Nitrile-diyne substrates

Unlike tethered diynes that are commonly seen in [2 + 2 + 2]-pyridine syntheses, nitrile-diyne substrates are less explored. Recently, Snyder and coworkers reported microwave promoted cobalt-catalyzed [2 + 2 + 2]-reaction of nitrile-diynes 275 to afford tetrahydronaphthyridines 276 in moderate to excellent yields. ... 

The ideal substrates for these reactions are 1,6-dienes [37-38], for example (Scheme 7), dimethyl diallylmalonate is easily transformed into cyclopentane derivatives, as a mixture of cis and trans isomers. The methodology also applies to analogous enynes [39-40], diynes [41], or eneallenes [42]. The radical acceptor in the cyclization step can even be an imino group [43a-c], or a nitrile [43d]. 

A highly practical method for the catalytic formation of substituted pyridines from a variety of unactivated nitriles and a,high functional compatibility and regioselectivity at rt to 50°C (Scheme 3.5). This system was also applied in the synthesis of polymers by polymerization of diyne-nitrile monomers [19]. With 2-(2-(hept-2-yn-l-yl)non-4-yn-l-yl) malononitrile or 2,2-di(but-2-yn-l-yl)malononitrile as the substrate, the corresponding polymers can be selectively produced. 

Okamoto and coworkers reported a cobalt-catalyzed cycloaddition reaction of nitriles and a,cobalt chloride hexahydrate (C0CI2 6H2O)/ zinc-catalyzed [2 -I- 2 + 2] cycloaddition reaction from the corresponding substrates with excellent regioselectivity (Scheme 3.10). More specifically, symmetrical and unsymmetrical 1,6-diynes and 2-cyanopyridine reacted in the presence of 5 mol% of dppe, 5 mol% of... 

Hoveyda-Grubbs catalyst has been applied in [2 + 2 + 2] cyclotri-merizations of diynes with nitriles as well [34], In the presence of 5 mol % of catalyst in DCE at 90° C, excellent yields can be obtained with activated nitriles and low to moderate yields with nonactivated nitriles. Both terminal and internal alkynes are applicable as substrates. 

A Ni/SIPr (1 2) combination catalyzed the cycloaddition of diynes and nitriles into pyridines. Aryl, heteroaryl as well as alkyl nitriles were reactive under ambient conditions (Equation (10.23)). In contrast with aryl isocyanates vide supra), the reaction was not dependent on the electronic demand on the aryl nitrile since both electron-rich and electron-poor substrates gave similar results. Finally, and similarly to isocyanates reactions, the larger substituent was introduced in the 3-position of the pyridine ring. 

The above section considered anionic cyclization of enediynes and related molecules in a one-pot process, in contrast to the known classical multi-step methods [260, 327-329]. One-step anionic cycloaromatization of enediynes is also an effective method for the synthesis of biarenes [328]. Depending on the reaction conditions and substrate structure, the process can go by two routes. For example, when a methoxide ion attacks the nitrile function of enediyne 3.691, there follows a cascade of cycloaromatization reactions by an anionic pathway, affording phenanthridinones 3.692 in 50% yield after chromatographic purification. On the other hand, reaction of enediyne 3.691 with sodium methoxide in methanol in the presence of two equivalents of tetra-butylammonium iodide at reflux leads to biaryl derivative 3.693 in 56-64% yield. Diynes 3.691 were synthesized in 40-98% yield by the Pd-catalyzed coupling reaction of 2-ethynylbenzonitrile 3.689 with 2-alkynyliodbenzenes 3.690 (Scheme 3.72) [327]. A similar procedure was applied to the cycloaromatization of a series of (Z)-l-aryl-3-decene-l,5-diynes 3.694 to produce biphenyls 3.695 in yields from 14% to 34% (Scheme 3.73) [327]. 

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