4.4- dimethyl-2- -oxazolone

The checkers obtained erratic results in this step, possibly because of surface effects or trace impurities in the pressure vessel. In two other runs, only 16.8-18.8 g of crude product were obtained. In one case, high boiling oligomers were formed, but none of the desired product was produced. Impurities in the diene or dienophile did not appear to be the problem since runs which employed recrystallized 3-acetyl-2(3H)-oxazolone and redistilled 2,3-dimethyl butadiene also gave variable results. 

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. 

Treatment of the phenacyliminium salt 114, derived from 5,7-dimethyl[l,2,4]-triazolo[l,5-fl]pyrimidine 113 and phenacyl bromide, with 2 equiv of triethylamine gives rise to the 2-iminooxazoline 118 by way of the in situ generated intermediary A -ylides 115. Acidic hydrolysis affords the 3-(2-pyrimidinyl)-2(3//)-oxazolone... 

The PCC oxidation of 3-amino-4,5-diphenyl-2(3//)-oxazolone 96 affords mono-diazobenzyl 286 as the primary decomposition product obtained via loss of carbon monoxide from the postulated A -nitrenolactam 285. Oxidation of 96 with tert-BuOCl/NEt3 at 108 °C results in a deep green solution of 285, which reacts with dimethyl sulfoxide (DMSO) to give the sulfoximide 288 (Fig. 5.68). ... 

TABLE 6.7. BOULTON-KATRITZKY REARRANGEMENT PRODUCTS FROM 5,5-DIMETHYL-2-ETHOXY-4-(p-TOLYLIMINO)-4(5i7)-OXAZOLONE AND HETEROCUMULENES ... 

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. 

Oxazolone At-oxides 91 have been obtained by heating a solution of 5-isonitroso-2,2-dimethyl-l,3-dioxane-4,6-dione 90 with the corresponding ketone in toluene. It has been postulated that the reaction occurs through an intermediate nitrosoketene that is generated from 90 via loss of CO2 and acetone, respectively. 

Finally, hydrosilylation of 2-aLkenyl-5(47f)-oxazolones in the presence of an appropriate catalyst normally afforded p-addition compounds, for example, 141, although 4,4-dimethyl-2-vinyl-5(47f)-oxazolone 140 also yielded the corresponding oc-addition compound 142 (Scheme 7.41). ° ... 

For a,a-dialkylamino acids enantiomerization is not a problem. The preparation of 4,4-dimethyl-2-[(9-fluorenylmethyl)oxy]-5(4F/)-oxazolone, an intermediate used in the synthesis of ( )-mirabazole C has been described. Recently, two new 2-aIkoxy-5(4F/)-oxazolones derived from Toac (2,2,6,6-tetramethyl-4-amino-l-oxy-piperidine-4-carboxylic acid) that incorporate Z or 9-fluorenylmethoxycarbonyl (Fmoc) protection at C-2 have been described. The Toac analogues were synthesized as part of a study of the crystal structure and ab initio calculations for these interesting systems. 

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... 

It was also reported " that the reaction of 4,4-disubstituted-2-(trifluoromethyl)-5(4f/)-oxazolones 251 with 2,2-dimethyl-3-(dimethylamino)-2//-azirine afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(l//)-ones 252 (Scheme 7.81). In this case, the reaction only occurs when electron-withdrawing substituents are present at C-2 of the oxazolone. 

Alternatively, oxazolones have been used as reagents to activate and to couple N-protected dicarboxylic amino acids wherein the carboxylate moiety acts as the nucleophile. For example, 2,4-dimethyl-5(4//)-oxazolone 255 reacts with N-benzyloxycarbonyl-L-aspartic acid to give a mixture of the anhydrides 256 and 257. Subsequent reaction of 256 and 257 with phenylalanine methyl ester hydrochloride and A-methylmorpholine produces a mixture of the a-isomer 258 and p-isomer 259 of Al-benzyloxycarbonyl-aspartylphenylalanine methyl ester (Scheme 7.83). °... 

The simplest amino acid in the series, dimethylglycine or 2-aminoisobutyric acid (Aib), has been widely studied and 4,4-dimethyl-2-substituted-5(4//)-oxazolones have been used to incorporate Aib into model small peptides and into hnear oligopeptides in order to perform structural smdies. Dipropylglycine (Dpg) has been incorporated into model peptides using 4,4-dipropyl-2-(trifluoromethyl)-... 

Munchnones 298 obtained in situ by N-alkylation of 5(4/f)-oxazolones undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate to give Al-alkylpyr-roles 299. 1,3-Dipolar cycloaddition of munchnones with triphenylvinylphos-phonium bromides affords tri- and tetrasubstituted pyrroles 300. In this case, the interaction of the phosphonium group with the carbonyl group leads to high levels of regioselectivity (Scheme 7.99 Table 7.27, Fig. 7.29). ... 

Figure 7,32, 2-Alkenyl-4,4-dimethyl-5(4/f)-oxazolone monomers for polymerization reactions.

Dimethyl-2-vmyl-5(4/i/)-oxazolone (VDMO) 140 and 4,4-dimethyl-2-isopro-penyl-5(4//)-oxazolone 328 have been extensively investigated as monomers (Fig. 7.32). Copolymeiization of 140 or 328 with other monomers, for example, acrylates or acrylamides produces reactive polymers that are conveniently further modified by nucleophilic reaction with alcohols, amines, or other nucleophiles. ""... 

The second group of saturated 5(47/)-oxazolones used as intermediates for polymer synthesis are the 2,2 -bis(oxazolones) with 2,2 -bis[4,4-dimethyl-5(47/)-oxazolone] 329 being the simplest member of the series (Fig. 7.33). These compounds, are prepared by cyclization of the corresponding bis(amino acids) and give a wide variety of polymers after ring opening with diamines, dialcohols or other nucleophiles. The physical chemical properties of these polymers depend on the nature of the substituents and the size of the chain. Some selected references describe representative examples. 

Alternatively, a spacer can be inserted between the heterocyclic rings to further modify the properties of the polymer. Although various spacers have been used, aromatic rings are probably the most frequently employed. In this case, 2,2 -(p-phenylene)bis[4,4 -dimethyl-5(4//)-oxazolone] 330 is the most common monomer (Fig. 7.34). Again, representative examples are described in selected references... 

Reaction of hippuric acid and A, A -dimethylacetamide in the presence of phosphorous oxychloride affords 4-[l-(dimethylamino)ethylidene]-2-phenyl-5(4//)-oxazolone 424 " ° that is converted to 4-benzoylaminopyrazolones 425 via ring opening and cyclization with hydrazines (Scheme 7.139). " ° 4-(A, Af-Dimethyl-aminomethylene)-2-substituted-5(477)-oxazolones react similarly. 

Bromo-1 -(dimethylaminoethylidene)] -2-phenyl-5(47/)-oxazolone 426, obtained by bromination of 424, reacts with A, Al-dimethyl-Al -heteroarylformamidines to afford the interesting heterocyclic unsaturated oxazolones 428 (Scheme 7.140). ... 

Diels-Alder reactions of 4-heteromethylene-5(4/7)-oxazolones have been described. ( )-4-(Chloromethylene)-5(4//)-oxazolone 737 reacts with 2,3-dunethyl-butadiene in the presence of ethylaluminum dichloride to afford the cycloadduct 738. The cycloaddition reaction is characterized by high diastereoselectivity and occurs without appreciable isomerization of the dienophile. Further synthetic transformations of 738 yield 1-amino-3,4-dimethyl-6-hydroxy-cyclohex-3-enecar-boxylic acid 739 (Scheme 1.121) Examples of Diels-Alder reactions of acyclic dienes and unsaturated 5(4//)-oxazolones are shown in Table 7.50 (Fig. 7.61). 

Z)-4-[(5)-2,2-Dimethyl-l,3-dioxolan -ylmethylene]-2-phenyl-5(47/)-oxazolone 632 can react as a dienophile in diastereoselective Diels-Alder reactions. Thus, 632 undergoes a thermally induced Diels-Alder reaction with cyclic dienes, for example, cyclopentadiene and cyclohexadiene, to afford a mixture of the four... 

The X-ray crystal structure of fZ)-4-[(5)-2,2-dimethyl-l,3-dioxolan -ylmethyl-ene]-2-phenyl-5(4//)-oxazolone has been determined. " The analysis shows an almost planar disposition for the entire molecule with the exception of the dioxolane ring that adopts an envelope conformation. As such, the dioxolane ring is mainly situated on the si,si diastereotopic face of the olefinic bond, a situation that accounts for the observed diastereoselectivity in Diels-Alder reactions. 

Benzyloxy-4-isopropyl(or 4-terf-butyl)-4-methyl-5(4//)-oxazolones 780 have been prepared from an A-benzyloxycarbonylamino acid 779 using l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC HCl) as the cyclization agent (Scheme 7.237). Treatment of 780 with tetramethylfiuoroformamidinium hexafiuorophosphate (TFFH) has shown that they are possible intermediates in the fluorination of a-methyl-a-alkyl amino acids by TFFH. 

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