Abstract
Transition metal-catalysed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements ‘C–H activation’ strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop general para-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of the reaction conditions.
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Acknowledgements
We thank the donors of the Herman Frasch Foundation for Chemical Research (701-HF12), the National Science Foundation (NSF, CHE-1455163) and the National Institute of General Medical Sciences (R35 GM124661) for supporting this work. NMR instrumentation was provided by NIH (S10OD016360, S10RR024664 and P20GM103418) and NSF Grants (9977422 and 0320648). P.H.-Y.C. acknowledges financial support from the Bert and Emelyn Christensen Professorship and the Vicki & Patrick F. Stone family. P.H.-Y.C., T.F., M.A.G. and A.C.B. acknowledge the NSF (CHE-1352663) and the computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF, CHE-1102637). T.F. acknowledges the Summer Fellowship Award from the department of Chemistry at Oregon State University.
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F.d.A. and M.-H.Y. contributed equally. R.A.A. and M.-H.Y. created the project. R.A.A., M.-H.Y., F.d.A., M.S. and S.K. designed the experiments. M.-H.Y., M.S. and S.K. optimized the reaction conditions. M.-H.Y., F.d.A., M.S. and S.K. explored the substrate scope. F.d.A. designed and conducted the mechanistic experiments. R.A.A. supervised the synthetic and mechanistic portions of the experimental work. T.F. used density functional theory (DFT) to compute the key transition states and intermediates in the different proposed mechanisms, which ultimately led to pinpointing the operative pathway; A.C.B. performed the initial DFT computations; M.A.G. performed energy refinements at various levels of theory to verify that the DFT results were in line with experimental results. P.H.-Y.C. supervised the computational aspect of the work and also contributed to the DFT energy refinements. All the authors contributed to the writing and editing of the manuscript.
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Supplementary Information
Experimental details for synthetic chemistry, including: general synthetic information and procedures, data for reaction optimization, characterization of substrates and products, data supporting mechanistic investigations. Computational details, including: complete authorship of Gaussian 09 and Gaussian 16, computational procedure, reaction coordinate diagram with higher-in-energy intermediates, exploration of para-selectivity of arylation process, reaction coordinate diagram with dimethyl substrate, coordinates for relevant computed structures. NMR spectra supporting the characterization of substrates and products and mechanistic studies
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de Azambuja, F., Yang, MH., Feoktistova, T. et al. Connecting remote C–H bond functionalization and decarboxylative coupling using simple amines. Nat. Chem. 12, 489–496 (2020). https://doi.org/10.1038/s41557-020-0428-1
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DOI: https://doi.org/10.1038/s41557-020-0428-1
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