Mechanistic evaluation of the nickel-catalyzed [2+2+2]-cycloaddition reaction of alkynes and nitriles

Chapter 1 describes detailed mechanistic studies that were conducted on three discreet Nickel-catalyzed [2+2+2] cycloaddition reactions of diyne and nitriles to afford pyridines. Reaction profiles demonstrated in all cases a heterooxidative coupling mechanism, contrary to other common cycloaddition catalysts.;Through kinetic analysis of the Ni(IPr)2-catalyzed cycloaddition, observed regioisomerism of the products, and stoichiometric reactions, Ni(IPr) 2 appears to have catalyzed the cycloaddition by proceeding via a heterooxidative coupling mechanism. Strong coordination and considerable steric bulk of the carbene ligands facilitates selective initial binding of the nitrile, inducing an &eegr;1-(IPr)2Ni(NCR) catalytic resting state.;Chapter 2 then reports on the reaction of Ni(COD)2, IPr, and nitriles to afford dimeric [Ni(IPr)RCN]2 in high yields. These dimers are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles, wherein the dimeric state was found to be largely preserved throughout the reaction. Observations suggest a mechanism whereby the catalyst is activated by partial dimer-opening followed by binding of exogenous nitrile and subsequent oxidative heterocoupling, leading to pyridine products.;Comparative investigations into the mechanism of the cycloaddition of diynes and nitriles catalyzed by a complementary Ni(COD)2/Xantphos catalyst are discussed in Chapter 3. Kinetic analysis of two Ni/Xantphos catalysts reveal zeroeth-order in all substrates but catalyst, suggesting a (Xantphos)Ni(diyne) resting state with rate-limiting partial phosphine dissociation.;Chapter 4 then describes the discovery of cyanamides as highly active substrates for cycloaddition with alkynes and diynes. The observed reactivity was further investigated by utilizing a number of cyanamides with diverse functional groups. A variety of bicyclic N,N-disubstituted-2-aminopyridines were prepared from both terminal- and internal-diynes with cyanamides in a selective manner. Two examples of three-component cycloadditions were conducted and found to be selective and high yielding.;Chapter 5 expands on Chapter 4 illustrating the cross-coupling of alkyl cyanamides with a number of aryl, heteroaryl, and vinyl halide and pseudohalide coupling partners. The synthesis was possible via a modification of reported Pd-catalyzed amidation methods. The reactions proceed selectively under mild conditions with reasonable reaction times in moderate to excellent yields.