Couplings, aldehyde/alkyne

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. 

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... 

The field of nickel-catalyzed reductive couplings has seen substantial interest in the past decade and numerous advances have been made in the area. There now exist several protocols, including simple aldehyde/alkyne coupling, diastereoselec-tive variants using transfer of chirality, asymmetric variants using either chiral... 

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. 

For the BBrj-mediated aldehyde-alkyne coupling reaction, another pathway (pathway D) plays the dominate role due to the instant generation of the di(bromovinyl)boron bromide intermediate when the alkyne and boron tribromide are mixed (Schane 23.23). 

SCHEME 23.21 Boron halide-mediated aryl aldehyde-alkyne coupling. 

SCHEME 23.22 Three different pathways for BClj-mediated aldehyde-alkyne coupling under controlled reaction conditions. 

SCHEME 23.23 Additional pathway for BBrj-mediated aldehyde—alkyne coupling. 

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...

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. 

Enantioselective catalysts have been developed for cyclization of dienyl aldehydes and coupling of aldehydes with alkynes (Equations (74) and (75)). For reactions with dienes see Refs 433 and 433a, and for reactions with alkynes see Refs 433b I33e. Chiral monodentate phosphines have proved to be effective. 

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. 

Sml2 -promoted, intramolecular ketone/alkyne couplings were reported in 1990 (equation 32)92. Yields were low (30-50%) for unactivated alkynes (Y = H or CH3), but improved to 50-75% when Y = Si(CH3)3, Ph or CC Et. Also, yields were typically much better for ketones than for aldehydes. 

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

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