Heteroarenes direct arylation

The direct arylation of heteroaryls is particularly attractive due to the fact that these moieties are present in many biologically active compounds [58], Recently, etinkaya and co-workers reported the direct arylation of benzoxazoles and ben-zothiazoles with aryl bromides catalysed by a bis-NHC-palladium complex [59], Also, Sames and co-workers have described the C-H arylation of different SEM-protected heteroarenes, catalysed by NHC-Pd complex 28 (Scheme 7.12, pathway a) [60],... 

When electronic effects dominate the reactivity of an aromatic substrate, regiose-lectivities can be accomplished in intermolecular direct arylation reactions. Thus far, this approach proved predominantly applicable to the functionalization of heteroarenes with the aid of either palladium- [21], copper-, or rhodium-catalysts [22-27],... 

Ackermann L, Althammer A, Fenner S (2008) Palladium-catalyzed direct arylations of heteroarenes with tosylates and mesylates. Angew Chem Int Ed 48 201-204... 

Intermolecular direct arylations of heteroarenes with aryl halides were thus far predominantly accomplished with palladium or rhodium complexes [31, 39,75, 76], Hence rhodium catalysts proved applicable to various electron-rich heteroarenes. In contrast, less expensive and more versatile palladium catalysts allowed for direct arylations of both electron-rich and electron-deficient substrates. Generally, the problem of achieving regioselectivities in direct arylation reactions of heteroarenes is less pronounced than it is for simple arenes, since in many cases the heteroatom can be considered as an endocyclic directing group. 

C—H bond arylations of electron-deficient heteroarenes, such as azines, remain highly challenging. An elegant and versatile solution was recently elaborated, however, through a redistribution of electron density in the starting pyridine by chemical modification [77, 78]. It was found that pyridine N-oxides smoothly underwent regioselectively palladium-catalyzed direct arylations with a variety of aryl bromides (Scheme 9.36) [77a]. 

However, for the preparation of compounds with Ar-HetAr or HetAr-HetAr bonds bearing 3-, 4- or 5-substituted electron-deficient heterocyclic moieties, direct arylations using halogenated electron-deficient heteroarenes as electrophiles are usually superior. Selected examples of such couplings are summarized in Table 9.1. 

Palladium-catalyzed arylations of simple electron-rich five-membered heteroarenes with one heteroatom, such as furans, thiophenes, and pyrroles, with aryl iodides, bromides, or chlorides are among the most frequently studied direct arylation reactions [31, 39, 85]. These reactions usually afforded five-membered heterocycles, which were arylated at the position adjacent to the heteroatom in moderate to good yields. These reactions were mainly accomplished with electrophilic catalysts and proceeded more efficiently using aryl bromides with electron-withdrawing groups. This is in agreement with an electrophilic SEAr-type mechanism relying on a palladium(0)/palladium(ll) manifold [86]. Selected results of catalytic direct arylations of simple electron-rich five-membered heteroarenes (124—126) with aryl iodides, bromides, or chlorides are summarized in Table 9.2. 

In contrast, N-methylpyrrole underwent direct arylations atthe 3-position [93], and a comparable result was obtained in direct arylations of N-phenylpyrrole employing the electron-deficient rhodium complex 114, in combination with Ag2C03 under microwave irradiation [74b]. Selected examples of regioselective arylations of substituted five-membered heteroarenes are summarized in Table 9.3. 

Several nickel-based catalyst systems have been proven to catalyse C-H arylation of heteroarenes with aryl halides. For example, a combination of Ni(OAc)2 and bipy or dppf catalyses the C-H arylation of azoles including thiazoles, benzothiazoles, oxazoles, benzoxazoles, and benzimidazoles with aryl chlorides, bromides and iodides as well as aryl triflates in the presence of LiOtBu or Mg(OtBu)2. The Ni(OAc)2/dppf/LiOtBu system is more effective for aryl chloride or triflate electrophiles. Nickel-catalysed direct allq ny-lation of azoles with all yl bromides was also carried out. Ni(COD)2/l,2-bis(diphenylphosphino)benzene (dppbz) is an effective catalyst and LiOtBu is a suitable base for this transformation. In some cases, a catalytic amount of Cul additive promotes the coupling. ... 

Transition-metal-catalyzed direct arylation of heteroarenes 12MR087. 

The regioselechvihes of direct arylations can be controlled when the electrordc properhes of a given arene dominate its reachvity. This holds true for a variety of heteroarenes, and has enabled highly regioselechve palladium-catalyzed direct funchonahzahons of electron-rich, as well as electron-deficient arenes (these are... 

Intermolecular direct arylations of heteroarenes, such as indoles, pyrroles or (benzo)furans, were, thus far, predominantly achieved with palladium catalysts (see Chapter 10). However, rhodium complexes proved also competent for the direct functionaUzations of various valuable heteroarenes with comparable or, in some cases, improved catalytic performance. Thus, rhodium-catalyzed C—H bond functionalizations of various N-heterocycles, were elegantly developed by Bergman, Ellman and coworkers. Here, the use of a catalytic system comprising [RhCl(coe)2]2 and PCys led to direct arylations of unprotected benzimidazoles with aryl iodides... 

The beneficial effect of copper salts in stoichiometric quantities for palladium-catalyzed direct arylations of N-heterocycles was reported by Miura and coworkers in 1998 [53,54]. However, it was only recently that catalytic amounts of inexpensive Cul were found to enable direct arylations of heteroarenes [55, 56]. Remarkably, a variety of N-heterocycles could be arylated in high yields of isolated products with aryl iodides as electrophiles (Scheme 9.40). Unfortunately, this ligand-free catalytic system required the use of a relatively strong base, thereby limiting its functional group tolerance. 

Various methodologies for catalytic direct arylations via C—H bond activation employing transition metals other than palladium have been developed in recent years. In particular, rhodium- and ruthenium-based complexes have enabled the development of promising protocols for catalytic direct arylations. Whilst rhodium catalysts were found broadly applicable to the direct aryiation of both arenes, as well as heteroarenes, ruthenium-catalyzed chelation-assisted C—H bond function-ahzations could be used for the conversion of a variety of attractive organic electrophiles. In addition, inexpensive copper and iron salts have recently been shown as economically attractive alternatives to previously developed more expensive catalysts. Given the economically and environmentally benign features of selective C—H bond functionalizations, the development of further valuable protocols is expected in this rapidly evolving research area. 

A variety of methods for the catalytic direct arylation of aromatic and heteroaromatic compounds via the cleavage of C—H bonds has been developed during recent years. As complementary synthetic tools for conventional cross-couplings in the preparation of biaryls and arylated heteroarenes that require neither stoichiometric metallation nor halogenation, these reactions may be both useful and economical in a variety of situations. Consequently, it is highly likely that a major effort will be made in the near future to enhance the catalytic efficiency and regioselectivity of these reactions. 

Although the majority of direct arylations have been catalyzed by palladium, rhodium, and ruthenium, some additional studies have also focused on direct arylations catalyzed by first-row metals, such as iron and copper. For example, an iron-catalyzed direct arylation reaction between arylzinc reagents and 2-arylpyridine derivatives has been reported (Equation 19.146). Several direct couplings of heteroarenes with aryl halides (Equation 19.147) or hypervalent iodine reagents ° catalyzed by copper halides have also been reported. 

Regioselectivity for direct arylation of electron-rich heteroarenes ... 

Catellani [61] reported a palladium/norbomene-catalyzed synthesis of heteroatom-containing o-teraryls from aryl iodides and heteroarenes (including indoles and pyrroles) through double C-H arylation. Fagnou s group [62] applied their own protocol (Pd(II)/Ag(I)/carboxylic acid) to achieve the direct arylation of azaindoles. Itami [63] demonstrated the first iridium-catalyzed C-H arylation of heteroarenes (involving indoles and pyrroles) with aryl halides. 

In 2011, C-H arylations of indoles and pyrroles with aryliodonium salts as coupling partner were reported by Sanford [65] and Ackermarm [66]. As mentioned earlier, previous studies from the Sanford group [52] had shown that palladium catalysts can assist the direct arylation of indoles using aryliodonium salts more recent studies attempted the coupling of aryliodonium salts with more sterically hindered heteroarenes such as 2,5-disubstituted pyrroles. Meanwhile, Ackermann reported a transition-metal-free direct C-H coupling of indoles and aryliodonium salts. 

Daugulis [67] reported a palladium-catalyzed C-H arylation of heteroarenes with aryl chlorides. Although a number of methods of direct arylation of five-membered heteroarenes with aryl halides, including less reactive aryl chlorides, had been reported, thus, the direct arylation of N-substituted indoles, pyrroles, and furans with aryl chloride had been elusive except for Ohta s work [5]. Ohta s group succeeded in the C-H arylation of such heteroarenes with aryl chlorides using a combination of Pd(OAc)2, a bulky Buchwald ligand, and inorganic bases (Scheme 17.14). 

While primary electrophiles proved successful, secondary alkyl halides proved troublesome. Alkyl iodides were the most efficient but bromides and chlorides could also be successfully employed by using a catalytic amount of Nal to promote halide exchange. Copper iodide proved to be a beneficial cocatalyst to achieve satisfactory yields. An array of experiments gave the conclusion that the reaction proceeds via in situ formation of the metallated heteroarene, as already suggested for nickel/copper- and copper-catalyzed direct arylation and alkynylation of aromatic heterocycles [44, 52]. It was also suggested that nickel nanoparticles play an important role in the catalysis. 

Since a few years, ruthenium- and iridium-based polypyridyl complexes are privileged photocatalysts in visible light photocatalysis. However, organic dyes should constitute a valuable alternative not only due to their relatively lower cost and wider availability but also by giving access to new transformations. The direct arylation of heteroarenes (e.g., furan, thiophene, and pyrrole)... 

Pyridine, an electron deficient heteroarene is difficult to arylate through direct and selective C—H arylation. The presence of the Fe-MCPA combination enables products to form with high regioselectivity in this case. In other words, the methodology offers an opportunity to directly arylate electron-deficient heteroarenes. 

Transition Metal-Catalyzed Direct Arylation of Thiophenes with Heteroarenes... 

Direct Arylation of Benzoxazoles and Related Heterocycles. Benzoxazole 3 was functionalized with a variety of arenes and heteroarenes in the presence of catal)4ic amounts of [Pd(phen)2](PFe)2 (eq 3). In particular, heteroaryl iodides provided excellent yields of the comesponding products. The reaction... 

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