Metal-free cyclotrimerization for the de novo synthesis of pyridines.

The de novo synthesis of pyridines from smaller molecules has attracted a lot of interest since pyridine is one of the most important heterocyclic structural motifs in numerous areas of organic chemistry. Many developed syntheses, such as the Kr hnke or the Hantzsch reaction, rely on condensation reactions of smaller molecules, but a number of synthetic approaches including cycloaddition reactions have also been documented. Over the last few decades the use of transitionmetal-catalyzed transformations of rather simple alkynes and nitriles to generate pyridines has led to the establishment of the [2+2+2] cycloaddition as an efficient tool to even access complex organic frameworks containing pyridine rings. The cross-cyclotrimerization reaction, which leads to pyridines, can be catalyzed by a large range of early to late transition metals; sometimes, however, two metals are needed to complete the cyclization. The formal mechanism of the reaction comprises two consecutive steps for the intraas well as the intermolecular case. In the first step two alkynes or a diyne are oxidatively cyclized to give a metallacyclopentadiene. The second step can be imagined as either an insertion or a [4+2] cycloaddition reaction with a nitrile, after which the formation of the pyridine is complete. While the exclusively intramolecular construction of arenes from tethered triynes or cyanodiynes by transitionmetal catalysis is well known, the uncatalyzed reactions, especially of the latter, have not so far been investigated. The thermal reaction of different triynes at rather high temperatures (up to 200 8C) in a microwave indeed yields the expected tricyclic arenes in up to 87% yield. However, Sakai and Danheiser have now described an interesting version of the uncatalyzed formal [2+2+2] cycloaddition of cyanodiynes that yields functionalized pyridines. The transformation is based on pericyclic cascade reactions and requires thermal energy to proceed successfully, with reaction temperatures higher than 115 8C needed. In a preceding publication, Danheiser and co-workers investigated the formal metal-free, bimolecular [2+2+2] cycloaddition reaction of diynes with electron-deficient alkenes and alkynes (Scheme 1). These investigations led to the proposal that a