Propargylation of Ugi Amide Dianion: An Entry into Pyrrolidinone and Benzoindolizidine Alkaloid Analogues

Abstract

Propargylation of Ugi adducts under the addition of excess sodium hydride in DMSO leads to direct formation of pyrrolidinone enamides, which are useful precursors of iminium intermediates and may be trapped by various nucleophiles. This approach has been applied to the formation of benzoindolizidine alkaloids with high diversity via a Ugi/propargylation/Pictet-Spengler cyclization.

Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts

“…The results are gathered in Scheme 2. As observed in our previous studies (Zidan et al, 2017, 2018), an aryl group tethering the peptidyl position is required for efficient allylation. Indeed, Ugi adduct 1j prepared from isovaleraldehyde failed to form the expected 3j probably due to the inability to form the dianionic intermediate with this less acidic substrate.…”

“…For this reason, most transformations involving the peptidyl position of Ugi adducts are limited to intramolecular reactions (Bossio et al, 1997; Trifilenkov et al, 2007; Salcedo et al, 2008; El Kaïm et al, 2011; Tyagi et al, 2013; Zhang et al, 2013; Ben Abdessalem et al, 2015; Ghandi et al, 2015; Vachhani et al, 2015; Li et al, 2016). We recently proposed a dianionic amide strategy to raise the nucleophilic behavior of Ugi adducts derived from aromatic aldehydes and demonstrated the interest of this approach using bis-electrophilic derivatives prone to trap the dianions and form heterocycles (Scheme 1) (Zidan et al, 2017, 2018). Following the high yielding cyclizations observed in these studies, we decided to explore more thoroughly the synthetic potential of these dianions (Thompson, 1994; Langer and Freiberg, 2004) toward more simple electrophiles.…”

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

“…Aromatic aldehyde derived Ugi adducts are relatively acidic at the peptidyl position and may undergo deprotonation under basic conditions. The resulting anion can be trapped by various electrophiles, as demonstrated by El Kaïm and coworkers [70–74] . Using this strategy, the research group synthesized densely functionalized pyrrolines 115 by addition of Ugi adducts 114 to acrylonitrile under microwave irradiation (Scheme 38).…”

The Merger of Isocyanide‐Based Multicomponent Reaction and Ring‐Closing Metathesis (IMCR/RCM)

“…The observed drop in the yield of 20 a could partly be explained by the fact that substrate with free hydroxyl group undergoes homodimerization in the presence of Grubbs catalyst. [22] By taking the advantage of acidic peptidyl proton of Ugi adduct derived from aromatic aldehydes, [23] El Kaïm and coworkers published [24] the base-mediated allylation at peptidyl position followed by RCM to construct small series of sixmembered cycloolefins 23 (Scheme 5). Initially, the Ugi-4CR between aldehyde, allylamine, isocyanide, and carboxylic acid under conventional reaction conditions resulted in the formation of Ugi adduct 21 in excellent to quantitative yields (68-97 %).…”