3-Substituted indoles, alkylation forms

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). 

A detailed study of the enantioselective gold-catalysed allylic alkylation of substituted indoles (1) forming tertrahydrocarbazoles has been investigated both experimentally and theoretically at the B3LYP/LDBS level of theory. The results indicate that the reaction 0 occurs by an intramolecular 5n2 attack by C(2) of the indole ring on the double bond... 

Methyl trifluoropyruvate alkylates a series of substituted indoles catalysed by the chiral non-racemic 2,2/-bipyridylcopper(II) triflate complex (32) to form methyl 3,3,3- trifluoro-2-hydroxy-2-indole-3-yl propanoates [e.g. (33)] in high enantiomeric excess and good yield.37... 

The Friedel-Crafts alkylation of the parent pyrrole and of substituted indoles with a,P-unsaturated acyl phospho-nates 468 <2003JA10780> and 2-acyl iV-methylimidazoles 469 catalyzed by the chiral bis(oxazolinyl)pyridine (pybox)/scandium(lIl) triflate complex 467 exhibits good enantioselectivities over a broad range of substrates (Scheme 97, Equation 113) <2005JA8942>. The desired alkylation products 470-472 were formed in good yields and enantioselectivities. 

The phenylhydrazone of ethyl pyruvate on heating with sulfuric acid in acetic acid forms indole-2-carboxyIic acid (58%). When the phenylhydrazone has nuclear substituents like alkyl, halo, or nitro groups, the corresponding 4-, 5-, 6-, or 7-substituted indoles are obtained. When pbenylhydrazine is added to a boiling mixture of cyclohexanone and... 

Finally, in this category there must be included cyclisations of the benzylic anions derived from ortho-isocyano-toluenes the scheme shows this route in its simplest form. However, the synthesis is very flexible, for example the initial benzylic anion can be alkylated with halides or epoxides before the ring closure, thus providing 3-substituted indoles and, additionally, the final A -hthioindole can be A -alkylated by adding a suitable electrophile before work-up. ... 

The saltlike alkali metal compounds of indole react with electrophiles such as haloalkanes, acyl halides, sulfonyl halides and trimethylchlorosilane to form the corresponding 1-substituted indoles. 1-Benzylindole isomerizes to 2-benzylindole when heated in polyphosphoric acid [47]. 1-Phenyl-sulfonylindole is lithiated in the 2-position by n-butyllithium. Subsequent alkylation with haloalkanes and cleavage of the phenylsulfonyl residue with sodium hydroxide yields 2-alkylindole. 

The indole formation from o-tolylisocyanide 23, which is brought about by metallation with lithium dialkylamides, is related to the Madelung synthesis. The lithium compound 24 can undergo cyclization to form indole (via iV-lithioindole) or, after alkylation and renewed metallation, to produce 2-substituted indoles ... 

Light-induced electron transfer from an indole to an alkyl, vinyl, or aryl halide would be expected to yield a radical anion which can ionize by loss of halide ion. This would give a radical that can attack an indole and so lead to products of substitution. Examples of this reaction for all three categories of halide have been observed. Photolysis of an aqueous methanol solution of indole with methyl chloroacetate gives a mixture of all the possible isomers of methyl indolylacetate in low yield. The 4-substituted isomer is formed in greatest amount (6.2%) and the yields of the six other isomers vary from 0.24 to 2.55% [62]. Photolysis... 

Treatment with a Lewis acid initiates a rearrangement very like those occurring when 3-substituted indoles are attacked by electrophiles (p. 746 of the textbook). The aromatic ring is a better migrating group than the primary alkyl alternative and an indole can finally be formed. 

The Saegusa indole synthesis involves the strong-base promoted cyclization of ort/ o-tolylisocyanides to indoles (Scheme 1) [1-5], Thus the Saegusa indolization resembles the Madelung indole synthesis. The reaction proceeds by a 5-endo-dig cyclization of 2 to form indole (equation 1). The isocyanide anion 2 was alkylated and subsequently cyclized to form 3-substituted indoles (equation 2). The quenching of 2 with epoxides yielded tryptophols (equation 3 and 4 and 5). Reaction of the ultimately formed N-lithioindole with electrophiles gave Af-substituted indoles (equation 4). 

Davies et al. disclosed a one-pot indole synthesis from cyclohexene 154 and tosylazide (155).The reaction proceeds via a click reaction to form the triazole, followed by Rh-based decomposition, pyrrole formation, and oxidation to indole 156. The indoles (and azaindoles) are formed in very good yield and may be substituted with alkyl-, aryl-, or silyl-proteaed alcohols (13JA11712). 

You et al. reported the iridium-catalyzed enantioselective functionalization of indoles and pyrroles. In the event, indole 181 is transformed, via an intramolecular allylic alkylation, into a spirocyclic intermediate at C3, which then undergoes selective methylene migration to form 182 with no loss of enantiopurity (up to 99% ee is obtained).The indole ring can tolerate substitution with various halogens or methoxy groups, while pyrroles can be substituted with alkyl or aryl groups (13JA8169). 

Enantioselective Friedel-Crafts alkylation reactions were performed between substituted indoles and methyl trifluoropyruvate, using a chiral nonracemic C2-symmetric 2,2 -bipyridyl copper triflate complex as catalyst. The active copper(II) catalyst was generated in situ. The corresponding 3,3,3-trifluoro-2-hydroxy-2-indolyl-propionic acid methyl esters were formed in good yield (up to 79%), and in up to 90% enantiomeric excess (eq 18). 

Addition to Enones. Vinylboronic acids 11 can be added in a 1,4-fashion to indole-enones 10 in the presence of 15 mol% Ugand, 10 mol% Mg(OtBu)2, 4A molecular sieves, and 1,2-dichloroethane as the solvent at 70 °C (eq 4). Both 2- or 3-substituted indoles are tolerated, as well as aryl- or alkyl-substituted boronic acids or esters. Under these mild conditions, protection of the indole NH is not necessary, although Boc or Me groups do not affect either the yields or enantioselectivities. Boronic acid 11 reacts with the BINOL ligand to form a reactive boronic ester, which is believed to form an ate complex with the carbonyl group of the electrophile. The exact role of Mg(OtBu)2 is not known, but a likely possibility is deprotonation of the BINOL ligand. 

Subsequently, the chiral phosphoric acid catalyzed Friedel-Crafts alkylation attracted much attention and became the subject of comprehensive investigations. In particular, the reaction with indole was investigated extensively because it provided pharmacologically important 3-substituted indole derivatives in enantio-merically enriched forms. The groups of You [35], Terada [36], and AntUla [37] almost simultaneously developed a highly enantioselective Friedel-Crafts reaction of indoles 75 with aromatic imines 74 (Scheme 11.20). Interestingly, their reactions... 

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