2- Oxazolidones synthesis

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Chiral 3,3-disubstituted cyclopentanones. Taber et al have extended a synthesis of cyclopentanones by a rhodium catalyzed intramolecular C—H insertion (11,459) to a synthesis of (+ )-a-cuparenone (3), which contains a chiral quaternary center. Thus the chiral a-diazo-p-keto ester 1, prepared by alkylation of a chiral oxazolidone (11, 379-381) on treatment with Rh2(OAc)4 is converted into 2 in 67% yield. This product is converted in several steps into (+ )-3. 

The direct synthesis of aryl- or alkyl nitriles from cyanide and organohalide precursors is revered in synthetic chemistry, as the nitriles represent a flexible functionality that can easily be converted into (for example) carboxylic acids, esters, amides, amidines, amines and various hetero cycles [67], such as thiazoles, oxazolidones, triazoles and tetrazoles [68]. The tetrazole group... 

Of similar nature are chiral halogenations using auxiliary groups. Typical examples are the conversion of esters to enantiomerically pure halohydrins (precursors to chiral epoxides) using camphor-10-sulfonic acid derivatives583 and the chiral synthesis of a-amino acid synthons via diastereoselective bromination of TV-acyl oxazolidone derivatives584. 

A stereoselective synthesis of ( )-ephedrine and ( )-methylephedrine has been described (318). The method utilizes a carbanion, in which the negative charge is located a to the nitrogen, formed by deprotonation of 1. Subsequent reaction with benzaldehyde yields the 2-oxazolidone 2, and thermal removal of the diphenylphosphinyl group gives the 2-oxazolone 3. Hydrogenation of 3 proceeds with perfect stereoselectivity to yield the erythro isomer 4, which is easily converted to ( )-ephedrine or ( )-W-methylephedrine. 

Intramolecular asymmetric allylic substitution reactions have been applied to the synthesis of optically active cyclic compounds. The high efficiency of the dihydroxylated ferrocenylphosphine 8b has been shown in the cyclization of 2-butenylene dicarbamates 52 to form optically active 4-vinyl-2-oxazolidones 53, which are... 

In aliphatic serie, we have developed the synthesis of N-(2-hydroxyethyl) oxazolidone (IV) at an industrial scale,... 

N-(2-Hydroxyethyl) oxazolidone (IV) should be also a valuable intermediate for the synthesis of N-arylpipera-zines which are widely used in the preparation of pharmaceuticals such as the neuroleptic Fluanisone. 

The synthesis and properties of 2-oxazolidones and 2-oxazolidone-containing polymers have been reviewed by Pankroatov et al (115). It is interesting to note that some isocyanate cyclotrimerization catalysts also act as catalysts for urethane, oxazolidone and/or carbodiimide linkages. 

Diastereoslective Michael addition of the amino group in the polymer-supported amino ester 171 to 4,4,4-trifluorocrotonamide 170 is another application of 4-substituted 2-oxazolidone for fluoroamino acid synthesis (see Scheme 9.38) [64]. 

Synthesis of 4-amino-2-pyrazolin-5-ones is usually achieved by treatment of an a-amido-/3-aldehydo- or /9-ketoester with hydrazines according to the classical method for preparation of 2-pyrazolin-5-ones. Variants on this procedure consist of using an a-amidoester which has /9-substituents whose reaction is equivalent to that of a /9-carbonyl substituent. Such compounds are D-benzylpenicilloic acid a-methyl ester,1027 ethyl phenylpenaldate243 and the acetal of an a-amido-/9-formyl ester.59,243 Cornforth has isomerized 2-phenyl-4-hydrazino-methylidyneoxazolidone to 4-benzamido-2-pyrazolin-5-one. The same compound was obtained by treatment of 1-ethoxyvinyl-2-phenyl-oxazolidone with phenylhydrazine.319... 

Although several attempts have been made to explain the formation of the oxazoles and oxazolidones from a common intermediate (previously reviewed),1-4 the mechanism of the reaction is not yet completely understood. Further, the synthesis is not unambiguous as it may give a mixture... 

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