Theoretical investigation on the mechanism and enantioselectivity of organocatalytic asymmetric Povarov reactions of anilines and aldehydes. Issue 8 (30th November 2020)

• Record Type: Journal Article
• Authors: Lu, Nan; Liang, Hui; Qian, Ping; Lan, Xiaozheng; Miao, Chengxia
• Is Part Of: International journal of quantum chemistry. Volume 121:Issue 8(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-30
• Subjects: cyclization -- cycloaddition -- M06‐2X functional -- Povarov reaction -- tetrahydroquinoline; Quantum chemistry -- Periodicals; 541.28
• DOI: 10.1002/qua.26574
• Languages: English
• ISSNs: 0020-7608

Abstract

Abstract: The mechanism is investigated for organocatalytic asymmetric Povarov reaction of anilines and aldehydes using M06‐2X functional. Two molecule of aldehyde condense with aniline and catalyst giving N‐arylimine and enamine. The reaction is stepwise involving [2 + 2] cycloaddition and ring‐opening/cyclization. Four competitive paths exist in step 1 leading to isomers of quaternary nitrogen heterocycle as cycloadduct. Step 2 is sequential with proton transfer and concerted ring‐opening/cyclization in two feasible orders. Each path in step 1 divides into two in step 2 producing isomers of tetrahydroquinoline (THQ) bonded with catalyst as cyclization product. The reactive nucleophilic adduct with two charge centers in step 1 supports the recovery of catalyst and generation of aldehyde assisted by water. THQ alcohol is obtained in the following intramolecular Friedel–Crafts reaction. The enantio‐ and diastereoselectivity are both thermodynamic control with preferred path yielding the most stable isomer with 2S3S or 1R2S3S configuration. The path bias is in line with the reduction degree of energy barrier in solvent compared with gas phase. Our conclusion is verified by Multiwfn analysis and the predicted ee, dr value of THQ scaffold in experiment. Abstract : The mechanism of organocatalytic asymmetric Povarov reaction of anilines and aldehydes has been investigated by M06‐2X functional. The reaction is stepwise with [2 + 2] cycloaddition forming quaternary nitrogen heterocycle and ring‐opening/cyclization leading to tetrahydroquinoline. The nucleophilic adduct with charge center supports recovery of catalyst and following intramolecular Friedel–Crafts reaction. The enantio‐ and diastereoselectivity are thermodynamic control with preferred path yielding the most isomer and agree with the reduction degree of energy barrier in solvent.