C3-arylation

Other synthetic candidates worthy of mention inclnde the C3 aryl trioxanes (75a and 75b) " and the endoperoxide analogue (76) ". These latter compounds have oral activity (ED50) as low as 0.5 mgkg in mice infected with Plasmodium berghei. 

C3 Aryl ttioxanes (75a, 75b) 5 steps (R) Dye-sensitized photo- oxygenation 30 nM (NF54) 10 mgkg i Toxicity studies reved that 11b has a similar tiierapeutic index to artelinic acid 109, no... 

Trioxane antimalarials C3-aryl, 1325-6, 1327, 1332 carbon-centered radicals, 1283-99, 1309 dimers, 283... 

A nonclassical substrate for the Heck reaction is 2,3-epoxycyclohexanone. The reactivity of this molecule under Heck coupling conditions is most likely attributed to its in situ isomerization to 1,2-cyclohexanedione. The 1,2-diketone subsequently reacts with aryl bromides as an olefin via the enol tautomer. Thus, within 5 to 30 min of directed microwave heating of the aqueous PEG mixture, up to 13 different C3-arylations were conducted using less than 0.05 mol % palladium acetate and no phosphine ligand (Scheme 12) [51]. 

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). 

They found that combination of the Ir(T) catalyzed C-H borylation and Suzuki coupling sequence led to a two-step, one-pot C-H Suzuki arylation that enabled direct transformation of the N-Boc pyrrole to the C3 arylated intermediate in 78% yield. Following installation of the required acyl group, an application of their oxidative Pd-catalyzed C-H alkenylation reaction enabled formation of the key structural architecture of the natural deliver the natural product. The orthogonal selectivity characteristics displayed by these C-H functionalization processes makes possible iterative functionalization of the heteroaromatic pyrrole core. Utilization of the highly versatile C-H borylation - Suzuki coupling to install the aromatic functionality opens up possibilities of facile analogue synthesis via this route. 

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 28 Selective C3-arylation of N-tosylindoles with chloropyrazines.

Scheme 29 Direct C3-arylation of IV-magnesium salts. Conditions Pd(OAc)2 (2.5 mol%), PPhs (10 mol%), CsOAc (2 equiv), dioxane, 125° C, 24 h. Abbreviation HMDS, hexamethyldisilazane.

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). 

In 2009, Larrosa and co-workers developed the first decarboxylative direct C-H arylation methodology that allowed the intermolecular coupling of a variety of electron-poor benzoic acids with N-pivaloylindoles (090L5506). Remarkably, this process occurs with high chemo- and regioselectivity in both coupling partners and led to the formation of C3-arylated products exclusively, with good yields (Scheme 45). The authors proposed... 

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