Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access ß,ß-Difluorinated Carbocycles.

Cyclic ß,ß-difluoro-carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C-CF2-C>∠C-CH2-C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,ß-unsaturated esters and amides, and processes them to one-carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)-enabled O-activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r.) together with X-ray structural analyses and product derivatization.

para-Selective dearomatization of phenols by I(i)/I(iii) catalysis-based fluorination.

The regio- and enantio-selective dearomatization of phenols has been achieved by I(i)/I(iii) catalysis enabled fluorination. The process is highly para-selective, guiding the fluoride nucleophile to the distal C4 position of the substrate to generate fluorinated cyclohexadienones in an operationally simple manner. Extensive optimization has revealed key parameters that orchestrate enantioselectivity in this historically challenging transformation. A range of diversely substituted substrates are disclosed (20 examples, up to 92 : 8 e.r.) and the reaction displays efficiency that is competitive with the current state of the art in hydroxylation chemistry: this provides a preparative platform to enable OH to F bioisosterism to be explored. Finally, the utility of the products in accessing densely functionalized cyclic scaffolds with five contiguous stereocenters is disclosed together with crystallographic analyses to unveil fluorine-carbonyl non-covalent interactions.

Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols.

Partially saturated, fluorine-containing rings are ubiquitous across the drug discovery spectrum. This capitalises upon the biological significance of the native structure and the physicochemical advantages conferred by fluorination. Motivated by the significance of aryl tetralins in bioactive small molecules, a reaction cascade has been validated to generate novel gem-difluorinated isosteres from 1,3-diaryl cyclobutanols in a single operation. Under the Brønsted acidity of the catalysis conditions, an acid-catalysed unmasking/fluorination sequence generates a homoallylic fluoride in situ. This species serves as the substrate for an I(I)/I(III) cycle and is processed, via a phenonium ion rearrangement, to an (isolable) 1,3,3-trifluoride. A final C(sp3)-F bond activation event, enabled by HFIP, forges the difluorinated tetralin scaffold. The cascade is highly modular, enabling the intermediates to be intercepted: this provides an expansive platform for the generation of structural diversity.

Z-Selective Pd-catalyzed 2,2,2-trifluoroethylation of acrylamides at room temperature.

A straightforward 2,2,2-trifluoroethylation of acrylamides by Pd-catalyzed C-H bond activation was reported by using a fluorinated hypervalent iodine reagent as a coupling partner. At room temperature, this additive-free approach allowed the synthesis of Z-2,2,2-trifluoroethylated acrylamides (19 examples, up to 73% yield) in a stereoselective manner. Under these mild reaction conditions, the methodology turned out to be functional group tolerant and mechanistic studies gave us a better understanding of the transformation.

Copper-based fluorinated reagents for the synthesis of CF2R-containing molecules (R ≠ F).

Over the years, the development of new methodologies for the introduction of various fluorinated motifs has gained a significant interest due to the importance of fluorine-containing molecules in the pharmaceutical and agrochemical industries. In a world eager to eco-friendlier tools, the need for innovative methods has been growing. To address these two challenges, copper-based reagents were developed to introduce CF2H, CF2RF, CF2CH3, CF2PO(OEt)2 and CF2SO2Ph motifs on a broad range of substrates. Copper-based fluorinated reagents have the advantage of being inexpensive and generally in situ generated or prepared in a few steps, which make them convenient to use. In this review, an overview of the recent advances made for the synthesis of fluorinated molecules using copper-based fluorinated reagents will be given.