Rearrangements substitution

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. 

The method begins with collecting all available information on substances xi, X2,..., xi,... that are similar to the substance in question x°. These should be the substances that have the same basic structure as x°, but with some small structure differences, such as the number of repeated units, substitution of atoms by other atoms or small groups, rearrangement of the positions of substitution, rearrangement of the skeleton of the molecule, etcetera. The next move would be to subdivide the set S into structure-based subsets Sa, Sb,. .. and to observe the differences among their structures and their property values. One then proposes empirical structure-property relations for instance the members of family Sa tend to have higher values of y than members of family Sb, and within a family S, the property y may be positively... 

Construction of the closely related NSAID bromefenac (46-8) depends on the Gassman indolone synthesis [46] for incorporation of the acetic acid chain. That reaction involves an anion-initiated electrocyclic rearrangement related conceptually to the little-known Hauser ortho substitution rearrangement. The simplest example of the latter depends on the formation of a carbanion by abstraction of one of the acidic protons from a benzyltrimethyl quaternary salt to give I (the... 

Keywords 17a-hydroxy-20-ketosteroid, acyloin rearrangement, substitutive rearrangement, stereoselective, gas-solid reaction... 

Direct evidence for the prototropic route in a substituted crotonic acid was obtained from reactions of j8,j8-dimethylacrylic acid (258) (Owen and Sultanbawa, 1949a). With alkoxides, both unsaturated alkoxy acids (259) and (260) were isolated, and differentiation between the substitution-rearrangement route (258) —(259) - (260) and the rearrangement -> substitution -> rearrangement route (258) (261) - ... 

In this mode, an umpolung of reactivity for the nucleophile occurs, leading to many useful transformations. More complex pathways are not unusual these include addition to multiple bonds, vinylic and acetylenic substitution, rearrangements - some involving ring-expansion or ring-contraction - generation of reactive intermediates, etc. Solvent effects, especially solvent participation, may add new dimensions to reactivity. 

It is clear that during nucleophilic reactions of allylic halides carrying one EWG various other reaction pathways can occur in addition to MIRC reactions, e.g. addition, substitution, rearrangement and eliminationFor example, reaction of ethyl 4-bromocrotonate (273) with sodium ethoxide in ethanol only affords minor amounts of the 2-ethoxycyclopropane carboxylate (274) in addition to the substitution (276) and the addition-substitution (275) product (equation 83). Nevertheless, a cyclopropane... 

In most cases, treatment of allylic halides containing one ASG with a nucleophile does not result in formation of electrophilic cyclopropanes (MIRC product) instead, other reaction pathways are followed, e.g. addition, substitution, rearrangement and elimination reactions.However, with certain alkenes or nucleophiles or under the appropriate conditions a conjugate addition-nucleophilic substitution pathway is favored, resulting in cyclopropanes substituted with one ASG. Representative examples are compiled in Tables 20 and 21 where organometallic compounds or active methylene compounds are used as the nucleophilic species in combination with allyl bromides containing an ester or a sulfone as ASG. 

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