Copper 2,3-disubstituted indoles

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

A copper-catalyzed tandem reaction between 2-alkynylarylideneanilines 135 and alcohols provided a novel route to A-(alkyloxybenzyl)indoles 136 <04TL35>. A stable tungsten carbene complex was isolated from a reaction involving 135 (R, = Me), f-butyl vinyl ether, and tungsten hexacarbonyl <04CL16>. 2,3-Disubstituted indoles were prepared by the cyclization of 2-... 

Another method for the regioselective functionalization of indoles is the halogen-metal reaction. The regioselective iodine-copper exchange reaction of 2,3-diiodoindole 203 with dineophylcuprate (neophil = nphyl) provided cuprate 204 which underwent reactions with electrophiles to produce 2-substituted indoles 205 <04OL1665>. A second iodine-copper exchange then afforded a synthesis of 2,3-disubstituted indoles. 

R= -Bu) afforded l,3-benzodiazepin-4-one (22). With 15 (R=cyclohexyl), amixture of indole-3-carboxamide (25%) and l,3-benzodiazepin-4-one (58%) was obtained. The latter cyclized product probably arises from a nitrogen-copper species. In a full account of their indole syntheses methodology, Saegusa presented more examples of the chemistfy already given in this chapter, plus a new application was the synthesis of 2,3-disubstituted indoles 24. Thus, as shown in equation 4 (Scheme 3) base-induced alkylation of ortto-(acylmethyl)phenyl isocyamides 10 prior to cyclization led to 2,3-disubstituted indoles 24 [5]. 

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... 

Reddy and colleagues devised a novel method for the divergent synthesis of 2,3-disubstituted indoles or 2,4,5-trisubstituted pyrroles from a-diazoketone 126. In the presence of copper(II) triflate, treatment of a-diazoketone 126 with enamine 129 gave pyrrole 130 if 126 was instead treated with aniline derivative 127, indole 128 resulted. The study culminated in the formal synthesis of indole-containing natural product homofascaplysin C (130L464). 

In the procedures mentioned for indole synthesis, enamines are the corresponding intermediates which could be prepared by reacting 2-haloanilines with ketones as well. As early as 1984, a copper-mediated indole synthesis from 2-iodoaniline with acetoacetates was developed.In this procedure, acetoacetates were treated with NaH to give enolates before the addition of Cul and 2-iodoaniline. The desired 2,3-disubstituted indoles were isolated in moderate to good yields (Scheme 2.113). In 1999, FeBr2 or hv was reported to promote this reaction as well. Using DMSO as a solvent and KOtBu as a base, the desired indoles were formed in good yields. 

Shen in 2012 reported an Ir/Cu synergistic catalytic C—H bond activation for the one-pot trifluoromethylation reaction (Scheme 9.19). This catalytic process involves sequential iridium-catalyzed C—activation borylation and copper-catalyzed trifluoromethylation of arenes with a variety of functional groups. This tandem procedure was successfully applied to the 2,6-disubstituted pyridine, benzofuran, benzothiazole, indole, and substituted quinoline systems. 

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