A new methodology for the synthesis of 3-amino-1H-indole-2-carboxylates |
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Authors: | Jitendra R. Harjani Andrew X. TangRaymond S. Norton Jonathan B. Baell |
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Affiliation: | Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia |
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Abstract: | A new methodology has been developed for the synthesis of 3-amino-1H-indole-2-carboxylates. 2-Aminobenzonitriles were protected as benzyl (2-cyanophenyl)carbamates and converted into corresponding glycinate esters using sodium hydride and bromoacetate esters. Sodium hydride efficiently promotes the addition of the glycinate α-carbon to the cyano group at low temperatures, resulting in the formation of the desired indole core with 3-amino and 2-carboxylate groups. This new methodology uses Pd–C mediated hydrogenolysis with molecular hydrogen, providing neutral conditions for removal of the N-carbamate protecting group. This methodology demonstrates good functional group tolerance towards a variety of substituents in the aromatic ring and ester groups. The overall yield of 3-amino-1H-indole-2-carboxylates obtained by this four-step methodology is at least 30% or higher with yields as high as 50% realised for three of the indoles investigated in this study. |
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