been straightforward.8 As recently as 2002, unselective reactions
of this type, leading to the need for eventual separation of
isomers and the waste of products, have been reported.1c In
response to this problem, we now report a convenient and highly
selective one-pot synthesis of a range of 2-substituted 4-meth-
ylthiophenes via lithiation of commercially available 3-meth-
ylthiophene with lithium 2,2,6,6-tetramethylpiperidide (LiTMP).
Reactions of electrophiles with 3-substituted thiophenes
generally give predominantly 2,3-disubstituted products.8 Only
when the original substituent is either highly sterically hindered
or strongly electron withdrawing does substitution take place
preferentially at the 5-position (to give a 2,4-disubstituted
product). This approach is therefore not appropriate for the
general synthesis of simple 2,4-disubstituted thiophenes.
Lithiation of thiophene is highly R-selective.9 For 3-substi-
tuted thiophenes with a substituent that directs metalation (e.g.,
dimethylaminocarbonyl, dimethylaminomethyl, methanethiyl),
lithiation is directed to the 2-position, R- to both the substituent
and the ring sulfur atom.9,10 For 3-substituted thiophenes with
a substituent that does not direct metalation, for example,
3-methylthiophene, lithiation occurs at both the 2- and 5-posi-
tions, but the 5-position usually predominates.9 More sterically
hindered 3-substituents increase the predominance.11 However,
to our knowledge, the only exclusively 5-selective substitutions
of 3-methylthiophene reported until now have been those of its
lithiated derivative with extremely hindered electrophiles, and
in such cases, the reported yields of products are low to
moderate.1d,7 There is therefore still a great need for a high-
yielding general method for highly regioselective 5-substitution
of simple 3-substituted thiophenes with unhindered electrophiles.
In connection with an ongoing research project, we needed
a convenient and high-yielding synthesis of 2,4-dimethylth-
iophene (2). Published syntheses of 2 and potentially adaptable
syntheses of other 2,4-disubstituted thiophenes often involved
several steps, required costly or unavailable starting materials,
or gave low yields.6,12,13 The simplest method, reported by Sice´
in 1954, involved lithiation of 3-methylthiophene (1) with
n-BuLi, which is not very selective,1c,14 followed by reaction
with dimethylformamide and subsequent reduction.15
Highly Selective 5-Substitution of
3-Methylthiophene via Directed Lithiation
Keith Smith* and Mark Lewis Barratt
Centre for Clean Chemistry, Chemistry Department, UniVersity
of Wales, Swansea, Singleton Park, Swansea SA2 8PP, U.K.
ReceiVed September 30, 2006
Lithiation of 3-methylthiophene with lithium 2,2,6,6-tetra-
methylpiperidide (LiTMP) is highly selective at the 5-posi-
tion, and reaction with a range of electrophiles gives high
yields of the corresponding 2,4-disubstituted thiophenes, even
when unhindered electrophiles are used.
Substituted thiophenes are important building blocks for
pharmaceuticals,1 conductive polymers,2,3 photochromic dithi-
enylethene molecular switches,4,5 liquid crystals,6 molecular
machines,7 etc. In light of the ubiquity of thiophenes, we were
surprised to find that the synthesis of simple 2,4-disubstituted
thiophenes from monosubstituted thiophenes has generally not
* To whom correspondence should be addressed. Fax: +44 (0)1792 295261.
Tel: +44(0)1792 295266.
(1) Recent examples: (a) Denton, T. T.; Zhang, X.; Cashman, J. R.
J. Med. Chem. 2005, 48, 224. (b) Conde, S.; Pe´rez, D. I.; Mart´ınez, A.;
Perez, C.; Moreno, F. J. J. Med. Chem. 2003, 46, 4631. (c) Collins, I.;
Moyes, C.; Davey, W. B.; Rowley, M.; Bromidge, F. A.; Quirk, K.; Atack,
J. R.; McKernan, R. M.; Thompson, S.-A.; Wafford, K.; Dawson, G. R.;
Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro, J. L. J. Med. Chem.
2002, 45, 1887. (d) Espaze, F.; Hamon, J.; Hirbec, H.; Vignon, J.; Kamenka,
J.-M. Eur. J. Med. Chem. 2000, 35, 323.
(2) Recent reviews: (a) Guernion, N. J. L.; Hayes, W. Curr. Org. Chem.
2004, 8, 637. (b) Roncali, J. J. Mater. Chem. 1999, 9, 1875. (c) Kraft, A.;
Grimsdale, A. C.; Holmes, A. B. Angew. Chem., Int. Ed. 1998, 37, 402.
(3) Recent examples: (a) Jiang, X.; Patil, R.; Harima, Y.; Ohshita J.;
Kunai, A. J. Phys. Chem. B 2005, 109, 221. (b) Buga, K.; Kepczynska, K.;
Kulszewicz-Bajer, I.; Zago´rska, M.; Demadrille, R.; Pron, A.; Quillard, S.;
Lefrant, S. Macromolecules 2004, 37, 769. (c) Berlin, A.; Zotti, G.; Zecchin,
S.; Schiavon, G.; Vercelli, B.; Zanelli, A. Chem. Mater. 2004, 16, 3667.
(d) Albertin, L.; Bertarelli, C.; Gallazzi, M. C.; Meille, S. V.; Capelli,
S. C. J. Chem. Soc., Perkin Trans. 2 2002, 1752.
(4) Recent reviews: (a) Matsuda, K.; Irie, M. J. Photochem. Photobiol.
C 2004, 5, 169. (b) Raymo, F. M.; Tomasulo, M. J. Phys. Chem. A 2005,
109, 7343. (c) Irie, M. Chem. ReV. 2000, 100, 1685. (d) Feringa, B. L.; van
Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. ReV. 2000, 100,
1789.
(5) Recent examples: (a) de Jong, J. J. D.; Browne, W. R.; Walko, M.;
Lucas, L. N.; Barrett, J.; McGarvey, J. J.; van Esch, J. H; Feringa, B. L.
Org. Biomol. Chem. 2006, 4, 2387. (b) Asano, Y.; Murakami, A.; Kobayashi,
T.; Goldberg, A.; Guillaumont, D.; Yabushita, S.; Irie, M.; Nakamura S.
J. Am. Chem. Soc. 2004, 126, 12112. (c) Jukes, R. T. F.; Adamo, V.; Hartl,
F.; Belser, P.; De Cola, L. Inorg. Chem. 2004, 43, 2779. (d) Peters, A.;
Branda, N. R. Chem. Commun. 2003, 954. (e) Kim, M.-S.; Sakata, T.; Kawai
T.; Irie, M. Jpn. J. Appl. Phys. 2003, 42, 3676.
(8) Meth-Cohn, O. Comp. Org. Chem. 1979, 4, 789.
(9) (a) Gschwend, H. W.; Rodriguez, H. R. Org. Reactions (NY) 1979,
26, 35. (b) Ramanathan, V.; Levine, R. J. Org. Chem. 1962, 27, 1667. (c)
Catoni, G.; Galli, C.; Mandolini, L. J. Org. Chem. 1980, 45, 1906.
(10) (a) Slocum, D. W.; Gierer, P. L. J. Org. Chem. 1976, 41, 3668. (b)
Taylor, E. C.; Vogel, D. E. J. Org. Chem. 1985, 50, 1002.
(11) (a) Go¨tz, G.; Sheib, S.; Klose, R.; Heinze, J.; Ba¨uerle, P. AdV. Funct.
Mater. 2002, 12, 723. (b) Detty, M. R.; Hayes, D. S. Heterocycles 1995,
40, 925. (c) O’Donovan, A. R. M.; Shepherd, M. K. Tetrahedron Lett. 1994,
35, 4425.
(12) (a) Morton, A. A. The Chemistry of Heterocyclic Compounds, 3rd
ed.; McGraw-Hill: New York, 1946; pp 39-55. (b) Joule, J. A.; Mills, K.;
Smith, G. Heterocyclic Chemistry, 3rd ed.; Chapman & Hall: Oxford, 1995;
pp 368-377. (c) Gilchrist, T. L. Heterocyclic Chemistry, 2nd ed.;
Longman: London, 1992; pp 214-223. (d) Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 2001, 2491.
(13) (a) Hartough, H. D. J. Am. Chem. Soc. 1951, 73, 4033. (b) Parham,
W. E.; Mayo, G. L. O.; Gadsby, B. J. Am. Chem. Soc. 1959, 81, 5993. (c)
Nishimura, H.; Mizutani, J. J. Org. Chem. 1975, 40, 1567. (d) Takeshita,
M.; Tashiro, M. J. Org. Chem. 1991, 56, 2837. (e) Belen’kii, L. I.; Yakubov,
A. P. Tetrahedron 1984, 40, 2471. (f) Kang, K.-T.; Hwang, Y. B.; Kim,
M. Y.; Lee, S. K.; Lee, J. G. Bull. Korean Chem. Soc. 2002, 23, 1333.
(14) Boelens, M. P.; de Valois, J.; Wobben, H. J.; van der Gen, A.
J. Agric. Food. Chem. 1971, 19, 984.
(6) Kim, E. K.; Lee, K. U.; Cho, B. Y.; Kim, Y. B.; Kang, K.-T. Liquid
Crystals 2001, 28, 339.
(7) Lomas, J. S.; Lacroix, J.-C.; Vaissermann, J. J. Chem. Soc., Perkin
Trans. 2 1999, 2001.
(15) Sice´, J. J. Org. Chem. 1954, 19, 70.
10.1021/jo062024f CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/10/2007
J. Org. Chem. 2007, 72, 1031-1034
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