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. 2008 Oct 8;130(40):13285-93.
doi: 10.1021/ja8045519. Epub 2008 Sep 10.

Insights into directing group ability in palladium-catalyzed C-H bond functionalization

Lopa V Desai  1 , Kara J Stowers, Melanie S Sanford
Affiliations

Insights into directing group ability in palladium-catalyzed C-H bond functionalization

Lopa V Desai et al. J Am Chem Soc. .

Abstract

This paper describes a detailed investigation of factors controlling the dominance of a directing group in Pd-catalyzed ligand-directed arene acetoxylation. Mechanistic studies, involving reaction kinetics, Hammett analysis, kinetic isotope effect experiments, and the kinetic order in oxidant, have been conducted for a series of different substrates. Initial rates studies of substrates bearing different directing groups showed that these transformations are accelerated by the use of electron-withdrawing directing groups. However, in contrast, under conditions where two directing groups are in competition with one another in the same reaction flask, substrates with electron-donating directing groups react preferentially. These results are discussed in the context of the proposed mechanism for Pd-catalyzed arene acetoxylation.

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Figures

Figure 1
Figure 1
Examples of Biologically Active Molecules Containing Multiple Potential Directing Groups
Figure 2
Figure 2
Hammett Plot for Competition Experiments in AcOH/Ac2O
Figure 3
Figure 3
Hammett Plot for Competition Experiments in AcOH/Ac2O Corrected for Concentration of Unprotonated Benzylpyridine
Figure 4
Figure 4
Hammett Plot for Competition Experiments in Benzene
Figure 5
Figure 5
Hammett Plot for Individual Kinetics in AcOH/Ac2O
Figure 6
Figure 6
Hammett Plot for Individual Kinetics in AcOH/Ac2O Corrected for Concentration of Protonated Benzylpyridine
Figure 7
Figure 7
Hammett Plot for Individual Kinetics in Benzene
Figure 8
Figure 8
Relative Reactivity of Directing Groups from Competition Studies in AcOH/Ac2O and C6H6
Figure 9
Figure 9
Proposed Catalytic Cycle for Pd-Catalyzed C–H Bond Acetoxylation
Figure 10
Figure 10
Kinetic Isotope Effect Experiment
Figure 11
Figure 11
Hammett Plot for Stoichiometric Cyclopalladation of Benzylpyridines 1a–7a
Scheme 1
Scheme 1
Palladium-Catalyzed Chelate-Directed C–H Bond Functionalization
Scheme 2
Scheme 2
Competition Studies Between Two Different Directing Groups (L and L’)
Scheme 3
Scheme 3
Competition Between Benzylpyridines 2a and 6a
Scheme 4
Scheme 4
Individual Kinetic Studies
Scheme 5
Scheme 5
Competition Between Benzylpyridine 6a and Benzylpyrazole 10a
Scheme 6
Scheme 6
Highly Selective Oxime Ether-Directed C–H Acetoxylation of Substrate 15a
Scheme 7
Scheme 7
Amide Directed C–H Functionalization of Product 15b
Scheme 8
Scheme 8
Equilibrium for Substrate Binding Under Competition Conditions
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