Synthesis and deprotonation of 2-(halophenyl)pyridines and 1-(halophenyl)isoquinolines

The Journal of Organic Chemistry
Florence MonginFrancis Marsais

Abstract

The ability of the 2-pyridyl and 1-isoquinolyl groups to direct metalation was studied in the benzene series. For this purpose, 2-(halophenyl)pyridines and 1-(halophenyl)isoquinolines were prepared. Interestingly, nucleophilic addition reactions on the azine ring were not observed under kinetic control using butyllithium, and the substrates were cleanly deprotonated on the benzene ring: the azine ring acidifies the adjacent hydrogen H2' (N-H2' interaction through space and/or inductive electron-withdrawing effect) and probably favors the approach of butyllithium (chelation). Under thermodynamic conditions using lithium dialkylamides, the presence of the azine group makes the lithio derivative at C2' more stable (chelation and/or inductive electron-withdrawing effect). This was evidenced in two ways: (1) syntheses of 2-halophenyllithiums (F, Cl, Br) substituted at C6 by a 2-pyridyl or 1-isoquinolyl group without elimination of lithium halide and (2) iodine migration from C2' to C4' when treating 2-(3-halo-2-iodophenyl)pyridines or 1-(3-fluoro-2-iodophenyl)isoquinoline with LTMP. Comparisons between the 2-pyridyl and fluoro units showed the latter was the stronger directing group for deprotonation.

References

Jun 7, 2003·The Journal of Organic Chemistry·Yves Fort, Alain L Rodriguez

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Citations

Sep 8, 2015·European Journal of Medicinal Chemistry·Margaréta VojtičkováAndrej Boháč
Feb 9, 2006·Chemical Communications : Chem Comm·Hongjun Ren, Paul Knochel
Aug 13, 2011·Dalton Transactions : an International Journal of Inorganic Chemistry·Ludivine FetzerMichel Pfeffer
Apr 16, 2013·Chemistry : a European Journal·Raghu Ram KadiyalaFlorence Mongin
Dec 5, 2008·The Journal of Organic Chemistry·Ghenia Bentabed-AbabsaBelén Abarca
Oct 13, 2007·The Journal of Organic Chemistry·Miguel Angel RodríguezPeter H Seeberger

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