C3-arylated indoles

A related example from He and co-workers demonstrated that phosphinous ligands on Pd(0) are also able affect an indole arylation reaction. A small selection of C3 arylated indoles can be realized using this method. Of particular note is the C3 selectivity observed in this reaction, when compared to the work of Sames who observed C2 selectivity (Scheme 15). 

Larrosa and coworkers reported the coupling of ortho-substituted electron-deficient benzoic acids with Af-pivaloylindole to form C3-arylated indoles (Scheme 4.11) [16]. 

Scheme 1 Indole C2- and C3-arylation strategies traditional versus C-H activation.

This review aims to survey the methodologies currently available to perform regioselectively the C2- and C3-arylation of indoles (09AGE9608, 09ASC673, 11PHC(22)1). Our discussion is limited to reactions that are catalyzed by transition metals. Traditional cross-coupling reactions (Scheme 1, Eq. 1) will not be discussed here as this field goes beyond the... 

Based on this observation the authors proposed that both C2- and C3-arylation pathways proceed via electrophilic addition of Pd(II) at the more electron-rich C3 position. This C3-palladated indole may then either undergo deprotonation and reductive elimination to give the 3-arylindole, or experience a C3 to C2 Pd migration, which then would lead to the C2-... 

Scheme 31 Direct Pd-catalyzed C3-arylation of NH-free indoles.

Following Zhang and He s work, Ackermann and Barfuesser developed a protocol using a Pd-complex derived from air-stable heteroatom-substituted secondary phosphine oxides (HASPO) for the selective C3-arylation of a variety of functionalized NH-free indoles with bromoarenes (09SL808). Optimized conditions gave good-to-high yields and allowed the use of sterically hindered substrates (Scheme 32). 

In 2008, Cusati and Djakovitch reported for the first time the use of a Pd heterogeneous catalyst ([Pd(NH3)4/NaY]) for the C3-arylation of NH-free indoles (08TL2499). The use of 1 mol% of catalyst allowed the C3-arylation of unsubstituted, 2-Me and 2-Ph indoles in moderate-to-good 5delds (Scheme 33). 

Scheme 45 Decarboxylative C3-arylation of indoles with benzoic acids.

An excellent review by Djakovitch on transition metal-catalyzed, direct and site-selective Nl, C2-, or C3-arylation of indole nucleus was published in 2009 [205]. 

By extenuating the reaction temperatures, Gaunt et al. was able to selectively phenylate C3-position of indole nucleus using aryliodonium salts [215]. At temperatures below 60°C, Cu(OTf)2-catalyzed C3-arylation took place selectively between N-acylindoles with aryliodonium salts using dtbpy as the agent to prevent indole dimerization. 

Rhodium-catalyzed selective C3-arylation of indoles was reported by Itami et al. in 2006 [217], Using a ihodium complex bearing a strong p-accepting phosphine ligand, they achieved a moderate selectivity of 2.4 1 for C3/C2 arylations as shown below. 

The synthesis of dictyodendrins A and F was realized through a sequential C—H functionahzation strategy inclusive of an initial C3 arylation, a site-selective double C—H alkylation with an aryldiazoacetate derivative and a subsequent Suzuki-Miyaura cross-coupHng with indole-3-boronic acid pinacol ester 107 (2015JAC644). A formal 67r-electrocyc-lization of the resultant tetrasubstituted pyrrole 108 fashioned the required pyrrolo-[2,3-c]carbazole core (109) which was further elaborated to the targets. 

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. 

Scheme 40 Pd-catalyzed cross-dehydrogenative C3-arylation of W-acetyl-IH-indoles.

Joucla, L. and Djakovitch, L. 2009. Transition metal-catalysed, direct and site-selective N1-, C2- or C3-arylation of the indole nucleus 20 years of improvements. Adv. Synth. Catal. 351(5) 673-714. 

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