Imidazole ring amides

The cyclization of o-substituted amides 206 was used for the preparation of a series of purine derivatives 207. In this case, the amine behaved as a nucleophile toward the amide function followed by ring closure to the imidazole ring (Scheme 75) [133]. 

A modification of this method, related to the Beckmann rearrangement, entails treatment of a ketoxime with one equivalent of CDI, then four to five equivalents of a reactive halide such as allyl bromide or methyl iodide (R3X) under reflux in acetonitrile for 0.5-1.5 h. Quatemization of the imidazole ring effectively promotes the reaction by increasing the electron-withdrawing effect. The target amides then are obtained by hydrolysis. High yields, neutral conditions, and a very simple procedure make this modification of the synthesis of amides by azolides a very useful alternative. 1243... 

The methylimidazolide reacts more slowly with an alcohol (cf. c-QHnOH) but not with respect to an amine (cf. C-QH11NH2) in comparison with the unsubstituted imi-dazolide. Introduction of an additional alkyl group into the imidazole ring further retards the transphosphorylation. Thus, the 2-ethyl-4-methylimidazolide did not react with cyclohexanol within 70 h at room temperature, while with cyclohexylamine an amide was produced, albeit with a reduction in yield.[190] Hence, a certain degree of selectivity towards amines was achieved with the 2-ethyl-4-methylimidazolide. Selectivity toward amines and alcohols was also observed with the 2-ethyl- or isopropyl-4-nitroimidazolide. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Two factors are responsible for the high reactivity of the imidazolides as acylating reagents. One is the relative weakness of the amide bond. Because of the aromatic character of imidazole, there is little of the N —> C=0 delocalization that stabilizes normal amides. The reactivity of the imidazolides is also enhanced by protonation of the other imidazole nitrogen, which makes the imidazole ring a better leaving group. 

The cleavage mechanism of the caspases is shown schematically in Fig. 15.5. They use a typical protease mechanism with a catalytic diad for cleavage of the peptide bond. The nucleophilic thiol of an essential Cys residue forms a covalent thioacyl bond to the substrate during the catalysis. The imidazole ring of an essential histidine is also involved in catalysis and this facilitates hydrolysis of the amide bond in the sense of an acid/base catalysis. 

The preparation of a pair of iminohydantoins invokes the addition of amide nitrogen to a cyano group for formation of the imidazole ring. The products exhibit unexpectedly quite different biological activities. Reaction of the cyanamide (92-1) from para-chloroaniline and cyanogen bromide with A-methylchloroacetamide (92-2) can be visualized to lead initially to the alkylation product (92-3). Cyclization by addition to the nitrile group then affords clazolamine (92-4) [98], a compound described as a diuretic. 

Acylation of the theophylline diamine intermediate (26-6) with phenylacetyl chloride affords the corresponding amide (28-2). Base catalyzed cyclization then leads to the purine (28-3) that now includes a quite lipophilic benzyl group on the fused imidazole ring. The molecule is then provided with a side chain that incorporates basic nitrogen, arguably to improve water solubility. The anion from (28-3) is thus first alkylated with bromochloroethane to afford the chloroethyl product (28-4). The displacement of chlorine with ethanolamine affords the bronchodilator bamifylline (28-5) [28]. 

Crystallographic studies of native cysteine proteinases and enzyme-inhibitor complexes have been used to interpret much or the kinetic data for cysteine protemsse-caUlyzed hydrolysis of amide bonds. Analysis of the crystal structures of papain [16]. caricain [38], actinidain [56], etc. shows that these structures are closely related. The active site of all these cysteine proteinases contains the Cys-25 sulfhydryl group in close proximity to the His-159 imidazole ring nitrogens, where the latter can abstract the sulfhydryl proton to facilitate attack on the substrate amide carbonyl group [17]. 

The 6th rank in terms of acylation reactivity that is attributed to the acyl imidazolides in Table 6.1 (entry 10) is also plausible. In the acyl imidazolides, the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the -electron sextet, which makes the imidazole ring an aromatic compound. This is why acyl imidazolides, in contrast to normal amides (entry 2 in Table 6.1) can act as acylating agents. Nevertheless, acyl imidazolides do not have the same acylation capacity as acylpyridinium salts because the aromatic stabilization of five-mem-bered aromatic compounds—and thus of imidazole—is considerably smaller than that of six-membered aromatic systems (e. g., pyridine). This means that the resonance form of the acyl imidazolides printed red in Table 6.1 contributes to the stabilization of the C=0 double bond. For a similar reason, there is no resonance stabilization of the C=0 double bond in N-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

While some of the mechanistic details for the examples described in this chapter have not yet been fully elucidated, it is clear from the scope of the examples discussed herein that the photochemistry of enaminones and enamidones is a fascinating research area. The novel sequence for the annelation of imidazole rings onto a preexisting structure, the synthesis of perhydroindoles via vinylogous amide [2 + 2] photocycloaddition chemistry and the enamide cyclization reactions all underscore the enormous utility of these chromophores in the development of new reactions and novel synthetic methods. 

A new method of synthesis162 of the imidazole ring by the use of A-cyaniminodithiocarbonic esters (41) involves formation of the 4 5-bond. Reaction of (42) with KNCO in acetic acid yielded the corresponding amide (43) which was cyclized by sodium hydroxide to the substituted purine (44). Treatment of (42) with Raney nickel and hydrogen produced 4-amino-5-carbethoxy-l-methyl-4-imidazo-line (45), which could also be cyclized to a purine (46).162... 

Phakellins (41, 42), tetracyclic derivatives in which both the pyrrole and the amidic nitrogen atoms are involved in the formation of a linkage with carbon atoms of the imidazole ring, represented the first members of the family of oroidin-related cyclic bromopyrrole alkaloids to be isolated. They were found in 1971 by Sharma et al. in the marine sponge Phakelliaflabellata their structure was confirmed by X-ray diffraction analysis of a single crystal of the monoacetyl derivative of 41 [70]. Complete spectral data were provided by the same authors a few years later [71]. 

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