Direct arylation of arenes with

The first case involves direct arylation of arenes with aryl halides via a Pd(0)/Pd (II) cycle (Scheme 8). After initial oxidative addition of Pd(0) into the aryl halide, the C-H bond activation event takes place at the Ar-Pd(II)-X species 4 and is followed by C-C bond forming reductive elimination and regeneration of Pd(0). 

Ackermann L, Mulzer M (2008) Dehydrative direct arylations of arenes with phenols via ruthenium-catalyzed C-H and C-OH bond functionalizations. Org Lett 10 5043-5045... 

Scheme 9.31 Palladium-catalyzed direct arylations of arenes with the aryl bromide 94 and pivalic acid as additive.

The direct arylation of arenes with stannaries ArSnCls is similarly catalyzed by PdCl2 and proceeds with CuCh as oxidant [152]. In this instance, a different mechanism was suggested based on the transmetallation between the stannane and a Pd(lV) salt, followed by an electrophilic aromatic substitution and reductive elimination. Arylzinc reagents also arylate 2-arylpyridines in the presence of iron catalysts [153]. 

The use of a Lewis-basic donating group to facilitate metal coordination prior to the C—H functionalization event is not required in all cases. Direct arylation of arenes with aryl iodides and bromides in the absence of a directing group has been described by Fagnou (Scheme 3.2). 

Transition-metal-catalyzed direct arylation of arenes with aryl halides via cleavage of aryl C—H bonds serves as a straightforward method for aryl-aryl bond formation [3], Hence, direct arylation of two aromatic rings tethered by aromatic/alkenyl moieties or heteroatoms (i.e. intramolecular variant of the direct arylation) constitute efficient syntheses of PAHs such as benzofurans, carbazoles, dibenzothiophenes, dibenzosiloles, and phenanthrenes. In this section we overview the progress with subsections categorized by product structures [5]. 

Under Lewis-acid-catalyzed conditions, electron-rich arenes can be added to alkenes to generate Friedel-Crafts reaction products. This subject will be discussed in detail in Chapter 7, on aromatic compounds. However, it is interesting to note that direct arylation of styrene with benzene in aqueous CF3CO2H containing H2PtCl6 yielded 30-5% zram-PhCH CHR via the intermediate PhPt(H20)Cl4.157 Hydropheny-lation of olefins can be catalyzed by an Ir(III) complex.158... 

Scheme 33 Rh-catalyzed directed C-H arylation of arenes with arylboron reagents by Miyamura et al. [124]...

Direct arylations of arenes are, however, not restricted to palladium-catalyzed transformations, but were also accomplished with, inter alia, iridium complexes. Thus, the direct coupling of various aryl iodides with an excess of benzene in the presence of [Cp IrHCl]2 afforded the corresponding biaryl products, but usually in moderate yields only (Scheme 9.30) [69]. The reaction is believed to proceed via a radical-based mechanism with initial base-mediated reduction of iridium(III) followed by electron transfer from iridium(II) to the aryl iodide. Rather high catalyst loadings were required and the phenylation of toluene (90) under these reaction conditions provided a mixture of regioisomers 91, 92, and 93 in an overall low yield (Scheme 9.30) [69]. 

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. 

As already mentioned, the C-H/C-X coupling between simple arenes and aryl halides to form biphenyl derivatives is difficult in terms of reactivity and regiose-lectivity without directing group. In 2004, Fujita and Yamaguchi [28] reported the iridium-catalyzed direct arylation of benzene with aryl iodides. For example, when the reaction was carried out in the presence of the [Cp IrHCl]2 catalyst (5mol%) and KOt-Bu (3.3 equiv.) at 80°C, 4-methoxybiphenyl 34 was obtained in 66% yield. However, when substituted arenes were used instead of benzene, several... 

Independently, elegant mechanistic studies by Echavarren provided support for the CMD mechanism in palladium-catalyzed direct arylation of arenes.Thus, an intramolecular competition experiment with substrate 85, revealed that the less nucleophilic, but more C-H acidic fluori-nated arene was preferentially functionalized (Scheme 22). 

In an effort to move away from precious metal catalysts, various reports in recent years have focused on the use of first-row metal catalysts for direct arylations [57-60]. As a representative example of these new developments, we illustrate in Scheme 23.15 the chelate-assisted ortho-C-H arylation of arenes with Fe catalysts [61]. With iron being cheap, nontoxic, and ubiquitous, this protocol is highly attractive for pharmaceutical syntheses. Using the catalyst precursor Fe(acac)j in conjunction with bidentate pyridine ligands, Zn-aryl reagents as aryl transfer reagents and 1,2-dichloroisobutane as the oxidant, excellent yields of the arylated product were obtained. An interesting feature of this reaction is the hydrolysis of the imine moiety after work-up. The reaction conditions tolerate additional functionalities such as cyanides, chlorides, triflates, tosylates, and thiophenes. 

Diaryliodonium salts are frequently used as photoinitiators in cadmiic polymerization, and aryl radicals are generated with ruthenium- or itidium-based photocatalysts [10]. hi 2012, Sanford exploited this feature in a combined Pd/Ir-catalyzed system for photoredox arylations of arenes with N-directing groups. The generation of aryl radicals allowed ort/io-arylations at room temperature in MeOH, i.e., much milder conditions than previously described [216]. 

Scheme 16 Products in metal-catalyzed arylations of arenes with directing groups...

Direct arylation of arene derivatives with aryl iodides and bromides proceeds in the presence of catalytic amounts of iron(II) acetate and bathophenanthroline (Scheme 4-228, Table 4-1). ... 

Fagnou and co-workers reported on the use of a palladium source in the presence of different phosphine ligands for the intramolecular direct arylation reaction of arenes with bromides [56]. Later, they discovered that new conditions employing palladium complex 27 promoted the direct arylation of a broad range of aryl chlorides to form six- and five-membered ring biaryls including different functionalities as ether, amine, amide and alkyl (Scheme 7.11) [57]. 

Furthermore, ir-arene complexes of transition metals are seldom formed by the direct reaction of benzene with metal complexes. More usually, the syntheses require the formation of (often unstable) metal aryl complexes and these are then converted to ir-arene complexes. The analogous formation of w-adsorbed benzene at a metal surface via the initial formation of ff-adsorbcd phenyl, merits more consideration than it has yet been given. It is to be hoped that the recognition and study of structure-sensitive reactions will allow more exact definition of the sites responsible for catalytic activity at metal surfaces. The reactions of benzene, using suitably labeled materials, may prove to be useful probes for such studies. 

The direct borylation of arenes was catalyzed by iridium complexes [61-63]. Iridium complex generated from [lrCl(cod)]2 and 2,2 -bipyridine (bpy) showed the high catalytic activity of the reaction of bis (pinaco la to) diboron (B2Pin2) 138 with benzene 139 to afford phenylborane 140 (Equation 10.36) [61]. Various arenes and heteroarenes are allowed to react with B2Pin2 and pinacolborane (HBpin) in the presence of [lrCl(cod)]2/bipyridne or [lr(OMe)(cod)]2/bipyridine to produce corresponding aryl- and heteroarylboron compounds [62]. The reaction is considered to proceed via the formation of a tris(boryl)iridium(lll) species and its oxidative addition to an aromahc C—H bond. 

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]. 

The remarkable stability of ruthenium complexes could, further, be exploited for direct arylations between simple arenes as pronucleophiles and inexpensive, broadly available phenols as proelectrophiles. Notably, this operationally simple dehydrative direct arylation was achieved with a highly chemo- and regioselective ruthenium catalyst, along with a sulfonyl chloride, and proceeded overall through the functionalizations of both C-H as well as C-OH bonds (Scheme 29) [85],... 

Ruthenium-catalyzed direct arylations of the arene 58 with the secondary phosphine oxide (l-Ad)2P(0)H (54) as preligand allowed for the use of inexpensive aryl chlorides as electrophiles (Scheme 9.22) [55], Importantly, the protocol proved applicable to both electron-deficient and electron-rich aryl chlorides. 

Among the few known methods for catalytic direct arylations of simple arenes with aryl halides, early examples are represented by direct arylations of azulene (Scheme 9.29) [67] and of benzene [68]. 

A highly active catalytic system for direct arylation reactions of nonactivated arenes relied on a homobimetallic rhodium complex. Thus, treatment of [bis(2-pyridyl) amino]diphenylphosphane (109) with [Rh(cod)Cl]2 led to the formation of a complex 108, which, according to X-ray crystal structure analysis, consisted of [Rh(cod) Cl2] anion and a rhodium cation stabilized by two P,N-ligands (Scheme 9.34) [73]. This bimetallic rhodium complex (108) allowed the direct arylation of benzene (87) with the aryl chloride 106 with a turnover number (TON) of 780 under comparably mild reaction conditions. 

---