The 2 x 3 toolbox of organometallic methods for regiochemically exhaustive functionalization of aromatic and heterocyclic substrates
There are not so many fluorine, trifluoromethyl and trifluoromethoxy contg. arenes and heterocycles that are com. available and inexpensive. To exploit this bonanza optimally, one should be able to introduce addnl. substituents, in particular functional groups, at any unoccupied position. This would give rise to a manifold of new building blocks to be incorporated into more elaborate structures and tested for therapeutic or pesticidal activity. The fluorine labels in the core materials could be used to modulate biol. key parameters such as acidity, lipophilicity and isosterism. At the same time they can help to control the regioisomeric outcome of any chem. transformation. The required regiochem. flexibility was achieved by implementing mechanism-based modifications into the two std. methods for the generation of organometallic intermediates, the permutational hydrogen/metal interconversion ("metalation") and the permutational halogen/metal interconversion. The set ("toolbox") of two times three "mutant methods" which has emerged from these endeavors relies on the deployment of sterically shielding or electronically activating protective groups, basicity gradient-driven transmetalations or heavy halogen migrations and reagent-mediated or solvent-mediated optional site selectivities. As soon as the metal is properly positioned, it can be replaced by any kind of electrophile, the possibilities being virtually infinite. This approach to regioexhaustive functionalization will be illustrated by a series of typical case studies. By applying the principles specified above to 3-fluoro-phenol, all four possible carboxylic acids (2-fluoro-6-hydroxybenzoic acid, 2-fluoro-4-hydroxy- benzoic acid, 4-fluoro-2-hydroxybenzoic acid and 3-fluoro-4-hydroxybenzoic acid) were readily and selectively obtained. Other model studies focused on the prepn. of fluoroindolcarboxylic acids (all 12 isomers carrying the substituents in the benzo ring), derivs. of (trifluoromethyl)indoles and (trifluoromethoxy)indoles, (trifluoromethyl)pyridinecarboxylic acids (all 10 isomers), and halo(trifluoromethyl)pyridinecarboxylic acids, derivs. of fluoropyridines, difluoropyridines, 4-bromo-2-(trifluoromethyl)quinolines and (trifluoromethyl)pyrazoles. [on SciFinder (R)]
Institut de Chimie moleculaire et biologique Ecole Polytechnique Federale de Lausanne,Lausanne,Switz. Conference; Meeting Abstract written in English.
Record created on 2006-03-03, modified on 2016-08-08