Synthesis of imidazoles

Many biologically active therapeutic agents contain five-membered heterocycles.92 The imidazole ring system is of particular interest since it is a component of histidine and its decarboxylation metabolite histamine. The wide applicability of the imidazole pharmacophore can be attributed to its hydrogen bond donor-acceptor capability as well as its high affinity for metals which are present in many protein active sites (e.g. Zn, Fe, Mg). Furthermore, improved pharmacokinetics and bioavailability of peptide-based protease inhibitors have been observed by replacing an amide bond with an imidazole. 

Based on a four component condensation reaction (the Ugi reaction ), Mjalli et developed a solid-phase protocol for the synthesis of tetrasubstituted imidazoles. Because of the limited number of commercially available isocyanides, the selected strategy started with the generation of an isocyanide component tethered to Wang resin. 

Reagents and conditions-, i) PhjP, CCI4, EtaN, CHjCIa ii) arylglyoxals 210, R -NHj, R -COOH  

The length of the isocyanide linker, the electronic nature of the aryl glyoxals, the use of different primary amines (with exception of aniline), as well as the use of both aliphatic and aromatic carboxylic acids, showed no effect on the yield of the imidazoles 213. 

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A/-Chloroamidines are usehil for preparation of biocidal imidazoles (106) and thiadiazolines (107). Ai-Chloroguanidines, RNHC(=NC1)NHR, serve as starting materials for synthesis of imidazoles, oxadiazoles, and thiadiazoles (108,109). 

A number of microwave-assisted multicomponent methods for the synthesis of imidazoles have been reported [68-71 ]. The irradiation of a 1,2-diketone and aldehyde with ammonium acetate in acetic acid for 5 min at 180 °C in a single-mode reactor provides alkyl-, aryl-, and heteroaryl-substituted imidazoles 39 in excellent yield (Scheme 14) and this method has been used for the rapid and efficient preparation of two biologically active imidazoles, lepidiline B and trifenagrel [68]. 

Scheme 15 Other microwave-assisted methods for the synthesis of imidazoles...

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

R = Aromatic R = H, aliphatic, yields 85-90% Scheme 13 Synthesis of imidazoles on alumina... 

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... 

Silica gel or zeolite HY have also been used successfully for the synthesis of imidazoles, isoxazoles, and pyrazoles [59], under irradiation, without solvent (Scheme 8.39). 

Liu W et al (2010) Compact biocompatible quantum dots viaRAFT-mediated synthesis of imidazole-based random copolymer ligand. J Am Chem Soc 132 472-83... 

It has been demonstrated that the reaction of azole A -oxides with cycloalkane thiones offers a simple and efficient route to azole-thiones. The described reaction sequence has subsequently been found to constitute a useful synthesis of imidazole-2(3//)-thiones (see Scheme 16). 

Gelens E, De Kanter FJJ, Schmitz RF et al (2006) Efficient library synthesis of imidazoles using a multicomponent reaction and microwave irradiation. Mol Divers 10(1) 17-22 Acke DRJ, Orru RVA, Stevens CV (2006) Continuous synthesis of tri- and tetrasubstituted imidazoles via a multicomponent reaction under microreactor conditions. QSAR Comb Sci 25(5-6) 474-483... 

Ferraccioli and co-workers (131,132) employed the reaction of mtinchnones with N-(phenylsulfonyl)imines as a general synthesis of imidazoles (228) (Table 10.6). Regioselectivity is very high and was determined using NOE measurements. The authors utilize the perturbation MO treatment, which is less approximate than the FMO method, to predict correctly the observed regiochemistry. 

Synthesis of imidazoles, oxazoles and thiazoles from acylamino ketones 569... 

Few publications are devoted to the synthesis of imidazole derivatives the reaction between A-chloro-A -benzenesulfonylamidines with enamines shown in Scheme 9 serves as an example (87T4785). 

The synthesis of imidazoles and the evaluation of their pharmacological activities can therefore be considered to be the key to a better understanding of the histamine receptors. Further new developments such as combinatorial technologies and the uprise of molecular biology will certainly play an important role in the need for and the synthesis and evaluation of new substituted imidazoles in the coming years. 

Figure 4. The synthesis of imidazoles using conventional condensation aproaches.

An alternative way to synthesize imidazoles in a more flexible manner is to use a synthon. An example of such a synthon approach, is the synthesis of imidazoles using tosylmethyl isocyanide (TOSMIC). The original procedure using this synthon gave only moderate overall yields of the substituted imidazoles18, mainly due to the poor yield in the first step (figure 7). 

However, recently the yield of the first step of this imidazole synthesis was improved dramatically by replacement of the basic catalyst (tBuOK) by a milder basic catalyst, sodium cyanide19. Due to these milder reaction conditions a greater variety of aldehydes, one of the starting materials for the synthesis of imidazoles, can be used increasing the flexibility of the method20 even more. This synthon approach can also be used to prepare the bioiscsteric substituted thiazole analogs21. 

Figure 8. Improved synthesis of imidazoles using TosMIC.

Figure 15.22 Synthesis of imidazole-based cationic lipids.

Scheme 2.31. Synthesis of imidazole wo tandem Ugi-4CR/Davidson reactions.

The utility of TOSMIC in MCR reactions has also received recent interest in the pharmaceutical arena as an approach to the preparation of imidazoles 91. Originally reported by van Leusen in 1977 [76], and involving cycloaddition of tosyl-methyl isocyanides to carbon-nitrogen double bonds, recent elegant work by Sisko et al. has heightened its profile with the description of a one-pot synthesis of imidazole 92, a potent inhibitor of p38 MAP kinase, implicated with the release of the pro-inflammatory cytokine TNF-a (Scheme 11.19) [77]. In this particular example a fluorinated analogue of TOSMIC 90, is employed. 

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>. 

Vasiliy Bakulev was bom in Ekaterinburg, Russia. He obtained his Ph.D. in 1979, under the guidance of Prof. Vladimir Mokrushin, on the synthesis of imidazole derivatives. Then he studied electrocyclic reactions of diazocompounds and azomethyneylides and, in 1990, defended the second thesis of Doctor of Science (similar to Habilitation Degree) at Moscow State University. He received a diploma of Professor in 1998. Jointly with Wim Dehaen, he published a book on the chemistry of 1,2,3-thiadiazoles in 2004. He is currently professor at the Organic Synthesis and Technology Department of the Urals State Technical University (Ekaterinburg, Russia). 

The synthesis of imidazoles has also been effected using this cyclization procedure.100 The synthesis which is analogous to that of the thiazole case utilizes a-cyanoalkyl cyanamides (158) and yields products having the structure 159. Hydrogen bromide, only, was used... 

Casey, M., Moody, C.J. and Rees, C.W. (1984) Synthesis of imidazoles from alkenes. Journal of the Chemical Society, Perkin Transactions 1, (8), 1933-1941. 

The photolysis of enaminonitriles provides a convenient and direct one-step synthesis of imidazoles. l,6-Dihydroimidazo[4,5-d]imidazole was prepared by the photochemical rearrangement of 3-aminopyrazole-4-carbonitrile (76JOC19) and by photolysis of 4-aminoimidazole-5-carbonitrile (74JA2014) (equation 71). The precise nature of the reaction intermediates (if any) formed on irradiation of enaminonitriles remains to be determined. However, the direct photochemical inversion of the nitrile to isocyanide is a possibility. 

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