Difluorocarbene-Mediated Cascade Cyclization: The Multifunctional Role of Ruppert–Prakash Reagent

Abstract

A difluorocarbene-mediated cascade cyclization reaction for rapid access to gem-difluorinated 3-coumaranone derivatives was developed. The difluorocarbene acts as a bipolar CF 2 building block, which enables a homologation cyclization process via sequentially reacting with the phenolate and the ester group on the same substrate. The potential application of this synthetic approach is demonstrated by a late-stage modification of diethylstilbestrol. Mechanistic studies revealed the multiple crucial roles played by the Ruppert−Prakash reagent.

TMSCF3-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism

“…We began by identifying conditions under which the conversion of ethyl salicylates 2a–e H to coumaranones 4a – e could be effectively and safely monitored in situ by 19 F NMR spectroscopy . This required several further adjustments to the preparative methodology reported by Zhao . First, in addition to reducing the scale of the process from 5 to 0.5 mL, the concentration of the TBAT was reduced from 110 to 15 mM so that the full sequence of steps in the overall reaction could be analyzed in detail over a suitable time frame.…”

“…On applying the standard workup, , the C(3)-TMS group in 9c TMS undergoes protonolysis, and ketone 4c is obtained. Thus, any Kondo-silylation that occurs under Zhao’s conditions is ‘traceless’ in the absence of in situ analysis. By increasing the ratio [TMSCF 3 ] 0 /[ 2c TMS ] 0 to extend the duration of stage III, the conversion of 3c TMS into Ar-silylated 9c TMS was increased to >98%, and on addition of D 2 O, coumaranone 3-[ 2 H]- 4c (>98% D) was generated, Scheme b, see Section S8.2 in the Supporting Information.…”

“…Since its introduction in 1984, TMSCF 3 ( 1 ) has been a reagent of choice for the addition of CF 3 to electrophiles. , Over the past decade, the scope of application of 1 has expanded considerably and now includes, for example, the transfer of CF 2 and C–H silylation. − The majority of the reactions of TMSCF 3 ( 1 ) require the addition of a silaphilic anion, and a growing body of evidence indicates that this liberates a transient trifluoromethylcarbanion­(oid) “[CF 3 ] − ” from the TMS group. , Through kinetic and NMR spectroscopic studies, we recently established that reactions of TMSCF 3 initiated by [Ph 3 SiF 2 ] − [Bu 4 N] + (“TBAT”), a readily handled surrogate for “[F] − ”, proceed via anionic chain reactions, Scheme …”

In Situ Studies of Arylboronic Acids/Esters and R3SiCF3 Reagents: Kinetics, Speciation, and Dysfunction at the Carbanion–Ate Interface

“…It is now a core reagent in the synthesis of fluorochemicals, available at scale, easy to handle, relatively cheap, and the starting material for many other CF 3 -transfer reagents. , Recent advances by Prakash and Hu have greatly expanded the application of TMSCF 3 as a versatile CF 2 -source, − e.g. , for generation of difluorocyclopropa­(e)­nes, , TFE, perfluoroalkylmetallics, and other difluoromethylenes . In all applications, the reagent is used in excess, typically 2–5 equiv.…”

Difluorocarbene-Triggered Acyl Rearrangement Reaction: A Strategy for the Direct Introduction of the gem-Difluoromethylene Group

“…One of its typical conversions is [2 + 1] cycloaddition with alkenes or alkynes to generate difluorocyclopropanes or difluorocyclopropenes (Scheme a), which can undergo ring opening to construct gem -difluoromethylenated compounds under certain conditions . Owing to the presence of an empty p orbital, difluorocarbene is also intrinsically electrophilic that can be attacked by a nucleophile, following by interacting with other intra- or intermolecular electrophiles (Scheme b) . In addition, although the use of transition metal difluorocarbenes is still quite challenging on account of their unpredictable reactivities, metal–:CF 2 -involved catalytic coupling provides a powerful strategy to assemble the CF 2 group (Scheme c) .…”