Copper direct arylation

A systematic investigation of the copper-catalyzed reaction between 2-bromobenzoic acid and the anions of 1,3-dicarbonyl compounds has established the optimum conditions for the direct arylation of the /3-dicarbonyl moiety (75T2607). The use of sodium hydride as the base and copper(I) bromide as catalyst is recommended. The absence of a protic solvent ensures that competitive attack on the bromobenzoic acid by a solvent-derived base leading to a salicylic acid is eliminated. For larger scale reactions the addition of toluene offers some practical advantages. 

The palladium-catalyzed and the copper-cocatalyzed direct arylation of imidazole 1-oxides 280 shown in Scheme 83 may involve transmetallation (2008JA3276, 2009JA3291). However, classical transmetallation like conversion of imidazolyllithium compounds to imidazolylzinc compounds has not been reported. 

Two methodologies for the direct C-2 arylation of thiazoles have been reported. The first one is mediated by both palladium and copper <07T1970>. Thus, the C-2 arylation of thiazole and benzothiazole with aryl iodides is carried out using copper iodide (2 equiv.) and a catalytic amount of palladium acetate under base-free conditions. The other method involves copper-catalyzed arylation with aryl iodides in the presence of lithium t-butoxide <07JA12404>. In general, reactions with lithium tert-butoxide provide better yields than those with potassium fert-butoxide. In addition, arylation with phenyl bromide, chloride or tosylate fails to provide any desired arylation products. 

Palladium and copper-catalyzed arylation of C-H bonds by aryl halide reagents is reviewed. The emphasis of the review is on directing-group-containing arene and alkane arylation catalyzed by palladium and on sp2 C-H bond arylation catalyzed by copper. Literature up to early 2009 is covered. 

Various transition metals (Pd, Rh, Ru, Cu, Fe, etc.) have been shown to be effective for cross-coupling reactions involving C-H bond activation in recent years (for copper, see [33-38] for iron, see [39, 40]). Pd(II) salts have emerged as the preferred catalysts to promote the C-H bond cleavage in catalytic direct arylation reactions. This process can be classified into two parts, the organometallic reagent is replaced by a simple arene in one case, and the aryl halide is replaced by a simple arene in another (Scheme 4). 

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],... 

Scheme 9.37 Copper-catalyzed direct arylation of the monoarylated pyridine N-oxide 117.

Recently, a more reactive catalytic system was devised which allowed the use of less expensive aryl bromides as arylating reagents. This was accomplished with sterically hindered ligand 161 under microwave irradiation (Scheme 9.44) [111]. Note that more recently direct arylations of azoles were achieved with less expensive copper [112] or nickel complexes [113]. 

Copper(I) and metals of the nickel triad have been used to effect allylation, aryladon, vinylation and acylation reactions of zinc homoenolates. Transient homoenolates generated under Pd catalysis and Ag catalysis have also been used for direct arylation and acylation of silyloxycyclopropanes. 

Other reported syntheses in this category include a copper-catalyzed preparation of 2-acylindoles from 2-bromobenzaldehydes (14EJ0511) and a rhodium-catalyzed direct arylation of a-diazoimines which furnishes... 

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). 

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). 

Copper-catalyzed direct arylation of aromatic C—H bonds 12CJO1041. Copper-catalyzed Ulbnann-type coupling reactions in water 13CJO760. Copper-mediated oxidative direct C—C (hetero)aromatic cross-coupling 12CC10704. 

Based on this proposal, ruthenium-catalyzed direct arylations with aryl halides in less-coordinating apolar solvents (e.g. toluene) were probed. Interestingly, this catalytic system enabled regioselective C—H bond functionahzations at the aromatic moieties of N-aryl-substituted 1,2,3-triazoles (Scheme 9.33) [44]. It is noteworthy, that the regioselectivity of this ruthenium-catalyzed transformation proved complementary to that obtained when applying either palladium- or copper-based catalysts (vide infra). 

Iridium-, Copper- and Iron-Catalyzed Direct Arylations 327... 

Scheme 9.40 Copper-catalyzed direct arylation of caffeine (113).

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. 

Importantly, a copper catalyst modified with N,N-bidentate ligand 1,10-phenan-throline (115) enabled the direct arylation of electron-deficient fluoroarenes (Scheme 9.41) [57]. The high catalytic efficacy allowed also for the use of aryl bromides as electrophiles, and K3PO4 as mild base. 

As 1,4-disubstituted 1,2,3-triazoles are usually prepared through copper-catalyzed 1,3-dipolar cycloadditions of terminal alkynes with organic azides, the use of a single copper complex for a direct arylation-based sequential catalysis was probed. Thereby, a modular chemo- and regioselective synthesis of fully-substituted 1,2,3-triazoles was achieved (Scheme 9.43). Notably, the overall reaction involved the selective coupUng of four components through the formation of one C—C- and three C—N-bonds [58]. 

Scheme 9.41 Copper-catalyzed direct arylation of electron-deficient arene 116.

Scheme 9.42 Copper-catalyzed direct arylation of 1,2,3-triazole 94.

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. 

Finally, coupling reactions that occur without a leaving group, a main group metal reagent, or both have been reported. These "direct arylation" reactions are a form of C-H bond activation, typically of aromatic or heteroaromatic C-H bonds. Due to the close relationship between these processes and cross-coupling reactions, however, direct arylations are described in the final section of this chapter after copper-catalyzed coupling processes. 

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. 

Recently, Hong [112] developed a selective C-H arylation of xanthene at its C2 position by palladium catalysis. Zhang [113] reported ligand-free conditions under Cu nanoparticles, and Hlavac [114] demonstrated a direct arylation of purines using palladium and copper catalysts in sohd phase. 

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. 

An efficient and simple tandem protocol for the synthesis of 1,2,3-triazole-fused imidazo-[l,2-a]pyridines was reported in 2013. The reactions followed a copper-catalyzed tandem azide-allq ne cycloaddition (CuAAC), Ullmann-type C-N coupling, and intramolecular direct arylation sequence and showed high generality and functional group tolerance. Good yields (59-77%) of 1,2,3-triazole-fused imidazo[l,2-a]pyridines were produced in a single step (Scheme 3.7). 

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