Tricomponent Catalytic α,α-Difluorination of Acid Chlorides

Abstract

The selective α,α-difluorination of carbonyl compounds remains a challenge in modern organic synthesis; current methods often incorporate stepwise processes and/or harsh conditions, providing unsatisfactory mixtures of mono- and difluorinated products. In this communication, a practical, mild, and one-pot method for the selective α,α-difluorination of readily available acid chlorides is reported in which three separate catalysts act synergistically to form products in outstanding selectivity and fair to excellent yields.

A Polycomponent Metal‐Catalyzed Aliphatic, Allylic, and Benzylic Fluorination

“…[4] To date, the most notable methods for alkane fluorination [5] involve the use of stoichiometric quantities of difficult-to-handle or indiscriminate reagents such as elemental fluorine, [6] cobalt trifluoride (polyfluorination), [7] or the potentially explosive cesium fluoroxysulfate. [9,10] For the purposes of this study, we chose first to focus our efforts on the well-characterized adamantane system 1 and its fluorinated derivatives. What is more, a mild procedure using safe, commercially available alternatives would be complementary to pioneering methods, and perhaps be applicable to closely related allylic and benzylic substrates.…”

“…[10] To this end, we added KB(C 6 F 5 ) 4 (10 mol %) to our reaction and were gratified to find a substantial increase in the rate of formation and yield of 2 (Table 1). [10] To this end, we added KB(C 6 F 5 ) 4 (10 mol %) to our reaction and were gratified to find a substantial increase in the rate of formation and yield of 2 (Table 1).…”

“…Herein, we report the fluorination of a series of aliphatic, benzylic, and allylic substrates using a polycomponent catalytic system involving commercially available Selectfluor, the putative radical precursor Nhydroxyphthalimide (NHPI), an anionic phase-transfer catalyst (KB(C 6 F 5 ) 4 ), and a copper(I) bisimine complex. [9,10] For the purposes of this study, we chose first to focus our efforts on the well-characterized adamantane system 1 and its fluorinated derivatives. Initial catalyst screening employed a variety of transition-metal salts, Selectfluor, and adamantane in dry MeCN (1 mL) and was stirred for 24 h at room temperature.…”

“…Our group has shown that reactions employing Selectfluor concomitant with a metal cocatalyst can be accelerated by the addition of a phase-transfer catalyst as a solubilizing agent and presumed metal counteranion exchanger. [10] To this end, we added KB(C 6 F 5 ) 4 (10 mol %) to our reaction and were gratified to find a substantial increase in the rate of formation and yield of 2 (Table 1). [11] In a parallel effort toward making the reaction more homogeneous, we also sought the use of a ligand to bring CuI into solution more effectively and to modulate its reactivity.…”

Catalytic Asymmetric Mono‐Fluorination of α‐Keto Esters: Synthesis of Optically Active β‐Fluoro‐α‐Hydroxy and β‐Fluoro‐α‐Amino Acid Derivatives

“…[12] Difluorinated compounds might also be formed, albeit with difficulty. [13] Based on our previous results, we envisaged that the use of mildly basic catalysts would permit the asymmetric fluorination of a-keto esters. [10,14] Herein we report the first example of highly enantioselective mono-fluorination of a-keto esters catalyzed by Pd-m-hydroxo complexes 1.…”