Direct arylations indoles

Recent progress in the palladium-catalysed direct arylation of simple arenes involving both intra- and inter-molecular reactions has been reviewed.55 The review includes a mention of mechanistic aspects. A new Pd11-catalysed method for the direct 2-arylation of indoles and pyrrole has been reported.56 This IMesPd(OAc)2-catalysed... 

Lautens has applied the direct arylation strategy to enable the coupling of a variety of heteroaromatics as the terminal step of the Catellani reaction sequence. A variety of /V-bromoalkyl nitrogen heterocycles including indoles [77-79], azaindoles [78], pyrroles [78, 80], pyrazoles [80, 81], and indazoles [81] have successfully undergone an ortfto-alkylation/direct arylation reaction to afford a wide variety of heterocyclic products in good to excellent yields (Scheme 33). The reaction conditions... 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

Larrosa reported the direct C2-arylation of indoles with aryl iodides at room temperature (Scheme 24) [46]. The mild conditions allow a broad range of functionalities on both coupling partners and the method is particularly advantageous due to the large pool of commercially available aryl iodides. 

The most common mechanism of C-H bond cleavage in the arylation examples discussed above has been assumed to be electrophilic aromatic substitution involving reaction of an electrophilic palladium catalyst with an electron rich, nucleophilic aromatic ring. In order to effect direct arylation on simple, electron deficient arenes, a basic directing group or intramolecular reaction is usually necessary to enable formation of a metalocycle. As a brief introduction to the effect of this area on the functionalization of indoles and pyrroles, we provide an overview of the mechanistic... 

In 1981, Itahara reported the palladium acetate-mediated direct arylation of pyrroles and indoles with arenes [59], With (sub)stoichiometric Pd(OAc)2 in benzene and acetic acid, arylation of 1-benzoylpyrrole and 1-acetylindole occurred with moderate to excellent conversions, but gave generally low yields of the desired cross-coupling products (Scheme 14). Direct arylation of isoxazole in the presence of stoichiometric amount of Pd(OAc)2 was also reported by Nakamura et al. [60]. 

Direct arylations of benzo[fo]furans, benzo[b]thiophenes, and indoles displayed different regioselectivity patterns. The chemical behavior of benzo[b]furans and benzo[fo]thiophenes are rather similar to those of non-benzannelated furans and thiophenes, respectively (Table 9.4). 

Table 9.4 Catalytic direct arylations of benzofurans, benzothiophenes, and indoles. 

Recent Advances in the C2 and C3 Regioselective Direct Arylation of Indoles... 

Scheme 9 Annulated indoles via a tandem alkylation/direct arylation reaction.

Recently, Zhang and coworkers reported a direct palladium-catalyzed C-2 arylation of indoles with potassium aryltrifluoroborate salts [204]. Remarkably, the direct arylation took place at room temperature when acetic acid was used as the solvent. 

Oestxeich found that the direct arylation of indolines could be accomplished without over oxidation to the corresponding indole under palladium-catalysis with air (open flask), oxygen (balloon), or copper(II) acetate as the oxidant. Indolines can be unsubstituted or substituted as C2/C3 and the reaction performs well on gram scale (250, 18 examples, 18—90% isolated yield) (140L6020).A directed C2-functionalization/C7-alkenylation was discovered by Xu,Yi, and colleagues. With a rhodium catalyst, indole derivatives were functionalized with acetates at C2 (22 examples, 62—92% yield) the newly obtained products could be alkenylated at C7 with a rhodium/copper system (251,3 examples, 68—78% yield) (14CC6483). 

Reactions of indoles with metal-bound carbenoids 13AHC(110)43. Recent advances in the C2 and C3 regioselective direct arylation of indoles 12AHC(105)309. 

Bressy, C., Alberico, D. and Lautens, M. (2005) A route to annulated indoles via a paUadium-catalyzed tandem alkylation/direct arylation reaction. J. Am. Chem. Soc., 127,13148-9. 

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