Ortho-aminobenzophenone

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

From SAR studies, introduction of an amino group at the ortho position of the B-ring was expected to maintain the quasi cis conformation to obtain more potent anti-tubulin agents and also increase water solubility by potential salt formation. A variety of 2-aminobenzophenone derivatives was then synthesized via Grignard reaction of (3,4,5-trimethoxyphenyl)magnesium bromide with several commercially available or synthesized substituted 2-nitrobenzaldehydes, followed by oxidation of the obtained benzhydrol derivatives with PDC to 2-nitrobenzophenones, which were in turn reduced to the corresponding aminobenzophenones with Fe/AcOH (Scheme 19). 

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