O

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.

Procedure [3]

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 [3], Thus, this approach allows for the synthesis of products which are not directly accessible by the original Ugi reaction.

Was this article helpful?

0 0

Post a comment