Oxazoles, as intermediates

Organomercury derivatives of heterocycles in synthesis 85MI12. Organosilicon and organotin derivatives of thiazole and oxazole as intermediates in organic synthesis 88G211. 

Panek and co-workersdescribed syntheses of suitably bis-functionalized tris-oxazoles as intermediates leading to kabiramide C, halichondramide, and ulapualide A based on sequential application of a modified Hantzsch condensation methodology (Scheme 1.395). For example, condensation of cinnamide with ethyl... 

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

Modification of the oxazole, as in 13 allowed for the formation of vitamin Ba analogs, such as 15 via intermediate pyridine 14. 

Oxazol-5(4//)-ones as intermediates in the formation of macrolides, cyclodep-sipeptides, and cyclopeptides 99JHC1539. 

Pyrrolo[ 1,2-c]oxazolc itself was used for further elaboration of more complex molecules. The main members of this family that are used as intermediates in organic synthesis are the 3-oxo and 5-oxo perhydro derivatives. One can find also a number of 1,3-dioxo, 3,5-dioxo, 3,7-dioxo, and 5,7-dioxo perhydropyrrolo[l,2-r ]oxazoles that were prepared and/ or converted into another valuable compounds. 

FIGURE 1.18 2-AI koxy-5(4/7)-oxazol ones as intermediates in reactions of IV-alkoxycarbo-nylamino acids.22 After removal of the symmetrical anhydride from a reaction mixture containing Boc-valine and ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride, the filtrate contained a novel activated form of Boc-valine (20% yield) that was established to be the 2-alkoxy-5(4H)-oxazolone. Slow addition of Boc-valine to ethyl-(3-dimethylamino-propyl)-carbodiimide hydrochloride in dilute solution gave a 55% yield. Petrol = petroleum ether, bp 40-60°. 

The thermally induced Cornforth rearrangement can be rationalized by postulating the dicarbonylnitrile ylid 103 as intermediate. It is especially the natures of the substituents R and R" that determine the direction of the rearrangement. For example, heating of 5-alkoxy-4-(aminocarbonyl)oxazole (102, R = OAlkyl, R" = NR2) readily gives in a good yield rearrangement into the isomeric 5-(substituted amino)-4-(alkoxycarbonyl) oxazole (104, R = OAlkyl, R" = NR2) (Scheme IV.40). 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

The chemistry and synthetic applications of oxazoles were first covered in 1986 in an comprehensive volume edited by I. J. Turchi (Volume 45 of The Chemistry of Heterocyclic Compounds series). In the meantime, the number of synthetic strategies directed toward oxazole assembly as well as the use of these versatile heterocycles as intermediates, catalytic ligands, and pharmaceutical building blocks has vastly increased. We felt that a supplement and update of oxazole chemistry would be welcomed by the international chemistry community, and we are delighted that Dr. Palmer and his colleagues have accomplished this onerous mission. This volume represents another outstanding service to the organic and... 

Ferrini and Marxer65 have recently shown that vinylene carbonate reacts with primary amides, in the presence of polyphosphoric acid, to yield 2-substituted oxazole derivatives. Yields are low (2-34%), and phenoxy- and phenyl-acetamide, p-methylbenzamide, and salicylamide do not give oxazole derivatives. Although the reaction has been interpreted according to Scheme 3, the nucleophilic attack of a nitrile molecule (from the amide dehydration), with a nitrilium salt as intermediate (Scheme 4), cannot be excluded.06... 

In consideration of conceivable strategies for the more direct construction of these derivatives, nitriles can be regarded as simple starting materials with which the 3+2 cycloaddition of acylcarbenes would, in a formal sense, provide the desired oxazoles. Oxazoles, in fact, have previously been obtained by the reaction of diazocarbonyl compounds with nitriles through the use of boron trifluoride etherate as a Lewis acid promoter. Other methods for attaining oxazoles involve thermal, photochemical, or metal-catalyzed conditions.12 Several recent studies have indicated that many types of rhodium-catalyzed reactions of diazocarbonyl compounds proceed via formation of electrophilic rhodium carbene complexes as key intermediates rather than free carbenes or other types of reactive intermediates.13 If this postulate holds for the reactions described here, then the mechanism outlined in Scheme 2 may be proposed, in which the carbene complex 3 and the adduct 4 are formed as intermediates.14... 

Imidazoles are amphoteric compounds with a basic, pyridine-type nitrogen (they are about 106 times more basic than oxazoles and 104 times more basic than thiazoles173), and (where the NH is unsubstituted) a weakly acidic, pyrrole-type amino nitrogen in the ring. In consequence, imidazoles readily form salts with acids and often form salts (or complexes) with metals. The sparingly soluble silver salts formed by imidazoles have been used by Giesemann et al.174 as intermediates in the synthesis of 1-triphenylmethylimidazoles. Normally, however, the salts formed with acids are more important in isolation and purification procedures. 

A whole set of related powerful isocyanide-based MCRs has been developed by Zhu s research group. By varying the structures of the starting materials and slightly changing the reaction conditions, the group was able to produce different hetereocyclic scaffolds selectively. For example, heating a methanolic mixture of an aldehyde, an amine and an isocyanoacetamide 9-80 allowed the clean formation of 5-amino-oxazoles 9-82 (Scheme 9.16) [56]. It can be assumed that, in the formation of the products 9-82, the imines 9-79 as well as the adducts 9-81 act as intermediates. 

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192-194], They later reported an interesting example of the Ugi-Reissert process using this feature (237, Scheme 34a) [195], This strategy enabled the direct addition of isocyanides to the Ai-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. 

Aqueous mixtures containing a-hydroxyketones (3-hydroxy-2-butanone, l-hydroxy-2-propanone, l-hydroxy-2-butanone) or a-dicarbonyls (2,3-butanedione, 2,3-pentanedione) and ammonium sulfide were reacted at 25 °C for 2 hr. Among the heterocyclic flavor compounds formed were oxazoles, oxazolines, thiazoles, thiazolines and pyrazines. 2-(l-Hydroxyalkyl)-3-oxazolines and 2-( 1 -hydroxyalkyl)-3-thiazolines were major intermediate compounds identified in a-hydroxyketone systems and on the other hand, 5-hydroxy-3-oxazolines and 5-hydroxy-3-thiazolines were proposed as intermediate compounds in o-dicarbonyl systems. 

Amidooxazoles are produced from nitriles and C,A-diacylimines (161), which are formed in situ by the action of Lewis acids on A-(methoxyalkyl)amides <90JOC5225>. The later compounds are available by treatment of 2-aryloxazoles with bromine in methanol. A mixture of oxazole isomers is obtained in quantitative yield from acetonitrile, other nitriles also give diamide products (162). The reaction proceeds through a nitrilium ion intermediate (163) that may form the oxazoles by one of two pathways, one of which includes the diamides as intermediates (Scheme 76). 

As many oxazolines (but only one oxazole, trimethyloxazole, L.ll) were identified in beef systems, always heated at lower temperatures than those used for coffee roasting, it seems reasonable to consider them as intermediates in oxazole formation. Hirai et al. (1973) and Peterson et al. (1975) actually observed that the peak area for 2,4,5-trimethyl-3-oxazoline is large to very large in boiled beef extracts. The work of Jassmann and Schulz (1963) had previously shown that this 2,4,5-trimethyl-3-oxazoline results from thermal interaction of ammonia, acetaldehyde and acetoin, all compounds that have been reported to be present in cooked beef, as well as in coffee volatiles. 

In a related synthesis, acetylenic carbinols (63) have been claimed to condense directly with nitriles in the presence of concentrated sulfuric acid to give substituted oxazoles.133 Intermediates of the type represented by 64 have in fact been prepared independently as their hydrochlorides and are known to give oxazoles on treatment with sulfuric acid.140... 

Disubstituted perhydropyrrolo[2,l-6]oxazoles (215) can be obtained by reaction between proline and some aromatic and nonenolizable aldehydes. An azomethine ylide (216) has been postulated as intermediate in this reaction (Equation (25)) <85G569>. 

Although isocyanides have been spectroscopically detected as intermediates in the analogous P4 isoxazole to oxazole phototransposition [22], they have... 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

Shortly thereafter, Ghosh and Liu" reported a convergent and enantioselective synthesis of 1183. In their strategy, macrolactonization of 1259 is the key step for assembling the core structure. Further disconnection of 1259 then revealed the oxazole dienylamine 1203 (R = CH3), D-alanine, and the 5-hydroxy-2-alkenoic acid 1228 as intermediate synthetic targets (Scheme 1.322). 

The synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

A facile assembly of 2,4-orthogonally-functionalised oxazoles as useful bidirectional linchpins was achieved by treatment with diazomethane of acyl isocyanates, generated in situ from acyl halides 132 oxazolones 133 were converted to the oxazole triflates 134, useful intermediates for further synthetic elaborations as highlighted by the synthesis of 135 via Wittig and Stille reactions <01SL1739>. This linchpin tactic was used in the stereocontrol led total synthesis of the potent cytostatic agent (+)-phorboxazole A <01JA10942>. 

The reaction of A-sulfonyl propargylamides with a base catalyst gives 5-sulfonylmethyl oxazoles via 1,4-sulfonyl migration and a two-step mechanism in the cyclization with allenes as intermediates (Scheme 77). °... 

---