Theoretical investigations of the reaction between 1,4-dithiane-2,5-diol and azomethine imines: mechanisms and diastereoselectivity

Abstract

In the present study, mechanistic insights into the domino reaction between 1,4-dithiane-2,5-diol and azomethine imines were derived from the computational study with B3LYP and M06-2X functionals. On the whole, the domino process comprises two consecutive reactions: cleavage of 1,4-dithiane-2,5-diol leading to mercaptoacetaldehyde and [3 + 3] cycloaddition of mercaptoacetaldehyde with azomethine imines. The cleavage of 1,4-dithiane-2,5-diol can take place via multiple possible pathways (1A–1E), and pathway 1E in which double-methanol molecules mediate the proton transfer process is the most energetically favorable, with an energy barrier of 19.9 kcal mol⁻¹. For the [3 + 3] cycloaddition, three possible pathways (2F–2H) were explored. The calculated energy profiles reveal that pathway 2H with activation energies ranging from 6.9 to 10.2 kcal mol⁻¹ is more energetically favorable than pathways 2F and 2G. Specifically, pathway 2H comprises three reaction steps: deprotonation of mercaptoacetaldehyde by DABCO allows for the formation of the thiol anion, which subsequently launches a nucleophilic attack on azomethine imines followed by intramolecular cyclization resulting in the final products. The calculated results are in agreement with the experimental observations that the reaction can proceed most efficiently in the presence of both DABCO and methanol. Furthermore, the hydrogen bonding interaction is identified to be the main factor determining the observed diastereoselectivity The current systematic theoretical study gives a full scenario of the reaction between 1,4-dithiane-2,5-diol and azomethine imines catalyzed by DABCO, and thus provides some valuable clues for further investigation and development of this kind of important reaction.