Synthesis of novel 2-aminothieno[3,2-d]thiazoles and selenolo[3,2-d] thiazoles

Article abstract of DOI:10.1016/j.tet.2011.09.134

In this work, we described the synthesis of 3-isothiocyanatoselenophenes starting from 3-aminoselenophenes (using thiophosgene). Those compounds were then converted to the corresponding thioureas in the presence of ammonium hydroxide. Cyclization in 2-ami

Full text of DOI:10.1016/j.tet.2011.09.134

Tetrahedron 67 (2011) 9352e9357
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Synthesis of novel 2-aminothieno[3,2-d]thiazoles and selenolo[3,2-d]thiazoles
*
ꢀ
Germain Revelant, Stephanie Hesse , Gilbert Kirsch
ꢀ
ꢀ
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago, 57070 Metz, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2011
Received in revised form 20 September 2011
Accepted 27 September 2011
Available online 5 October 2011
In this work, we described the synthesis of 3-isothiocyanatoselenophenes starting from 3-
aminoselenophenes (using thiophosgene). Those compounds were then converted to the correspond-
ing thioureas in the presence of ammonium hydroxide. Cyclization in 2-aminoselenolo[3,2-d]thiazoles
was
achieved
using
DDQ.
2-Aminothieno[3,2-d]thiazoles
were
obtained
from
3-
isothiocyanatothiophenes using the same pathway.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isothiocyanates
Thioureas
Thienothiazoles
Selenolothiazoles
Cyclization
1. Introduction
chlorothiophene by a multi-step synthesis with the intermediate
production of chloronitrothiophene.9 To the best of our knowledge,
there is no report on selenolo[3,2-d]thiazoles.
Thiazoles are major scaffolds in heterocyclic chemistry, showing
various pharmacological activities like antimicrobial1,2 or anti-in-
flammatory.3 Benzothiazoles have also been described for anti-
cancer activity4 and Riluzole is marketed to treat amyotrophic lat-
eral sclerosis (Fig. 1). Thiazoles condensed with heterocycles pres-
ent also interesting properties as herbicides,5 for example, or more
recently as selective cardiodepressant products (I).6 Synthesis of
condensed thiazoles with five-membered heterocycles could be
achieved by two ways: either by construction of the thiazole ring
from the five-membered heterocycle or by creation of the hetero-
cycle from thiazole.7 Two pathways for the formation of thieno[3,2-
d]thiazoles have been described, for example, 2-phenylthieno[3,2-
d]thiazole has been synthesized by condensation of 5-chloro-4-
formyl-2-phenylthiazole with thioglycolic acid,8 whereas 2-
mercaptothieno[3,2-d]thiazole has been obtained from 2-
Since many years, our lab is working on the synthesis of het-
erocyclic compounds with potential biological activity, especially
products containing polysubstituted thiophenes.10 In a previous
work, we described the synthesis of 3-aminothiophenes and their
use as starting material to obtain isothiocyanates and N,N0-di-
substituted thioureas.11 Here we extended this methodology to
obtain new 3-isothiocyanatoselenophenes. In a second part of
this work, we used those scaffolds as well as thienyl iso-
thiocyanates to prepare 2-aminothienothiazoles and 2-
aminoselenolothiazoles.
2. Results and discussion
3-Aminoselenophene-2-carboxylates 1 were first saponified by
refluxing for 4 h with an aqueous solution of potassium hydroxide
to give the corresponding carboxylic acids 2, which were next
decarboxylated by heating with oxalic acid in isopropanol.12 The
obtained aminoselenophenes 3 were finally treated with thio-
phosgene in presence of sodium hydrogenocarbonate to give the
targeted isothiocyanates 4 in moderate to good yields (Scheme 1
and Table 1).
S
N
N
R
R2
MeO2C
N
NH2
S
F3CO
R1
CO2Me
Riluzole
N
H
I
Synthesis of monosubstituted thioureas 5 was performed by
stirring the highly reactive isothiocyanates in dichloromethane
with a solution of ammonium hydroxide (Scheme 2). The targeted
thioureas were obtained in moderate to good yields in both thio-
phene and selenophene series (Table 2).
Fig. 1. Examples of thiazole-containing biologically active compounds.
* Corresponding author. Tel.: þ33 3 87 54 71 97; fax: þ33 3 87 31 58 01; e-mail
address: hesse@univ-metz.fr (S. Hesse).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.134

G. Revelant et al. / Tetrahedron 67 (2011) 9352e9357
9353
NH2
were different. However, HRMS showed that it was an isomer as the
two compounds have the same molecular weight. The different
data let us to consider that we obtained compound 50g (Table 2,
entry 9). While the IR spectrum of 5g showed typical signals from
the thioureas (NH2, NH, and C]S), the spectrum of 50g presented
neither the characteristic duplet from the NH2 nor the signal from
the C]S, but a strong peak at 1653 cmꢀ1, which may correspond to
a C]N group. For compound 5g, the NH group gave a broad signal
at 9.82 ppm, which is not present in 1H NMR spectrum of com-
pound 50g. In the latter, one H-atom appears at 8.23 ppm and
a second appears at 10.48 ppm. All the other signals (for aromatic
hydrogens and methoxy group) are quite similar. The same obser-
vations have been done with the 13C NMR spectra where all signals
are identical except one: in compound 5g, there is a signal at
180.5 ppm (C]S), whereas it is missing in compound 50g and
replaced by a new one at 159.1 ppm, which may correspond to the
C]NH group.
NH2
1a-d
2a-d
i
R1
COOEt
R1
COOH
Se
Se
ii
NH2
NCS
iii
R1
R1
Se
Se
4a-d
3a-d
R
1 = Ph, 4-ClPh, 4-MePh, 4-MeOPh
Scheme 1. Synthesis of 3-isothiocyanatoselenophenes. Reagents and conditions: i.
KOH/H2O, EtOH, reflux, 4 h; ii. Oxalic acid, i-PrOH, 40 ꢁC; iii. CSCl2, NaHCO3, CHCl3, rt,
2 h.
The last step of this work was the intramolecular cyclization of
the thioureas into condensed thiazoles. Cyclization of thienylth-
ioamides or thienyl monothiooximes have been achieved by action
of potassium ferricyanide K3Fe(CN)6.14 Disubstituted thioureas have
also been cyclized in presence of bromine as oxidizing agent.15 Here
we decided to use the pathway described by Bose and Idrees16 for
the oxidative cyclization of aryl thioformanilides using 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ). In this very convenient
procedure, thiourea was stirred with DDQ in dichloromethane at rt
to give the corresponding thienothiazoles and selenolothiazoles in
good yields (49e91%, Table 2). A simple purification by chroma-
tography was required only to remove by-products from the DDQ.
We also tried to perform the cyclization on compound 50g under
the same conditions as before to check if the isomeric form of the
thiourea has an influence on the structure of final compound. One
more time, analyses showed some differences with results for
compound 6g. On 1H NMR, the disappearance of one of the CH
signal from thiophene ring proved that the cyclization occurred.
However the presence of two NH signals and a missing NH2 peak
revealed that we did not obtain compound 6g but probably an
isomer 60g. It was surprising but may be explained via the mech-
anism of DDQ-induced cyclization proposed by Bose16and Wang.17
In compound 5g the thiyl radical may be formed after isomeriza-
tion, whereas it could be produced directly from isothiourea 50g
that giving two different compounds (Scheme 3).
Table 1
Isothiocyanatoselenophenes prepareda
Entry
1
Product 4
Yield (%)
57
NCS
4a
Se
NCS
2
3
4b
62
Se
Cl
NCS
4c
95
68
Se
NCS
4
4d
Se
MeO
a
3-Isothiocyanatothiophenes 4eeh were previously synthesized by a similar
pathway.11b
NH2
R2
NCS
R2
HN
i
S
3. Conclusion
R1
X
R1
X
4a-h
5a-h
In conclusion, we performed the synthesis of new heterocycle-
condensed 2-aminothiazoles in good yields using an easy three-
step procedure from the corresponding heteroaryl-amine. These
compoundscould be consideredas interestinganalogsof aniline and
be used in a lot of various synthetic protocols involving aryl-amine.
ii
Compounds a to d : X = Se
Compounds e to h : X = S
R2
N
NH2
4. Experimental section
S
R1
X
6a-h
4.1. General
Scheme 2. Synthesis of selenolo- and thieno[3,2-d]thiazoles. Reagents and conditions:
i. NH3/H2O, CH2Cl2, rt, overnight; ii. DDQ, CH2Cl2, rt, 4 h.
Melting points were determined on a Stuart SMP3 apparatus
and are uncorrected. 1H and 13C NMR spectra (
d in ppm) were
Recently, Saeed et al. have described another methodology,
which allows obtaining directly phenylthiourea by heating the
corresponding aniline with ammonium thiocyanate in presence of
hydrochloric acid.13 We were particularly interested in this pro-
cedure as it would be more user-friendly: the reaction occurs in one
step and without using thiophosgene. However, when 5-(4-
methoxyphenyl)-3-aminothiophene was reacted with ammonium
thiocyanate in those conditions, we did not obtain the expected
thiourea 5g as both 1H and 13C NMR spectra of the two compounds
recorded on an AC Bruker 250 MHz spectrometer in CDCl3 or
DMSO-d6. MS spectra were recorded with a MicroTof-Q98. IR
spectra were recorded with a PerkineElmer FTIR Baragon 1000PC
instrument equipped with Spectrum (PerkineElmer) software
version 5.3.1.
Petroleum ether (PE) used refers to the fraction boiling in the
range 35e60 ꢁC.
3-Aminoselenophene-2-carboxylates
according to Ref. 18.
1
were synthesized

9354
G. Revelant et al. / Tetrahedron 67 (2011) 9352e9357
Table 2
Thioureas and thieno/selenothiazoles prepared
Entry
1
Thiourea 5
Yield (%)
47
Thiazole 6
Yield (%)
86
H
N
N
NH2
NH2
6a
S
5a
Se
S
Se
H
N
N
NH2
Cl
NH2
Cl
2
3
4
5
6
7
8
61
62
81
86
77
64
87
30a
64
76
49
86
83
50
91
65
6b
S
5b
Se
S
Se
H
N
N
NH2
NH2
6c
S
5c
Se
S
Se
H
N
N
NH2
MeO
MeO
NH2
6d
S
5d
Se
S
Se
H
N
N
NH2
NH2
6e
S
5e
S
S
S
H
N
N
NH2
Cl
Cl
NH2
NH2
6f
S
5f
S
S
S
H
N
N
NH2
MeO
MeO
6g
S
5g
S
S
S
H
N
N
NH2
NH2
6h
5h
S
S
S
S
H
N
H
N
NH
MeO
MeO
9
5'g
6'g
NH
SH
S
S
S
a
Obtained via a different pathway (described in text).
3-Isothiocyanatothiophenes 4eeh were previously synthesized
and described in Ref. 11b.
J¼7.1 Hz, 2H, CH2), 6.70 (s, 2H, NH2), 7.20 (s, 1H, CH), 7.22 (d,
J¼8.75 Hz, 2H, 2ꢂ CH), 7.44 (d, J¼8.75 Hz, 2H, 2ꢂ CH). 13C NMR
(62.5 MHz, DMSO-d6):
d
¼14.5 (CH3), 20.8 (CH3), 59.3 (CH2), 96.5
(C), 119.5 (CH), 125.7 (2ꢂ CH), 129.7 (2ꢂ CH), 131.9 (C), 138.9 (C),
152.2 (C), 157.2 (C), 164.7 (C]O).
4.2. Aminoselenophene-2-carboxylates 1aed
4.2.1. Ethyl 3-amino-5-phenylselenophene-2-carboxylate
(1a). Yield: 50%; red solid; mp 87 ꢁC. 1H NMR (250 MHz, DMSO-
4.2.4. Ethyl 3-amino-5-(4-methoxyphenyl)selenophene-2-
carboxylate (1d). Yield: 45%; red solid; mp 135 ꢁC. 1H NMR
d6):
d
¼1.24 (t, J¼7.1 Hz, 3H, CH3), 4.16 (q, J¼7.1 Hz, 2H, CH2), 6.73 (s,
(250 MHz, DMSO-d6):
d
¼1.23 (t, J¼7.1 Hz, 3H, CH3), 3.78 (s, 1H, CH),
2H, NH2), 7.27 (s, 1H, CH), 7.39e7.42 (m, 3H, 3ꢂ CH), 7.55e7.57 (m,
2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
¼14.5 (CH3), 59.4
d
4.14 (q, J¼7.1 Hz, 2H, CH2), 6.69 (s, 2H, NH2), 6.97 (d, J¼8.75 Hz, 2H,
2ꢂ CH), 7.14 (s, 1H, CH), 7.50 (d, J¼8.75 Hz, 2H, 2ꢂ CH). 13C NMR
(CH2), 96.0 (C), 120.1 (CH), 125.8 (2ꢂ CH), 129.2 (2ꢂ CH), 134.6 (CH),
138.5 (C), 152.0 (C), 157.1 (C), 164.7 (C]O).
(62.5 MHz, DMSO-d6):
d
¼14.5 (CH3), 55.3 (OCH3), 59.3 (CH2), 94.9
(C), 114.5 (2ꢂ CH), 118.7 (CH), 127.2 (2ꢂ CH), 138.8 (C), 152.1 (C),
157.4 (C), 160.1 (C), 164.7 (C]O).
4.2.2. Ethyl 3-amino-5-(4-chlorophenyl)selenophene-2-carboxylate
(1b). Yield: 80%; orange solid; mp 137 ꢁC. 1H NMR (250 MHz,
DMSO-d6):
d
¼1.23 (t, J¼7.1 Hz, 3H, CH3), 4.16 (q, J¼7.1 Hz, 2H, CH2),
6.73 (s, 2H, NH2), 7.28 (s, 1H, CH), 7.47 (d, J¼8.75 Hz, 2H, 2ꢂ CH),
4.3. Synthesis of aminoselenophenecarboxylic acids 2aed;
general procedure
7.58 (d, J¼8.75 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
d
¼14.5 (CH3), 59.5 (CH2), 96.5 (C), 120.8 (CH), 127.5 (2ꢂ CH), 129.2
(2ꢂ CH), 133.5 (C), 133.7 (C), 150.3 (C), 157.0 (C), 164.6 (C]O).
To a stirred solution of the appropriate selenophene (15 mmol)
in EtOH (15 mL) was added a solution of KOH (4 equiv) in H2O
(8 mL). The mixture was heated at reflux for 4 h and then the sol-
vent was evaporated. The residue was poured into H2O (25 mL) and
acidified to neutral pH with orthophosphoric acid. The precipitate
4.2.3. Ethyl 3-amino-5-(4-methylphenyl)selenophene-2-carboxylate
(1c). Yield: 43%; brown solid; mp 111 ꢁC. 1H NMR (250 MHz,
DMSO-d6):
d
¼1.23 (t, J¼7.1 Hz, 3H, CH3), 2.30 (s, 1H, CH), 4.16 (q,

G. Revelant et al. / Tetrahedron 67 (2011) 9352e9357
9355
NH2
NH2
NH2
N
HN
N
S
S
DDQ
SH
S
S
S
MeO
MeO
MeO
MeO
5g
N
NH2
S
S
6g
NH
SH
NH
H
N
HN
HN
NH
DDQ
S
S
S
S
S
MeO
MeO
MeO
6'g
5'g
Scheme 3. Proposed mechanism for the DDQ-mediated cyclization of 5g and 50g.
was filtered, washed with H2O (2ꢂ10 mL) and PE (2ꢂ10 mL), and
4.4.1. 5-Phenyl-3-selenophenamine (3a). Yield: 71%; pale brown
solid; mp 153 ꢁC. 1H NMR (250 MHz, DMSO-d6):
¼6.49 (s, 1H, CH),
dried.
d
7.25e7.29 (m, 2H, 2ꢂ CH), 7.35 (t, J¼7.0 Hz, 2H, 2ꢂ CH), 7.48 (d,
4.3.1. 3-Amino-5-phenyl-2-selenophenecarboxylic acid (2a). Yield:
88%; pale brown solid; mp 99 ꢁC. 1H NMR (250 MHz, DMSO-d6):
J¼7.0 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
¼101.3 (CH),
d
121.3 (CH), 125.1 (2ꢂ CH), 127.8 (CH), 129.3 (2ꢂ CH), 135.5 (C), 143.9
d
¼7.26 (s, 1H, CH), 7.38e7.45 (m, 3H, 3ꢂ CH), 7.53e7.61 (m, 2H, 2ꢂ
(C), 146.4 (C).
CH). 13C NMR (62.5 MHz, DMSO-d6):
d
¼97.6 (C), 120.3 (CH), 125.3
(CH), 125.6 (2ꢂ CH), 127.8 (C), 128.9 (2ꢂ CH), 135.5 (C), 156.4 (C),
166.6 (C]O).
4.4.2. 5-(4-Chlorophenyl)-3-selenophenamine (3b). Yield: 91%;
yellow solid; mp 177 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼6.44 (s,
1H, CH), 7.24 (s, 1H, CH), 7.40 (d, J¼8.25 Hz, 2H, 2ꢂ CH), 7.49 (d,
4.3.2. 3-Amino-5-(4-chlorophenyl)-2-selenophenecarboxylic
acid
J¼8.25 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
¼99.3 (CH),
d
(2b). Yield: 78%; pale brown solid; mp 114 ꢁC. 1H NMR (250 MHz,
121.9 (CH), 126.7 (2ꢂ CH), 129.1 (2ꢂ CH), 131.7 (C), 134.8 (C), 144.8
DMSO-d6):
d
¼7.26 (s, 1H, CH), 7.46 (d, J¼8.0 Hz, 2H, 2ꢂ CH), 7.57 (d,
(C), 162.8 (C).
J¼8.0 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
¼98.4 (C),
d
121.9 (CH), 126.6 (2ꢂ CH), 129.1 (2ꢂ CH), 131.7 (C), 134.9 (C), 144.6
(C), 149.1 (C), 166.3 (C]O).
4.4.3. 5-(4-Methylphenyl)-2-selenophenamine (3c). Yield: 92%;
green solid; mp 220 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼2.29 (s,
3H, CH3), 6.48 (s, 1H, CH), 7.18 (d, J¼8.0 Hz, 2H, 2ꢂ CH), 7.24 (s, 1H,
4.3.3. 3-Amino-5-(4-methylphenyl)-2-selenophenecarboxylic
acid
CH), 7.40 (d, J¼8.0 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
(2c). Yield: 88%; pale brown solid; mp 161 ꢁC. 1H NMR (250 MHz,
d
¼20.8 (CH3), 100.5 (CH), 120.6 (CH), 124.9 (2ꢂ CH), 129.6 (2ꢂ CH),
DMSO-d6):
d
¼2.27 (s, 3H, CH3), 7.13e7.19 (m, 3H, 3ꢂ CH), 7.34e7.50
132.8 (C), 137.2 (C), 143.8 (C), 146.4 (C).
(m, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
¼20.6 (CH3), 96.1
d
(C), 125.1 (CH), 129.5 (2ꢂ CH), 132.8 (C), 137.2 (2ꢂ CH), 146.3 (C),
148.9 (C), 156.2 (C), 166.8 (C]O).
4.4.4. 5-(4-Methoxyphenyl)-2-selenophenamine (3d). Yield: 81%;
yellow solid; mp 176 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d
¼3.76 (s,
3H, CH3), 6.44 (s, 1H, CH), 6.92 (d, J¼8.0 Hz, 2H, 2ꢂ CH), 7.12 (s, 1H,
4.3.4. 3-Amino-5-(4-methoxyphenyl)-2-selenophenecarboxylic acid
CH), 7.42 (d, J¼8.0 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
(2d). Yield: 95%; brown solid; mp 156 ꢁC. 1H NMR (250 MHz,
d
¼55.2 (OCH3), 99.9 (CH), 114.4 (2ꢂ CH), 120.1 (CH), 126.4 (2ꢂ CH),
DMSO-d6):
d
¼3.80 (s, 3H, CH3), 6.96 (d, J¼8.0 Hz, 2H, 2ꢂ CH), 7.29
128.3 (C), 143.8 (C), 146.2 (C), 159.0 (C).
(s, 1H, CH), 7.47 (d, J¼8.0 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz,
DMSO-d6):
d
¼55.2 (OCH3), 96.3 (C), 114.4 (2ꢂ CH), 120.1 (CH),
4.5. Synthesis of isothiocyanatoselenophenes 4aed; general
procedure
124.1 (2ꢂ CH), 126.3 (C), 128.8 (C), 146.1 (C), 148.8 (C), 159.9 (C]
O).
To a stirred mixture of NaHCO3 (10 mmol) in CHCl3/H2O
(8:6 mL) was added CSCl2 (575 mg, 5 mmol), followed by dropwise
addition of a solution of the corresponding aminoselenophene
(5 mmol) in CHCl3 (15 mL). The mixture was stirred at rt for 2 h. The
layers were separated and the organic layer was washed with H2O
(15 mL), dried (MgSO4), and evaporated. The residue was poured
into PE (15 mL), filtered, and evaporated.
4.4. Synthesis of aminoselenophenes 3aed; general
procedure
To
a
stirred solution of the appropriate amino-
selenophenecarboxylic acid (15 mmol) in i-PrOH (15 mL) was
added anhydrous oxalic acid (1 equiv). The reaction was stirred at
40 ꢁC until CO2 evolution ceased. The mixture was cooled to rt and
Et2O (25 mL) was added. The precipitate was filtered, washed with
PE (2ꢂ10 mL), and dried.
4.5.1. 3-Isothiocyanato-5-phenylselenophene
(4a). Yield:
57%;
brown oil. 1H NMR (250 MHz, CDCl3):
d¼7.25 (d, J¼1.5 Hz, 1H, CH),

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G. Revelant et al. / Tetrahedron 67 (2011) 9352e9357
7.35e7.42 (m, 3H, 3ꢂ CH), 7.49e7.53 (m, 2H, 2ꢂ CH), 7.69 (d,
CH), 114.8 (C), 121.5 (CH), 126.7 (2ꢂ CH), 127.7 (C), 128.1 (CH), 139.0
(C), 159.1 (C), 180.6 (C]S). HRMS (ESI): m/z calcd for
[C12H12N2OSSeþH]þ: 312.9908; found: 312.9823.
J¼1.5 Hz, 1H, CH). 13C NMR (62.5 MHz, CDCl3):
¼122.4 (CH), 123.8
d
(CH), 126.0 (2ꢂ CH), 126.2 (C), 128.6 (CH), 129.1 (2ꢂ CH), 129.3 (C),
134.9 (C), 150.2 (C).
4.6.5. N-(5-Phenyl-3-thienyl)thiourea (5e). Yield: 86%; orange
4.5.2. 3-Isothiocyanato-5-(4-chlorophenyl)selenophene (4b). Yield:
solid; mp 198 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d
¼7.31 (t,
62%; dark red oil. 1H NMR (250 MHz, CDCl3):
d
¼7.26 (d, J¼1.5 Hz,
J¼7.25 Hz, 1H, CH), 7.38e7.44 (m, 3H, 3ꢂ CH), 7.52 (s, 1H, CH), 7.59
1H, CH), 7.28 (d, J¼9.0 Hz, 2H, 2ꢂ CH), 7.37 (d, J¼9.0 Hz, 2H, 2ꢂ CH),
(d, J¼7.25 Hz, 2H, 2ꢂ CH), 9.89 (s, 1H, NH). 13C NMR (62.5 MHz,
7.61 (d, J¼1.5 Hz, 1H, CH). 13C NMR (62.5 MHz, CDCl3):
d
¼122.8
DMSO-d6):
d
¼119.9 (CH), 125.0 (2ꢂ CH), 127.8 (CH), 129.1 (2ꢂ CH),
(CH), 124.1 (CH), 127.1 (2ꢂ CH), 127.3 (C), 129.3 (2ꢂ CH), 129.9 (C),
133.4 (CH), 137.9 (C), 140.9 (C), 141.3 (C), 180.7 (C]S). HRMS (ESI):
134.5 (C), 135.7 (C), 148.7 (C).
m/z calcd for [C11H10N2S2þH]þ: 235.0358; found: 235.0360.
4.5.3. 3-Isothiocyanato-5-(4-methylphenyl)selenophene (4c). Yield:
4.6.6. N-(5-(4-Chlorophenyl)-3-thienyl)thiourea (5f). Yield: 77%;
95%; dark red oil. 1H NMR (250 MHz, CDCl3):
d
¼2.40 (s, 3H, CH3),
pale brown solid; mp 164 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼7.44
7.20 (d, J¼8.0 Hz, 2H, 2ꢂ CH), 7.24 (d, J¼1.5 Hz, 1H, CH), 7.32 (d,
(s, 1H, CH), 7.46 (d, J¼8.5 Hz, 2H, 2ꢂ CH), 7.53 (s, 1H, CH), 7.62 (d,
J¼8.0 Hz, 2H, 2ꢂ CH), 7.57 (d, J¼1.5 Hz,1H, CH). 13C NMR (62.5 MHz,
J¼8.5 Hz, 2H, 2ꢂ CH), 9.88 (s, 1H, NH). 13C NMR (62.5 MHz, DMSO-
CDCl3):
d
¼21.2 (CH3), 121.8 (CH), 123.2 (CH), 125.8 (2ꢂ CH), 126.0
d6):
d
¼120.6 (CH), 126.7 (2ꢂ CH), 129.1 (2ꢂ CH), 132.2 (CH), 135.4
(C), 129.1 (2ꢂ CH), 129.9 (C), 132.2 (C), 138.7 (C), 150.4 (C).
(C), 138.1 (C), 139.8 (C), 140.9 (C), 180.7 (C]S). HRMS (ESI): m/z
calcd for [C11H9ClN2S2þH]þ: 268.9968; found: 268.9931.
4.5.4. 3-Isothiocyanato-5-(4-methoxyphenyl)selenophene
(4d). Yield: 68%; brown oil. 1H NMR (250 MHz, CDCl3):
d
¼3.78 (s,
4.6.7. N-(5-(4-Methoxyphenyl)-3-thienyl)thiourea (5g). Yield: 64%;
3H, CH3), 6.84 (d, J¼9.0 Hz, 2H, 2ꢂ CH), 7.18 (d, J¼1.5 Hz, 1H, CH),
pale orange solid; mp 208 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼3.76
7.36 (d, J¼9.0 Hz, 2H, 2ꢂ CH), 7.54 (d, J¼1.5 Hz, 1H, CH). 13C NMR
(s, 3H, CH3), 6.97 (d, J¼8.5 Hz, 2H, 2ꢂ CH), 7.26 (s, 1H, CH), 7.41 (s,
(62.5 MHz, CDCl3):
d
¼55.4 (OCH3), 114.4 (2ꢂ CH), 114.6 (C), 121.2
1H, CH), 7.52 (d, J¼8.5 Hz, 2H, 2ꢂ CH), 9.82 (s, 1H, NH). 13C NMR
(CH), 122.7 (CH), 127.3 (2ꢂ CH), 127.5 (C), 127.8 (C), 150.1 (C), 160.0
(62.5 MHz, DMSO-d6):
d
¼55.2 (OCH3), 110.8 (C), 114.5 (2ꢂ CH),
(C).
118.8 (CH), 126.1 (CH), 126.4 (2ꢂ CH), 137.7 (C), 141.4 (C), 159.0 (C),
180.5 (C]S). HRMS (ESI): m/z calcd for [C12H12N2OS2þH]þ:
265.0464; found: 265.0474. IR (KBr): 3360, 3259 (NH2), 3142 (NH),
4.6. Synthesis of thioureas 5aeh; general procedure
1250 (C]S) cmꢀ1
.
To a stirred solution of the corresponding isothiocyanate
(3 mmol) in CH2Cl2 (10 mL) was added ammonia (25% in H2O,
0.5 mL). The mixture was stirred at rt overnight. PE (20 mL) was
added and then the precipitate was filtered, washed with Et2O
(10 mL), and dried.
4.6.8. N-(4,5-Dihydronaphto[1,2-b]-3-thienyl)thiourea (5h). Yield:
87%; brown solid; mp 215 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d
¼2.61
(t, J¼8.0 Hz, 2H, CH2), 2.88 (t, J¼8.0 Hz, 2H, CH2), 7.15e7.31 (m, 4H,
4ꢂ CH), 7.51 (s, 1H, CH), 9.30 (s, 1H, NH). 13C NMR (62.5 MHz,
DMSO-d6):
d
¼21.7 (CH2), 27.8 (CH2),115.2 (C),121.9 (CH),127.0 (CH),
4.6.1. N-(5-Phenyl-3-selenophenyl)thiourea (5a). Yield: 47%; brown
127.1 (C), 128.1 (CH), 130.8 (CH), 133.3 (C), 133.9 (C), 134.3 (CH),
135.6 (C), 181.6 (C]S). HRMS (ESI): m/z calcd for [C13H12N2S2þH]þ:
261.0515; found: 261.0534.
solid; mp 180 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d
¼7.30 (t, J¼7.5 Hz,
1H, CH), 7.39 (t, J¼7.5 Hz, 2H, 2ꢂ CH), 7.55 (d, J¼7.5 Hz, 2H, 2ꢂ CH),
7.62 (s, 1H, CH), 8.02 (s, 1H, CH), 9.88 (s, 1H, NH). 13C NMR
(62.5 MHz, DMSO-d6):
d
¼122.9 (CH), 125.4 (2ꢂ CH), 127.8 (CH),
4.7. One-step synthesis of thiourea; synthesis of N-[5-(4-
129.1 (2ꢂ CH),135.4 (CH),139.2 (C),144.1 (C),165.2 (C),180.7 (C]S).
HRMS (ESI): m/z calcd for [C11H10N2SSeþH]þ: 282.9802; found:
282.9754.
methoxyphenyl)-3-thienyl]carbamimidothioic acid (50g)
To a stirred solution of the corresponding thiophenamine
(1 mmol) in DMF (5 mL) were added concd HCl (1 mL) and am-
monium thiocyanate (1.5 mmol). The mixture was stirred at 80 ꢁC
for 3 h. After cooling to rt, the mixture was poured into water
(30 mL) and the precipitate formed was filtered, washed with water
(2ꢂ10 mL), and dried to afford the crude product, which was pu-
rified by chromatography on silica gel (cyclohexane/EtOAc, 1:1).
Yield: 30%; yellow solid; mp 78 ꢁC. 1H NMR (250 MHz, DMSO-
4.6.2. N-(5-(4-Chlorophenyl)-3-selenophenyl)thiourea (5b). Yield:
61%; brown solid; mp 172 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼7.43
(d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.57 (d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.64 (s,1H,
CH), 8.01 (s, 1H, CH), 9.81 (s, 1H, NH). 13C NMR (62.5 MHz, DMSO-
d6):
d
¼117.6 (C), 123.6 (CH), 127.0 (2ꢂ CH), 129.0 (2ꢂ CH), 132.3
(CH), 134.3 (C), 139.2 (C), 145.2 (C), 180.7 (C]S). HRMS (ESI): m/z
calcd for [C11H9ClN2SSeþH]þ: 316.9410; found: 316.9345.
d6):
CH), 7.42 (s, 1H, CH), 7.51 (d, J¼8.5 Hz, 2H, 2ꢂ CH), 8.23 (s, 1H, NH),
10.48 (s, 1H, NH). 13C NMR (62.5 MHz, DMSO-d6):
d
¼3.77 (s, 3H, CH3), 6.97 (d, J¼8.5 Hz, 2H, 2ꢂ CH), 7.26 (s, 1H,
4.6.3. N-(5-(4-Methylphenyl)-3-selenophenyl)thiourea (5c). Yield:
62%; yellow solid; mp 183 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼55.2 (OCH3),
108.1 (CH), 114.5 (2ꢂ CH), 116.2 (CH), 126.0 (C), 126.5 (2ꢂ CH), 136.1
(C), 141.7 (C), 158.8 (C), 159.1 (C). HRMS (ESI): m/z calcd for
[C12H12N2OS2ꢀH]þ: 263.0307; found: 263.0305. IR (KBr): 3269
d
¼2.29 (s, 3H, CH3), 7.20 (d, J¼7.75 Hz, 2H, 2ꢂ CH), 7.43 (d,
J¼7.75 Hz, 2H, 2ꢂ CH), 7.54 (s, 1H, CH), 7.94 (s, 1H, CH), 9.80 (s, 1H,
NH). 13C NMR (62.5 MHz, DMSO-d6):
d¼20.7 (CH3), 116.1 (C), 122.2
(NH), 1653 (C]N) cmꢀ1
.
(CH), 125.3 (2ꢂ CH), 129.6 (2ꢂ CH), 132.7 (CH), 137.4 (C), 139.0 (C),
146.9 (C), 180.6 (C]S). HRMS (ESI): m/z calcd for
[C12H12N2SSeþH]þ: 296.9959; found: 296.9912.
4.8. Synthesis of thiazoles 6aeh; general procedure
To a stirred solution of the corresponding thiourea (1 mmol) in
CH2Cl2 (10 mL) was added DDQ (1 equiv). The mixture was stirred
at rt for 4 h. The layer was washed with a 2 M aqueous solution of
NaOH (2ꢂ10 mL), dried (MgSO4), and evaporated to afford the
crude product, which was purified by chromatography on silica gel
(cyclohexane/EtOAc, 1:1).
4.6.4. N-(5-(4-Methoxyphenyl)-3-selenophenyl)thiourea
(5d). Yield: 81%; brown solid; mp 185 ꢁC. 1H NMR (250 MHz,
DMSO-d6):
(s, 1H, CH), 7.48 (d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.91 (s, 1H, CH), 9.85 (s,
1H, NH). 13C NMR (62.5 MHz, DMSO-d6):
¼55.3 (OCH3), 114.5 (2ꢂ
d¼3.77 (s, 3H, CH3), 6.95 (d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.45
d

G. Revelant et al. / Tetrahedron 67 (2011) 9352e9357
9357
4.8.1. 5-Phenylselenolo[3,2-d][1,3]thiazol-2-amine (6a). Yield: 86%;
green solid; mp 149 ꢁC. 1H NMR (250 MHz, DMSO-d6):
(C). HRMS (ESI): m/z calcd for [C12H10N2OS2þH]þ: 263.0307; found:
d¼7.13 (s,
263.0299.
2H, NH2), 7.26 (t, J¼7.5 Hz, 1H, CH), 7.37 (t, J¼7.5 Hz, 2H, 2ꢂ CH),
7.57 (d, J¼7.5 Hz, 2H, 2ꢂ CH), 7.68 (s, 1H, CH). 13C NMR (62.5 MHz,
4.8.8. 4,5-Dihydronaphto[1,2-b]thieno[3,2-d][1,3]thiazol-2-amine
DMSO-d6):
d
¼116.5 (C), 116.9 (CH), 124.9 (2ꢂ CH), 127.4 (C),
(6h). Yield: 91%; yellow solid; mp 233 ꢁC. 1H NMR (250 MHz,
129.1(2ꢂ CH),136.1 (C),147.7 (C),158.2 (C),171.0 (C). HRMS (ESI): m/
DMSO-d6):
d
¼2.79 (t, J¼7.0 Hz, 2H, CH2), 2.91 (t, J¼7.0 Hz, 2H, CH2),
z calcd for [C11H8N2SSeþH]þ: 280.9646; found: 280.9641.
7.10e7.29 (m, 4H, 4ꢂ CH), 7.30 (s, 2H, NH2). 13C NMR (62.5 MHz,
DMSO-d6):
d
¼22.2 (CH2), 27.9 (CH2), 116.5 (C), 121.3 (CH), 126.5 (C),
4.8.2. 5-(4-Chlorophenyl)selenolo[3,2-d][1,3]thiazol-2-amine
126.8 (CH), 127.0 (C), 128.1 (CH), 131.6 (C), 133.9 (CH), 135.1 (C),
155.6 (C), 170.9 (C). HRMS (ESI): m/z calcd for [C13H10N2S2þH]þ:
259.0358; found: 259.0354.
(6b). Yield: 64%; green solid; mp 186 ꢁC. 1H NMR (250 MHz, DMSO-
d6):
d
¼7.15 (s, 2H, NH2), 7.40 (d, J¼8.5 Hz, 2H, 2ꢂ CH), 7.60 (d,
J¼8.5 Hz, 2H, 2ꢂ CH), 7.72 (s, 1H, CH). 13C NMR (62.5 MHz, DMSO-
d6):
d
¼117.4 (C), 117.6 (CH), 126.5 (2ꢂ CH), 128.9 (2ꢂ CH), 131.6 (C),
4.8.9. 5-(4-Methoxyphenyl)thieno[3,2-d][1,3]thiazol-2(1H)imine
135.1 (C), 146.0 (C), 158.2 (C), 171.1 (C). HRMS (ESI): m/z calcd for
(60g). Yield: 65%; orange solid; mp 259 ꢁC. 1H NMR (250 MHz,
[C11H7ClN2SSeþH]þ: 314.9253; found: 314.9253.
DMSO-d6):
(d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.68 (s, 1H, CH), 8.19 (s, 1H, NH), 10.18 (s,
1H, NH). IR (KBr): 3369 (NH), 2921 (NH), 1687 (C]N) cmꢀ1
d¼3.60 (s, 3H, CH3), 6.91 (d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.42
4.8.3. 5-(4-Methylphenyl)selenolo[3,2-d][1,3]thiazol-2-amine
.
(6c). Yield: 76%; green solid; mp 135 ꢁC. 1H NMR (250 MHz, DMSO-
d6):
d
¼2.33 (s, 3H, CH3), 7.12 (s, 2H, NH2), 7.17 (d, J¼8.0 Hz, 2H, 2ꢂ
CH), 7.45 (d, J¼8.0 Hz, 2H, 2ꢂ CH), 7.61 (s, 1H, CH). 13C NMR
Acknowledgements
(62.5 MHz, DMSO-d6):
d¼20.7 (CH3), 115.8 (C), 116.3 (CH), 124.8 (2ꢂ
ꢁ
ꢀ
We thank the ‘Ministere de l’Enseignement Superieur et de la
Recherche’ for a Ph.D. grant to G.R. We thank also Veronique Vail-
CH), 129.6 (2ꢂ CH), 133.4 (C), 136.8 (C), 147.9 (C), 158.2 (C), 170.9 (C).
HRMS (ESI): m/z calcd for [C12H10N2SSeþH]þ: 294.9802; found:
294.9796.
ꢁ
lant and Agnes Crepet for recording NMR.
4.8.4. 5-(4-Methoxyphenyl)selenolo[3,2-d][1,3]thiazol-2-amine
(6d). Yield: 49%; brown solid; mp 201 ꢁC. 1H NMR (250 MHz,
References and notes
DMSO-d6):
d
¼3.76 (s, 3H, CH3), 6.92 (d, J¼9.0 Hz, 2H, 2ꢂ CH), 7.10 (s,
1. Karegoudar, P.; Karthikeyan, M. S.; Prasad, D. J.; Mahalinga, M.; Holla, B. S.;
Kumari, N. S. Eur. J. Med. Chem. 2008, 43, 261.
2H, NH2), 7.49 (d, J¼9.0 Hz, 2H, 2ꢂ CH), 7.53 (s, 1H, CH). 13C NMR
(62.5 MHz, DMSO-d6):
d¼55.2 (OCH3), 114.4 (2ꢂ CH), 115.7 (CH),
2. Vijesh, A. M.; Isloor, A. M.; Prabhu, V.; Ahmad, S.; Malladi, S. Eur. J. Med. Chem.
ˇ
2010, 45, 5460.
ˇ
126.3 (2ꢂ CH), 128.9 (C), 147.7 (C), 154.2 (C), 158.2 (C), 158.8 (C),
170.9 (C). HRMS (ESI): m/z calcd for [C12H10N2OSSeþH]þ: 310.9751;
found: 310.9756.
3. Moldovan, C. M.; Oniga, O.; Parvu, A.; Tiperciuc, B.; Verite, P.; Põrnau, A.; Crisan,
O.; Bojita, M.; Pop, R. Eur. J. Med. Chem. 2011, 46, 526.
4. Kok, S. H. L.; Gambari, R.; Chui, C. H.; Yuen, M. C. W.; Lin, E.; Wong, R. S. M.; Lau,
F. Y.; Cheng, G. Y. M.; Lam, W. S.; Chan, S. H.; Lam, K. H.; Cheng, C. H.; Lai, P. B. S.;
Yu, M. W. Y.; Cheung, F.; Tang, J. C. O.; Chan, A. S. C. Bioorg. Med. Chem. 2008, 16,
3626.
5. Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Andreani, F.; Gehret, J.-C.
Pharm. Acta Helv. 1996, 71, 247.
6. Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.; Ugenti, M. P.; An-
dreani, A.; Di Toro, R.; Bedini, A.; Spampinato, S.; Marinelli, L.; Novellino, E.;
Chiarini, A. J. Med. Chem. 2008, 51, 1592.
4.8.5. 5-Phenylthieno[3,2-d][1,3]thiazol-2-amine (6e). Yield: 86%;
green solid; mp 186 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d¼7.25 (s,
2H, NH2), 7.27 (t, J¼7.25 Hz, 1H, CH), 7.39 (t, J¼7.25 Hz, 2H, 2ꢂ CH),
7.50 (s, 1H, CH), 7.62 (d, J¼7.25 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz,
DMSO-d6):
d
¼114.1 (CH), 117.9 (C), 124.6 (2ꢂ CH), 127.3 (CH), 129.1
(2ꢂ CH), 134.4 (C), 143.0 (C), 157.4 (C), 170.7 (C). HRMS (ESI): m/z
7. Smirnova, N. G.; Zavarzin, I. V.; Krayushkin, M. M. Chem. Heterocycl. Compd.
2006, 42, 144.
8. Kvitko, I. Y. A.; Khozeeva, R. V.; Fedorova, N. S.; Smirnova, V. A.; El’tsov, A. V.
Khim. Geterotsikl. Soedin. 1979, 474.
calcd for [C11H8N2S2þH]þ: 233.0202; found: 233.0202.
4.8.6. 5-(4-Chlorophenyl)thieno[3,2-d][1,3]thiazol-2-amine
9. Astrakhantseva, N. I.; Zhiryakov; Abramenko, P. I. Khim. Geterotsikl. Soedin. 1975,
1607.
10. (a) Hesse, S.; Perspicace, E.; Kirsch, G. Tetrahedron Lett. 2007, 48, 5261; (b)
Thomae, D.; Perspicace, E.; Xu, Z.; Henryon, D.; Schneider, S.; Hesse, S.; Kirsch,
G.; Seck, P. Tetrahedron 2009, 65, 2982.
11. (a) Abdillahi, I.; Revelant, G.; Datoussaid, Y.; Kirsch, G. Synthesis 2010, 15, 2543;
(b) Revelant, G.; Hesse, S.; Kirsch, G. Synthesis 2010, 19, 3319.
12. Barker, J. M.; Wood, M. L.; Huddleston, P. R. Synth. Commun. 1995, 3729.
13. Saeed, S.; Rashid, N.; Jones, P. G.; Ali, M.; Hussain, R. Eur. J. Med. Chem. 2010, 45,
1323.
(6f). Yield: 83%; green solid; mp 202 ꢁC. 1H NMR (250 MHz, DMSO-
d6):
d
¼7.25 (s, 2H, NH2), 7.43 (d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.53 (s, 1H,
CH), 7.64 (d, J¼8.75 Hz, 2H, 2ꢂ CH). 13C NMR (62.5 MHz, DMSO-d6):
d¼114.7 (CH), 118.5 (C), 126.2 (2ꢂ CH), 128.9 (2ꢂ CH), 131.6 (C),
133.3 (C), 141.5 (C), 157.4 (C), 170.8 (C). HRMS (ESI): m/z calcd for
[C11H7ClN2S2þH]þ: 266.9812; found: 266.9810.
14. Yarovenko, V. N.; Smirnova, N. G.; Bulgakova, V. N.; Zavarzin, I. V.; Krayushkin,
M. M. Zh. Org. Khim. 2003, 39, 1232.
15. Moneam, M. I. A.; El-Dean, A. M. K. Phosphorus, Sulfur Silicon Relat. Elem. 2003,
178, 2639.
16. Bose, D. S.; Idrees, M. Tetrahedron Lett. 2007, 48, 669.
17. Lo, W. S.; Hu, W. P.; Lo, H. P.; Chen, C. Y.; Kao, C. L.; Vandavasi, J. K.; Wang, J. J.
Org. Lett. 2010, 12, 5570.
4.8.7. 5-(4-Methoxyphenyl)thieno[3,2-d][1,3]thiazol-2-amine
(6g). Yield: 50%; yellow solid; mp 232 ꢁC. 1H NMR (250 MHz,
DMSO-d6):
d
¼3.76 (s, 3H, CH3), 6.95 (d, J¼8.75 Hz, 2H, 2ꢂ CH), 7.35
(s,1H, CH), 7.37 (s, 2H, NH2), 7.54 (d, J¼8.75 Hz, 2H, 2ꢂ CH). 13C NMR
(62.5 MHz, DMSO-d6):
d¼55.2 (OCH3), 112.9 (CH), 114.4 (2ꢂ CH),
116.5 (C),126.1 (2ꢂ CH),127.1 (C),143.2 (C),157.3 (C),158.7 (C),170.6
18. Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2008, 1600.