The homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF2 transfer agent is reported. Activating TMSCHF2 with potassium tert-amylate enables a convenient access to the difluorinated homologation reagent, which adds to the acylating partners. The high chemoselectivity showcased in the presence of variously multifunctionalized Weinreb amides, jointly with uniformly high yields, enables the strategy of general applicability without requiring any stabilization element for the putative carbanion.

The new motif – α,α-difluoromethyl thioamide – has been assembled starting from isothiocyanate (as thioamide precursor) and a formal difluoromethyl-carbanion generated from commercially available TMSCHF2.

Thioformamides are easily prepared – under full chemocontrol – through the partial reduction of isothiocyanates with the in situ generated Schwartz reagent.

The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp 3 -type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanionlike species can act as nucleophiles, thus making it of general applicability. E mbodying a halogen-containing functionality within a carbon skeleton profoundly influences the physicochemical features, thus properly modulating the reactivity profile of the array. 1 Accordingly, solid synthetic methodologies levered on different logics (e.g., radical, electrophilic, and nucleophilic) have been designed and thoroughly applied. 2 In this sense, the introduction of metalated α-halogenated carbon species (MCR 1 R 2 Hal, i.e., the so-called carbenoid reagents) reacting under a nucleophilic or electrophilic regime (Scheme 1, path a), depending on the nature of the metal, has emerged as a valuable tool for delivering synthons featuring the exact degree of functionalization requested (i.e., halogen loading). 3 As a result, common downsides associated with the use of conceptually different approaches, such as polyhalogenations, can be conveniently skipped. The initial installation of the CR 1 R 2 Hal unit, that is, a homologative event, is later exploited en route to the construction of more complex molecular architectures accessible through a single synthetic operation, as, for example, illustrated in the versatile Matteson homologation of sp 3 -hybridized boron electrophiles, elegantly adapted by Aggarwal to the assembly line concept. 4 Regrettably, carbon-based platforms suitable for homologations with halocarbenoids are restricted to sp 2 -type systems: For example, our group demonstrated that homologations of carbonyl-type derivatives conduct, through a single operation, to more sophisticated architectures (quaternary aldehydes 5 and aziridines). 6 Also, olefins are amenable substrates for C1 insertions into cyclopropanes. 7 In this scenario, the endeavored homologations of (primary) sp 3 -carbon platforms resulted in uncontrollable multi-insertion phenomena (up to four consecutive homologations) of questionable synthetic value,

Homologation strategies provide highly versatile tools in organic synthesis for the introduction of a CH2 group into a given carbon skeleton. The operation can result in diverse structural motifs by tuning of the reaction conditions and the nature of the homologating agent. In this Account, concisely contextualizing our work with lithium carbenoids (LiCH2X, LiCHXY etc) for homologating carbon-centered electrophiles, we focus on the assembly of three-membered cycles featuring fluorinated substituents. Two illustrative case studies are considered: (1) the development and employment of fluorinated carbenoids en route to rare α-fluoroepoxides and aziridines, and (2) the installation of up to halomethylenic groups on trifluoroimidoylacetyl chlorides (TFAICs) for preparing CF3-containing halo- and halomethylaziridines. Collectively, we demonstrate that the initial homologation event generated by the installation of the carbenoid, upon modulation of the conditions, serves as a tool for creating fluorinated building blocks in a single operation.