Regioselective alkenylation and alkylation of 2-pyridone derivatives are achieved through inter- and intramolecular insertion of alkynes, 1,3-dienes, and alkenes into the C(6)-H bond by nickel/AlMe(3) catalysis. Coordination of the heterocycles to the Lewis acid cocatalyst through their basic carbonyl oxygen is considered to be responsible for the regioselective activation of the C-H bonds, probably through oxidative addition to nickel(0).

Formamides having 1-arylalkyl groups on nitrogen undergo an unprecedented dehydrogenative [4 + 2] cycloaddition reaction with alkynes via nickel/AlMe(3) cooperative catalysis to give highly substituted dihydropyridone derivatives in good yields. Notably, the transformation proceeds through double functionalization of C(sp(2))-H and C(sp(3))-H bonds in the formamides.

Formamides are found to undergo addition reactions across alkynes and 1,3-dienes by nickel/Lewis acid catalysis to give a variety of alpha,beta- and beta,gamma-unsaturated amides with stereo- and regioselectivity. Intramolecular insertion reactions of olefins into the C-H bonds of formamides also proceed under similar conditions. The presence of Lewis acid cocatalysts is crucial, and formamide coordination to the Lewis acid is considered to be responsible for the activation of their formyl C-H bonds probably through oxidative addition to nickel(0).

Lewis acid cocatalysts such as organoaluminum and -boron compounds dramatically improve the efficiency of the nickel-catalyzed arylcyanation of alkynes. Electron-rich aryl cyanides, which exhibit poor reactivity in the absence of Lewis acids, smoothly undergo the arylcyanation reaction under the nickel/Lewis acid dual catalysis. Excellent chemoselectivity is observed for aryl cyanides having a chloro or bromo group, which allows a single-step access to a synthetic intermediate of P-3622, a squalene synthetase inhibitor. The scope of the arylcyanation is also expanded to norbornadiene. Alkenylcyanation of alkynes is achieved under the nickel/Lewis acid dual catalysis to give cyano-substituted 1,3-dienes stereoselectively.

Nickel/Lewis acid dual catalysis is found to effect the carbocyanation reaction of alkynes using acetonitrile and substituted acetonitriles to give a range of variously substituted acrylonitriles. The addition of propionitrile across alkynes is also demonstrated briefly to give the corresponding ethylcyanation products in good yields, whereas the reaction of butyronitrile gives significant amounts of hydrocyanation products due possibly to ¢-hydride elimination of a propylnickel intermediate. The reaction of optically active ¡-phenylpropionitrile suggests a reaction mechanism that involves oxidative addition of a CCN bond with retention of its absolute configuration.Stereoselective construction of polysubstituted alkenes has been a major subject in organic synthesis.1 To this end, we 2 and others 3 have demonstrated carbocyanation reaction 4 of alkynes catalyzed by nickel or palladium as a new entry to stereochemically well-defined and atom economical protocols for the synthesis of tri-or disubstituted acrylonitriles, versatile synthetic intermediates for polysubstituted alkenes. We have recently disclosed that a Lewis acid (LA) cocatalyst significantly improves the efficiency of the nickel-catalyzed carbocyanation of unsaturated bonds, and allows a wide variety of nitriles including aryl, 2d alkenyl, 2d alkynyl, 2e,2f and allyl 2g cyanides to participate in the reaction. We further anticipated carbocyanation using alkyl cyanides might be feasible under similar dual catalysis, because some alkyl cyanides were reported to undergo oxidative addition to nickel(0) through the activation of C(sp 3 )CN ·-bonds. 5 In this paper, we report a full scope of the carbocyanation reaction of alkynes with acetonitrile under nickel/AlMe 3 dual catalysis. The reactions of propionitrile and butyronitrile with alkynes are also described briefly. Also demonstrated is the addition reaction of substituted acetonitriles such as aryl-and silylacetonitriles as well as protected amino-and hydroxyacetonitriles to give regio-and stereoselectively a wide variety of tri-and disubstituted acrylonitriles having allylic functional groups. 6Results and Discussion Nickel/Lewis Acid-Catalyzed Carbocyanation of Alkynes Using Acetonitrile.First, we investigated the reaction of acetonitrile (1a) with 4-octyne (2a) in the presence of a nickel/LA cooperative catalyst and found that AlMe 3 , AlMe 2 Cl, and BPh 3 were effective as a LA cocatalyst. After screening several combinations of catalysts and conditions, we found that the reaction of 1a (10 mmol) with 2a (10 mmol) proceeded in the presence of Ni(cod) 2 (5 mol %), PPh 2 (t-Bu) (10 mol %), and AlMe 3 (20 mol %) in toluene at 80°C to give the corresponding cis-methylcyanation product 3aa in 71% yield after 4 h (Entry 1 of Table 1).2d Exclusive cis-addition of 1a was unambiguously confirmed by NOE experiments. In the absence of the LA cocatalyst, the methylcyanation product was not observed in any detectable amount. Use of CH 3 CN-d 3 as a nitrile substrate gave 3aa-d 3 of 99% deuterium content, sug...