Structure of oxazoles

Figure 12.8.5 The molecular structure of oxazole. Figure 12.8.6 The molecular structure of biphenyl.

The classical structure of oxazole (159) is partly inconsistent with its aromatic character and small dipole moment, but a set of resonance structures involving dipolar forms such as 160 and 161 as contributors... 

Fig. 17. Structures of oxazole-containing macrolides produced by bacteria.

Figure S.9 Structure of oxazoles (bond lengths in pm, bond angles in degrees).

Details of bond lengths and bond angles for all the X-ray structures of heterocyclic compounds through 1970 are listed in Physical Methods in Heterocyclic Chemistry , volume 5. This compilation contains many examples for five-membered rings containing two heteroatoms, particularly pyrazoles, imidazoles, Isoxazoles, oxazoles, isothlazoles, thlazoles, 1,2-dlthloles and 1,3-dlthloles. Further examples of more recent measurements on these heterocyclic compounds can be found in the monograph chapters. 

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). 

The structure of the two oxazoles 30 and 32 was proved by mass spectrometry (69JOC999). 

The mass spectra of azolides are not very specific, since they depend to a large extent on the structures of the respective acyl groups. Flash vacuum pyrolyses of azolides has been studied for 1-acyl-1,2,4-triazoles and benzotriazolides by tandem mass spectrometry (MS/MS). 461 Rearrangements of triazolides resulted in the formation of oxazoles. 471... 

Analysis of intermolecular interactions in the crystal structures of oxime molecules has been used to answer that question. In all available complex structures with one central metal ion we found no coordinative bonds from the oxime oxygen to the metal, but exclusively coordination between the nitrogen atom and the metal ion (data were retrieved from the Cambridge Crystallographic Database [14]). In a comprehensive study Bohm et al. investigated complexes of oxazoles, methoxypyridines, and oxime ethers with water [15]. On the basis of interaction energies obtained... 

Rearrangements of oxazoles 392 and 393 (Scheme 62). which assume nucleophilic attack of the side-chain at the C(5) position and consequent fission of the ring O—C(5) bond, have been considered [76JCS(PI)315]. Nevertheless, the phenylhydrazide 394 does not rearrange into the expected 395 and remains unchanged under various conditions. In this context, unsuccessful attempts are reported for some structurally related 4-substituted oxazoles, whereas specific examples concerning oxazolium substrates 393 are not mentioned [76JCS(P1)3I5]. 

Polymerization of terephthalic acid with 4,6-diamino-l,3-benzenediol via oxazole formation (Eq. 2-219) proceeds with a sharp and continuous decrease in reaction rate with increasing polymer molecular weight [Cotts and Berry, 1981]. Reaction becomes progressively more diffusion-controlled with increasing molecular size due to the increasing rigid-rod structure of the growing polymer. 

Scheme 38 Structures of Dihydrooxazole- and Oxazole-Containing Peptides...

The synthesis of oxazole- and dihydrooxazole-containing cyclic peptides has gained considerable interest in view of the structural characterization of the natural products. In fact, in various cases a final structural elucidation was provided only by total synthesis as originally proposed structures had to be corrected because of epimerization, difficult stereochemical assignment, and/or impurities.1523,524,554,5551... 

It is evident from the structure of the oxazol-5(4//)-one, also sometimes called an azlactone or oxazolinone, why it is so susceptible to epimerization. Removal of the a-proton generates a five-membered ring with six n-electrons, an aromatic system according to the Hiickel 4n + 2 rule (Scheme 5). 

Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1J3 (61%), IL-1 a (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. 

An interesting reaction is the formation of oxazoles (CLIII and CLIV) via heating the photoproducts, obtained by the action of aromatic aldehydes on the monoxime derivatives of CXLIX and CL, respectively. The oxazoles are readily obtained by allowing the aldehyde to react with the corresponding monoxime in the presence of piperidine in the dark.m-200 On the other hand, whereas irradiation of 1,2-naphthoquinone-1-benzoylimide (CLVI) with aromatic aldehydes led to CLVII, the monoimine derivative of CXLIX gave photoproducts of structures (CLVa or CLVb).198-199... 

In oxazole (167) (95MI5) and isoxazole (168) [88ZN(B)328] N-M coordination prevails. The possibility of O coordination (169) is less likely. Examples of the C-coordinated derivatives of oxazole (170) and isoxazole (171) are known [89JOM(372)287]. The complexes of composition CrL2 based on 3-methyl-5-phenyl- and 3,5-diphenylisoxazole were assigned a polymeric structure with the -coordinated framework (78ZOB418). The other example is the interaction of the cyano complexes [M(CN) (cp)(dppe)] (M = Fe, Ru) or [Fe(cp)(dppe)(CNH)]Br with gem-dicyano-epoxide to afford the oxazol-2-yl complexes with the C-coordination mode... 

The photochemical addition of both aliphatic and aromatic aldehydes to o-quinones monoimines has been widely used in the preparation of oxazoles [Eq. (92)].340 An intermediate amide has been isolated in a number of cases, and can be thermally converted into the oxazole. The reaction, therefore, does not appear to be a cycloaddition. An analogous addition occurs between o-quinones and aldehydes, and the photoproducts have been shown to have an acyclic structure341 rather than the previously assigned 1,3-dioxole structure. 

The flash vacuum pyrolysis of 1-acyltriazoles at 520 °C gave a mixture of oxazole (16%) and 68 in 33% yield to which was tentatively assigned the isoindolo[l,2-4][l,2,3,5]benzotetraazepine structure, based only on mass and NMR spectrometric evidence and its acidity. Benzotetrazepine 68 is believed to be formed by radical recombination of the first formed diradical from 1-acyltriazoles, and followed by addition of benzotriazole, itself formed by fragmentation of 1-acyltriazole (Equation 12) <1999AJC775>. 

Draw the structure of pyrrole, furan, thiophene, furfural, indole, oxazole, imidazole, thiazole, purine. 

Treatment of aromatic carboxaldehyde (diaminomethylene)hydrazones (105) with hot acetic anhydride or benzoyl chloride affords l,4-diacyl-3-acylamino-5-ary 1-4,5-dihydro- 1H-1,2,4-traizoles (106) in 75-95% yields. In contrast, when the 4-pyridine analog of 105 was employed, the unusual hemianimal triazole derivative (107) was obtained. The structures of the novel compounds were determined by spectral methods and in several cases by x-ray structural analysis. Mechanistic considerations are discussed [95M733]. The oxazole-1,2,4-triazole (108) was prepared by cyclization of the corresponding oxazolecarbonyl-thiosemicarbazide with bicarbonate, alkylation at the sulfur and oxidation to the sulfoxide with MCPBA [95JHC1235]. 

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. 

The compounds calcimycin (A23187, 168) and nocobactin (187) contain the common feature of an oxazole ring but otherwise differ widely in functionality they are grouped together on the basis of their being cation ionophores. Calcimycin (A23187, 168) occurs in Streptomyces chartreusensis, from which it may be isolated as the mixed magnesium-calcium salt (89, 90). The structure of the free acid, a crystalline solid, was determined spectroscopically to be 168... 

The physicochemical properties of oxazoles to 1972 have been comprehensively reviewed by Lakhan and Ternai (3) whose work constitutes a point of departure for this section. Mention is made here only of those properties relevant to the detection, isolation, structure elucidation, and behavior of the natural compounds. The oxazole moiety in nature is usually embedded in a variety of functionality, and the rather innocuous properties of the parent molecule do not dominate or influence the behavior of the oxazole alkaloids to the extent that these compounds can be collectively regarded as displaying any characteristic set of physicochemical properties. Table III lists the physical and spectral properties of the compounds covered in this chapter. 

C-NMR data for some of the more complex and/or recently discovered alkaloids have been reported (Table III). The structure of the trisoxazole portion of ulapualide B (63) was elucidated largely by analysis of fully coupled and partially decoupled 13 C-NMR spectra. A series of simple oxazoles has been subjected to systematic analysis by 13 C-NMR spectroscopy and provides useful models (125). 

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