ORGANIC
LETTERS
2005
Vol. 7, No. 24
5535-5537
Selective 4-Arylation of Pyridines by a
Nonmetalloorganic Process
E. J. Corey* and Yuan Tian
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
Received October 12, 2005
ABSTRACT
Mild and position-selective nucleophilic 4-arylation of pyridines has been accomplished by the use of triflic anhydride N-activation.
4-Arylpyridines1 are usually prepared by one of three
approaches: (1) cross-coupling reactions,2 such as the
palladium-catalyzed Suzuki reaction, Stille reaction, or
Negishi reaction (Scheme 1, eq 1) starting with pyridyl
halides or triflates; (2) nucleophilic addition of arylmetallic
reagents to pyridinium compounds followed by rearomati-
zation (Scheme 1, eq 2);3 or (3) reactions that form the
pyridine ring last. Herein, we report a position-selective
addition of π-basic aromatic compounds directly to pyri-
dinium compounds that have been activated by N-trifluo-
romethylsulfonation with triflic anhydride. This process
depends on a method for strong electrophilic activation of
pyridines that we expect will be more widely useful.
Although trifluoromethanesulfonic (triflic) anhydride in
combination with 2,6-lutidine is often used as a reagent
combination for the conversion of hydroxy compounds to
the corresponding triflates,4 pyridine itself or its derivatives
in which the ring nitrogen is not sterically screened by 2-
and 6-substituents are generally not applicable as catalysts
for triflate ester formation probably because N-triflylation
intervenes. The sharp difference between triflic anhydride
Scheme 1
(1) (a) Micetich, R. G. Pyridine and Its DeriVatiVes, Supplement Part
Two; Abramovitch, R. A., Ed.; John Wiley & Sons: New York, 1974. (b)
Kartrizky, A. R., Rees, C. W., Eds.; ComprehensiVe Heterocyclic Chemistry,
The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds;
Pergamon: New York, 1984; Vol. 2.
(2) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Black-
well: UK, 2000; pp 83-84. (b) Katritzky, A. R.; Pozharskii, A. F. Handbook
of Heterocyclic Chemistry, 2nd ed.; Pergamon: New York, 2000; p 40.
(3) (a) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315.
(b) Akiba, K.; Iseki, Y.; Wada, M. Tetrahedron Lett. 1982, 23, 429. (c)
Akiba, K.; Iseki, Y.; Wada, M. Bull. Chem. Soc. Jpn. 1984, 57, 1994. (d)
Zhang, D.; Liorente, I.; Liebesking, L. S. J. Org. Chem. 1997, 62, 4330.
(e) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell: UK,
2000; pp 66 and 96-98. (f) Katritzky, A. R.; Pozharskii, A. F. Handbook
of Heterocyclic Chemistry, 2nd ed.; Pergamon: New York, 2000; p 210.
10.1021/ol052476z CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/28/2005