Structural Determinants of Alkyne Reactivity in Copper-Catalyzed Azide-Alkyne Cycloadditions

Abstract

This work represents our initial effort in identifying azide/alkyne pairs for optimal reactivity in copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. In previous works, we have identified chelating azides, in particular 2-picolyl azide, as "privileged" azide substrates with high CuAAC reactivity. In the current work, two types of alkynes are shown to undergo rapid CuAAC reactions under both copper(II)-(via an induction period) and copper(I)-catalyzed conditions. The first type of the alkynes bears relatively acidic ethynyl C-H bonds, while the second type contains an N-(triazolylmethyl)propargylic moiety that produces a self-accelerating effect. The rankings of reactivity under both copper(II)-and copper(I)-catalyzed conditions are provided. The observations on how other reaction parameters such as accelerating ligand, reducing agent, or identity of azide alter the relative reactivity of alkynes are described and, to the best of our ability, explained.

Determining the Origin of Rate‐Independent Chemoselectivity in CuAAC Reactions: An Alkyne‐Specific Shift in Rate‐Determining Step

“…Deuterium kinetic isotope effect (KIE) experiments of the alkyne C À Hw ere informative.Z hu et al reported ap rimary KIE of 2.3 when using an aryl alkyne (such as 5) and am arked increase in the initiation time associated with oxidative homocoupling. [8] In agreement with these data, we observed primary KIEs (e.g.,KIE for 2 = 2.66) and asignificant increase in initiation time (see SI). In contrast aK IE of only 1.17 was observed for 1 (Figure 2a), indicating that Cuacetylide formation was not rate limiting.…”

“…[3,5] 3) Fokin et al have developed chemoselective CuAACr eactions of 1-iodoalkynes that, due to their mechanistically distinct operation, have allowed for highly chemoselective reactions versus conventional terminal alkynes. [6] Based on work by Finn and Fokin, [7] and Zhu, [8] acetylide formation is the rate-determining step (RDS) of the CuAAC reaction (Scheme 1). [9] Chemoselective discrimination of alkynes is therefore possible by exploiting differences in their respective rates of acetylide formation.…”

“…Modification of the alkyne to incorporate groups that facilitate am ore rapid insertion of Cu into the alkyne CÀHbond has been astrategy employed by Finn, Hsung,a nd others in order to leverage chemoselective control in systems containing two alkynes, [10] with mechanistic investigations focusing on this first key mechanistic event of the catalytic cycle. [7][8][9]11] Here we analyze the mechanistic origins of rate-independent chemoselectivity in CuAACr eactions of an aryl ynamine class of alkyne.Kinetic and spectroscopic investigations support the transition of the RDS from acetylide formation to azide ligation/migratory insertion.…”

“…[12] To probe and compare the reactivity of different classes of alkyne more broadly,w ep erformed as eries of competition experiments where equistoichiometric quantities of two terminal alkynes compete for one equivalent of ac ommon azide component (benzyl azide,B nN 3 )u sing established reaction conditions (Scheme 2, see the Supporting Information (SI) for all triazole products). [4,8,12] Thea lkyne selection was based on representative members of six specific classes-aromatic ynamine (1), tertiary propiolamide (2), ynamide (3), propargyl alkyne (4), aryl alkyne (5), and alkyl alkyne (6). Previous work by Finn has shown that 2 is ahighly reactive substrate under conventional CuAACc onditions,o utcompeting 4-6 in competition experiments.…”

CuII‐Catalyzed Oxidative Formation of 5‐Alkynyltriazoles

“…Highly electron‐deficient alkynes such as ethynyl ketones failed to result in alkynyltriazole formations for a different reason. These alkynes (1) are not as prone to oxidation but highly reactive in the cycloaddition with an azide, and (2) tend to undergo the redox neutral Michael addition with MeOH in the presence of a base. Therefore, protiotriazole, bistriazole, and the solvent adduct to the alkyne were common products from these reactions (Scheme S4).…”