Ag^I‐Promoted Cascade for Difluoromethylation of Activated Alkenes to Difluoromethylated Oxindoles

Abstract

A simple AgI‐mediated direct difluoromethylation reaction of activated alkenes by using TMSCF2COOEt (TMS = trimethylsilyl) under mild reaction conditions has been described. This reaction tolerates a variety of functional groups and allows for a highly efficient synthesis of various difluoro‐containing oxindoles. Mechanistic investigations indicate that a difluoromethyl radical initiated the cascade sequence by undergoing an addition reaction to the alkene.

Difluoromethylation Reactions of Organic Compounds

“…The subsequent addition of the CF 2 COOEt radical intermediate to an activated C=C bond of the N ‐arylacrylamide affords radical intermediate A , which undergoes an intramolecular radical cyclization to generate intermediate B . The oxidation of B produces the corresponding carbocation C , and loss of H + and rearomatization affords the desired difluoromethylated oxindole D …”

“…First, aC F 2 COOEt radical intermediate is generated andf urther stabilized by the combination of AgI and PhI(OAc) 2 .T he subsequenta ddition of the CF 2 COOEt radical intermediate to an activated C=Cb ond of the N-arylacrylamide affords radical intermediate A,which undergoes an intramolecular radical cyclization to generate intermediate B.T he oxidation of B produces the corresponding carbocation C,a nd loss of H + and rear-omatization affords the desired difluoromethylated oxindole D. [80] Jian and colleagues [19] have informed in 2017 ad ifluoromethylationr eaction of olefins towards the synthesis of difluoromethylated 2,3-dihydrofurans and indolines. They employ ICF 2 CO 2 Et as difluoromethylating reagent, Pd(PPh 3 ) 4 as catalyst, DPPF as ligand,i n1 ,4-dioxane as solvent for 20 ha t8 08C.…”

“…Wang, Hao and colleagues have recently reported on a thermal Ag‐promoted cascade reaction for the difluoromethylation of activated alkenes towards the synthesis of oxindoles. They employ TMSCF 2 CO 2 Et as difluoromethylating agent, AgNO 3 , NaOAc as base, PhI(OAc) 2 as oxidant in N ‐methylpyrrolidone (NMP) as solvent.…”

“…In the presence of radical scavengers such as TEMPO, the formation of difluoromethylated oxindole is inhibited, and a TEMPO‐CF 2 COOEt adduct is detected quantitatively. These results suggest that addition of a generated CF 2 COOEt radical to an alkene initiates the cascade sequence. The authors propose a reaction mechanism such as that shown in Scheme .…”

Silicon-Based Reagents for Difluoromethylation and Difluoromethylenation Reactions

“…Nphenylmethacrylamide), several (ethoxycarbonyl)difluoromethyl-containing oxindoles were synthesized. 108 Mechanistically, the alkene-based radical intermediate formed by the attack of the CF 2 CO 2 Et radical closes the ring to form an aryl radical, which further undergoes oxidation to form an arenium ion and a deprotonation to rearomatize to the aryl system. Furthermore, the silver-mediated chemistry has also been employed for the direct C-H (ethoxycarbonyl)difluoromethylation of arenes 100 and preparation of an electrophilic SCF 2 CO 2 Et transfer reagent.…”