Heck reaction of aryl bromide (IX) with vinyl tributyltin (X) in the presence of palladium catalyst gave the vinyl tetrahydronaphthalene (XI), which was converted to the primary alcohol (XII) by means of hydroboration with borane in THF followed by oxidative treatment with H2O2 and NaOH. Reaction of alcohol (XII) with p-toluenesulfonyl chloride and Et3N produced the corresponding tosylate (XIII) (1). This was then condensed with 6-fluoro-3-(4-piperidinyl)benzisoxazole (XIV), yielding adduct (XV). Finally, basic hydrolysis of the ester group of (XIV) provided the title carboxylic acid.
Heck reaction of aryl bromide (IX) with vinyl tributyltin (X) in the presence of palladium catalyst gave the vinyl tetrahydronaphthalene (XI), which was subjected to oxidative double-bond cleavage to aldehyde (XII) using NaIO4 in the presence of a catalytic amount of OsO4. Aldehyde reduction with NaBH4 provided alcohol (XIII). This was then converted to the corresponding bromide (XIV) by treatment with carbon tetrabromide and triphenylphosphine.
Acylation of 2-(1-piperazinyl)phenol (XV) with ethyl chloroformate produced the carbamate (XVI). After protection of the phenolic hydroxyl of (XVI) as the corresponding tosylate (XVII), reduction of the carbamate group of (XVII) with LiAlH4 gave rise to the N-methylpiperazine (XVIII). The tosylate group of (XVIII) was then removed by hydrolysis with KOH in aqueous ethanol, yielding phenol (XIX). The Williamson's ether synthesis between phenol (XIX) and bromide (XIV) provided adduct (XX). Finally, basic hydrolysis of the ester group of (XX) furnished the title carboxylic acid
Bromination of the coumarin derivative (I) with Br2 in DMF afforded the bromo coumarin (II). Diels-Alder cycloaddition between bromo coumarin (II) and ethyl 3-(trimethylsilyl)propiolate (III) with concomitant decarboxylation furnished the tetrahydronaphthalene (IV). After desilylation of (IV) with trifluoroacetic acid, the resultant ester (V) was reduced to alcohol (VI) using the combination LiAlH4-AlCl3. Further oxidation of the alcohol function of (VI) to aldehyde (VII) was performed with 4-benzylpyridinium dichromate (BPDC) in CH2Cl2. Wittig reaction of aldehyde (VII) with methyl (triphenylphosphoranylidene)acetate produced the arylacrylate ester (VIII), which was then reduced to the saturated ester (IX) employing NaBH4 in the presence of CoCl2.