Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters

Abstract

Difluoromethyl groups possess specific steric and electronic properties that invite their use as chemically inert surrogates of alcohols, thiols, and other polar functional groups important in a wide assortment of molecular recognition processes. We report here a method for the catalytic, asymmetric, migratory geminal difluorination of β-substituted styrenes to access a variety of products bearing difluoromethylated tertiary or quaternary stereocenters. The reaction uses commercially available reagents (mCPBA and HF•pyridine) and a simple chiral aryl iodide catalyst, and is carried out readily on gram scale. Substituent effects and temperature-dependent variations in enantioselectivity suggest that cation-π interactions play an important role in stereodifferentiation by the catalyst.

Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines

“…Due to its membrane permeability, difluoromethyl group (CF 2 R) is routinely employed in search for lead structures in drug discovery in recent years16, and has thus inspired the development of new reagents and strategies for the synthesis of difluoromethyl-containing compounds49505152535455565758. However, there are very few catalytic asymmetric approaches to access such chiral building blocks containing difluoromethyl groups, using a direct fluoroalkylation strategy58.…”

“…However, there are very few catalytic asymmetric approaches to access such chiral building blocks containing difluoromethyl groups, using a direct fluoroalkylation strategy58. We were naturally eager to extend the methodology to other fluoroalkylsulfonyl chlorides as radical precursors for the synthesis of the potentially useful chiral β-difluoromethyl or difluoroacetyl amines.…”

Metal-free syntheses of oxazoles and their analogues based on λ3-iodane-mediated cycloisomerization/functionalization reactions or [2+2+1] cycloaddition type reactions

“…29 Very recently, catalytic fluorinative transformations using (difluoroiodo)arenes (ArIF2) catalysts, which are in situ generated from ArI precatalyst, m-chloroperbenzoic acid (mCPBA) and HF·pyridine (HF·Py) or aq. HF, have been reported by Kitamura's 30 and Jacobsen's groups, 31 and then have been extended to the aminofluorination of alkenyl amines by Shibata et al (Scheme 9). 32 However, metal-free and catalytic fluorinative transformations of alkynes had been unknown.…”

A convenient approach to difluoromethylated all-carbon quaternary centers via Ni(ii)-catalyzed enantioselective Michael addition

“…6 Very recently, Hoveyda reported an efficient enantioselective addition of readily accessible Z-g-substituted boronic acid pinacol ester compounds to uoroalkyl-substituted ketones.…”

“…To the best of our knowledge, only two successful examples involving chiral allcarbon quaternary center bearing a diuoroalkyl group have been reported by Zhou and Jacobsen. 4b,6 Therefore, the development of efficient and concise method for the construction of all-carbon quaternary stereocenter featuring CF 2 H group is of great signicance and highly desirable for medicinal research. As a continuation of our ongoing research to explore efficient and economical asymmetric methodology, 10 we herein report our recent ndings on the addition of b-diuoromethyl nitroalkene with 2-acetyl azarenes.…”