Oxazole, Thiazole, and Imidazole

The positional reactivity order becomes 2 5 4 in the electrophilic bromodechlorination of 2,4,5-trichlorothiazole (76JHC1297). This finding indicates that the 5- and 4-positions are mutually strongly deactivated by the -/ effect of the adjacent chlorine, which is enhanced by the short C-4—C-5 bond length. 

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Condensation of aryl halides with various active methylene compounds is readily promoted by catalytic action of palladium to give the corresponding arene derivatives containing a functionalized ethyl group [7]. Yamanaka et al. extended this chemistry to haloazoles including oxazoles, thiazoles and imidazoles [8]. Thus, in the presence of Pd(Ph3P)4,2-chlorooxazole was refluxed with phenylsulfonylacetonitrile and NaH to form 4,5-diphenyl-a-phenylsulfonyl-2-oxazoloacetonitrile, which existed predominantly as its enamine tautomer. In a similar fashion, 4-bromooxazole and 5-bromooxazole also were condensed with phenylsulfonylacetonitrile under the same conditions. 

Halo ketones 218 react with amides (100 C, no solvent), thioamides (reflux in EtOH), and amidines to give oxazoles, thiazoles, and imidazoles (219 220 Z = O, S, NH), respectively (Scheme 108). Intermediates of type 221 can sometimes be isolated. This is the most important thiazole synthesis, and both the thioamide and the halo ketone components can be varied widely . 

Considerable parallelism emerges from an examination of the major methods for the construction of oxazole, thiazole and imidazole ring systems. 

Unangst, P.C., Connor, D.T., Cetenko, W.A., Sorenson, R.J., Kostlan, C.R., Sircar, J.C., Wright, C.D., Schrier, D.J. and Dyer, R.D. (1994) Synthesis and biological evaluation of 5-[[3,5-Bis(l,l-dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and imidazoles Novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity. J. Med. Chem. 37 322-328. 

Sodium Salts of Stabilized Carbanions. The carbosubstitution in 4- and 5-bromo-2,4- or 5,6-diphenyl-l,3-azoles 140 (oxazoles, thiazoles, and imidazoles) with phenylsul-fonylacetonitrile in the presence of a strong base is promoted by palladium catalysis... 

The extensive work carried out by Beller in recent years has contributed to the field with a series of interesting examples, most of them based on the system palladium/di-1 -adamantyl- -butylphosphine (BuPAdj). Thus, they reported the use of ammonia as the nitrogen source for the palladium-catalyzed aminocarbonylation of aryl halides, providing a straightforward method to prepare primary amides with excellent applicability and functional group tolerance [4]. In the same group, the first carbonylative C—H activation reactions of heteroarenes to form diaryl ketones 4 were developed [5], A series of nonpreactivated heteroarenes 3 (oxazoles, thiazoles, and imidazoles) were successfully carbonylative coupled to a wide range of aryl iodides (Scheme 3.2). To avoid the formation of the noncarbonylative... 

Oxazole-, thiazole-, and imidazole-based tricyclic compounds (60) NajCOs or BuOK, DMF, (MWl, 200-220 X, Ih) IkP kinase (IKK) inhibitor [68]... 

Selenium heterocycles receive far less mention in the literature than do such homologs as oxazole, thiazole, or imidazole. In fact, preparative methods of selenium heterocycles are much more limited than for the other series, mainly because of manipulatory difficulties arising from the toxicity of selenium (hydrogen selenide is even more toxic) that can produce severe damage to the skin, lungs, kidneys, and eyes. Another source of difficulty is the reactivity of the heterocycle itself, which can easily undergo fission, depending on the reaction medium and the nature of the substituents. 

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.). 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Lewis, J. R. 2000. Amaryllidaceae, muscarine, imidazole, oxazole, thiazole, and peptide alkaloids, and other miscellaneous alkaloids. Natural Product Reports, 17 57-84. 

Sulfur Heterocyclics. Sulfur containing compounds (thiols, thiophenes, thiazoles,. .. etc.) play a major role in the flavor of raw and processed foods. These compounds have characteristic flavor notes and the flavor thresholds are mostly low. Several reviews (ill, 112, 113) demonstrate the important role of sulfur compounds in food flavors. Organoleptic properties of these compounds may be pleasant, strong nut-like odor of U-methyl-5-vinylthiazole which is present in cocoa (llU) objectionable pyridine-like odor of thiazole (115) quinoline-like odor of benzothia-zole (ll6) strong tomato leaf-like odor of isobutylthiazole (117) and bread crust flavor of acetyl-2-thiazoline (ll8). A mixture of oxazoles, thiazoles, thiazolines, imidazoles, trithiolanes and... 

With certain 4,4-bis(trifluoromethyl)-3-aza-l-oxabutadienes this transformation can be achieved on heating with metals (91CZ253), especially zinc (89CHE1418) or with zinc/ultrasound (91CZ253). The fluorine atom at C—5 can be readily replaced by various nucleophiles (88S194). Via this route, 4-trifluoromethyl-l,3-oxazoles, -1,3-thiazoles, and -imidazoles can be introduced into many compounds of biological interest (Scheme 85). 

Oxazoles readily undergo Diels-Alder type cycloaddition across the 2,5-positions, in parallel with the behaviour of furans (18.7). Thiazole and imidazole do not show this mode of reactivity, however they do react with highly electrophilic alkynes via initial electrophilic addition to the nitrogen, then nucleophilic intramolecular cyclising addition (cf the comparable reactivity of quinohnes, 9.13). ... 

Oxazole itself, in contrast to isoxazole, thiazole, and imidazole has been found to undergo Diels-Alder reaction with dienophiles.340 341 Isonicotinic acid esters (182, R = COOR ) and isonicotinonitriles (182, R = CN) are... 

A number of kinetic studies on hydrogen exchange of derivatives of furan, thiophene,pyrrole,selenophene, imidazole, oxazole, thiazole, and indole have been reported. The kinetic picture is the same as for benzene derivatives reactions follow pseudo first-order kinetics and the values increase markedly as the acidity of the medium increases. 

Figure 5 Innate reactivity of IH-imidazole, oxazole, thiazole, and their benzo analogs.

Among the five-membered ring heterocyclics with more than one hetero-atom, the derivatives of imidazole, oxazole, thiazole and 1,2,4-triazole are particularly important. 

Synthetic routes to NHCs are very flexible, and a vast nimiber of structures are possible. NHCs based on imidazole and imidazolidine cores are the most common, although 1,2,3- and 1,2,4-triazole and oxazole, thiazole, and benzimidazole cores have also been used (among others). Several researchers, most notably Cavell and coworkers, have also explored the chemistry of so-called ring-expanded NHCs, where a six-, seven-, or eight-membered ring forms the core of the NHC [50]. By suitable modification of the synthetic route, it is possible to introduce a variety of substituents on the backbone of the core, or at the N-sub-stituents. This enormous flexibility has contributed to the rapid growth of this area of chemistry. 

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