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The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2-(phenylacetoxy)acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI). The condensation of (VI) with 4-(methylsulfanyl)phenylboronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene gives 4-[4-(methylsulfanyl)-phenyl]-3-phenylfuran-2(5H)-one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.

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4) The oxidation of 4-(methylsulfanyl)acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane/methanol gives the corresponding sulfone (XI), which is brominated with Br2/AlCl3 in chloroform, yielding the expected phenacyl bromide (XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4-(methylsulfonyl)phenyl]phenylacetyl-ene (XIII) with CO catalyzed by Rh4(CO)12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.

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6) The reaction of 4-bromothioanisole (XIV) with furan-2(5H)-one (XV) by means of tert-BuLi/CuI in ethyl ether, followed by silylation with trimethylsilyl chloride gives 4-[4-(methylsulfanyl)phenyl]-2-(trimethylsilyloxy)-3,4-dihydrofuran (XVI), which is desilylated with palladium acetate in acetonitrile to afford the furanone (XVII). The iodination of (XVII) with I2 in pyridine yields 3-iodo-4-[4-(methylsulfanyl)phenyl]furan-2(5H)-one (XVIII), which is condensed with phenylboronic acid (XIX) by means of triphenylarsine and a Pd catalyst in refluxing benzene, giving 4-[4-(methylsulfanyl)phenyl]-3-phenylfuran-2(5H)-one (VIII), already described in Scheme 1. Finally, this compound is oxidized with monoperoxyphthalic acid magnesium salt in dichloromethane/methanol.

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7) The Friedel-Crafts condensation of thioanisole (XX) with acetyl chloride (XXI) by means of AlCl3 in dichlorobenzene gives the corresponding acetophenone (X), which is oxidized with H2O2/WO4Na2 to the ketosulfone (XI). The bromination of (XI) with Br2 in acetic acid/48% HBr affords the phenacyl bromide (XII), which is condensed with phenylacetic acid sodium salt (XXIII) in DMF, giving the phenacyl ester (XXII). Finally, this compound is cyclized by means of diisopropylamine in DMF.

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The Friedel Crafts acylation of thioanisole (I) with acetyl chloride (II) and AlCl3 in chloroform gives 4-(methylsulfanyl)acetophenone (III), which is oxidized with monoperoxyphthalic acid (MMPP) in methanol/dichloromethane to yield 4-(methylsulfonyl)acetophenone (IV). The bromination of (IV) with Br2 and AlCl3 in chloroform affords 4-(methylsulfonyl)phenacyl bromide (V), which is finally cyclized by means of DBU and TEA in acetonitrile to provide the target furanone derivative.