Aldehydes and Alkynes

Reactions between aldehydes and alkynes to give propargyl alcohols are also described in Kitazume and Kasai s paper [55]. Here, various aldehydes such as benzaldehyde or 4-fluorobenzaldehyde were treated with alkynes such as phenylethyne or pent-l-yne in three ionic liquids [EDBU][OTf], [BMIM][PFg], and [BMIM][BF4] (Scheme 5.1-27). A base (DBU) and Zn(OTf)2 were required for the reaction to be effective the yields were in the 50-70 % range. The best ionic liquid for this reaction depended on the individual reaction. 

The combination of Ni(COD)2/NHC complexes with EtaSiH as the reducing agent has also proved to be effective in inter molecular couplings of aldehydes and alkynes (Scheme 9) [21]. A broad range of substrates underwent couplings, including aromatic, non-aromatic, and terminal alkynes as well as branched, unbranched, and aromatic aldehydes. The regioselectivity with... 

A number of chiral monodentate phosphines have been examined in asymmetric nickel-catalyzed reductive couplings of aldehydes and alkynes. The best results to date have been obtained with (+)-NMDPP (16) [33]. Aromatic internal alkynes and branched aldehydes participate with excellent enantiose-lectivity (Scheme 15), although yields and enantioselectivities were somewhat lower with other combinations of aldehydes and alkynes. In a complemen-... 

A broad array of mechanistic pathways may be considered in the different variants of nickel-catalyzed reductive couplings of aldehydes and alkynes, and a generalized overview of possible mechanisms has been previously described [10]. Whereas a comprehensive mechanistic study has not been presented, a number of key observations have been illustrated that provide insight into how the nickel-catalyzed reductive couplings of aldehydes and alkynes proceed. It should be stressed at the outset that the different reaction variants may proceed by different mechanisms. 

The initially proposed mechanism [14], and one that continues to be considered as the likely pathway for most variants, involves the oxidative cyclization of a Ni(0) complex of an aldehyde and alkyne to a metallacycle (Scheme 18). Metallacycle formation could proceed independently of the reducing agent via metallacycle 19, or alternatively, metallacycle 20a or 20b could be formed via promotion of the oxidative cyclization transformation by the reducing agent. Cleavage of the nickel-oxygen bond in a o-bond metathesis process generates an alkenyl nickel intermediate 21. In the variants involv-... 

The nickel-catalyzed reductive coupling of aldehydes and alkynes is only one member of a growing class of processes that involve the three-component addition of two rr-components and a reducing agent (Scheme 24). An... 

A variety of alternate methods for the reductive coupling of aldehydes and alkynes have been developed. A number of important hydrometallative strategies have been developed, although most of these methods require the stoichiometric formation of a vinyl metal species or metallacycle. A very attractive hydrogenative coupling method has recently been developed, and its scope is largely complementary to the nickel-catalyzed methods. A very brief overview of these methods is provided below. 

Montgomery J, Sormunen GJ (2007) Nickel-Catalyzed Reductive Couplings of Aldehydes and Alkynes. 279. 1-23... 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

Oxidative nickel-catalyzed coupling of aldehydes and alkynes to generate allylic alcohols. Intermolecular and intramolecular examples are both effective, and the transmetalating agent (MR" ) may be an organosilane, organoborane, organozinc, or alkenylzirconium. ... 

The mechanism was proposed to involve the formation of a nickel metallacycle by the oxidative cyclization of Ni(0) with the aldehyde and alkyne, followed by conversion of the metallacycle to product by a transmetalation/reductive elimination sequence. If R possesses a P-hydrogen, then P-hydride elimination after the transmetalation step generates the product with R = H in some instances. The mechanism was shown to be ligand dependent, and the mechanism depicted below is undoubtedly oversimplified. ... 

More recently, the scope of the Ni catalysed alkyne carbozincation has been extended to the cases of co-alkynyl aldehydes and even mixtures of aldehydes and alkynes.65 These reactions are generally accompanied by alkylation with organozincs (Scheme 11.20). 

TABLE 10.6. Propargylic Amine Formation from Aldehydes and Alkynes... 

Two general protocols exist for nickel-catalyzed reductive couplings of aldehydes and alkynes. The first employs (+)-NMDPP as a chiral monodentate phosphine ligand. Internal aromatic alkynes were shown to undergo reductive coupling in good yields with enantioselectivities ranging from 42% to 96% (Scheme 8.28) [51]. 

In contrast, Cu(I) catalysis makes possible the efficient synthesis of 3,5-disubstituted isoxazoles 57 from aromatic or aliphatic aldehydes and alkynes. Stable nitrile oxides can be isolated and subsequently submitted to the reaction... 

Nickel-Catalyzed Reductive Couplings of Aldehydes and Alkynes 3... 

---