Indolone formation

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. 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

Under analogous conditions, the 3-cyanomethylene-2-indolones 213 react with barbituric acid and its derivatives 191 with the formation of spiro-annulated pyranopyrimidines 223 (88JIC202, 90H(31)31)... 

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... 

The formation of indolones is reported to occur under a variety of conditions. In many cases the indolones themselves are not stable under the reaction conditions, particularly those involving nucleophiles or... 

An intriguing showcase for polycyclizations based upon hetero-domino reactions is outlined in Scheme 30, where the catalyst 89 gives rise to the formation of a mixture of indolone skeletons 92-94 with a preference for the generation of tetracycle 94 as a result of an intramolecular allylic substitution-Heck sequence. 

Murphy and co-workers introduced the use of a water-soluble phosphine oxide to synthesise indolones in excellent yields in water by a radical reaction array (aryl radical formation, HAT, cyclisation and rearomatisation) mediated by the reagent diethylphosphine oxide (DEPO).15 The reaction also features yet... 

The indole 46 was obtained by reaction of 1 with aminoacetaldehyde in the presence of p-toluene sulfonic acid to give the enamine intermediate 45, which subsequently cyclized with hydrochloric acid. An increase in acid concentration led to the formation of dimers, while less concentrated acid gave no products (33IJCS663) (Scheme 7). The condensation of 1 with 2-azido-l,l-diethoxyethane followed by cycliza-tion gave indolone 46 (06TL2151) (Scheme 7). 

An electrophilic annelation reaction was the key step in a synthesis of azepino[3,4-i> indole-1,5-dione 179 <04EJ04606>. Intramolecular cyclization reactions of oxazolone-substituted indoles led to the formation of either p-carbolines or cyclopenta[I>]indolones depending on the reaction conditions <04EJO1286>. 

The reaction of N-protected 3-formyl and 3-acetylindole with ra-chloroperoxybenzoic acid has been investigated. 1-Benzenesulfonyl-3-formyl and 1-acetyl-3-formyl indoles gave modest yields of 3-indolones via hydrolysis of unstable formate esters. Some of the corresponding 2-hydroxyindol-3-ones were also formed. The 3-acetoxy derivative of 1-benzenesulfonylindole is more stable and was isolated in 80% yield from the oxidation of 3-acetyl-l-benzenesulfonylindole. <94S411>... 

B.R. Dinesh, A.R. Baba, K.U. Sankar, D.C. Gowda, Synthesis of indolones and quinolones by reductive cyclisation of o-nitroaryl adds using zinc dust and ammonium formate, J. Chem. Res. 5 (2008) 287-288. 

The indolin-3-one 115 is conveniently prepared by FVP of the benzi-soxazole 113 at 700 °C (Scheme 24). Electrocyclic formation of the nitrene 114, which then inserts intramolecularly into CH, is the most likely mechanism (2015UP3). There has been considerable progress in generating heterocycle-fiised analogs of such indolones, so-called heteroindoxyls. 

Aniline derivatives have been used to synthesize the indoline system. A large variety of indoline alkaloid substructures are available in a very efficient way. Enamine derivatives such as 39 bearing electron withdrawing substituents on the olefinic double bond were transformed in high yields (Scheme 7). Two syn/anti isomers 41 and 42 were isolated. The isomeric ratio of the final products was influenced by a photostationary equilibrium between the substrates 39 and 40. The reaction was applied to the synthesis of a variety of derivatives of the alkaloid aspidospermidine." In this context, the cyclization products 43 were transformed into the polycyclic indole derivatives 44,45, and 46. Polycyclic indolone compounds 48 have been successfully produced by cyclization of enaminone derivatives 47 carrying a quinoline substituentIn these cases and contrary to the examples 41,42, and 43, the products 48 resulted from an oxidation of the cyclization product (also compare the formation of 30 in Scheme 5). 

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