Copper‐Catalyzed Amine–Alkyne–Alkyne Addition Reaction: An Efficient Method For the Synthesis of γ,δ‐Alkynyl‐β‐amino Acid Derivatives

Abstract

A simple and efficient method for the synthesis of gamma,delta-alkynyl-beta-amino acid derivatives by a copper-catalyzed three-component amine-alkyne-alkyne addition reaction was developed. Various gamma,delta-alkynyl-beta-amino acid derivatives were synthesized in moderate to good yields in one step. With chiral prolinol derivatives employed as the amine component, excellent diastereoselectivities (up to >99:1 diastereomeric ratio (dr)) were obtained. The scope of the reaction and further transformations of the resulting amino acid derivatives, such as deprotection and cyclization are also described.

α-Tertiary Propargylamine Synthesis via KA2-Type Coupling Reactions under Solvent-Free CuI-Zeolite Catalysis

“…Nevertheless, purification of obtained mixtures allowed the unambiguous identification of the major side products as propargylamines 4′ (Scheme ). Side products 4′ result from another attractive, but unwanted here, cascade reaction starting with an alkyne hydroamination step instead of a ketone-amine condensation step, thus making the ketone futile . As specified in Scheme , the proportion of side products 4′n – 4′r could be far from negligible.…”

Application of Glaser–Hay Diyne Coupling To Constrain Nα-Amino Acid Amides via a N–N Bridge

“…The reaction of alkynes with tertiary amines was reported for unrelated substrates, including the addition of amines to methylcyanobutadiyne, the formation of allenyltriethylamine salt, and the formation of a zwitterionic intermediate from DABCO and dimethyl acetylenedicarboxylate . An analogous copper-catalyzed amine–alkyne–alkyne addition using secondary amines yielded γ,δ-alkynyl-β-amino acids …”

“…31 An analogous copper-catalyzed amine−alkyne−alkyne addition using secondary amines yielded γ,δ-alkynyl-β-amino acids. 32 Attempts to avoid the formation of this adduct using other bases (DIPEA, DBU, and DABCO) were unsuccessful, and the corresponding adducts were obtained in all cases for compounds 5{1,1}, 5{1,2}, 5{1,3}, 5{2,1}, and 5{3,1}. TEA product 7 was isolated and fully characterized.…”

Heteroatom methods

“…Yields were moderate to good (Scheme 50). 85 An efficient synthesis of 1,3-dihydro-2H-3-benzazepin-2-ones also employed a hydroamination reaction step, having assembled the bulk of the molecule by an Ugi reaction (Scheme 51). 86…”