Azoles imidazoles

Antifungal drugs are classified according to their mode of action and/or their chemical class. Four chemical classes have mainly contributed to the actual armentory of antifungal drugs the broadest class is the one of azoles (imidazoles and triazoles), followed by polyenes, allylamines and morpholines. Some individual compounds are used in dermatology. 

As shown in Fig. 5, the pX,s of the azoles (imidazoles, 1,2,4-triazoles, and tetrazoles) which do not protonate next to an NH group are linearly related to the pX,s of the corresponding pyridines. It is interesting to notice that the... 

Among these 1,3-azoles, imidazole is the most basic compound. The increased basicity of imidazole can be accounted for from the greater electron-releasing ability of two nitrogen atoms relative to a nitrogen atom and a hetero-atom of higher electronegativity. Some of the physical properties of these compounds are presented below. 

The acid-base properties of 4-nitroso-5-aminopyrazoles 50 have been studied. In particular, protonation sites have been determined where salts 51 are formed [66], The effects produced on II, 13C, and 15N chemical shifts by protonation and by hydrogen-bonding solvents on five azoles (imidazole, 4,5-dimethylimidazole, pyra-zole, 3,5-dimethyl-pyrazole, and 4,5-dihydro-3-methyl-2//-benz[g]indazole) have been determined experimentally. Phase effects on the 13C chemical shifts of the C-4 atom of pyrazole were discussed, based both on empirical models and on GIAO calculations of absolute shieldings in different complexes. The special case of the chemical shifts of pyrazoles in the solid state, where they form multiple N-H N hydrogen bonds, was also studied theoretically [88],... 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

The range of reactions which are possible at the ring nitrogens of imidazole and benzimidazole has been outlined (Section 4.02.1.3). As they are the most basic of the azoles, imidazoles are particularly prone to such reactions as protonation, alkylation and acylation, and they readily become involved in complex formation with transition metals. Benzimidazoles, too, are reactive, but less so than the non-condensed species. 

The reaction between heteroaromatic iV-oxides and 2-chloro, 5-dihydroimidazole 955 results in a formal ureida-tion of the heteroaryls. This reaction was extended to 2- and 4-picoline iV-oxides for the synthesis of 956 and 957, respectively (Scheme 232) <2002JHC911>. The 2-bromine of nitronyl nitroxide 958 is easily displaced with sodium azolides to give spin-labeled azoles (imidazole, pyrazole, triazole) 959 which are prone to hydrolysis to hydroxamide acid anion 960 <2004T99>. 

Studies of crystal structure have been made for imidazole the results from a low-temperature study are illustrated in Fig. 1. In 4,5-di-t-butylimidazole the ring dimensions are essentially similar, although the 4,5-bond is slightly stretched. Among derivatives of imidazole which have been examined are histidine hydrochloride, 4-acetylamino-2-bromo-5-isopropyl-l-methylimidazole, 4-acetyl-5-methyl-2-phenylimid-azole, imidazole-4-acetic acid hydrochloride, imidazole imidazolium... 

Azoles Imidazoles, Thiazoles and Oxazoles Reactions and Synthesis... 

The three 1,3-azoles, imidazole, thiazole and oxazole, are aU very stable compounds that do not autoxidise. Oxazole and thiazole are water-miscible liquids with pyridine-like odours. Imidazole, which is a solid at room temperature, and 1-methylimidazole are also water soluble, but are odourless. They boil at much higher temperatures (256 °C and 199 °C) than oxazole (69 °C) and thiazole (117 °C) this can be attributed to stronger dipolar association resulting from the very marked permanent charge separation in imidazoles (the dipole moment of imidazole is 5.6 D cf. oxazole, 1.4 D thiazole, 1.6 D) and for imidazole itself, in addition, extensive intermolecular hydrogen bonding. The dihydro- and tetrahydro-1,3-azoles are named imidazoline/imidazolidine, thiazoline/thiazolidine and oxazoline/oxazolidine. 

The imidazo[l,2-ft]pyrazole, imidazo[l,5-a]imidazole, imidazo[l,2-a]imidazole, imidazo[2,l- ]ox-azole, imidazol[2,l-6]thiazole, and imidazo[l,5-c]thiazole ring systems have all been prepared by more than one of the different types of synthetic route described in Sections 8.04,9 and 8.04.10. The various routes to each of these heterocycles are summarized in Table 4. For example, the imidazo[2,l-ft]thiazole skeleton has been synthesized by (5 - - 0) routes (types B, C, and D), (4 - - 1) routes (types BC and CD), and by (3 -I- 2) routes (type BD) (for a summary of this classification see Scheme 10). By far the most common route to this system is the (3 - - 2) ring closure discussed in Section 8.04.9.3.2. Tetramisole (34), the most important compound of this type in terms of commercial... 

Azoles imidazoles, thiazoles, and oxazoles reactions and synthesis... 

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