The Regioexhaustive Functionalization of Difluorophenols and Trifluoro­phenols Through Organometallic Intermediates

Abstract

2, 2, 2, 3, 3, 2,4,5-trifluorophenol and 2,3,4-trifluorophenol were converted into all 18 possible di-or trifluorinated hydroxybenzoic acids (1a-c, 4a-c, 9a-c, 12a,b, 14a-c, 17a,b, 18a,b), all of them new compounds. The phenolic hydrogen atom was replaced by a methoxymethyl or, less frequently, by a triisopropylsilyl group, which exerted an ortho activating or ortho shielding effect, respectively. Sites flanked by two electronegative substituents (fluorine, alkoxy) were deprotonated with particular ease. They had to be silenced by the reversible attachment of a metalation-blocking trimethylsilyl group or of a metalation-deflecting chlorine atom if the metal was to be introduced elsewhere. In all cases but one, the stage was thus set for an intramolecular competition between metalation at an oxygen-adjacent or a fluorine-adjacent site. It proved indeed possible to secure the desired regioflexibility in either way by relying on an appropriate substrate-reagent matching. This demonstrates once more the potential of the organometallic approach to diversity-oriented synthesis.The three fluorophenols represent milestones in the development of the organometallic approach to diversity-oriented synthesis. 1,2 The ortho and para isomers, after protection of the free phenols as anisoles 3 or methoxymethyl ethers 4 were found to undergo perfectly site-controlled metalation (and subsequent carboxylation) at either the oxygen-or halogen-adjacent position depending on the mechanism-matched choice of the reagent. The meta isomer acted as one of the first substrates to illustrate the concept of regioexhaustive functionalization by its transformation into each of the four possible fluorohydroxybenzoic acids (Scheme 1). 2 Under these circumstances it deemed us worthwhile to extend our studies to difluorophenols and trifluorophenols. Most of such compounds are commercial if often expensive. On the other hand, many of them can be efficaciously prepared from cheap starting materials such as 1,2-difluorobenzene, 1,4-difluorobenzene, 1-bromo-3,5-difluorobenzene and 1-bromo-2,4,5-trifluorobenzene by hydrogen/metal or halogen/metal permutation followed by dimethoxyborylation 5,6 and oxidation.As demonstrated below, it proved possible to introduce a metal atom into any vacant position of five difluorophenols and two trifluorophenols selected as model compounds. The organometallic intermediates thus generated were always intercepted by carbon dioxide and only occasionally also by other electrophiles (in particular, chlorinating and silylating reagents). It is nevertheless tacitly understood that in the same way as the 18 fluorinated hydroxybenzoic acids described below were accessed, aldehydes, alcohols, amines, sulfonic acids, phosphonic acids and countless other functionalized products could be made. 7

Fit-for-Purpose Synthesis of a KRASG12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

“…Ultimately, we focused our research on the generation of the ortho -fluorinated aryllithium amides at low temperature. We found that a regioselective ortho- deprotonation using LiTMP, followed by trapping with triisopropyl borate provided >99% of fluoro-arylboronic acid 14 after an acidic quench.…”