F. Marsais, G. Quéguiner*
1983
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Influential Citations
77
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Journal
Tetrahedron
Abstract
Abstract Metallation of π-deficient heterocyclic compounds is first reviewed, which shows the important recent developments in this research area. A particular aspect of this reaction is then given with the study of the 3-fluoropyridine metallation regioselectivity. Lithiation of 3-fluorophyridine is chemoselective at low temperatures using butyllithium-polyamine chelates or lithium diisopropylamide. Protophilic attack by these strong bases can be directed either at the 2- or 4-position depending on the lithiation conditions. Various reaction parameters are thus studied such as solvent, temperature, reaction time, lithium-chelating agent as well as metallating agent. The high regioselectivity of 3-fluoropyridine lithiation is theoretically discussed, in particular in terms of kinetic of thermodynamic control of the metallation. Chelation between butyllithium and 3-fluoropyridine is proposed, which completely modifies the heterocycle reactivity toward the lithiating agent. This is confirmed by theoretical quantum calculations performed on different models of 3-fluoropyridine using the CNDO/2. These results allow to select the best 3-fluoropyridine-metallation conditions which lead to 3-fluoro-2-lithiopyridine on the one hand and to 3-fluoro-4-lithiopyridine on the other hand. Each of the lithiated isomers is then reacted with a great variety of electrophiles which gives very conveniently the corresponding 2,3- or 3,4-disubstituted pyridines.