Copper-catalyzed indole synthesis

The relative inexpensive copper and its variable oxidation states have elevated it to prominence for indole synthesis numerous recent reviews are available [1-8], 

Applications of the original Castro-Stephens indole synthesis were described by Yamamoto (A-benzyhndole, 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

Several investigators have uncovered additional copper-catalyzed indole syntheses from 2-ethynylanilines accompanied by in situ indole functionahzation. Yamamoto and colleagues reported the synthesis of Af-(alkoxybenzyl) indoles from the copper-catalyzed tandem reaction between 2-alkynyl-Af-arylideneanihnes and alcohols (Cul, toluene, 100°C, 55%-83%) [26], Ohno, Fujii, and coworkers employed a domino three-component copper-catalyzed process to prepare 2-(aminomethyl)indoles [27, 28] and 

P-carbohnes [29] (Schane 3, equation 1). A variety of secondary amines were employed, and the method was adapted to the preparation of pyrrolo[3,2-/lindoles and dipyrrolo[3,2-h 2, 3 -c]pyridines [30]. Cacchi and colleagues synthesized 3-aroylindoles from the copper-catalyzed cyclization of lV-(2-iodoaryl)enaminones (equation 2) [31]. The latter were prepared from 2-haloanilines and a,p-ynones, which can react directly with 2-iodoaniline under the copper protocol to give 3-benzoyl-2-phenylindole (76%), thus bypassing the enaminone. Patel described a copper-catalyzed 3-aroylindole synthesis from 2-alkynylated 

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Scheme 6 Copper-Catalyzed Indole Synthesis via Amination...

Huang [80] and Liu [81] independently described a copper-catalyzed indole synthesis involving 2-iodoaniline and allenes (e.g., ethyl buta-2,3-dienoate) in a process that involved in situ formation of an aza-Michael addition adduct (vinylogous carbamate) and intramolecular Hecklike cyclization. Both groups used similar reaction... 

Scheme 9 Copper-Catalyzed Indole Synthesis from 2-Haloanilines and p-Dicarbonyl Compounds...

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... 

In 2006, Zhou s group reported a copper-catalyzed asymmetric synthesis (it was described in the paper as Friedel-Crafts-type reaction) using Al-sulfonyl aldimines with indoles to provide a simple approach to optically active 3-indolylmethanamine derivatives with high enantioselectivity. A bis-oxazoline-copper complex was used (Scheme 6.37) [50]. 

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]. 

Transition-metal catalysis on solid supports can also be used for indole formation [43]. A palladium or copper-catalyzed procedure has been described for generation of a small indole library (Scheme 16.21) this is the first example of solid-phase synthesis of 5-arylsulfamoyl substituted indole derivatives. Whereas the best... 

In Chap. 6, a companion to the preceding chapter, Li and Gribble document Metal-Catalyzed Cross-Coupling Reactions for Indoles , which covers palladium, copper, rhodium, iron, and nickel cross-couplings of indole - a suite of reactions that has assumed great importance in indole synthesis and chemistry. 

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... 

The intramolecular amine-halogen copper-promoted indohzation was applied to the synthesis of more-complex indoles (Scheme , equations 1 ) [58-61]. Other examples in this category of copper-catalyzed amination are syntheses of the carbazole alkaloids murrayaquinone-A and ( )-bis-murrayaquinone-A [62], 3-aryl p-carbolin-l-ones [63, 64], carbazoles from donble C-N cyclization [65], pyrrolo[2,3-c]... 

The copper(I)-catalyzed reaction between 2-haloani-lines and p-dicarbonyls (or equivalent compounds), irrespective of the actual pathway, is an extremely versatile and efficient indole synthesis, and many applications are known. 

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. 

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