2-Oxazolidinones isocyanates

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Propargyl alcohol (332) and (328) react readily with isocyanates in the presence of a basic catalyst to give 4-methylene-2-oxazolidinones (334) and 4-methylene-2-imidazolinones (336), respectively (63JOC991). In the absence of sodium methoxide the intermediate methanes (333) and ureas (335) were obtained and on treatment with sodium methoxide underwent ring closure. Moderate to excellent yields were obtained. 

Reaction of the glycol, 70, affords an oxazolidinone rather than the expected carbamate (71) on fusion with urea. It has been postulated that the urea is in fact the first product formed. This compound then undergoes 0 to N migration with loss of carbon dioxide reaction of the amino alcohol with the isocyanic acid known to result from thermal decomposition of urea affords the observed product, mephenoxolone (74) this compound shows activity quite similar to that of the carbamate. An analogous reaction on the glyceryl ether, 75, affords metaxa-lone (76). 

Tamariz and coworkers [42] have described a versatile, efficient methodology for preparing N-substituted-4,5-dimethylene-2-oxazolidinones 42 (Figure 2.5) from a-diketones and isocyanates and have also studied their reactivity in Diels-Alder reactions. This is a method for synthesizing polycyclic heterocyclic compounds. Some of the reactions of diene 42 are summarized in Scheme 2.18. The nitrogen atom seems to control the regiochemistry of the reaction. 

N-(2-Hydroxypropyl)carbamates (8.139, Fig. 8.13,b) are prodrugs that resemble the A-(2-hydroxyphenyl)carbamates discussed above. Here, activation yielded the tranquilizer mephenoxalone (8.140, Fig. 8.13,b) and an alcohol or a phenol such as paracetamol. Other active oxazolidinones could be obtained by replacing the MeO group in 8.139 (Fig. 8.13, b) with another substituent. For this series, the mechanism of activation is not an intramolecular nucleophilic attack, but, rather, decomposition of the deprotonated carbamate group as shown in Fig. 8.7,b, Reaction b, with the intermediate isocyanate being trapped to form the oxazolidinone ring. 

In the reaction of the conformationally restricted epoxy alcohol 84 and methyl or benzyl isocyanate, the epoxy carbamate 85 was formed. Cycliza-tion of 85 in tetrahydrofuran in the presence of sodium hydride gave the oxazinone 86 in approximately 20% yield, and the oxazolidinone 87 (R = Me, CH2Ph) in 40-60% yield. The formation of the two products can be rationalized by different nucleophilic attacks on the urethane nitrogen. With increasing nucleophilicity of the nitrogen, the regioselectivity of the reaction is shifted toward the formation of 87 (92TL3009). 

Tamariz et al. reported the synthesis of mukonine (11) based on a regioselective Diels-Alder reaction of N-phenyl-4,5-dimethylidene-2-oxazolidinone (634) with methyl propiolate (635). The diene 634 was prepared in moderate yield from the condensation reaction of 2,3-butanedione (632) with phenyl isocyanate (633). In an optimized reaction procedure using drastic basic hydrolytic conditions (KOH/ MeOH), followed by methylation with dimethyl sulfate, the adduct 636, was... 

The tandem condensation of isocyanates with an a-ketol in DMF leads to the 2-oxazolidinone derivatives 308 that are dehydrated to the 2(3//)-oxazolones 309 by refluxing in DMSO (Fig. 5.80). ... 

Isocyanates insert into RO and RN bonds. Cyclic ethers, such as oxiranes, are known to undergo reactions with isocyanates to form 2-oxazolidinones in high yield (38—40). 

Carbon disulfide reacts with ethylene oxide to give ethylene trithiocarbonate (90), and isocyanates yield derivatives of 2-oxazolidinone (91). 

Less satisfactory results have been frequently encountered in the related asymmetric cycloaddition of a vinyl epoxide to an isocyanate as in Scheme 8E.30 [160]. The modest enantioselectivities of this process are indicative of the competitive intramolecular nucleophilic addition with enantioface exchange. When the oxazolidinone was generated from an achiral substrate, somewhat higher enantioselectiviites were obtained presumably due to superposition of the enantioselection obtained in the ionization step. 

Another method for producing a chiral 3-carbon fragment, this time directly as a protected 5-hydroxymethyl-3-oxazolidin-2-one, is illustrated in scheme 9 (77). In this case, the amide 20 is converted to the 4-trityl ether 24. This undergoes very facile Hofmann rearrangement to give the 5-trityloxymethyl-3-oxazolidin-2-one 26 via the intermediate isocyanate 25. The oxazolidinone 26 is a protected version of 3-amino-1,2-dihydroxypropane. 

If 2-methoxy-l-naphthyl isocyanate is used, the N-aryloxazolidinone can be cleaved by CAN to furnish the corresponding N-unsubstituted oxazolidinone in 70-85% yield. 

The standard preparation of 2-oxazolidinones is by treatment of /3-amino alcohols with phosgene or its synthetic equivalents ethyl chloroformate, dialkyl carbonates or even urea (equation 174). Isocyanates react with oxiranes in the presence of amines to yield 2-oxazolidinones (equation 175) (79LA200). The action of isocyanates on cyclic carbonates results in 2-oxazolidinones (equation 176) and photolysis of alkyl azidoformates affords oxazolidinones via intermediate nitrenes (equation 177). 

A well known reaction for the synthesis of oxazolidinones, cycloaddition of isocyanates to epoxides, was applied to resin linked substrates for the synthesis of libraries of isoxazolidinones 198 <03JCC789>. 

The reaction proceeds with total regio- and diastereoselectivity, as shown by H-NMR spectroscopy. /J-Iodo isocyanates are generally unstable, their purification is difficult and it is convenient to convert them into more stable derivatives. /Hodo carbamates were readily and stereose-lectively prepared by warming the isocyanate with an appropriate alcohol and successive thermal nucleophilic displacement yielding 2-oxazolidinones, e.g., 19 - 20 (see Table 3). Furthermore, when trans-iodo isocyanates were treated with an alcohol in basic medium, the carbamates form first and were immediately converted into the corresponding aziridines, e.g, 19 -> 21. 

Alternatively, carbamate anions like those involved in the formation of 13 can be generated efficiently by trapping the alkoxide of zwitterionic 7t-allylpalladium complexes from vinyl epoxides with isocyanates55 57. Table 6 shows that cyclic vinyl epoxides lead exclusively to 2-oxazolidinones with retention of configuration which is independent of isocyanate substitution. Triisopropyl phosphite is the ligand of choice to assure a high turnover number. 

Analogous reactions of acyclic vinyl epoxides 15 with 4-toluenesulfonyl isocyanate also proceed with complete retention of configuration55. Enantiomerically pure epoxides such as 15b and c are readily available and reductive removal of the 4-toluenesulfonyl substituent from 16 is easily achieved. The transformation of 15c to 2-oxazolidinone 16c was used as the key conversion in a short enantioselective synthesis of acosamine55. 

To a yellow solution of the catalyst prepared by simply stirring 25.0 mg (0.12 mmol) of triisopropyl phosphite with 10.4mg (0.01 mmol) of Pd,(dba)3 CHC13 in 0.5-1.OmL of THF are added 2l9mg (1.1 mmol) of 2-methoxy-l-naphthyl isocyanate. 1 mmol of the epoxide 17a-g is added in one portion, either neat or dissolved in 1 mL of THF, and the resultant mixture is stirred at r.t. for 12—24 h until conversion is complete. Evaporation of the solvent in vacuo and flash chromatography affords the pure 2-oxazolidinones 18 a-g in the yields given in Table 7. 

Isocyanides react with epoxides in the presence of gallium(lll) chloride to form 0 ,/3-unsaturated a-amino imino-lactones <20030L4991>. Oxazolidinones are formed on solid phase by the reaction between epoxides and isocyanates <2003JC0789>. 

The enantioselective total synthesis of the cytokine modulator (-)-cytoxazone using a syn-stereoselective aldol addition and a Curtius rearrangement as key steps was described by J.A. Marco et al. The key intermediate acid was treated with DPPA and triethylamine in toluene at reflux. This step furnished the oxazolidinone directly and in good yield through an in situ capture of the isocyanate group by the free secondary alcohol functionality. Removal of the protecting group led to the formation of the natural product. 

Another approach to oxazolidinones is shown in Scheme 12. l-AUcylated 1,2-diols were bound to chlorosulfonylated resin 44 to produce hydroxysulfonates 45. Treatment with tosyl isocyanate gave carbamates 46, which were cychzed with DBN (l,5-diazabicyclo[4.3.0]non-5-ene) at room temperature to yield the oxazolidinones 47. The base was finally removed by filtration through silica [22],... 

Another standard method for the synthesis of 2-oxazolidinones is by reaction of epoxides with isocyanates. Although 4,5-disubstituted derivatives are not readily accessible by this route, it has been shown that iminodioxolanes (192) add to epoxides in the presence of AICI3 to afford these oxazolidinones in high yield <9lJOC2684>. The reaction proceeds through a spirocyclic intermediate (193) (Scheme 96). The reaction of vinyl epoxides with aryl isocyanates is facilitated by palladium catalysis (Equation (28)) <89TL3893>. The products are obtained by a double inversion process, but... 

Thermolysis of the oxazolidinone (393) yields a mixture of methyl isocyanate and the ketol PhCOCMejOH. The 3//-indole (395) is obtained when the methyleneoxazolidinone (394) is heated with zinc chloride. ... 

Thioacyl isocyanates react with 2-bromoethanol to give urethanes (215), which generally react with base to give oxazolidinones (214) however, when R is t-butyl, the 1,5,3-oxathiazepinone (216) is obtained in 60% yield. 

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