Copper heteroarenes

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],... 

Copper-mediated alkylation or alkenylation has been used widely in arenes but is rarely applied to 7r-deficient heteroarenes. Aliphatic Grignard... 

Copper Reactants. Application of the Pd/Cu-catalyzed cross-coupling, the Sonogashira reaction, with monosubstituted or protected acetylene gives rise to a variety of ethynyl-heteroarenes (Schenae 27). Reactions with trimethylsilylacetylene or phenylacetylene in... 

Carbazoles 292 and azaindoles were trifluoromethylated selectively to 294 under copper catalysis with the Ruppert—Prakash reagent in the presence of trimethyl borate, 1,10-phenanthroline, and KF as a base. This reaction is also applicable to a variety of other arenes and heteroarenes (140L4268). 

Further elaborations/modifications of the oxazole ring were also described. For example, a new POCN-pincer palladium catalyst was used in the copper-mediated arylation of the C-2 position of benzoxazoles and oxazoles with aryl iodides in satisfactory yields (14DT16084). An original method for the direct amination of heteroarenes including benzoxazoles was reported involving a one-pot heteroarene C-H zincation followed by a copper catalyzed electrophilic amination (14AGE4667). 

Miura and Hirano reported a copper-mediated cross-couphng reaction between 2-arylazines 102 and 1,3-azoles 100 including (benz)oxazoles and xanthines giving the products 103 (Scheme 45) (2011JA2160). The corresponding arylated heteroarenes were obtained in moderate yields under rather harsh conditions (high temperature in the presence of superstoichiometric... 

Dai and Yu reported a copper-mediated C—H alkynylation of heteroarenes 127 bearing an N-2-(2-oxazohnyl)phenylcarboxamide directing group (Scheme 60) (2014JA11590). Alkynylation of IH-pyrrole, IH-indole,... 

Recently, Dai and Yu reported a copper-based strategy for the direct amination of heteroarenes including (benzo)furans, IH-indoles, and pyridines (127 136) (Scheme 68) (2014JA3354). The C—H activation... 

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. 

An interesting selectivity was uncovered in the direct cross-dehydrogenative coupUng between N-protected indoles and arenes (Scheme 11.40) [151]. Thus, whereas 2-arylated indoles 67a were preferentially obtained from N-acetyhndole in the presence of Cu(OAc)2, the reaction of N-pivalolyUndole with AgOAc led to 67b, with excellent selectivities. The reason for this C-2/C-3 selectivity is most likely due to the formation of higher-order palladium clusters or paUadium/copper clusters under the different reaction conditions. A related reaction between aryl-boronic acids and arenes or heteroarenes also proceeds under oxidative conditions with Pd(OAc)2 as catalyst [76]. A catalytic cycle initiated by an electrophihc attack of Pd(II) on the arene, followed by transmetallation with the aryl boronic acid and reductive elimination, was suggested. In this transformation, Cu(OAc)2 as stoichiometric oxidant could be replaced by O2, and for indoles, arylation at C-2 was observed. 

T -Arene complexes containing late metals have been known for many years, but the scope and utility of these complexes have increased in recent years. Copper(I) and silver form labile arene complexes of various stoichiometries that are apparently T -arene complexes. A few of these complexes have been structurally characterized. More recently, a large number of V-arene and heteroarene complexes of osmium, rhenium, molybdenum, and tungsten have been prepared for the purpose of dearomatization of the arene or heteroarenes. Two examples are shown in Figure 2.33. This dearomatization creates a diene or vinyl unit that imdergoes the organic chemistry of ttiese isolated units, instead of the chemistry of an arene. n -Arene complexes of rhodium and platinum have been characterized structurally and studied in the context of their likely intermediacy in the oxidative addition of arene C-H bonds. ... 

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. 

As an alternative to catalysis by noble metals, Hu and coworkers [51] developed a nickel/copper-catalyzed direct chemo- and regioselective alkylation of various electron-rich (thiophene) and electron-poor (oxazole and thiazole) heteroarenes with alkyl halides, including those containing a -hydrogen atom (Scheme 19.31). 

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. 

Scheme 19.31 Nickel/copper-catalyzed direct alkylation of heteroarenes.

For a long time, rhodium catalysts were privileged for the transformation of carbonyl functions into olefins [82]. Nevertheless, as copper became more successful, a new methodology based on this inexpensive metal has been welcome. Lebel et al. developed a process, similar to the one based on the Willdnson catalyst using [Cu(Cl)(NHC)] (Scheme 8.30) [83]. Using these copper complexes, they were able to expand the scope to a large variety of substrates. Aliphatic alkenes, dienes, styrenes and heteroarenes were successfully functionalized. Whereas the rhodium systems underwent decomposition in the case of substrates with a nitro moiety, copper complexes showed high tolerance and... 

D. D. Vachhani, A. Sharma, E. Van der Eycken, Angew. Chem. Int. Ed. 2013, 52, 2547-2550. Copper-catalyzed direct secondary and tertiary C-H alkylation of azoles through a heteroarene-amine-aldehyde/ketone coupling reaction. 

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