Activation of Primary Amines by Copper(I)-Based Lewis Acid Promoters in the Solventless Synthesis of Secondary Propargylamines

Abstract

Primary amines are activated by copper(I)-based Lewis acid promoters in an A3-coupling one-pot solventless reaction with aldehydes and phenylacetylene for the synthesis of secondary propargylamines. The reaction is promoted by a CuSO4/NaI system, a practical precursor of the in situ generated effective CuI/I2 system, that worked well, but only in a restricted number of examples. Substitution of I2 with CeCl3·7H2O in a one-pot two-step reaction provided good yields and a wider applicability, with the added value given by a safer procedure.

Diastereoselective Synthesis of Secondary Propargylamines Exploiting CuI-Based Promoters and Determination of Their Relative Configuration by DFT-GIAO Conformational Analysis

“…Spectra obtained from enriched chromatographic fractions, in agreement with literature 9 Oil, CuSO4/NaI 63% (6h); CeCl37H2O 58% (6h).…”

“…Recently, we have developed a methodology for the synthesis of secondary propargylamines by activation of primary amines through CuI-based promoters, 9 contributing to bridge this gap. A certain diastereoselectivity, observed in the reactions involving chiral aldehydes or amines, prompted us to investigate more deeply the stereochemical aspects of the reaction, expanding its applicability to the diastereoselective synthesis of enantiopure secondary propargylamines.…”

“…In our previous research, 9 two different copper(I)-based promoting systems, CuSO 4 /NaI and CuI/CeCl 3 ·7H 2 O, were used to promote solventless A 3 coupling among amines, aldehydes, and phenylacetylene, both characterized by ease of use, low toxicity, and cost. The CuSO 4 /NaI couple in stoichiometric ratio proved to be a good and practical precursor for the in situ generation of CuI and I 2 , the real reacting species.…”

A3 Coupling Reaction in the Synthesis of Heterocyclic Compounds

“…The A 3 coupling reactions were extensively studied under microwave [6y,18] and ultrasonic irradiation [19] . The reactions proceeded smoothly in water or even under solvent‐free conditions [20] . It found application in the synthesis of natural products, [21] polymers and biologically active compounds [22]…”

“…[19] The reactions proceeded smoothly in water or even under solvent-free conditions. [20] It found application in the synthesis of natural products, [21] polymers and biologically active compounds. [22] Several excellent reviews and monographs on the A 3 coupling reaction were published in the literature in recent years.…”