Preparation of 2,3,4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives

Abstract

N-Benzyl- or N-tosyl-N-(4-methyl-3-pentenyl)amino aldehyde benzylimines, which are obtained from alanine, leucine, or phenylalanine methyl esters in five steps, can be cyclized diastereoselectively in the presence of Lewis acids to give 3-amino-2,4-dialkyl-substituted piperidines. The product distribution and diastereoselectivity depends on the type of Lewis acid and nitrogen-protecting group. Benzyl-protected imines give 2-alkyl-3-(benzylamino)-4-isopropenyl piperidines with FeCl(3) and 2-alkyl-3-(benzylideneamino)-4-isopropylpiperidines with TiCl(4). Tosyl-protected imines show a decreased level of selectivity. The relative configurations of the piperidines were established by NMR and X-ray crystal structure analyses. Iminium ion cyclization followed by two competitive ionic pathways, i.e. either proton elimination or hydride transfer are discussed for these reactions.

Quaternary Ammonium Leucine-Based Surfactants: The Effect of a Benzyl Group on Physicochemical Properties and Antimicrobial Activity

“…Subsequently, the aqueous phase was extracted using diethyl ether. The organic phase was collected, dried with anhydrous sodium sulfate, filtered and the solvent evaporated under vacuum, yielding a colourless oil [17].…”

Regioselective Synthesis of Isochromenones by Iron(III)/PhSeSePh-Mediated Cyclization of 2-Alkynylaryl Esters

“…20 The effectiveness of the iron salts as Lewis acids was evaluated in the synthesis of piperidine derivatives starting from N-tosylimines. 21 Recently, others 22 and we 23 have shown that FeCl 3 /diorganyl dichalcogenides is an alternative system to the classical protocols to promote cyclization of unsaturated substrates. Besides, the incorporation of an organoselenium or organotellurium group in the structure of molecules has attracted much attention due to their applications in several different reactions, 24 such as selenoxide syn elimination, [2,3]-sigmatropic rearrangement, cyclization, and cross-coupling reactions, as well as their biological properties.…”

“…Bolm and co-workers have demonstrated that FeCl 3 and 2,2,6,6-tetramethyl-3,5-heptanedione (TMHD) are effective as a catalytic system for an iron-catalyzed intramolecular O-arylation reaction of 2-haloanilines in the synthesis of benzoxazole derivatives . The effectiveness of the iron salts as Lewis acids was evaluated in the synthesis of piperidine derivatives starting from N -tosylimines . Recently, others and we have shown that FeCl 3 /diorganyl dichalcogenides is an alternative system to the classical protocols to promote cyclization of unsaturated substrates.…”

Reactions of Allylsilanes with Iminium Salts: Ene Reactions with Inverse Electron Demand

“…In a recent review on imino ene reactions, only few examples with inverse electron demand have been reported. , Though allylsilanes are well documented to act as electron-rich ene components in ene reactions, the role of allyltrimethylsilane ( 2a ) as an enophile seems to be without precedent.…”