2- Substituted imidazoles, preparation

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]. 

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-... 

With sUght modifications of these conditions it is possible to prepare mono N-substituted imidazoles (Scheme 5), the reaction working well with aliphatic amines but not with many aromatic amines. The imsymmetrical... 

Burgess followed a similar strategy for the preparation of the salts 8 (Scheme 7). On that occasion several routes to mono-N-substituted imidazoles were explored yielding the desired compoimds in variable yields depending on the nature of the amines. The chirality was introduced via alkylating reagents 9 bearing chiral oxazolines [15]. 

Gade and Bellemin-Laponnaz have reported the synthesis, in good yields, of chiral oxazoline-imidazoliums salts 10a (Scheme 8) obtained by reaction of 2-bromo-4(S)-t-butyl oxazoline with several mono-N-substituted imidazoles [16]. Similaly an imidazolium salt 10b bearing a paracyclophane substituent was prepared by Bolm [17]. 

The O-silylated acyloins such as 1920 c and 1927 are useful synthons for preparation of five-membered aromatic heterocycles such as the substituted imidazole 1925, pyrrole 1926, and furan 1928 [119] (Scheme 12.35). 

Further examples for the preparation of 4(5)-substituted imidazoles with AT-sulfa-moylimidazoles are given below. In these cases both the sulfamoyl and the silyl groups are used as protecting functions (bisprotection of the imidazole moiety). 163... 

From silylated iV-sulfamoyl-protected imidazoles or pyrazoles, imidazolyl or pyr-azolyl anions can be generated with the strong base CsF (carbodesilylation) and subsequently treated with electrophiles. In this way 5-substituted imidazoles or pyrazoles can be prepared after the deprotection of N(l) [181... 

Table 20-1. N-Substituted imidazoles and triazoles prepared by transfer reactions of azolides A—F with tertiary alcohols of the triphenylmethanol type and analogues.

The microwave activation of Michael additions in the preparation of N-substituted imidazoles afforded excellent yields in very short reaction times under mild reaction conditions, Scheme 10.9. Basic clays (Li+, Cs+) exchanged montmorillonites were found to be very active and selective catalysts for the Michael addition of imidazole and ethyl acrylate [54]. 

The 4(5)-amino-2-substituted imidazoles (45) and (46) have been prepared (50JCS2775) by condensation of aminoacetonitrile (30) with the thio-iminoether hydrochloride salts (40) and (41), respectively. These 4(5)-aminoimidazoles (45, 46) were isolated as their hydrochloride salts in yields of 36 and 90% (Scheme 3). 

This procedure provides a convenient synthesis of aminomalononitrile, which has been demonstrated to be a useful intermediate for the preparation of substituted imidazoles, thiazoles, oxazoles, purines, and purine-related heterocycles.2 It is also a convenient starting material for the preparation of diamino-maleonitrile.2, 4... 

Acetylated Meldrum s acid 172 and a-aminoesters 173 have been used as the building blocks to prepare the substituted imidazoles 174, which are then cyclized to give optically active dihydro products 175 <20030L3907> (Scheme 7). A modified four-component LJgi reaction has been used to prepare dihydro products 177 from the intermediate functionalized imidazole 176, isonitriles, and amines (Equation 24) <2005EJ04670>. 

Two independent papers have reported the synthesis of nitrogen-heterocycle complexes of the type [RhCl3(py-X)3] (py-X = 3-Etpy, 3-CNpy, 4-Etpy, or 4-CNpy) and rr(ans-[RhY2L4] (Y = Cl or Br L = several substituted pyridines, isoquinoline, pyrimidine, pyrazole, thiazole, and substituted imidazoles). All the compounds were prepared catalytically by boiling RhCl3.3H20 with ethanolic solutions of L. It is interesting that 2-substituted... 

A similar type of transmetalation was also seen with l,2-dimethyl-5-trimethylstannylimidazole, which gave the 5-lithio derivative at -100°C, but rearranged to the 2-lithiomethyl derivative at higher temperatures [83JCS(P1)271]. However, transmetalation does not occur with Grignard reagents and 5-substituted imidazoles can be successfully prepared via this route (Scheme 49) (81 Mil 82OPP409). 

In a recent study, Fernandez-Bertran et al. used mechanochemical reactions to prepare a number of hemin complexes with amino acids such as arginine, histidine, lysine, methionine and tryptophan. The basic amino acids react with the hemin peripheral propionic acid groups, while arginine is also able to form a pentacoordinated complex at the Fe(III) centre. The reactions were followed by IR and Mossbauer spectroscopies [77a]. The solid-state reaction of hemin with KCN, Na2S and various substituted imidazoles has also been investigated [77b]. 

Imidazo[4,5-r-]isoxazole 39 <1999J(P1)817>, first prepared by Tennant et al., undergoes reduction of the N-O bond under classical hydrogenation conditions, to yield the substituted imidazole 43 in excellent yield (Equation 7). 

In conclusion, although satisfactory condensation reactions are available to prepare most of the desired substituted imidazoles, there is a continuing interest in new, less elaborate and more flexible, synthesis routes. 

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. 

In conclusion, the deprotonation approach to functionalise imidazoles has proved to be feasable and constitutes a new flexible method for the preparation of especially 4(5)-mono-substituted imidazoles in a straight forward manner (figure 12). 

Since the disclosure of thioperamide 1 (K = 4 nM) as a potent and selective histamine H3 receptor antagonist [1], there has been a large number of 4(5)-substituted imidazole derivatives prepared and evaluated for their H3 receptor affinity. Most of the efforts directed towards the design of new H3 antagonists have... 

Carboximidoyl chlorides may be reacted with oximes to give 30-65% yield of amidines, which may then be used to form imidazoles in good yields, by treatment with TsOH (equation 201)716. Highly substituted imidazoles may be prepared in a simple one-pot synthesis by treating vicinal tricarbonyl compounds with an aldehyde and ammonium acetate (equation 202)717. The reaction occurs in 66-90% yield and seems to be general in scope. 

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