Recent Advances in Alkyne Hydroamination as a Powerful Tool for the Construction of C−N Bonds

Abstract

Alkyne hydroamination reaction has attracted many researchers due to its capability to form the required C−N bonds in the synthesis of the biologically and pharmacologically active N‐heterocycles. Hence, in this review, a comprehensive and updated summary of the research progress in this area (from 2014 on) is presented. In order to provide an easier access to the required information, a brief and concise description of the reaction mechanisms and preparation of precursors is also included, where possible. Accordingly, the alkyne hydroamination reactions are classified and summarized based on the type of hydroamination (inter‐ or intramolecular) and each class is further subdivided according to the number of members in the rings, so as to help the researchers in designing new N‐hetrocycles.

Endo-Selective Intramolecular Alkyne Hydroamidation Enabled by NiH Catalysis Incorporating Alkenylnickel Isomerization

“…Consequently, phenyl-substituted alkynyl dioxazolone 3 was chosen for the initial screenings to access six-membered lactam scaffolds that would be challenging to obtain by the previous strategies (Table 1). [1][2][3][4]37 Pleasingly, the use of NiCl 2 •glyme (5 mol%), 6,6′-dimethyl-2,2′-bipyridine ligand L2 (7.5 mol%), DMMS (2.0 equiv), H 2 O (1.0 equiv), and DMA solvent at 25 °C resulted in the desired endocyclic enamide 4 with excellent selectivity albeit in poor yield (entry 1). The low efficiency in this case was attributed to unwanted consumptions of the reactant by some sort of oligomerization, presumably caused by intermolecular C−N bond formation.…”

“…Intramolecular C–N bond-forming functionalization of alkynes is a valuable synthetic transformation − leading to privileged N-heterocyclic scaffolds that are widely present in natural products and pharmaceutical compounds. , The conventional approach relies on activation of unsaturated C–C bonds by π-coordination, typically utilizing precious transition metals (Scheme a). − Despite the significant developments, cyclization with amides, especially primary ones, remains challenging due to their low nucleophilicity, which could also suffer from the competing O-cyclization. − Another main difficulty in this process is to attain a precise regiocontrol ( exo vs endo ), as the selectivity often becomes unpredictable with altered product ring sizes . For example, the competition between 5- exo - and 6- endo-dig cyclization tends to be critically affected even by subtle modifications of the reactant structures. ,, In addition, the endocyclic pathway is yet limited for the formation of six-membered and larger rings, generally requiring certain functional groups, such as benzo-fusion − or carbonyl- or heteroatom-tether, , to achieve the endo selectivity.…”

Gold-Catalyzed Intermolecular Alkyne Hydrofunctionalizations—Mechanistic Insights

“…Compared to these reactions, though, alkyne hydroamination is a much broader reaction class, since there is a plethora of molecules containing a nucleophilic NH function that can be used as reactants. It is not within the scope of this review to broadly cover all the possible nitrogen-containing nucleophilic substrates that have been employed in this reaction, and the interested reader is referred to other more comprehensive contributions on this subject [71,72]. Here, we will focus on the nitrogen nucleophiles that have been most frequently employed for mechanistic studies, in order to shed light on the key parameters that need to be optimized for achieving best catalytic performance.…”

Silylium ion Migration Dominated Hydroamidation of Siloxy-alkynes

“…Hydroamidations have attracted very attentions for it's an atomic-economy way to construct enamides [1][2][3][4][5][6][7][8][9] . Further, the substrates of this reaction are easily-accessible.…”