Copper-Catalyzed Synthesis of Indoles

The indole nucleus is present in various bioactive molecules and many selective protocols for its construction have been developed. Classical methods for the indole synthesis include the Fischer indole synthesis, the Batcho-Leimgruber synthesis from o-nitrotoluenes and dimethylformamide acetals, the Gassman synthesis from N-haloanilines, the reductive cyclization of o-nitrobenzyl ketones, and the Madelung cyclization of A/ -acyl-o-toluidines [42,43]. 

Cacchi and coworkers developed an efficient Cul-catalyzed synthesis of a mul-tisubstituted indole skeleton from readily available A/ -aryl enaminones with wide functional group tolerance including the whole range of halogen substituents. For 

Patel et al. reported that CuBr catalyzed the synthesis of 3-aroylindoles from 0-alkynylated A/ ,A/ -dimethylamines through oxidative process using aqueous TBHP 

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Scheme 2.93 Copper-catalyzed synthesis of indoles from 2-iodoanilines.

Scheme 7 Copper-Catalyzed Synthesis of Complex Indoles via Amination...

Ackermann engineered a copper-catalyzed process to achieve the A-arylation/hydroamination synthesis of indoles (Scheme 4, equation 1) [35], In similar fashion, A-acylindoles and NH-indoles were made available using A-unsubstituted amides and carbamates in place of anilines. In these latter reactions, a vicinal diamine ligand improved the cyclizations. Miura and Hirano reported a... 

After copper and palladium, rhodium is the third most important transition metal for the synthesis of the indole ring. For a 2007 review on this reaction, see Patil and Paiil [1], Some early examples (Scheme 1) are Alper s rhodium reaction of 2-aryl-2/7-azirines to give 2-styiylindoles (equation 1) [2], Watanabe s Rh-catalyzed Fischer indole synthesis (equation 2) [3], Ucciani s 3-methylindole synthesis via the hydroformylation of o-nitrostyrene (equation 3) [4], and Burst s preparation of 3-acetyl-2-hydrox-yindoles from the Rh-catalyzed decomposition and carbenoid aromatic C-H bond insertion (equation 4) [5]. Narasaka extended Alper s 2-aryl-2//-azirine reaction to a Rh(II)-catalyzed synthesis of 2,3-disubstituted indoles [6], and both Cenini [7] and Alper [8] stretched the deoxygenation of o-nitrostyrenes to give indoles. Burst s Rh-catalyzed decomposition of a-diazo carbonyl compounds was used by Bauban [9] and Jha [10] in the synthesis of substituted oxindoles. 

The first reported Au-catalyzed indole synthesis was that of Utimoto and coworkers (Scheme 1, equation 1) [5], Like copper, palladium, and rhodium, gold effects the cycliza-tion of o-alkynylanilines to indoles with ease. This basic electrophilic cyclization was improved upon by MarineUi [6, 7], was adapted to the synthesis of indole libraries [8, 9], was used with supported gold nanoparticles and o-alky-nylnitroarenes under hydrogenation conditions in a one-pot indole synthesis [10], and was employed in total syntheses of the alkaloids (-)-mersicarpine [11] and voacangalactone [12]. There have been an abundance of extensions to the Au-catalyzed cyclization of o-aUcynylanilines to afford 2,3-disubstituted indoles. Arcadi and colleagnes introduced both a,p-enones [13] and 1,3-dicarbonyl compounds... 

Concise Synthesis of Indole-Fused 1,4-Diazeines through Copper(I)-Catalyzed Domino Three-Component CoupUng-Cyclization-iV-Arylation under Microwave Irradiation Yusuke Ohta, Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno Org. Lett. 2008,10, 3535-3538. Reproduced with permission... 

General Procedure for Synthesis of 1,2,3,4-Tetrahydro-P-carboline by Domino Copper-Catalyzed Three-Component Indole Formation and Cyclization with t-BuOK Synthesis of 2-Methyl-l-propyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-hjindole (6a) and 2-Methyl-l-propyl-l,2,3,4-tetrahydropy-razino[l,2-a]indole (8a) (Table 1, Entry 11)... 

Concise Synthesis of Indole-Fused 1,4-Diazepines through Copper(I)-Catalyzed Domino Three-Component Coupling-Cyclization- -Arylation under Microwave Irradiation... 

The advent of palladium- and copper-catalyzed C—N bond-forming methodology has sparked the development of a range of new routes to benzimidazoles. Like the synthesis of indoles, these routes incorporate intramolecular and intermolecular C—N bond formations as well as tandem C—N bond-forming processes. Indeed, many of these routes are analogous to the corresponding indole syntheses, as shown in Scheme 24.10. 

Intermolecular C—O bond formation has been less well investigated in the synthesis of benzofurans. However, Anderson et al. reported a route involving such a step using o-chloroalkyne substrates such as 58 (Scheme 24.29, disconnection D-3) [118]. These substrates have been used in the synthesis of indoles (Scheme 24.5), and indazoles (Scheme 24.19), and in this case a combination of potassium hydroxide and a palladium catalyst derived from the bulky monophosphine ligand t-butyl XPhos 59 led to benzofuran derivatives (Scheme 24.32). Zhao et al. went on to develop a copper-catalyzed version of this process utilizing o-iodoalkynes such as 60 [119]. 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

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]. 

In a simple extension of this indole work, Collini and Ellingboe27 introduced an extra element of diversity by using a method originally exemplified in solution.28 This allowed for the synthesis of trisubstituted indoles. The method, shown in Scheme 6, involves the Sonogashira palla-dium/copper co-catalyzed step to introduce the initial alkyne diversity. After conversion of the aniline group to the trifluoroacetamide, a second palla-... 

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