Indoles, 1-substituted, lithiation

Organometallic intermediates continue to be important in the synthetic methodology for substitution of pyrroles and indoles. Numerous lithiation techniques have been reported and provide a range of useful reaction conditions. The pyrrolyl dimer (120) (really a dimeric equivalent of pyrrole-2-carbaldehyde) can be lithiated at the 5- and 5 -positions. Electrophilic substitution then yields 5-substituted pyrrole-2-carbaldehydes (121) (Scheme 34) <88TL777>. The related monomeric ald-iminium salts (122) yield similar products after anion formation, bromination, lithiation, and electrophilic attack (Scheme 35) <88HCA2053>. In a similar process, the dimer (120) can be brominated at C-4 and converted into 4-substituted pyrrole-2-carbaldehydes <88TL3215>. 

Among the less conventional substrates for lithiation are the y -chroniium complexes of indole. Lithiation occurs preferentially at C2 but can be directed to the carbocyclic ring if the 2-position is blocked. The complex of l-(methoxymethyl)indole is lithiated at position 7, if the 2-position is blocked by a TMS group. 7-Substituted indoles can be obtained in 70-95% yield <89T5955>. The chromium can be removed photochemically (Scheme 120). 

Sestelo and Sarandeses generated tris(indol-2-yl)indium 49 for use in palladium-catalyzed cross-coupling reactions (Scheme 9) [227]. Lithiation of 4 with n-butyllithium followed by treatment with indium trichloride gave 49 which was used directly in palladium-catalyzed cross-coupling reactions leading to 2-arylin-doles 50. These same authors exploited this chemistry to prepare indole-substituted maleimides [228]. 

The recent use of M-indole-substituted gulonic amides by Quirion and coworkers demonstrates diastereoselective lithiation and alkylation of 86 to afford a... 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Widdowson expanded his hexacarbonylchromium chemistry to the synthesis and lithiation of Cr(CO)3-Af-TIPS indole (29), leading to 4-iodoindole 30 after oxidative decomplexation [37]. Stannylation at C-4 could also be achieved using this method (62% yield), and comparable chemistry with 3-methoxymethylindole leading to C-4 substitution was described. 

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. 

As with pyrrole, the a-lithiation of N-substituted indoles occurs readily [790R1 84MI2], and reaction can also be performed in the presence of a number of reactive functional groups at C-3. Thus the 3-carboxylic acid, 3-diethylamide, and 3-aldehyde derivatives of N-methylindole (9,10, and 11) have all been a-lithiated (87JOC104 91M17), the latter via its a-(N-methylpiperazino) alkoxide 12. 

Since normal electrophilic addition to indoles occurs at the 3-position, the lithiation of compounds containing removable N-substituents has received a lot of attention over the years, because of its importance as a route to 2-substituted indoles. As a result, a variety of different protection systems are now available as shown in Table II. 

Synthesis of 2-Substituted Indoles via a-LiTHiATioN of N-Protected Derivatives... 

Directed -lithiation of N-substituted indoles at the 3-position has been achieved with some 2-substituted indoles. Thus for example, N-t-Bu-1-methylindole-2-carboxamide can be lithiated at C-3 with 5-BuLi and TMEDA, but when a similar reaction was attempted with the 1-ben-zenesulfonyl analog, cleavage to an acetylene occurred readily, even at -78°C (Scheme 20)(86H2127). 

Lithiation can be diverted away from C-2 of indole by the use of a bulky N-substituent. Although 1-methylgramine is cleanly lithiated at C-2, l-(triisopropylsilyl)gramine is lithiated selectively at C-4 and can lead to useful 4-substituted indoles electrophiles include 1,2-dibromoethane, DMF, and diphenyl sulfide (Scheme 60) (93H(36)29). 

Lithiation can also be induced in the conventional way from halo compounds, for example, the sodium salt of 5-bromoindole can be converted to the 5-lithio derivative by treatment with t-butyllithium, and in turn leads to various 5-substituted indoles (92H(34)1169). 

With an excess of the lithiating agent, 1-benzenesulfonylindoles form dilithiated derivatives, which may be dialkylated or dideuterated (81JHC807). Reaction with carbonyl compounds, however, may result in the formation of the 2-substituted indole with cleavage of the protecting group (Scheme 37), although the reaction with benzoyl chloride yields the sultam (134). 

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