Fluorine in an heteroaromatic context

The organometallic approach to the functionalization of arenes and heteroarenes has recently been investigated by our group introducing modifications of the standard methods. This includes, in particular, the basicity-driven heavy halogen migration, which allows the introduction of a functional group at a not directly accessible position. Then, some attentions were reported toward nucleophilic aromatic substitution and especially to a regio-controlled attack at heteroarenes. Bulky trialkylsilyl groups were used to shield a given position by steric congestion against both electrophilic and nucleophilic attack. Using different electrophiles, commercially available 2,6-difluoropyridine was selected as substrate for a large proliferation of derivatives through organolithium intermediates. To allow for more regioflexibility, one can either rely on protective groups or introduce iodine which will be subsequently submitted to a basicity gradient-driven relocation and eventually a halogen/metal exchange. A systematic investigation was undertaken to explore the scope and the limitations of this latter option. Di-, tri- and tetrahalopyridines are used to explore the substituent effect in nucleophilic substitutions with the pyridine ring. An activating substituent as chlorine directed the nucleophilic substitution at the vicinal fluorine atom. Unprecedented was the finding that bulky 3-trialkylsilyl group effectively shielded the fluorine at the adjacent 2- and 4-positions, reorienting the nucleophilic substitution to the 6-position. To exploit the regioselectivity established by the "silyl trick", some halopyridines, such as 2,4,5-trifluoropyridine or 2,4-dichloro-6-hydrazinopyridine, were prepared for the fist time. Highly substituted derivatives isolated during nucleophilic substitutions were the starting point for the development of more complex structures such 2-amino-5-bromo-4-chloro-6-fluoro-3-nitropyridine obtained by using some of the developed techniques.