Baylis–Hillman-derived N,N′-disubstituted piperazines: structural and preliminary computational studies

Elucidating Latent Mechanistic Complexity in Competing Acid-Catalyzed Reactions of Salicylaldehyde-Derived Baylis–Hillman Adducts

“…We thus conclude that rapid and irreversible O -alkyl cleavage of the substrate 5a affords the stable β-hydroxy acid intermediate 10a , which is slowly consumed in the reaction sequence 10a → 11a → 6a , a pattern consistent with the experimental results illustrated in Figure . [The preference for a conjugate addition–elimination sequence rather than S N ′ displacement of the protonated hydroxyl group by the chloride anion is supported by comparative studies on related systems and the relative condensed local softness values for the carbonyl (3.97) and hydroxylic (0.91) carbons using the electrophilic Fukui functions ( f + ) evaluated at a B3LYP/6-31G­(d) level.] Noteworthy in the formation of the major isomer 6a is the multifaceted role of HCl in (i) acid catalysis of O -alkyl cleavage of tert -butyl ester 5a , (ii) deprotonation (by the conjugate base Cl – ) of the tert -butyl cation, (iii) conjugate addition to α,β-unsaturated acid 10a , and (iv) acid catalysis of the dehydration of enediol 11a .…”

“…We have previously observed that treatment of methyl vinyl ketone (MVK)-derived Baylis–Hillman adducts with HCl afforded α-chloromethyl-α,β-unsaturated products, apparently via a conjugate addition–elimination pathway, and it seemed reasonable to explore this approach to access the desired cinnamate ester–AZT conjugates 8a – e (Scheme ). The concomitant formation of both 2-(chloromethyl)­cinnamic acids 6a – e and 3-(chloromethyl)­coumarin derivatives 7a – e and the ready cyclization of compound 6a to give coumarin derivative 7a at elevated temperature prompted us to undertake detailed kinetic and theoretical studies to elucidate the mechanistic details.…”