Heterocycles Containing More Than Two Heteroatoms

In systems that contain more than two heteroatoms in the same ring, the trends in properties that this book describes are taken to fnrther extremes. In particular, the additional heteroatoms, in both six- and flve-membered systems, lead to a snppression of electrophilic substitution and a slowing of electrophilic addition to nitrogen. On the other hand, fnrther increases in tendencies for nucleophilic substitution and addition, and in the five-membered componnds further increases in acidities of M-hydrogen, are found. 

Multi-heteroatom heterocycles are comparatively rare in nature, however in medicinal chemistry they are of very considerable significance, for example analogues of the pyrimidine and purine nucleosides have been extensively studied (see examples in Chapter 33). 

4-dimethylaminophenylpentazole. The pentazolate anion has been detected by mass spectrometry.  

The additional heteroatoms make these systems less basic, but more acidic than comparable 1,2- and 

3-azoles. Each is subject to the same kind of tautomerism as discussed for the 1,2- and 1,3-azoles (Chapter 25 Introduction and 24.1.1.1), in which the tautomers are equivalent. Also, in these systems, tautomerism generates different arrangements of imine nitrogen and A-hydrogen components. 

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Heterocycles Containing More Than Two Heteroatoms 559 The ring system is relatively resistant to both oxidation and reduction, as exemplified below. 

Heterocycles Containing More Than Two Heteroatoms 573 Benzotriazolyl is a useful leaving group for nucleophilic substitutions in 1,2,3-thiadiazoles. ... 

Two-ring heterocycles containing more than one heteroatom Purines... 

In this section, only a small portion of marketed drugs are shown to illustrate the importance of hetereocyclic chemistry in drug discovery. Many drugs containing saturated heterocycles, heterocycles with more than two heteroatoms, and non-heterocycles. In the ensuing chapters, the most popular types of heterocycles in drug discovery are reviewed for their physical and chemical properties, their constructions in the context of medicinal chemistry, and their potential liabilities as drugs when applicable. 

Heterocyclic compounds, or heterocycles, are molecules with rings that contain more than one type of atom they are to be distinguished from carbocycles, which are molecules with rings that contain only carbon atoms. The heterocyclic compounds of greatest interest to medicinal chemists have carbon rings containing one or two heteroatoms— atoms other than carbon. 

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. 

A large number of polycyclic heterocycles containing two or more six-membered rings that share two or more carbon atoms are known. For the majority of these systems, only one of the six-membered rings contains the heteroatoms and the other rings are fused carbocyclic rings such as cyclohexane, benzene, naphthalene, and in rare examples, anthracene. Systems in which more than one of the six-membered rings contain heteroatoms are also briefly discussed these include spiro-cyclic compounds and substituted naphthalenes. 

Many heterocycles containing two or more heteroatoms can exist in more than one tautomeric form. Both external (polarity of the solvent, intramolecular hydrogen bonding) and internal (relative resonance stabilization of the conjugated system, stabilities of the functionalities) factors influence such tautomeric equilibria. For five- and six-membered rings, frequently more than one tautomer preserves the aromatic character. Comparisons of tautomeric equi-... 

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