Titanium(IV) isopropoxide mediated solution phase reductive amination on an automated platform: Application in the generation of urea and amide libraries

Amine libraries and their derivatives are important targets for high throug hput synthesis because of their versatility as medicinal agents and agroche micals. As a part of our efforts towards automated chemical library synthes is, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident library synthesizer of Argonaut Technologies. An array of 24 secondary amines was p repared in high yield and purity from 4 primary amines and 6 carbonyl compo unds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on t he Trident(TM). The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonam ides. A number of polymer-assisted solution phase protocols were employed f or parallel work-up and purification of the products in each step.