Oxidative coupling of indoles

Scheme 26 Alternative proposed catalytic cycle for oxidative coupling of indoles and aryl iodides (Gaunt and Beck)...

Scheme 11 Copper-catalyzed oxidative coupling of indoles with tetrahydroisoquinolines...

Scheme 52 Itahara s first intermolecular oxidative coupling of indoles.

Explain the regiochemical outcome for the oxidative coupling of indole vs. pyrrole. ... 

In all of the aforementioned cases, the palladium(II)-catalysed indole alkenylation occurred preferentially at the 3-position of the indole moiety, which is consistent with the natural reactivity of indole towards electrophihc aromatic substitution reactions. More recently, a palladium(ll)-catalysed direct oxidative coupling of indole and alkenes was described by Gaunt and coworkers [28] that exploits a selective, solvent-controlled C—H functionalization of free NH indoles and leads to the substitution of the indole core at either the 2- or the 3-position. 

An intriguing oxidative coupling of indoles with a-amino ketones can selectively afford a-aryl a-imino and a-aryl a-oxo carbonyl compounds under argon and air atmosphere, respectively (Scheme 2.8) [38]. The mechanistic studies demonstrated that stronger oxidizing conditions favored the hydrolysis process, and the traditional acidification hydrolysis is unlikely. Later, oxidative phosphonation and alkylation of a-amino ketones with diarylphosphine [39] and ethers [40] were reported. 

Most of the early applications of palladium to indole chemistry involved oxidative coupling or cyclization using stoichiometric Pd(II). Akermark first reported the efficient oxidative coupling of diphenyl amines to carbazoles 37 with Pd(OAc)2 in refluxing acetic acid [45]. The reaction is applicable to several ring-substituted carbazoles (Br, Cl, OMe, Me, NO2), and 20 years later Akermark and colleagues made this reaction catalytic in the conversion of arylaminoquinones 38 to carbazole-l,4-quinones 39 [46]. This oxidative cyclization is particularly useful for the synthesis of benzocarbazole-6,11-quinones (e.g., 40). 

The reaction of //-protected dehydroalanine methyl esters (e.g. 56, 59) with other indoles 58 can also be effected to give the corresponding dehydrotryptophans 60, invariably as the Z-isomers [81]. Murakami, Yokoyama and co-workers also studied oxidative couplings of acrylates, acrylonitrile, and enones with 2-carboethoxyindole, 1-benzylindole, and l-benzyl-2-carboethoxyindole and PdCfe and CuCk or Cu(OAc) 2 to give C-3 substitution in 50-84% yields [82, 83]. 

Oxidative homocoupling of aromatic and heteroaromatic rings proceeds with Pd(OAc)2 in AcOH. Biphenyl (165) is prepared by the oxidative coupling of benzene [104,105], The reaction is accelerated by the addition of perchloric acid. Biphenyl-tetracarboxylic acid (169), used for polyimide synthesis, is produced from dimethyl phthalate (168) commercially [106], Intramolecular coupling of the indole rings 170 is useful for the synthesis of staurosporine aglycone 171 [107]. 

As part of an examination of an oxidative coupling of methyl 6-hydroxyindole-2-carboxylate with primary amines which enabled the development of a facile preparation of 2-substituted methyl pyrrolo[2,3-e]benzoxazole-5-carboxylates, the reaction of this indole with 1,2-diaminoethane and excess Mn02 gave compound (83) in an apparent intramolecular interception of a transient intermediate o-quinone monoimine (Equation (46)) <88JOC5163>. 

The glyoxylative-decarbonylative coupling rationalizes as follows (Scheme 27). After the oxidative addition of indole-3-glyoxylyl chloride 38, adduct 39 undergoes a migratory de-insertion and elimination of carbon monoxide furnishing the acyl-Pd... 

In a series of papers on the total syntheses of alkaloids, Baran and coworkers have recently reported that enolates of carbonyl compounds undergo oxidative coupling with indoles and pyrroles in the presence of oxidants such as copper(II) and iron(III) salts . A detailed study of the oxidative cyclization reported in equation 15 has shown that 26 is converted into 27 with the highest yields when Fe(acac)3 is the oxidant, presumably due to its high redox potential (+1.1 V vs. the ferrocenium/ferrocene couple in THF solution ), which is the most positive among all the oxidizing agents tested for the transformation. 

Table 1 Pd-catalyzed oxidative cross-coupling of indoles with simple arenes...

The proposed iminium intermediate 2 in the oxidative alkylation reaction implied that other C-H based nucleophiles could undergo oxidative addition reactions to the C-H bond of tertiary amines. Li and co-workers demonstrated the cross-coupling of indoles 18 with tertiary amines 6 using simple copper salts as catalyst (Scheme 11) [27]. 

The catalytic oxidative coupling of two dissimilar arenes is also possible, for example, iV-acetyl indoles, or benzofurans, with benzene and other simple arenes. The mechanism involves sequential metallations in the two rings. The regioselectivity can be controlled by the choice of oxidant, Cu(OAc)2 favouring C-3 and AgOAc, C-2 substitution in 1-acetylindole. ... 

Scheme 54 Selective C3-C3 oxidative coupling of anilines and indoles.

Scheme 56 Zhang and Li s oxidative coupling of N-protected indoles with pyridine N-oxides.

Intermolecular Pd oxidative couplings with indoles are well established, although initial results were unpromising. For example, Billups found that indole reacts with allyl acetate (Pd(acac)/Ph3P/HOAc) to give a mixture of 3-allyl-(54%),... 

Overman s retrosynthetic analysis is depicted in Scheme 1. Pentacyclic ketone 4, derived from allylic alcohol 7 by an aza-Cope-Mannich rearrangement of formaldiminium ion derivative 6 furnished 3 through the C5 hemiketal disconnection. An intramolecular oxidative coupling of a dienolate generated from indole-... 

This racemic synthesis of actinophyllic acid (3) was accomplished in eight steps with an overall 15% yield from the readily available indole di-ferf-butyl malonate 9. The intramolecular oxidative coupling of ketone and malonate enolates and an aza-Cope-Mannich rearrangement for the construction of the unprecedented actinophyllic acid ring skeleton are the key transformations. 

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