As part of a case study, rational strategies for the preparation of all ten 2-, 3-, or 4-pyridinecarboxylic acids and all nine 2-, 3-, 4-, or 8-quinolinecarboxylic acids bearing trifluoromethyl substituents at the 2-, 3-, or 4-position were elaborated. The trifluoromethyl group, if not already present in the precursor, was introduced either by the deoxygenative fluorination of suitable carboxylic acids with sulfur tetrafluoride or by the

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As a further test of the concept of regioexhaustive functionalization, 2‐chloro‐6‐(trifluoromethyl)pyridine, 2‐chloro‐5‐(trifluoromethyl)pyridine and 3‐chloro‐4‐(trifluoromethyl)pyridine were each converted into the three possible carboxylic acids 2, 4, 6, 8, 10, 12, 16, 17 and 20. This was achieved by employing several, but not all of the organometallic “toolbox methods”: transformation of a more basic organometallic species into a less basic isomer by transmetalation‐equilibration, site discriminating deprotonation with lithium N,N‐diisopropylamide or lithium 2,2,6,6‐tetramethylpiperidide, regio‐divergent iodine migration and steric screening of acidic positions by a bulky trialkylsilyl group. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

In a model study, 3‐fluorophenol and 3‐fluoropyridine were converted into the each time four possible carboxylic acids by passing through the corresponding organometallic intermediates. As an attempt to generalize the findings reveals, a restricted set of principles and methods suffices to cope with all standard scenarios. The most valuable and versatile tools for the regiochemically exhaustive functionalization of a great variety of substrate patterns are the optionally site‐selective metalation (either by reagent/substrate matching or by peripheral coordination control), the use of activating or congesting protective groups and the basicity gradient‐driven heavy halogen migration (followed by halogen/metal permutation). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Heating with bromotrimethylsilane converts 2‐chloropyridine into 2‐bromopyridine and 2‐chloro‐6‐methylpyridine into 2‐bromo‐6‐methylpyridine. Both 2‐chloropyridines and 2‐bromopyridines give the corresponding iodo compound when treated with in situ generated iodotrimethylsilane. Although 3‐ and 4‐chloropyridine are completely inert, 2,4‐dichloropyridine undergoes the halogen/halogen exchange simultaneously at the 2‐ and 4‐position. Halogen displacement takes place exclusively at the 2‐position with 2,3‐dichloropyridine and 2,5‐dichloropyridine. In agreement with the intermediacy of N‐trimethylsilylpyridinium salts as a prerequisite for the occurrence of halogen exchange, neither 2‐fluoropyridine and 2‐fluoro‐6‐methylpyridine nor any 2,6‐dihalopyridine reacts. Finally, bromine/chlorine and iodine/chlorine substitution can also be accomplished with 2‐ or 4‐chloroquinoline, 1‐chloroisoquinoline, 2‐chloropyrimidine, chloropyrazine and 2,3‐dichloroquinoxaline as substrates. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002)