Bis(difluoromethyl)trimethylsilicate Anion: A Key Intermediate in Nucleophilic Difluoromethylation of Enolizable Ketones with Me₃SiCF₂H

Abstract

A pentacoordinate bis(difluoromethyl)silicate anion, [Me3Si(CF2H)2]−, is observed for the first time by the activation of Me3SiCF2H with a nucleophilic alkali‐metal salt and 18‐crown‐6. Further study on its reactivity by tuning the countercation effect led to the discovery and development of an efficient, catalytic nucleophilic difluoromethylation of enolizable ketones with Me3SiCF2H by using a combination of CsF and 18‐crown‐6 as the initiation system. Mechanistic investigations demonstrate that [(18‐crown‐6)Cs]+[Me3Si(CF2H)2]− is a key intermediate in this catalytic reaction.

Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate–Carbanion Dichotomy by Stopped-Flow NMR/IR

“… 36 , 38 However, they do not yield direct detail on the kinetics and mode of transfer of CF 3 from TMSCF 3 ( 1a ) to a carbonyl electrophile, using a catalytic fluoride-based initiator (M + X – ), at ambient temperature. 12 , 13 …”

“…12 A faster process, using a soluble initiator (Bu 4 NF· x H 2 O; 0.6 mol %, TBAF) was reported soon after, by Prakash and Olah. 13 Acidic workup affords the corresponding trifluoromethylated alcohols in good yield, Scheme 1 .…”

Radical Hydrodifluoromethylation of Unsaturated C-C Bonds via an Electroreductively Triggered Two-pronged Approach

“…[75][76] The requisite starting material 20 was prepared with good efficiency in three steps from commercially available 2-(4hydroxyphenyl)propanoic acid (17). As anticipated, the desired hydrodifluoromethylation was smoothly proceeded under the standard conditions (21). Hydrolysis of 21 was facile under basic conditions, leading to the formation of difluoromethyl analogue of Ibuprofen (22) in 28% overall yield (5 steps).…”

“…[1][2][3][4][5][6][7] Particularly, the installation of difluoromethyl (CF2H) functionality instead of CH3 or CF3 groups in biorelevant chemical structures has been an area of intensive research in drug development due to the highly polarized C−H bond of CF2H that serves as a bioisostere of hydrogen bonding donors such as hydroxyl, thiol, and amine groups. [8][9][10][11] In this context, difluoromethylative functionalization, where a difluoromethyl anion, [12][13][14][15][16][17][18][19][20][21] carbene [22][23][24][25][26][27] or radical precursor [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] is engaged in the direct transfer of the CF2H unit, has been vigorously pursued as a strategy with great promise in organic synthesis. Particularly, radical hydrodifluoromethylation in which CF2H • and H • equivalents add across to unsaturated C−C  bonds has become a central strategy to access a relatively limited class of aliphatic hydrocarbons that contain difluoromethyl group.…”