Palladium‐Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds with Aryl Halides by CH Bond Activation

Abstract

In recent years, palladium‐catalyzed direct C2 or C5 arylation of heteroaromatic compounds with aryl halides by CH bond activation has become a popular method for generating carbon–carbon bonds. For this reaction, a wide variety of heteroaromatics, such as furans, thiophenes, pyrroles, thiazoles, oxazoles, imidazoles, pyrazoles, indoles, triazoles, or even pyridines, can be employed. C3 and C4 arylations of heteroaromatics by CH bond activation have also been described. Such reactions initially attracted much less attention than the C2 or C5 arylations due to the lower reactivity of the C3 and C4 positions. How‐ ever, in more recent years, several results from using modified and improved catalysts and reaction conditions have been reported, which permit C3 and C4 arylations in synthetically useful yields. Several intramolecular cyclizations of 2‐substituted heterocycles have been described, with formation of a CC bond on C3 resulting in the formation of five‐ to nine‐membered rings incorporating pyrroles, indoles, thiophenes, furans, isoxazoles, or pyridines. Intermolecular C3 or C4 direct arylations are still quite rare for some heteroaromatics and are in several cases not highly regioselective. For such reactions, the best results have been obtained using pyrroles, thiophenes, or furans. For selected substrates, regioselective arylation at C3 or C4 of the heteroaromatic compounds took place under appropriate reaction conditions. Only a few examples of intermolecular couplings using oxazoles, thiazoles, imidazoles, isoxazoles, pyrazoles, triazoles, or pyridines have been reported. For most of these reactions, aryl iodides or bromides have been used as coupling partners, although a few examples with aryl chlorides are also known. This method allows the synthesis of complex molecules in only a few steps, and will provide access to a very wide variety of new heteroaryl derivatives in the next years.

Toward an Ideal Synthesis of (Bio)molecules through Direct Arene Assembling Reactions

“…5 However, most of the reactions were known to occur preferentially at the α-position of thiophene rings when both α-and β-positions are available, and a general method for the selective functionalization of the β-position had not been reported. 6 In 2009, our group established a general protocol for the programmed synthesis of tetraarylthiophenes 4 through sequential CH couplings (Scheme 1). 7 During this experiment, the β- selectivity observed in the arylation of methoxy-substituted thiophenes 1 with iodoarenes 2 under the catalysis of PdCl 2 / P[OCH(CF 3 ) 2 ] 3 /Ag 2 CO 3 was an intriguing phenomenon.…”

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

“…On the other hand, carbons C-2 and C-5 of the pyrrole ring are known to be more reactive than C-3 and C-4 in the Pd-catalyzed direct arylations. [24] In 1995, Gryko and co-workers reported that Nalkyl-2-arylpyrroles and 1,2-diarylpyrroles could be obtained in modest to good yields by treatment of 1 equiv. of (hetero)aryl iodides with 5 equiv.…”

Toward Ideal Arene Assembly: Catalytic C-H Bond Arylation of Aromatic Compounds

“…In particular, the deve lopment of a catalyst promoting the hard to achieve arylation at the β position of the thiophene ring was crucial. 32 Extensive screening led to the development of two new Pd catalysts (Cat A and Cat B) for the second and third arylations of 3, respectively (Scheme 17). 30 We fi rst found that the otherwise diffi cult C4 selective arylation of 4a with iodoarenes can be promoted by the catalyst PdCl 2 With two regiodivergent C H arylation catalysts in hand, the third C H arylation for making 2,4,5 triaryl 3 methoxythiophenes 6 was next examined for two possible routes, one via 8, the other via 5 (Scheme 18).…”