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H. J. Jeong et al.
LETTER
alkyl-substituted benzothiophenes. Thus, methyl 2-
acetylthio)benzoate (1j) and methyl 2-(heptylthio)ben-
zoate (1k) cyclized intramolecularly to give 2j and 2k
in 70% and 65% yields respectively. According to the
results obtained, substitution of the aromatic ring did not
significantly affect the product yield but it was slightly
lower in the case of molecules with electron-donating
groups (Table 2, entries 6, 9, 10 and 11). All of these re-
actions proceeded via an intramolecular carbon–carbon
bond formation reaction between two carbonyl groups.
M.; Smith, R. L.; Sondey, J. M.; Strohmaier, K. M.; Sugrue,
M. F.; Varga, S. L. J. Med. Chem. 1989, 32, 2548.
(d) Zhang, T. Y.; O’Toole, J.; Proctor, C. S. Sulfur Rep.
(
4
f
4f
1999, 22, 1. (e) Pelkey, E. T. Prog. Heterocycl. Chem. 1999,
11, 102. (f) Irie, M.; Uchida, K. Bull. Chem. Soc. Jpn. 1998,
71, 985.
(
2) Hsiao, C.-N.; Kolasa, T. Tetrahedron Lett. 1992, 33, 2629.
(3) Jordan, V. C. J. Med. Chem. 2003, 46, 1081.
(4) (a) Campaigne, E. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katritzky, A. R.; Rees, C. W.; Bird, C.
W.; Cheesemann, G. W. H., Eds.; Pergamon Press: Oxford,
1984, 863. (b) Hsiao, C.-N.; Bhagavatula, L.; Pariza, R. J.
The reaction seems to proceed via an initial reduction of
Synth. Commun. 1990, 20, 1687. (c) Kolasa, T.; Brooks, D.
W. Synth. Commun. 1993, 23, 743. (d) Bianchini, C.; Meli,
A. Synlett 1997, 643. (e) Russell, R. K.; Press, J. B. In
Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Amsterdam, 1996, 679. (f) Arnoldi, A.; Carughi,
M. Synthesis 1988, 155. (g) Kim, S.; Yang, J.; DiNinno, F.
Tetrahedron Lett. 1999, 40, 2909. (h) Gallagher, T.; Pardoe,
D. A.; Porter, R. A. Tetrahedron Lett. 2000, 41, 5415.
6
,8,9,10
two carbonyl groups to form the pinacolate
followed
by elimination as in the usual McMurry reaction. It seems
that by reducing the stoichiometric amount of Zn, its ac-
tivity is partially reduced which in turn controls the over-
all reaction by sustaining the thioester group until the C2–
C3 bond in the benzothiophene is formed from the two
carbonyl groups in substrate 1.
(
i) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett.
We found that the ratio of Zn and TiCl was pivotal to the
4
2
2
001, 3, 651. (j) Hessian, K. O.; Flynn, B. L. Org. Lett.
003, 5, 4377. (k) Hessian, K. O.; Flynn, B. L. Org. Lett.
McMurry reaction of methyl (2-substituted benzoyl-
thio)benzoates 1 and that the addition of LiAlH improves
4
2006, 8, 243.
the yield of the desired benzothiophenes 2.
(5) For reviews on McMurry reactions, see: (a) Fürstner, A.;
Bogdanović, B. Angew. Chem., Int. Ed. Engl. 1996, 35,
In summary, we have established the first synthetic meth-
odology for the preparation of 2-substituted benzo-
thiophenes using a modified McMurry reaction. The
present method provides a simple and facile process for
the direct synthesis of 2-substituted benzothiophenes
from methyl 2-(substituted aroylthio)benzoates or methyl
2442. (b) McMurry, J. E. Chem. Rev. 1989, 89, 1513.
(
c) Dushin, R. G. In Comprehensive Organometallic
Chemistry II, Vol. 12; Hegedue, L. S., Ed.; Pergamon:
Oxford, 1995, 1071; and references therein. (d) Talukdar,
S.; Nayak, S. K.; Banerji, A. J. Org. Chem. 1998, 63, 4925.
(e) Aleandri, L. E.; Bogdanović, B.; Gaidies, A.; Jones, D. J.;
Liao, S.; Michalowicz, A.; Rozière, J.; Schott, A.
J. Organomet. Chem. 1993, 459, 87. (f) Bogdanović, B.;
Bolte, A. J. Organomet. Chem. 1995, 502, 109.
2
-(substituted acylthio)benzoates.
(
g) Fürstner, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 164.
Acknowledgment
(
6) Nishio, T.; Okuda, N.; Kashima, C. J. Heterocycl. Chem.
1988, 25, 1437.
7) A mixture of Zn dust (3.0 mmol) and LiAlH (0.2 mmol) in
S.G.L. thanks the Gyeongsang National University for his sabbati-
cal year program in 2005. This work was supported by the Brain
Korea 21 project in 2006 (to S.H.J., S.N.K. and U.A.Y.).
(
4
CH Cl (30 mL) was stirred for 30 min at 0 °C. To the
2
2
reaction mixture TiCl (2.0 mmol) was added dropwise and
4
the temperature was brought slowly to r.t.. The reaction
mixture was suspended for 1 h at r.t. and substrate 1 (1a–k,
References and Notes
1
.0 mmol) was added slowly. The reaction mixture was
(
1) For reviews on the synthesis and application of
benzothiophenes, see: (a) Bradley, D. A.; Godfrey, A. G.;
Schmid, C. R. Tetrahedron Lett. 1999, 40, 5155.
heated at reflux with stirring for 30 min to 2 h and allowed
to cool to r.t. It was then passed through a short silica gel
column using EtOAc as eluent to eliminate inorganic salts.
The filtrate was evaporated, and the residue was purified by
flash column chromatography using n-hexane–EtOAc (5:1)
as eluent to afford pure 2a–k.
(
b) Connor, D. T.; Cetenko, W. A.; Mullican, M. D.;
Sorenson, R. J.; Unangst, P. C.; Weikert, R. J.; Adolphson,
R. L.; Kennedy, J. A.; Thueson, D. O.; Wright, C. D.;
Conroy, M. C. J. Med. Chem. 1992, 35, 958. (c) Graham, S.
L.; Shepard, K. L.; Anderson, P. S.; Baldwin, J. J.; Best, D.
B.; Christy, M. E.; Freedman, M. B.; Gautheron, P.;
(
(
8) Fürstner, A.; Ernst, A. Tetrahedron 1995, 51, 773.
9) Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org.
Chem. 1994, 59, 5215.
Habecker, C. N.; Hoffman, J. M.; Lyle, P. A.; Michelson, S.
R.; Ponticello, G. S.; Robb, C. M.; Schwam, H.; Smith, A.
(
10) McMurry, J. E.; Fleming, M. P.; Kees, K. L.; Krepski, L. R.
J. Org. Chem. 1978, 43, 3255.
Synlett 2007, No. 9, 1407–1410 © Thieme Stuttgart · New York