1.4- Diaryl-substituted imidazole

Nevertheless, there are certainly a number of painful limitations. There is no simple and efficient method for the synthesis of unsymmetrical N,N -diaryl-substituted imidazolium salts, very desirable compounds. Furthermore, the Buchwald-Hartwig-like cross-coupling reaction of N-monosubsti-tuted imidazoles with arylhalides, which would result in the formation of imidazolium salts, has not been reported yet. However, unsymmetrical N,N -... 

A review on the synthesis and biological activity of vicinal diaryl-substituted 1H-imidazoles has been published <07T4571>. A focus review highlighted the recent progess in the catalytic synthesis of imidazoles <07CAJ568>. 

Bromo- and iodoimidazoles are useful intermediates for further functionalization. 4(5)-Aryl- I //-imidazoles 57 can be efficiently and selectively prepared by palladium-catalyzed Suzuki-Miyaura reaction of commercially available 4(5)-bromo-l//-imidazole 56 with arylboronic acids under phase-transfer conditions, which then underwent highly selective palladium-catalyzed and copper(I) iodide mediated direct C-2-arylation with a variety of aryl bromides and iodides under base-free and ligandless conditions to produce 2,4(5)-diaryl-l//-imidazoles 58 in modest to good yields <07JOC8543>. A new procedure for the synthesis of a series of substituted 2-phenylhistamines 60 utilizing a microwave-promoted Suzuki... 

Lithiation of l-aryl-17/-imidazoles followed by quenching with electrophiles provided a route to 1,2-diaryl, l-aryl-2-cycloalkyl- and l-aryl-2-heterocycle-substituted imidazoles <05H(65)2721>. Isoprene-catalyzed lithiation of imidazole provided a synthetic route to 2-(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles <05X11148>. 2-Lithiobenzimidazoles were efficiently acylated with esters, lactones and lactams <05TL5081>. 

Synthesis and biological activity of vicinal diaryl-substituted l//-imidazoles , Beilina, F., Cauteruccio, S., and Rossi, R., Tetrahedron, 2007, 65, 4571. 

The N-heterocychc carbene-paUa(iitim(II)-l-methyhmidazole [NHC-Pd(II)-Im] catalyst system utilized in this procedure required potassium i-butoxide as base and the inclusion of 0.5 equiv. of water for optimal activity and produced higher yields when electron-rich aryl hahdes were introduced as coupling partners. Touzani, Doucet, and coworkers estabhshed that 2,5-diarylation of 1-substituted imidazoles by aryl bromides (160 X = CH) was promoted by the use of 2 mol% Pd(OAc)2 in the presence of the base CsOAc (2014TET8316). Optimal yields were observed with 1-methyhmidazole (159) while l- -butyhmidazole, l-aryHmidazole, and 1 -benzylimidazole all displayed reduced yields. One example of diheteroar-ylation using 3-bromopyridine (160 X = N, R = H) afforded the coupled product 161 (X = N, R = H) in 72% yield. 

Alditol-l-yl substituted pyrroles or pyrazoles (e.g. 88 and 89) were obtained by addition to per-<7-acetylated 1,2-dideoxy-l-nitro-D- a/acm- and D-manno-l-hep-tenitols of the sodium salt of tosylmethyl isocyanide or the zwitterionic diaryl nitrile imines (e.g. PhC=N -N Ph), respectively. A general one-pot synthesis of alditol-l-yl substituted imidazoles (e.g. 90) involved reaction of aldoses with... 

The most general synthesis of substituted 6,7-dihydro-5/f-pyrrolo[l,2-a]imidazoles has been described in several patents. The starting materials are pyrrolidine derivatives such as the 2-iminopyrrolidine or 2-pyrrolidone (Scheme 8) <89EUP306300, 92MI 802-01 >. In the first case, the 2-iminopyrrolidine reacts with the chloroketone (57) at 40°C to give the dihydro pyrrolo[l,2-a]im-idazole (58). In the second case the 2-pyrrolidone was A -acylated by 4-picolyl chloride and the product (59) cyclocondensed with a nitrile to give the 2,3-diaryl-6,7-dihydro-5//-pyrrolo[l,2-a]im-idazole (60). 

Most of 4,5-diary 1-2-trifluoromethylimidazoles have been synthesized by the methods shown in Scheme 12.8. The imidazoles 60 are synthesized by the condensation of trifluoroacetaldehyde equivalent with applicable diaryl-1,2-diketones, where a carbonyl group is replaced with imino group in situ in the presence of ammonium acetate. The imidazole 63 is synthesized by the sequential substitution-condensation reactions of a-bromoketone 62 with trifluoroacetiminoa-mide 61. ... 

Compounds tested and found active in vitro against M. tuberculosis include 5-arylamino-3-pheny1thiazolidin-2,4-diones 2,3-diaryl-5-arylazo-4-thiazolidinethione-1,1-dioxides N-substituted benzisothia-zolin-3-thiones 5 4-(indol-3-yl)-imidazoles , indol-3-ylcarboxylic acids and hydrazides 3-halophenylazoindoles , 3,4-dihydropyrido[2,3-d]pyri-dazin-1[2H]-one 5, Schiff bases from isoniazid and substituted benzalde-hydes °, 5-n-butylpyridine-2-carboxylic acid hydrazide, 4-thiosemicar-bazido-2-[(5-nitrofuryl)vinyl]quinolones and butadiene analogs3-thio-4 3H)quinazolone derivatives, and N- ji-tolyl)-N -(2-benzothiazolyl)-N "-alkylquanidines. ... 

Direct Carbonylative Coupling. Unsymmetrical diaryl ketones were synthesized via the direct carbonylative coupling of aryl iodides and heteroarenes in the presence of catalytic [PdCl(cinnamyl)]2, l,3-bis(diphenylphosphino)propane (dppp) as the ligand, and stoichiometric Cul. Thus, heterocycles such as oxazoles, benzoxazoles, thiazoles, benzothiazoles, and imidazoles reacted, with 4-iodoanisole in 56-75% yields (eq 1). Aryl iodides containing a variety of electron-donating or electron-withdrawing substitutents were tolerated in the reaction (eq 2) however, aryl bromides provided only traces of products. The role of the stoichiometric copper salt was to form a heteroaryl-Cu species, which could easily transmetallate to Pd. No reaction was observed in the absence of the Cul additive. 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

In the heterocyclic field, sulphur substitutions include the sulphonation of quinoline to produce mainly the 8-acid, plus the 5-, 6-, and 7-acids, the chlorosulphonation of 2-(3,4-dicholorophenyl)- and 2-(3-pyridyl)-imidazole (on the imidazole ring) and of 2-(4-chlorophenyl)imidazole on both aromatic rings, the tosylation at N-3 of some 2-(monosubstituted amino)-l,3,4-thiadiazoles (which isomerise to products that are sulphonylated on the exocyclic nitrogen), and the thiolation of 2-methylindolizine with diaryl disulphides to form (53). ... 

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