5-(hydroxymethyl)oxazoles: Versatile scaffolds for combinatorial solid-phase synthesis of 5-substituted oxazoles

A scheme combining the preparation of building blocks in solution followed by solid-phase combinatorial chemistry has been developed to side-chain div ersify 5-(hydroxymethyl)oxazole scaffold (1) into ail ethers, thioethers, s ulfones, sulfonamides, and carboxamides. Protected heterocyclic scaffolds 2 were linked to the solid phase and N-terminal derivatized using active est er chemistry, providing chemset 4(1-4,1-4). The free side-chain hydroxyl of 4 was smoothly converted to aryl ethers 6 under Mitsunobu conditions, with a broad range of substituted phenols. Alternatively, quantitative conversi on of hydroxyl to bromide followed by displacement with alkyl and aryl thio ls gave thioethers 8, Thioethers were optionally oxidized to sulfones 9. Br omide displacement by azide, followed by reduction to amine and acylation w ith a range of carboxylic acids and sulfonyl chlorides gave carboxamides 11 and sulfonamides 13, respectively. Crude purity at typically >90% was obse rved for each of the five modifications detailed. A series of 20 compounds, exemplifying each modification, was reprepared, purified, and fully charac terized.