2,4-Oxazolidinediones reactions

Oxazolidine-4,5-dione, At-benzoyl-synthesis, 6, 231 Oxazolidinediones reactions, 6, 214 structure, 6, 179 Oxazolidine-2,4-diones as anticonvulsants, 1, 166 NMI 6, 181 reactions, 6, 214 s mthesis, 6, 231 OxazoIidine-2,5-diones crystal structure, 6, 185 reactions, 6, 214 polymers, 1, 307 s mthesis, 6, 231 Oxazolidine-4,5-diones synthesis, 6, 231 Oxazolidines... 

One of the standard methods for construction of the basic heterocyclic ring was elaborated not long after the turn of the century. Thus, condensation of ethyl lactate with guanidine leads to the imine of the desired ring system (47), possibly by a reaction scheme such as that outlined below. Hydrolysis affords the oxazolidinedione (48). Methylation in the presence of base gives 49. 

Administration of trimethadione (Tridione) may result in hematologic changes, such as pancytopenia (decrease in all the cellular components of the blood), leukopenia, aplastic anemia, and thrombocytopenia Also reported are various types of skin rashes, diplopia (double vision), vomiting, changes in blood pressure, CNS depression, photosensitivity, and fatal nephrosis. Because these dm have been associated with serious adverse reactions and fetal malformations, they should be used only when other less toxic dm are not effective in controlling seizures. The oxazolidinediones may precipitate a tonic-clonic seizure... 

OXAZOLIDINEDIONES. The oxazolidinediones are used only when other, less-toxic dm have not been effective in controlling the seizure disorder because they have been associated with fetal abnormalities and serious adverse reactions. 

OXAZOLIDINEDIONES. Drowsiness is the most common adverse reaction and, as with the other anticonvulsants, tends to subside with continued use Visual disturbances may also occur. The patient with a visual disturbance is assisted with ambulation and oriented carefully to the environment. The nurse ensures that the environment is safe The patient may be especially sensitive to bright lights and may want the room light to be kept dim. Because photosensitivity can occur, the nurse must keep the patient out of the sun. The nurse instructs the patient to use sunscreens and protective clothing until the individual effects of the drug are known. 

Reaction of 1 with excess 103 in toluene gives the mixed carbamate (104) in 21% yield after chromatography on silica gel. Reduction of the S—S bond present in this carbamate is accomplished with zinc dust in acetic acid to give the A(-(2 -mercaptoethyl) oxazolidinedione (105) in high yield. Dimerization of 105 is then achieved by reaction with excess aqueous potassium ferricyanide to give the disulfide (106). 

Benkovic and co-workers also isolated spirocyclic 2-amino-4(5/7)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with 0-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H2 0 as the solvent they demonstrated that there was no incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray. 

In principle then, these saturated imides and derivatives are beyond the scope of this chapter. However, the synthesis and reactions of some 3-unsubstituted derivatives of 179 are included in the interest of completeness. No attempt has been made to provide an exhaustive review of all examples of 2,4-oxazolidinediones. Rather, selected examples from the recent literature that illustrate general synthetic approaches or novel reactions are described. 

Spirocyclic 2,4-oxazolidinedione analogues have been prepared and evaluated as cholinergic agents by Japanese workers (Scheme 6.52). For example, condensation of the a-hydroxy ester 226 with urea produced 227a quantitatively, whereas reaction with thiourea afforded 227b in poor yield together with 228. 

On the other hand, Wyeth-Ayerst chemists ° encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium terf-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,... 

Further refinements in the reaction conditions resulted in a general synthesis of 3,5-dialkyl- and 3,5,5-trialkyl-2,4-oxazolidinediones including trimethadione... 

Oxidation of 5-substituted barbimric acids 258 with concomitant ring contraction has been shown to afford 2,4-oxazolidinediones 260 (Scheme 6.58). Similarly, examples of 5-aryl- and 5-heteroaryl-2,4-oxazolidinediones, for example, 231 and 233-240 (Table 6.8 and Fig. 6.19) have been prepared from alloxan hydrate 261. Thus, conversion of 261 to the dilauric acid intermediates 262 and reaction with sodium hydroxide gave the target compounds.Swiss chemists isolated 265 as a side product (12% yield) from the oxidation of the thymidine base in 263 during their preparation of 264 (Scheme 6.58). 

Mannich reactions of 2,4-oxazolidinediones, particularly spirocyclic analogues, for example, 214, and 218-220, usually proceed readily at N-3 in good to excellent... 

Functionalizing C-5 of 2,4-oxazolidinediones is generally accomplished by alkylation or Knovenagel reaction (Schemes 6.66-6.69). For example, treating 251 (R = H, Ri = Me) with 3 equiv of LDA followed by two equivalents of a protected bromo alcohol and deprotection with dilute hydrochloric acid gave the... 

The Knoevengal reaction has been an extremely versatile method to functionalize C-5. Literally hundreds of 5-alkenyl- and 5-alkyl-2,4-oxazolidinedione analogues have been prepared in this manner. Generally, 2-thio-2,4-oxazolidine-dione, 104, is used in these reactions although 179 has been used successfully as well. Some representative examples follow. 

Schnur and co-workers " summarized typical reactions that can be performed on functional groups of substituted 2,4-oxazolidinediones without ring opening. These reactions include reduction with iron-acetic acid, chlorosulfonation, nucleophilic displacements of aromatic fluorides, and acid hydrolysis with HCl/formic acid. Nonetheless, there are examples of useful ring cleavage reactions involving 2,4-oxazolidinediones. 

Oxazolidinediones are synthesisized by reaction between an isocyanate or a urea and an c < hydroxy carboxylic acid... 

These procedures, as well as being applicable to cephalosporins and penicillins, proved viable with cephamycin C and provide a practical route to 7-ACMA. Reaction of protected cephamycin 467 with oxalyl chloride and anhydrous sodium carbonate (dioxane) followed by aqueous treatment, afforded 37% oxamic acid (469), 34% dioxamic acid (470), and protected a-aminoadipic acid (471) (85%). Further quantities of the desired product were obtained by acid hydrolysis of 470 to 469 in 87% yield. An interesting result of hydrolysis of each oxazolidinedione moiety in putative intermediate 468 is the formation of a different functional group in 469. Deacylation with diphenylcarbodiimide (CH2CI2) converted 469 to 7-ACMA benzhydryl ester 472 (56%) and trione 473. The stereointegrity of both chiral centers and the olefin position were verified by transformation of methoxyamine 472 to cefoxitin by standard means. The same sequence could also be performed without isolation of delicate 472. 

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