Imidazoles 2,4-diaryl

Imidazole, 1,2-diamino-4-phenyl-oxidation, S, 440, 454 Imidazole, 4,5-diaryl-synthesis, S, 481 Imidazole, diazoreactions, S, 96... 

Triazepine, 5-benzyl-3,7-diaryl-4,6-dihydro-imidazole synthesis from, 5, 497... 

Bristol-Myers Squibb has recently disclosed two different series of carbamate-based FAAH inhibitors. The first of these is a series of 4,5-diaryl-imidazoles in which 30 compounds are specifically claimed, an example being compound (57). This compound is reported to have an IC50 value of < 10 nM. In addition, (57) was also active in vivo in rodent models of chemo-induced, thermal and neuropathic pain [72]. The second series of compounds is based on oxime carbamoyl FAAH inhibitors such as (58). Compound (58) is reported to have an IC50 value of < 10 nM and activity in rodent models of inflammatory pain, thermal pain and inflammatory oedema [73]. 

Patent applications from Pfizer disclosed 1,5-diaryl-pyrazoles bearing bioisosteric replacements for the 3-carboxamide moiety. One application showed that the amide could be replaced by a-aminoketones as exemplified by compound (416) [284]. The corresponding alcohols and their ethers were also described, including compounds that allowed the amine substituent and ether to form a ring system, such as a morpholine unit. This application also allowed for the replacement of the 1,5-diaryl-pyrazole by a 1,2-diaryl-imidazole bearing a 3-carbonyl substituent, as exemplified by compound (417). A further patent application from Pfizer claims compounds in which imidazoles replace the 3-carboxamide moiety in the 1,5-diaryl-pyrazole... 

A closely related protocol for the synthesis of imidazoles was independently investigated by Sparks and Combs (Scheme 6.199) [362]. Here, the authors employed readily available unsymmetrical keto-oximes as building blocks, initially leading to N-hydroxyimidazoles. Diaryl keto-oximes were condensed with various aldehydes (1.1 equivalents) in the presence of 4 equivalents of ammonium acetate under microwave conditions at 160 °C. In this way, the N-hydroxyimidazoles were formed... 

A related series of diaryl pyrrolo[l,2-a]imidazoles, represented by SK F 104351 (149), 104493 (150) and 105809 (151), has been reported to show similar profiles [360,366]. In mice and rats, SK F 105809 was a prodrug for the active methyl sulphide SK F 105561 (152), which was about 10-fold more potent in vitro than SK F 86002 [367]. The in vivo profile of SK F 105809, which is reported to be in clinical trials, was similar to that of SK F 86002. 

Die aus l,2-Bis-[amino-imino-methyl]-hydrazin mit Benzoinen gebildeten 1,2-Bis-[4,5-diar-yl-imidazol-2-yl]-hydrazine (Hydrazo-imidazole) werden bereits bei ihrer Herstellung durch Luftsauerstoff zu den entsprechenden Bis-[4,5-diaryl-2-imidazolyl]-diazenen oxi-diert109 ... 

Statt der N-Acyl-Verbindungen konnen auch die entsprechenden a-Chlor-immonium-chloride cyclisiert werden. So erhalt man durch Einleiten von Ammoniak in Losungen von N-Aryl-N-(aryl-chlor-methylen)-N-(l,2-diaryl-2-oxo-ethyl)-ammonium-chloriden in Dichlormethan 1,2,4,5-Tetraaryl-imidazole in sehr guten Ausbeuten von 85-97% (insgesamt 10 Deriva-te)240... 

Aus den entsprechenden 5-Benzyl-3,7-diaryl-3,4,6,7-tetrahydro-5H-l,2,5-triazepinen erhalt man beim Kochen mit Brom in Methanol l-Benzyl-4-phenyl-imidazoI (49%) bzw, 1-Benzyl-4-(4-methyl-phenyl)-imidazol (36%). Bei 20° entstehen dagegen die entsprechenden 3,6-Diaryl-pyridazine443. 

Diaryl-5-thiono-4,5-dihydro- oder 5-Alkylthio-4,4-diaryl-4,5-dihydro-imidazole lagern sich in Gegenwart von Lewissauren wie Aluminiumchlorid oder Galliumbromid unter Entschwe-felung in 4,5-Diaryl-imidazole um1220,1221 z.B. ... 

The heteroaryl Heck reaction is an efficient tool for the introduction of other five membered heteroaromatic systems too (for more details see Chapter 6.4.). Chloropyrazines reacted readily with oxazole to give the coupled product (7.57.), consisting solely of the 5-oxazolyl isomer.77 Extension of the reaction to imidazole led to a similar observation,78 and the expected 5-pyrazyl-imidazole derivative was isolated in acceptable yield. Reactions using thiophene as the masked olefin gave similar results. Under forcing conditions the 2,5-diarylation of fiiran was also observed.77... 

A short synthesis of imidazoles 47 was discovered on the basis of the reaction of 3,5-diaryl-l,2,4-dithiazolium triiodides 46 (X = I3) with glycinates or aminoacetonitrile. Intermediate (thiocarbonyl)amidines 48 were oxidized in situ to 1,2,4-thiadiazolium salts 49 by the triiodide anion resulting in imidazoles 47. The same reaction with 3,5-diaryl-l,2,4-dithiazolium perchlorates 46 (X = C104) stops at the formation of amidines 48 due to the lack of an oxidizing counterion (Scheme 3) <1997JOC3480>. 

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 -... 

Imidazole rings also survive most oxidation conditions, but photosensitized oxidation of imidazoles can give diaryl-benzamidines through a hydroperoxide, e.g. 199. 

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... 

With phosphoryl chloride in alkali, imidazole gives the diphosphoryl imidazole (71) while 1-methylimidazole gives an analogous product. Such iV-phosphorylimidazoles play an important role in enzymic transphosphorylation. When two moles of imidazole (or benzimidazole) react with one mole of dialkyl (or diaryl) phosphoric acid chloride, the compounds (72) are formed, and di- and tri-imidazolides of phosphoric acid (e.g. 73) can be obtained similarly from phosphoric acid dichloride or from phosphoryl chloride (Scheme... 

Many of the classical methods grew out of the earliest synthesis of imidazole, which was achieved in 1858 by Debus [1] when he allowed glyoxal, formaldehyde and ammonia to react together. Although the earliest modifications of this method used a-diketones or a-ketoaldehydes as substrates [2, by the 1930s it was well established that a-hydroxycarbonyl compounds could serve equally well, provided that a mild oxidizer (e.g. ammoniacal copper(ll) acetate, citrate or sulfate) was incorporated [3. A further improvement was to use ammonium acetate in acetic acid as the nitrogen source. All of these early methods have deficiencies. There are problems associated with the synthesis of a wide range of a-hydroxyketones or a-dicarbonyls, yields are invariably rather poor, and more often than not mixtures of products are formed. There are, nevertheless, still applications to the preparation of simple 4-alkyl-, 4,5-dialkyl(diaryl)- and 2,4,5-trialkyl(triaryl)imidazoles. For example, pymvaldehyde can be converted quite conveniently into 4-methylimidazole or 2,4-dimethylimidazole. However, reversed aldol reactions of pyruvaldehyde in ammoniacal solution lead to other imidazoles (e.g. 2-acetyl-4-methylimidazole) as minor products [4]. Such... 

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