Indoles substituted, formation

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]. 

There have been a number of refinements to the procedure, both in the enamine formation and in the reduction. Furthermore, the procedure can be adapted to 2-substituted indoles by introducing an acyl substituent on the enamine intermediate. 

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. 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

Compared to the cyclic ketones, the coupling of aliphatic aldehydes to prepare 3-substituted indoles was less successful, except for phenyl acetaldehyde, which afforded 3-phenyl indole 83 in 76% yield (Scheme 4.22). The lack of imine formation or the instability of the aliphatic aldehyde towards the reaction conditions may be responsible for the inefficiency of these reactions. Therefore, a suitable aldehyde equivalent was considered. With the facile removal of a 2-trialkylsilyl group from an indole, an acyl silane was tested as a means of preparing 3-substituted indoles. Indeed, coupling of acetyl trimethylsilane with the iodoaniline 24 gave a 2 1 mixture of 2-TMS-indole 84 and indole (85) in a combined 64% yield. Evidently, the reaction conditions did lead to some desilylation. Regardless, the silyl group of 84 was quantitatively removed upon treatment with HC1 to afford indole (85). 

Other quinoline A-oxide derivatives have been examined. A 1,3-oxazepine is the major product of irradiation of 2-cyanoquinoline A-oxide whereas lactam formation predominates on irradiation of 4-methylquinoline N-oxide in aqueous ethanol.60 Lactam formation has been shown to be influenced by an external magnetic field and on this basis it has been proposed that the first step in this transformation is the formation of an excited radical-ion pair.61 1,3-Oxazepines undergo further reaction on prolonged irradiation. The synthesis of 4-substituted indoles, for example, has been accomplished in this way by irradiation of 5-substituted quinoline A-oxides.62... 

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

With this tandem hydroformylation/hydrazone formation/Fischer indolization 3-substituted indoles such as valuable intermediates for the synthesis of pharmaceuticals as well as pharmaceuticals can be obtained in a very... 

The formation of 2-(indolin-2-yl)indole dimers from indole-3-acetic acid and its propyl ester in trifluoroacetic acid and phosphoric acid has been studied." The reaction involves electrophilic attack of the protonated species (24) on the free substituted indole to give the trans stereochemistry at the C(2)-C(3) bond. 

A Neber route to substituted indoles 532, complementary to the Fischer indole synthesis, was recently developed (equation 235). Formation of azirine 531 from the oxime was smoothly induced, for example using MsCl/DBU or DIAD/BU3P or PhsP, and the intermediate was isolated. Thermal rearrangement of the azirine (40 to 170 °C, depending on the azirine structure) produced the indoles 532 directly in usually good yields (84-88% from the azirine). 

With an excess of the lithiating agent, 1-benzenesulfonylindoles form dilithiated derivatives, which may be dialkylated or dideuterated (81JHC807). Reaction with carbonyl compounds, however, may result in the formation of the 2-substituted indole with cleavage of the protecting group (Scheme 37), although the reaction with benzoyl chloride yields the sultam (134). 

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