Asymmetric [2 + 2] cycloaddition of isatin with ketene catalyzed by N, N'-dioxide-Sc(III) complex: Mechanism and selectivity

Abstract

• [2 + 2] cycloaddition of ketene occurred via a concerted [ π 2 s +( π 2 s + π 2 s )] mechanism. • Bulky substituent induced the re -face of ketene to attack the si -face of isatin, enhancing ee % and dr . • N -benzylisatin coordinated to Sc 3+ ion in bidentate fashion, forming reactive species. The mechanism and stereoselectivity of the phenylethylketene with isatin catalyzed by a chiral N,N′- dioxide-Sc(III) complex were studied at the B3LYP-D3(BJ)/6–311G(d,p)//B3LYP-D3(BJ)/def2-SVP(SMD,CH 2 Cl 2 ) theoretical level. The calculations indicated that the reaction occurred in a one-step but asynchronous manner. The four-membered product was formed by nucleophilic attack of the electron-rich O(2) atom in the N -benzylisatin toward the electron-deficient C(β) atom in ketene in the initial stage of reaction, which was responsible to the high regioselectivity of the cycloaddition. The π-π stacking interaction between two deformed reactants stabilized the corresponding transition state, affording the enantiomer with S,R -configuration as major product in background reactions. The N -benzylisatin coordinated to the Sc 3+ in bidentate manner, forming a hexacoordinated scandium-complex reactive species in the catalytic process. Different from the non-catalytic reaction, the C α -C 1 bond was formed prior to the construction of C β -O 2 bond. The ortho - i Pr in the aniline of chiral N,N′- dioxide ligand shielded re -face of isatin, and induced the ketene to attack the isatin from less hindered si -face, leading to good enantioselectivity of product. Suffering from the steric repulsion from benzyl group in N -benzylisatin, the phenylethylketene substrate preferred to approach the si- face of N -benzylisatin with its re -face, affording predominant product with S,S -configuration. Variation of substituent in reactants and ligand structure would modify the shielding degree of ortho - i Pr toward prochiral face of isatin, adjusting the stereoselectivity. Steric hindrance from bulky substituents in chiral N, N ’-dioxide ligand and the Bn group in isatin as well as Et group in ketene contributed to high enantio‑ and diastereoselectivity of product.