Accessing N‐Stereogenicity through a Double Aza‐Michael Reaction: Mechanistic Insights

Abstract

Further development of the chemistry and applications of chiral compounds that possess configurationally stable stereogenic nitrogen atoms is hampered by the lack of efficient strategies to access such compounds in an enantiomerically pure form. Esters of propiolic acid and chiral alcohols were evaluated as cheap and readily available Michael acceptors in a diastereoselective synthesis of N-stereogenic compounds by means of a double aza-Michael conjugate addition. Diastereomeric ratios of up to 74:26 and high yields were achieved with (-)-menthyl propiolate as a substrate. Furthermore, a detailed mechanistic investigation was undertaken to shed some light on the course of this domino transformation. Kinetic studies revealed that the protic-solvent additive acts as a Brønsted acid and activates the ester toward the initial attack of the tetrahydrodiazocine partner. Conversely, acidic conditions proved unfavorable during the final cyclization step that provides the product.

Unprecedented Double aza‐Michael Addition within a Sapphyrin Core

“…However, typically, the conjugate addition of N‐nucleophiles to DMAD affords mono addition adducts (enamines), whereas the reaction with N , N′ ‐dinucleophiles gives cyclic compounds in which one N‐atom is linked to an acetylenic‐derived carbon atom and the second is linked to a carbonyl group . Similarly, the double aza‐Michael addition of N , N′ ‐dinucleophiles to propynoic acid or its esters affords products in which both N‐atoms are linked to the terminal carbon atom . In fact, as far as we know, this is the first example of the addition of a N , N′ ‐dinucleophile to DMAD that results in the formation of a product in which the two N‐atoms are linked to the two erstwhile acetylenic carbon atoms, with the concomitant formation of two sp 3 carbon centers…”

“…[56][57][58] Similarly,t he double aza-Michael addition of N,N'-dinucleophiles to propynoic acid or its esters affords products in which both N-atoms are linked to the terminal carbon atom. [59,60] In fact, as far as we know,t his is the first example of the addition of a N,N'-dinucleophile to DMAD that results in the formation of ap roduct in which the two N-atoms are linked to the two erstwhilea cetylenic carbon atoms,w ith the concomitant formationoft wo sp 3 carbon centers. [61]…”

Rigid-to-Flexible Conformational Transformation: An Efficient Route to Ring-Opening of a Tröger’s Base-Containing Ladder Polymer

“…This feature originates from the conformational restriction in the bicyclic structure. In contrast, thecorresponding protons (g and h) in model-3 15 and poly-3 were observed equivalently, meaning that the diazacyclooctane unit undergoes a rapid ringflipping motion. As expected, the 1 H NMR signal of the Nmethylene protons of poly-3 significantly broadened at low temperatures, since the ring flipping becomes sluggish (Figures S1 and S2).…”

“…The product afforded a welldefined 1 H NMR spectrum in CDCl 3 (Figure 3e), which agreed well with that observed for model-3 (Figure 3f). 10 For example, the 1 H NMR spectrum of model-3 15 showed characteristic signals arising from protons of the N-methyl group (j) at 2.91 ppm and an aromatic proton (c) in the ortho-position relative to the N-H group at 6.55 ppm, along with the N-methylene protons (g) and (h) at 4.39 and 4.21 ppm, respectively. The corresponding signals were clearly observed in the 1 H NMR spectrum of the polymeric product at 2.85 (j), 6.55 (c) aromatic protons (a, b, and d) for the polymeric product and model-3 were similar to each other (Figure 3e,f).…”