A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives.

Corte Corte,Vicario Vicario,Palacios Palacios,Marigorta Marigorta

doi:10.3390/molecules24162951

Corte Corte, Vicario Vicario + Show 2 more

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https://doi.org/10.3390/molecules24162951

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Abstract

Brønsted acids catalyze a multicomponent reaction of benzaldehyde with amines and diethyl acetylenedicarboxylate to afford highly functionalized γ-lactam derivatives. The reaction consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.

Highlights

Multicomponent reactions (MCRs) [1,2] are valuable processes where three or more substrates, which are ssiimmultaneously added, react in a single vessel to form a nnew sstructure tthat contains substantial portions of aallll tthhee ssttaarrttiinngg mmaatteerriiaallss
TThhee hhyyddrroollyyssiiss ooff tthhee ccyycclliicc eennaammiinnee ssuubbssttrraattee ccaann pprroovviiddee eennooll ddeerriivvaattiivveess aanndd, mmoorreeoovveerr, aa sseeccoonndd aattttaacckk ooff tthhee aammiinnee oonn tthhee ccaarrbbooxxyyllaattee ccaann aaffffoorrdd aammiiddee ddeerriivvaattiivveess
ReBsuasltesd. on our previous experience in MCRs for the synthesis of 3-amino 1,5-dihydro-2H-pyrrol-2-ones [11,14], we firstly used BINOL-derived phosphoric acid 9 as a BrøBnasseteddonacoiudr pcaretavliyosuts ienxptehreienthcereien-cMomCRpsonfoernttheresaycnttihonesios fofb3e-nazmailndoeh1y,5d-deih2y, dpro-t-o2lHu-idpyinrerol3((2tRSh-cor=heneeep-msc-Mo[e1me21Cp),1.6o4HHn],eo4nw)w,teaenvfrieedrras,dctoltiyienotlunhysyetlhodafecBeeIbntNeyanlOmeznLiane-lddedeeiacrhniayvdrdeb/deoorxpyi2hml,aoitsnpep-eth8oionulrutsieicidrnmaignceeirddefli39autaex(ssiRntaghBa=dtriørcpenh-ssMluotelretdoCfmra6oHcemit4dh),tachnaaetenaraldeysascstdtoiiionlevntehthnoyeftl aamceitnyelesnuebdsictraartbeox3ywlaitteh8buensiznagldreehflyudxien2g odricahllkoyrnome 8etwhaenree aosbssoerlvveendt i(nScthheemceru2d).eH(Toawbeleve1r, Eonntlryyth1e). enamine and/or imine intermediates that result from the reaction of amine substrate 3 with benzaldehyde 2 or alkyne 8 were observed in the crude (Table 1, Entry 1)

Summary

Introduction

Multicomponent reactions (MCRs) [1,2] are valuable processes where three or more substrates, which are ssiimmultaneously (or almost) added, react in a single vessel to form a nnew sstructure tthat contains substantial portions of aallll tthhee ssttaarrttiinngg mmaatteerriiaallss. Enamine and/or imine intermediates that result from the reaction of amine substrate 3 with benzaldehyde 2 or alkyne 8 were observed in the crude (Table 1, Entry 1). When enantiomerically pure chiral phosphoric acids were used as catalysts, very poor enantioselectivities were observed with a maximum enantiomeric excess of 5% This may be attributable to the high temperatures required for the reaction conditions because of the steric hindrance present in the enamine substrate, together with the additional deactivation of the nucleophile due to the presence of two carboxylate groups. We report a Brønsted acid-catalyzed MCR procedure for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones where diethyl acetylenedicarboxylate, amines, and benzaldehyde are used as substrates This is the first example of such a reaction using phosphoric acids as catalyst. The hydrolysis process of 1,5-dihydro-2H-pyrrol-2-ones from enamine substrates to the enol derivatives 11 was not previously reported

Materials and Methods

Findings

42. Winstein-Holnes values