Arylation of imidazoles

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

Under copper catalyzed conditions azoles (i.e. imidazoles) couple not only with aryl halides but also with arylboronic acids. The reaction, run in the presence of oxygen, follows a unique path (for details see Chapter 2.5.). From the synthetic point of view, the arylation of imidazole proceeds in good yield, although the regioselectivity in the arylation of 4-substituted imidazoles is only moderate (6.70.),102... 

Arylations of weak organic nucleophiles are best achieved with iodonium salts possessing nucleofugic anions and, in some cases, can be facilitated with transition metal catalysts. Recent examples include Cu(II)-catalyzed S-phenyla-tions of 1-benzothiophenes with diphenyliodonium triflate [118], and Co(II)-catalyzed N-arylations of imidazoles with diaryliodonium tetrafluoroborates (Scheme 42) [119]. 

Protons at C2 of imidazole 1-oxides 228 are acidic and are exchanged with deuterium even in weakly acidic solution. The exchange rate increases with increasing pH (2004S2678). Although the mechanism is not fully understood, the palladium-catalyzed direct arylation of imidazole 1-oxides most likely involves deprotonation so that the observed regi-oselective arylation reflects the propensity to proton abstraction found to decrease in the order C2 > C5 > C4 (2009JA3291). 

The palladium-catalyzed and the copper-cocatalyzed direct arylation of imidazole 1-oxides 280 shown in Scheme 83 may involve transmetallation (2008JA3276, 2009JA3291). However, classical transmetallation like conversion of imidazolyllithium compounds to imidazolylzinc compounds has not been reported. 

The mildness of the conditions of reaction and the regioselectivity of the /V-arylation of imidazoles allowed the A-arylation of the azolic nitrogen of a protected histidine 87, even with the organolead reagent 88 derived from tyrosine, thus realizing the link between two aminoacid derivatives moieties (Equations (89) and (90)).1... 

Benzotriazole was found to be an efficient ligand for the Cu(I) iodide-catalyzed N-arylation of imidazoles with aryl and heteroaryl halides <07TL4207>. The first enantioselective conjugate addition reaction of I //-benzotriazole with a variety of enones catalyzed by a cinchona alkaloid thiourea affords Michael adducts in good yields with moderate to good enantioselectivities has been reported <07S2576>. 

Phosphoramidite 216b was reported as an effective ligand for copper to catalyze C-N bond formation in N-arylation of imidazole or benzimidazole with aryl iodides <2006T4435>. The reaction could be carried out at 90 °C and produced moderate to high yields (65-90%). 

Preformed, stable copper catalysts, such as aminoarenethiolate copper(l) are also effective catalysts for mediating N-arylation of imidazole and benzimidazole (Figure 39) <20050L5241>. 

In contrast to the apparent need to conduct the copper-catalyzed reactions of arylboronic acids and amines in the presence of oxygen, the A-arylation of imidazoles was reported with 5 mol% of [Cu(OH)tmeda]2Cl2 in a mixture of NMP and water under a nitrogen atmosphere (equation 74)302. 

Diarylimidazoles were prepared by Suzuki cross-coupling reactions of imidazole halides with arylboronic acids <05H(65)1975>. Suzuki cross-coupling reactions of 6-bromoimidazo[l,2-a]pyridines have been developed <05H(65)2979>. Cul-catalyzed iV-arylation of imidazoles and benzimidazoles with aryl bromides was achieved in a near-homogeneous system that utilized tetraethylammonium carbonate as base, 8-hydroxyquinoline as ligand and water as cosolvent <05JOC10135>. 

This system catalyzed N-arylation of imidazole and pyrazole and benzimidazole with aryl bromides. N-Amidation and O-arylation were also catalyzed using this reagents system [8, 9] (Scheme 5.4). 

N-Arylimidazoles Arylation of imidazoles is efficiently catalyzed by a copper complex in the air. 

In 1999 Combs and colleagues published a procedure for N-arylation of imidazoles, pyrazole, and 1,2,3-triazole attached to a solid support [124]. Interestingly, they used p-tolyl boronic acid as the arylating agent when employing Cu(II) cataly-... 

A stoichiometric quantity of 1,10-phenanthroline (L13) was the first ligand used for copper-catalyzed arylation of imidazole with aryl iodides (Table 9.4, entry 1) [18]. As an ejctension of this methodology, Cu2O/4,7-dimethoxy-l,10-phenanthroline (LI4) was found to be more effective, the coupling reaction occur-ing at 80-110 °C in the presence of CS2CO3 and using n-PrCN as a solvent (entry 2 ) [19, 20]. 

In addition, ethyl 2-oxocyclohexanecarboxylate (L19) [27] could promote the copper-catalyzed N-arylation of imidazoles and benzimidazoles under relatively mild reaction conditions (45-75 °C) (entry 6). 

Elucidating the Mechanism of Cu(ll]-Catalyzed Arylation of Imidazole and Phenylboronic Acid by a Multitechnique Approach... 

A new procedure for iV-arylation of imidazole that obviates added ligands entirely has been described, where Ullmann-type coupling is achieved under very mild conditions (<40 °C in DMF). Although aryl iodides are needed, and the procedure calls for 20 mol% Cul, considerable variety within the aryl substrate can be tolerated a nitro group, bromide, ester, amide, anil aldehyde all smoothly couple. Noteworthy is the observation that neither a free phenolic OH nor an anilino 1 2 group within the iodide competes with imidazole. 

Typical procedure for N-arylation of imidazole with chloroarenes. l-(2-Chloro-4-nitrophenyl)-IH-imidazole ... 

The less-weU studied C-2 arylation of imidazoles and benzimidazoles using aryl chlorides was reported by Shao and coworkers (2014JOC5806). 

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