Hydroxyindoles ketones

Reactions of quinones with enamino ketones have not been reported, but ethyl (S-anilinocrotonate (94), an enamino ester, has been shown to condense (71) with p-benzoquinone to give l-phenyl-2-methyl-3-carbethoxy-5-hydroxyindole (95). 

In acidic or slightly basic aqueous media, Ai-hydroxyindoles can be prepared after electrolysis of a-(o-nitrophenyl) ketones vide supra Scheme 9) [13], at a working potential corresponding to the first cathodic wave. In an acidic medium, indoles are directly obtained at a working potential corresponding to the second cathodic wave. 

The hydroxyiamino group will react with an adjacent side chain carbonyl function. Thus, 2-nitrobenzyl ketones 17 are reduced to the N-hydroxyindole [92]. Side... 

The chlorosulfonium compounds can also be used for the synthesis of oxindoles, the stable tautomeric form of 2-hydroxyindoles. The a -methylthio ketone is replaced by ethyl methylthioacetate and the products of the Sommelet-Hauser rearrangement are cyclized to 3-methylthiooxindoles. The methylthiooxindoles are reductively desulfurized with Raney nickel (equation 102) (74JA5508). 

Since both 2-nitrophenyl ketones and 2-substituted-l-hydroxyindoles are far more stable than the corresponding aldehydes and 2-H indoles, respectively, reduction of these ketones to the 1-hydroxyindoles is relatively easy. 

The polarographic reduction of a number of 2-nitrobenzyl ketones is stated (73BSF3040) to give quantitative yields of 1-hydroxyindoles, but it proved difficult to isolate the products over reduction gave indoles. 

The development of a new synthesis of 1-hydroxyindoles 131, via a lead-promoted intramolecular reductive cyclization of the o-nitrobenzyl ketones (or aldehydes) 132 in the presence of tetraethylammonium formate (TEAF), offers a new useful route to this interesting class of compounds <03JOC9865>. 

Mild hydrogenation of a nitro-ketone followed by heating the resulting cyclized solid in toluene gives a l-hydroxyindole. 

In the Nenitzescu synthesis of 5-hydroxyindoles, an A-aryl substituted amino-propenoic ester may be used, albeit with a low yield of product [2343]. Better yields may be obtained by reacting the quinone at ambient temperature with an enaminonitrile [3246]. The methylthio group may be removed by heating with Raney nickel. Magnesium methyl carbonate is sometimes used to carboxylate a methyl ketone but when it is warmed with the methyl ketone (35.3), it causes cyclization of the keto side-chain [2747]. A dioxopyrimidine aldehyde (35.4) is cyclized in moderate yield by heating with carbonate in DMF [2668]. 

An early report of annulation of an iminophosphorane (formed in situ) to a malonylidene function describes the synthesis of a thienopyrrole in high yield [3084a]. A different procedure gives the isomeric [3,4-c] product [3492a]. A styryl phenyl ketone is converted into a 1-hydroxyindole by warming with potassium cyanide [2163] the chemistry of 1-hydroxyindoles has been reviewed [3906]. 

When the Fischer synthesis is applied to an unsymmetrical ketone, either one of two isomers or a mixture of them may be produced. (+)-3-MethylcycIopen-tanone gives a mixture of I- and 2-methylcyclopent[0]indoles, and the relative amounts of these formed under various conditions are analysed [3222]. Further work has recently been published on the Fischer indolization of -methoxy-phenyl- -phenylhydrazones of an unsymmetrical ketone (ethyl pyruvate). Cyclization in acid occurs mostly on to the more electron-rich benzene ring whereas under nonacidic (for example, thermal) conditions there is less regio-selectivity [3539]. 2-Methoxyphenylhydrazine sometimes behaves anomalously and does not yield the expected 7-methoxyindole, but when o-4-toluenesuIphonyl-or o-4-trifluoromethylsulphonyI-phenylhydrazine is used to prepare the hydra-zone, the main product is the 7-sulphonyloxyindole which may be hydrolysed to the 7-hydroxyindole with alkali [3629]. 

Indoles and Carbazoles. - Formation. 2-Arylindoles (132) are formed by intramolecular Wittig reaction of the phosphonium salts (131). The hydroxamic acids PhN(OH)COCH2COR (R = alkyl or aryl) cyclize in boiling toluene to mixtures of indoles (133) and 3-isoxazolones (134). Irradiation of a solution of o-iodoaniline and the potassium enolate of acetone affords 2-methylindole. The enamino-ketone (135) cyclizes photochemically to 1,2-dimethylindole (136) with elimination of acetaldehyde/ The styrene derivative (137), obtained by the action of Meerwein s acetal, Me2NCH(OMe)2, on o-nitrotoluene, yields 1-hydroxyindole on treatment with zinc/ Azidobenzocyclobutanes (138 R = Me, Ph, or CH2Ph) are converted into indoles (133) by the action of concentrated sulphuric acid/ ... 

Ch. 8 Hydroxyindoles, Indole Alcohols, and Indolethiols Ch. 9 Indole Aldehydes and Ketones... 

As alluded to earlier, the reductive cyclization of nitro ketones often leads to A-hydroxyindoles when the intermediate reduction prodnct, a hydroxylamine, undergoes cyclization. This path can be made dominant if desired. Thus, as shown in Scheme 12, several researchers have developed such a methodology. Acheson may have been the first chemist to achieve this reaction. A two-phase zinc reduction of o-nitrophenylacetaldehyde yields the unstable N-hydroxyindole, which was trapped as the more stable (distillable) A-acetoxyindole (equation 1) [85]. Wong and colleagues use a lead-promoted reductive cyclization approach to Al-hydroxyindoles in excellent yields (equation 2 and 34-37) [86]. Wojciechowski s team employed a VNS synthesis of the A-hydroxyindole precursors (equation 3) [87]. 

The process has been extended to carboxylic acids, anhydrides, and acid chlorides by using an inert solvent such as sulfolane. 4-Oxo-4,5,6,7-tetrahydroindoles are selectively a-chlorinated, allowing facile transformation to 4-hydroxyindoles (eq S). The ability of the reaction to form a-chloro ketones selectively has been further improved by the use of trimethylsilyl enol ethers as substrates. Recently, phase-transfer conditions have been employed in a particularly difficult synthesis of RCH(Cl)C(0)Me selectively from the parent ketones (eq 4). ... 

---