Heterocycles with two hetero-atoms

Five-Membered Ring Heterocycles with Two Hetero Atoms Imidazoles, Benzimidazoles, 1H-pyrazoles, Oxazoles, Isoxazoles, Thiazoles, and Indazoles... 

Five-Membered Ring Heterocycles with Two Hetero Atoms... 

The 1,3- and 1,2-azoles, five-membered rings with two hetero atoms, present a fascinating combination of hetero atom types - in all cases, one hetero atom must be of the five-membered heterocycle (pyrrole, thiophene, furan) type and one of the imine type, as in pyridine imidazole with two nitrogen atoms illustrates this best. Contributor 39 is a particularly favourable one. 

The optically active 1,3-oxathiane derivative 81, synthesized as a chiral auxiliary (cf. Scheme 30), has been reported. The isomers were assignend by X-ray diffraction in the solid state trans) and by NOE experiments in solution cis) (97CPB778). Rules for the specification of the absolute configuration of the enantiomers R or S) for 1,3-oxathianes and other heterocycles with at least two hetero atoms were proposed and proved... 

Five-membered heterocycles with two vicinal chalcogen atoms in the ring system can be used as stable precursors for sulfur as well as for selenium-containing hetero-1,3-dienes in cycloaddition reactions. Consequently, 3//-1,2,4-thiaselenazoles have been used for the in situ formation of 4,4-bis(trifluoromethyl)-l-thia-3-azabuta-1,3-dienes, which exist at room temperature only as 4,4-bis(trifluoromethyl)-2//-l,3-thiazetes. This strategy was applied to the synthesis of the first stable selenophosphorane from bis(trifluoromethyl)-substituted 3//-diselenazol and 2-methoxy-1,3,2-dioxaphospholan [78AG(E)774] (Scheme 83). 

A number of routes involve formation of the bond between the two hetero atoms typical is the conversion of di(2-cyanophenyl) disulfide into 3-chlorobenzoisothiazole with chlorine and into 3-aminobenzoisothiazoles with magnesium amides, as shown, one half of the starting material is converted directly into the heterocycle, the second half requiring oxidation. 

For reversible additions, for example of a proton, the position of equilibrium depends on the pA of the heterocycle, and this in turn is influenced by the substituents present on the ring electron-releasing groups enhance the basicity and electron-withdrawing substituents reduce the basic strength. The p of simple pyridines is of the order of 5, while those for 1,2- and 1,3-azoles depend on the character of the other hetero atom pyrazole and imidazole, with two nitrogen atoms, have values of 2.5 and 7.1 respectively. 

A A Five-membered ring heterocyclics with two or more hetero-atoms... 

Selenazole is the selenium-containing compound in the series of heterocyclic 5-membered ring azoles with two different hetero atoms, of which the first two members are oxazole and thiazole. The numbering of the ring system is according to the scheme given (1). 

Six membered heterocyclics can be synthesized in various ways. Nitrogen analogues of stilbene, like the anilides of benzaldehyde or acetophenone sometimes form azaphenanthrenes 19). Similarly the plasma reaction of azobenzene yields a small amount of diazaphenanthrene 19>. Better results are observed in the cyclization of hydroxy, amino or nitro compounds. Suitable starting materials are molecules with two phenyl groups linked by a carbon or hetero atom. 

This section is concerned with methods for the ring formation of heterocyclic systems containing one, two or more hetero atoms, with the enamine nitrogen being included or not in the new heterocycle created. 

Katiitzky, A. R., Drum, C., Advances in Heterocyclic Chemistry Prospect and Retrospect, 40,1. Katiitzky, A. R., Jones, P. M., The Literature cf Heterocyclic Chemistry, Part II, 25, 303. Katiitzky, A. R., Lagowski, J. M., Prototropic Tautomerism qF Heteroaromatic Compounds. I. General Discussion and Methods cf Study, 1,311 //. Six-Membered Rings, I, 339 III. Five-Membered Rings and One Hetero Atom, 2, 1 IV. Five-Membered Rings with Two or More Hetero Atoms. 2,27. 

Six-Membered Heterocyclic Compounds with a Single Nitrogen Atom in the Ring to which are Fused Two or More Carbocyclic Ring Systems, and Six-Membered Ring Compounds where the Hetero-Atom is Phosphorus, Arsenic, Antimony or Bismuth. Alkaloids Containing a Six-Membered Heterocyclic Ring System... 

We can now look at more specific examples, and see how the principles above can lead to the aromatic heterocycles. In the first of the two broad categories, where only C-hetero atom bonds are needed, and for the synthesis of five-membered heterocycles, precursors with two carbonyl groups related 1,4 are required 1,4-diketones, for example react with ammonia or primary amines to give 2,5-disubstituted pyrroles. 

Some of the components shown in these examples have two electrophilic centres and some have a nucleophilic and an electrophilic centre in other situations components with two nucleophilic centres are required. In general, components in which the two reacting centres are either 1,2- or 1,3-related are utilised most often in heterocyclic synthesis, but 1,4- ( e.g. HX-C-C-YH) (X and Y are hetero atoms) and 1,5-related ( e.g. 0=C-(C)3-C=0) bifunctional components, and also reactants which provide one-carbon units (formate, or a synthon for carbonic acid - phosgene, Cl2C=0, or a safer equivalent) are also important. Amongst many examples of 1,2-difunctionalised compounds are 1,2-dicarbonyl compounds, enols (which first react in a nucleophilic sense at carbon and then provide an electrophilic centre (the carbonyl carbon), Hal-C-C=0, and systems with HX-YH units. Amongst often used 1,3-difunctionalised compounds are the doubly electrophilic 1,3-dicarbonyl compounds and a,P-unsaturated carbonyl compounds (C=C-C=0), doubly nucleophilic HX-C-YH (amidines and ureas are examples), and a-amino- or a-hydroxycar-bonyl compounds (HX-C-C=0), which have an electrophilic and a nucleophilic centre. 

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