A new synthesis of benzo[b]thiophene-2-thiolates and their derivatives via base-promoted transformation of 4-(2-mercaptophenyl)-1,2,3-thiadiazoles

Article abstract of DOI:10.1021/ol401981w

A reaction of 4-(2-mercaptophenyl)-1,2,3-thiadiazoles with an oxidant in the presence of 1.1 equiv of base afforded good yields of benzo[4,5]thieno[3,2- d][1,2,3]thiadiazoles via the intramolecular oxidative nucleophilic substitution of a hydrogen (ONHS) pathway. The reaction of 4-(2-mercaptophenyl)-1,2,3- thiadiazoles in the presence of ≥2 equiv of base gave 2-mercaptobenzo[b] thiophenes via an anionic ring-opening/ring-closure pathway.

Full text of DOI:10.1021/ol401981w

ORGANIC
LETTERS
2013
Vol. 15, No. 15
4038–4041
A New Synthesis of Benzo[b]thiophene-
2-thiolates and Their Derivatives via
Base-Promoted Transformation of
4‑(2-Mercaptophenyl)-1,2,3-thiadiazoles
Fedor S. Teplyakov, Tatiana G. Vasileva, Mikhail L. Petrov, and Dmitry A. Androsov*
Department of Organic Chemistry, Saint-Petersburg State Institute of Technology,
Moskovskii prospekt 26, Saint-Petersburg 190013, Russia
da_androsov@hotmail.com
Received July 15, 2013
ABSTRACT
A reaction of 4-(2-mercaptophenyl)-1,2,3-thiadiazoles with an oxidant in the presence of 1.1 equiv of base afforded good yields of
benzo[4,5]thieno[3,2-d][1,2,3]thiadiazoles via the intramolecular oxidative nucleophilic substitution of a hydrogen (ONHS) pathway. The
reaction of 4-(2-mercaptophenyl)-1,2,3-thiadiazoles in the presence of g2 equiv of base gave 2-mercaptobenzo[b]thiophenes via an anionic
ring-opening/ring-closure pathway.
5-Unsubstituted-1,2,3-thiadiazoles are reactive com-
pounds which find use in organic chemistry as a conve-
nient and easily available source of acetylenic thiolates.1
These highly reactive thiolates may undergo further trans-
formations affording various acyclic, alicyclic, and hetero-
cyclic compounds containing sulfur.2
As a continuation of our previous studies3 dealing
with the synthesis of 2-mercaptobenzo[b]furans and -indoles
via intramolecular cyclization of ortho-hydroxy- and
-aminothioketenes, in this work, we present a method
for the synthesis of 2-mercaptobenzo[b]thiophenes from
4-(2-mercaptophenyl)-1,2,3-thiadiazoles. Some aspects of
4-(2-mercaptophenyl)-1,2,3-thiadiazoles peculiar to reac-
tivity as compared with those of 4-(2-hydroxyphenyl)-
1,2,3-thiadiazoles and 4-(2-aminophenyl)-1,2,3-thiadiazoles
will be discussed in this paper (Scheme 1).
Benzo[b]thiophen-2-thiol and its 5- and 7-chloro deriva-
tives were prepared by treatment of the approriate 2-benzo-
[b]thienyl-lithium derivative with sulfur in 55À68% yield.4
A high-temperature reaction of H2S with 2-chlorobenzo-
[b]thiophene gave mainly the corresponding thiol in 23%
yield.5
(1) (a) Raap, R.; Micetich, R. G. Can. J. Chem. 1968, 46, 1057–1063.
(b) Rodionova, L. S.; Petrov, M. L.; Petrov, A. A. Zh. Org. Khim. 1978,
14, 2050–2054.
(2) (a) Petrov, M. L.; Petrov, A. A. Usp. Khim. 1987, 56, 267–286. (b)
L’abbe, G.; Haelterman, B.; Dehaen, W. J. Chem. Soc., Perkin Trans. 1
1994, 16, 2203–2204. (c) Terenteva, N. A.; Petrov, M. L.; Potekhin,
K. A.; Struchkov, K. A.; Galishev, V. A. Zh. Org. Khim. 1994, 30, 344–
350. (d) Terenteva, N. A.; Petrov, M. L.; Shishkin, O. V.; Struchkov,
K. A.; Potekhin, K. A.; Galishev, V. A. Russ. J. Org. Chem. 1995, 31,
825–830. (e) Forster, W. R.; Isecke, R.; Spanka, C.; Schaumann, E.
Synthesis 1997, 8, 942–948. (f) Takimiya, K.; Morikami, A.; Otsubo, T.
Synlett 1997, 3, 319–321. (g) Petrov, M. L.; Zmitrovich, N. I. Russ. J.
Gen. Chem. 1999, 69, 245–256.
(3) (a) D’hooge, B.; Smeets, S.; Toppet, S.; Dehaen, W. Chem.
Commun. 1997, 1753–1754. (b) Abramov, M. A.; Dehaen, W.; D’hooge,
B.; Petrov, M. L.; Smeets, S.; Toppet, S.; Voets, M. Tetrahedron 2000,
56, 3933–3940. (c) Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529–
1531. (d) Petrov, M. L.; Dehaen, W.; Abramov, M. A.; Abramova, I. P.;
Androsov, D. A. Russ. J. Org. Chem. 2002, 38, 1510–1518. (e) Petrov,
M. L.; Teplyakov, F. S.; Androsov, D. A.; Yekhlef, M. Russ. J. Org.
Chem. 2009, 45, 1727–1729. (f) Petrov, M. L.; Yekhlef, M.; Teplyakov,
F. S.; Androsov, D. A. Russ. J. Org. Chem. 2012, 48, 728–735.
Benzo[b]thiophen-2-thiol was used for the synthesis of
novel 1,4-dithiins, aspentaceneanalogs, which consisted of
(4) (a) Yamamoto, T.; Ogawa, S.; Sato, R. Tetrahedron Lett. 2004,
45, 7943–7946. (b) Chapman, N. B.; Hughes, C. G.; Scrowston, R. M.
J. Chem. Soc. C 1970, 18, 2431–2455.
(5) Voronkov, M. G.; Deryagina, E. N.; Klochkova, L. G.;
Nakhmanovich, A. S. Zh. Org. Khim. 1976, 12, 1515–1521.
r
10.1021/ol401981w
Published on Web 07/25/2013
2013 American Chemical Society

5 (77%) on addition of acetyl chloride directly to the
reaction mixture, thus avoiding isolation of the intermedi-
ate product 4 (Scheme 3).
A similar reaction of the 4-(2-chloro-5-(trifluoromethyl)-
phenyl)-1,2,3-thiadiazole 2b with potassium thioacetate in
DMF at 50 °C failed to give the desired product. An
attempt to promote the reaction by applying a higher
temperature resulted in accumulation of decomposition
products.
Scheme 1. 5-exo-dig Cyclization of ortho-Mercaptophenylthio-
ketene
the parent 1,4-dithiin withtwo benzo[b]thiophenes on both
sides. These compounds may find application in organic
field-effect transistor (OFET) manufacture.4a
Scheme 3. Synthesis of 2-(1,2,3-Thiadiazol-4-yl)thiophenols
A compound having a 2-mercaptobenzo[b]thiophene
moiety at the C(2) position of 1β-methylcarbapenem was
found to be the potent inhibitor of class B metallo-
β-lactamases, also having antimicrobial activity against
β-lactamase-producing bacteria, synergisticaly enhancing
the effect of imipenem and ceftazidime.6
Herein, we would like to report a convenient one-pot
synthesis of 2-mertcaptobenzo[b]thiophenes having
electron-donating and -withdrawing substituents on
the phenyl ring, as well as its various S-derivatives.
The reaction involves a base-promoted transformation
of the new readily available 4-(2-mercaptophenyl)-1,2,3-
thiadiazoles via an anionic ring-opening/ring-closure
pathway. In the course of our study we also observed
an unexpected formation of benzo[4,5]thieno[3,2-d]-
[1,2,3]thiadiazoles, representing a rare case of the oxida-
tive nucleophilic substitution of hydrogen (ONHS)
reaction with the participation of the sulfur nucleophile.
In order to obtain entry to 4-(2-mercaptophenyl)-
1,2,3-thiadiazoles, we first prepared 4-(2-chlophenyl)-
l,2,3-thiadiazoles 2a and 2b by treating ethoxycarbonyl-
hydrazones of 2-chloroacetophenones 1a and 1b with
thionyl chloride in accordance with the HurdÀMori
procedure (Scheme 2).1a,7
We next studied base-catalyzed anionic ring opening
of thiadiazoles 3 and 5 (Scheme 4). The reaction of 3 with
1.1 equiv of KOH in THF in the presence of MeI gave
methyl sulfide 6, while the heterocyclic ring remained
intact. The treatment of the thiadiazole 3 with 3 equiv of
t-BuOK in THF in the presence of MeI resulted in the
formation of ethynyl sulfide 7. The treatment of thiadia-
zole 3 or 5 with 3 equiv of t-BuOK in THF followed by
the addition of (a) dilute hydrochloric acid to weakly
acidic pH giving a 76% yield of benzo[b]thiophene-2-thiol
8; (b) water and an alkylating agent affording benzo-
[b]thiophene-2-sulfides 9aÀ9f (Table 1); and (c) water
and an arylating agent (2,4-dinitrochlorobenzene) giving
a mixture of monoarylation 10 and diarylation 11 prod-
ucts evidenced the contribution of an anion-radical mech-
anism of the aromatic nucleophilic substitution.
Scheme 2. Synthesis of 4-(2-Chlorophenyl)-1,2,3-thiadiazoles
We further studied oxidation reactions of thiadiazoles 3
and 5, as well as oxidation reactions of their deprotonation
and decompositions products (Scheme 5). It was estab-
lished that the oxidation of the neutral form of the
thiadiazole 3 by iodine in THF at 20 °C gave dimerization
product 12 in 92% yield. The oxidation of thiadiazoles 3
and 5 by iodine, after treatment of the reaction mixture
with 1.1 equiv of sodium hydride, in THF at 20 °C,
unexpectedly led to the formation of the benzo[4,5]thieno-
[3,2-d][1,2,3]thiadiazoles 13a and 13b. Finally, the decom-
position of thiadiazole 3 with 3 equiv of t-BuOK in THF
at 20 °C followed by the addition of iodine gave 2,2-
dithiobisbenzo[b]thiophene 14 in 79% yield. In the case
The reaction of 4-(2-chloro-5-nitrophenyl)-1,2,3-thia-
diazole 2a with potassium thioacetate in DMF at 20 °C
afforded the corresponding thiophenol 3 in 80% yield. The
reduction of the nitro group in compound 3 with zinc
powder in acetic acid gave unstable para-aminothiophenol
4 (63%) that could be stabilized as its N-acetyl derivative
(6) Nagano, R.; Adachi, Y.; Imamura, H.; Yamada, K.; Hashizume,
T.; Morishima, A. Antimicrob. Agents Chemother. 1999, 43, 2497–2503.
(7) Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359–5364.
Org. Lett., Vol. 15, No. 15, 2013
4039

Scheme 4. Reactions of 2-(1,2,3-Thiadiazol-4-yl)thiophenols in
the Presence of Base
Figure 1. Single crystal X-ray structure of compound 9b.
Scheme 5. Reactions of 2-(1,2,3-Thiadiazol-4-yl)thiophenols in
the Presence of Base and Oxidizing Agent
Table 1. Synthesis of Benzo[b]thiophenes-2-sulfides
entry
compd
R
R1
yield, %
of intramolecular proton transfer from the heterocyclic
ring to the sulfur anion. Direct deprotonation of the
heterocyclic ring was achieved by addition of the second
equivalent of t-BuOK and resulted in the formation of
dianion 16 (the formation of an 1,2,3-thiadiazol-5-yl inter-
mediate dianion 16 was not observed in our experiment,
but was supported by data reported in the literature3a,8).
The subsequent thiadiazole ring opening accompanied
by liberation of nitrogen gave dithiolate 17, which could
be trapped as its dimethyl derivative 7 (Scheme 4). Addi-
tion of a proton donor, such as water, to the reaction
mixture resulted in partial protonation of dithiolate 17
affording alkynethiol 18, which existed in equilibrium
with its highly reactive thioketene tautomer 19. An intra-
molecular addition of nucleophilic thiophenolate to the
electrophilic thioketene moiety of 19 led to the formation
of benzo[b]thiophene-2-thiolate 20, which could partici-
pate in further protonation, alkylation, arylation, and
oxidation reactions (Schemes 4, 5).
1
2
3
4
5
6
9a
9b
9c
9d
9e
9f
NO2
CH3
78
62
75
73
71
85
NO2
CH2C6H5
NO2
CH2C(O)NH(4-MeOC6H4)
CH3
NHAc
NHAc
NHAc
CH2C6H5
CH2C(O)NH(4-MeOC6H4)
of thiadiazole 5, having the electron-donating acetamido
group on the benzene ring, the oxidation resulted in the
formation of the complex mixture of oligomeric materials.
X-ray crystallographic analysis of the compound 9b
evidenced that the benzo[b]thiophene fragment and the
nitro group are coplanar, whereas the benzo[b]thiophene
and the benzylsulfenyl fragments adopt an orthogonal
configuration (Figure 1).
A plausible mechanism of the benzo[b]thiophene-2-thio-
late formation is shown in Scheme 6. Addition of the first
equivalent of t-BuOK to a solution of the thiadiazole in
THF resulted in the formation thiophenolate 15. Unlike
the related phenolates,3a,b we did not observe the subse-
quent decomposition of the thiadiazole ring as a result
(8) Thomas, E. W.; Zimmermann, D. C. Synthesis 1985, 945–948.
Org. Lett., Vol. 15, No. 15, 2013
4040

Scheme 6. Mechanism of the Base-Promoted Transformation of
2-(1,2,3-Thiadiazol-4-yl)thiophenols
Figure 2. Single crystal X-ray structure of compound 13a.
a rare example of the oxidative nucleophilic substitution
of hydrogen (ONHS) reaction with the participation of
a sulfur nucleophile.9 Another, conventional HurdÀMori
approach7 was employed for the synthesis of 6-chloro-8-
methylbenzothieno[3,2-d][1,2,3]thiadiazole from a semicar-
bazone of 6-chloro-4-methylbenzo[b]thiophene-3(2H)one.10
X-ray crystallographic analysis of compound 13a
evidenced the planar molecular geometry. A comparison
of X-ray data for compound 13a with those of 1,2,3-
benzo[4,5]thiadiazole11 indicated that the bond lengths
and the bond angles were insignificantly varied in the
It is worthy of note that even under the influence of
excess t-BuOK (g3 equiv), decomposition of the thiadia-
zole ring of the thiophenolate 15 occurs relatively slowly
(few hours), which is nontypical for the related pheno-
lates.3a,b Rapid and almost quantative formation of benzo-
[4,5]thieno[3,2-d][1,2,3]thiadiazoles 13 (Scheme 6) on ad-
dition of such a relatively mild oxidant as iodine may
explain the slow rate of heterocyclic ring decomposition
in compound 15. Apparently, thiophenolate anion 15
having higher nucleophilicity compared to the related
phenolate tends to form stable tricyclic intramolecular
anionic adduct 21. For this reason, the concentration of
the thiophenolate 15 in the reaction mixture is relativly
low, thus preventing its rapid conversion to the deproton-
ated intermediate 16 and, after a series of transforma-
tions, to the final cyclization product 20. Formation of
the benzo[4,5]thieno[3,2-d][1,2,3]thiadiazoles 13a and 13b
by oxidative aromatization of the adduct 21 represents
ꢀ
˚
range of 0.008À0.018 A and 0.36°À1.00° correspondingly
(Figure 2).
In summary, we have developed a new convenient
approach to 2-mercaptobenzo[b]thiophenes and benzo-
[4,5]thieno[3,2-d][1,2,3]thiadiazoles from the readily avail-
able 4-(2-mercaptophenyl)-1,2,3-thiadiazoles.
Supporting Information Available. Experimental de-
tails and characterization data of new compounds along
1
with copies of H, 13C NMR, mass spectra, and X-ray
data (for compounds 9b and 13a). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) Mayr, A. J.; Carrasco-Flores, B.; Cervantes-Lee, F.; Pannell, K. H.;
ꢀ
(9) Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631–
)
ꢀ
Parkanyi, L.; Raghuveer, K. J. Organomet. Chem. 1991, 405, 309–322.
2666.
(10) Meier, H.; Trickes, G.; Laping, E.; Merkle, U. Chem. Ber. 1980,
113, 183–192.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
4041