Aldehydes, alkynic

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...

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

Scheme 25 Hydroboration and hydrozirconation strategies for aldehyde/alkyne reductive coupling...

Scheme 26 Carboalumination strategy for aldehyde/alkyne alkylative coupling...

A variety of aldehyde/alkyne reductive couplings involving the stoichiometric use of early transition metals (Ti and Zr) have been developed (Scheme 27) [68-70]. The low cost and ease of handling of titanium alkox-ides render these stoichiometric processes very practical despite the lack of catalytic turnover. Recent variants of stoichiometric processes involving titanium alkoxides have demonstrated impressive scope in relatively complex applications [71-73]. 

Although the titanium-based methods are typically stoichiometric, catalytic turnover was achieved in one isolated example with trialkoxysilane reducing agents with titanocene catalysts (Scheme 28) [74], This example (as part of a broader study of enal cyclizations [74,75]) was indeed the first process to demonstrate catalysis in a silane-based aldehyde/alkyne reductive coupling and provided important guidance in the development of the nickel-catalyzed processes that are generally more tolerant of functionality and broader in scope. 

Recently, four-component coupling reactions of aldehydes, alkynes, dienes, and dimethylzinc catalyzed by a nickel complex have been reported (Equation (78)).435 Similarly, l,c< -dienynes react with carbonyl compounds and dimethylzinc in the presence of an Ni catalyst to afford the corresponding cyclized products. 

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. 

This system also worked well in ionic liquids.518 Li etal. found silver-phosphine complexes to promote aldehyde-alkyne coupling in water. When triphenylphosphinesilver chloride was used as a catalyst in water, the only detected product was the aldehyde addition product instead of the adduct derived from imine (Scheme 111).519... 

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

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... 

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. 

Aldehyde -> Alkyne Elongation via Carbene and Carbenoid Rearrangements... 

Seyferth s diazomethane phosphonic acid dimethyl ester, which enables the aldehyde —> alkyne elongation shown in Figure 14.30, is unstable. This is why Bestmann replaced it by a less sensitive synthetic equivalent, namely diazo acetone phosphonic acid dimethyl ester (Formula C in Figure 14.31), since with potassium methoxide—which is proportionately present in a solution/suspension of solid potassium carbonate in dry methanol—the dia-... 

Fig. 14.32. Aldehyde alkyne chain elongation via [l,2]-rearrangement of a vinyl carbenoid (Corey—Fuchs procedure). The aldehyde and phosphonium ylide A generated in situ undergo a Wittig olefina-tion and form the 1,1-dibro-moalkene (B). In the second stage, the dibromoalkene is reacted with two equivalents of n-BuLi and the vinyl carbenoid D is formed stereoselectively. The carbenoid undergoes H migration to form the alkyne C. The alkyne C reacts immediately with the second equivalent of n-BuLi to give the lithium acetylide and is reconstituted by reprotonation during aqueous workup.

Fig. 11.28. Aldehyde alkyne chain elongation via [1 -rearrangement of a vinyl carbene (Seyferth procedure). First, a Horner-Wadsworth-Emmons olefination of the aldehyde is carried out to prepare alkene A. Upon warming to room temperature, alkene A decomposes and gives the vinyl carbene B. From that, the alkyne is formed by way of a [1,2]-rearrangement.

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