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Mechanism and Origins of Stereoinduction in an Asymmetric Friedel-Crafts Alkylation Reaction of Chalcone Catalyzed by Chiral N, N'-Dioxide-Sc(III) Complex.

Yini ZuoNa YangXunkun HuangChang-Wei HuZhishan Su
Published in: The Journal of organic chemistry (2018)
The mechanism and selectivity of the asymmetric Friedel-Crafts (F-C) alkylation reaction between indole and chalcone catalyzed by chiral N, N'-dioxide-Sc(III) complexes were investigated at the M06/6-311+G(d,p)//M06/[LANL2DZ,6-31G(d)](SMD,CH2Cl2) level. The reaction occurred via a three-step mechanism: (i) the C3-Cβ bond formation by interacting the most mucleophilic C3 center of indole with the most electrophilic Cβ center of chalcone; (ii) the abstraction of the proton at the C3 atom of indole by counterion OTf-; (iii) proton transfer from HOTf to the Cα atom of chalcone, generating the F-C alkylation product. The reaction preferred to occur along the favorable re-face attack pathway, producing the dominant R-product. The turnover frequency (TOF) of catalysis was predicted to be 1.59 × 10-7 s-1, with a rate constant of K( T) = 1.58 × 10-7 exp(-29057/ RT) dm6·mol-2·s-1 over the temperature range of 248-368 K. Activation strain model (ASM) and energy decomposition analysis (EDA), as well as noncovalent interaction (NCI) analysis, for the stereocontrolling transition state revealed that the substituent attached to the N atom of the amide subunits as well as the amino acid backbone of ligand played important roles in chiral inductivity. The benzyl group with structural flexibility tended to form strong π-π stacking with substrate as well as the terminal phenyl group of chalcone, stabilizing re-face attack transition state.
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