Imidazole library

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

The cyclization of 1,2-dicarbonyl compounds with aldehydes in the presence of NH4OAC to give imidazoles was employed in a combinatorial study that compared conventional and microwave heating in the preparation of a library of sulfanyl-imidazoles (Scheme 15). The study employed an array of expandable reaction vessels that could accommodate a pressure build-up system for heating without loss of volatile solvents or reagents. A 24-membered library of imidazoles (48 and 49) was prepared in 16 min instead of the 12 h required using conventional heating [45]. 

The construction of a custom-built parallel reactor with expandable reaction vessels that accommodate the pressure build-up during a microwave irradiation experiment has also been reported [88]. The system was used for the parallel synthesis of a 24-member library of substituted 4-sulfanyl-lH-imidazoles [88]. 

A different multicomponent route to imidazoles has been described by the group of O Shea, involving the diversity-tolerant three-component condensation of an aldehyde, a 2-oxo-thioacetamide, and an alkyl bromide (5 equivalents) in the presence of ammonium acetate (Scheme 6.201) [364]. This allowed the preparation of a 24-membered 4(5)-alkylthio-lH-imidazole demonstration library from 21 different aldehydes, 12 alkyl bromides, and two 2-oxo-thioacetamides. The library was synthesized in a parallel format using a custom-built reaction vessel. Alkylthioimidazoles... 

A parallel library of optically active bicyclic tertiary amines 127 bearing N-chiral bridgehead nitrogen atoms was readily prepared by condensation of primary amines, cyclic amino acids 126, and aldehydes. This method gives access to a large variety of substituted hexahydro-l/7-pyrrolo[l,2-/ ]imidazol-l-ones of type 127 (Scheme 16). These... 

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... 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

Coleman, C.M., MacElroy, J.M.D., Gallagher, J.F. and O Shea, D.F., Microwave parallel library generation comparison of a conventional- and microwave-generated substituted 4(5)-sulfanyl-lH-imidazole library, /. Comb. Chem., 2002, 4, 87-93. 

Coleman and co-workers36 performed a three-component reaction employing 2-oxothioacetamides, aldehydes and alkyl halides in ethanol with Na2 C03 as the catalyst to form a 24-member library of substituted 4-sulphonyl-l-ff-imidazoles (Scheme 5.20). The products were formed in yields of 40-96% and purities of 20-96%. The library was synthesised in a custom-built reaction block with expandable reaction vessels. The expandable reaction blocks were designed to accommodate the expanding gas volume caused by the elevated temperature without releasing any of it into the cavity. Unfortunately, this approach limited the temperatures used in the reactions to the boiling point... 

Allthough this SPS route averted some of the problems inherent to the synthesis of substituted imidazoles via condensation approaches, the value of the synthesized libraries of compounds is of a limited interest for the histamine receptor research field. First, there is only a limited number of glyoxals, one of the four reaction components, available as precursor. Secondly, only tri- and tetra-substituted imidazoles can be prepared via this method. And finally, the linker (H0-C(=0)-(CH2)2-), a pharmacophore not common to histaminergic ligands, remains present in the final product. 

These drawbacks ask for further development of new solid phase synthesis methods to prepare imidazole libraries for the discovery of compounds active at histaminergic receptors. 

Condensation of 1,2-diketones with aldehydes in the presence of NH4OH constitutes an efficient approach towards trisubstituted imidazoles. Impressively, under dielectric heating conditions (180 °C), the cyclocondensation reaction required merely 5 min to go to completion [39]. Moreover, analytically pure products were easily isolated from the reaction mixture by a neutralization-filtration sequence. The high speed of the reaction combined with the ease of product isolation rendered the cyclocondensation especially suitable for the generation of imidazole libraries (Scheme 15). 

Scheme 16 Preparation of a library of imidazoles under microwave irradiation...

Scheme 17 Microwave-accelerated parallel synthesis of 4(5)-sulfanyl-lH-imidazole library...

Workers at Ontogen [82,83] reported the use of the OntoBLOCK system which utilizes a Tecan robot. They have implemented this technology for solid-phase synthesis to generate over 50 000 compounds corresponding to libraries of pyrroles, phosphonates, phosphinates, lactams, imidazoles, hydantoin imides and thioimides, oxazoles, and b-lac-tams. These libraries have resulted in potent and selective inhibitors of iNOS, PTPases and cdc25 phosphatase and compounds that reverse the P-glycoprotein (Pgp)-based multiple drug resistance (MDR) phenomenon in cellular assays and in animal models [98],... 

Sarshar S, Siev D, Mjalli AMM, Imidazole libraries on solid support, Tetrahedron Lett., 37 835-838, 1996. 

In the imidazolium salts 63, obtained by nucleophihc substitution of the iodo-derivative 61 by an imidazole 62, the oxazoline is bnked by the carbon atom in the 4-position. Coordination of the bidentate bgand to the Ir(COD) + complex fragment is then achieved by in situ deprotonation (Scheme 43). This modular design allows facile and rapid access to a large ligand library by variation of the substituents in the 2-position of the oxazoline and at the terminal N-atom of the heterocyclic carbene. 

With these techniques, libraries have been created of many classes of NCEs some of which include peptides, peptoids, prostaglandins, imidazoles, alkaloids, heparins, oxazoles, benzodiazepines, and P-lactams. 

Activation of amide bonds with an acid (usually at elevated temperatures) to facilitate the 1,2- (or 2,3-) bond formation is a useful method to prepare imidazoles and benzimidazoles (see Section 4.02.9.2(i)). For example, )3-ketoester 1093 possessing a diamino acid (diaminobutanoic acid or ornithine) group is activated by AcOH to form bicyclic imidazole 1094 <2003SL780>. A library of imidazolines, exemplified in Scheme 265, was prepared from Ugi products under acidic conditions <1999TL7925>. 

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