Arylation of indoles

A novel method has been developed for the selective N-arylation of indoles with aryl electrophiles in the presence of potassium fluoride adsorbed onto basic alumina <96TL299>. 

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

In terms of A -substitution, Hartwig reported improved conditions for the Pd(0) catalyzed N-arylation of indoles and pyrrole <99JOC5575>. It was found that when commercially available P(<-Bu)3 was employed as ligand and cesium carbonate as base, the reaction between indoles 95 and unhindered aryl bromides 96 or chlorides occurred under milder conditions than the Pd(OAc)2/DPPF system previously reported yielding the A/-arylated products 97. Alternatively, it has been found that pyrrole- and indole-2-carboxylic acid esters can be selectively 7V-arylated with phenylboronic acids in the presence of cupric acetate and either tiiethylamine or pyridine <99T12757>. 

The 7V-arylation of indoles has been achieved both in palladium and copper catalyzed coupling reactions. In an early example Hartwig succeeded in converting indole to 1-arylindoles in excellent yield, using a palladium -dppf catalyst and caesium carbonate as base (6.71.)."a Buchwald99b and... 

C-Arylation of indoles can be accomplished by means of palladium-catalyzed coupling reactions, such as the Suzuki coupling (Entry 7, Table 15.7) or Stille coupling with resin-bound 2-bromoindoles [88] or 5-bromoindoles [75]. 2-Iodoindoles have been prepared on polystyrene by iododesilylation of 2-silylindoles with NIS (Entry 8, Table 15.7), and these can be C-arylated with arylboronic acids [73]. 

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... 

Mild N-arylations of indoles can be achieved in good yields by nucleophilic substitution reactions of the sodium salt of indole on various haloarenetricarbonylchromium complexes. Thus, o-fluoroanisole-Cr(CO)3 33a reacts with the indole N anion within 0.75 h at 0 °C to give complex 3m (Nu = indolyl) in 83 % yield. The chloro derivatives require longer reaction times and higher temperatures (Scheme 18) [37]. The authors were able to extend this procedure to the introduction of two indole rings on the same aromatic nucleus. 

Methods have been described for the A-aroylation of indole sodium salts using A-aroylbenzotriazoles <07S3673> and the CuOAc-mediated A-arylation of indoles using aryl iodides <07EJO2147>. 

Catalytic N-arylation of indoles is mainly limited to aryl iodides and bromides <1998JA827, 20000L1403>. The combination of Pd(OAc>2 and DPPF catalyzed the formation of A -aryl azoles 181 in the presence of CS2CO3 or Bu ONa with electron-rich, electron-neutral, or electron-poor aryl halides (Equation 35) <1998JA827>. 

The Pd(OAc)2/SIPr HCl/NaOH system (where SIPr= l,3-bus(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene) is efficient for the N-arylation of diverse indoles with aryl bromides (Equation 39) but not effective for the reaction with aryl chlorides <2001JOC7729>. Pd(dba)2 or PdCl2/SIPr-HCl/NaOH systems did not effect the arylation of indole. 

In 1998, Hartwig also described the arylation of indoles using Pd catalysis [ 109]. With the DPPF/Pd-system, good to excellent yields of the desired product was obtained with electron-deficient aryl bromides. 

The use of (t-Bu)3P/Pd-catalysts in the arylation of indoles has been reported by both the Hartwig and Watanabe groups [50,118]. Moderate to good yields are observed in the coupling reactions, however, side products resulting from C-ary-lation at the 3-position are commonly isolated as well. Similarly, both groups reported the arylation of carbazoles as well. 

General Procedure for the N-Arylation of Indoles (Excerpted with permission from [119]. 2000 American Chemical Society) A Schlenk tube was charged with sodium ferf-butoxide (1.4 mmol), Pd2(dba)3 (0.005 mmol), and 4 (0.015 mmol). The Schlenk tube was fitted with a septum and attached to a Schlenk line. After the air atmosphere was replaced with argon, toluene (2 ml), aryl bromide (1.0 mmol), and the indole (1.2 mmol) were added. After the septum was replaced with a teflon valve, the reaction was sealed and heated to 80- 100°C with stirring until starting material was consumed as judged by GC analysis. The reaction mixture was cooled to room temperature, diluted with ether (20 ml), filtered, and concentrated. The crude reaction mixture was then purified by flash chromatography on silica gel. 

Colacino E, Villebrun L, Martinez J, Lamaty F (2010) PEG34OO-CU2O-CS2CO3 an efficient and recyclable microwave-enhanced catalytic system for ligand-free Ullmann arylation of indole and benzimidazole. Tetrahedron 66 3730-3735... 

Abdrakhmanov and co-workers observed the cycloaddition of iV-(l-methyl-2-butenyl)aniline or 2-( l-methyl-2-butenyl)anilme with PdClj/DMSO to give a 69% yield of a mixture of 2-ethyl-3-methylmdole and 2,4-dimethylquinoline [87]. The authors propose that a Claisen rearrangement is initially involved. A similar oxidative cyclization of a 5-amino-indoleacrylate was the starting point for syntheses of CC-1065 and related compounds [88]. In an elegant mechanistic analysis, Sarnes has developed a general Pd-catalyzed arylation of indoles, at C-2 or C-3 depending on the reaction conditions [89]. 

Scheme 12 Sames strategy towards regioselective intermolecular arylation of indoles...

In general these methods, developed by Sames for C-H arylation of indoles, do not follow the expected electrophilic regiochemistry, instead showing high C2 selectivity (Scheme 14). Sames described how their mechanistic experiments point towards a mechanism involving electrophilic C-H activation [29], First, the reaction was shown to be first order in both substrate and catalyst. Moreover, a Hammett... 

Sames and co-workers also demonstrated that rhodium(I) catalysts also facilitate a C-H arylation of indole at the C-2 position (Scheme 16). While not explicitly described in their paper, they infer that the pivolate ligand may be involved in an internal proton-transfer, and it seems likely that this is in line with a CMD type activation step reported by Fagnou and Echaverran [20, 21] (opinion of Gaunt and... 

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]. 

Scheme 19 Sanford s oxidative C2-arylation of indoles and pyrroles...

Using this concept the Sanford group found that direct C2-arylation of indoles and pyrroles could be effected under remarkably mild conditions with aryl iodo-nium salts and palladium(II) catalysts (Scheme 19) [42], The high C2 selectivity of the functionalization is attributed to a mechanism involving initial palladation at C3 followed by fast palladium migration to C2 under acidic conditions as initially proposed by Gaunt [43] and Sames [29], The reaction also works well for simple pyrroles, again with C2 selectivity. 

Scheme 21 Controllable and selective Cu-catalyzed C-H bond arylation of indole...

Scheme 24 Larrosa s C2-arylation of indoles with aryl iodides...

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. 

Arylation of indoles can also be carried out via arylpalladium acetates generated from boronic acids or trifluoroborate salts " and palladium acetate. The reactions are catalytic in palladium, cycling of the Pd(ll) being effected by the use of a re-oxidant (Cu(ll)/air). The reaction works well on NH and A-methyl indoles but fails with the A-acetyl derivative. 

Although occasional examples had been described earlier, the design and development of new highly active ligands for palladium gave new impetus to transition-metal-catalysed aminations. A number of relatively complex ligands were used in earlier work, but simpler versions, such as JohnPhos, have now become prominent. " These methods work well with heterocycles, for example A-arylation of indoles, using triflates, bromides and chlorides. ... 

More promising results were obtained for cross-dehydrogenative arylations with heteroarenes, since pronounced differences in reactivities gave improved chemos-electivity. In elegant studies it was shown that palladium-catalyzed oxidative arylations of indoles could be accomplished with unactivated arenes, which were used as solvents, in the presence of Cu(OAc)2 as terminal oxidant [130]. Notably, these reactions proceeded with high regioselectivities, leading predominantly to arylations at position C-3 (Scheme 9.51). 

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