2.4- Oxazolidinediones

Acetone cyanohydrin is obtained from the interaction of acetone and hydrocyanic acid, which on subsequent hydrolysis followed by esterification with ethanol yields ethyldimethylglycolate. This is condensed with urea in the presence of sodium ethoxide to yield 5, 5-dimethyl-oxazolidinedione-2, 4-dione. Trimethadione is finally obtained by treating the resulting product with dimethyl sulphate in the presence of sodium hydroxide. 

It is employed as an anticonvulsant in grand mal epilepsy to arrest status epilepticus and in petit mal epilepsy as a means of resisting control to other treatments. When administered alone trimethadione 

5-Ethyl-3, 5-dimethyl-2, 4-oxazolidinedione 2, 4-Oxazolidinedione, 5-ethyl-3, 5-dimethyl- Paramethad B.P. 1973, U.S.P, Ind. P. 

Sodium derivative of 5-ethyl-5-methyl-2, 4-oxazolidinedione is obtained by refluxing urea and ethyl-a-hydroxy-a-methylbutyrate for 24 horns in the presence of sodium methoxide, due to eondensation followed by cyclization. N-methylation is carried out by treatment with dimethyl sulphate. 

It is usually used in the treatment of petit mal epilepsy and possesses similar actions to those of trimethadione. It is relatively less effective and does not exhibit myasthenia-gravis-like syndrome in patients. 

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Therapeutic Function Anticonvulsant Chemical Name 3,5,5-trimethyl-2,4-oxazolidinedione Common Name Troxidone Structural Formula ... 

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. 

Alkyl- or 3-aryl-2,4-oxazolidinediones via photochemical cyclization, ° organonickel-mediated carbonylation, ° cyclization of A-alkenyl-a-acet-amides, ° carboxylation and cyclization of 2-propynamides, °" cyclization of (9-carbamates of a-hydroxy acetic acids and esters,cyclization of a-hydroxy acetamides,and catalytic asymmetric dihydroxylation (ADH) of A-alkenoyl-2-oxazolidinones. ... 

Arylideneamino)-2,4-oxazolidinediones via cyclization of arylidine benzi-lic acid hydrazides ° and 3-amino-2,4-oxazolidinediones from perhydro-l,5,2-dioxazine-3,6-diones. °... 

Alkoxy-2,4-oxazolidinediones via cyclization of A-aIkoxy-2-hydroxycar-boxamides, " and cyclization of 2-hydroxycarbohydroxamic acids. 

There are no reports that alkylation of a 2,4-oxazolidinedione generates a 2-alkoxy-4(5f/)-oxazolone. Alkylation of the sodium or potassium salt of a... 

The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene. A third very useful approach is cyclodehydration of 0-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate. However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfo-nyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point. 

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. 

TABLE 6.8. 5-ARYL-2,4-OXAZOLIDINEDIONES EROM CYCLIZATION OE a-HYDROXY IMIDATES ... 

Doya " disclosed an improved process for preparation of 2,4-oxazohdinediones from a-hydroxy esters and urea in a recent patent. The process effects condensation of the starting materials using a metal oxide, for example, lead oxide at 100-250 °C followed by fractional distillation to recover any unreacted a-hydroxy ester. The product is then isolated by distillation. The recovered starting material can be recycled. 5-Methyl-2,4-oxazolidinedione, 212 (R = Me) was isolated in 80.4% yield of 99.4% purity in this manner. 

TABLE 6.9. SPIROCYCLIC 2,4-OXAZOLIDINEDIONES EROM CYCEIZATION OE a-HYDROXY IMIDATES"... 

Imperial Chemical Industries (ICI) chemists " prepared a novel series of spirocyclic 2,4-oxazolidinediones 243 derived from 7-substituted isatins (Scheme 6.54). The key intermediate a-acyloxy amides 242 were readily prepared from 241 in three steps. Base-catalyzed cyclization of 242 then afforded the target compounds that were reported to be potent inhibitors of aldose reductase. Pfizer chemists approached 5-substituted isatin spirocyclic analogues 243 via a-hydroxy esters 244 that were converted to the corresponding a-carbamyloxy esters 245 in good yield using chlorosulfonyl isocyanate. Cyclization of 245 with potassium ferf-butoxide then produced 243 in acceptable yield (Scheme 6.54 Table 6.10, Fig. 6.20). 

Sollhuber s group " extended the scope of their earlier work using chlorosulfonyl isocyanate to synthesize spirocyclic 2,4-oxazolidinediones. They prepared 188a, 214, 218, and 232 together with several additional examples using this methodology. 

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,... 

TABLE 6.10. SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM 5- OR 7-SUBSTITUTED ISATINS... 

Oxazolidinediones can be obtained from electrochemical reduction of a-halo amides in the presence of carbon dioxide. Originally, the 2,4-oxazolidine-... 

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). 

Figure 6.21. A naturally occurring 2,4-oxazolidinedione from roasted perilla seed.

A variety of 2,4-oxazolidinedione moieties have been prepared as precursors to A-acyliminium ions. These, in turn, have been used in synthetic approaches to 13-aza-16-oxasteroids, interesting and novel heterocycles, " and natural products such as ( )-p-conhydrine, 294b, ( )-6>-methylpaUidinine, 297, 4-oxa-2-aza-podophyllotoxin, 299, and morphine, 302. Introduction of the 2,4-oxazolidinedione can be achieved by conventional alkylation. However, it is normally introduced through Mitsunobu chemistry using diisopropyl azodicar-boxylate or diethyl azodicarboxylate. " The former reagent is favored by... 

TABLE 6.11. 3-ALKYL-2,4-OXAZOLIDINEDIONES FROM AEKYLATION OE 2,4-OXAZOLIDINEDIONES ... 

Kano and co-workers.Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key N-acyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from A -acyliminium ion cyclization are shown in Schemes 6.61-6.63, pp. 110-112. 

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. 

TABLE 6.12. IMIDAZOLONES FROM 5,5-DIMETHYL-2,4-OXAZOLIDINEDIONE AND 2//-AZIRINES ... 

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