Divergent Synthesis of Organofluorinated Molecules from Titanium Mediated Deoxygenation of Free Alcohols

Abstract

Comprehensive Summary Alcohols as among the most widely occurring organic compounds known, deoxygenative transformations of free alcohols as partners in radical addition reactions remain formidable challenges with great opportunities to achieve new and useful transformations. Herein, we report a protocol via C—O bond cleavage and C—C bond‐forming reaction of trifluoromethyl alkenes with free alcohols assisted by titanium reagents via a deoxygenative radical strategy, enabling the divergent synthesis for functional‐group‐rich organofluorinated compounds in high efficiencies. In this transformation, tertiary alcohols by Ti‐catalysis could be converted to trifluoromethyl alkanes without defluorination in acidic conditions, while benzyl alcohols are employed by Ti‐mediated activation to supply the gem‐difluoroalkenes with defluorination in the presence of a base. This protocol is applicable for a broad range of trifluoromethyl alkenes with good functional group tolerance and a variety of tertiary alcohols and benzyl alcohols (including primary, secondary, and tertiary alcohols), and is scalable to the gram level. Remarkably, the utility of this protocol is demonstrated by several derivatizations and late‐stage functionalization of drug molecules. The successful applications in scale up reactions and late‐stage functionalization of several drug molecules demonstrate its potential synthetic value in drug discovery settings.

Iron‐Catalyzed Reductive C(aryl)—Si Cross‐Coupling of Diaryl Ethers with Chlorosilanes

“…Catalytic C(aryl)—O activation of phenol and phenol derivatives is an ecological strategy to assemble aromatic feedstock chemicals. [ 35‐41 ] In particular, the direct functionalization of C(aryl)—O bond of aryl ethers is important for the transformation of oxygen‐rich lignocellulosic plant biomass like lignin to well‐defined aromatic compounds. Despite great interest and recent advance on catalytic C(aryl)—O activation of aryl alkyl ethers [ 42‐52 ] and hydrogenolysis of diaryl ether C(aryl)—O bonds (Scheme 1b), [ 53‐57 ] the chemo‐ and regioselective functionalization of the C(aryl)—O bonds of diaryl ethers, especially highly substituted biaryl ethers relevant to those found in lignin, has remained a challenge.…”

Photoinduced defluorinative alkylation of trifluoromethyl alkenes with carbonyl derivatives by C–C bond scission

“…In recent years, defluorinative alkylation of α-trifluoromethyl styrenes via a radical/polar crossover pathway also provides new opportunities to prepare structurally diversified gem -difluoroalkenes, 6 and considerable progress has been made in the development of different types of alkyl radical precursors. For example, the groups of Molander, 7 Wang, 8 and others 9 have demonstrated some elegant examples based on catalysing the cleavage of carbon-heteroatom bonds (such as carbon-halogen/-boron/-silicon/-oxygen bonds) in the presence of transition-metal catalysts or photocatalysts (Scheme 1a). Alternatively, the synthesis of gem -difluoroalkenes by catalytic carbon–carbon bond cleavage (Scheme 1b, left), especially using carboxylic acids and their derivatives as convenient radical precursors, has also been well developed by the groups of Zhou, 10 Fu 11 and others.…”