131 ꢁC;
J¼1.1 Hz; CH3), 2.93 (s, 3H; CH3), 7.42–7.47 (m, 2H; Ar), 7.61–7.67
(m, 3H; Ar), 8.04 (q, 1H, J¼1.1 Hz; H5), 8.08–8.12 (m, 1H; Ar), 8.16–
8.22 (m, 2H; Ar), 8.53 (s, 1H; NH), 9.47 (s, 1H, NH); 13C NMR
Rf¼0.39 (CH2Cl2/AcOEt, 7:3); 1H NMR (200 MHz, CDCl3)
d 1.11 (t, 6H,
J¼7.1 Hz; 2CH3), 1.93 (d, 3H, J¼1.1 Hz; CH3), 3.06–3.50 (m, 4H;
N(CH2)2), 6.36 (q, 1H, J¼1.1 Hz; H5), 6.76 (s, 1H; NH), 7.04–7.16 (m,
1H; Ar), 7.17–7.30 (m, 1H; Ar), 7.42–7.56 (m, 1H; Ar), 7.96–8.06 (m,
(125 MHz, DMSO-d6)
d 13.68, 17.86, 117.80 (2C), 117.95, 124.51,
125.13 (2C), 125.31, 125.57, 128.09, 132.73, 134.32, 141.48, 145.45,
145.94, 151.70, 179.73; HRMS m/z calcd C18H17N4O3S2 [MꢀI]þ:
401.0737; found: 401.0734.
1H; Ar); 13C NMR (75 MHz, CDCl3)
d 13.68 (2C), 16.09, 41.65 (2C),
106.81, 124.60, 125.78, 127.31, 129.16, 130.59, 136.04, 141.06, 154.26,
188.60; HRMS m/z calcd C17H24N3OS2 [MþH]þ: 322.1042; found:
322.1044.
4.4.5. 3-(2-(3-(3,5-Bis(trifluoromethyl)benzyl)ureido)phenyl)-4-
methyl-2-(methylthio)thiazol-3-ium iodide (1e). Yield: 99% (127 mg,
4.3.5. 3-(2-(4-Methyl-2-thioxothiazol-3(2H)-yl)phenyl)-1,1-dipropyl-
white solid); mp 177–179 ꢁC; 1H NMR (300 MHz, CD3OD)
d 2.24 (d,
urea (3i). Yield: 64% (302 mg, orange oil); Rf¼0.29 (CH2Cl2/AcOEt,
3H, J¼1.1 Hz; CH3), 2.94 (s, 3H; CH3), 4.43 (d, 1H, J¼19.8 Hz; CHA),
4.49 (d, 1H, J¼19.8 Hz; CHB), 7.38–7.52 (m, 2H; Ar), 7.66–7.72 (m,
1H; Ar), 7.76 (q, 1H, J¼1.1 Hz; H5), 7.85–7.93 (m, 4H; Ar); 13C NMR
9:1); 1H NMR (300 MHz, CDCl3)
d
0.89 (t, 6H, J¼7.4 Hz; 2CH3), 1.38–
1.63 (m, 4H; 2CH2), 1.92 (d, 3H, J¼1.1 Hz; CH3), 2.99–3.13 (m, 2H;
NCH2), 3.21–3.36 (m, 2H; NCH2), 6.36 (q, 1H, J¼1.1 Hz; H5), 6.74 (s,
1H; NH), 7.05–7.11 (m, 1H; Ar), 7.18–7.26 (m, 1H; Ar), 7.44–7.53 (m,
(75 MHz, CD3OD)
d 14.23, 18.40, 43.75, 117.81, 121.89 (1C, sept,
J¼4 Hz), 124.86 (2C, q, J¼272 Hz), 126.67, 126.85, 127.53, 128.92 (2C,
q, J¼4 Hz), 129.00, 132.72 (2C, q, J¼33 Hz), 134.11, 136.40, 144.53,
148.25, 157.15, 181.81; HRMS m/z calcd C21H18F6N3OS2 [MꢀI]þ:
506.0790; found: 506.0800.
1H; Ar), 7.98–8.04 (m, 1H; Ar); 13C NMR (75 MHz, CDCl3)
d 11.20
(2C), 16.08, 21.68 (2C), 49.34 (2C), 106.76, 124.55, 125.73, 127.29,
129.03, 130.56, 136.09, 141.04, 154.63, 188.63; HRMS m/z calcd
C17H24N3OS2 [MþH]þ: 350.1355; found: 350.1353.
4.5. General procedure for the preparation of thiazolium
salts 1f–n
4.4. General procedure for the preparation of thiazolium
salts 1a–e
Urea 3 (100 mg; 3a 0.29 mmol, 3b 0.28 mmol, 3e 0.20 mmol, 3f
0.33 mmol, 3 g 0.29 mmol, 3 h 0.31 mmol, 3i 0.29 mmol) was sus-
pended in the corresponding alkyl iodide (2 mL) and the mixture
refluxed for 1 h under magnetic stirring. The resulting solid was
then filtered off and washed with petroleum ether.
To a solution of urea 3 (100 mg; 3a 0.29 mmol, 3b 0.28 mmol, 3c
0.21 mmol, 3d 0.26 mmol, 3e 0.20 mmol) in CH3CN (5 mL), CH3I
(10 equiv) was added and the solution stirred at room temperature.
After 24 h the solvent was partially evaporated and the resulting
solid filtered off.
4.5.1. 2-(Ethylthio)-4-methyl-3-(2-(3-phenylureido)phenyl)thiazol-
4.4.1. 4-Methyl-2-(methylthio)-3-(2-(3-phenylureido)phenyl)thiazol-
3-ium iodide (1f). Yield: 98% (143 mg, white solid); mp 119–121 ꢁC;
3-ium iodide (1a). Yield: 97% (137 mg, white solid); mp 156–158 ꢁC;
1H NMR (300 MHz, CD3OD)
d
1.52 (t, 3H, J¼7.4 Hz; CH3), 2.29 (d, 3H,
1H NMR (300 MHz, CD3OD)
d
2.30 (d, 3H, J¼1.1 Hz; CH3), 2.97 (s, 3H;
J¼1.1 Hz; CH3), 3.46 (dq, 1H, J¼7.4 Hz, JAB¼19.8 Hz; CHA), 3.53 (dq,
1H, J¼7.4 Hz, JAB¼19.8 Hz; CHB), 6.99–7.06 (m, 2H; Ar), 7.21–7.59
(m, 6H; Ar), 7.68–7.77 (m, 1H; Ar), 7.86 (q, 1H, J¼1.1 Hz; H5), 8.01–
CH3), 6.99–7.07 (m, 1H; Ar), 7.22–7.55 (m, 6H; Ar), 7.70–7.75 (m, 1H;
Ar), 7.86 (q, 1H, J¼1.1 Hz; H5), 8.05–8.08 (m, 1H; Ar); 13C NMR
(75 MHz, CD3OD)
d
14.29, 18.40, 118.07, 120.30 (2C), 124.34, 126.50,
8.08 (m, 1H; Ar); 13C NMR (75 MHz, CD3OD)
d 13.27, 14.35, 31.83,
126.86, 127.22, 129.01, 129.91 (2C), 134.16, 136.25, 139.85, 148.34,
154.28, 181.99; HRMS m/z calcd C18H18N3OSþ2 [MꢀI]þ: 356.0885;
found: 356.0884.
118.12, 120.30 (2C), 124.33, 126.64, 126.89, 127.50, 129.03, 129.90
(2C), 134.09, 136.14, 139.87, 148.04, 154.27, 180.19; HRMS m/z calcd
C19H20N3OS2 [MꢀI]þ: 370.1042; found: 370.1042.
4.4.2. 4-Methyl-2-(methylthio)-3-(2-(3-p-tolylureido)phenyl)thiazol-
4.5.2. 2-(Ethylthio)-4-methyl-3-(2-(3-p-tolylureido)phenyl)thiazol-
3-ium iodide (1b). Yield: 97% (136 mg, white solid); mp 137–
3-ium iodide (1g). Yield: 94% (135 mg, white solid); mp 142–
139 ꢁC; 1H NMR (300 MHz, CD3OD)
d
2.28 (s, 3H; CH3), 2.30 (d, 3H,
144 ꢁC; 1H NMR (300 MHz, CD3OD)
d
1.41 (t, 3H, J¼7.3 Hz; CH3), 2.19
J¼1.1 Hz; CH3), 2.96 (s, 3H; CH3), 7.06–7.11 (m, 2H; Ar), 7.20–7.24
(m, 2H; Ar), 7.40–7.52 (m, 2H; Ar), 7.69–7.75 (m, 1H; Ar), 7.85 (q, 1H,
J¼1.1 Hz; H5), 8.02–8.05 (m, 1H; Ar); 13C NMR (75 MHz, CD3OD)
(d, 3H, J¼0.9 Hz; CH3), 2.23 (s, 3H; CH3) 3.45 (q, 2H, J¼7.3 Hz; SCH2),
7.04–7.12 (m, 2H; Ar), 7.23–7.30 (m, 2H; Ar), 7.31–7.40 (m, 1H; Ar),
7.54–7.61 (m, 1H; Ar), 7.62–7.72 (m, 1H; Ar); 8.07 (q, 1H, J¼0.9 Hz;
H5), 8.10–8.16 (m, 1H; Ar), 8.16 (br s, 1H; NH), 8.69 (br s, 1H; NH);
d
14.26, 18.28, 20.78, 111.00, 117.89, 120.62 (2C), 126.42, 126.81,
128.94, 130.38 (2C), 134.18, 136.38, 137.13, 139.42, 148.47, 165.40,
181.89; HRMS m/z calcd C19H20N3OS2 [MꢀI]þ: 370.1042; found:
370.1041.
13C NMR (75 MHz, CD3OD)
d 12.92, 13.70, 20.35, 30.09, 118.12,
118.60 (2C), 123.66, 124.53, 124.55, 127.95, 129.29 (2C), 131.42,
132.58, 135.02, 136.27, 145.85, 151.95, 177.86; HRMS m/z calcd
C20H22N3OS2 [MꢀI]þ: 384.1199; found: 384.1202.
4.4.3. 3-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)phenyl)-4-
methyl-2-(methylthio)thiazol-3-ium iodide (1c). Yield: 97% (126 mg,
4.5.3. 3-(2-(3-(3,5-Bis(trifluoromethyl)benzyl)ureido)phenyl)-2-
white solid); mp 186–188 ꢁC; 1H NMR (500 MHz, DMSO-d6)
d
2.21
(ethylthio)-4-methylthiazol-3-ium iodide (1h). Yield: 96% (126 mg,
(d, 3H, J¼0.9 Hz; CH3), 2.93 (s, 3H; CH3), 7.42–7.48 (m, 1H; Ar), 7.61–
7.66 (m, 1H; Ar), 7.68 (br s, 1H; Ar), 7.70–7.75 (m, 1H; Ar), 8.04 (q,
1H, J¼0.9 Hz; H5), 8.07 (br s, 2H; Ar), 8.09–8.12 (m, 1H; Ar), 8.60 (s,
white solid); mp 179–181 ꢁC; 1H NMR (300 MHz, CD3OD)
d 1.49 (t,
3H, J¼7.4 Hz; CH3), 2.25 (d, 3H, J¼1.1 Hz; CH3), 2.94 (s, 3H; CH3),
3.44 (q, 2H, J¼7.4 Hz; CH2), 4.42 (d, 1H, J¼19.8 Hz; CHA), 4.49 (d, 1H,
J¼19.8 Hz; CHB), 7.38–7.53 (m, 2H; Ar), 7.65–7.73 (m, 1H; Ar), 7.75
(q, 1H, J¼1.1 Hz; H5), 7.84–7.92 (m, 4H; Ar); 13C NMR (75 MHz,
1H; NH), 9.45 (s, 1H; Ar); 13C NMR (125 MHz, DMSO-d6)
d 13.65,
17.98, 114.99 (1C, sept, J¼3 Hz), 118.10, 118.01–118.23 (m, 2C), 123.16
(2C, q, J¼273 Hz), 124.71, 125.35, 125.58, 128.11, 130.74 (2C, q,
CD3OD)
d
13.27, 14.29, 31.77, 43.78, 117.73, 121.92 (1C, sept, J¼4 Hz),

1856
A.L. Doukara et al. / Tetrahedron 66 (2010) 1852–1858
124.87 (2C, q, J¼272 Hz), 126.93, 126.98, 127.88, 128.98 (2C, q,
J¼4 Hz), 129.01,132.72 (2C, q, J¼33 Hz) 134.08, 136.35, 144.54,
148.06, 157.12, 179.99; HRMS m/z calcd C22H20F6N3OS2 [MꢀI]þ:
520.0947; found: 520.0950.
(300 MHz, CDCl3)
d
2.31 (s, 3H; CH3), 2.41 (s, 3H; CH3), 7.03 (br s,
12.60,
1H; NH), 7.08–7.33 (m, 4H; Ar); 13C NMR (75 MHz, CDCl3)
d
20.84, 120.12 (2C), 129.62 (2C), 134.28, 135.06, 166.35; HRMS m/z
calcd C9H12NOS [MþH]þ: 182.0634; found: 182.0632.
4.5.4. 2-(Ethylthio)-3-(2-(3-isopropylureido)phenyl)-4-methyl-
thiazol-3-ium iodide(1i). Yield: 99% (149 mg, white solid); mp 170–
4.6.3. S-Methyl 3,5-bis(trifluoromethyl)phenylcarbamothioate (2c.).
Yield: 93% (45 mg, white solid); mp 111–113 ꢁC; Rf¼0.74 (CH2Cl2/
172 ꢁC; 1H NMR (300 MHz, CD3OD)
d
1.11 (d, 3H, J¼6.5 Hz; CH3),1.13
AcOEt, 9:1); 1H NMR (200 MHz, CDCl3)
d 2.47 (s, 3H; CH3), 7.31 (br s,
(d, 3H, J¼6.5 Hz; CH3), 1.53 (t, 3H, J¼7.4 Hz; CH3), 2.26 (d, 3H,
J¼1.1 Hz; CH3), 3.49 (q, 2H, J¼7.4 Hz; SCH2), 3.78 (sept, 1H,
J¼6.5 Hz; CH), 7.32–7.42 (m, 1H; Ar), 7.45–7.52 (m, 1H; Ar), 7.62–
7.72 (m,1H; Ar), 7.86 (q,1H, J¼1.1 Hz; H5), 7.93–7.99 (m,1H; Ar); 13C
1H; NH), 7.60 (s, 1H; Ar), 7.94 (s, 2H; Ar); 13C NMR (75 MHz, CDCl3)
d
12.69,117.47 (sept,1C; J¼4 Hz),118.90 (q, 2C; J¼3 Hz),122.95 (q, 2C;
J¼273 Hz), 132.57 (q, 2C; J¼33 Hz); 139.06, 166.98; HRMS m/z calcd
C10H6F6NOS [MꢀH]ꢀ: 302.0080; found: 302.0081.
NMR (75 MHz, CD3OD)
d 12.69, 13.67, 22.50 (2C), 31.16, 42.57,
117.45, 125.49, 125.62, 126.37, 128.30, 133.35, 136.03, 147.37, 155.66,
179.50; HRMS m/z calcd C16H22N3OS2 [MꢀI]þ: 336.1199; found:
336.1199.
4.6.4. S-Methyl 4-nitrophenylcarbamothioate (2d)16. Yield: 96%
(39 mg, white solid); mp 197–199 ꢁC; Rf¼0.65 (CH2Cl2/AcOEt, 9:1);
1H NMR (300 MHz, CDCl3)
d 2.47 (s, 3H; CH3), 7.35 (br s, 1H; NH),
7.56–7.64 (m, 2H; Ar), 8.18–8.25 (m, 2H; Ar); 13C NMR (75 MHz,
4.5.5. 2-(Decylthio)-4-methyl-3-(2-(3-phenylureido)phenyl)thiazol-
CDCl3) d 12.77, 118.47 (2C), 125.31 (2C), 143.36, 143.44, 166.73;
3-ium iodide (1j). Yield: 96% (171 mg, white solid); mp 51–53 ꢁC;
HRMS m/z calcd C8H7N2O3S [MꢀH]ꢀ: 211.0183; found: 211.0182.
1H NMR (300 MHz, CD3OD)
d 0.85–0.94 (m, 3H; CH3), 1.19–1.52
(m, 14H; (CH2)7), 1.80–1.93 (m, 2H; CH2), 2.30 (d, 3H, J¼1.0 Hz;
CH3), 3.42–3.51 (m, 2H; SCH2), 6.98–7.06 (m, 1H; Ar), 7.21–7.30
(m, 2H; Ar), 7.33–7.54 (m, 4H; Ar), 7.68–7.76 (m, 1H; Ar), 7.85 (q,
1H, J¼1.0 Hz; H5), 7.99–8.05 (m, 1H; Ar); 13C NMR (75 MHz,
4.6.5. S-Methyl 3,5-bis(trifluoromethyl)benzylcarbamothioate (2e.).
Yield: 96% (48 mg, white solid); mp 87–89 ꢁC; Rf¼0.69 (CH2Cl2/
AcOEt, 9:1); 1H NMR (300 MHz, CDCl3)
d 2.39 (s, 3H; CH3), 4.59 (d,
2H, J¼6.1 Hz; CH2), 5.91 (br s, 1H; NH), 7.68–7.83 (m, 3H; Ar); 13C
CD3OD)
d
14.37, 14.42, 23.71, 28.90, 29.74, 30.07, 30.37, 30.48,
NMR (75 MHz, CDCl3)
d
12.43, 44.32, 121.63 (1C, sept; J¼4 Hz),
30.60, 33.02, 37.31, 117.98, 120.27 (2C), 124.33, 126.69, 126.93,
127.58, 129.00, 129.92 (2C), 134.11, 136.14, 139.89, 148.14, 154.22,
180.34, HRMS m/z calcd C27H36N3OS2 [MꢀI]þ: 482.2294; found:
482.2296.
123.13 (2C, q; J¼273 Hz), 127.61 (2C, q; J¼3 Hz), 132.03 (2C, q;
J¼33 Hz); 140.58, 168.79; HRMS m/z calcd C11H8F6NOS [MꢀH]ꢀ:
316.0236; found: 316.0237.
4.6.6. S-Ethyl phenylcarbamothioate (2f)15. Yield: 93% (34 mg,
white solid); mp 71–73 ꢁC; Rf¼0.79 (CH2Cl2/AcOEt, 9:1); 1H NMR
4.5.6. 2-(Decylthio)-4-methyl-3-(2-(3-p-tolylureido)phenyl)thiazol-
3-ium iodide (1k). Yield: 97% (170 mg, white solid); mp 147–
(300 MHz, CDCl3)
d
1.35 (t, 3H, J¼7.4 Hz; CH3), 2.99 (q, 2H, J¼7.4 Hz;
149 ꢁC; 1H NMR (200 MHz, CDCl3)
d
0.78–0.97 (m, 3H; CH3),
CH2), 7.06 (br s, 1H; NH), 7.06–7.15 (m, 1H; Ar), 7.27–7.48 (m, 4H;
1.12–1.52 (m, 14H; (CH2)7), 1.73–1.97 (m, 2H; CH2), 2.24 (d, 3H,
J¼0.9 Hz; CH3), 2.26 (s, 3H; CH3), 3.20–3.68 (m, 2H; SCH2),
6.96–7.13 (m, 3H; Ar), 7.16–7.26 (m, 1H; Ar), 7.44–7.70 (m, 4H;
ArþH5), 7.68–7.76 (m, 1H, Ar), 8.29–8.42 (m, 1H; Ar), 8.50 (s, 1H;
Ar); 13C NMR (75 MHz, CDCl3)
d 15.54, 24.69, 119.73 (2C), 124.35,
129.09 (2C), 137.72, 165.87; HRMS m/z calcd C9H12NOS [MþH]þ:
182.0634; found: 182.0634.
NH), 9.20 (s, 1H; NH); 13C NMR (50 MHz, CDCl3)
d
14.05, 14.50,
4.6.7. S-Ethyl p-tolylcarbamothioate (2g)15. Yield: 96% (37 mg,
white solid); mp 79–81 ꢁC; Rf¼0.82 (CH2Cl2/AcOEt, 9:1); 1H NMR
20.73, 22.60, 27.49, 28.74, 28.92, 29.18, 29.24, 29.40, 31.79, 37.29,
117.18, 118.94, 123.82, 124.11, 125.88, 126.37, 129.11, 131.99, 132.97,
135.73, 136.43, 146.09, 152.67, 179.19; HRMS m/z calcd C28H38N3OS2
[MꢀI]þ: 496.2451; found: 496.2457.
(300 MHz, CDCl3)
d
1.35 (t, 3H, J¼7.4 Hz; CH3), 2.33 (s, 3H; CH3),
2.99 (q, 2H, J¼7.4 Hz; CH2), 7.07 (br s, 1H; NH), 7.10–7.32 (m, 4H;
Ar); 13C NMR (75 MHz, CDCl3)
d 15.55, 20.81, 24.64, 120.01 (2C),
134.18, 135.11, 165.83; HRMS m/z calcd C10H14NOS [MþH]þ:
4.6. General procedure for the preparation of
196.0791; found: 196.0796.
S-alkylcarbamothioates 2a–k
4.6.8. S-Ethyl3,5-bis(trifluoromethyl)benzylcarbamothioate(2h). Yield:
94% (56 mg, white solid); mp 73–75 ꢁC; Rf¼0.74 (CH2Cl2/AcOEt, 9:1);
To a solution of thiazolium salt 1 (100 mg; 1a 0.21 mmol, 1b
0.20 mmol, 1c 0.16 mmol, 1d 0.19 mmol, 1e 0.16 mmol, 1f
0.29 mmol, 1 g 0.20 mmol, 1 h 0.15 mmol, 1i 0.22 mmol, 1j
0.16 mmol, 1 k 0.16 mmol) in CH3CN (5 mL), NEt3 (1 equiv) is added
and the solution stirred at room temperature. After 15 min the
solvent is evaporated and CH2Cl2 (15 mL) is added. The organic
layer is then washed with brine (3ꢂ10 mL), dried over MgSO4 and
evaporated to dryness. The resulting S-alkylcarbamothioates 2 and
thiazolobenzimidazole 7 are purified by silica gel chromatography
(CH2Cl2/AcOEt, 9:1).
1H NMR (300 MHz, CDCl3)
d
1.32 (t, 3H, J¼7.4 Hz; CH3), 2.96 (q, 2H,
J¼7.4 Hz; CH2), 4.59 (q, 2H, J¼6.1 Hz; CH2), 5.80 (br s, 1H; NH), 7.70–
7.85 (m, 3H; Ar); 13C NMR (75 MHz, CDCl3)
d
¼15.53, 24.58, 44.21,
121.57 (1C, sept; J¼4 Hz), 123.14 (2C, q; J¼273 Hz), 127.58 (2C, q;
J¼3 Hz), 132.02 (2C, q; J¼33 Hz); 140.64, 168.39; HRMS m/z calcd
C12H10F6NOS [MꢀH]ꢀ: 330.0393; found: 330.0390.
4.6.9. S-Ethyl isopropylcarbamothioate (2i)8. Yield: 97% (31 mg,
white solid); mp 60–62 ꢁC; Rf¼0.80 (CH2Cl2/AcOEt, 9:1); 1H NMR
(300 MHz, CDCl3)
d
1.15 (d, 6H, J¼6.5 Hz; 2CH3), 1.26 (t, 3H,
4.6.1. S-Methyl phenylcarbamothioate (2a)14,15. Yield: 95% (33 mg,
white solid); mp 77–79 ꢁC; Rf¼0.76 (CH2Cl2/AcOEt, 9:1); 1H NMR
J¼7.4 Hz; CH3), 2.88 (q, 2H, J¼7.4 Hz; SCH2), 3.76–4.25 (m, 1H; CH),
5.26 (br s, 1H; NH); 13C NMR (75 MHz, CDCl3)
d 15.66, 22.77 (2C),
(300 MHz, CDCl3)
d
2.43 (s, 3H; CH3), 6.99–7.21 (m, 2H; NH and Ar),
24.15, 43.56, 166.14; HRMS m/z calcd C6H13NOS [MþH]þ: 148.0791;
7.27–7.46 (m, 4H; Ar); 13C NMR (75 MHz, CDCl3)
d
12.62, 119.73
found: 148.0790.
(2C), 124.44, 129.13 (2C), 137.69, 166.23; HRMS m/z calcd C8H10NOS
[MþH]þ: 168.0478; found: 168.0472.
4.6.10. S-Decyl phenylcarbamothioate (2j)17. Yield: 97% (47 mg,
white solid); mp 64–66 ꢁC; Rf¼0.70 (CH2Cl2/AcOEt, 9:1); 1H NMR
4.6.2. S-Methyl p-tolylcarbamothioate (2b)15. Yield: 94% (34 mg,
white solid); mp 107–109 ꢁC; Rf¼0.87 (CH2Cl2/AcOEt, 9:1); 1H NMR
(500 MHz, CDCl3) d 0.85–0.90 (m, 3H; CH3), 1.20–1.43 (m, 14H;
(CH2)7), 1.62–1.70 (m, 2H; CH2), 2.97 (t, 2H, J¼7.3 Hz; SCH2), 7.00 (br

A.L. Doukara et al. / Tetrahedron 66 (2010) 1852–1858
1857
s, 1H; NH), 7.07–7.13 (m, 1H; Ar), 7.29–7.34 (m, 2H; Ar), 7.39–7.43
(m, 2H; Ar); 13C NMR (DeptQ 135, 125 MHz, CDCl3)
14.10, 22.66,
168 (2a), 182 (2b), 189 (7), 294 (2j), 308 (2k); [MþNa]þ: 190 (2a),
204 (2b), 211 (7), 316 (2j), 330 (2k).
d
28.77, 29.12, 29.28, 29.50, 29.52, 30.28, 30.36, 31.87, 119.64 (2C),
124.33, 129.11 (2C), 137.78, 165.90; HRMS m/z calcd C17H28NOS
[MþH]þ: 294.1886; found: 294.1884.
Acknowledgements
ALD and MAM are grateful to BFA program (French-Algerian
exchange program) for grants.
4.6.11. S-Decyl p-tolylcarbamothioate (2k). Yield: 95% (47 mg,
white solid); mp 66–68 ꢁC; Rf¼0.85 (CH2Cl2/AcOEt, 9:1); 1H NMR
(300 MHz, CDCl3)
d 0.88 (m, 3H; CH3), 1.18–1.46 (m, 14H; (CH2)7),
1.57–1.73 (m, 2H; CH2), 2.31 (s, 3H; CH3), 2.96 (t, 2H, J¼7.3 Hz;
Supplementary data
SCH2), 6.98 (br s, 1H; NH), 7.08–7.15 (m, 2H; Ar), 7.25–7.32 (m, 2H;
Ar); 13C NMR (75 MHz, CDCl3)
d
14.10, 20.83, 22.66, 28.78, 29.13,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.020.
29.29, 29.50, 29.52, 30.31 (2C), 31.87, 119.90, 129.59, 134.12,
135.16,165.88; HRMS m/z calcd C18H30NOS [MþH]þ: 308.2042;
found: 308.2041.
References and notes
1. (a) Fowler, C. J.; Haverlock, T. J.; Moyer, B. A.; Shriver, J. A.; Gross, D. E.; Mar-
quez, M.; Sessler, J. L.; Hossain, M. A.; Bowman-James, K. J. Am. Chem. Soc.
2008, 130, 14386–14387; (b) Davis, A. P. Coord. Chem. Rev. 2006, 250, 2939–
2951; (c) Chen, Z.-H.; He, Y.-B.; Hu, C.-G.; Huang, X.-H. Tetrahedron: Asymmetry
2008, 19, 2051–2057; (d) Miyaji, H.; Hong, S.-J.; Jeong, S.-D.; Yoon, D.-W.; Na,
H.-K.; Hong, J.; Ham, S.; Sessler, J. L.; Lee, C.-H. Angew. Chem., Int. Ed. 2007, 46,
2508–2511; (e) Stibor, I.; Holakovsky, R.; Mustafina, A. R.; Lhotak, P. Collect.
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4.7. General procedure for the preparation of
S-alkylcarbamothioates 2l–n
To a solution of urea 3 (100 mg; 3g 0.29 mmol, 3h 0.31 mmol,
3i 0.29 mmol) EtI (1.5 mL) is added and the solution stirred at
room temperature for 24 h. The solvent is evaporated and the
resulting solid (used without further purification) is solubilised
in CH3CN (5 mL). Then, NEt3 (1 equiv) is added and the solution
stirred at room temperature. After 15 min the solvent is evap-
orated and the resulting S-alkylcarbamothioates 2 and thiazo-
lobenzimidazole 7 are purified by silica gel chromatography
(CH2Cl2/AcOEt, 9:1).
4.7.1. S-Ethyl azepane-1-carbothioate (Molinate) (2l)5f,18. Yield: 95%
(51 mg, colourless oil); Rf¼0.85 (CH2Cl2/AcOEt, 9:1); 1H NMR
(200 MHz, CDCl3)
d
1.27 (t, 3H, J¼7.4 Hz; CH3), 1.47–1.62 (m, 4H;
2CH2), 1.73 (br s, 4H; 2CH2), 2.89 (q, 2H, J¼7.4 Hz; SCH2), 3.43 (t,
2H, J¼6.0 Hz; NCH2), 3.54 (t, 2H, J¼6.0 Hz; NCH2); 13C NMR
(75 MHz, CDCl3)
47.58, 167.76.
d 15.33, 24.52, 26.93, 27.16, 27.85, 28.35, 47.25,
4.7.2. S-Ethyl diethylcarbamothioate (Ethiolate) (2m)5f,18. Yield:
96% (48 mg, colourless oil); Rf¼0.82 (CH2Cl2/AcOEt, 9:1); 1H NMR
2. Roussel, C.; Roman, M.; Andreoli, F.; Del Rio, A.; Faure, R.; Vanthuyne, N.
Chirality 2006, 18, 762–771.
(400 MHz, CDCl3)
d
1.15 (br s, 6H; 2CH3), 1.27 (t, 3H, J¼7.4 Hz;
3. Roussel, C.; Andreoli, F.; Roman, M.; Hristova, M.; Vanthuyne, N. Molecules
2005, 10, 327–333. Thiazolobenzimidazole 7 is a by-product of the reaction
which is worth collecting. It was shown to lead to a very useful and un-
precedented chemistry, pending patents EP 08291046 and US 12/329,739.
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167.20.
d 13.37 (2C), 15.34, 24.47, 41.88 (2C),
4.7.3. S-Ethyl dipropylcarbamothioate (EPTC) (2n)5f,18. Yield: 96%
(52 mg, colourless oil); Rf¼0.83 (CH2Cl2/AcOEt, 9:1); 1H NMR
(300 MHz, CDCl3)
d
0.89 (t, 6H, J¼7.4 Hz; 2CH3), 1.27 (t, 3H,
J¼7.4 Hz; CH2), 1.59 (br s, 4H; 2CH2), 2.88 (q, 2H, J¼7.4 Hz; SCH2),
3.26 (br s, 4H; N(CH2)2); 13C NMR (75 MHz, CDCl3)
15.34, 21.13, 21.54, 24.57, 49.05, 49.60, 167.76.
d 11.22 (2C),
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4.8. 3-Methyl-thiazolo[3,2-a]benzimidazole (7)3
For entries 2a–n, the isolated yield in 7 was always larger than
95%.
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4.9. Procedure for the cross reaction
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To a solution of thiazolium salts 1a (0.065 mmol) and 1k
(0.065 mmol) in methanol (3 mL), NEt3 (1 equiv, 0.130 mmol) was
added and the solution stirred at room temperature for 30 min.
Then, the solvent was evaporated and the crude resulting solid
recovered and analysed by mass spectroscopy, four peaks corre-
sponding the 2a, 2k, 2b and 2j were observed. ESI-MS m/z [MþH]þ:

1858
A.L. Doukara et al. / Tetrahedron 66 (2010) 1852–1858
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