Substrate Range of the Titanium TADDOLate Catalyzed Asymmetric Fluorination of Activated Carbonyl Compounds

Abstract

Abstract The substrate range of the [TiCl 2 (TADDOLate)] (TADDOL= α , α , α ′, α ′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol)‐catalyzed asymmetric α ‐fluorination of activated β ‐carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol‐% of TiCl 2 (naphthalen‐1‐yl)‐TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F‐TEDA (1‐(chloromethyl)‐4‐fluoro‐1,4‐diazoniabicyclo[2.2.2]octane bis‐[tetrafluoroborate]) at room temperature. A series of α ‐methylated β ‐keto esters (3‐oxobutanoates, 3‐oxopentanoates) with bulky benzyl ester groups (60–90% ee) or phenyl ester (67–88% ee) have been fluorinated readily, whereas α ‐acyl lactones were also readily fluorinated, but gave lower inductions (13–46% ee). Double stereochemical differentiation in β ‐keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5 : 3.5. For the first time, β ‐keto S ‐thioesters were asymmetrically fluorinated (62–91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3‐diketones (up to 40% ee) and β ‐keto amides (up to 59% ee). General strategies for preparing activated β ‐carbonyl compounds as important model substrates for asymmetric catalytic α ‐functionalizations are presented (>60 examples).