Cascade Reactions Involving Alkynes

SCHEME 6.20 Palladium-catalyzed oxidative cascade cyclization. 

SCHEME 6.21 Palladium-catalyzed alkene difunctionalization reactions. 

Alkynes are widely used in palladium-catalyzed processes. In general, alkynes show three distinct important reactivities in palladium-catalyzed transformations (1) insertion of alkyne into the X—Pd bond (X=carbon, heteroatom, metal) to form a vinylpalladium intermediate, which lacks a suitable P-hydride for elimination and 

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Finally, a novel three-component radical cascade reaction involving isonitriles has just been published [6]. In this paper, aromatic disulfides, alkynes, and isonitriles have been reported to react under photolytic conditions to afford -arylthio-substituted acrylamides 49 or acrylonitriles 50 in fair yields as mixtures of the E and Z geometric isomers (Scheme 21). The procedure entails addition of a sulfanyl radical to the alkyne followed by attack of the resulting vinyl radical on the isonitrile. A fast reaction, for example, scavenging by a nitro-derivative (route a) or f-fragmentation (route b), is necessary in order to trap the final imidoyl radical, since addition of vinyl radicals to isonitriles seems to be a reversible process. The reaction provides very easy access to potentially useful poly-functionalized alkenes through a very selective tandem addition sequence. 

Triazole Derivatives. Triazole derivatives are known to possess tumor necrosis factor-a (TNF-a) production inhibitor activity. The synthesis of triazole derivatives can be achieved from alkynes or diynes by a tandem cascade reaction involving 1,3-dipolar cycloaddition, anionic cyclization and sigmatropic rearrangement on reaction with sodium azide. Some of the benzoyl triazole derivatives were considered to be potent local anaesthetics and are comparable with Lidocaine. The triazoles can also be prepared from benzoyl acetylenes,triazoloquina-zoline derivatives, 2-trifluoromethyl chromones, aliphatic alkynes, 2-nitroazobenzenes, ring opening of [ 1,2,4]triazolo [5,1-c] [2,4]benzothiazepin-10 (5//)-one, alkenyl esters and dendrimers. A number of these reactions are outlined in eqs 44 8. 

A cascade reaction involving 1,3-dipolar cycloaddition of ketenimine was reported by Li et al. [69], The transformation combines a CuAAC reaction, a Lewis add-catalyzed 6-endo cyclization of Af -(2-alkynylbenzylidene)hydrazide, a [2+3] cycloaddition, and an aromatization in a single step to afford 2-amino-//-pyrazolo[5,l-a] isoquinolines 102 in good to excellent yields (Schane 5.66). The copper-catalyzed three-component reaction of sulfonyl azides, alkynes, and nitrones also involves 1,3-dipolar cycloaddition between ketenimine and nitrone (Scheme 5.67) [70]. The nitrone substrates in this transformation could be generated in situ from benzalde-hydes and hydroxylamines. 

The most recent findings on these reactions were reported by Liu and coworkers who developed a series of cascade reactions involving one or more alkyne... 

Later, a nickel-catalyzed cascade conversion of propargyl halides and propargyl alcohol into a pyrone in water was reported. The reaction involved a carbonylation by CO and a cyanation by KCN (Eq. 4.55).96 Recently, Gabriele et al. explored a facile synthesis of maleic acids by palladium catalyzed-oxidative carbonylation of terminal alkynes in aqueous DME (1,2-dimethoxyethane) (Eq. 4.56).97... 

The vast majority of radical cascades initiated by addition of higher main group (VI)-centered radicals to alkynes focus predominantly on S-centered radicals, mainly thiyl radicals, whereas considerably fewer intermolecular addition reactions involving radicals with the unpaired electron located on selenium or even tellurium are known. 

Another interesting cascade involving nitrones is the copper catalyzed reaction with alkynes to produce p-lactams that was originally reported by Kinugasa (72CC466). Stoichiometric amounts of copper(I) phenylacetylide (61) react with various aryl nitrones 62 in pyridine to give p-lactams 63 in 50-60% yield (equation (2)). In each case, only the czs-lactams were isolated. 

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