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The stereochemistry and mechanistic insight in the annulations of one ketene molecule with two imine molecules ([2(k)+2(i)+2(i)] annulation) are studied by using six-membered 3,4-dihydroisoquinoline as an imine probe. A concerted hetero-Diels-Alder cycloaddition mechanism is proposed to explain the stereochemical outcomes. In most cases, the zwitterionic 2-aza-1,3-butadiene-type intermediates, generated from ketenes and imines, undergo endo hetero-Diels-Alder cycloaddition with the second imine molecule. For ketenes with electron-donating substituents, (2,4)-cis-(4,5)-cis-[2(k)+2(i)+2(i)] annuladducts formed stereospecifically, while, for ketenes with electron-accepting substituents, (2,4)-cis-(4,5)-trans-[2(k)+2(i)+2(i)] annuladducts are generated stereospecifically. The [2(k)+2(i)+2(i)] annulations of aryloxyketenes and 3,4-dihydroisoquinoline give stereodivergent products due to the occurrence of the stepwise nucleophilic annulation. However, in the [2(k)+2(i)+2(i)] annulations of seven-membered cyclic imine dibenzo[b,f][1,4]oxazepine, the zwitterionic aza-butadiene-type intermediates exclusively undergo exo hetero-Diels-Alder cycloadditions with another molecule of imine to yield (2,4)-trans-(4,5)-trans-[2(k)+2(i)+2(i)] annuladducts stereospecifically, regardless of the ketene substituents. The mechanistic model not only discloses the nature of the [2(k)+2(i)+2(i)] annulations, but also can be used to explain and predict the stereochemistry of the [2(k)+2(i)+2(i)] annuladducts from different ketenes and imines.

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