Recent Advances in Visible Light-Mediated Radical Fluoro-alkylation, -alkoxylation, -alkylthiolation, -alkylselenolation, and -alkylamination.

In the last few years, many reagents and protocols have been developed to allow for the efficient fluorofunctionalization of a diverse set of scaffolds ranging from alkanes, alkenes, alkynes, and (hetero)arenes. The concomitant rise of organofluorine chemistry and visible light-mediated synthesis have synergistically expanded the fields and have mutually benefitted from developments in both fields. In this context, visible light driven formations of radicals containing fluorine have been a major focus for the discovery of new bioactive compounds.

Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes.

An efficient method for the direct C(sp)-H difluoromethylation of terminal alkynes and the desilylation-difluoromethylation of (trimethylsilyl)acetylenes is disclosed. The copper-catalyzed transformation provides access to a wide range of structurally diverse CFH alkynes in good yields, utilizing a (difluoromethyl)zinc reagent and an organic oxidant. The difluoromethylation of important synthons and API's is showcased.

-Halofluorocyclopropanes via [2 + 1] Cycloadditions of In Situ Generated CFX Carbene with Alkenes.

An efficient and operationally simple synthesis of -bromofluorocyclopropanes under mild conditions has been developed. The method employs ethyl dibromofluoroacetate (EDBFA) as an accessible and inexpensive source of the bromofluorocarbene (:CFBr) intermediate. The protocol provides the bromofluorocyclopropane products in excellent yields, including examples synthesized in multigram scales.

Nickel and Copper Catalyzed ipso-Phosphonodifluoromethylation of Arylboronic Acids with BrCF P(O)(OEt) for the Synthesis of Phosphonodifluoromethylarenes.

A convenient method for the direct ipso-phosphonodifluoromethylation of arylboronic acids via nickel-copper co-catalysis is disclosed. This work, which utilizes inexpensive first row transition metals, represents a facile alternative to the traditional palladium catalyzed approach. The method utilizes inexpensive commodity chemicals and substrates while tolerating a variety of biologically relevant functional groups.

Direct Synthesis of Tri-/Difluoromethyl Ketones from Carboxylic Acids by Cross-Coupling with Acyloxyphosphonium Ions.

A simple and straightforward approach to the synthesis of trifluoromethyl and difluoromethyl ketones from widely available carboxylic acids is disclosed. The transformation utilizes an acyloxyphosphonium ion as the active electrophile, conveniently generated in situ from the carboxylic acid substrate by using commodity chemicals. The utility of the reaction system is exemplified by its chemoselectivity, with tolerance to a variety of important functional groups.

Chemoselective - and -Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones with TMSCFBr.

An operationally simple protocol for direct - and -difluoromethylation of 2-pyridones, quinolinones, and isoquinolinones using commercially available TMSCFBr is disclosed. The chemoselectivity is modulated by simple variations in temperature, solvent, and strength of the base. Diverse, synthetically relevant functional groups are tolerated, including functional groups that have reported reactivity with TMSCFBr.

Aqueous Base Promoted -Difluoromethylation of Carboxylic Acids with TMSCFBr: Bench-Top Access to Difluoromethyl Esters.

A method for the -difluoromethylation of carboxylic acids using commercially available TMSCFBr is disclosed. The devised benchtop reaction system is air-stable and offers mild reaction conditions while using readily available reagents and solvents. The method is applicable to both aliphatic and aromatic carboxylic acids while demonstrating compatibility with a range of commonly encountered functional groups.

Siladifluoromethylation and Deoxo-trifluoromethylation of P-H Compounds with TMSCF: Route to P-CF Transfer Reagents and P-CF Compounds.

A method for siladifluoromethylation of dialkyl phosphonates and secondary phosphine oxides with TMSCF to produce nucleophilic P-CF- transfer reagents is disclosed, with multigram scale reactions included. Condition-dependent divergent reactivity under the established conditions is demonstrated by the formation of trifluoromethylphosphines. Both one-pot transformations are operationally simple and employ inexpensive materials.

C(sp)-H Trifluoromethylation of enamides using TMSCF: access to trifluoromethylated isoindolinones, isoquinolinones, 2-pyridinones and other heterocycles.

A method for the direct C(sp2)-H trifluoromethylation of enamides, including biologically relevant isoindolinones, isoquinolinones and 2-pyridinones using TMSCF3 under oxidative conditions is presented. The protocol is convenient, operationally simple and exhibits high tolerance across a multitude of relevant handles and functional groups.

Direct Difluorination-Hydroxylation, Trifluorination, and C(sp)-H Fluorination of Enamides.

A direct double functionalization involving both difluorination and hydroxylation of enamides is reported. With the appropriate combination of an electrophilic fluorinating reagent and HO, the most convenient and ecofriendly hydroxylating agent, the preparation of 3-(difluoroalkyl)-3-hydroxyisoindolin-1-ones was achieved under basic or Brønsted acidic conditions. Suitable conditions for trifluorination as well as C(sp)-H fluorination were also identified.