Issue 6, 2016

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

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 of coumarins which are proficient substrates for carbopalladation. Furthermore, our model is able to account for the opposite selectivities observed for enaminone and chromone, and explains how a less reactive coupling partner leads to a switch in selectivity.

Graphical abstract: Unraveling innate substrate control in site-selective palladium-catalyzed C–H heterocycle functionalization

Supplementary files

Article information

Article type
Edge Article
Submitted
28 Nov 2015
Accepted
02 Mar 2016
First published
08 Mar 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2016,7, 3900-3909

Author version available

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

H. Choi, M. Min, Q. Peng, D. Kang, R. S. Paton and S. Hong, Chem. Sci., 2016, 7, 3900 DOI: 10.1039/C5SC04590H

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements