Synthesis of trifluoromethyl-containing isoindolinones from tertiary enamides via a cascade radical addition and cyclization process

Abstract

A radical trifluoromethylation reaction of tertiary enamides was investigated and trifluoromethyl-containing isoindolinones were prepared under mild conditions. Using TMSCF 3 as a radical source, PhI(OAc) 2 as an oxidant and KHF 2 as an additive, tertiary enamides were converted to isoindolinones via a cascade addition and cyclization process in moderate to good yields.In recent years, triuoromethyl-containing azaheterocycles have attracted much attention for their potential application in the elds of pharmaceutical and agricultural chemistry.

Recent Progress in Aryltrifluoromethylation Reactions of Carbon‐Carbon Multiple Bonds

“…[64] Nonphotocatalytic methods were reported by Nevado and coworkers (Togni's reagent II + nBu 4 NI + NaHCO 3 , 11 examples, 22-85% yield) [42] as well as Tan, Liu, and coworkers [Me 3 SiCF 3 + PhI(OAc) 2 + KF + Na 2 CO 3 , 5 examples, 50-70% yield]. [45] The analogous transformation of N-vinylated benzamides yielded isoindolinones or trifluoromethylated alkenes depending on the substituents of the nitrogen and the aromatic ring, [76] while trifluoromethylation/cyclization of N-allylated arylsulfonamides provided 1,2-benzothiazinane dioxide derivatives. [77] Trifluoromethylation/cyclization of protected N-(2-methylallyl)anilines resulted in indolines.…”

Transition metal-free advanced synthetic approaches for isoindolinones and their fused analogues

“…10 Herein, we are interested in the synthetic pathways for isoindolinones and their fused analogues from available starting materials that do not contain any isoindolinone scaffolds in the initial step. Although there is a greater number of reports available on transition-metal catalyzed reactions 11 a – g via the reduction of the number of reaction steps to obtain the most available isoindolinone-based structures, transition metal-free protocols 12–53 offer various advantages over transformations involving transition metal catalysts. Transition metal-catalyzed protocols have the following drawbacks: (a) most metals are very sensitive to air and moisture, (b) toxic metals can easily mixed with drainage water during work-up, and (c) the high cost of metal catalysts is another barrier in the pharmaceutical industry.…”

“…TMSCF 3 (radical source), PhI(OAc) 2 (oxidant) and KHF 2 (additive) were used for this conversion to obtain the isoindolinone in excellent yield at 80 °C in CH 3 CN, taking n -butyl- N -(2-propenyl) benzamide 122 as the starting substrate (Scheme 34). 42 They tried with different additives including NaF, KHF 2 , and NaHF 2 to obtain the desired product with fruitful yields. Different N -substitutions, n -Bu, n -propyl, and cyclopropyl gave the target product with good to moderate yields.…”