Overcoming the internal alkyne problem in [2+2+2] cycloadditions John M. Halford-McGuff, David B. Cordes, Alexandra M. Z. Slawin and Allan J. B. Watson University of St Andrews, UK Since their discovery in 1948, [2+2+2] cycloadditions have been widely employed. 1,2 The modularity of the reaction allows for rapid structural diversity to be rapidly obtained. There are three main types of this reaction, intramolecular, semi-intramolecular and intermolecular.
The semi-intramolecular cycloaddition is restricted typically to terminal alkynes unless they are “electron deficient”. 3 However, with no general set of conditions available for all alkynes, it is difficult to study the mechanistic aspects of this reaction. We disclose a set of conditions that allow for the successful implementation of internal alkynes using a rhodium(I)– BINAP catalyst system which exhibits exemplary functional group tolerance whilst also being robust to the presence of air and water. With these conditions, we were able to study the reaction and made some key discoveries. Firstly, the reaction is not truly preferential towards electronically poor alkynes. This apparent electronic preference is a result of the coordinating nature of many of these alkynes allowing for enhanced binding to the metal catalyst. The root of the internal alkyne problem is poor catalytic turnover when substituents are sterically demanding, with catalytic turnover being inversely proportional to the sum of the steric parameters. This behaviour is very predictive, so much so that the steric bulk of substituents can be calculated from the yield of the reaction. References 1. W. Reppe, O. Schlichting, K. Klager, and T. Toepel, Justus Liebigs Ann. Chem. , 1948, 560 , 1-92. 2. G. Domínguez, and J. Pérez-Castells, Chem. Soc. Rev. , 2011, 40 , 3430-3444. 3. Example references with this claim: K. Tanaka, Y. Sawada, Y. Aida, M. Thammathevo, R. Tanaka, H. Sagae, and Y. Otake, Tetrahedron , 2010, 66 , 1563-1569; E. Lindner, R. M. Jansen, H. A. Mayer, W. Hiller, and R. Fawzi, Organometallics , 1989, 8 , 2355-2360; A. Deiters and J. A. Teske, J. Org. Chem. , 2008, 73 , 342-345.
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