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Keywords:
ß-amino acids; tandem reactions; radical-polar crossover; fert-butanesulfinamide; zinc radical transfer
Abstract
We demonstrate that a-(aminomethyl)acrylates are suitable acceptors for 1.4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1.4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this Sfj2 process which represents a rare example of alkylzinc-group transfer to a tertiary a-carbonyl radical. The zinc enolate thus formed readily undergoes ß-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N-H bonds undergo protodemetalation to provide ultimately the 1.4-addition adduct. In the presence of carbonyl acceptors, aldol condensation occurs providing overall a tandem 1.4-addition-aldol process. When a tert-butanesulfinyl moiety is present on the nitrogen atom, these electrophilic substitution reactions occur with good levels of chiral induction, paving the way to enantioenriched ß2-amino acids and ß2'2-amino acids.
Introduction
Dialkylzinc reagents react in aerobic medium with a range of a.ß-unsaturated carbonyl compounds to provide the corresponding zinc enolates (Scheme T) [1.2]. While simple, this reaction offers attractive features: T) it proceeds under mild conditions in the absence of any transition-metal catalyst; 2) the 1.4-addition step can be combined with condensation reactions of the zinc enolate with electrophiles in protocols wherein all the reactive partners can be introduced from the start, given that dialkylzinc reagents offer a large functional group tolerance; and 3) the radical character of the process allows for the use of alkyl iodides as alkyl source in multicomponent reactions. Trialkylboranes can react in a similar way with enones [3] whereas, distinctively, suitable acceptors for the reaction with dialkylzinc reagents also include a.ß-unsaturated carboxylic acid derivatives such as a.ß-unsaturated (di)esters [4.5], /V-enoyloxazolidinones [6.7], /V-enoyloxazolidines [8], or alkylidenemalonates [9-11]. These reactions follow a free-radical chain process wherein alkyl radicals (R") add across the C-C double bond of the 1.4-acceptor. activated by complexation with the dialkylzinc. to deliver an enoxyl radical that undergoes homolytic substitution at zinc (Sh2) to produce a zinc enolate and a new R" that propagates the radical chain (Scheme T). Initiation occurs upon oxidation of the dialkylzinc reagent by oxygen. The feasibility of such 1.4-addition reactions is fully reliant on the ease of the intermediate enoxyl radical to undergo alkylzincgroup...