3- Acyl-2-oxazolones

Korte, F., Storiko, K. Acyl-lactone rearrangement. XV. The rearrangement of 4-acyl-5-oxazolones. Chem. Ber. 1960, 93, 1033-1042. 

Particularly useful dienophiles are iV-acyl-oxazolones - the products are protected c/x-l,2-amino-alcohols. ... 

Considerable attention has been paid to the reactions of oxazoles with typical Diels-Alder alkene dienophiles. The adducts can be transformed into pyridines by different routes (section 5.15.1.4). Electron-releasing substituents on the oxazoles increase the rate of reaction 5-alkoxyoxazoles are comparable in reactivity to typical all-carbon dienes. Particularly useful dienophiles are AT-acyl-oxazolones - synthons for c/j-l,2-amino-alcohols. ... 

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

Carbamates can be used as protective groups for ammo acids to minimize race-mization in peptide synthesis. Raccmi/ation occurs during the base-catalyzed coupling reaction of an W-protected, catboxyl-uc ivated amino acid, and takes place in the intermediate oxazolone that foro S readily from an N-acyl protected amino... 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

When an a-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. This is called the Dakin-West reaction The mechanism involves formation of an oxazolone. The reaction sometimes takes place on carboxylic acids even when an amino group is not present. A number of N-substituted amino acids, RCH-(NHR )COOH, give the corresponding N-alkylated products. 

Acyl halides (see Section 2.14) There have been no reports of their use. The tendency for them to form oxazolones is exceedingly high. 

FIGURE 4.14 Reactions of activated A-alkoxycarbonylamino acids in the presence of tertiary amine. Acyl halides and mixed and symmetrical anhydrides generate 2-alkoxy-5(4/7)-oxazolone in the presence of tertiary amine. Aminolysis of 2-alkoxy-5(47f)-oxazolone in the presence of E N led to partially epimerized products. OAct = activating group. 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

FMF Chen, NL Benoiton. High-performance liquid chromatography of 2,4-disubsti-tuted-5(4//)-oxazolones, anhydrides and other activated forms of A-acyl- and A-alkoxycarbonylamino acids. Int J Pept Prot Res 36, 476, 1990. 

A 3-acyl-4,5-unsubstituted-2(3//)-oxazolone 157 smoothly undergoes electrophilic addition with Br2 (or NBS) and PhSeCl in methanol to give frani-5-bromo-4-methoxy- and frani-4-methoxy-5-phenylselenenyl-2-oxazolidinones 158, respectively, with full regio- and trans-selectivity (Fig. 5.39). Both substituents thus... 

The 2(3/T)-oxazolone homopolymer 217 and the 2(37f)-oxazolone copolymer 219 with a carbon-carbon bond backbone structure are readily obtained by heating a 3-acyl-2(3/7)-oxazolone alone or with styrene, respectively, at 70 °C in the presence of BPO with the exclusion of air." " ° The A -acetyl polymers serve as regioselective and chemoselective acylating reagents for amines and alcohols (Fig. 5.53). ° ... 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

The Friedel-Crafts type acylation of 4-methyl-2(3/7)-oxazolone 256 with acyl chlorides in the presence of AICI3 proceeds smoothly to give the 5-acyl -methyl-2(3F/)-oxazolones 257 (Fig. 5.62). ... 

The parent 2(3/i/)-oxazolone moiety functions as a bifunctional leaving group when carboxyl groups are activated for acylations and condensations, similar to other five- and six-membered heterocycles such as imidazole, triazole, and 2-pyridinethiol. The excellent leaving ability of a 2(3//)-oxazolone moiety has led to the development of versatile reagents. Thus, 3-acyl- and 3-alkoxycarbonyl-2(3//)-oxazolones serve as ready-to-use -type agents for the regioselective and chemoselective N-protection of amino alcohols, amino phenols and polyamines. 

The above reagents serve as condensing reagents and have different reactivities for peptides 279, p-lactams 281, esters, thioesters, and mixed phosphates, as well as for the direct preparation of 3-acyl-2(3F/)-oxazolones. The bis(2-oxo-3-oxazohnyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67). ... 

Abou-Gharbia and co-workersdescribed a general synthesis of 5,5-diphenyl-2-substituted-4(57f)-oxazolones as an extension of their earlier work. Reaction of diphenylketene with a series of A-acylsulhlimines lOa-d produced an intermediate A-acyl a-lactam that then rearranged to afford lla-d in 56-80% yield (Scheme 6.5). Examples are shown in Table 6.1 (Fig. 6.2). 

Base-catalyzed cyclization of A -benzoyl-a-chloroacetamide is a classical method used to prepare 2-phenyl-4(5//)-oxazolone. Extension of this methodology to the A -aroylcinnamides 35 afforded a series of 5-arylidene analogues 37 albeit in unstated yield (Scheme 6.12). " Thus, acylation of the sodium salt of a benzamide with a cinnamoyl chloride gave the imides 35 that were converted to 36 via a bromination-dehydrobromination sequence. Cyclization to 37 was affected with sodium hydride in 1,2-dimethoxyethane (DME). The authors noted that catalytic reduction of 37 afforded the 5-(arylidene)oxazolidine from which 37 could be regenerated in the presence of air. 

It was shown previously that saturated 5(4//)-oxazolones or 2-oxazolm-5-ones with only one substituent at C-4 can be considered as the tautomeric form of saturated 5(2//)-oxazolones or 3-oxazolin-5-ones. These compounds can also be considered as amino acid derivatives and, indeed, cyclization procedures are the most commonly used to prepare these compounds. The cyclization reaction employs a variety of cyclodehydrating agents and the general method is shown in Scheme 7.23, with an A-acyl-a-amino acid being the most typical starting material used. In this way, 5(4//)-oxazolones derived from most natural amino acids 99 (R3 = H) have been obtained by heating the corresponding A-acyl derivatives in the presence of acetic anhydride. 

Cyclization of A-acyl-oc-amino acids under acidic reaction conditions is sometimes problematic due to the difficulty in separation of the desired oxazolone from by-products while avoiding decomposition of the reactive oxazolone. This finding is particularly true in the case of 2-phenyl-5(47i)-oxazolone, an interesting compound that is a very useful intermediate to prepare a variety of novel products. The use of carbodiimides as dehydrating agents has been described as a means to improve the results. In particular, treatment of an A-acyl-a-amino acid with A-cyclohexyl-A -2-(A-methylmorpholinio)ethylcarbodiimide p-toluensulfo-nate (Scheme 7.25) is especially useful as a general synthesis of the desired saturated 5(47i)-oxazolones 101 in excellent yields.This same carbodiimide was used to study the kinetics of the formation of saturated 5(47i)-oxazolones from N-protected dipeptides... 

The use of mixed anhydrides derived from Al-acyl-a-amino acids has become an interesting strategy for synthesis of saturated 5(4//)-oxazolones 101 (Scheme 7.26). For example, reaction of Al-acyl-a-amino acids with methyl chloroformate in the presence of Al-methylmorpholine affords racemic 5(47/)-oxazolones. 

The use of N-acylated-a-amino nitriles, nitrones, or a-amino amides as starting compounds have also been reported. N-Acylated-a-amino nitriles were converted into 5(477)-oxazolones 101 in the presence of ethyl chlorooxoacetate (Scheme 1.21). ... 

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