Other Five-Membered Heterocycles Azoles

It is possible to introduce a second heteroatom (and even a third and fourth) into five-membered heterocycles. The most important of these are the azoles, in which the second heteroatom, located at position 3, is nitrogen. 

Azoles are five-membered heterocycles with an 0, N, or S atom at position 1 and an N atom at position 3. 

Analogs in which the two heteroatoms are adjacent are also known. 

Consequently, the N-3 nitrogen is basic and can be protonated. The imidazolium ion is very stable because the positive charge can be delocalized equally over both nitrogens. Imidazole is even more basic than pyridine, and as a consequence, the pK of the imidazolium ion (7.0) is greater than the pK of the pyridinium ion (5.3). 

Porphyrins What Makes Blood Red and Grass Green  

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The synthesis of several complex l,4-(oxa/thia)-2-azole derivatives 260-262 from other five-membered heterocycles has been reported in CHEC-II(1996) <1996CHEC-II(4)535>. 

Table 7 Reactivities of Some Azoles and Other Five-membered Heterocycles in Acid-catalyzed Deuteriodeprotonation <74JCS(P2)399>...

The work of Pinto et al. and some others [76,77] on the optimization of the heterocycUc core had led to the discovery of a novel pyrazole SN429. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of a new series of FXa inhibitors (15-19) for which Eq. 11 was formulated [72]. The continuation of research on FXa inhibitors led to new variety of compounds. However, the lack of chirality of the isox-azole derivatives, such as SA862 [78] and its high affinity for FXa, made it an attractive template for further optimization. A significant study was performed for the use of other five-membered heterocyclic templates in which... 

The biological activity of azoles and their derivatives (indoles, purines, etc.) and their abundance as structural motif in natural products made them a prime target and test ground in the development of catalytic transformations. This chapter is mainly dedicated to the reactions of monocyclic five membered heterocycles and indole. The chemistry of other condensed systems of importance, such as purines, is discussed in Chapter 8. 

We have looked at the five-membered aromatic heterocycles pyrrole, furan and thiophene in Section 11.5. Introduction of a second heteroatom creates azoles. This name immediately suggests that nitrogen is one of the heteroatoms. As soon as we consider valencies, we discover that in order to draw a five-membered aromatic heterocycle with two heteroatoms, it must contain nitrogen A neutral oxygen or sulfm atom can have only two bonds, and we cannot, therefore, have more than one of these atoms in any aromatic heterocycle. On the other hand, there is potential for having as many nitrogens as we like in an aromatic ring. 

The azoles (oxazole, imidazole, and thiazole) are five-membered aromatic heterocycles that have two heteroatoms in the ring. One of the heteroatoms in each of these heterocycles is an sp2-hybridized nitrogen that contributes one electron to the 6n aromatic system and has a basic nonbonded lone pair. The other heteroatom (oxygen, nitrogen, or sulfur) contributes two electrons to the 6n system. The imidazole skeleton is present in the amino acid histidine. The thiazole ring occurs in thiamin (vitamin B. ... 

Isoxazole 4.1, pyrazole 4.2, and isothiazole 4.3 are the parent structures of the 1,2-azole family of heterocycles, having a nitrogen atom plus one other heteroatom in a 1,2-relationship in a five-membered ring. 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

Azoles are heterocyclic compds characterized by a five membered ring contg nitrogen. They include diazoles, triazoles and tetrazoles, as well as compds contg other atoms such as O and S in the ring oxazoles, dioxazoles, thiazoles, thiadiazoles etc. Some azoles or their derivs are expl, for example the tri-azoles and the tetrazoles Refs l)K.A.Jensen A.Friediger, Kgl DanskeVidenskabSelskab, Math-FysMedd... 

Electrophilic substitution in the azoles is intermediate in facility between pyridine on the one hand and pyrroles, thiophene and furans on the other the presence of the electron-withdrawing imine unit has an effect on the five-membered aromatic heterocycles just as it does when incorporated into a six-membered aromatic framework, i.e. the comparison is like that between benzene and pyridine (chapter 4). The order of reactivity - pyrrole > furan > thiophene - is echoed in the azoles, though the presence of the basic nitrogen complicates such comparisons. The regiochemistry... 

Five-membered aromatic heterocycles, thiophenes, furans, pyrroles, and other jt-excessive systems are reluctant, of course, to react with nucleophilic reagents. Contrary to that, nitro- or aza-activated derivatives of azoles undergo nucleophilic displacement of hydrogen rather smoothly. A great deal of both oxidative Sn (AO) and eliminative Sn (AE) reactions in the series of nitroazoles (nitropyrrole, nitrofuran, nitrothiophene) or aza-activated azoles (imidazoles, thia-zoles, oxazoles), as well as their benzo analogues, have been documented in the literature [10-18, 45, 123-128]. 

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. 

DFT calculations for other heterocycles (neutral azoles, protonated forms) have been reported (94T2405, for semiempirieal ealeulations see 93ZOR1297 see also AMI, MNDO, and PM3 ealeulations for neutral five-and six-membered nitrogen heteroeyeles). 

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