Heterocycles imidazole derivatives

In a recent study, another method for microwave-assisted heterocycle synthesis leading to a small set of imidazole derivatives has been reported [54], These pharmaceutically important scaffolds were synthesized utilizing polymer-bound 3-N,N-(dimethylamino)isocyanoacrylate. This polymer support was easily prepared by treatment of [4-(bromomethyl)phenoxy]methyl polystyrene with a twofold excess of the appropriate isocyanoacrylate potassium salt in N,N-dimethylformamide (Scheme 7.37). The obtained intermediate was subsequently treated with N,N-di-methylformamide diethyl acetal (DMFDEA) in a mixture of tetrahydrofuran and ethanol to generate the desired polymer-bound substrate. 

For the first time, the possibility of carrying out preparative inverted spin trapping was demonstrated by the oxidative methoxylation of heterocyclic nitrones derived from AH -imidazole-1,3-dioxide (219) (Scheme 2.79) (513, 514). 

The most common methods suitable for the synthesis of different azolium compounds will be discussed here. Two routes are particularly useful for the preparation of the imidazolium salts (1) substitution reactions at the nitrogen atoms of imidazole [25] and (2) multicomponent reactions for the generation of an Af,Af -substituted heterocycle which are particularly useful for the synthesis of imidazolium salts bearing aromatic, very bulky, or particularly reactive N,N -sub-stituents (Fig. 3a,b) [26]. Both methods offer the opportunity to produce unsym-metrically substituted imidazolium salts of type 1 either by stepwise alkylation of imidazole or by the synthesis of an W-arylated imidazole derivative followed by 77 -alkylation [27]. Nevertheless, the method of choice for the preparation of the imidazolium salts 1 is the 77,77 -substitution of imidazole. Several other methods for the preparation of imidazolium salts with previously unattainable substitution patterns have also been described [28, 29]. 

As previously indicated (see pp. 88-91), formation of heterocyclic compounds, mainly pyrazines, was found only in the ammonolysis of some aldose nicotinates33 35 and acetates and benzoates of ketoses.39 37 For ketose esters, whose behavior differed from that of the aldose esters, the formation of imidazole derivatives was also observed these heterocyclic compounds also result from the direct action of ammonia upon the corresponding free sugars, but the presence of the esterifying acyl groups evidently increases their ease of formation and raises their yields. 

The high reactivity of the dinitrate may be used to obtain heterocyclic compounds. An ingenious method of forming imidazol derivatives was developed by Payman and Fargher [102] ... 

The imidazole derivative (217) underwent a series of reactions with diazomethane which resulted in the formation of products (222) and (223). Thus, AT-methylation of compound (217) gave compound (219), which participated in a 1,3-dipolar cycloaddition giving cycloadduct (220). This cycloadduct then eliminated nitrous acid and the resulting product tautomerized giving heterocycle (221), which was further methylated giving a mixture of the products (222) and (223) <82IJC(B)997>. Thiazole derivative (218) underwent a similar reaction. 

An impressive range of nucleophiles was successful for arylboronic acids in the presence of Cu(OAc)2 and base, which included amine, anilines, amides, imines, ureas, carbamates, sulfonamides, and aromatic heterocycles (e.g., imidazoles, pyrazoles, triazoles, tetrazoles, benzimidazoles, and indazoles) (Equation (226)) 996 997 1000-1011 For all the reactions investigated with A-nucleophiles, the use of Et3N resulted in yields superior to those obtained with pyridine, but pyridine was the base of choice for the preparation of imidazole derivatives from heteroarenes. For the tetrazole, NMO and DBU were studied as alternative bases. There are mechanistic studies.999,1002-1013... 

Pyrimidine and purine derivatives serve in DNA and RNA to specify the genetic code. Imidazole derivatives enhance the catalytic activity of enzymes. We will consider these important heterocyclic derivatives in more detail in Chapters 23 and 24. 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

The five-membered aromatic heterocycles pyrrole 8, furan 9, and thiophene 10 are formally derived from the cyclopentadienyl anion 2 by replacement of one GH group with NH, O, or S, each of which contributes two n-electrons to the aromatic sextet. Heteroatoms of this type have in classical structures only single bonds and are called pyrrole-like. Other five-membered aromatic heterocycles are derived from compounds 8, 9 and 10 by further replacement of CH groups with N, 0+, or S+, e.g., imidazole 15. 

In the sense of an inter molecular amination with heterocyclic amidine derivatives, such as amino azines and diazines, and 2-chloro-3-iodopyridines followed by an intramolecular amination, Maes and coworkers [93] have established a facile synthesis of dipyrido[l,2-a 3, 2 -d]imidazole and its benzo-and aza-analogs 101-106 (Scheme 36). 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

A general review on the use of electrochemical methods for the synthesis of N-heterocycles and natural products includes a section on imidazole derivatives. Thin-layer chromatographic methods for the separation of imidazole alkaloids have been briefly reviewed. Pharmacological effects of pilocarpine (15) have been summarized as part of an excellent review on convulsant alkaloids. ... 

Five-membered conjugated heterocycles which contain nitrogen atoms (azoles) have been thoroughly investigated by nitrogen NMR spectroscopy (ref. Id, pp. 204-218). Some additional data are now available (Table XVIII). There are two types of nitrogen atoms in such heterocyclic structures, e.g. the case of imidazole derivatives [24]. The... 

Microwave-assisted heterocycle synthesis has also been used to prepare a small set of pharmaceutically important imidazole derivatives [54]. The procedure utilized an initially prepared polymer-bound 3-N,N-(dimethylamino) isocyanoacrylate. The best results in imidazole synthesis were obtained by microwave-assisted reaction of an eightfold excess of the polymer-supported isonitrile suspended in 1,2-dimethoxyethane (DME) with the corresponding amines (Scheme 16.31). Cleavage with 50% trifluoroacetic acid in dichloromethane afforded the desired heterocyclic scaffolds in moderate yields. 

Numerous applications have been found for the uses of imidazole derivatives as ionic liquids and A -heterocyclic carbenes and their use in organic chemistry has been well discussed in books or reviews. Thus, in this chapter, the use of non-heteroaromatic amidine compounds as functional tools in asymmetric synthesis and the related chemistry after presentation of the preparation method of amidines will mainly be discussed. 

It is clear from the foregoing discussion that heterocyclic w-quinodimethanes can now take their place in the standard annoury of the synthetic chemist. The flexibility available for the generation of such species should allow them to fonn the basis of routes to a wide variety of fused heterocycles. There is, however, still. scope for improvements such as even milder, general approaches towards their generation and there are notable gaps in the list of analogues which have so far been produced. For example, there is as yet no convenient route to the potentially very useful imidazole derivatives. 

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