DFT mechanistic study on tandem sequential [4 + 2]/[3 + 2]addition reaction of cyclooctatetraene with functionalizedacetylenes and nitrile imines

Abstract

The mechanistic pathways for the tandem sequential [4 + 2] / [3 + 2] and[3 + 2]/[4 + 2] cycloaddition reaction of functionalized‐acetylenes withcyclooctatetraene (COTE) and nitrile imines for the formation of thebiologically‐active tricyclic cyclobutane‐condensed pyrazoline systems, andthe subsequent cycloreversion/thermolysis of these adducts, have been studiedusing density functional theory (DFT) at the M06‐2X/6‐31G(d) and 6‐311G(d,p)levels with the aim of providing mechanistic rationale for the regioselectivitiesand stereoselectivities. Along the [4 + 2] / [3 + 2] addition sequence, it hasbeen found that the initial 6π‐electrocyclic ring‐closure of the COTE is therate‐determining step irrespective of the type of substituent on the parent acet-ylene or the nitrile imine. The mechanistic channels along the [4 + 2] / [3 + 2]addition sequence show that the addition of the dipole across the unsubstitutedolefinic bond in the cyclohexadiene moiety in theendofashion is the mostfavored, which is in agreement with experimentally observed selectivity. Theresults show that the thermolysis proceeds with relatively high activation bar-riers toward formation of the monocyclic pyrazolines among other products.The decomposition of the tandem adducts has been found to be controlledsolely by kinetic factors. An exploration of a [3 + 2] / [4 + 2] addition sequenceas a mechanistic possibility reveals that in contrast to the [4 + 2] / [3 + 2] addi-tion sequence, the Diels‐Alder addition step is the rate‐determining. The[3 + 2] / [4 + 2] addition order is found as an approach with better selectivityas it leads to formation of only tandem adducts where the nitrile imines areattached to the substituted olefinic bond in the cyclohexadiene subunit. Theresults show that the monocyclic pyrazolines obtained from the thermolysisof the [4 + 2] / [3 + 2] tandem adducts could easily be obtained from a direct1,3‐dipolar addition of the alkynes with the dipoles which has been found toproceed rapidly with low activation barriers. The results are rationalized withperturbation molecular orbital theory.