Oxazolinone synthesis

OzTaetoprim, 302 Oxawniquine, 372 Oxantel, 303 Oxaprozin, 263 Oxazepam, 402 Oxazole synthesis, 263 Oxazolinone synthesis,... 

Hydroxymethylation (formaldehyde) of nitro-imidazole 76 affords 77, which is oxidized to aldehyde 78. To prepare the other fragment for this convergent synthesis, reaction of epichlorohydrin with morpholine leads to the aminoepoxide 79, which is reacted with hydrazine to afford 80. Reaction of this substituted hydrazine with dimethyl carbonate affords oxazolinone 81 by sequential ester interchange reactions. Condensation of 81 with aldehyde 78 affords the antitricho-... 

Scheme 4.15 Proposed mechanism for the synthesis of iV-methyl oxazolinones from oximes.

The syntheses in Schemes 13.36 and 13.37 illustrate the use of chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.36 establishes the configuration at the carbon which becomes C-4 in the product. This is an enolate alkylation in which the steric effect of the oxazolinone substituents directs the approach of the alkylating group. Step C also uses the oxazolidinone structure. In this case, the enolborinate is formed and condensed with the aldehyde intermediate. This stereoselective aldol condensation establishes the configuration at C-2 and C-3. The configuration at the final stereocenter is established by the hydroboration in step D. The selectivity for the desired stereoisomer is 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methyl-alkenes in which the remainder of the alkene constitutes a relatively bulky 135... 

B. E. Maryanoff, Oxazoles and Oxazolines in Organic Synthesis, Oxazolinones, in J. Turchi, The Chemistry of Heterocyclic Compounds, 45, 963 (1986). 

Treatment of an a-amino acid with an anhydride in the presence of pyridine, known as the Dakin-West reaction,[1431 gives access to a racemic a-amido ketone.1 44 1451 The mechanism involves formation of an oxazolinone (98)J146 In the modified Dakin-West reaction, the oxazolinone is reacted with an acid chloride (Scheme 33)J136 139] Due to the rapid epimer-ization of the oxazolinones, a diastereomeric mixture of product 99 is obtained. No detailed protocol has been published so far for the modified Dakin-West synthesis applied to (oxomethyleneamino) peptides, but the procedure is adapted from that already reported for (oxomethylene) peptides containing the tp[CO-CH2] link.1147 ... 

Acylaminocarboxylic acids 288 are converted into 5(4//)-oxazolinones 289 by acid anhydrides (Scheme 140). In an extension of this reaction, A-acyl derivatives of glycine 290 react with aldehydes with concomitant cyclization to give azlactones 291 (Scheme 141) this is the basis of the Erlenmeyer synthesis of amino acids. Treatment of amino acid derivatives 292 with PBr3 affords the thiazolidine-2,5-dione 293 (Scheme 142) <1971CB3146>. 

Extending the Hantzsch synthesis and in the course of producing new 4-aryl-l,4-dihydropyridines related to the powerful calcium antagonist Nifedipine (Adalat),16 arylalkylideneacetoacetates, ketones, and malonic esters (18 and 21) have been treated with ketenaminals (19) to give 2-amino-l,4-dihydropyridine-3-carboxylic esters 20 and 2217 (Scheme 7). This reaction was also applied to 4-arylalkylidene-2-methyl-l,3-oxazolinone-5.18... 

A detailed account of the preparation of 7-hydroxyaporphines using oxazolinones as protective groups has been given. The synthesis of thalphenine iodide (29) through photolysis of the phenolic tetrahydrobenzylisoquinoline (28) in basic solution, followed by quaternization, has been described in full. ... 

This is followed by [3,3]sigmatropic rearrangement of the enamine, involving the C=0 bond in the 5 position, which probably takes place by cleavage of the 3,4 N-0 bond. This reaction represents a new one-step synthetic method to construct an oxazolinone ring, used as precursors of 3-aminoaicohols in the synthesis of ephedrines (75). 

Merrifield s original idea was based on the general scheme of stepwise condensation of N-protected amino acids to the first one, which is linked with its carboxyl function by an ester bond to the insoluble polymer support. This way of solid phase peptide synthesis resulted from the well-known risk of racemization during activation of peptidic carboxyl components, which is minimized in activated amino acid derivatives, N-acylated by urethane-type protecting groups [40] (Fig. 7). Depending on the chosen method, the C-terminal activation of N-protected peptides tends to racemize a certain amount of the material because of the possible formation of an oxazolinone intermediate [41] (Fig. 8). 

Most of the activation methods known from conventional peptide synthesis in solution were explored on polymer concerning their desired reactivity in relation to side reactions, which are particularly unfavorable if the by-products are also bound to the support. Though urethane-masked amino acids generally are shielded from racemization under controlled conditions, this problem limits the use of peptidic building blocks C-terminally activated, since they tend to form the redoubtable oxazolinone intermediate from which the abstraction of a -proton is facilitated (Fig. 40). Recent results indicated a chance to overcome this problem and will be mentioned in the proper section of this chapter. 

Reissert compounds are useful in the preparation of the benzylisoquino-lines required for aporphine synthesis, and the field has been reviewed. Reissert intermediates have also been used in the preparation of 7-hydroxylated aporphines by the oxazolinone method. 

The oxazolinone 107, a new recoverable chiral auxiliary that gives a high level of asymmetric induction in model aldol reactions and Diels-Alder cycloadditions (in which the reactant is connected to the auxiliary by -acylation), has been synthesized from L-gulonic acid. The key step in its synthesis was the thermal intramolecular nitiene insertion shown in Scheme 21. The formation of oxazolinethiones on hydrolysis of isothiocyanato-sugar derivatives is covered in detail in Chapter 9, section 3.3. Base-catalysed reaction of StS-O-isopropylidene-D-xylofuranosylamine with P-isothiocyanato-alkanals led to tricyclic derivatives such as 108, considered as cyclonucleoside analogues. ... 

Scheme 9 Synthesis of 5-oxazolinone starting from a-amino acid and carboxylic acid.

In later publications, however, the same authors reported that the reaction of bis(5(4H)oxazolinones) derived from naturally occurring a-amino acids, that is, with at least one hydrogen atom at the 4 position, with amine-terminated polyethers and polyamides in the bulk at 175-200 °C is also possible. Scheme 12 shows the synthesis in which the bisox-azolinones derived from alanine, valine, phenylalanine, and methionine were obtained. 

---