Copper(I)-Catalyzed Substitution Reactions of Propargylic Amines: Importance of C(sp)−C(sp³) Bond Cleavage in Generation of Iminium Intermediates

Abstract

Substitution reactions of propargylic amines proceed in the presence of copper(I) catalysts. Mechanistic studies showed that C(sp)-C(sp(3)) bond cleavage assisted by nitrogen lone-pair electrons is essential for the reaction, and the resulting iminium intermediates undergo amine exchange, aldehyde exchange, and alkyne addition reactions. Because iminium intermediates are key to aldehyde-alkyne-amine (A(3)) coupling reactions, this transformation is effective not only for reconstruction of propargylic amines but also for chiral induction of racemic compounds in the presence of chiral catalysts.

Copper(I)-Catalysed Deacetylenative Cross-Coupling Reaction of Terminal Alkynes with Propargylic Amines via C(sp)-C(sp3) Bond Cleavage

“…Previously, we reported that the reaction proceeded in the presence of CuCl catalyst (20 mol%) and n-Oct 3 N (0.5 equiv) at 100 °C in THF for 24 hours, giving N,N-dihexyl-1-phenylnon-1-yn-3-amine (2a) in 33% yield (Table 1, entry 1). 10 We found that elevating the temperature to 130 °C affected the reaction yield: …”

“…11 Although the transformation was able to be utilized for the deacetylenative homocoupling reaction, which is one of the convenient reactions for the synthesis of symmetric 1,4-diamino-2-butynes, 12 the reaction conditions still need improvement prior to application in the deacetylenative coupling reaction of terminal alkynes with propargylic amines. 10 In the current study, we succeeded in the deacetylenative cross-coupling reaction of alkynes with various N-substituted propargylic amines under modified reaction conditions.…”

“…9 We have recently reported that propargylic amines undergo a substitution reaction in the presence of a copper(I) catalyst to afford substituted propargylic amines. 10 In this transformation, the C(sp)-C(sp 3 ) bond cleavage of propargylic amines 1 is the key step for the generation of copper acetylides 2 and iminium intermediates 3. Iminium intermediates 3 undergo fragment exchange with additional aldehydes, amines, and/or alkynes to yield substituted propargylic amines 1′-1′′′ (Scheme 1).…”

“…These products shown in Table 3 were not able to be obtained under the previously reported conditions. 10 In conclusion, we have developed an efficient method for the synthesis of 3-substituted propargylic amines 2 from corresponding propargylic amines 1, which employs the copper-catalyzed deacetylenative coupling reaction. A propargylic moiety selectively underwent the deacetylenative coupling in the presence of allylic moieties.…”

One-pot multicomponent route to propargylamines using ferric hydrogensulfate

“…Recently great efforts have been devoted to develop the methodology for generating propargylamines and some direct alkynylations of carbonyl compounds with terminal alkynes have been reported [24][25][26][27][28][29]. Several transition metal salts such as gold, copper, silver, and Cu/Ru system have been employed in water as well as in ionic liquids [25][26][27].…”