Solid-phase Synthesis of 7-Aryl-benzo[b][1,4]oxazin-3(4H)-one Derivatives on a BOMBA Resin Utilizing the Smiles Rearrangement

A general method has been developed for the solid phase synthesis of drug-like 7-aryl-benzo[b][1,4]oxazin-3(4H)-one derivatives 6. The method relies on a novel, microwave irradiation promoted cyclization reaction of the BOMBA resin bound, N-substituted-α-(2-chloro-4-bromophenoxy)acetamide 3 that takes place via a Smiles rearrangement. The 7-bromobenzo[ 1,4]oxazine 4, produced in this process is converted to 7-aryloxazin analogs 5 by utilizing Suzuki coupling with various substituted arylboronic acids. Finally, the target 7-aryl-benzo[b][1,4]oxazin-3(4H)-ones 6 are liberated from the resin by treatment with 5% TFA. The progress of the reactions involved in this preparative route can be monitored by using ATR-FTIR spectroscopy on a single bead. The target compounds, obtained by using this five-step sequence, are produced in high yields and purities.