Oxazoles and thiazoles

Of the 1,2-oxazole compounds, the arylhydrazone-l,2-oxazole derivatives exhibit high antifungal activity (Summers et al., 1968 Matolcsy et al., 1969 Eckhard et al., 1973). 

It is rather toxic to mammals, its acute oral lDj being for rats 126 mg/kg. Its vapour causes lung irritation. The 4-(3-chlorophenylhydrazono)-3-methyl-5-isoxazolone analogue, which is considerably less toxic to mammals, has therefore been synthesised. The acute oral lDj of metazoxolon (71) for femal rats is 3340 mg/kg, its dermal toxicity is higher than 1000 mg/kg (Purnell, 1973). 

Of the 3-hydroxy-isoxazoles, hymexazole (72) has proved the most active fungicide. For an antifungal action substitution in position 5 is indispensable. The 

Hymexazole (Tomita, 1973) is effective mainly against soil fungi and fungi causing diseases spreading with the seeds, such as Fusarium, Aphanomyces, Pythium and Corticium spp. Plant roots rapidly absorb the active substance from a nutrient solution or from the soil, the substance then being translocated into the leaves. In the plant tissues hymexazole is detoxicated into two main metabolites, 

4- isoxazolin-3-on, which are still fungitoxic but less toxic to mammals than hymexazole (Kamimura et ai, 1974 Murakoshi et al., 1974). A certain growth-stimulating effect on plants has also been observed for hymexazole (Ogawa and Ota, 1973 and 1974). Hymexazole is more efficient in the soil than in vitro, which is attributed to the synergistic effect of iron(III) and aluminium ions present in the soil (Takahi, 1973b). 

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This chapter is an attempt to present the important results of studies of the synthesis, reactivity, and physicochemical properties of this series of compounds. The subject was surveyed by Bulka (3) in 1963 and by Klayman and Gunther (4) in 1973. Unlike the oxazoles and thiazoles. there are few convenient preparative routes to the selenazoles. Furthermore, the selenium intermediates are difficult to synthesize and are often extremely toxic selenoamides tend to decompose rapidly depositing metallic selenium. This inconvenience can be alleviated by choice of suitable reaction conditions. Finally, the use of selenium compounds in preparative reactions is often complicated by the fragility of the cycle and the deposition of metallic selenium. 

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... 

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). 

The cyclizations of conjugated nitrile ylides forming substituted oxazoles and thiazoles were computed up to the MP4/6-31H-G level [OOJOC47]. Relative to 23, oxazole-4-carboxylic acid24 is stabilized by about -38.1 kcal/mol (Scheme 18). 

Reaction of the diphosphine ligand R2P(CH2)2PR2 (R = benzothiazolyl) (L) with [RhCl(PPh3)3] gives the exclusively P-coordinated product [RhCl(PPh3)(L)] (88JOM(338)C31, 92JCS(D)241), which is perhaps a common feature of the P-substituted derivatives of oxazole and thiazole. 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

Strecker aldehyde are generated by rearrangement, decarboxylation and hydrolysis. Thus the Strecker degradation is the oxidative de-amination and de-carboxylation of an a-amino acid in the presence of a dicarbonyl compound. An aldehyde with one fewer carbon atoms than the original amino acid is produced. The other class of product is an a-aminoketone. These are important as they are intermediates in the formation of heterocyclic compounds such as pyrazines, oxazoles and thiazoles, which are important in flavours. 

Davies et al. describe the preparation of both oxazole- and thiazole-containing derivatives of combretastatin. By formation of the ketoamide intermediate 60, in a 54% yield (Scheme 14), both classes of compounds may be obtained by altering the last step of the reaction [58]. To produce the oxazole 61 a cyclo-dehydration reaction was performed using triphenylphosphine-iodine-triethylamine, and the thiazole compound 62 was formed by thiona-tion using Lawesson s reagent, with an excellent yield (94%). 

The carbonylation of imidazole derivatives with several olefins takes place in high yields with the aid of an Ru3(CO)i2 catalyst.112,112a The carbonylation occurs exclusively at the a-position to the sp2 nitrogen (Equation (85)). A wide range of olefins can be utilized in this reaction, and a variety of functional groups are compatible under the reaction conditions. The (/i-H)triruthenium clusters such as 12 are proposed as a key species in this carbonylation reaction. Other five-membered A-heteroaromatic compounds, such as pyrazoles, oxazoles, and thiazoles, can be used for the carbonylation reactions, where the carbonylation takes place at the a-C-H bond to the sp2 nitrogen. 

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

Fig. 1 Naturally occurring oxazole- and thiazole-containing macrocycles...

Vitzthum, O. G. and P. Werkhoff. Oxazoles and thiazoles in coffee aroma. 

The intermolecular Heck reactions of oxazoles and thiazoles with olefins are not too common. They are rarely high yielding since in several cases they are biased by dehalogenation. Due to this reason the olefination of these systems is usually achieved through Stille coupling with vinylstannanes. 

Synthesis of imidazoles, oxazoles and thiazoles from acylamino ketones 569... 

Photoisomerization of pyrazoles, isoxazoles and isothiazoles into imidazoles, oxazoles and thiazoles, respectively, is described in Section 3.4.1.2.4. 

Superacid-promoted dicationic species containing heteroaromatic rings, where positive charge centres migrate through consecutive deprotonation-reprotonation steps, undergo cyclization reactions followed by aromatization and superacid-promoted elimination of benzene (Scheme 10).31 The process leads to the synthesis of aza-polycyclic aromatic compounds in moderate to good yields. Seven examples include pirazole, oxazole, and thiazole heterocycles. 

Anthraquinoneazoles. In contrast to the older yellow Algol dyes, which contain two thiazole rings (e g., 2,2-bisanthra [2,1 d thiazole-6,11-quinonyl), the red to blue oxazoles and thiazoles derived from l-aminoanthraquinone-2-carboxylic acid and 3-amino-2-hydroxy- or -mercaptoanthraquinones exhibit good lightfastness. The good fastness to atmospheric conditions and chlorine of the blue deriv-... 

OXAZOLE AND THIAZOLE FUSED WITH AZINES INTRODUCTION 644... 

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