Computational S_N2‐Type Mechanism for the Difluoromethylation of Lithium Enolate with Fluoroform through Bimetallic C−F Bond Dual Activation

Abstract

The reaction mechanism for difluoromethylation of lithium enolates with fluoroform was analyzed computationally (DFT calculations with the artificial force induced reaction (AFIR) method and solvation model based on density (SMD) solvation model (THF)), showing an SN 2-type carbon-carbon bond formation; the "bimetallic" lithium enolate and lithium trifluoromethyl carbenoid exert the C-F bond "dual" activation, in contrast to the monometallic butterfly-shaped carbenoid in the Simmons-Smith reaction. Lithium enolates, generated by the reaction of 2 equiv. of lithium hexamethyldisilazide (rather than 1 or 3 equiv.) with the cheap difluoromethylating species fluoroform, are the most useful alkali metal intermediates for the synthesis of pharmaceutically important α-difluoromethylated carbonyl products.

Studies of two different types of intramolecular C–H···F–C interactions from polyfluorinated diiodometal(II) diimine complexes

“…This is believed to be due to other intermolecular interactions from the compounds 55‐8F‐PtI 2 and 55‐8F‐PdI 2 , which slightly reduce the blue shifts. In this type of fluorinated dihalo Pt(II) diimine complexes, the C–H stretch from the free –CF 2 H group is usually below 3,000 cm −1 (Figure ). The vibrational data of 55‐8F‐PtI 2 are shown in Table .…”

“…Many −CF 2 H‐containing compounds have also been used as anesthetics, including the well‐known desflurane and isoflurane . Currently, difluoromethylation is under active development …”

Facile Bioinspired Preparation of Fluorinase@Fluoridated Hydroxyapatite Nanoflowers for the Biosynthesis of 5′-Fluorodeoxy Adenosine

“…A feature of nucleophilic fluoroalkylation is that the fluoroalkyl group is transferred to an electrophilic group, which is equivalent to a fluorocarbon anion or a fluoroalkyl metal species [9,10]. Through an electrophilic reaction [11], the promotion of lithium hexamethyldisilazide (LiHMDS) could be utilized to achieve the direct α-difluoromethylation of carbonyl compounds such as esters and CF 3 H. Fluoroalkyl radicals also play an important role as reactive intermediates in organofluorine chemistry [12], and AgF can act as a stabilizing intermediate to mediate fluorinative cross-coupling to prepare α-CF 3 alkenes and β-CF 3 ketones conveniently. However, for the chemical synthesis of some fluorinated pharmaceuticals such as 5 -fluorodeoxy adenosine, the process is cumbersome, and the final synthesis yield is low-approximately only 20% [13].…”

Defluorosilylation of trifluoromethane: upgrading an environmentally damaging fluorocarbon

“…2,24 However, there are only a handful of examples where trifluoromethane is employed as a {CF 2 H} + synthon through C-F functionalisation. [25][26][27][28][29][30] Mikami and co-workers used a highly nucleophilic boryl lithium reagent to demonstrate the defluoroborylation of HCF 3 to form an organoboron building block. 28 While a mechanistic study was not carried out for this system, a related computational study by Mikami on the a-difluoromethylation of lithium enolates was utilised to propose a pathway for the defluoroborylation.…”

“…28 While a mechanistic study was not carried out for this system, a related computational study by Mikami on the a-difluoromethylation of lithium enolates was utilised to propose a pathway for the defluoroborylation. 26 The authors suggest initial deprotonation of HCF 3 occurs to form LiCF 3 , before C-F cleavage then proceeds via an S N 2-type attack by the nucleophilic boryl lithium at LiCF 3 , in a bimetallic transition state. 26 While an important discovery, any application of the defluoroborylation methodology is limited by issues regarding scalability.…”