Azole structures

The useful biological properties of paclobutrazol have inspired further chemical synthesis of azole structures, culminating with the discovery of a series of tertiary alcohol compounds. The original synthetic strategy was conceived as a disconnection and reconnection analysis from paclobutrazol (Figure 5). These early compounds were good fungicides and further optimisation in this area has led to the commercial introduction of two products flutriafol and recently hexaconazole. 

Cations derived from azole structures by protonation of pyridine-type nitrogen atoms, e.g. [31], show an appreciable low-frequency shift... 

Heterocyclic compounds are ubiquitous in biology, medicine, and biochemistry, and the azoles form an important class of nitrogen heterocyclic compounds with five-membered aromatic rings that can contain one to five nitrogen atoms (other heteroatoms can also be present). Many drugs and pharmaceuticals are derived from azole structures. The structures of representative azoles are shown in Figure 6.1. Note that some of these compounds exist in tautomeric equilibrium in solution. 

The same reaction performed in ether at 0°C (336) gives the same major adduct, but the structure proposed by Acheson et al. corresponds to 86, although such a structure is hardly compatible with the presence of an isolated low-field proton. Very recently, in a reinvestigation of these cyclo-additions of DMA to azoles (338, 339), Acheson et al. were able to establish the correct structure of the adducts on the base of CNMR spectra and X-ray diffraction studies. The adduct of thiazole is represented by formula 87, and it results from the rearrangement of the... 

Firefly lucifenn is an example of an azole that contains a benzene ring fused to the five membered ring Such structures are fairly common Another example is benzimidazole present as a structural unit m vitamin B12 Some compounds related to benzimidazole include purine and its ammo substituted derivative adenine one of the so called het erocychc bases found m DNA and RNA (Chapter 28)... 

Complex tautomerism for azoles with heteroatoms in the 1,2-positions occurs for pyrazoles which are not substituted on nitrogen. Scheme 10 shows the four important tautomeric structures (148)-(151) for 3-methylpyrazolin-5-one, and (152) and (153) as examples of other possible structures. A detailed investigation of this system disclosed that in aqueous solution (polar medium) the importance of the tautomers is (149) > (151) (150) or (148), whereas in cyclohexane solution (non-polar medium) (151) > (148) (149) or (150). 

Orientation in azole rings containing three or four heteroatoms Effect of azole ring structure and of substituents Proton acids on neutral azoles basicity of azoles Proton acids on azole anions acidity of azoles Metal ions... 

Oxidation of azole anions can give neutral azole radicals which could, in principle, be tt (139) or a- (140) in nature. ESR spectra indicate structure (141 hyperfine splittings in G) for imidazolyl radicals, but both tt- and cr-character have been observed for pyrazolyl radicals. Tetrazolyl radicals (142 4 143) are also well known (79AHC(25)205). Oxidation of 2,4,5-triarylimidazole anions with bromine gives l,l -diimidazolyls (144) which are in equilibrium with the dissociated free radical (145) (70AHQ 12)103). 

Experimental values are collected in the McClellan book (B-63MI40400) and in a review on dipole moments and structure of azoles (71KGS867). Some selected values are reported in Table 3. The old controversy about the dipole moment of pyrazole in solution has been settled by studying its permittivity over a large range of concentrations (75BSF1675). These measurements show that pyrazole forms non-polar cyclic dimers (39) when concentration increases and, in consequence, the permittivity value decreases. 

Many names in common use for heteropolycycles provide little or no information about structure. Most such names were introduced long before any serious attempts were made to systematize nomenclature, and although more systematic equivalents can now be coined in many cases (for example, indole can be named benz[f)]azole or 1-azacyclopentabenzene), it is likely that the use of a substantial residue of trivial names will continue. However, one would not expect many new trivial names to be introduced in the future, except in the natural product area (see Section 1.02.4). 

The imbalance between and NMR studies in the solid state (Section VI,F) partly reflects the fact that it is easier to introduce N than into heterocyclic compounds, particularly azoles (DNMR in the solid state usually requires isotopic enrichment). Compared to solution studies, solid-state intermolecular proton transfer between tautomers has the enormous advantage that the structure of the species involved is precisely defined. 

While significant amounts of experimental data are available on the side-chain tautomerism of the functionalized azoles, most are of qualitative character and not fully systematic. No accurate structural correlations which would allow rehable predictions of the energy preferences of a specific tautomer or the state of a tautomeric equilibrium at given conditions have been developed. Nevertheless, trends can be discerned, some of which have previously been formulated [76AHC(S1), pp. 386-391, 443-446]. More recent studies discussed in this section have confirmed the validity of the following ... 

Whereas vicinal hydroxy, mercapto, and hydroselenoaldimines of azoles strongly prefer the aminomethylene tautomeric form (Section II,E,2), their metal chelates 380 are characterized by.pronounced equalization of bond lengths within the chelate ring, which makes their structures similar to those expected for the aldimine tautomeric type. 

Some triazepinones in which one of the nitrogen atoms belongs to a fused azole moiety have been reported. For instance, compound 63 was prepared (74JHC751) and its X-ray structure determined (75CSC317). Similarly, and NMR spectra and X-ray structural determination of 64 revealed that this compound exists as a 3//-tautomer with the 1,2,4-triazepine ring in a distorted boat conformation (88T7185). 

Tliey also described an interesting case of a porphyrin displaying simultaneously annular and functional tautomerism, very common in the azole series but very rare in porphyrins (88JOC1132). Tire only tautomers observed, 77a-77c, have an 18-atom 18-7r-electron structure similar to that of [18]diazaannulene.Tlie relative amounts of tautomers 77a-77c are solvent dependent for instance, in toluene-dg and in CD2CI2 they are 77a (53 and 78%), 77b (29 and 13%), and 77c (18 and 9%). 

A detailed structural study of aza analogs of sesquifulvalene as well as other heterocyclic betaines was performed by Alcalde and coworker (89CC1086 91JOC4223), who also reviewed the pyridinium azolates class... 

Dimethyl-, 3,5-diphenyl-, and 3,5-di-tert-butylpyrazolato potassium salts with [Cp RuCl]4 give the first structurally proven -coordinated complexes 48 (R = Me, t-Bu, Ph) in the azole series (99JA4536). 

The thermodynamic CH acidity of terminal acetylenes in the series of A-alkylpyrazoles was studied (83IZV466). These equilibrium CH acidity measurements were performed in DMSO by the method of remetallation (75ZOB1529). It reveals some regularities concerning the influence of the ring structure, the nature of other substituents, and the position of the ethynyl group on the acidity of ethynyl pyr azoles. 

The cyclization of l-alkoxybut-l-en-3-ynes with hydrazine was first achieved by Franke and Kraft (55AG395). By heating 1-methoxybut- l-en-3-yne with hydrazine sulfate in an aqueous alcohol medium they obtained 3(5)-methylpyrazole (13) in high yield. Winter (63HCA1754) used the cyclization of 1-methoxybut-l-en-3-yne with hydrazine hydrate and phenylhydrazine to establish the structure of the initial enyne ether [in this case a mixture of l-phenyl-3(5)-propylpyrazoles was obtained]. The reaction with hydrazine sulfate gives only one product, 3(5)-propyl-pyr azole. 

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