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, 132 (41), 14676-81

Regioselective Oxidative Arylation of Indoles Bearing N-alkyl Protecting Groups: Dual C-H Functionalization via a Concerted Metalation-Deprotonation Mechanism

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Regioselective Oxidative Arylation of Indoles Bearing N-alkyl Protecting Groups: Dual C-H Functionalization via a Concerted Metalation-Deprotonation Mechanism

Shathaverdhan Potavathri et al. J Am Chem Soc.

Abstract

The most direct method for synthesizing 2-arylindoles is oxidative coupling of an arene with an indole. We have shown that both the activity and regioselectivity of this cross-coupling reaction are correlated with the acidity of the medium. This insight has been applied to predict the best conditions for the oxidative cross-coupling of N-alkylindoles, an important class of substrates that has heretofore been incompatible with the harsh conditions required for oxidative cross-coupling. Both experimental and computational data indicate that the mechanism for C-H palladation of both the indoles and simple arenes is best described as concerted metalation-deprotonation, regardless of the substitution on the arene.

Figures

Figure 1
Figure 1
Limits of current oxidative coupling technology (SEM = 2-(Trimethylsilyl)ethoxymethyl, MOM = methoxymethyl, Bn = benzyl)
Figure 2
Figure 2
Oxidative coupling of benzofuran (1) and benzene as a function of acid concentration
Figure 3
Figure 3
Probing the mechanism of indole palladation
Figure 4
Figure 4
Potential mechanisms for palladating indole
Figure 5
Figure 5
The occupied frontier orbitals for the indoles that contribute to the interaction with the Pd(II) catalyst in the CMD transition state. The C-2 atomic contribution (%) and the energy (eV) for each orbital are shown
Figure 6
Figure 6
Probing the mechanism of palladation of the simple arene substrate

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