Biaryls are important structural motifs in complex molecules, such as natural products or bioactive compounds and widely applied in medical chemistry, crop protection or material sciences.[93] The preparation of biaryls is normally accomplished by transitions metal-catalyzed cross-coupling reactions for the formations of C(sp2)–C(sp2) bonds. In general, (pseudo)halides as electrophiles and organometallic species as nucleophiles are involved.
Keeping in mind the drawbacks of cross-coupling reactions (vide supra), direct C–H arylations represent a more attractive route for the synthesis of biaryls. Thereby, an unfunctionalized (hetero)arene is directly used as substrate.
The earliest example of a direct arylation reaction was reported by Ames in 1982 and Ohta in 1989.[94] The C–H functionalization proceeded through the intramolecular cyclization of 3-bromo-4-phenylaminocinnoline (43) (Scheme 26). Thereby, a variety of useful polycyclic aromatic compounds could be synthesized.[95] In 2004, Fagnou reported on an elegant synthetic route for the synthesis of six- and seven-membered cycles through intramolecular C–H arylation with a low catalyst loading.[96] Moreover, indoles, pyrroles, furans and thiophenes could be arylated in a chemo- and site-selective fashion.[97] Proposed mechanisms include precoordination of the palladium to the heteroatom, as well as an electrophilic mechanism involving ArPd(+II) species. The selectivity of the C–H arylations strongly depends on the electronic properties of the electrophiles and substrates, on the nature of the palladium catalyst, as well as the additives in the reaction.
Scheme 26: Early example of an intramolecular palladium-catalyzed direct arylation.
Electron-rich heteroarenes were amenable for palladium-catalyzed direct arylations, whereas their electron-deficient analogs were more difficult to address due to their less reactivity and instability of substrates. Arylation reactions of electron-deficient pyridines continued to be challenging. Arylpyridines could be obtained by traditional cross-couplings of prefunctionalized pyridines,[98] whereas direct C–H bond functionalizations were achieved only in recent years.[99] In 2005, Fagnou presented C–H functionalizations of pyridine N-oxides 45 via palladium-catalyzed direct arylations (Scheme 27).[100] Ongoing progress in the field and mechanistic studies illustrated that an acetate-assisted CMD pathway was a possible mechanism.[101]
Scheme 27: Carboxylate-assisted palladium-catalyzed direct arylation of pyridine N-oxide 45.
Intramolecular competition experiments with fluorinated arenes were accomplished by the group of Echavarren.[102] The experiments revealed that the functionalization takes place at the most acidic C–H bond in the substrate 49 (Scheme 28). The effect of the substituents and the resulting substitution pattern on the aryl excluded an electrophilic aromatic substitution as the mechanism. Additional computational studies supported a CMD-type mechanism.
Independently, the group of Fagnou reported the direct arylation of perfluoroarenes with similar results.[103]
Scheme 28: Intramolecular competition experiment by Echavarren.
An early example was presented by Satoh and Miura for the direct arylation of 2-phenylphenols 52 with aryl iodides 53 (Scheme 29).[104] The inorganic base Cs2CO3 was of crucial importance for the reaction. Monoarylated products were more favored by the use of Pd(OAc)2 as the catalyst, while more diarylated product formation was observed with PdCl2.
Scheme 29: Palladium-catalyzed arylation of 2-phenyl phenol (52).
Intensive studies on the heteroatom-substituted secondary phosphine (HASPO) ligands have been done by the group of Ackermann for direct C–H arylations.[105] The air-stable and easily accessible preligands provided access to several substituted aryl moieties, such as C-3 substituted indoles and pyridines through palladium catalysis.[106]
Rhodium-catalyzed direct arylations of 2-arylpyridines 55 with arylstannanes 56 were accomplishes by Oi and Inoue (Scheme 30).[107] Later on, less-toxic aryl boranes could be used as arylating agents by Satoh and Miura.[108]
Scheme 30: Rhodium-catalyzed arylation of 2-phenylpyridine (55).
Bedford and coworkers showed that phenols 59 could be used for the rhodium-catalyzed arylation (Scheme 31).[109] In the presence of the Wilkinson catalyst, the reaction proceeded via an ortho-metalation through chelation-assistance of the corresponding in situ formed phosphite. Several 2-arylated phenols, such as 61 could be synthesized by this elegant
Scheme 31: Phosphine-assisted direct arylation by Bedford.
An early ruthenium-catalyzed direct arylation was reported by Oi and Inoue with phenylpyridines 55 and aryl bromides 63 (Scheme 32).[30] Considerable progress in this area was accomplished by the group of Ackermann,[87, 110] among others when using phenylpyridines 55 and aryl chlorides[111] or aryl tosylates[112] as electrophiles.
Scheme 32: Ruthenium-catalyzed arylation of pyridine 55.
In palladium chemistry, the addition of carboxylic acid facilitates the direct arylation via a concerted deprotonation/metalation mechanism.[9] Carboxylate assistance was also useful in ruthenium-catalyzed arylation reactions.[113, 114]
The addition of various acids, such as mesitylcarboxylic acid (64), allowed inter alia for the direct arylation of triazoles, pyridines, pyrazoles or oxazolines with aryl halides 66 (Scheme 33).[113] A mechanism via concerted metalation-deprotonation was suggested.
Scheme 33: Carboxylate-assisted ruthenium-catalyzed C–H arylation.
Transition metal-catalyzed direct arylations have been studied in great detail, and a number of synthetically useful protocols was devised for the synthesis of bi(hetero)aryls. In contrast, the direct functionalization of unactivated C(sp3)–H bonds is a more difficult problem and therefore remains a challenge. In regard to the unsaturated hydrocarbons like alkanes, orbital interactions between the substrate and the metal center are unlikely to occur. An
alternative example of such cross-coupling chemistry for the arylation and alkylation of O-methyl hydroxamic acids with arylboronic reagents by the use of monodentate directing groups was reported by Yu.[115] Only a few direct arylations of unactivated C(sp3)–H bonds[116] could mechanistically be rationalized in terms of agostic three-center two-electron interactions, between the C–H bond and the metal atom.[6, 116] One of the earliest examples using the 8-aminoquinoline as a bidentate directing group was presented by the group of Daugulis (Scheme 34).[117, 118]
Later on, with 2-methylthioaniline as an auxiliary, Daugulis achieved selective monoarylations of primary C(sp3)–H bonds.[119]
Scheme 34: 8-Aminoquinoline-assisted palladium-catalyzed direct arylation by Daugulis.
A pyridine containing bidentate directing group, such as substrate 72, for arylation reactions with aryl bromides 60 and iodides under palladium catalysis, was recently reported by B.-F.
Shi (Scheme 35).[120] Furthermore, nickel-catalyzed functionalizations of 2,2-disubstituted propionamides were performed using aryl iodides and aryl bromides as the electrophiles.[121]
Scheme 35: Direct arylation of unactivated C(sp3)–H bonds by B.-F. Shi.