Copper‐Catalyzed Synthesis and Applications of Yndiamides

Abstract

The first synthetic route to yndiamides,anovel class of double aza-substituted alkyne,h as been established by the copper(I)-catalyzed cross-coupling of 1,1-dibromoenamides with nitrogen nucleophiles.T he utility of these compounds is demonstrated in ar ange of transition-metal-catalyzed and acid-catalyzed transformations to affordawide variety of 1,2diamide functionalized products.

Regio- and Stereoselective Addition of Brønsted Acids to Yndiamides: Synthesis of N,O,N- and N,S,N-Trisubstituted Ketene Acetals

“…Chemical shifts (δ) are quoted in ppm. 1 H NMR spectra were recorded using an internal deuterium lock for the residual protons in CDCl3 (δ 7.26). 13 C NMR spectra were recorded using an internal deuterium lock in CDCl3 (δ 77.0).…”

“…Yndiamides (1, Figure 1) are relatively new additions to the wider family of ynamides (2) and ynamines, featuring nitrogen (amide) substituents at both termini of an alkyne. 1 Ynamides display an inherent polarization of their triple bond due to the electron-donating nature of their single nitrogen atom, resulting in high regioselectivity in processes such as hydroalkoxylations and hydroaminations (Figure 1a). 2,3 In contrast, yndiamides typically present an overall non-polar structure due to balanced and opposing electron-donation into orthogonal alkyne -bonds by the two nitrogen substituents.…”

“…Yndiamides nonetheless offer unique opportunities in synthesis: they can display heightened reactivity over ynamides, or distinct reaction outcomes in the formation of doubly-nitrogenated products. 1,4 Achieving control over the regioselectivity of functionalization of an yndiamide is a fundamental challenge, but also one that broadens the applicability of this motif in organic synthesis by enabling the site-selective installation of new substituents. In previous work, we developed a gold-catalyzed oxidative functionalization of yndiamides (Figure 1b), 4a which likely proceeds via initial formation of a keteniminum ion following activation of the yndiamide triple bond by the gold(I) catalyst.…”

“…N-Sulfonyl yndiamides 1a and 1c were prepared by coppercatalyzed coupling of dibromoenamide 4 with benzyl (5a) or cyclohexylsulfonamide (5c) respectively. 1 Phosphoramidate yndiamide 1b was synthesized by equivalent coupling with the benzyl phosphoramidate 5b, itself prepared from 2,2dimethylpropane-1,3-diol, POCl3 and benzylamine in 77% yield.…”

“…8 It is worth noting that carbon-centred acids have not, to the best of our knowledge, been successfully added to ynamides at their acidic carbon atoms without the aid of transition metals. 2g, 9 Given the high regioselectivity observed in these intermolecular addition processes, we next questioned whether equivalent regiocontrol could be induced in intramolecular cyclization reactions in which the benzyl substituent would act as a nucleophile, a process that we had observed for symmetric yndiamides on treatment with TfOH, 1 and which is also known for ynamides. 10 We first explored the feasibility of this process [Cu] a…”