Tetronamides as Latent Acyclic Vinylogous Amides in Formal Aza-[3 + 3] Cycloaddition Reactions with α,β-Unsaturated Iminium Salts. An Unexpected Rearrangement and an Approach to Synthesis of Substituted Piperidines

Abstract

A detailed account regarding formal aza-[3 + 3] cycloaddition reactions of tetronamides with alpha,beta-unsaturated iminium salts is described here. This investigation uncovers regioisomeric cycloadducts that were not found in previous studies involving this formal cycloaddition and an unexpected rearrangement that led to pyridines and dihydropyridines. Both stereochemical and regiochemical issues raised in this study provide further mechanistic insights into this cycloaddition. With careful control of reaction temperatures, the desired formal cycloadducts are obtained. Ensuing transformation of these cycloadducts into functionalized piperidines establishes the concept of employing tetronamides as latent acyclic vinylogous amides for the formal aza-[3 + 3] cycloaddition.

A Formal [3 + 3] Cycloaddition Approach to Natural‐Product Synthesis

“…Scheme 36 It was not until recently when we examined the formal aza-[3 ϩ 3] cycloaddition reaction of tetronamide 165 as a latent acyclic vinylogous amide that we found substantial amounts of the head-to-tail regioisomers 168aϪc in addition to desired cycloadducts 167aϪc (head-to-head; Scheme 37). [80] A closer examination revealed that this is a temperature-dependent phenomenon: when the reaction temperature was less than 130°C, hardly any (Ͻ 5%) of the regioisomers 168aϪc was observed from their respective reactions, whereas when the temperature was raised above 130°C as much as 10Ϫ38% of 168aϪc could be detected. Scheme 37 We repeated the reaction of vinylogous amide 151 with 166b at temperatures above 150°C (Scheme 38).…”

“…Scheme 37 We repeated the reaction of vinylogous amide 151 with 166b at temperatures above 150°C (Scheme 38). [80] Only if we were careful could we detect the head-to-tail regioisomer 152aЈЈ in the 1 H NMR spectrum of the crude reaction mix-ture and isolate it in 4.5% yield. This result reaffirms that the reaction temperature is a critical factor, and explains why.…”

“…[54] Intriguingly, the final products that Hua isolated were pyridines 171 and 171ЈЈ, [81] which again are products that we found predominately in our studies using tetronamides. [80] …”

Asymmetric electrocyclic reactions

“…The major diastereomer is formed from an upward rotation of the inward methyl group; downward rotation is apparently disfavoured due to severe close interactions with the metal and its ligands. [144][145][146][147][148][149][150][151][152] In situ generated 1-azatrienes undergo efficient electrocyclization en route to 1,2-dihydropyridines, and chiral subsituents on the azatriene nitrogen or the C-terminus of the triene are effective in controlling the stereochemistry of the electrocyclic process (Scheme 30).…”

Efficient synthesis of tetrahydroquinolinones by acetic acid-mediated formal [3+3] cycloaddition

“…Several synthetic approaches to tetrahydroquinolinones have been described [6,7]. In related work, Hsung et al [8] reported a strategy to construct tetrahydroquinolinones by reacting vinylogous amides with a, b-unsaturated iminium salts.…”