Converting Core Compounds into Building Blocks: The Concept of Regiochemically Exhaustive Functionalization

Abstract

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)

Thorpe–Ingold Effect in Branch‐Selective Alkylation of Unactivated Aryl Fluorides

“…See the Supporting Information for details. Building upon the work of Schlosser, [22] regioselective lithiation of 35 can be achieved by asensible choice of the base.D eprotonation proceeding with either DABCO or DIPEA provides the compounds 36 and 39,r espectively. acac = acetylacetonate.…”

CF3‐Bearing Aromatic and Heterocyclic Building Blocks

“…Derivatives of 3-fluorophenol and 3-fluoropyridine that carry a given functional group at any of the four vacant positions may serve as typical examples to demonstrate the principle (Scheme 10). [51] …”

“…Therefore, deprotonation takes place at the 2-position this time and provides, after carboxylation and hydrogenolytic reduction, 3-fluoropyridine-2-carboxylic acid (34; 63 % overall yield; Scheme 11). [51] 2-Chloro-3-, 2-chloro-4-, and 2-chloro-6-(trifluoromethyl)pyridine can be purchased, although at prohibitive prices (20 000-25 000 E mol À1 ). To demonstrate the versatility of the method, we prepared 2-chloro-6-(trifluoromethyl)pyridine, [30] 3-chloro-2-(trifluoromethyl)pyridine, [56] 3-chloro-4-(trifluoromethyl)pyridine, [57] 5-chloro-2-(trifluoromethyl)pyridine, [58] 2-bromo-6-(trifluoromethyl)pyridine, [30] 3-bromo-5-chloro-2-(trifluoromethyl)pyridine, [56] and 5-bromo-2-chloro-4-(trifluoromethyl)pyridine [56] by applying the copper-mediated I/CF 3 displacement described above as the key step (Scheme 12).…”

Six‐Membered Heterocycles: Pyridines

“…Some pyridinium salts are commercially available reagents that are widely used. This is the case for pyridinium perbromide 173, which is employed as brominating agent, pyridinium dichromate (174, PDC) and pyridinium chlorochromate (175, PCC), used as mild and selective oxidizing agents, and pyridinium teflate (176), which is utilized as a source of teflic acid, a very weakly coordinating agent (Figure 16.13).…”