Reaction of an aldehyde, a primary amine, a carboxylic acid and an isonitrile leads to the formation of an oc-acylamino carboxamide 2. The initial step is the formation of a Schiff base as a result of the reaction of the aldehyde with the primary amine. This Schiff base is then attacked by the isonitrile, and acylation leads to intermediate 1. The formation of 2 is driven by the irreversible acylation step leading from 1 to 2. Thus, the Ugi reaction generally results in good yields over a broad range of building blocks and solvents. The preferred solvent is MeOH.
Due to the great variability of the individual building blocks the reaction leads to a great variety of structures and has found widespread application for the preparation of compound libraries for lead identification via general screening approaches.
The aldehyde (1.25 equiv.), the carboxylic acid (1.25 equiv.), and the amine (1.25 equiv.) were dissolved in methanol to an approximate concentration of 1 M in each component. This was kept for 10 min at rt and then added in one portion to a flask containing the iso-cyanide (1.0 equiv.). The resulting solution was stirred at rt for 12 h.The reaction was followed byTLC (1-5 % MeOH in DCM). On completion, the solvent was removed in vacuo, and the residue was purified (if desired) by flash chromatography on silica gel, eluting with a gradient of 0-5 % MeOH in DCM.
A restriction is the limited number of commercially available isonitriles. This problem was solved by the insertion of the universal isonitrile 3 derived from cyclohexene (Scheme 2). After insertion, this leads to the Ugi-product 4 which could be converted into different functionalities , Thus, this approach allows for the synthesis of products which are not directly accessible by the original Ugi reaction.
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