3-Substituted indoles, alkylation

Lithio-indoles are equally useful again, the position of attack depends on both solvent and the nature of the electrophile. It is important to note that when an iV-metallated 3-substituted indole alkylates at carbon, necessarily a 3,3-disubstituted-3//-indole is formed, which cannot re-aromatise to form an indole (see 20.1.1.6 for rearrangements of 3,3-disubstituted indolenines). 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

The Bartoli process has been employed effectively in the synthesis of 7-substituted indoles including 7-alkoxy (15), 7-alkyl (18) , and 7-formal indoles (21). Although the yields are only moderate, this process does provide a simple entry into indoles which were heretofore difficult to obtain. 

Coe et al. reported an efficient modification for the preparation of /-substituted indole analogs for biology screening in good yield. The intermediate P-nitrostyrene 44, prepared from the condensation of 43 with DMFDMA, underwent methanolysis and reduction to provide the aniline acetal intermediate 45. Alkylation of amine 45 was carried out employing standard conditions of reductive alkylation to provide A-alkyl analogs represented by 46. The indole 47 was generated by formation of the oxonium ion (from 46) under acidic conditions, followed by cyclization, accompanied by loss of methanol. 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

Taber and Tian have employed the Neber protocol to prepare a-aryl azirines that underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-... 

Pyrroles and indoles are alkylated by electrophilic alkenes in reactions catalyzed by acidic clays, which are often more effective than Lewis acids (88TL2577). Indoles are alkylated as usual at C-3, and the alkylation of 3-substituted indoles has also been shown to take place at C-3 with subsequent migration occurring to C-2. 

As indicated in Scheme 27, indoles may be alkylated by their acid-catalyzed reaction with alcohols. Similarly, r-butylation of pyrroles has been effected by the acid-catalyzed reaction with t- butyl acetate (B-77MI30502), and the diarylmethylation of 1-methylpyrrole from the acid-catalyzed reaction with the chromium trichloride complex of the diarylcarbinol has been described (78JA4124). The alkylation of indoles by alcohols in the presence of the aluminum alkoxide and Raney nickel appears to be efficient for the synthesis of 3-substituted indoles, but is less successful in the alkylation of 2-methylindole (79JHC501). The corresponding isopropylation of pyrrole produces 2,5-diisopropylpyrrole and 1-isopropylpyrrolidine, as the major products (79JHC501). 

Direct alkylation of indoles under neutral conditions has been observed for especially reactive alkyl halides. 3-Methylbutenyl bromide gives the 3-substituted indole in acetic acid-sodium acetate at room temperature (equation 170) (69TL2485). At higher temperature in acidic solution, 1,2-dimethylindole undergoes bisallylation (equation 171) (67CJC2628). a-Halo ketones including bromoacetone, 3-bromo-2-butanone and 2-chlorocyclohexanone can alkylate 2-substituted indoles in aqueous acetic acid, but the acidic conditions used in these reactions would probably be destructive of indole itself (72JOC2010). 

The dilithium derivatives of 2-alkyl-N-trimethylsilylanilines condense with esters to give C2-substituted indoles in generally satisfactory yield.1... 

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