2.3- Disubstituted indoles formation

Nucleophilic attack at a carbon atom, followed by a mesomeric shift to make a nitrogen atom quaternary, has been known for many years. The best example is the formation of 1,3,3-trisubstituted 3 -indole salts by the action of alkyl halides on 1,3-disubstituted indoles. 

Even 2,3-disubstituted indoles can be achieved if internal olefins are used. Regioselective hydroformylation of a styrene-type olefin and subsequent hy-drazone formation and Fischer indolization gives an intermediate indole with a quaternary center in 3-position. The regained aromaticity is the driving force for the rearrangement of one substituent into the 2-position of the indole core (Scheme 39). 

Alkylation of 2,3-disubstituted indoles generally leads to the formation of 2,3,3-trisub-stituted 3H-indoles, but it has been claimed that if the six-membered ring is activated to electrophilic attack, Friedel-Crafts alkylation occurs at the 5- or 6-positions (79MI30500). 

The reactions of 2-hydroxy-2-(3-indolyl)ethanoamides and of ethyl 2-hydroxy-2-(2-pyrrolyl) ethanoates with trialkyl ortho-esters follow similar routes with the initial formation of the enol ethers (295) and (297), followed by an ortho- Claisen rearrangement to give the 2,3-disubstituted indoles (296) and pyrroles (298) (79JOC1885,80TL4335). 

Running the Fisher indole synthesis on an unsymmetrical phenyl hydrazone gives a mixture of 2,3-disubstituted indoles. For example, reaction of the phenyl hydrazone, 34, with acid can give both 35 and 36 (Eqn. 22.26). Soluble acids and Amberlyst-15 give these two products in a 75 25 ratio at 100% conversion. With an H-M catalyst they are formed in a 65 35 ratio but over a dealuminated H-beta zeolite, the selectivity is reversed and 36 is produced in an 82% yield at 100% conversion.62 n was proposed that the preferential formation of 36 over the H-beta catalyst was the result of a restricted transition state selectivity. ... 

The presence of Cu+ markedly enhances the formation of allylated compounds (89, 91) from five-membered heteroaryl borates (88, 90) and allyl bromide, as mentioned above (87JHC377) (Scheme 35). Coupling of 59 with allyl bromide under the action of Cu+ occurs selectively at position -2 of the indole ring to give 93, in marked contrast to the formation of 2,3-disubstituted indole (92) described previously (Section III,B,1) (87JHC377) (Scheme 36). 

Indolenines (3//-indoles) are formed efQciently on Fischer cyclisation of the arylhydrazones of branched ketones note, again, the use of a weaker acid medium to promote formation of the more substituted ene-hydrazine required for indolenine formation. Subjected to higher temperatures of reaction, the arylhydrazones of branched ketones give rise to 2,3-disubstituted indoles, via a 2 3 migration (cf 20.1.1.6) in the first-formed indolenine. ... 

Buchwald and co-workers observed the persistent formation of 2-nitrophenols in an attempted arylation with reactive o-chloronitroarenes. They found an unusual effect of phenolic additives, and developed an annulative proach to highly substituted indoles. The arylation of acetophenone with 3-nitro -chlorobenzoate proceeded smoothly in the presence of 20 mol% 4-methoxyphenol and K3PO4 to give 25, which was methylated without isolation. Reduction of the methylated ketone 26 with TiCls afforded 2,3-disubstituted indole 27 in 61 % overall yield [22]. 

The olefination reaction took place chemoselectively at the amide carbonyl to give corresponding enamides 45. The RCM step was performed using Grubbs second-generation catalyst 3 in toluene either at 80 °C or at reflux. Unfortunately, in this case, formation of 2,3-disubstituted indoles was not observed probably owing to steric effects the results are summarized in Table 3. 

The Fukuyama indole synthesis is a novel tin-mediated chemical transformation of o-isocyanostyrene derivatives 1. Conversion of the a-stannoimidoyl radical 2 results in the formation of 3-substituted indoles 3a or 2,3-disubstituted indoles 3b,c. Alternatively, 2,3-disubstituted indoles were formed from 2-alkenylthioanilides 4 via imidoyl radical species 5 and followed by radical cyclization to form indole 6. 

The in situ formation of stannylindole 7 from a-stannoimidoyl radical 2 can be used imder the Stille conditions to afford a variety of 2,3-disubstituted indoles 8 and was used in the synthesis of indolocarbazoles. 2-Alkenylthioanilides 4a and 4b can be prepared by one of three general methods from quinolines 9 (Method A or B) or 2-iodoaniline 12 (Method C). ... 

Similarly to the synthesis of C3-functionalized benzo[i)]furans (Scheme 9.2), Nakamura employed the Zn/Cu-mediated cydization-substitution strategy for a facile assembly of 2,3-disubstituted indoles 130 (Scheme 9.49) (79,80]. This reaction involves the initial formation of 3-zincindole 128, which undergoes transmetalation with CuCN-LiCl complex to give the corresponding cuprate 129. The latter, upon reaction with a suitable electrophile, furnishes indole 130. 

Scheme 2 Synthesis of 2,3-disubstituted indoles via Pd-catalyzed cascade inteimolecular C-N bond formation and intramolecular Heck reaction...

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

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. 

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