ORGANIC
LETTERS
2000
Vol. 2, No. 6
803-805
Unusual C-6 Lithiation of
2-Chloropyridine-Mediated by
BuLi−Me2N(CH ) OLi. New Access to
2 2
6-Functional-2-chloropyridines and
Chloro-bis-heterocycles
Sabine Choppin, Philippe Gros, and Yves Fort*
Synthe`se Organique et Re´actiVite´, UMR CNRS-UHP 7565, Faculte´ des Sciences,
UniVersite´ Henri Poincare´-NancyI, BP 239, 54506, VandoeuVre-Les-Nancy, France
Received January 12, 2000
ABSTRACT
The reaction of 2-chloropyridine with alkylithium generally results in nucleophilic addition leading to the loss of chlorine atom while exclusive
directed ortho metalation is obtained using LDA. Herein it is shown that the BuLi−Me2N(CH ) OLi (BuLi−LiDMAE) superbase promotes an
2 2
unprecedented regioselective C-6 lithiation. The method was successfully applied to the preparation of potentially useful chlorinated pyridinic
and bis-heterocyclic synthons.
Among pyridine derivatives, 2-chloropyridine appears as a
particularly versatile compound. Indeed, the presence of a
C-Cl bond makes it potentially reactive toward nucleophiles
allowing the introduction of functional groups.1 The pyridinic
protons are also of interest since base abstraction could give
a metalated pyridine potentially reactive toward electrophilic
reagents. Unfortunately, the reaction with BuLi was trouble-
some since only addition products onto the azomethine bond
were obtained with, in some cases, untimely elimination of
the chlorine atom.2 Thus, the design of new methods allowing
metalation of 2-chloropyridine with retention of the C-Cl
bond could be of great synthetic value. From our knowledge,
only LDA efficiently accomplished this reaction inducing
exclusive lithiation at the C-3 position3,4 as a consequence
of the chlorine atom directing effect (DoM effect).5 All these
reactions were performed in THF and metalation in apolar
solvents was never reported.
In our recent works,6,7 we have shown that the basicity/
nucleophilicity ratio (B/N ratio) of BuLi could be signifi-
cantly increased in hexane by association with lithium
dimethylamino ethoxide (noted LiDMAE). As a conse-
quence, the obtained base BuLi-LiDMAE efficiently meta-
lated sensitive heterocycles.7 Moreover, 2-hetero-substituted
pyridines were regioselectively metalated at the unusual C-6
position.6,8 This prompted us to investigate the metalation
of 2-chloropyridine with BuLi-LiDMAE in apolar solvents.
(5) For reviews on directed orthometalation, see: (a) Snieckus, V. Chem.
ReV. 1990, 90, 879-933. (b) Marsais, F.; Que´guiner, G.; Snieckus, V.;
Epsztajn, J. AdV. Heterocycl. Chem. 1991, 52, 187-303.
(6) (a) Gros, Ph.; Fort, Y.; Que´guiner, G.; Caube`re, P. Tetrahedron Lett.
1995, 36, 4791-4794. (b) Gros, Ph.; Fort, Y.; Caube`re, P. J. Chem. Soc.,
Perkin Trans. 1 1997, 20, 3071-3080.
(7) Gros, Ph.; Fort, Y.; Caube`re, P. J. Chem. Soc., Perkin Trans. 1 1997,
24, 3597-3600.
(8) Gros, Ph.; Ben Youne`s-Millot, C.; Fort, Y. Tetrahedron Lett. 2000,
41, 303-306.
(1) Shepherd, R. G.; Fedrick, J. L. AdV. Heterocycl. Chem. 1965, 4, 145.
(2) Tre´court, F.; Marsais, F.; Gu¨ngor, T.; Que´guiner, G. J. Chem. Soc.,
Perkin Trans. 1 1990, 9, 2409-2415.
(3) Marsais, F.; Que´guiner, G. Tetrahedron 1983, 39, 2009-2021.
(4) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4137-
4140.
10.1021/ol005538o CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/23/2000