Oxazole-4-carboxylic acid esters

Nearly 1000 compounds have so far been identified in the volatile constituents of meat from beef, chicken, mutton and pork (6). The largest number of volatiles has been determined in beef and these were representative of most classes of organic compounds. Hydrocarbons, alcohols, aldehydes, ketones, carboxylic acids, esters, lactones, ethers, sulfur and halogenated compounds as well as different classes of heterocyclic substances (Figure 1) namely furans, pyrldlnes, pyrazines, pyrroles, oxazol(in)es, thiazol(in)es, thiophenes were present in cooked meat flavor volatiles as shown in Table I. Many of these compounds are unimportant to the flavor of meat and some may have been artifacts (16). 

The synthesis of 86 commenced with oxazole carboxylic acid 87. Base-catalyzed lithiation and coupling with isatin 88 followed by methyl ester formation and Boc deprotection provided tertiary alcohol 89. A second coupling of the amine 89 with carboxylic acid 90 followed by chlorination afforded chloride 91. Treatment of 91 with TBAF gave a 1 1 mixture of O-aryl ether 92 (CIO) in excellent yield. Refluxing 92 in chloroform resulted in the formation of 93 (70%, with 30% of the isomer), which was subjected to a three-step reaction sequence to furnish intermediate 86 (Scheme 16). 

Volatile components constitute about 0.1% of roasted coffee by weight Cojfea species, Rubiaceae), and more than 200 substances have been shown in green coffee. More than 800 compounds are known to make up the aroma of roasted coffee. Of these, only about 60 compounds have a significant role in the coffee aroma. Especially typical are a large number of heterocyclic compounds, mainly furans, pyrroles, indoles, pyridines, quinolines, pyrazines, quinoxalines, thiophenes, thiazoles and oxazoles, which arise in caramehsation and the MaiUard reaction during coffee roasting. In addition to heterocyclic products, other important volatiles are also some aliphatic compounds (hydrocarbons, alcohols, carbonyl compounds, carboxylic acids, esters, aliphatic sulfur and nitrogen compounds), alicyclic compounds (especially ketones) and aromatic compounds (hydrocarbons, alcohols, phenols, carbonyl compounds and esters). 

Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester " (2.50 g, 11.4 mmol)... 

The flask was fllled with (45,55)-4-methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2.50 g) and 70 mL of dry diethyl ether. The solution was cooled to —78 °C using a dry ice-acetone bath. 

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 

Esters of oxazole-4-carboxylic acids are easily hydrolyzed by hydrochloric acid to give salts of a-amino ketones (equation 5) the action of 2,4-dinitrophenjlhydrazine on the ester (133) in the presence of hydrochloric acid leads to the 2,4-dinitrophenylhydrazone (134). 

Thermal dehydration of o- (acylamino)phenols is the method of choice for the preparation of benzoxazoles (equation 96) and other annulated oxazoles. 0,iV-Diacyl derivatives of o-aminophenols cyclize at lower temperatures than do the monoacyl compounds. The synthesis is often carried out by heating the aminophenol with the carboxylic acid or a derivative, such as the acid chloride, anhydride, an ester, amide or nitrile. The Beckmann rearrangement of oximes of o-hydroxybenzophenones leads directly to benzoxazoles (equation 97). 

C—C—O—C+N. The formation of oxazoles from a-acyloxy ketones and ammonium salts was discovered in 1937 when it was found that treatment of benzoin benzoate with ammonium acetate in hot acetic acid gave triphenyloxazole in excellent yield. It has been shown that the reaction proceeds by way of intermediate enamines (equation 113). The synthesis is quite general and it is only.limited by the difficulty of obtaining the starting keto esters, particularly formates. The latter are probably intermediates in the preparation of cycloalkenooxazoles from acyloins and formamide in hot sulfuric acid (equation 114). Another variation is to heat a mixture of an a-bromo ketone, the sodium salt of a carboxylic acid and ammonium acetate in acetic acid (equation 115). 

Heating N- acetyl-5- (a-ketoalkyl)cysteine (308) for a brief period with acetic anhydride gives dihydro-2-methylthieno[3,4-d]oxazole-3a(4//)-carboxylic acids (310) (79JOC825). While the mechanism has not been investigated in detail, the isolation of several compounds suggests the existence of the intermediate spiro compound (309). Rearrangement to (310) is feasible since the anhydride character of (309) is changed to the ester character of (310). 

In order to install a benzophenone at the bicyclic scaffold we relied on the previously used oxazole linkage. To this end, the known amino-hydroxybenzophenone 37 (Aichaoui et al. 1990) was coupled to the free acid rac-38, which is available from Kemp s triacid in five synthetic steps. Remarkably, an 0-aeylation instead of the expected /V-acylalion was observed resulting in ester rac-39. As a consequence, oxazole formation was less straightforward but could eventually be achieved under more forceful conditions. The reaction sequence led to the racemic benzophenone rac-40, i.e. to a 1/1 mixture of the enantiomers (+)-40 and (-)-40, which was separated by chiral HPLC (Daicel Chiralpak AD). It is important to mention that a separation of enantiomers at an earlier stage is not sensible. While carboxylic acid 38 can be obtained in enantiomerically pure form, racemisation occurs upon activation, presumably due to a bridged symmetrical intermediate (Kirby et al. 1998) (Scheme 16). 

The use of a-ketol esters with formamide has been reported by Novelli and de Santis72 for the synthesis of oxazoles and imidazoles. It appears that in this case the reaction proceeds through reaction of the oxazole with formamide. The a-ketol esters are prepared by treating the corresponding a-bromoketones with the potassium salt of the appropriate carboxylic acid. 

The synthesis of the oxazole compound 45 starts with the coupling of the N-protected (/ )-methylcysteine compound 18 with threonine terf-butyl ester using bis(2-oxo-3-oxazolidi-nyl)phosphinyl chloride (BOP-Cl) [15] as a coupling reagent. Jones oxidation of the threonine hydroxy group leads to the ketoamide 44. The desired oxazole ring is closed by treatment with thionylchloride/pyridine. After deprotection, the oxazole, compound 45 is obtained. In the next step the oxazole compound 45 is coupled with the tris(thiazoline) compound 43 to yield the thioester 46. Now Fukuyama closes the fourth and last thiazoline ring (46 47). After conversion of the carboxylic acid function into a methyl-... 

Carboxylic acids and esters frequently must be protected against the attack of organometallic reagents, e.g. metal alkyls and hydrides, and reducing agents like LiAlH. For this purpose they usually are converted to orthoesters, oxazolines or oxazoles. 

There are many methods for the cleavage of 4,5-dihydrooxazoles once they have served their purpose. An effective method for hydrolyzing them back to carboxylic acids employs trifluoro-methanesulfonic anhydride <92SC13>. Intermediate ring-opened esters (100) are A(-methylated, then saponified to the acids (Scheme 34). The oxazoles may also be converted into aldehydes or nitriles. In a one-pot, two-step procedure, 4,5-dihydrooxazoles are transformed into alcohols (101) <93TIj4893>. Chloromethyl methyl ether converts the dihydrooxazoles into ring-opened amides in the first step, and these are reduced with diisobutylaluminum hydride (Scheme 35). 

Application of the Davidson oxazole synthesis to products of the Passerini reaction has expanded the usefulness of this well-known route <91LAll07>. The a-acyloxy ketones or a-acyloxy -keto esters employed in the Davidson synthesis are not readily available. However, the use of arylglyoxals as the carbonyl component of the Passerini reaction, along with cyclohexyl isocyanide and carboxylic acids, gives a wide variety of iV-cyclohexyl-2-acyloxy-3-aryl-3-oxopropionamides (151). Reaction of these intermediates with ammonium formate in acetic acid affords A -cyclohexyl-2,4-diaryl-5-oxazolecarboxamides (152) in fair yields (Scheme 69). 

Conventionally the acyl derivatives of acyloins and benzoins may readily be obtained by reaction with acid anhydrides. The acyloin esters can more conveniently be prepared by allowing the corresponding a-bromo ketones and the sodium or potassium salts of the appropriate carboxylic acid to react, either in ethanol or in the acid to be esterified. The esters may not necessarily be isolated, and the oxazoles are obtained directly by adding the ammonium salt to, or passing ammonia through, the mixture, which is then boiled.84 The reaction then becomes useful for the preparation of oxazoles (53) from a-bromo ketones and carboxylic acids.84 121... 

Infrared absorption spectral data for several oxazole derivatives,86 90 including alkyl-98 186 and aryl-263 264 substituted oxazoles, 2-amino- and substituted-amino derivatives109 112 136, 5-amino179 198-201 and 5-alkoxy-oxazoles,66 carboxylic acids,112 147 esters,126 179 184 carboxamides,199 200 4-acetyloxazoles,147 halogenoalkyl oxazoles,91 oxazolines,262 and benzoxazoles262 have been reported. 

Reaction of 2-phenyloxazole-4-carbonyl chloride with diazomethane affords the crystalline diazomethyl ketone, which fails to undergo the Wolff rearrangement.389 In general the esters are smoothly hydrolyzed by aqueous alkali, but attempts to hydrolyze 5-aminooxazole-4-car-boxylates result in disruption of the ring system.389 The behavior of oxazole-4-carboxylic acids has been described in greater detail in The Chemistry of Penicillin .2... 

Oxazoles substituted with a cyano group in the 2-, 4-, and 5-positions are known many of these can be reduced to aldehydes by the Stephen method2 and hydrolyzed by alkali to the related amides and carboxylic acids. 2-Phenyl-5-aminooxazole-4-carbonitrile on treatment with concentrated sulfuric acid forms the crystalline amide (240) further hydrolysis, however, is unsuccessful. The corresponding 4-carboxylic esters are also stable to hydrolysis.389... 

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