Catalyst‐Controlled Chemoselective Arylation of 2‐Aminobenzimidazoles

Abstract

The chemoselective and complementary Pd-and Cu-catalyzed N-arylation of 2-aminobenzimidazoles is described. Selective N-arylation of the amino-group was achieved with a Pd-catalyzed method, while selective N-arylation of azole nitrogen was achieved with a Cucatalyzed procedure. The utility of these complementary sets of conditions is demonstrated in several two-step, selective syntheses of di-arylated aminoazoles. Keywordspalladium; copper; C-N coupling; aminoazole; N-arylation Transition-metal catalyzed heteroatom-arylation reactions are emerging as valuable tools in organic synthesis, fuelled by the identification of more efficient catalyst systems with increased substrate scopes. [1] The synthetic utility of these transformations is increased if catalysts are both highly reactive and selective. This is particularly important for substrates with multiple heteroatom sites capable of undergoing reaction. Furthermore, the development of complementary sets of catalysts or conditions for the selective arylation of substrates possessing multiple nucleophilic sites enables the rapid, protecting group-free generation of molecular complexity with minimal synthetic manipulations. In this context, we have developed sets of procedures for the Pd-and Cu-catalyzed chemoselective arylation of aminobenzamides, [2a] 5-aminoindole, [2a] 4-(2-aminoethyl)aniline, [2a] amino alcohols, [2b] oxindoles [2c] and aminophenols. [2d] During our work on the N-arylation of nitrogen-containing heterocycles, [3] we became interested in the use of 2-aminobenzimidazoles as potential substrates for chemoselective Narylation reactions. Both N 1 -aryl-2-aminobenzimidazoles and 2-arylaminobenzimidazoles are found in a variety of medicinally important compounds including integrin α 4 β 1 antagonists, [4] mTOR inhibitors, [5] aurora kinase inhibitors, [6] Tie-2 kinase inhibitors, [7] Ca channel blockers, [8] and CXCR2 antagonists. [9 Thus, the selective syntheses of both of these isomers from a common core structure represent attractive alternatives to other previouslyemployed routes [10][11] and could provide rapid access to a diverse array of potentially bioactive 2-aminobenzimidazole derivatives (Scheme 1).While the efficient Cu- [12] and Pd-catalyzed [13] N 1 -arylations of some benzimidazole derivatives with aryl halides have been described, the chemoselective N-arylation of unprotected 2-aminobenzimidazoles with aryl halides has received little attention. [14][15][16] Potential challenges of such an approach include the formation of regioisomers and/or polyarylated products due to the presence of three adjacent nucleophilic nitrogens (N 1 , N 3 and C 2 -amino group), as well as the tautomeric nature of 2-aminobenzimidazoles. Herein, we report the successful development of an orthogonal set of Pd-and Cu-catalyzed chemoselective conditions for the N-arylation of unprotected 2-aminobenzimidazoles and related aminoazoles.We initiated our investigation by examining the Pd-catalyzed coupling of 2-aminobenzimidazole and bromobenze...

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…260 Similarly, Ueda and Buchwald reported the catalyst-controlled chemoselective arylation of 2-aminobenzimidazoles shown in Scheme 76b. 261 The Pd-catalyzed arylation of 2-amino-1H-benzimidazoles (346) led to the formation of the N2-arylation product (347). However, when the coupling was performed using Cu-catalyzed conditions, selective N1coupling was observed to obtain compound 348.…”

Room Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design

“…Accordingly, Ullman-type couplings have been reexamined as viable methods to form structurally diverse C-N bonds due to the diminished cost and immunotoxicity of Cu, 8,[25][26] as well as the orthogonal reactivity to Pd. [27][28] Since the initial report of Cu-catalyzed C-N coupling by Ullmann, [29][30] the development of several ligand scaffolds has enabled these aminations to proceed under increasingly milder conditions with broader reaction scopes. 8,25,31 Early variations involved the use of neutral ligands, such as trans-N,N′-dimethylaminocyclohexane-1,2-diamine, to facilitate amidation [32][33][34][35][36][37][38] or N-heterocycle arylation (Figure 1A).…”

Copper‐Catalyzed CNH2 Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

“…In 2012 Buchwald et al. developed elegant Pd‐catalyzed conditions for the chemoselective C‐2 NH 2 arylation of 2‐aminobenzimidazoles for the first time 10. Copper‐catalyzed arylboronic acid‐promoted N/O‐arylation, now referred as Chan–Lam‐type coupling, has emerged as a powerful synthetic tool 11.…”