Direct C-H Functionalization of Heteroarenes

We believe that numerous examples and methods for the direct metal-free C-H functionalization of arenes and heteroarenes, presented by an international team of chemists in six chapters of this volume, are not only complementary to each other, but also create the whole picture of the reactions, enabling one to estimate their current scope, synthetic potential and value as chlorine-free ecologically benign processes. 

Although much has been learnt about the reactivity and regioselectivity in direct functionalization of heteroarenes, the ability to manipulate and controllably switch the selectivity is extremely rare. In 2005, a method for direct and selective C2 or C3 elaboration of free-(NH) indoles using palladium-catalyzed C-H functionalization was developed by Gaunt and co-workers (Scheme 49) [43]. 

Although palladium-catalyzed cross-coupling reactions provide an efficient entry to C-arylated indoles, these reactions require the preparation of functionalized hetero-arenes such as boronates and halides. Therefore, C-arylation reactions of azole and related heteroarenes via direct C-H bond functionalization of the parent heteroar-enes would be much more favorable. In 2004, Sames reported a selective palladium-catalyzed C2-arylation of W-substituted indoles via direct C—H bond arylation [199]. Use CsOAc as the base and low concentration of the substrates proved to be critical for the success of this methodology. 

With Palladium Ackermans group [90] has been active in this area. In 2012, they reported a palladium-catalyzed direct C-H bond alkynylation of heteroarenes using ge/w-dichloroalkenes [90b]. The substrates used were oxazole, benzoxazole, and benzothiazole, and the catalyst formed from Pd(OAc)2 and the ligand Bis-[2-(diphenylphosphino)phenyl]ether (DPEPhos) (Figure 4.46). The scope was excellent, the procedure being tolerant of lots of functional groups. This method allowed for step-economical, environmentally benign, and direct functionalizations of various heteroarenes. 

A broadly applicable system for the arylation of various heterocycles with aryl bromides involves the employment of pivalic acid, along with Pd(OAc)2 and PCys (eq 160). It is h)q)othesized that the reaction involves a concerted metalation-deprotonation pathway. Other five-membered heterocycles react at the highlighted C-H position (eq 160). The same group also introduced electron-deficient fluoroarylphosphines for the direct functionalization of heteroarenes with aryl iodides. In the former report, low yields were obtained with 2-bromDpyridine or aryl halides bearing substituents such as nitro or cyano. A microwave-assisted protocol was instead developed that could overcome these limitations. ... 

The development and application of selective C-H functionalization processes toward heteroarene synthesis is rapidly evolving. In 2006, the first Handbook of Reagents for Organic Synthesis, Reagents for Direct Functionalization of C-H Bonds... 

Rossi, R. Beilina, E Lessi, M. Manzini, C. Cross-coupling of heteroarenes by C-H functionalization recent progress towards direct arylation and heteroarylation reactions involving heteroarenes containing one heteroatom. Adv. Synth. Catal. 2014, 356, 17-117. 

On the way to further extension of the scope of Cp Co "-catalyzed C-H functionalization, Glorius and coworkers developed a condensation reaction of 2-arylpyridine derivatives and diazoesters to form unique polycyclic heteroaromatics having 6//-pyrido[2,l-a]isoquinolin-6-one skeletons (Scheme 10.15) [38]. The reaction is achieved by the combination of a bench-stable Co precatalyst [Cp Co(CO)l2] [39], a silver salt (AgSbFg), and an acetate source (KOAc) in trifluoroethanol. The in situ-formed Cp Co catalyst is proposed to play a dual role in this condensation reaction. First, it promotes formal carbene insertion into the ortho C-H bond through pyridine-directed C-H metalation, cobalt-carbene formation, carbene insertion into the aryl-Co bond, and protodemetalation. Second, it acts as a Lewis acid to facilitate nucleophilic attack of the pyridine moiety to the ester group, which eventually leads to the product through aromatization and elimination of methanol. The thus-synthesized polycyclic heteroarenes exhibit bright and color-tunable fluorescence in solution and in the solid state. 

Ruthenium- and rhodium-catalytic systems for the direct cross-dehydrogenative coupling (CDC) of acrylamides with electron-deficient alkenes forming (Z, )-dienamides using copper(II) acetate as the oxidant has been developed. Both methods exhibit wide functional group compatibility and substrate flexibility. It is proposed that the reaction is initiated by cyclometalation of acrylamide by amide-directing C-H bond activation. Coordination of the alkene to the metal centre, followed by insertion of the carbon-carbon double bond, forms a seven-membered ruthacycle or rhodacycle species. Subsequent -elimination occurs to afford the desired (Z, )-dienamide. A CDC between two heteroarenes is effected with copper(II) acetate in the absence... 

The selective functionalization of heterocycles is of particular importance, because of the ubiquity of these structures in natural products and pharmaceutical agents. Direct utilization of a C-H bond [1] of heterocycles is a promising method for the preparation of heterocycles because no pre-functionalization is required. Although Friedel-Crafts acylation is the most commonly used method for introduction of keto functionality on an aromatic ring, it is not often applicable to N-heteroarenes because of deactivation of the Lewis acids by the coordination of N-heteroarenes and the electron-deficient aromatic character of N-heteroarenes. 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

The indole and pyrrole nucleus are common structural motifs in a range of natural products and medicinal agents (Fig. 1). Therefore, methods for their selective and efficient functionalization are important targets for chemical synthesis. The inherent reactivity of these heteroarenes has attracted widespread interest as ideal substrates for direct metal-catalyzed C-H bond functionalization reactions. However, related to their intrinsic reactivity is their sensitivity to harsh aerobic reaction conditions, and so methods to enable direct transformations on these heteroarenes must take this into account. 

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... 

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. 

By using 8-aminoquinoline benzamide substrates and picolinic acid auxiliaries as the directing groups, the Daugulis group reported a novel method for selective mono- or di-fluorination of arene and heteroarene C—H bonds. AgF was used as fluoride source and DMF, pyridine, or DMPU as solvent. This Cu-promoted C—H activation method shows excellent functional group tolerance and provides a straightforward way for the preparation of ortto-fluorinated benzoic acids (Scheme 9.14). ... 

C-H Bond Functionalization. The direct arylation of 2-ethylthiophene with bromobenzene and iodobenzene derivatives is observed to proceed best with PdBr2 in the presence of bipyridine and Ag2C03 over alternate palladium(II) and Pd(0) sources (eq 37). Optimal yields are obtained with the preformed catalyst. Other heteroarenes have been shown to react with iodoarenes in arylation reactions. 

Simple ruthenium(II) catalysts can now perform heterocycle directed alkylation and Friedel-Crafts type reactions at orf/io-positions of arenes and heteroarenes. The former reaction takes places without p elimination and the latter reaction takes place without addition of Lewis acid to form arenes containing a ketone, amide, or ester functionality. Hydroarylation of strained alkenes can be performed to obtain ortho alkyl (hetero)arenes and alkylation of sp C-H bond can be observed using alcohol as a precursor. 

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