Synthesis of 1‐Tri(di)fluoromethyl 1,4‐Diketones Enabled by Radical Brook Rearrangement

Abstract

Dedicated to Professor Martin Oestreich on the occasion of his 50th birthday and his receipt of the WACKER Silicone Award in 2021Herein, we disclose the first and simple one-pot-two-step process to the synthesis of 1-difluoromethyl 1,4-diketones, through Mn-catalyzed radical Brook rearrangement. The methodology is also amenable to the synthesis of 1-trifluoromethyl 1,4-diketones. The products are efficiently converted to fluoroalkyl substituted furans, thiophenes, pyrroles and pyridazines, which are important structural motifs in natural products and pharmaceuticals.

Radical Brook Rearrangements: Concept and Recent Developments

“…This approach was also employed in the synthesis of antitumor agent Z and its difluoromethyl analogue Z' in good yields. Later on, the same research group successfully utilized their method for radical cascade reactions, [86] the synthesis of 1-difluoromethyl-1,4diketones, [87] and allylations [88] involving radical Brook rearrangements.…”

Visible-Light-Induced Organocatalyzed [2+1] Cyclization of Alkynes and (Trifluoroacetyl)silanes

“…[54][55][56][57] Intermediate A then undergoes a 1,2-silyl transfer to generate the -CF 3 siloxycarbene B. 27,[77][78][79][80][81][82][83][84][85] Intermediate B and alkyne 1 undergo a [2+1] cyclization reaction to produce product 3. Although we cannot completely rule out the existence of a singlet carbene, the following experimental results support the participation of a triplet carbene: (a) cis-and trans-isomers of cyclopropane were formed in the reaction of cis-11 and acylsilane 2a; (b) no isomerization of compound cis-11 was observed; and (c) under standard conditions, we did not observe isomerization of compound 12a to compound 12a′ (Schemes 9b-d).…”

Visible-light-promoted defluorinated alkylation of trifluoromethyl alkenes initiated by radical [1,2]-Brook rearrangement: facile synthesis ofgem-difluoro homoallylic alcohol derivatives

“…9,10 Despite the tremendous progress, the radical Brook rearrangements via single-electron transfer (SET) remain significantly less explored, due to the difficulty associated with the formation of an alkoxy radical. 11,12 In 2017, Smith developed an elegant oxidative [1,2]-Brook rearrangement via a hypervalent silicon intermediate induced by photoredox-catalyzed single-electron transfer, in which hypervalent organosilicates as alkyl radical precursors provided an alternative to the formation of alkoxyl radicals. 13 It should be noted that recently Shen and co-workers successfully developed the first radical [1,2]-Brook rearrangement using α-silyl cyclobutanol derivatives under photocatalysis, wherein an alkoxyl radical can be generated and engaged in the following radical alkylation of trifluoromethyl alkenes (Scheme 2c, left).…”