Unexpected Behavior of 5-Phenoxypyrazole Derivatives

Abstract

The pyrazole ring is a prominent structural motif found in numerous pharmaceutically active compounds. Due to the easy preparation and rich biological activity, pyrazole framework plays an essential role in biologically active compounds and therefore represents an interesting template for combinatorial as well as medicinal chemistry. 1 Indeed, pyrazole-based derivatives have shown several biological activities as seen in COX-2, 2 p38 MAP kinase, 3 and CDK2/ Cyclin A inhibitors. 4 Many of them are currently being tested and/or clinically evaluated for new drug discovery. Previously, we studied the facile introduction of nucleophiles into 5-chloropyrazole, activated by the ortho-formyl group, by the nucleophilic aromatic substitution. 5 As part of a program, we were interested in 5-phenoxypyrazole derivatives, which produce drug-like structures that are constrained to a limited number of conformations by heterocyclic cores and hindered rotation by substituents. Thus, many pyrazole oxime ethers 6 were prepared by the Williamson synthesis of 5-phenoxypyrazole oximes and alkyl halides, as shown in eq. (1). However, 5-(4-chlorophenoxy)pyrazole derivatives mainly yielded p-chlorophenyl ethers derived from alkyl halides in this Williamson synthesis. Here, we would like to report unusual behavior of 5-phenoxypyrazole derivatives, etherification of alkyl halide by aid of 5-(4-chlorophenoxy)pyrazole oxime and nucleophilic displacement of 5-(4-nitrophenoxy)pyrazole.