Intermolecular C -H arylation

Although somewhat limited in scope, the groups of Lei/Kwong, Shi, and Shirakawa/Hayashi reported an interesting t-butoxide-mediated C-H/C-X coupling of unactivated arenes and haloarenes without any transition metal [40]. It is of note that there are other types of intra- and intermolecular C-H arylations that we were not be able to classify [41]. 

During the past few decades, intramolecular C-H arylation of simple arenes with aryl halides has been applied to the synthesis of biological compounds such as natural products, pharmaceuticals as well as organic materials. Herein, some recent applications of intra- and intermolecular C-H arylation of simple arenes with aryl halides are described (Scheme 17.10). 

Rhazinilam (Intramolecular and Intermolecular C-H Arylation of Pyrroles at the C4 Position)... 

Highly enantioselective intermolecular C-H insertion into cyclohexane and cyclopentane is possible using the Rh2(S-DOSP)4 carbenoids generated from aryl diazoacetates 172 to form 173 (Eq. 21) [121, 130]. The enantioselectivity is enhanced when the reactions are conducted at lower temperatures, without any deleterious effect on the catalytic activity or product yield [130]. Extending the reaction to other cyclic and acyclic hydrocarbons has revealed a dehcate balance required between the steric environment and the electronic state of the carbon undergoing C-H insertion [130]. The decreasing enantioselectivity and yield of C-H insertion into adamantane 174 (67% yield, 90% ee). 

Until recently, intermolecular C—H insertion reactions were more a curiosity than a synthetically productive undertaking. Davies and Antoulinakis discovered in the late 1990s that aryl- and vinyldiazoacetates undergo intermolecular insertion with a wide variety of hydrocarbons in high yield. With Rh2(5-DOSP)4 (12, Ar = C12H25C6H4) moderate-to-high enantioselectivities have been achieved, but diastereoselection is often low to moderate (e.g., Eq. 32, 33 ). Note that a... 

In 2009, Larrosa and co-workers developed the first decarboxylative direct C-H arylation methodology that allowed the intermolecular coupling of a variety of electron-poor benzoic acids with N-pivaloylindoles (090L5506). Remarkably, this process occurs with high chemo- and regioselectivity in both coupling partners and led to the formation of C3-arylated products exclusively, with good yields (Scheme 45). The authors proposed... 

Although aryl nitrenes often give poor yields of intermolecular C-H insertion products, the intramolecular reaction works well, and proceeds with retention... 

These examples illustrated the potential of ruthenium complexes for selective intermolecular C—H bond functionalization reactions. Furthermore, they sowed the seeds of ruthenium-catalyzed direct arylation reactions, which proved to be rather broadly appUcable [124—127]. 

A number of interesting one-pot or two-pot sequences of Pdarylation processes [14]. For example, a two flask sequence of Negishi coupling followed by intramolecular C—N bond formation has been employed for the synthesis of substituted indolines (Eq. (1.4)) [14a]. Lautens has recently described an elegant one-flask sequence of intermolecular C H bond functionalization followed by intramolecular N-arylation for the preparation of substituted indolines [14b]. As shown below (Eq. (1.5)), the Pd-catalyzed coupling of 2-iodotoluene with 2-bromopropylamine 5 in the presence of norbornene provided indoline 6 in 55% yield. 

As arylindole and arylpyrrole motifs are ubiquitous in natural products and pharmaceuticals [46, 47], the rapid construction of these units via C-H arylation is important in organic synthesis. Over the past few decades, numerous metal-catalyzed intramolecular C-H arylations of indoles/pyrroles have been reported however, their intermolecular counterparts have only begun to appear in the twenty-first century (with the notable exception of Ohta s result, see Scheme 17.2)... 

Contrary to heteroarenes, only few examples of intermolecular alkylations of the less reactive arenes have been reported. In a seminal example, perylene bisimides have been meta-alkylated with various alkyl halides under palladium catalysis and using CS2CO3 as the base (Scheme 19.25) [39]. The C-H activation step was again proposed to occur through the base-induced CMD mechanism (Scheme 19.18), and the exclusive functionaU2ation at the meta position can be correlated to the higher acidity of the meta C-H bond, as already shown in the related C-H arylation of electron-deficient arenes [29b,c]. 

More recently, a palladium-catalyzed intramolecular C-H arylation with mesylated compounds was reported by Kalyani and co-workers. A sequential mesylation-arylation protocol using phenols as substrates vras described as well. This method allows for the synthesis of diverse heterocyclic motifs, including dibenzofurans, carbazoles, and indoles, in good yields (Scheme 2.30). The intermolecular aiylations were efficient for the coupling of azoles with electronically diverse mesylates. 

Mechanisms of Direct Arylations A plausible mechanism for Pd -catalyzed intermo-lecular direct arylations with ArX (X=C1, Br, I) involves (i) oxidative addition of a Pd catalyst into an aryl halide, (ii) intermolecular C—H activation, and (iii) reductive elimination to release the aiylated prodnct and regenerate the catalyst (Scheme 24.2a) [1,5, 6,8]. 

To advance this project even further and increase the structural complexity and diversity of these target compounds, these workers also developed some sequential processes. They developed a sequential (or domino, as they called it) methine C-H arylation/Suzuki-Miyaura process (Scheme 4.17a) and a sequential (or domino) methine C-H and intermolecular arylation (Scheme 4.17b). 

An example of the construction of dibenzofurans by palladium-catalyzed C—H arylation was reported by Itatani in 1974 (Scheme 3.4) [17]. Compared with previous methods [18], this reaction could obviate the tedious synthetic route and is suitable for the preparation of substituted dibenzofurans with high efficiency. It should be noted that substituents on the benzene nucleus are believed to reduce the interaction between molecules and favor intramolecular coupling rather than intermolecular dimerization. 

Examples of the intermolecular C-P bond formation by means of radical phosphonation and phosphination have been achieved by reaction of aryl halides with trialkyl phosphites and chlorodiphenylphosphine, respectively, in the presence of (TMSlsSiH under standard radical conditions. The phosphonation reaction (Reaction 71) worked well either under UV irradiation at room temperature or in refluxing toluene. The radical phosphina-tion (Reaction 72) required pyridine in boiling benzene for 20 h. Phosphinated products were handled as phosphine sulfides. Scheme 15 shows the reaction mechanism for the phosphination procedure that involves in situ formation of tetraphenylbiphosphine. This approach has also been extended to the phosphination of alkyl halides and sequential radical cyclization/phosphination reaction. ... 

Recently, synthesis of aryl ketones by a combination of palladium-catalyzed C-H activation of arenes and intermolecular carbopalladation of nitriles has been reported (Equation (119)).474... 

An Ir(l)-catalyzed asymmetric intermolecular hydroarylation of norbornene with benzamide was reported in good to excellent enantiomeric excess, albeit in low yields, via the aryl C—H activation (Scheme 5.14). In some cases, the hydroami-nation products of norbornene were also formed in high enantioselectivities. 

Palladium(0)-catalyzed cross-coupling of aryl halides and alkenes (i.e., the Heck reaction) is widely used in organic chemistry. Oxidative Heck reactions can be achieved by forming the Pd -aryl intermediate via direct palladation of an arene C - H bond. Intramolecular reactions of this type were described in Sect. 4.1.2, but considerable effort has also been directed toward the development of intermolecular reactions. Early examples by Fu-jiwara and others used organic peroxides and related oxidants to promote catalytic turnover [182-184]. This section will highlight several recent examples that use BQ or dioxygen as the stoichiometric oxidant. 

Intermolecular insertion to aryl C—H bonds is possible. The asymmetric intramolecular reaction of the a-diazo compound 354 catalysed by Rh2[(S)-PTTL]4, Rh2[(S)—PTTL]4 = dirhodium tetrakis[N-phthaloyl(S)—t—leucinate], afforded indane... 

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