Indole formation synthesis

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]. 

General Procedure for the Hydroformylation/Enamine Formation. Synthesis of Indole Derivatives. A 300 ml autoclave equipped with a magnetic stirrer was charged with the... 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

The total synthesis of (+)-deethylibophyllidine was accomplished by J. Bonjoch and co-workers, who applied a regioselective Fischer indole synthesis as one of the key steps to obtain octahydropyrrolo[3,2-c]carbazoles. The indole formation was followed by a tandem Pummerer rearrangement-thionium ion cyclization to generate the quaternary spiro stereocenter. 

During the total synthesis of (+)-aspidospermidine by J. Aube et al., the final steps involved an efficient Fischer indolization of a complex tricyclic ketone." This ketone was unsymmetrical and the indole formation occurred regioselectively at the most substituted a-carbon in a weakly acidic medium (glacial AcOH). 

The total synthesis of ellipticine by Miller el al. [11] is one of the first syntheses of naturally occurring indole alkaloids using Pd(OAc), via the oxidative cyclization mechanism (Scheme 2). Exposure of 6-anilino-5,8-dimethylisoquinoline (9) to two equivalents of Pd(OAc)j in TFA/AcOH facilitated the oxidative cyclization to the desired ellipticine (10). Recently, the same indole formation strategy that uses the Pd(OAc),-mediated oxidative cyclization has been the cornerstone of several synthetic approaches directed toward ellipticine analogs. For instance, oxidative cyclization of diphenylamine 11 was carried out with Pd(OAc), in acetic acid to provide... 

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 ... 

Transition-metal catalysis on solid supports can also be used for indole formation [43]. A palladium or copper-catalyzed procedure has been described for generation of a small indole library (Scheme 16.21) this is the first example of solid-phase synthesis of 5-arylsulfamoyl substituted indole derivatives. Whereas the best... 

Indoles.—Formation. Intermediates in the Fischer indole synthesis have been detected by N n.m.r. spectroscopy. The formation of the indole (170) from the arylhydrazone (169) indicates preferential migration of the methyl group. ... 

Fukuyama devised a novel tin-mediated indole ring synthesis leading directly to 2-stannylindoles that can capture aryl and alkyl halides in a Pd-catalyzed crosscoupling termination reaction [110-112]. The presumed pathway is illustrated and involves initial tributylstannyl radical addition to the isonitrile 65, cyclization, and final formation of stannylindole 66. 

The mechanistic rationale for the dramatic Lewis acid effect on the course of the Engler indole/benzofuran synthesis involving styrenes is illustrated in Scheme 3. Whereas titanium forms a bidentate complex 11 with the C-1 carbonyl and C-alkoxy oxygens, which leads to the dihydroindole (equation 1), boron trifluoride engages in monodentate complexation 12 with the sulfonyl nitrogen, leading to dihydrobenzofuran formation (equation 2) [3, 4]. Likewise, the reaction between 11 and an enol ether derived from 4-piperidone is depicted in equation 3 [5]. 

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