gem ‐Difluoromethylene Alkyne‐Enabled Diverse C−H Functionalization and Application to the on‐DNA Synthesis of Difluorinated Isocoumarins

Abstract

Using gem-difluoromethylene alkynes as effectors, unprecedented diverse CÀHa ctivation/[4+ +2] annulations of simple benzoica cids are reported. The chemodivergent reaction outcomes are well-tuned by Rh/Ir-catalyzed system; in the Rh III catalysis,3-alkenyl-1H-isochromen-1-one and 3,4dialkylideneisochroman-1-one skeletons are afforded in asolvent-dependent manner whereas difluoromethylene-substituted 1H-isochromen-1-ones are generated under the Ir III-catalyzed system. Mechanistic studies revealed that unusually double b-F eliminations and fluorine effect-induced regioselective reductive elimination are independently involved to enable distinct reaction modes for divergent product formations.B esides,s ynthetic application in both the derivatization of obtained diene products and the on-DNAsynthesis of DNAtagged difluorinated isocoumarin have been demonstrated, which manifested great potential for synthetic utility of the developed protocols.

Synthesis of Difluorinated Dihydrobenzo[de]chromenes via Rh(III)‐Catalysed C‐H Couplings of 1‐Naphthols with Gem‐Difluoromethylene Alkynes

“…For example, in 2017 Loh and Feng pioneered the Rh(III)‐catalysed hydroarylation of gem ‐difluoromethylene alkynes with N ‐pivaloxyl aroylamides proceeded via an unconventional Lossen rearrangement owing to the introduction of fluorine atoms adjacent to the alkyne moiety (Scheme 1a) [6b] . Inspired by the seminal report, up to date, a tremendous amount of C−H activation strategies have been extensively explored by the groups of Huang, Wang, Rovis and us to extend the utility of gem ‐difluoromethylene alkynes and clarify the unique fluorine effects [6c–g,7] . Interestingly, diverse distinguished reaction modes involving one or two folds C−F bond cleavage could be realized by simple modification of the reaction conditions.…”

Multiple-fold C–F bond functionalization for the synthesis of (hetero)cyclic compounds: fluorine as a detachable chemical handle

“…Keeping the merit of multiple C–F bond fragmentation in mind, a continuing study in defluorine-mediated transformation was pursued by Xu, Zhou, and Yi. 95 The research group had illustrated that chemodivergent C–H functionalization/[4 + 2] annulation of simple benzoic acids with gem -difluoromethylene alkynes could be well-tuned by Rh/Ir-catalyzed systems (Scheme 51). gem -Difluoromethylene alkynes served as a two-carbon reactant.…”

“…Compared with Yi's example, 95 a newly established procedure for the selective notorious C(sp 3 )–F bond transformation of α,α-difluoromethylene alkynes exhibited disparate regioselectivity in terms of triple bond insertion (Scheme 53). 97 The weak coordination of the two nitrogen atoms in 1-arylpyrazolidinone with rhodium center accounts for its occurrence.…”

“…Yi et al demonstrated that 1,4-dihydroindeno[1,2-c]pyrazole framework could be accessed through a tandem sequence of C-H allenylation, [3 + 2] dipolar cycloaddition, and ring-opening aromatization rearrangement (Scheme 52). 96 Compared with Yi's example, 95 a newly established procedure for the selective notorious C(sp 3 )-F bond transformation of α,α-difluoromethylene alkynes exhibited disparate regioselectivity in terms of triple bond insertion (Scheme 53). 97 The weak coordination of the two nitrogen atoms in 1-arylpyrazolidinone with rhodium center accounts for its occurrence.…”

Recent advances in transition-metal catalyzed directed C–H functionalization with fluorinated building blocks

“…Diverse products were obtained by fine-tuning of Rh or Ir-catalytic activity (Scheme 39). 170 They found that in the case of Rh( iii ) catalysis, site-selective, solvent dependent and chemodivergent 3-alkenyl-1 H -isochromen-1-ones 201 and 3,4-dialkylideneisochroman-1-one derivatives 203 were formed. Furthermore, the nucleophilic attack on the cyclic ester produced the corresponding ring-opening products 204 .…”