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. 2013 Aug 28;135(34):12877-85.
doi: 10.1021/ja4064469. Epub 2013 Aug 16.

Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles: substrate scope and mechanistic investigation

M Alexander Düfert  1 , Kelvin L Billingsley, Stephen L Buchwald
Affiliations

Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles: substrate scope and mechanistic investigation

M Alexander Düfert et al. J Am Chem Soc. .

Abstract

The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is reported. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole, and azaindole halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and theoretical investigations.

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Conflict of interest statement

Notes

The authors declare the following competing financial interest(s): MIT has patents on the ligands used in this work for which SLB receives royalty payments.

Figures

Figure 1
Figure 1
Bioactive molecules containing free N-H azole moieties.
Figure 2
Figure 2
(a) Relative reactivity of heteroaryl halides in the Suzuki-Miyaura cross coupling and (b) pKa values (in H2O) of the parent compounds and relevant derivatives.
Figure 3
Figure 3
Effect of 1H- and 1-methyl-heterocyclic additives on the yield of the Suzuki coupling between 6-chloroindole and phenylboronic acid.,
Figure 4
Figure 4
Crystal structure of indazole-bridged Pd complex 14.
Figure 5
Figure 5
Effect of heterocyclic additives on the yield of the Suzuki-Miyaura coupling between 6-chloroindole and phenylboronic acid.,
Figure 6
Figure 6
Potential steric interaction in the postulated dimers containing 10d (A), 10c or 13c (B) or 13d (C).
Figure 7
Figure 7
Calculated energies in THF (B3LYP/6-31+G(d,p)) for the oxidative addition, reductive elimination and the equilibrium between 15 and 17. For oxidative addition, anionic aryl halides refer to the corresponding deprotonated azole chlorides.
Scheme 1
Scheme 1
Suzuki-Miyaura cross-coupling of unprotected and Bn-protected 3-chloroindazole (1a,b).
Scheme 2
Scheme 2
Synthesis of JNK3-inhibitor 8.
Scheme 3
Scheme 3
Influence of additives on the Suzuki-Miyaura reaction of 6-chloroindole.
Scheme 4
Scheme 4
Formation of dimer 14 from 15 or 16.
Scheme 5
Scheme 5
Influence of the halide substitution on the conversion of 3- and 4-haloindazoles.
Scheme 6
Scheme 6
Proposed catalytic cycle in the presence of indazole and potential intermediates 20, 21.
Scheme 7
Scheme 7
Comparison of different cross-coupling methods in the presence of unprotected indazole.
See this image and copyright information in PMC

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