5 -Oxazolones arylation

To minimize racemization, the use of nonpolar solvents, a minimum of base, low reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) is effective. (A carbamate, R = O-r-Bu, has been reported to form an oxazolone that appears not to racemize during base-catalyzed coupling.) ... 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

The enzymatic hydration of lactones is also documented, a variety of hydrolases having demonstrated activity. Very detailed kinetic studies have, for example, been published on the hydrolysis of oxazolones (7.78, R = H or Me, R = Me or aryl, R" = Me or Ph) catalyzed by a-chymotrypsin [163], These compounds are interesting from a chemical point of view, being enolic lac-... 

Cycloadditions have been carried out to 37/-indoles (222, 223) (125,126), N-arylmaleimides (224) (127,128), l,2), -azaphospholes (225) (129), 5(47/)-oxazo-lones (226) (130), and 4,5-dihydrooxazoles (230) (131). The primary cycloadducts from the reaction of oxazolones (e.g., 226 with diaryl nitrile imines), derived from tetrazoles in refluxing anisole, do not survive. They appear to lose carbon dioxide and undergo a dimerization-fragmentation sequence to give the triazole 228 and the diarylethene 229 as the isolated products (130). In cases where the two aryl substituents on the oxazole are not the same, then, due to tautomerism, isomeric mixtures of products are obtained. 

The reaction of ethyl A-arylcarbamates 3 with l-bromo-3,3-dimethyl-2-buta-none or l-bromo-3-ethyl-3-methyl-2-pentanone 4 in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) results in the one-step synthesis of 3-aryl-5-ferf-butyl-2(3/T)-oxazolones 7 in fair to good yields (Fig. 5.2 Table 5.1, Fig. 5.3). This method is efficient for the preparation of bulky 5-substimted-2(37f)-oxazo-lones. 

The A7-(a-hydroxyphenacyl)urethanes 8 react smoothly with aromatics in concentrated sulfuric acid to give Friedel-Crafts type products 9, which are readily converted into 4-aryl-5-phenyl-2(3/l)-oxazolones 10 on heating or by treatment with phosphorus pentachloride (Fig. 5.4)." ... 

TABLE 5.1. SYNTHESIS OF 3-ARYL-5-tert-BUTYL-2(3H)-OXAZOLONES FROM ETHYL A-ARYLCARBAMATES AND a-BROMO KETONES"... 

Protonation of the A -aryl-Af-(3-triisopropylsilylpropargyl) carbamate 37 with trifluoromethanesulfonic acid generates a (3-silylvinyl cationic intermediate 38 that is attacked by the carbamate carbonyl group (but not the aromatic ring) to give good yields of the 2(3/7)-oxazolone 40 (Fig. 5.9). ... 

TABLE 5.5. SYNTHESIS OE 5-ALKYL-3-ARYL-4-HALO-2(3H)-OXAZOLONES FROM iV-ARYL-iV-(HYDROXY)-a-HALO ACYLACETAMIDES... 

The intramolecular base-induced ring transformation of 3-phenacyl-2,4-thiazol-idinediones 105 with sodium hydroxide or triethylamine smoothly proceeds to give 5-aryl-2(3/7)-oxazolones 108 (Fig. 5.27). 

The first derivatives of the 4(5/f)-oxazolone ring system 1 were prepared almost 90 years ago when Traube and Ascher described the synthesis of 2-amino-4(5H)-oxazolones (pseudohydantoins) 2 via condensation of guanidine with a-hydroxy esters (Scheme 6.1). This is quite remarkable in that it was 36 years later before Sheehan and Izzo prepared the hrst example of a simple 2-aryl analogue via... 

There are relatively few syntheses of simple 2-alkyl- or 2-aryl-4(5/l)-oxazolones and these have been summarized previously. An excellent and comprehensive review of the synthesis and reactions of 4(5fl)-oxazolones covering the early literature up to 1983 has been published. Subsequent to this work extensions of earlier methods and a few additional examples have appeared in the literature and these will be described in detail. 

Barrett and Kohrt" ° and Kelly and Lang" independently reported the first examples of oxazole triflates (Scheme 6.17). In both cases, the requisite 2-aryl-4(5/7)-oxazolone, 56 or 59, was treated with trifluoromethanesulfonic anhydride (Tf20) to afford 60a or 60b, respectively, which were then coupled successfully with a variety of organostannanes. Kelly and Lang" attempted to extend this methodology to prepare the key oxazole triflates 63 in their approach to sulfomycin I. However, they were unexpectedly thwarted when 61 could not be cyclized to the requisite 4(57/)-oxazolone precursors 62. Schaus and Panek described an unproved procedure to prepare 56 in 90% yield very recently. 

Weiss and co-workersprepared a series of oxazohnylidene steroids 343 as luminescence dyes for application as potential intracellular diagnostic agents (Scheme 6.72). The key intermediate 2-aryl-5,5-dimethyl-4(57/)-thiooxazolones 341 were readily available from the corresponding 4(57/)-oxazolones 339. Reaction of 341 with 342, generated in situ from the hydrazone 340, gave 343 as expected. It was not possible to prepare 343 from 3-thio-androsta-l,4-dien-17-one since the requisite corresponding heterocyclic diazo compounds could not be prepared. 

Smith and co-workers adapted Sheehan and Izzo s original synthesis of 2-aryl-4(57/)-oxazolones and developed a general synthesis of 2-aIkylA(57/)-oxazo-lones. Teatment of an acid halide with AgNCO followed by diazomethane produced 344 that were immediately converted to the 2-alkylA-oxazole triflates 345. The authors noted that ethanol-free diazomethane was required to prepare 344. The oxazole triflates 345 were, in turn, key intermediates leading to a variety of 2,4-disubstituted oxazoles required for natural products (Scheme 6.73). 

Cyclizations with perfluoroacylating agents seem to be quite general for the synthesis of 5(2i7)-oxazolones with aromatic substituents directly bonded to the heterocyclic ring. For example, perfluoroacylation of a solution of an arylgly-cine containing a phosphorus trihalide affords 4-aryl-2-(perfluoroalkyl)-5(2//)-oxazolones (Table 7.1, Fig. 12) Similar results were obtained when amino nitriles were used as starting materials. ... 

The reaction of 2-aryl-4-phenyl-5(4/b-oxazolones 22 with 4-methylenetriazoles 23 was also studied. The direction of the alkylation was strongly dependent on the nature of the substituent on the aromatic ring at C-2 in 22. Thus, oxazolones with electron-rich aryl substituents gave predominantly alkylation at C-4 to yield 24. In contrast, the isomeric products 25 are preferentially obtained when using substrates with electron-withdrawing substituents (Scheme 7.7). 

Alkyl(aryl)-2-(trifluoromethyl)-5(277)-oxazolones have been used as intermediates to prepare 2-(trifluoromethyl)pyrroles interesting compounds frequently used as insecticides and acaricides. The oxazolones react with electron-dehcient unsaturated compounds in the presence of a base. Reaction of 5(277)-oxazolones, usually with a substituted aryl ring at C-4, with a wide variety of alkynes and alkenes has given rise to numerous 2-(trifluoromethyl)pyrroles 56. For example,... 

Similarly, reaction of 4-aryl-2-(trihuoromethyl)-5(277)-oxazolones 52 with substituted azo compounds, for example, PhN=NC02Et affords (trihuoromethyl)dihy-drotri azoles." ... 

The procedure is also useful for the synthesis of 4,4-disubstituted 5(477)-oxazolones. For example, cyclization of a 2-aryl(hetaryl)carbonylamino-2-arylpro-pionic acid afforded the corresponding oxazolones 99 (R3 = Me) that were evaluated as selective herbicides. ... 

Nitrones such as 102 gave 2-aryl-4-substituted-5(4//)-oxazolones 103 in the presence of acetic anhydride and triethylamine (Scheme 7.28). Selected examples of saturated-5(477)-oxazolones prepared via cyclization of amino acids are shown in Table 7.15 (Fig. 7.17). 

The alkylation of 2-aryl-4-phenyl-5(4//)-oxazolones like 22 is strongly dependent upon the nature of the substituent on the aromatic ring at C-2. For electron-rich... 

Arylation. Arylation of 2,4-diaryl-5(4//)-oxazolones 170 with activated aryl halides has been reported to proceed under phase-transfer conditions (Scheme 7.51). The yields of 2,4-diaryl-4-(2,4-dinitroaryl)-5(47/)-oxazolones 171 are often modest. Heteroarylation of 170 was accomplished using 2-chloro-3,5-dinitropyridine. Representative examples are shown in Table 7.19 (Fig. 7.21). 

TABLE 7.19. SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(47T)-OXAZOLONES VIA ARYLATION OF SATURATED 5(47/)-OXAZOLONES AT C-4... 

A general procedure for acylation of 2-aryl-5(4//)-oxazolones using an acylating agent in the presence of 4-(dimethylamino)pyridine and triethylamine has been described.The resulting products are useful intermediates for agrochemicals and drugs. 

Imines and Carbonyl Compounds. Simple 2-alkyl(aryl)-5-(4//)-oxazolones like 191 can react with aldehydes, ketones, imines, and oximes to afford the corresponding unsaturated analogues 192 (Scheme 7.58). In some cases, this procedure is especially advantageous over the classical one-pot synthesis.The chemistry of unsaturated 5(4//)-oxazolones like 192 will be discussed in detail in Section 7.4. 

Diazonujm Salts as Electrophu.es. 2-Aryl-5(47/)-oxazolones 225 couple readily with aryldiazonium salts to give the corresponding 4-arylazo derivatives 226 or 2-aryl-4,5-oxazoledione-4-arylhydrazones Structural studies revealed that... 

Ring opening of 2-aryl-5(477)-oxazolones 230, obtained from A-acylglycines, with A,A-dimethyl-2-aminoethanol provides choline esters of A-substituted amino... 

Racemization is not encountered when 4-unsubstituted-5(477)-oxazolones or 4,4-disubstituted-5(477)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(47/)-oxazolones function as glycine synthons in the synthesis of A-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(47/)-oxazolone with a-methylphenylalanine affords A-(trifluoroacetyl)glycyl-a-methylphenylalanine. 4,4-Disubstituted-5(4//)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate ot,ot-disubstituted amino acids. As an example, 4-(aryl-methyl)-2-phenyl-4-(trifluoromethyl)-5(4//)-oxazolones 260 are key intermediates... 

In a similar manner, aldazines afford pyridazinones 317 (Scheme 7.104). 1,3-Diazadienes such as l-aryl-4-(dimethylamino)-2-phenyl-l,3-diaza-l,3-butadienes or l-aryl-4-(dimethylamino)-2-methylthio-l,3-diaza-l,3-butadienes react with oxazolones and give rise to pyrimidin-6-ones 319 and 320 as single diastereo-... 

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