Preparation of 2-Aminopyridoimidazoles and 2-Aminobenzimidazoles via Phosphorus Oxychloride-Mediated Cyclization of Aminoureas

Abstract

The novel preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via the cyclization of (2-aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in the presence of phosphorus oxychloride is described. This methodology is demonstrated for a range of urea substrates with aminoimidazole products obtained in good yields and with excellent levels of purity.

Leveraging an Industrial–Academic Partnership To Optimize Small Molecule Process Development within the Pharmaceutical Industry

“…Preparation of 2-Aminopyridoimidazoles and 2-Aminobenzimidazoles via Phosphorus Oxychloride-Mediated Cyclization of Aminoureas. 4 As part of Lilly's studies towards the treatment of human malignancies, they wished to access the 2-aminoimidazole 2. A novel preparation of this desired intermediate 2 via the cyclization of (2-aminopyridin-3-yl)urea in the presence of phosphorus oxychloride was developed by Lilly (Scheme 2).…”

Copper-Catalyzed Domino Three-Component Approach for the Assembly of 2-Aminated Benzimidazoles and Quinazolines

“…6 Alternatively, condensations of 1,2-disubstituted aromatic units such as 1,2-diaminated arenes or ortho-carbonylated anilines, with carbodiimides, thioisocyanates, or amino-ureas followed by dehydrative cyclization, have also been reported (Scheme 1b). 7 While valuable, these methods suffer from the poor availability of the precursors. Limitations have been reduced through the development of strategies relying on metal-catalyzed C−N bond-forming reactions, 8 allowing more accessible orthofunctionalized aryl halides (Scheme 1c) to be used.…”

“…Performing a nucleophilic aromatic substitution (S N Ar) between 2-halogenated azoles and amines constitute one approach to build 2-aminated targets (Scheme a) . Alternatively, condensations of 1,2-disubstituted aromatic units such as 1,2-diaminated arenes or ortho-carbonylated anilines, with carbodiimides, thioisocyanates, or amino-ureas followed by dehydrative cyclization, have also been reported (Scheme b) . While valuable, these methods suffer from the poor availability of the precursors.…”