1-Methoxyindole, 2-lithiation

Indirect fluorination has been carried out using metallo-indoles. Hodgson et al used ipso substitution of 2- and 3-(trimethylstannyl)-l-(p-toluenesulfonyl)indoles. Of several fluorinating agents tried, cesium fluorosulfate was the best [43]. 5-Methoxyindoles lithiated in the 4-position were fluorinated by Wfluorobenzene-sulfonimide to prepare 4-fluoro analogs of serotonin and melatonin [44]. 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

Reaction of 3-substituted indoles with halogens can be more complex initial 3-halogenation occurs generating a 3-halo-3//-indole, ° but the actual products obtained then depend upon the reaction conditions, solvent etc. Thus, nucleophiles can add at C-2 in the intermediate 3-halo-3//-indoles when, after loss of hydrogen halide, a 2-substituted indole is obtained as final product, for example in aqueous solvents, water addition produces oxindoles (20.13.1) comparable methanol addition gives 2-methoxyindoles. 2-Bromination of 3-substituted indoles can be carried ont nsing A -bromosuccinimide in the absence of radical initiators. 2-Bromo- and 2-iodo-indoles can be prepared very efficiently via a-lithiation (20.5.1). 2-Halo-indoles are also available from the reaction of oxindoles with phosphoryl halides. Some 2,3-diiodo-indoles can be obtained by iodination of the indol-2-ylcarboxyfic acid. ... 

Lithiation of 1-methoxyindole takes place at C-2 and thus substituents can be introduced. Various nucleophilic substitutions, with departure of the 1-substituent can take place. One of the reactions below shows the introduction of a hydroxyl group onto the indole 5-position by aqueous acid treatment of a... 

One of the most effective A-substituents for C-2 lithiation of indoles and pyrroles is the t-butylcarbamoyl group, the lithiated derivatives of which react with a wide range of electrophiles such as trimethylsilyl chloride, A,7V-dimethylbenzamide, and carbon dioxide, to give the substituted products in 45-95% yield <9isi079>. Removal of the Af-group can be effected by treatment with lithium hydroxide in methanolic THF (Scheme 39). 1-Methoxyindole also can be lithiated selectively at C-2 and converted to substituted products hydrogenolysis removes the methoxy group <91H(32)22i>. Even 7V-phenylpyrrole can be selectively monolithiated at the pyrrole C-2 position. 

A new route to 2-substituted indoles derived from 1-methoxyindole was recently described. Dimethyl sulfate proved to be the reagent of choice for the methylation of the unstable 1-hydroxyindole to give 1 -methoxyindole in 51 % yield (eq 10). The resulting methoxyindole undergoes 0-lithiation at the 2-posilion using n-Butyllithium, and can be trapped with appropriate electrophiles. It should be noted that methylation of 1-hydroxyindole using lodomethane afforded only very low yields of the desired methoxyindole. 

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