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Pd-Catalyzed C–N Coupling Reactions Facilitated by Organic Bases: Mechanistic Investigation Leads to Enhanced Reactivity in the Arylation of Weakly Binding Amines

preprint
submitted on 09.01.2019 and posted on 10.01.2019 by Joseph Dennis, Nicholas White, Richard Liu, Stephen L. Buchwald
The ability to use soluble organic amine bases in Pd-catalyzed C–N cross-coupling reactions has provided a long-awaited solution to the many issues associated with employing traditional, heterogeneous reaction conditions. However, little is known about the precise function of these bases in the catalytic cycle and about the effect of variations in base structure on catalyst reactivity. We used 19F NMR to analyze the kinetic behavior of C–N coupling reactions facilitated by different organic bases. In the case of aniline coupling reactions employing DBU, the resting state was a DBU-bound oxidative addition complex, LPd(DBU)(Ar)X, and the reaction was found to be inhibited by base. In general, however, depending on the binding properties of the chosen organic base, increased concentration of the base can have a positive or negative influence on the reaction rate. We propose a model in which the turnover-limiting step of the catalytic cycle depends on the relative nucleophilicity of the base compared to that of the amine. This hypothesis guided the discovery of new reaction conditions for the coupling of weakly binding amines, including secondary aryl amines, which were unreactive nucleophiles in our original protocol.

History

Email Address of Submitting Author

jmdennis@mit.edu

Institution

Massachusetts Institute of Technology

Country

USA

ORCID For Submitting Author

0000-0003-3069-312X

Declaration of Conflict of Interest

None.

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