Indoles 1-lithio

Indol-2-ylcopper reagents can also be prepared from 2-lithioindoles and they have some potential for the preparation of 2-substituted indoles. 1-Methyl-indol-2-ylcopper can be prepared by reaction of 2-lithio-l-methylindole with CuBr[10]. It reacts with aryl iodides to give 2-aryl-1-methylindoles. Mixed cyanocuprate reagents can be prepared using CuCN[ll], The cyan-ocuprate from 1-methylindole reacts with allyl bromide to give 2-allyl-l-methylindole. 

Similar halogenations have been done on 2-lithio-l-phenylsulfonylindole[2], 2-Lithio-l-phenylsulfonylindole is readily converted to the 2-(trimethylsilyl) derivative[2,3]. 2-Trialkylstannylindoles can also be prepared via 2-lithio-indoles[4,5], 2-Sulfonamido groups can be introduced by reaction of a 2-lithioindole with sulfur dioxide, followed by conversion of the sulfinic acid group to the sulfonyl chloride with A-chlorosuccinimide[6]. 

Direct 3-silylation of A -substituted indoles has been ellected by reaction of the indoles with trimethylsilyl triflate in the presence of triethylamine[12]. The trimethylsilyl group has also been introduced via 3-lithio-l-(phenylsulfonyl)-indole[13]. 

In order to exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, benzenesulfonyl and dimethyl-amino have been used 81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (211) (8UOC3760). 

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

Indole, 3-hydroxymethyl-2-phenyl-stability, 4, 272 Indole, I-hydroxy-2-phenyl-synthesis, 4, 363 Indole, 2-iodo-synthesis, 4, 216 Indole, 3-iodo-reaetions, 4, 307 synthesis, 4, 216 Indole, 2-iodo-l-methyl-reaetions, 4, 307 Indole, 2-lithio-synthesis, 4, 308 Indole, 3-lithio-synthesis, 4, 308 Indole, 2-mereapto-tautomerism, 4, 38, 199 Indole, 3-mercapto-tautomerism, 4, 38, 199 Indole, 3-methoxy-synthesis, 4, 367 Indole, 5-methoxy-oxidation, 4, 248 Indole, 7-methoxy-2,3-dimethyl-aeetylation, 4, 219 benzoylation, 4, 219 Indole, 5-methoxy-l-methyl-reduetion, 4, 256 Indole, 5-methoxy-l-methyl-3-(2-dimethylaminoethyl)-reaetions... 

Tetrahydro-y-carbolines may be prepared by an internal Mannich-type reaction between 2-j8-aminoethyhndoles and formaldehyde. Kebrle et al. prepared 27 by the reaction of 2-lithio-l-methyl-indole with A-benzyl-A-ethylaminoacetone followed by debenzyl-ation treatment of 27 with formaldehyde led to the formation of the tetrahydro-y-carboline 28. Similarly, when the quaternary salts (30) of the Mannich bases (29) are heated at 100°, 1,2,3,4-tetrahydro-y-carbohnium salts (31) are formed. 

A novel approach to 3-substituted indolines and indoles via the anionic cyclization of 2-bromo-lV,lV-diallyanilines has been developed simultaneously by Bailey <96JOC2596> and Liebeskind <96JOC2594>. Thus, treatment of 2-bromo-lV,lV-diallylanilines 78 with 2 equivalents of BuLi at -78 °C leads to the formation of the intermediate 79 which may be trapped with an electrophile to afford 3-substituted indolines 80. Aside from ease of preparation, an additional benefit of the intramolecular carbolithiation of <7-lithio-W,Al-diallyl-anilines is the production of Al-allyl-protected indolines, which are easily deprotected using... 

As illustrated in the conversion of 111 to 112 below, a variety of indoles bearing chirality at C3 was accessed by O Shea and co-workers by means of a (-)-sparteine directed enantioselective carbolithiation of 2-propenyl anilines, followed by electrophilic trapping-cyclization of the lithio intermediates <06JACS10360>. 

Addition of methyllithium to the lactone 1219, followed by reduction with sodium borohydride in refluxing ethanol, afforded, almost quantitatively, ellipticine (228). Reaction of the compound 1219 with the lithio derivative of formaldehyde diethylmercaptal, and reduction with sodium borohydride in refluxing ethanol, led to the mercaptal 1221. Cleavage of the mercaptal 1221 with bis(trifluoroacetoxy) iodobenzene [Phl(OCOCF3)2] in aqueous acetonitrile gave the 11-formyl derivative, which was reduced with sodium cyanoborohydride (NaBHsCN) to 12-hydroxyellipticine (232) (710,711) (Scheme 5.202). The same group also reported the synthesis of further pyiido[4,3-fc]carbazole derivatives by condensation of 2-substituted indoles with 3-acetylpyridine (712). 

Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in s/fM-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the... 

Other l-benzenesulfonyl-2-lithio-3-substituted indoles to have been successfully prepared include the 3-lithioxyalkyl derivatives 23 and 24 (84JOC4518 85JOC5451), with the latter compound undergoing rapid in-... 

Methoxymethyl protection of the indole NH group has also been investigated in conjunction with lithio directing 2-substituents, and compounds successfully lithiated at the 3-position have included the 2-carboxylic acid [89H(29)1661], and the related diethylcarboxamide (Scheme 23) (90PAC2047). 

The stereochemistry of this reaction was also investigated (equation 42). Thus, geometrical isomers of 1-chlorovinyl p-tolyl sulfoxides Z-178 and -178 were synthesized from 4-phenyl-2-butanone and they were treated with t-PrMgCl followed by iV-lithio indole. As shown in equation 42, this reaction gave a mixture of isomers ( -179 and Z-179) in relatively good yields but with low stereoselectivity. 

A solution of 2-lithio-l-(phenylsulfonyl)indole was prepared by adding 1-(phenylsulfonyl)indole (11.7 mmol) dissolved in THF (30 ml) to a solution of LDA prepared from (i-Pr)2NH (1.12 eq) and n-BuLi (1.05 eq) in THF (30 ml) at — 75°C. The solution was stirred at — 70°C for 1 h and then warmed slowly to 5DC over 1 h. The solution was recooled to — 78JC. A solution of acetaldehyde (l.OOg, 22.7 mmol) in THF (5 ml) was added rapidly by syringe. The reaction mixture was then allowed to come slowly to room temperature and poured into 1% HC1 (350 ml). The solution was extracted with CH,C12 (3 x 250 ml) and the combined extract was washed with water (400 ml) and brine (2 x 400 ml) and then dried over K2C03. The solvent was evaporated in vacuo and the residue purified by chromatography to give the product (3.28 g, 93%). 

Solid-state structures of A-lithio- (27) and A-potassio- (28) indole-TMEDA complexes (90OM1485) show they aggregate as dimers. The lithioindole crystallizes as a syn-dimer, while the potassioindole forms the a / -dimer. 

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). 

The reactions of the lithio derivatives of benzo[ >]-fused systems indole, benzo[6]furan and benzo[h]thiophene are similarly diverse. Since indole and benzo[h]thiophene undergo electrophilic substitution mainly in the 3-position, the ready availability of 2-lithio derivatives by deprotonation with n-butyllithium is particularly significant and makes available a wide range of otherwise inaccessible compounds. The ready availability of 3-iodoselenophene and hence of 3-lithioselenophene (73CHE845) provides a convenient route to 3-substituted selenophenes. 2-Lithiotellurophenes are especially important precursors of tellurophene derivatives because of the restricted range of electrophilic substitution reactions which are possible on tellurophenes (77AHC(2l)ll9). 

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