Indoles oxidative coupling with

Srinivasan found that the typical stoichiometric Pd(OAc)2 conditions effect cyclization of 2-(N-arylaminomethyl)indoles to aryl-fused p-carbolines in low yield [e.g., 51 to 52] [73]. Similar to the chemistry observed with N-(phenylsulfonyl)pyrrole, 1,4-naphthoquinone also undergoes Pd(OAc)2 oxidative coupling with A-(phenylsulfonyl)indole to give 53 in 68% yield [74],... 

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. 

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%),... 

The first cross-dehydrogenative intermolecular arylation of a heteroarene with an arene was reported by Fagnou in 2007. N-acetyl-lH-indoles were coupled with simple arenes and selective C3-arylation was obtained (88 89) in the presence of Pd(TFA)2 as catalyst in combination with superstoichiometric Cu(OAc)2 as terminal oxidant (Scheme 40) (2007SCI1172). The N-acetyl group proved to be crucial as no reaction product was achieved with IH-indoles, furthermore N-methyl-lH-indoles gave only self-dimerized products. 

Itahara et al. [9] found that A-2,6-dichlorobenzoylindole (13) was oxidatively coupled with methyl acrylate (4b) in the presence of stoichiometric Pd(OAc)2 in acetic acid, affording the 3-alkenylated product 14 in 25% yield. Similarly, A-tosylindole (15) reacted with ethyl acrylate (4c) to generate the 3-alkenylated indole 16 in 48% yield (Scheme 9.2) [10]. Unlike what Fujiwara et al. [8b] had observed in the reaction with A-acetylindole (8) and methyl acrylate (4b), both cases did not produce any 2-alkenylated indoles, presumably due to the steric hindrance of the relatively bulky 2,6-dichlorobenzoyl and tosyl groups. 

Lautens and Hulcoop developed a Pd-catalyzed annula-tion of 3-aryl substituted pyrroles to yield indoles, following retro-Diels-Alder loss of cyclopentadiene (Scheme 2, equations 1 and 2) [4]. Miura, Satoh, and coworkers found that indoles were formed from Af-methylpyrrole-2 carboxylic acid and alkynes as catalyzed by palladium (equation 3) [5, 6]. The indoles themselves undergo this oxidative coupling with alkynes to form octa-substituted carbazoles, e.g.4[6]. 

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. 

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

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]. 

Oxidative cross-coupling with alkenes is possible with Pd(OAc)2 [109], The reaction proceeds by the palladation of benzene to form phenylpalladium acetate (164), followed by alkene insertion and elimination of /1-hydrogen. Heteroaromatics such as furan and thiophene react more easily than benzene [109]. Stilbene (177) is formed by the reaction of benzene and styrene. The complex skeleton of paraberquamide 179 was obtained in 80% yield by the Pd(II)-promoted coupling of the indole ring with the double bond in 178, followed by reduction of the intermediate with NaBELt [110]. 

A second group of 5 -nor-derivatives has been obtained by the coupling of vindoline with 5-norcatharanthine (173), prepared as described above.1066 Under the usual modified Polonovski reaction conditions, loss of a proton from C-6 or C-3 in the quaternary ion (214) derived from norcatharanthine Nb-oxide (213) was followed by coupling with vindoline, with formation of the bis-indole bases (215) and (216) (Scheme 26). In this reaction, cleavage of the 16,21 bond in the norcatharanthine component is not observed, in contrast to the behaviour of... 

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>. 

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