One‐Pot Access towards 4,5‐Disubstituted 2‐Amino‐1H‐imidazoles Starting from Mannich Substrates and their Transformation Utilities

• Published in: European journal of organic chemistry Vol. 2020; no. 46; pp. 7184 - 7196
• Main Authors: Makra, Zsófia, Bényei, Attila, Puskás, László G., Kanizsai, Iván
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 13.12.2020; Wiley Subscription Services, Inc
• Subjects: Chemical reactions; Chemistry; Chemistry, Organic; Groebke–Blackburn–Bienaymé reaction; Imidazole; Multicomponent reactions; Nitrogen heterocycles; One‐pot reactions; Physical Sciences; Ring cleavage; Science & Technology; Substrates; Utilities; reaction; VINYL AZIDES; ANALOGS; pot reactions; CLATHRODIN; Groebke– EFFICIENT SYNTHESIS; IDENTIFICATION; Blackburn– MARINE ALKALOIDS; Ring cleavage; One‐ Multicomponent reactions; 2-AMINOIMIDAZOLES; Nitrogen heterocycles; SAXITOXIN; Bienaymé GUANIDINE; CHEMISTRY
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202001253

An efficient protocol for the preparation of 4,5‐functionalised 2‐amino‐1H‐imidazoles as fragment‐like structures was developed in isolated yields up to 95 %. The demonstrated one‐pot manner includes an intramolecular oxidative annulation and ring cleavage sequence starting from Mannich precursors. The suggested one‐pot sequential synthetic methodology is easy to apply in automatic and robotic chemistry laboratories for which a rapidly increasing demand is foreseen because of the ongoing revolution in the field of continuous manufacturing of pharmaceutical drug substances and products. Further transformation utilities such as Groebke–Blackburn–Bienaymé 3CR and the formation of marine alkaloid analogs were also represented. We disclose an efficient one‐pot process towards C4/C5‐functionalized 2‐amino‐1H‐imidazole structures starting from the corresponding Mannich‐type substrates. The IBX/IPT‐mediated intramolecular oxidative annulation and hydroxylamine‐induced ring cleavage sequence were carried out under mild conditions affording the desired heterocycles in up to 95 % yield. Further modifications were also executed including GBB‐3CR and preparation of structurally modified marine alkaloid analogs.