Unraveling innate substrate control in site-selective palladium-catalyzed C-H heterocycle functionalization

Chemical Science
Hwanho ChoiSungwoo Hong

Abstract

Understanding the regioselectivity of C-H activation in the absence of directing groups is an important step towards the design of site-selective C-H functionalizations. The Pd(ii)-catalyzed direct arylation of chromones and enaminones provides an intriguing example where a simple substitution leads to a divergence in substrate-controlled site-selectivity. We describe computational and experimental studies which reveal this results from a switch in mechanism and therefore the selectivity-determining step. We present computational results and experimentally measured kinetic isotope effects and labelling studies consistent with this proposal. The C-H activation of these substrates proceeds via a CMD mechanism, which favors more electron rich positions and therefore displays a pronounced kinetic selectivity for the C3-position. However, C2-selective carbopalladation is also a competitive pathway for chromones so that the overall regiochemical outcome depends on which substrate undergoes activation first. Our studies provide insight into the site-selectivity based on the favorability of two competing CMD and carbopalladation processes of the substrates undergoing coupling. This model can be utilized to predict the regioselectivity ...Continue Reading

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Citations

Sep 15, 2017·Chemical Communications : Chem Comm·Mostafa GolshaniAlireza Ariafard
Aug 24, 2017·Chemistry : a European Journal·Bryony L ElbertDarren J Dixon
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Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Garazi UrgoitiaRaul SanMartin
Dec 29, 2020·The Journal of Organic Chemistry·Savio CardozaVibha Tandon
Dec 27, 2018·The Journal of Organic Chemistry·James Luccarelli, Robert S Paton
Dec 4, 2020·The Journal of Organic Chemistry·Juan TangHua Chen

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