Benzylic Phosphates as Electrophiles in the Palladium-Catalyzed Asymmetric Benzylation of Azlactones

Abstract

Palladium-catalyzed asymmetric benzylation has been demonstrated with azlactones as prochiral nucleophiles in the presence of chiral bisphosphine ligands. Benzylic electrophiles are utilized under two sets of reaction conditions to construct a new tetrasubstituted stereocenter. Electron density of the phenyl ring dictates the reaction conditions, including the leaving group. The reported methodology represents a novel asymmetric carbon-carbon bond formation in an amino acid precursor.

Production of Csp3–Csp3 Bonds through Palladium‐Catalyzed Tsuji–Trost‐Type Reactions of (Hetero)Benzylic Substrates

“…[21] As exemplified by the results shown in Equation (5) 2 and Pd(dba) 2 leading to low levels of conversion. Various aryl carbonates and nucleophilic species were coupled under the optimum conditions [Equation (6)]. [20] When using equimolar mixtures of different substrates [Equation (7)], the authors observed that both pmethoxy and p-trifluoromethyl groups accelerated the benzylic substitution.…”

“…In the presence of the (η 3 -allyl)Pd-(Cp)/(S,S)-Trost-stilbene/tBuOH combination, methyl 4-methoxybenzyl carbonate afforded the benzylation compound with high ee but in low yield [Equation (96)]. [6] Much better results were obtained with substrates bearing a more labile leaving group such as benzylic phosphates. [6,63] Thus, the effective catalytic reaction was carried out in the presence of the above combination either with cesium carbonate as catalytic base in dichloromethane at room temperature [Equation (97) [63] These results demonstrate dependence of the reactivity both on the aromaticity disruption of the substrate and on the nature of its leaving group.…”

“…of the leaving group on the reactivity of 1-naphthylmethyl derivatives, the displacing ability order being OCOCF 3 ≈ OCOC 6 H 4 (p-NO 2 ) ≈ OCO 2 Me > F > OAc. [9] According to Tunge and co-workers, the rate of η 3 -benzyl formation is lower than that of η 3 -allyl formation and depends on the substrate structure (Scheme 3).…”

“…[5] This report is the cornerstone of the Tsuji-Trost-type reactions of benzylic systems. According to Trost and Czabaniuk, [6] two pathways are plausible for the formation of cationic η 3 -benzylpalladium complexes: coordination of Pd 0 to the aromatic nucleus followed by ionization (Scheme 2, path a), or displacement of the leaving group by Pd 0 to afford a cationic η 1 -benzylpalladium complex, [7] which isomerizes to the η 3 -benzylpalladium cation (Scheme 2, path b). Path b would be the favored pathway, [6,8] but this could depend on the nature of the leaving and aryl groups.…”

“…Path b would be the favored pathway, [6,8] but this could depend on the nature of the leaving and aryl groups. [6] Brown, Gouverneur, and co-workers have observed the influence of the nature Scheme 1. Catalytic cycle of the Tsuji-Trost reaction.…”