Suzuki-Miyaura Cross-Coupling of Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and Mechanistic Investigation

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.

4‐Arylation of N‐Acylamino‐ and Aminopyrazoles by the Suzuki–Miyaura Cross‐Coupling Reaction

“…[21,22] In particular, five-membered nitrogen-rich heterocycles bearing an unprotected amino group were found problematic coupling partners in palladium-catalyzed cross-coupling reactions. [23][24][25][26] However, the development of more robust catalysts has overcome this obstacle, allowing the cross-coupling of the previously challenging substrates.…”

A General Suzuki Cross-Coupling Reaction of Heteroaromatics Catalyzed by Nanopalladium on Amino-Functionalized Siliceous Mesocellular Foam

“…7,35 In the above-mentioned reaction a color change of the palladium from black to transparent was noticed in the end of the reaction indicating that the palladium may have been deactivated by nitrogen coordination. 7 However, by using the corresponding methylated derivative, the N-methyl pyridone, 10, could be prepared but in a disappointingly low yield. In general, 1 mol% catalyst loading was used for all reactions reported herein.…”

Efficient synthesis of 3-aryl-1H-indazol-5-amine by Pd-catalyzed Suzuki–Miyaura cross-coupling reaction under microwave-assisted conditions

“…9 In the same year, Buchwald et al prepared the c-Jun N-terminal kinase 3 inhibitor in two steps through the Suzuki-Miyaura cross-coupling reaction of (NH) free 3-chloro-1H-indazol-6-amine with phenylboronic acid under their second generation precatalyst and a Pd-catalyzed C-N bond-forming reaction on the NH 2 . 10 Herein, we report a simple and an economic synthetic method of 3-aryl-1H-indazol-5-amine through Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of (NH) free 3-bromo-indazol-5-amine with arylboronic acids, aiming at the synthesis of 3-aryl-1H-indazol-5-amine derivatives for library biological active screening in our company's projects. To evaluate the activity of the combination of different catalysts and ligands (Scheme 1), phenylboronic acid 1 and 3-bromo-1H-indazol-5-amine 2 were chosen as a model reaction in dioxane/H 2 O = 10/1 at 130°C in the presence of K 3 PO 4 as the base for 30 min under microwave-assisted conditions ( Table 1).…”