A transition metal-catalyzed [2+2+2] cycloaddition between ,-diynes and 3,4-pyridynes has been realized for the first time, producing isoquinolines in good yields by using a nickel(0) catalyst.
10A transition metal-catalyzed [2+2+2] cycloaddition of alkynes is a useful and highly atom-economic way to construct various aromatic rings. Initially, a [2+2+2] cycloaddition of diyne 1a with the precursor 2a was investigated using a palladium catalyst according to the optimized conditions of the above-mentioned arynes.5 However, the desired product 3a was not obtained, and 1a was recovered in 95% yield. After various attempts to 35 find a good catalyst for this reaction, it was found that nickel is suitable as a catalyst in the [2+2+2] cycloaddition of 3,4-pyridynes. That is, to a mixture of Ni(cod) 2 (10 mol%), PPh 3 (40 mol%), and CsF (3 equivalents to 2a) in CH 3 CN was added a solution of diyne 1a (2 equivalents to 2a) and 3,4-40 pyridyne precursor 2a in CH 3 CN via a canula at room temperature, and the mixture was stirred for 3 hours. After the usual work-up, the isoquinoline derivative 3aa was obtained in 43% yield along with dimer 4a in 28% yield (Table 1, run 1). Increasing both the ratio of 2a to 1a and the 45 amount of the catalyst loading from 10% to 20% slightly improved the yield of 3aa to 50% (run 2). To suppress the formation of the dimer 4a, we investigated the protocol for addition of substrates. When a solution of diyne 1a was added to a mixture of the precursor 2a, nickel catalyst, and 50 CsF using a syringe pump over a period of 3 hours, the yield of 3aa was improved to 58% and the formation of the dimer 4a was also reduced (run 3). Furthermore, when 4 equivalents of 2a with respect to 1a were used, the yield of the product reached 62% (run 4). According to this optimal protocol, the 55 loading of the catalyst could be reduced to 10 mol%, giving 3aa in 63% yield (run 5).