Oxazoles, imidazoles, and thiazoles

Oxazole 3.1, imidazole 3.2, and thiazole 3.3 are the parent structures of a related series of 1,3-azoles containing a nitrogen atom plus a second heteroatom in a five-membered ring. 

They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole (see Chapter 4). Their aromaticity derives from delocalisation of a lone pair from the second heteroatom, 3.4a-e. 

The imidazole ring occurs naturally in histamine 3.5, an important mediator of inflammation and gastric acid secretion. A quaternised thiazole ring is found in the essential vitamin thiamin 3.6. There are few naturally occurring oxazoles, apart from some secondary metabolites from plant and fungal sources. 

Oxazole, imidazole, and thiazole can be formally derived from furan, pyrrole, and thiophene respectively by replacement of a CH group by a nitrogen atom at the 3 position. The presence of this pyridine-like nitrogen deactivates the 1,3-azoles towards electrophilic attack and increases their susceptibility towards nucleophilic attack (see later). These 1,3-azoles can be viewed as hybrids between furan, pyrrole, or thiophene, and pyridine. 

Imidazole (pjfa=7.0) is more basic than oxazole (pA a=0.8) or thiazole (p/fa=2.5). This increased basicity arises from the greater electron-releasing capacity of two nitrogen atoms relative to a combination of nitrogen and a heteroatom of higher electronegativity. Also note that a symmetrical resonance-stabilised cation 3.7a,b is formed. 

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Oxazole, imidazole and thiazole systems contain a five-membered ring and two hetero-atoms, one of which is a nitrogen atom. The hetero-atoms are separated by a carbon atom in the ring. The second hetero-atoms are oxygen, nitrogen and sulphur for oxazole, imidazole and thiazole systems, respectively. 

These compounds are isomeric with the 1,2-azoles, e.g. isoxazole, pyrazole and iso thiazole. The aromatic characters of the oxazole, imidazole and thiazole systems arise from delocalization of a lone pair of electrons from the second hetero-atom. 

Electrophilic substitutions Although oxazole, imidazole and thiazoles are not very reactive towards aromatic electrophilic substitution reactions, the presence of any electron-donating group on the ring can facilitate electrophilic substitution. For example, 2-methoxythiazole is more reactive... 

Nucleophilic aromatic substitutions 1,3-azoles are more reactive than pyrrole, furan or thiaphene towards nucleophilic attack. Some examples of nucleophilic aromatic substitutions of oxazole, imidazole and thiazoles and their derivatives are given below. In the reaction with imidazole, the presence of a nitro-group in the reactant can activate the reaction because the nitro-group can act as an electron acceptor. 

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. ... 

Electrophilic substitution reactions of oxazoles, imidazoles, and thiazoles... 

We have previously discussed the reduced reactivity to electrophiles of oxazole, imidazole, and thiazole, as compared to furan, pyrrole, and thiophene, which results from the presence of the pyridine-like nitrogen atom. This behaviour is paralleled by increased reactivity to nucleophiles. Nucleophilic attack on furan, pyrrole, and thiophene derivatives only occurs when an additional activating group is present, as in the displacement reaction giving thiophene 3.41. 

The first hyperpolarizabilities (/3) of the donor-acceptor (D-A) systems containing several 1,3-heteroatom 7t-bridging units (oxazole, imidazole, and thiazole) have been studied by the ab initio method (HF/6-31G) <2004JMT(677)173>. The static first and second hyperpolarizabilities of amino- and nitro-substituted chromophores containing thiazole rings have been calculated by the ab initio TDHF method. The computed nonlinear polarizabilities correlate well with frontier orbital energies and hardness parameter (77) <2003CPL(376)116>. 

Oxazoles, imidazoles and thiazoles are lithiated in the 2-position, and pyrazoles and isothiazoles in the 5-position. With isoxazoles, w-butyllithium causes ring-opening. 

Oxazoles, Imidazoles, and Thiazoles. Resin-bound benzenesulfinic acid 52 obtained from sodium benzenesulfinate resin 43 (Scheme 12.13) could be treated with excess TEA and aldehyde in the presence of thiazohum catalyst to provide a-ketoamide in situ. Further reactions of the a-ketoamide with PPha/I, Lawesson s reagent, and EtOH/amine generated substituted oxazoles 56, imidazoles 57, and thiazoles 58 (Scheme 12.14). 

Comparative studies have been undertaken between different heterocyclic series, especially the azoles, thiazoles. oxazoles. imidazoles, and selenazoles. In a large number of these studies, the heterocycles are condensed w ith aromatic nuclei. 

Thiazole, (III), oxazole, imidazole, and pyrazole gyrase inhibitors prepared by Charifson (3) were effective against the bacterial DNA gyrase two B subunits and used in treating antibiotic resistance. 

Oxazoles are readily converted to a variety of other heterocyclic rings, including pyrroles, pyrazoles, pyrimidines, imidazoles, and thiazoles by nucleophilic addition... 

The standard, acidic Mannich conditions do not allow simple substitutions of the imidazole and thiazole systems with the much less basic oxazole an intramolecular Mannich cyclisation has been described. ... 

Imidazole and thiazole ring from oxazole ring... 

The carbon atoms of azole rings can be attacked by nucleophilic (Section 4.02.1.6 electrophilic (Section 4.02.1.4) and free radical reagents (Section 4.02.1.8.2). Some system for example the thiazole, imidazole and pyrazole nuclei, show a high degree of aromati character and usually revert to type if the aromatic sextet is involved in a reaction. Othei such as the isoxazole and oxazole nuclei are less aromatic, and hence more prone to additio reactions. 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

In addition to the reactions described in the preceding section, alkyl groups in the 2-positions of imidazole, oxazole and thiazole rings show reactions which result from the easy loss of a proton from the carbon atom of the alkyl group which is adjacent to the ring (see Section 4.02.3.1.2). 

In general, methyl groups in the 4- and 5-positions of imidazole, oxazole and thiazole do not undergo such deprotonation-mediated reactions, even when the ring is cationic. 

Hydroxy-imidazoles, -oxazoles and -thiazoles (484 Z = NR, O, S) can isomerize to 2-azolinones (485a). These compounds all exist predominantly in the azolinone form and show many reactions similar to those of the pyridones. They are mesomeric with zwitterionic and carbonyl canonical forms e.g. 485a 485b Z = NR, O, S). 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

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. 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

Hetero-benzylic anionic reagents, derived from 2-alkyl-l,3-oxazoles, -1,3-thiazoles and -imidazoles and related compounds, are not covered in this section because these resemble metallo 1-azaenolates in their reactivity (Section D.l.3.5.). 

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