Transition-metal-catalyzed pyridine synthesis

Cycloaddition catalyzed by transition metal complexes. Advances in Synthesis Catalysis, 348, 2307-2327 (b) Varela, J.A. and Saa, C. (2008) Recent advances in the synthesis of pyridines by transition-metal-catalyzed [2 + 2 + 2] cycloaddition. Synthesis, 2571-2578. 

Starting from optically active nitriles, Botteghi and co-workers [32] have applied the cobalt-catalyzed reaction for the prepartion of optically active 2-substituted pyridines (eq. (8)). The chiral center is maintained during the alkyne-nitrile co-cyclization reaction. This reaction has recently been extended to the synthesis of bipyridyl compounds having optically active substituents [33] and provides an access to chiral ligands of potential interest in transition metal-catalyzed asymmetric synthesis. 

This behaviour correponds to the observation that other unsaturated hydrocarbons, e.g. alkynes, allenes or 1,3-butadienes, which readily undergo transition metal catalyzed cyclooligomerizations, do also incorporate CX multiple bonds in such cycloadditions only with difficulty in most cases 207 208). Besides the well known cobalt-catalyzed pyridin synthesis from alkynes and nitriles98 cocyclooligomerizations have been achieved with alkynes on one side and isocyanates 209), carbodiimides210) and carbondioxide 211) on the other side as well as with 1,3-butadienes and aldehydes 212), carbondioxide213 and 2-aza- or 2,3-diaza- 1,3-butadiene214. ... 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

Recent advances on the synthesis of piperidines through ruthenium-catalyzed ring-closing metathesis reactions 12H(84)75. Rhodium-catalyzed [2+2+2] cycloaddition for the synthesis of substituted pyridines, pyridones, and thiopyranimines 12H(85)1017. Synthesis of 2,2 -bipyridines by transition metal-catalyzed alkyne/nitrile [2+2+2] cycloaddition reactions 12H(85)1579. 

In 2012, Maes and co-workers reported a new transition-metal-catalyzed methodology for the direct C2-H functionalization of piperidines [67], via pyridine-directed Ru-catalyzed C(sp )-H alkylation with alkenes [68]. Based on previous work [69-73], they discovered that a combination of a bulky alcohol (2,4-dimethyl-3-pentanol) and a catalytic amount of a carboxylic acid [74] is necessary to avoid side reactions such as isomerization and/or reduction of the alkene reactant (Scheme 11). They successfully applied this method to the total synthesis of ( )-... 

Pyridine is an important class of nitrogen-containing heterocycles found in various natural products, pharmaceuticals, and materials (Scheme 1.1). Based on its importance, numerous synthetic procedures have been developed for their preparation [1]. In this book volume, the main achievements on transition metal-catalyzed p5Tidines synthesis are discussed. Based on the reaction types, the whole volume is catalogued by intramolecular cyclization and intermolecular cyclization reactions. 

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