Aldehyde-alkyne-amine coupling

2 REACTIONS CATALYZED BY COPPER, SILVER, OR GOLD 12.2.1 Aldehyde-Alkyne-Amine Coupling 

The coupling of the three components -aldehyde, alkyne and amine- has been called A3 coupling. 7 It delivers propargyl amines, which are important synthetic intermediates and, in contrast to previously used routes, avoids the use of strong-base reagents such as BuLi, ethylmagnesium bromide or LDA, and the need for the kinds of solvents necessary for these reagents. 

Subsequent research revealed that with different soluble silver salts only low conversions between 25% and 45% could be obtained, which was due to the in situ reduction of the more noble silver. However, with AgCl, AgBr, and Agl, good catalytic activity was observed.9 For example, with as little as 0.2 mol% Agl in water at 100°C, excellent yields could be obtained. 

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X. Yao, C.-J. Li, Org. Lett. 2005, 7, 4395-4398. Phosphine-triggered complete chemo-switch from efficient aldehyde-alkyne-amine coupling to efficient aldehyde-alkyne coupling in water. 

P. Li, L. Wang, Y. Zhang, M. Wang, Tetrahedron Lett. 2008, 49, 6650-6654. Highly efficient three-component (aldehyde-alkyne-amine) coupling reactions catalyzed by a reusable PS-supported NHC-Ag(I) under solvent-free reaction conditions. 

The A (aldehyde-alkyne-amine) coupling reaction represents a benchmark transformation to evaluate the catalytic activity of new NHC-Ag complexes. A variety of propargyl amines were efficiently synthesized by this method in the presence of diverse NHC-Ag complexes. In some cases, supported catalysts allowing recycling could also be used without loss of efficiency. ... 

Wei C, Li Z, Li CJ (2004) The development of A -coupling (aldehyde-alkyne-amine) and AA -coupling (asymmetric aldehyde-alkyne-amine). Synlett 1472-1483 Bariwal JB, Ermolat ev DS, Van der Eycken EV (2010) Efficient microwave-assisted... 

M. Wang, P. Li, L. Wang, Eur. J. Org. Chem. 2008, 2255-2261. Silica-immobilized NHC-Cu(I) eomplex an efficient and reusable catalyst for A3-coupling (aldehydes-alkyne-amine) under solventless reaction conditions. 

Finally, two reports describing the use of polymer-supported NHC-Ag compounds in three-component aldehyde-alkyne-amine reaction and Suzuki coupling have been published. " ... 

The coupling reactions of alkynes and aldehydes catalyzed by iron(III) salts have been discussed above (Scheme 10, routes B and C). The three-component coupling of aldehydes, alkynes, and amines is equivalent to the coupling reaction between alkynes and imines. Wang et al. reported such a three-component coupling catalyzed by FeCls in the absence of any ligand (Scheme 17) [33]. 

Scheme 19 Synthesis of quinolines by iron(III)-catalyzed three-component coupling/hydroaryla-tion of aldehydes, alkynes, and amines...

Catalytic coupling reaction of aldehydes, alkynes, and secondary amines promoted by less than 3 mol.% of Ag(l) salt was reported by Li et al,517 In this reaction, pure water was used as solvent and Agl was found to be the best catalyst without need of any additives or co-catalysts (Table 9). The reaction mechanism has been proposed as shown in Scheme 110. 

Solvent-Free Three-Component Coupling of Aldehyde, Alkyne and Amine 213... 

Li and coworkers have reported a novel silver-catalyzed, three-component coupling of an aldehyde, an amine, and an alkyne, and the first example of a direct addition of a silver acetylide to an aldehyde to produce propargylic alcohols (Scheme 1.41).103-105 Treatment of an aldehyde with a silver halide and secondary amine gave propargylic amines in good yields in organic solvent, water, or ionic liquids. The proposed mechanism suggests addition of a silver acetylide to the iminium ion formed in situ. 

In a closely related reaction, Li et al.101 devised a silver-catalyzed three-component coupling between aldehydes, alkynes, and amines. This transformation was really efficient in water and in an ionic liquid, although both required overnight heating at 100°C (Table 10.6). In this reaction, a silver acetylide that was sufficiently nucleophilic to add to the iminium ion that formed by condensation of the amine on the aldehyde was certainly produced.8... 

Li and co-workers374,374a reported the three-component coupling reaction of an aldehyde, an amine, and a terminal alkyne catalyzed by a silver salt in water. Of various precatalysts examined, water-insoluble silver iodide gave the highest yields of the propargyl amines 452 (Scheme 137). The reaction probably proceeds via attack of a silver acetylide, generated in situ from the silver salt and the alkyne, to the iminium ion derived from the aldehyde and the... 

Various aliphatic aldehydes, alkynes and dialkyl amines have been coupled using silver(I) iodide as catalyst in [C4Ciim][BF4] with moderate to excellent yield, as illustrated in Scheme 9.8.[34] The nature of the aldehyde has a much greater influence on the outcome of the reaction in the ionic liquid than in water. With aliphatic aldehydes, the reaction proceeded cleanly with hardly any trimer formation whereas aromatic aldehydes afforded complex product mixtures. 

Li Z, Jiang Z, Su W. Fast, solvent-free, highly enantioselective three-component coupling of aldehydes, alkynes, and amines catalysed by the copper(II)pybox complex under high-vibration ball-milling. Green Chem 2015 17 2330-4. 

Use of iron(iii) oxide has been reported for a number of other organic transformations, most notably a 3-component aldehyde, alkyne and amine coupling, and for the C(sp )-H borylation of arenes using bis(pinacolato)diboron. ... 

Highly functionalized olefins are easily accessible via silyformylation of alkynes. When coupled to other reaction systems, silylformylation reactions become even more powerful. Eilbracht et al. demonstrated that stabilized phosphorous ylides 74 could be trapped by P-silylated a-P-unsaturated aldehydes formed via silylformylation of alkynes in a one-pot synthesis. The tandem reaction proceeds with high yields for both alipathic and aromatic terminal alkynes. Protected propargyl alcohols also showed good reactivity however, propargyl amines react with low selectivity. The reaction shown below is the best-afforded result for this process. ... 

A -Coupling and Related Reactions Three-component coupling of aldehydes, alkynes, and amines (A -coupling) is a powerful methodology for the synthesis of propargylamines [88], which has been widely explored using Cu-, Ag-, or Au-based catalysts (see Section 3.4.2). 

K. Mohan Reddy, N. Seshu Babu, I. Suiyanarayana, P S. Sai Prasad, N. Lingaiah, Tetrahedron Lett. 2006, 47, 7563-7566. The silver salt of 12-tungstophosphoric acid an efficient catalyst for the three-component coupling of an aldehyde, an amine and an alkyne. 

M. Kidwai, V. Bansal, A. Kumar, S. Mozumdar, Green Chem. 2007, 9, 742-745. The first Au-nanoparticles catalyzed green synthesis of propargylamines via a three-component coupling reaction of aldehyde, alkyne and amine. 

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