Five-membered heterocycles imidazole

As shown in Scheme 2, two heteroatom-carbon bonds are constructed in such a way that one component provides both heteroatoms for the resultant heterocycle. By variation of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the use of the appropriate oxidation level in the carbonyl-containing component, further oxidized derivatives of these ring systems result. These processes are analogous to those utilized in the formation of five-membered heterocycles containing one heteroatom, involving cyclocondensation utilizing enols, enamines, etc. 

Histidine is one of the 20 naturally occurring amino acids commonly found in proteins (see Chapter 4). It possesses as part of its structure an imidazole group, a five-membered heterocyclic ring possessing two nitrogen atoms. The pAl for dissociation of the imidazole hydrogen of histidine is 6.04. 

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin Bt) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. 

Imidazole Fused to Another Five-Membered Heterocycle. 284... 

For five-membered heterocycles other than thiazole, (such as pyrazole [27], imidazole [28], and triazole [29]) the effect of replacement of just one pyridine moiety in 1 is greater and the [Fe N6]2+ derivatives in these instances show crossover behaviour. The [Fe N6]2+ derivative of 2-(pyridin-2-yl)imidazole 19 (Dq(Ni2+) 1150 cm-1 [22]) was shown relatively early on to be a crossover system [28]. In solid salts and in solution the transition is continuous and centred above room temperature. The dynamics for the 5T2— Ai relaxation for this system have been investigated by a number of techniques [30-32] and Beattie and McMahon have shown that in solution there is not only a spin equilibrium but also a ligand dissociation process, very reasonably ascribed to the high spin form of the tris complex [32]. 

Introduction of the azido group into the azine heterocycle can also be accomplished starting with azine derivatives bearing a five-membered heterocycle as a leaving group in this position. Table 8 shows three such conversions where the leaving groups are isoxazolone (entry a), imidazole (entry b), and triazole (entry c) substituents. 

Five-membered heterocycles with two heteroatoms have the jr-electron deficiency of Y-type heteroatoms compensated by the jr-electron excessive character of the X-type atoms therefore, this category includes some of the most stable heterocycles. For example, NMR spectral data and chemical behavior (e.g., resistance to oxidation by potassium permanganate) suggest that pyrazole and imidazole have delocaliza-... 

Some of the ring expansion reactions discussed in Section 2.03.3.3.1 can be extended to five-membered heterocycles containing two or more heteroatoms. Reaction of imidazoles and pyrazoles with dichlorocarbene, for example, gives chloropyrimidines together with small amounts of chloro-pyrazines or -pyridazines, and oxidative ring expansion of 1-aminopyrazole with nickel peroxide gives 1,2,3-triazine (this, in fact, constitutes the only known synthesis of the unsubstituted triazine). There are, however, a number of interesting and useful transformations which are unique to five-membered polyheteroatom systems. 

Methyl I-azirine-3-acrylates 318 (R1 = H) have recently been reported to yield five-membered heterocycles, e.g., triazoles 320 (35% yield) or imidazoles 322 (62% yield), by reaction with hydrazine and formamidine (91JOC7) (Scheme 70). The mechanism postulated by the authors to account for the formation of 320 and 322 implies initial addition of the... 

PYRAZOLES, PYRAZOLINES, AND PYRAZOLONES. The compounds of this article, i.e., five-membered heterocycles containing two adjacent nitrogen atoms, can best be discussed according to the number of double bonds present. Pyrazoles contain two double bonds within the nucleus, imparting an aromatic character to these molecules. They are stable compounds and can display the isomeric forms. (1) and (2). when properly substituted. Pyrazoles are scarce in nature when compared to the imidazoles (3), which arc widespread and have a central role in many biological processes. 

The reactivity of the five-membered heterocycles pyrrole, furan, thiophen and imidazole (Fig. 8-10) is characterised by interactions with electrophilic reagents. The precise nature of these reactions depends upon the particular ring system. Thiophens undergo facile electrophilic substitution, whereas the other compounds exhibit a range of polymerisation and other Lewis acid-initiated reactions upon treatment with electrophiles. We saw a number of examples of Lewis acid-promoted reactions of furans and pyrroles in Chapter 6. Although reactions of complexes of five-membered heterocyclic ligands have not been widely investigated, a few examples will illustrate the synthetic potential. 

A fundamental investigation of the kinetics and the mechanism of nitration of five-membered heterocycles containing nitrogen is due to Ridd and his co-workers.125 126 They studied the reaction of pyrazole and imidazole with nitric acid in 90-99% sulfuric acid. 

The ending -ole is systematic and refers to a five-membered heterocyclic ring. All the flve-membered aromatic heterocycles with nitrogen in the ring are sometimes called the azoles. Strictly speaking, pyrrole is "azole, pyrazole is 1,2-diazole", and imidazole is 1,3-diazole. These names are not used but oxazole and thiazole are used for the oxygen and sulfur analogues of imidazole. 

A great number of publications deal with the reaction of nitration [7-20], At the same time, volumes literature on nitro heterocycles has not been systematized until the present time. Direct nitration of some five-membered heterocycles such as pyrroles, furans, thiophenes, pyrazoles, imidazoles, and thiazoles has been discussed by Katritzky [21, 22], Some synthetic routes to nitrated six-membered nitrogen-containing aromatic heterocycles [23], as well as the nitration of oxo-pyrimidines and -imidazoles [24], and quantum-chemical studies of the nitration of benzazoles [25] have been reported. 

The photochemical addition of 2H-azirines to the carbonyl group of aldehydes, ketones and esters is completely regiospecific (77H143). Besides the formation of the isomeric oxazolines 18 from 3 and ethyl cyanoformate, there is also formed the imidazole 19 from addition to the C = N in the expected regioselective manner. Thioesters lead to thiazolines 20, while isocyanates and ketenes produce heterocycles 21 (Scheme 4). The photocycloaddition of arylazirines with a variety of multiple bonds proceeds in high yield and provides a convenient route for the synthesis of five-membered heterocyclic rings. Some of the dipolarophiles include azodicarboxylates, acid chlorides, vinylphospho-nium salts and p-quinones. 

In this paragraph a small series of five-membered heterocycles will be considered. Maps of W (r) in the molecular plane are presented for pyrrole (XV), imidazole (XVI), pyrazole (XVII), oxazole (XVIII) and isoxazole (XlX) in Figs. 20 to 24. 

The 1,3- and 1,2-azoles, five-membered rings with two heteroatoms, present a fascinating combination of heteroatom types - in all cases, one heteroatom 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. 

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