Indoles intermolecular approaches

As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,... 

Muthusamy et al. (89) approached the formation of decahydrobenzocarbazoles 191 utilizing an indolic five-membered olefin 190 as the dipolarophile in reaction with a carbonyl yhde derived from 189. This intermolecular approach is strategically similar to an intramolecular approach to aspidosperma alkaloids developed by Padwa (Scheme 4.47). 

A type Ilae reaction has been reported by Willis and co-workers who prepared N-substituted indoles via Pd-catalyzed coupling of 2-(2-haloalkenyl)-aryl halides with a variety of amines <06ASC851>. In an alternative intermolecular approach to ring construction, Tang and Hu have reported a Pd-catalyzed coupling of o-alkynylhalobenzenes with amines to afford 1,2-disubstituted indoles <06ASC846>. 

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cydization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(ll) iodide induced a 6-exo-trig cydization, furnishing a samarium enolate intermediate... 

One of the first examples of radical cydization reactions in the total syntheses of indole alkaloids was Stork s approach towards ( )-gelsemine (55) [58] featuring a mixed acetal 6-exo radical cydization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cydization conditions led to the cii-fiised bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,P-unsaturated ester 119 was secured when the selenide underwent... 

Curran described an efficient, approach to the BCD ring system of the penitrem indole alkaloids that exploits a Sml2-mediated radical-anionic sequence.11 Treatment of iodide 17 with Sml2 and HMPA gave 18, the product of radical cyclisation-intermolecular Barbier addition, in satisfactory yield (Scheme 6.6). 

The above approach of an intermolecular ortho-alkylation followed by an intermolecular Mizoroki-Heck coupling was later extended to heteroaryl iodides by Lautens [48], Using a Pd(OAc)2/triarylphosphine catalyst system, 3-iodothiophene, -benzothiophene, and -indole were transformed to the o/t/zo-alkylation/Mizoroki-Heck coupling products in good to excellent yields (Scheme 17). Unfortunately, 2-iodoheteroaryls were found to be poor substrates for the reaction. 

Within this scheme fall several variants in which the aminochrome precursors 28 are obtained by different approaches. Usually, biomimetic syntheses have been utilized for the rapid preparation of up to hundreds of milligrams of pure indoles but are hardly amenable to substantial scale-up, mainly because of the limited solubility of the substrate, the limited efficiency of the cyclization step and the competition with intermolecular processes becoming predominant at higher concentrations and interfering with the synthesis. 

In an approach to the gastrin receptor antagonist (+)-AG-041, the Iwabuchi group has prepared the nitrogen-substituted spirocycle 153 by means of an oxidative intermolecular aza-spiro-annulation (Scheme 38) [82], Accordingly, indole 151 was treated with dirhodium catalyst 152 in the presence of PHl(OAc)2 and MgO to afford spirocycle 153 in 70% yield and 96% ee. The deuterium labeling was necessary for successful implementation of the spirocyclization. 

Intermolecular carbopalladation of a triple bond as in 457 by an in sitw-formed organopalladium triflate and subsequent intramolecular nucleophibc trapping gives rise to indoles 458 (Scheme 8.86) [600]. The versatihty of this approach derives from the fact that the triflate may be varied in a wide range. 

Indole is one of the most important heterocyclic scaffolds for drug discovery. Approaches for indole synthesis using hydroamination as a key step in their syntheses has been an ongoing area of investigation over the past several years [329, 330]. Early examples focused on one-pot intermolecular hydrohydrazination followed by the Lewis-acid-catalyzed Fischer indole synthesis [331, 332] (Scheme 15.102) or one-pot intermolecular hydroamination followed by cross-coupling to either form a C-N bond (via the Buchwald-Hartwig amination) [333] (Scheme 15.103) or a C-C bond (via a Heck reaction) [334, 335] (Scheme 15.104). Alternatively, o-alkynylanilines can be used directly as substrates for intramolecular hydroamination (Scheme 15.105) [198, 200, 336-340]. These approaches have been thoroughly reviewed [10]. 

Lundurine A could be synthesized from indoloazocine TTT-12 after cycloprop-anation of the indole ring. The intermediate III-12 would be formed by gold(III)-catalyzed cyclization of the alkynylindole ni-13, (See Ref. [118] and [133] in Chap. 1) which arises from III-14 upon conversion of the ester group into a homologated alkyne." Compound III-14 would be assembled from an enantiome-rically pure pyroglutamic ester derivative III-16 and an indole derivative III-15. Two approaches were considered for the cyclopropanation reaction from TTT-12 derivatives (Scheme 4.12) the intermolecular (A) and intramolecular (B). 

In the first part of this chapter, we have optimized the synthetic sequence to obtain alkynylindole III-29 from 2-(l//-indol-3-yl)acetonitrile or methyl 2-(l//-indol-3-yl)acetate in 7 steps (Scheme 4.77). Furthermore, the azocino indole skeleton of lundurine A III-30 has been readily synthesized using AuCla or other gold complexes as catalysts via 8-endo-dig cyclization of alkynylindole substrate III-29 (see Ref. [134] in Chap. 1). However, the intermolecular cyclopropanation of indoloazocine III-35 was unsuccessful under all the tested conditions. Thus, we have demonstrated that the intermolacular approach is viable for the total synthesis of lundurines. 

Sakai N, Annaka K, Konakahara T (2004) Palladium-catalyzed coupling reaction of terminal alkynes with aryl iodides in the presence of indium tribromide and its application to a one-pot synthesis of 2-phenylindole. Org Lett 6 1527-1530. doi 10.1021/ol036499u Sakai N, Annaka K, Eujita A, Sato A, Konakahara T (2008) InBr 3-promoted divergent approach to polysubstituted indoles and quinolines from 2-ethynylanilines switch from an intramolecular cyclization to an intermolecular dimerization by a type of terminal substituent group. J Org Chem 73 4160-4165. doi 10.1021/jo800464u... 

Another approach to the indole core was developed by Barluenga. The reaction of 2-bromophenylamines 20 and alkenyl halides (21 or 22) underwent a cascade Pd-catalyzed intermolecular vinyl amination and intramolecular Heck reaction process to provide 2-substituted or 1,3-disubstituted indoles (23 or 24) (Scheme 7) [35]. 

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