Indoles, 2-methyl-, chlorination

Most of the substitution reactions of di-, tetra, and hexa-hydro-carbolines and of their oxo derivatives are similar to those of the parent indole or indolenine derivatives. Nitration and bromination of harma-line (l-methyl-3,4-dihydro-j8-carbolme) are referred to in Section IV, A, 1. Sulfonation and azO COupling ° proceed as expected for indole derivatives. The preparation of chlorinated and iodinated derivatives of 6-nitroharmaline has been reported,but their structures have not been established. 

As with the pyrroles, N-chloroamides have been widely employed in indole chlorination [66JOC2627 80H( 14)867 81JOC2054]. Chloroindolen-ines may be isolated under controlled conditions [80H( 14)867 81JOC2054], 2-Phenyl-, l-methyl-2-phenyl-and 3-methyl-2-phenyl-indoles were converted by 1-chloroisatin (NCI) into the 3-chloro derivatives... 

The incorporation of an indole ring system often leads to an improvement in the light fastness. A suitable example is Cl Acid Blue 123 (6.177), which is derived from 4,4 -dichlorobenzophenone. Condensation with l-methyl-2-phenylindole in the presence of phosphorus oxychloride produces the triarylmethane ring system. Replacement of the chlorine atoms with p-phenetidine, followed by sulphonation, gives the dye. 

Indole-2-carboxylic acid, 3-methyl-ethyl ester chlorination, 4, 215 Indolecarboxylic acids decarboxylation, 4, 286 esterification, 4, 287 Indole-2-carboxylic acids esters... 

When ( )-A-formyl-4-fluorotryptophan methyl ester is irradiated in methanol, replacement of fluorine by methoxy takes place387. Because of the strength of the C—F bond, homolysis cannot occur under photolytic conditions. Heterolysis, however, may occur in a polar medium and the aryl cation is probably stabilized by resonance involving the lone electron pair on the indole nitrogen atom. The chlorine atom in the diuretic furosemide is... 

As initially reported by Greci and coworkers83 and later by Greci, Eberson and coworkers84, l-methyl-2-phenylindole (22) treated with A-chlorobenzotriazole (BT-CI, 23) is monochlorinated to 24 and also yields dimeric structures, some of which themselves are chlorinated and dichlorinated (equation 56). Product 27 was mentioned only in the more recent paper. The mechanism in equation 57 was suggested in the initial paper. The formation of products 25-28 was ascribed to the interaction between various substituted indole-radical cations and adventitious water in the medium. The later study confirmed that the substituted indole-radical cation 22a is an intermediate and that the formation of... 

The same condensation-cyclization sequence with 4-methoxy-phenylhydrazine (292), however, proceeded in only 17% yield (113), so an alternative synthesis was devised for the important 8-oxygenated derivatives, such as 293 and 294, which employed a more conventional Fischer indole reaction (Scheme 47) (113). In the event, condensation of keto ketal 295 with hydrazine 280 gave hydrazone 296. Cyclization in hot diphenyl ether gave ketone 297, which, upon dehydrogenation, protection of the phenol as the benzoate, and chlorination gave 298. Deprotection and/or methylation afforded the target chloro-y-carbolines (299-301). 

To avoid the expense of keto ketal 295, Bisagni et al. (116) devised an alternative synthesis that began with 4-methoxycyclohexanone 302 (Scheme 48). The usual Fisher indolization, dehydrogenation, and chlorination gave methoxy derivative 303. A sequence of demethylation and/or methylation provided the target 8-methoxy- and 8-hydroxy-y-carbolines, which were transformed into the amine derivatives (e.g., 304, 305). By the same route (Scheme 48), Bisagni and team (116) converted hydrazine 306 to the 4-demethyl-y-carbolines (307-310). 

Indok synthesis. Gassman and van Bergen have used a modification of the above-mentioned procedure for synthesis of 2-substituted indoles from anilines. The aniline IS treated as above with a chlorinating reagent at — 65° and then an equivalent of methyl-thio-2-propanone at the same temperature. An equivalent of a base (usually triethyl-amine) is added. Workup affords the indole derivative (2) in 60-70% yield. The thio-methyl group is removed with Raney nickel (>70% yield). The keto sulfide can be varied thus nse of methyl phenacyl sulfide [CH3SCH2C(=0)C5H5]4 in the synthesis leads to 2-phenylindoles. 

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