Synthesis of 3-Carbonyl Trisubstituted Furans via Pd-Catalyzed Aerobic Cycloisomerization Reaction: Development and Mechanistic Studies

Abstract

Herein, we report the synthesis of 3-carbonyl-trisubstituted furans via Pd-catalyzed oxidative cycloisomerization reactions of 2-alkenyl-1,3-dicarbonyl scaffolds, using molecular oxygen as the sole oxidant to regenerate active palladium catalytic species, featuring good functional tolerance and mild reaction conditions. Deep investigation of intermediates and transition states of the reaction mechanism were conducted via experimental and DFT studies, providing a detailed mechanistical profile. The new developed methodology presents a greener alternative to Wacker-type cycloisomerizations and avoids the use of stoichiometric amounts of oxidants and strong acid additives.

Ready Access to Densely Substituted Furans Using Tsuji–Wacker-Type Cyclization

“…Hashmi and Ma et al independently reported the Pd-catalyzed dimerization of allenyl ketones to afford di- and trisubstituted furans (Scheme b,c). , Additionally, the Widenhoefer group demonstrated the synthesis of 2,3,5-trisubstituted furans from oxidative alkoxylation of α-alkenyl β-diketones by using PdCl 2 (CH 3 CN) 2 (Scheme d) . Recently, a very similar kind of synthesis of 3-carbonyl trisubstituted furans via a palladium-catalyzed oxidative cycloisomerization reaction of the 2-alkenyl-1,3-dicarbonyl moiety was reported by the Ferreira group …”

“…18 Recently, a very similar kind of synthesis of 3-carbonyl trisubstituted furans via a palladium-catalyzed oxidative cycloisomerization reaction of the 2-alkenyl-1,3-dicarbonyl moiety was reported by the Ferreira group. 19 It is also worth mentioning that the intramolecular acetalization of a dihydroxy-substituted geminal alkene to provide fused perhydrofurans under Wacker-type conditions was reported by Alonso et al 20 Even, the group of Runeberg 21 and Gracza 22 disclosed the remarkable synthesis of oxaheterocyclic core intermediates differently via Pd-catalyzed Tsuji− Wacker type cyclization, where they unexpectedly got disubstituted furan as a byproduct. Rao et al used I 2 and DBU to cyclize the diols with an olefin in the middle of their reaction sequence.…”

Recent Advances in Palladium-Catalyzed Oxidative Couplings in the Synthesis/Functionalization of Cyclic Scaffolds Using Molecular Oxygen as the Sole Oxidant

“…Recently, our group reported a significant contribution towards the aerobic Wacker-type cycloisomerization protocol for the synthesis of 3-carbonyl trisubstituted furans by using 2-alkenyl-1,3-dicarbonyl scaffolds, an underexplored substrate in this approach, and avoiding the use of stoichiometric amounts of oxidants and strong acid additives (Scheme 5). 20 These mild conditions demonstrated good functional group tolerance and afforded good to excellent yields. In addition, a detailed study of the mechanism was carried out through DFT calculations and by kinetic and multivariate linear regression (MLR) analysis.…”

Synthesis of Polysubstituted Furans: An Update Since 2019

“…Interested in metal‐catalyzed aerobic oxidative processes, [53] Ferreira et al. in 2021 explored the synthesis of 3‐carbonyl‐trisubstituted furans 45 via Pd‐catalyzed Wacker‐type cycloisomerization of 2‐alkenyl‐1,3‐dicarbonyl scaffolds 44 using O 2 as the sole oxidant under mild reaction conditions in good to moderate yields [54] . The mechanistic investigations are supported by DFT calculations, NMR experiments, multivariate regression analysis and KIE experiments.…”