Indole derivatives oxidative coupling

One of the starting materials, the bromoindolinemesylate 183 was obtained from the commercially available 5-hydroxyindole by mesylation followed by successive treatment of the resulting indole derivative with sodium cyanoborohydride and bromine. Coupling of 183 with the known boronic acid 184 in the presence of zero valent palladium complex led directly to the lactam 185, the intermediate carbinolamine 186 formed initially in the reaction suffering facile aerial oxidation during work-up. On reduction with sodium (2-methoxyethoxy)aluminium-hydride, the amide 185 yielded the aminophenol 187 which on chromatography underwent oxidative aromatisation to 182 in 54% yield. 

Catechol melanin, a black pigment of plants, is a polymeric product formed by the oxidative polymerization of catechol. The formation route of catechol melanin (Eq. 5) is described as follows [33-37] At first, 3-(3, 4 -dihydroxyphe-nyl)-L-alanine (DOPA) is derived from tyrosine. It is oxidized to dopaquinone and forms dopachrome. 5,6-Dihydroxyindole is formed, accompanied by the elimination of C02. The oxidative coupling polymerization produces a melanin polymer whose primary structure contains 4,7-conjugated indole units, which exist as a three-dimensional irregular polymer similar to lignin. Multistep oxidation reactions and coupling reactions in the formation of catechol melanin are catalyzed by a copper enzyme such as tyrosinase. Tyrosinase is an oxidase con-... 

The oxidative coupling reactions of benzofuran and N-substituted indoles with benzene and derivatives have also been achieved using oxygen as an oxidant (Equation 11.37) [76]. This methodology for synthesizing heterocoupled biaryls... 

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-... 

Retrosynthetically, a base-catalyzed dimerization of 127 would afford stephacidin B. Avrainvillamide (127) was simplified as vinyl iodide 128 by cleavage of the dihydropyrano [2,3-g]indole-l-oxide moiety and palladium mediated coupling. An aminoacyl radical addition from 129 gave access to 128, while 129 could be derived from cyanide 130 through a hemiaminal formation/dehydration and conjugate addition. Finally, Strecker-like reaction of ketone 131 would fulfill nitrile 130 [55] (Scheme 22). 

Furstner indole synthesis is not necessarily performed in a two-step fashion, instead it can be efficiently carried out via an instant method. Under such conditions, TiCb is added to form a complex with oxoamide substrates before the addition of an excess amount of zinc once TiCb is reduced to an active oxidation state, it immediately mediates the alkylidenation of two adjacent carbonyl functionalities. Furthermore, unlike McMurry Coupling, the Furstner indole synthesis is not restricted to THF or DME, it can also be performed in solvents such as EtOAc, DMF, and CH3CN, although it does not work in toluene and MeOH. What is more, a variety of reducible and acid or base-labile functionalities at other sites of the substrates can sustain the Eiirstner indole synthesis. Eor example, 2-N-o -ketoacylamidophenyl ketone with a more electrophilic a-keto group cyclizes only to a indole derivative. In addition, a pair of phenyl/mesityl or benzyl/t rt-butyl groups at C-2 and C-3 in either possible arrangement does not affect the overall yield of indole derivatives to a noticeable extent. ... 

The alkaloids of this group are derivatives of the pyrrolo[de]phenanthridine (lycorine type) and the 2-benzopirano-[3,4-gf]indole (homolycorine type) skeletons, and both types originate from an ortho-para phenol oxidative coupling (Fig. 4). 

This group includes the alkaloids derived from 5,10b-ethanophenanthridine (crinine and hemanthamine types), 2-benzopyrano[3,4-c]indole (tazettine type), phenanthridine (narciclasine type), and 5,11-methanomorphanthridine (montanine type) skeletons, originating from a para-para phenol oxidative coupling (Fig. 8). 

Recently, Fagnou reported a very interesting, atom-economical route to the 1,2,3-trisubstituted indole derivatives 273 via the Rh(II)-catalyzed oxidative coupling-indolization reaction (Scheme 9.95) [251]. Accordingly, simple acetanilides 271, upon a directed C-H activation with the Rh(II)-catalyst [252] followed by a subsequent carborhodation-indolization sequence of alkyne 272, gave N-acylated indoles 273. Both electron-rich and electron-deficient acetanilides 271, possessing different functionalities were perfectly tolerated under these reaction conditions. In the case of unsymmetrical alkyl-alkyl-substituted acetylenes, a mixture of indole products... 

Evano and colleagues disclosed a modular indole synthesis via the intramolecular carbocupration of N-aryl-ynamides (124 125) (130L3122).A series of indole derivatives was prepared by Jiao via the palladium-catalyzed aerobic oxidative intramolecular hydroamination and C-H functionalization of N-alkynylanilines (13T4408). Suh reported a microwave-assisted synthesis of 3-functionalized indoles via an intramolecular arene-alkene coupling of o-iodoanilino enamines (13T7211). 

Copper salts and complexes are used either as oxidant or as catalysts in the presence of a ligand/additive. Cu(acac)2 in THF has been used for oxidative coupling between an indole and a chiral nickel(II) complex (4) in the presence of lithium diisopropylamide (base). The resulting adduct, formed in 63% yield with >99% de, disproportionates readily to 3-indolylglycine derivatives in high yields. 

The C-H/C-H coupling of protected indoles with unactivated arenes takes place using air and copper as oxidants (eq 153). A mixture of C-2 and C-3 arylation is obtained, and the ratio is dependent on the protecting group employed. Benzofuran and its derivatives participate in a similar oxidative coupling under similar reaction conditions.Later, it was demonstrated that switching from acetic acid to 1,4-dioxane as the solvent, selective C-2 arylation could be obtained when Cu(OAc)2 was the oxidant in contrast, use of AgOAc as the oxidant favored arylation at the C-3 position. 

With the preliminary results in hand, it was crucial that the C2 group on the indole could be readily removed. The C2 carboxylic acid derivatives of coupling products were initially employed toward this endeavor (Scheme 4). There are relatively few decarboxylation methods on indole acids reported in the literature, most of which utilize harsh reaction conditions. Nevertheless, Jagan tested several of the reported methods, including the use of copper chromite in quinoline at 215 °C, copper(I)oxide in DMA at 200 °C, and substoichiometric amounts of indole acid copper salts at 200 Much to his dismay, most of these reactions led to decomposition. Moreover, adjusting temperature or switching to microwave heating failed to provide the desired decarboxylation. 

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