Pyrazine palladium-catalyzed reactions

Undheim and Benneche reviewed the Pd-catalyzed reactions of pyrimidines, among other ji-deficient azaheterocycles including pyridines, quinolines and pyrazines, in 1990 [1] and 1995 [2], A review by Kalinin also contains some early examples in which C—C formation on the pyrimidine ring is accomplished using Pd-catalyzed reactions [3]. In this chapter, we will systematically survey the palladium chemistry involving pyrimidines. 

Pyrazines undergo nearly all of the same reactions as pyrimidines, from nucleophilic substitution (SnAt) to palladium-catalyzed cross coupling reactions. Displacement of the chlorides via SnAt reactions with nitrogen (157 158) and sulfur-based nucleophiles (158... 

A variety of N-, 0- and 5-heterocyclic halides have been found to undergo the palladium-catalyzed al-kene substitution reaction. Halogen derivatives of furan, thiophene, pyridine, pyrazine, uracil, indole, quinoline and isoquinoline, for example, undergo the reaction. Iodoferrocene also reacts normally. 

Terminal alkenes can be used in a palladium-catalyzed alkenylation reaction of pyridine, pyrazine, quinoxaline, and pyridazine N-oxides 109 as reported by Chang (Scheme 53) (2008JA9254). This approach delivers regioselective C2-alkenylation products 110 and requires silver carbonate in a superstoichiometric amount as external oxidant. 

Many examples exist of synthetically useful intermolecular paUadium-catalyzed arylations of Jt-excessive heterocycles [4, 7, 50-56]. The reaction has also been extended to the direct arylation of pyridine, diazine and azole N-oxides with aryl halides [57]. Interestingly, tuning the ligand and base allows selective sp or sp activation of alkyl pyridine or pyrazine N-oxides [58], Palladium-catalyzed sp activation of alkylanines [59] and benzyUc arylation of benzoxazoles has also been described [60]. 

Procedures employing less harsh reaction conditions for the functionalization of pyrazine-based compounds were reported in 2013. The Buch-wald group developed two procedures for adding functional groups to the pyrazine core. The first was a selective palladium-catalyzed monoarylation of ammonia under mild reaction conditions using bulky biarylphosphine... 

A. Keivanloo, M. Bakherad, H. Nasr-Isfahani, S. Esmaily, Highly efficient synthesis of 5,6-disubstituted 5H-pyrrolo-[2,3-l ]-pyrazine-2,3-di-carbonitriles through a one-pot palladium-catalyzed coupling reaction/cyclization in water. Tetrahedron Lett. 53 (2012) 3126-3130. 

Transition metal-catalyzed cross-coupling reactions of halogenopyrazines is an efficient synthetic method for alkyl-, alkenyl-, and alkynylpyrazines (Section 6.03.5.4.2). Palladium and nickel complexes are particularly effective as catalysts in this reaction. The Wittig reaction of halogenomethyl-pyrazines likewise leads to the formation of alkenylpyrazines (Section 6.03.8.1). Dehalogenation of halogeno pyrazines is a very practical synthetic method for alkyl- or aryl-substituted pyrazines. For example, phenylpyrazine has been prepared by catalytic hydrogenolysis of the 2-chloro-3-phenyl compound in the presence of triethylamine. This product is also obtained by decarboxylation of... 

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