Rh-Catalyzed Intermolecular Syn-Carboamination of Alkenes via a Transient Directing Group

Alkenes are the most ubiquitous pro-chiral functional groups accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes are particularly important, as they can be used to access highly complex molecular architectures.1,2 Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation reactions,3,4,5,6 are well-established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbonand nitrogen-based functionalities stereoselectively across an alkene has not been reported. In this manuscript, we describe the Rh(III)-catalyzed syn carboamination of alkenes initiated by a C–H activation event that uses enoxyphthalimides as the source of the carbon and the nitrogen functionalities. The reaction methodology allows for the stereospecific formation of one C–C and one C–N bond across an alkene in a fully intermolecular sense, which is unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a novel cyclopentadienyl ligand to control the reactivity of Rh(III). The results provide a new route to functionalized alkenes and are expected to lead to the more convergent and stereoselective assembly of amine-containing acyclic molecules. The prominence and importance of nitrogen functionality in biologically relevant molecules is undeniable,7 and stereoselective methods for introducing nitrogen atoms into organic molecules remain a subject of intense interest. Alkene hydroamination is an emerging technology for the introduction of nitrogen functionality (Fig. 1a).8,9,10 On the other hand, incorporation of carbon-based coupling partners is more limited, in spite of the crucial role of C-C bond forming reactions in synthesis. Among these, Heck-type approaches are noteworthy for their ability to introduce a carbon fragment in a stereoselective manner under typically mild conditions.11,12 Both the hydroamination and Heck-type reactions have the same strategic drawback: only one end of the alkene is functionalized. Simultaneous Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence and requests for materials should be addressed to T.R. ([email protected]). Supplementary Information is available in the online version of the paper. Author Contributions T. P. and T. R. conceived this concept and prepared the manuscript. T. R. directed the investigations. T. P. developed and studied the reaction. Author Information The authors declare no competing financial interests. HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2016 May 05. Published in final edited form as: Nature. 2015 November 5; 527(7576): 86–90. doi:10.1038/nature15691. A uhor M anscript