1- indole 2-lithiation

Chloroperoxidase catalysis by, 58, 302 in chlorination of pyrazoles, 57, 337 Chlorophyll, thioaldehyde synthetic intermediate to, 55, 3 Chlorosulfonyl isocyanate, reaction with 2-arylhydrazono-3-oxobutanoate, 59, 148 Chromatography, of [l,2,4]triazolo[l,5-a]-pyrimidines, 57, 106 Chrom-3-enes, see 2//-l-Benzopyrans Chromium tricarbonyl complexes of 3,5-diphenyl-l-(alkyl- or oxido-)-thiabenzenes, 59, 206, 227 indoles, lithiation of, 56, 181, 184 of pyridine, 58, 160 pyridines, lithiation of, 56, 230, 239 of 2f/-thiopyrans, 59, 227 Chromones, see l-Benzopyran-4-ones Cinnamonitrile, a-cyano-, condensations with thio-, seleno-amides, 59, 184, 186 Cinnoline, nitration, MO calculation, 59, 302... 

Benzo[fe]thiophenes, benzo[fc]furans and A -blocked indoles lithiate on the heterocyclic ring, a to the heteroatom. Lithiation at the other hetero-ring position can be achieved via halogen exchange, but low temperatures must be maintained to prevent equilibration to the more stable 2-lithiated heterocycle. 

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). 

In a related procedure A -melhyl-o-loluidine can be A-lithiated, carboxylated and C-lithiated by sequential addition of n-butyllithium, CO2, and n-butyl-lithium[5]. The resulting dilithiated intermediate reacts with esters to give 1.2-disubstituted indoles. 

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

Synthetic procedures involving other types of intermediates can be based on 2-lithiation. An indirect 2-alkylation can be carried out via indol-2-ylborates which can be prepared by addition of 2-lithioindoles to trialkylboranes. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Lithiation and Subsequent Transformations. Lithiation is the most geneial means of intioducing a 2-substituent on the indole hng. Three intermediates have been used most frequendy in this context. These ate 1-phenylsulfonylindole (19), l-/-butoxycarbonylindole (20), and hthium indole-l-carboxylate (21). 

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). 

Jap-KIingermarm reactions, 4, 301 oxidation, 4, 299 reactions, 4, 299 synthesis, 4, 362 tautomerism, 4, 38, 200 Indole, 5-amino-synthesis, 4, 341 Indole, C-amino-oxidation, 4, 299 tautomerism, 4, 298 Indole, 3-(2-aminobutyl)-as antidepressant, 4, 371 Indole, (2-aminoethyl)-synthesis, 4, 278 Indole, 3-(2-aminoethyl)-synthesis, 4, 337 Indole, aminomethyl-reactions, 4, 71 Indole, 4-aminomethyl-synthesis, 4, 150 Indole, (aminovinyl)-synthesis, 4, 286 Indole, 1-aroyl-oxidation, 4, 57 oxidative dimerization catalysis by Pd(II) salts, 4, 252 Indole, 1-aroyloxy-rearrangement, 4, 244 Indole, 2-aryl-nitration, 4, 211 nitrosation, 4, 210 synthesis, 4, 324 Indole, 3-(arylazo)-rearrangement, 4, 301 Indole, 3-(arylthio)-synthesis, 4, 368 Indole, 3-azophenyl-nitration, 4, 49 Indole, 1-benzenesulfonyl-by lithiation, 4, 238 Indole, 1-benzoyl photosensitized reactions with methyl acrylate, 4, 268 Indole, 3-benzoyl-l,2-dimethyl-reactions... 

An indole protected by a Mannich reaction with formaldehyde and dimethyl-amine is stable to lithiation. The protective group is removed with NaBH4 (EtOH, THE, reflux). The related piperidine analogue has been used similarly for the protection of a triazole. ... 

Introduction of an iodine to C-2 of indole can be accomplished using lithium derivatives. Since direct iodination tends to give mixtures it is essential to activate the 2-position at the expense of the inherently more reactive 3-position. This has been done by lithiating 1-f-butoxycarbonylin-doles (25) and then converting them into iodo derivatives before deprotection (85JHC505) (Scheme 19). Alternatively carbon dioxide can be used... 

Indolylborates 142 (Z = Me, Boc, OMe), available via regioselective C-2 lithiation of indoles 141, are capable of undergoing palladium-catalyzed carbonylative cross-coupling... 

Several methods for synthesizing IV-protected (usually with electron-withdrawing groups) 2-and 3-haloindoles have been developed and the resulting haloindoles are much less prone to decomposition than the unsubstituted compounds. Bromination of A/-(phenylsulfonyl)indole (3), which is readily available via lithiation [9, 10] or phase-transfer chemistry [11, 12], affords 3-bromo-l-(phenylsulfonyl)indole (4) in nearly quantitative yield [12],... 

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. 

In continuation of his extraordinarily versatile and efficient directed-metalation technology, Snieckus employed indole 87 to selectively lithiate C-4 and to effect a Negishi coupling with 3-bromopyridine to give 88 in 90% yield [110]. In contrast, a Suzuki protocol gave 88 in only 19% yield (with loss of the TBS group). 

Palmisano and Santagostino first reported Stille reactions of indole-ring stannylindoles with their detailed studies of 1V-SEM stannane 159 [170], Thus 159, which is readily prepared by C-2 lithiation of A-SEM indole and quenching with Bu3SnCl (88%), couples under optimized Pd(0)-catalyzed conditions to give an array of cross-coupled products 160. Some other examples and... 

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