Highly Efficient and Diastereoselective Gold(I)‐Catalyzed Synthesis of Tertiary Amines from Secondary Amines and Alkynes: Substrate Scope and Mechanistic Insights

Abstract

An efficient method for the synthesis of tertiary amines through a gold(I)-catalyzed tandem reaction of alkynes with secondary amines has been developed. In the presence of ethyl Hantzsch ester and [{(tBu)(2)(o-biphenyl)P}AuCl]/AgBF(4) (2 mol %), a variety of secondary amines bearing electron-deficient and electron-rich substituents and a wide range of alkynes, including terminal and internal aryl alkynes, aliphatic alkynes, and electron-deficient alkynes, underwent a tandem reaction to afford the corresponding tertiary amines in up to 99 % yield. For indolines bearing a preexisting chiral center, their reactions with alkynes in the presence of ethyl Hantzsch ester catalyzed by [{(tBu)(2)(o-biphenyl)P}AuCl]/AgBF(4) (2 mol %) afforded tertiary amines in excellent yields and with good to excellent diastereoselectivity. All of these organic transformations can be conducted as a one-pot reaction from simple and readily available starting materials without the need of isolation of air/moisture-sensitive enamine intermediates, and under mild reaction conditions (mostly room temperature and mild reducing agents). Mechanistic studies by NMR spectroscopy, ESI-MS, isotope labeling studies, and DFT calculations on this gold(I)-catalyzed tandem reaction reveal that the first step involving a monomeric cationic gold(I)-alkyne intermediate is more likely than a gold(I)-amine intermediate, a three-coordinate gold(I) intermediate, or a dinuclear gold(I)-alkyne intermediate. These studies also support the proposed reaction pathway, which involves a gold(I)-coordinated enamine complex as a key intermediate for the subsequent transfer hydrogenation with a hydride source, and reveal the intrinsic stereospecific nature of these transformations observed in the experiments.

[2.2]Paracyclophanediyldiphosphane Complexes of Gold

“…Because we aimed to study first only differences in reactivity of 1 and 3 , we used simple substrates without functional groups such as aniline, mesidine, phenylacetylene, ethynylcyclohexene, and 5‐phenylpent‐4‐yn‐1‐amine. Based on the published reaction conditions37m we studied the inter‐ and intramolecular hydroamination reaction using 5 mol‐% of 1 or 3 in combination with 10 mol‐% AgBF 4 (Au/Ag, 1:1) (Table 5). The unoptimized reactions, which proceeded regiospecifically, were monitored by 1 H NMR spectroscopy using ferrocene or hexamethylbenzene as internal standard.…”

Air‐Stable, Dinuclear and Tetranuclear σ,π‐Acetylide Gold(I) Complexes and Their Catalytic Implications

“…To address this point and due to the interest in imines in organic synthesis and industrial chemistry, [24][25][26][27] we have selected the Au I -catalyzed coupling of amines with terminal alkynes with the goal of isolating the real active species formed during the catalytic process. [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] The reaction of hepta-1,6-diyne (1) with gold complexes 2 [43] or 3 [44] was initially studied (see Scheme 2). Slow addition of n-hexane to solutions containing 1 and complexes 2 or 3 gave, after 12 h at À30 8C, colorless crystals of the air-stable dicationic tetragold complexes 4 and 5, respectively, in good yields with respect to the initial Au I complexes 2 and 3 (76 and 62 %; see the Experimental Section in the Supporting Information).…”

Redox Amination Scope of Benzylic Ketones with Indoline: Synthetic and Mechanistic Insights

“…Bi(NO 3 ) 3 ·5H 2 O (0.1 m M )‐Catalyzed reaction of indoline ( 1 ; 500 mg, 4.2 m M ) with acetophenone ( 5c ; 504 mg, 4.2 m M ) was performed at 120°C for 3 h in MeCN according to GP1. N ‐(1‐Phenylethyl)indoline ( 10c ) . 405 mg, 40%, dark viscous liquid, eluent: EtOAc/hexane (30%), Rf = 0.72 (254 nm).…”