Probing N‐Alkoxy Effects in Domino Reactions of α‐Bromoacetamide Derivatives Towards Functionalized γ‐Lactams

Abstract

The main objective of the present work is to better delineate the positive impact of N‐alkoxy versus N‐alkyl moieties in domino reactions. The key role of the metallic counterion of the basic reagent via a templating effect has been established, giving an insight over the superiority of N‐alkoxy α‐bromoacetamides compared to their N‐alkyl analogues. The former demonstrated enhanced reactivity and efficiency, thus requiring milder conditions and leading to a wider scope of γ‐lactams in good to excellent yields ranging from 67 to 98%. Overall, this study contributes to the emerging point of view that N‐alkoxy nitrogenated compounds are useful building blocks with powerful but still under‐developed synthetic potential, in particular in domino reactions.

A concise approach to 2-pyrrolin-5-one scaffold construction from α-halohydroxamates and β-keto compounds

“…These findings demonstrated that the electron-donating groups -OBn or other -OR groups could remarkably improve the reaction efficiency. 20 Considering the higher reactivity of non-substituted α-bromohydroxamates than that of α-substituted α-bromohydroxamates and previous reports, 13,15a a plausible mechanism of the reaction process is proposed in Scheme 1. α-Halohydroxamate was reacted with NaI to yield the corresponding iodide. Subsequently, the resulting carbanion of β-keto nitrile under basic conditions could attack α-iodohydroxamate via an S N 2 process to afford the intermediate I, which subsequently underwent intramolecular nucleophilic addition to produce the cyclized product II, followed by intramolecular dehydration under acidic conditions to furnish the product 3aa.…”

“…These findings demonstrated that the electron-donating groups –OBn or other –OR groups could remarkably improve the reaction efficiency. 20 Considering the higher reactivity of non-substituted α-bromohydroxamates than that of α-substituted α-bromohydroxamates and previous reports, 13,15 a a plausible mechanism of the reaction process is proposed in Scheme 1. α-Halohydroxamate was reacted with NaI to yield the corresponding iodide.…”

N-Benzyloxyacrylamides as Bisnucleophiles in an Organocatalyzed Domino aza-Michael/Morita-Baylis-Hillman Sequence

“…The use of N-methylacrylamide led to no conversion, confirming the need for the alkoxy moiety onto the nitrogen atom. 5 We then turned our attention toward enals and enones 2 in reaction with acrylamide 1b as depicted in Scheme 2, and The impact of steric effects was confirmed when enals carrying cycloalkyl substituents on the β position were engaged, only with moderate to acceptable yields ranging from 20 to 55% being obtained depending on the size of the ring. 12 Functionalized enals bearing alkene or protected heteroatoms were also nicely tolerated forming 3l−3n in 60−80% yield.…”

“…Hamada and co-workers published in 2012 a well-designed iminium-based enantioselective aza-Michael/Michael sequence starting from N -alkoxyacrylamides (Scheme b) . This organocatalytic reaction implied equipping the acrylamides 1 with an N -alkoxy moiety (R 1 = OR 1 ) to increase aza-nucleophilicity and a β-ester (R″ = CO 2 R) to cause umpolung of the α-center into an electrophilic site. On reaction with cinnamaldehyde derivatives or cyclic enones, these custom [1,3]-N,Cα-dipolar acrylamides gave, after subsequent NaBH 4 reduction in MeOH of the aldehyde function, the desired densely functionalized γ-lactams 4 .…”

“…The use of N -methylacrylamide led to no conversion, confirming the need for the alkoxy moiety onto the nitrogen atom . We then turned our attention toward enals and enones 2 in reaction with acrylamide 1b as depicted in Scheme , and aliphatic enals were first tested.…”