Final Report Summary - RCYCSS (Rhodium-catalysed ynamide carbometallation for stereoselective synthesis) This project was originally aimed at the development of a recently discovered reaction that enables the controlled synthesis of highly substituted enamides (enamides are increasingly important chemical building blocks for organic synthesis) from the rhodium-catalysed carbometallation of ynamides. This reaction proceeds under mild conditions and employs a commercially available rhodium complex as a precatalyst along with organozinc compounds as organometallic reagents. A reasonably wide range of enamides can be accessed using this chemistry, and preliminary investigations suggest that these new compounds display useful reactivities in a variety of reactions. This initial work was published in J. Am. Chem. Soc. 2009, 131, 3802 and J. Org. Chem. 2009, 74, 7849. However, much more work was required to fully develop the scope of both the enamide synthesis itself, and of the synthetic applications of the enamide products. At the start of the project, the Fellow focused upon further development of the rhodium-catalysed ynamide carbometallation by attempting to incorporate the basic process into a sequenced reaction, whereby the intermediate alkenylorganometallic species would be trapped with a nitroalkene. Unfortunately, initial efforts were unsuccessful, and no reaction with the nitroalkene was observed. However, when the organometallic reagent employed was sodium tetraphenylborate, we observed a totally unexpected reaction involving a (2+2) cycloaddition of the ynamide with the nitroalkene to form a cyclobutenamide. This mechanistically intriguing reaction was studied further, and after some further investigations we managed to find effective reaction conditions to promote the (2+2) cycloaddition of a range of ynamides with nitroalkenes to form a variety of cyclobutenamides. This work was published in Org. Lett. 2012, 14, 4934. In the next phase of the project, the Fellow targeted the use of ynamides in attempted rhodium-catalysed oxidative annulations with 2-aryl 1,3-dicarbonyl compounds, involving overall twofold C-H activation. The resulting products would be interesting cyclic building blocks. Although initial experiments involving ynamides were not successful, we found that 2-aryl cyclic 1,3-dicarbonyl compounds underwent oxidative annulation with simple alkynes under both rhodium and ruthenium catalysis, in the presence of stoichiometric copper acetate as an oxidant to provide spiroindene products. Due to ruthenium being much cheaper than rhodium, ruthenium catalysis was selected for an in-depth investigation of the reaction scope. A variety of 2-aryl cyclic 1,3-dicarbonyls (including those based on 1,3-cyclohexanediones, Meldrum's acid, and barbituric acid derivatives) underwent efficient annulation with a range of alkynes to provide various spiroindenes in generally good yields. This work was published recently in Angew. Chem., Int. Ed. 2012, 51, 12115. Finally, the Fellow followed up the use of 2-aryl cyclic 1,3-dicarbonyl compounds in C-H activations by demonstrating their reaction with terminal alkenes in oxidative C-H alkenylations. These reactions were found to be successful using either palladium or ruthenium catalysis, and the initial alkenylation products generally underwent cyclisation to form benzopyrans. This work was published in Org. Lett. 2013, 15, 570. In summary, work by the fellow on this project has led to a number of fundamental discoveries: (a) new (2+2) cycloadditions of ynamides with nitroalkenes to form cyclobutenamides; (b) demonstration of 2-aryl cyclic 1,3-dicarbonyl compounds as effective substrates for directed C-H functionalisation reactions; (c) a new mode of catalytic alkyne oxidative annulation that results in products containing all-carbon quaternary centres. This work has provided new tools for chemists to prepare important chemical building blocks effectively and concisely, which could have positive consequences for fields such as medicinal chemistry, agrochemistry, and materials science.
