Coupling of 4-chloro-3-nitrocinnamic acid (I) with 1-acetylpiperazine (II) using EDC gave rise to the corresponding amide (III). Displacement of the chlorine atom of (III) with 2-isopropylthiophenol (IV) in the presence of K2CO3 furnished the title thioether.
Reaction of 3,4-dichlorobenzalzehyde (I) with methyl 3-mercaptopropionate in the presence of K2CO3 in hot DMF afforded the thioether (II). Subsequent condensation of (II) with malonic acid under Knoevenagel conditions produced the substituted cinnamic acid (III), which was further converted to the corresponding acid chloride (IV) upon treatment with oxalyl chloride and a catalytic amount of DMF. Coupling of acid chloride (IV) with N-acetylpiperazine (V) furnished amide (VI). Treatment of (VI) with potassium tert-butoxide caused the elimination of methyl acrylate, producing the potassium thiolate (VII). Thiolate (VII) was then condensed with 1-methyl-7-bromoindole (VIII) to give the title compound.
Nucleophilic substitution of 4-fluoro-3-(trifluoromethyl)benzaldehyde (II) with 6-mercaptobenzodioxan (I) afforded the sulfanyl aldehyde (III). Knoevenagel condensation of aldehyde (III) with malonic acid furnished the cinnamic acid derivative (IV), which was subsequently converted to acid chloride (V) by treatment with oxalyl chloride. Acid chloride (V) was then coupled with ethyl nipecotate (VI), yielding amide (VII). The ethyl ester group of (VII) was finally hydrolyzed using NaOH in aqueous ethanol.
The intermediate silyl sulfide (II) was prepared by palladium-catalyzed displacement of 5-bromo-1-methylindole (I) with potassium (triisopropylsilyl)sulfide. Alternatively, 5-iodoindole (III) was N-methylated with iodomethane and NaH, yielding 5-iodo-1-methylindole (IV), which was then reacted with potassium (triisopropylsilyl)sulfide to give (II). Condensation of silyl sulfide (II) with the aryl triflate (V) in the presence of CsF as the desilylating reagent furnished the diaryl sulfide (VI). Knoevenagel condensation of aldehyde (VI) with malonic acid (VII) gave rise to the cinnamic acid derivative (VIII). This was then coupled with ethyl isonipecotate (IX), producing amide (X). The ethyl ester of (X) was finally hydrolyzed with NaOH to yield the title sodium carboxylate salt.
In a related method, electrophilic bromination of 2,3-dichlorophenol (XI) gave (XII). Heck reaction of bromide (XII) with methyl acrylate (XIII) produced the cinnamic acid derivative (XIV). Sulfonylation of the phenolic hydroxyl of (XIV) with trifluoromethanesulfonic anhydride in pyridine furnished the aryl triflate (XV). This was coupled with the silyl sulfide intermediate (II) in the presence of CsF to produce the diaryl sulfide (XVI). After methyl ester (XVI) hydrolysis, the resultant cinnamic acid (VIII) was coupled with methyl isonipecotate (XVII) to furnish amide (XVIII). The title compound was then obtained by methyl ester (XVIII) hydrolysis with LiOH, followed by treatment with methanolic NaOH.