EP0830361A4 - VINYLSULFOXIDES AND METHOD FOR THEIR SYNTHESIS - Google Patents

VINYLSULFOXIDES AND METHOD FOR THEIR SYNTHESIS

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Publication number
EP0830361A4
EP0830361A4 EP96918211A EP96918211A EP0830361A4 EP 0830361 A4 EP0830361 A4 EP 0830361A4 EP 96918211 A EP96918211 A EP 96918211A EP 96918211 A EP96918211 A EP 96918211A EP 0830361 A4 EP0830361 A4 EP 0830361A4
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EP
European Patent Office
Prior art keywords
alkyl
labile
compound
alkoxy
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP96918211A
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German (de)
English (en)
French (fr)
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EP0830361A1 (en
Inventor
James A Aikins
Randal S Miller
Tony Y Zhang
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Eli Lilly and Co
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Eli Lilly and Co
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Priority claimed from US08/483,130 external-priority patent/US6372945B1/en
Priority claimed from US08/478,706 external-priority patent/US5659087A/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0830361A1 publication Critical patent/EP0830361A1/en
Publication of EP0830361A4 publication Critical patent/EP0830361A4/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the present invention is directed to novel vinyl sulfoxides and to a new process for the synthesis of same, in particular diarylvinyl sulfoxides. These compounds are useful for the synthesis of benzo[b] thiophenes .
  • Benzo[b] thiophenes have been prepared by a number of different synthetic routes.
  • One of the most widely used methods is the oxidative cyclization of o-mercaptocinnamic acids. This route is limited to the preparation of benzo[b] - thiophene-2-carboxylates.
  • 2-Phenylbenzo[b]thiophenes are prepared by acid-catalyzed cyclization of 2-phenylthioacetal- dehyde dialkyl acetals .
  • Unsubstituted benzo[b]thiophenes are prepared by catalytic condensation of styrene and sulfur.
  • the present invention is directed to novel vinyl sulfoxides and to a new process for their synthesis, in particular diarylvinyl sulfoxides. Specifically, the present invention is directed to a compound of the formula
  • R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
  • R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
  • R 3 is a thermally-labile or acid-labile C 2 -C ⁇ o alkyl, C 4 -C 10 alkenyl, or aryl(C -C ⁇ o alkyl) group.
  • the present invention includes individually the E and Z isomers, or mixtures thereof, of the formula II compounds. These E and Z regioisomers are represented by the following structures:
  • Another aspect of the present invention is a process for preparing a compound of the formula
  • R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino;
  • R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
  • R 3 is a thermally-labile or acid-labile C 2 -C ⁇ o alkyl, C 4 - C 10 alkenyl, or aryl(C ⁇ -C ⁇ o alkyl) group having a tertiary carbon atom adjacent to the sulfur atom; comprising the steps of:
  • R 2 and R 3 are as defined above; with an oxidizing agent to produce a benzyl sulfoxide of the formula: wherein R2 and R 3 are as defined above;
  • R l , R 2 , and R 3 are as defined above;
  • R is C0(C ⁇ -C 6 alkyl) , CO(aryl) , CO(arylalkyl) , S0 2 (C ⁇ -C 6 alkyl) , S0 2 (aryl), S0 2 (arylalkyl) , C0 2 (C ⁇ -C 6 alkyl) , C02(aryl), CO2 (arylalkyl) , or CON(C ⁇ -C ⁇ alkyl) 2; and
  • Another aspect of the present invention is a process for the regioselective synthesis of the Z isomer of the formula II compounds.
  • the present invention relates to a process for preparing a compound of the formula
  • R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino;
  • R is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino;
  • R3 is a thermally-labile or acid-labile C 2 -C ⁇ o alkyl, C 4 - C 10 alkenyl, or aryl(C ⁇ -C ⁇ o alkyl) group having a tertiary carbon atom adjacent to the sulfur atom; comprising the steps of:
  • R 2 and R 3 are as defined above; with a strong base to form a benzylic anion; (2) condensing said benzylic anion with a benzaldehyde of the formula
  • R is as defined above;
  • Rl R2 and R3 are as defined above;
  • R 4 is CO(C ⁇ -C 6 alkyl), CO(aryl), CO(arylalkyl) , S ⁇ 2 (C ⁇ -C 6 alkyl), S0 2 (aryl), S0 2 (arylalkyl) , C0 2 (C ⁇ -C 6 alkyl), C0 2 (aryl), C0 (arylalkyl) , or CON(C ⁇ -C 6 alkyl) 2 ;
  • R 8 is hydrogen, halo, amino, or hydroxyl
  • Rg is hydrogen, halo, amino, or hydroxyl
  • R 5 and R ⁇ are independently C 1 -C 4 alkyl, or R 5 and Re together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
  • HX is HCl or HBr; comprising the steps of:
  • R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino;
  • R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
  • R 3 is a thermally-labile or acid-labile C 2 -C 10 alkyl, C4-C 1 0 alkenyl, or aryl (C 1 -C 10 alkyl) group to prepare a benzothiophene compound of the formula
  • R 5 , Rg, and HX are as defined previously; and R 7 is chloro, bromo, or hydroxyl; in the presence of BX' 3 , wherein X' is chloro or bromo;
  • Ci-Cg alkyl represents a straight or branched alkyl chain having from one to six carbon atoms.
  • Typical C ⁇ Cg alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and the like.
  • C 1 -C 4 alkyl represents a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, i-butyl, and t-butyl.
  • C 1 -C 4 alkoxy represents groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and like groups.
  • halo refers to fluoro, chloro, bromo, or iodo groups.
  • aryl represents groups such as phenyl and substituted phenyl.
  • substituted phenyl represents a phenyl group substituted with one or more moieties chosen from the group consisting of halo, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trichloromethyl, and trifluoromethyl.
  • Examples of a substituted phenyl group include 4-chloro- phenyl, 2, 6-dichlorophenyl, 2, 5-dichlorophenyl, 3,4-dichloro ⁇ phenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4- dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4- hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitro- phenyl, 4-nitrophenyl, 2, 4-dinitrophenyl, 4-methylphenyl, 4- ethylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butyl- phenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3- difluorophenyl, 2, 6-difluorophenyl, 2, 6-dimethylphenyl, 2-
  • arylalkyl represents a C 1 -C 4 alkyl group bearing one or more aryl groups. Representatives of this group include benzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl (such as p-chlorobenzyl, p-bromobenzyl, p- iodobenzyl) , 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4- phenylbutyl, 2-methyl-2-phenylpropyl, (2,6- dichlorophenyl)methyl, bis (2, 6-dichlorophenyl) ethyl, (4- hydroxyphenyl)methyl, (2, 4-dinitrophenyl)methyl, diphenylmethyl, triphenylmethyl, (p-methoxyphenyl) - diphenylmethyl, bis (p-methoxyphenyl)methyl, bis (2- nitrophenyl)methyl, benz
  • arylalkoxy represents a C 1 -C 4 alkoxy group bearing one or more aryl groups. Representatives of this group include benzyloxy, o-nitrobenzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (such as p-chlorobenzyloxy, p-bromobenzyloxy, p-iodobenzyloxy) , 1-phenylethoxy, 2-phenylethoxy, 3- phenylpropoxy, 4-phenylbutoxy, 2-methyl-2-phenylpropoxy, (2, 6-dichlorophenyl)methoxy, bis (2, 6-dichlor ⁇ phenyl)methoxy, (4-hydroxyphenyl)methoxy, (2, 4-dinitropheny1)methoxy, diphenylmethoxy, triphenylmethoxy, (p-methoxyphenyl) - diphenylmethoxy, bis (p-methoxyphenyl)methoxy, bis (p
  • thermally-labile or acid-labile C 2 -C 10 alkyl, C 4 -C 1 0 alkenyl, or aryl(C ⁇ C ⁇ o alkyl) group represents a group that is readily removed from the sulfoxide (SO) group under heating or by treatment with the acid catalyst.
  • the thermally-labile or acid-labile C2-C1 0 alkyl groups are straight or branched alkyl chains having from two to ten carbon atoms and having at least one beta-hydrogen atom.
  • thermally-labile or acid-labile C 2 -C 10 alkyl groups include ethyl, n-propyl, i-propyl, 1, 1-dimethyl- propyl, n-butyl, sec-butyl, t-butyl, 1, 1-dimethylbutyl, 2- methylbutyl, 3-methylbutyl, 1-methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl, 3,3-dimethylbutyl, n- pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, n-hexyl, and the like.
  • the thermally-labile or acid-labile C 4 -C 10 alkenyl groups are straight or branched alkenyl chains having from four to ten carbon atoms, at least one site of unsaturation, and either a beta-hydrogen or delta-hydrogen atom.
  • thermally-labile or acid-labile C 4 -C 10 alkenyl groups include 2-butenyl, 3- butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2- pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl- 3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2- methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like.
  • thermally-labile or acid-labile aryl(C ⁇ -C ⁇ o alkyl) represents thermally-labile or acid-labile C 2 -C 10 alkyl groups additionally containing one or more aryl groups and aryl- substituted methyl groups.
  • Representative aryl (C 1 -C 10 alkyl) groups include benzyl, diphenylmethyl, triphenylmethyl, p- methoxybenzyl, 2-phenylethyl, 2-phenyl-propyl, 3-phenyl ⁇ propyl, and the like.
  • thermalally-labile or acid- labile C2-C10 alkyl, C 4 -C10 alkenyl, or aryl (C 1 -C 10 alkyl) group having a tertiary carbon atom adjacent to the sulfur atom includes, but is not limited to, such groups as t- butyl, 1, 1-dimethylpropyl, 1, 1-dimethylbutyl, 1-ethyl-l- methylpropyl, 1,1-dimethylpentyl, 1-ethyl-1-methylbutyl, 1,1- diethylpropyl, 1, 1-dimethylhexyl, triphenylmethyl, and the like.
  • acid chloride includes acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N,iV-dimethylaminocarbonyl chloride.
  • acyl chlorides such as acetyl chloride and benzoyl chloride
  • sulfonyl chlorides such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chlor
  • the acid chloride is a sulfonyl chloride. More preferably, the acid chloride is methanesulfonyl chloride.
  • the compounds of the present invention can be prepared by a number of routes. One method for preparing the formula II compounds is shown in Scheme 1.
  • a formula IX compound is converted to a styryl sulfide by reaction with a mercaptan of the formula HSR 3 in the presence of a Lewis acid.
  • the formula III compound is then oxidized to a styryl sulfoxide, a compound of formula II compound.
  • a formula IX compound wherein Ri and R 2 are as defined above, is treated with a Lewis acid, such as titanium(IV) chloride.
  • a Lewis acid such as titanium(IV) chloride.
  • This reaction is carried out in an anhydrous organic solvent, such as dry tetrahydrofuran, at a temperature of about 0°C to about 35°C.
  • an amine base and a mercaptan of the formula HSR 3 , where R 3 is as defined above.
  • the mercaptan and amine base are added as a solution in the reaction solvent.
  • a representative amine base is triethylamine.
  • the reaction is generally heated to a temperature of about 35°C to about 65°C, preferably at about 50°C.
  • the products of this reaction can be purified using techniques well known in the chemical arts, such as by crystallization or chromatography.
  • the formula III compound, where Ri, R 2 , and R 3 are as defined above, is then oxidized to produce the formula II compounds.
  • Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid, and hydrogen peroxide.
  • This oxidation reaction is typically run in an organic solvent, such as toluene, methylene chloride, chloroform, or carbon tetrachloride.
  • the reaction is generally carried out at a temperature of about -30°C to about 15°C, preferably at about -20°C.
  • the products of the reaction are easily purified by recrystallization.
  • R 3 is t-butyl
  • the crystalline product of this reaction sequence is the E regioisomer of formula II.
  • the Z regioisomer of the formula II compounds can be prepared selectively by a route as shown in Scheme 2.
  • a benzyl alcohol, a formula V compound is reacted with a mercaptan of the formula R 3 SH to produce a benzyl sulfide, a formula VI compound.
  • This benzyl sulfide is reacted with a strong base, forming a benzylic anion, which is condensed with a benzaldehyde.
  • This condensation product is reacted with an acid chloride and the resulting intermediate ester treated with a second strong base to produce a styryl sulfide, a formula IIIZ compound.
  • This styryl sulfide is then oxidized with an oxidizing agent to produce the formula IIZ compound.
  • the first step in the synthesis of the Z styryl sulfoxide compounds is the conversion of a benzyl alcohol to a benzyl sulfide, formula VI compound.
  • the reaction of the formula V compound, where R 2 is as defined above, with a mercaptan of the formula R 3 SH, wherein R 3 is a thermally- labile or acid-labile C 2 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl(C ⁇ -C ⁇ o alkyl) group having a tertiary carbon atom adjacent to the sulfur atom, in the presence of a Lewis acid produces the benzyl sulfide, a formula VI compound.
  • Suitable Lewis acids for this transformation are zinc bromide, zinc chloride, zinc iodide, ferric chloride, titanium(IV) chloride, aluminum trichloride, and aluminum tribromide, preferably zinc iodide.
  • the reaction is generally carried out in an organic solvent, such as 1,2-dichloroethane or methylene chloride. When the reaction is carried out at room temperature, the reaction is complete after about 18 hours.
  • the benzyl sulfide is reacted with a strong base to form a benzylic anion.
  • Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; and alkyllithiums, such as n- butyllithium, t-butyllithium, sec-butyllithium, and methyllithium.
  • the preferred strong base for this reaction is n-butyllithium.
  • the preferred solvent for this reaction is dry tetrahydrofuran.
  • the reaction is carried out at a temperature of about -35°C to about -15°C.
  • the benzylic anion is condensed with a benzaldehyde to prepare an intermediate condensation product.
  • the benzaldehyde has the general formula R ⁇ (CgH 4 )CHO, wherein Ri is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino.
  • Ri is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino.
  • the benzylic anion is prepared and the condensation product is formed in si tu by adding the benzaldehyde to the cold solution of the benzylic anion.
  • the condensation product is treated with an acid chloride to produce an intermediate ester.
  • Representative acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1- butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N,V-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride.
  • methanesulfonyl chloride is added to the reaction mixture shortly after formation of the condensation product.
  • This intermediate ester is reacted with a second strong base to produce a styryl sulfide, a formula IIIZ compound where Ri, R 2 , and R 3 are as defined above.
  • Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec- butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide.
  • the preferred strong base for this reaction is potassium t-butoxide. Generally, this reaction is carried out at about 15°C to about room temperature, preferably at room temperature.
  • the styryl sulfide is oxidized to prepare the corresponding styryl sulfoxide.
  • Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m- chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide; and hydrogen peroxide.
  • the oxidizing agent is peracetic acid. This oxidation is typically carried out in an organic solvent, such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1, 2-dichloroethane, or chloroform; preferably methylene chloride.
  • This oxidation can be carried out at a temperature of about -40°C to about 0°C.
  • the benzyl sulfide intermediate (formula VI compound) can be used to produce a mixture of E and Z isomers of the styryl sulfoxides, the formula II compounds. This synthesis is outlined in Scheme 3.
  • the benzyl sulfide prepared as described above, is oxidized to produce the corresponding benzyl sulfoxide.
  • This benzyl sulfoxide is reacted with a strong base, and the resulting anion condensed with a benzaldehyde.
  • the condensation product is reacted with an acid chloride and the resulting intermediate ester reacted with a second strong base to produce the styryl sulfoxide.
  • Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m- chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide; and hydrogen peroxide.
  • the oxidizing agent is peracetic acid.
  • This oxidation is typically carried out in an organic solvent, such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1,2-dichloroethane, or chloroform; preferably at a temperature of about -30°C to about 5°C.
  • the benzyl sulfoxide, formula X compound wherein R 2 and R 3 are as defined above, is reacted with a strong base to produce a benzylic anion.
  • Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide.
  • the preferred base for this transformation is n-butyllithium.
  • This deprotonation reaction is carried out in a dry organic solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at a temperature of about -25°C.
  • the benzylic anion is condensed, without isolation, with a benzaldehyde compound of the formula p-Ri (C 6 H 4 )CHO, wherein Ri is as defined above.
  • Ri is as defined above.
  • about one equivalent of the benzaldehyde is added to the cold solution prepared as described in the preceding paragraph.
  • the resulting diastereomeric mixture of condensation products may be isolated, or preferably used in the next step without isolation.
  • the condensation product is optionally treated with a base, such as n-butyllithium, and reacted with an acid chloride.
  • acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p- toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N, N- dimethylaminocarbonyl chloride; preferably a sulfonyl chloride.
  • the acid chloride is added to the cold reaction mixture, then the resulting mixture is allowed to warm to room temperature.
  • methanesulfonyl chloride is added to the reaction mixture shortly after formation of the condensation product, which eliminates the need to add additional base.
  • the resulting intermediate ester is reacted with a second strong base to produce the E and Z styryl sulfoxides, formula II compounds where Ri, R 2 , and R 3 are as defined above.
  • second strong bases for this elimination reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t- butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec- butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide.
  • the preferred base for this transformation is potassium t-butoxide.
  • a 20% excess, such as 1.2 equivalents, of the second base are added.
  • this reaction is carried out at a temperature of about 15°C to about room temperature, preferably at room temperature.
  • the intermediate styryl sulfoxides are useful for the synthesis of 2-arylbenzo[b] thiophenes as shown in Scheme 4.
  • the intermediate styryl sulfoxide compounds are heated and treated with acid catalysts to produce the formula I compounds.
  • acid catalysts for this reaction include Lewis acids or Br ⁇ nsted acids.
  • Representative Lewis acids include zinc chloride, zinc iodide, aluminum chloride, and aluminum bromide.
  • Br ⁇ nsted acids include inorganic acids, such as sulfuric and phosphoric acids; carboxylic acids, such as acetic and trifluoroacetic acids; sulfonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1- butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic, 1- hexanesulfonic, 1, 5-naphthalenedisulfonic, 1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, and p-toluene ⁇ sulfonic acids; and polymeric arylsulfonic acids, such as Nafion®, Amberlyst®, or Amberlite®.
  • the more preferred acid catalysts are sulfonic acids, such as methanesulfonic acid, benezene-sulfonic acid, camphorsulfonic, and p- toluenesulfonic acid.
  • the most preferred acid catalyst is p- toluenesulfonic acid.
  • a solution of the acid catalyst in organic solvent such as toluene, benzene, xylene, or a high-boiling halogenated hydrocarbon solvents, such as 1,1,2-trichloro-ethane, is heated to about 80° to about 140°C, and treated with a solution of the styryl sulfoxide in the same solvent.
  • an excess amount of the acid catalyst is used, preferably two equivalents of the acid.
  • the final concentration of the starting compound is about 0.01 M to about 0.2 M, preferably 0.05 M.
  • best yields are obtained when the styryl sulfoxide is slowly added to the heated acid solution over a period of about 20 minutes to about three hours.
  • residual water is removed from the reaction solution by the use of a Dean-Stark trap or Soxhlet extractor, and the reaction is purged with purified nitrogen.
  • the formula I compounds are useful as intermediates in the synthesis of a series of 3-aroyl-2-arylbenzo[b] - thiophenes.
  • An improved synthesis of a group of these 3-aroyl-2-arylbenzo[b] - thiophenes from the formula I compounds, wherein Ri and R 2 are hydrogen, C 1 -C 4 alkoxy, or arylalkoxy, is outlined in Scheme 5.
  • the benzothiophene Formula I compound wherein Ri and R 2 are hydrogen, C1-C4 alkoxy, or arylalkoxy, is acylated with the formula XI compound, wherein R7 is chloro or hydroxy, in the presence of boron trichloride or boron tribromide; boron trichloride is preferred.
  • the reaction can be carried out in a variety of organic solvents, such as chloroform, methylene chloride, 1, 2-dichloroethane, 1, 2, 3-dichloropropane, 1,1,2,2- tetra-chloroethane, 1, 2-dichlorobenzene, chlorobenzene, and fluorobenzene.
  • the preferred solvent for this synthesis is 1,2-dichloroethane.
  • the reaction is carried out at a temperature of about -10°C to about 25°C, preferably at 0°C.
  • the reaction is best carried out at a concentration of the benzothiophene formula I compound of about 0.2 M to about 1.0 M.
  • the acylation reaction is generally complete after about two hours to about eight hours.
  • the acylated benzothiophene is converted to a formula XI compound wherein Rs and/or R 9 are hydroxy, without isolation of the product from the acylation reaction.
  • This conversion is performed by adding additional boron trihalide or boron tribromide and heating the reaction mixture.
  • additional boron trihalide or boron tribromide Preferably, two to five molar equivalents of boron trihalide are added to the reaction mixture, most preferably three molar equivalents.
  • This reaction is carried out at a temperature of about 25°C to about 40°C, preferably at 35°C. The reaction is generally complete after about 4 to 48 hours.
  • the acylation reaction or acylation/dealkylation reaction is quenched with an alcohol or a mixture of alcohols.
  • Suitable alcohols for use in quenching the reaction include methanol, ethanol, and isopropanol.
  • the acylation/dealkylation reaction mixture is added to a 95:5 mixture of ethanol and methanol (3A ethanol).
  • the 3A ethanol can be at room temperature or heated to reflux, preferably at reflux.
  • the Formula XII compound conveniently crystallizes from the resulting alcoholic mixture.
  • 1.25 mL to 3.75 mL of alcohol per millimole of the benzothiophene starting material are used.
  • the amount (percentages) of 6-hydroxy-2- (4- hydroxyphenyl) -3- [4- (2-p ⁇ per ⁇ dmoethoxy)benzoyl] - benzo[b]thiophene hydrochloride m the crystalline material (potency) was determined by the following method. A sample of the crystalline solid (5 mg) was weighed into a 100-mL volumetric flask, and dissolved in a 70/30 (v/v) mixture of 75 mM potassium phosphate buffer (pH 2.0) and acetonitrile.
  • % potency peak area - b sample volume (mL) x m sample weight (mg)
  • the amount (percentage) of solvent, such as 1,2- dichloroethane, present in the crystalline material was determined by gas chromatography.
  • a sample of the crystalline solid (50 mg) was weighed into a 10-mL volumetric flask, and dissolved in a solution of 2-butanol (0.025 mg/mL) in dimethylsulfoxide.
  • a sample of this solution was analyzed on a gas chromatograph using a DB Wax column (30 m x 0.53 mm ID, 1 ⁇ particle) , with a column flow of 10 mL/min and flame ionization detection.
  • the column temperature was heated from 35°C to 230°C over a 12 minute period.
  • the amount of solvent was determined by comparison to the internal standard (2- butanol) .
  • a solution of desoxyanisoin (12.82 g) in tetrahydrofuran (100 mL) was treated with titanium (IV) chloride (10.43 g) .
  • titanium (IV) chloride 10.43 g
  • the reaction mixture was cooled to maintain the temperature below 35°C.
  • the resulting mixture was stirred at 30°C.
  • this mixture was treated with a solution of 2-methyl-2-propane- thiol (6.76 mL) and triethylamine (16.70 mL) in tetrahydro ⁇ furan (15 mL) .
  • the resulting mixture was stirred at 50°C.
  • Example IIA The crystalline compound prepared as described in Example IA was dissolved in toluene (150 mL) , and the resulting solution cooled to about -20°C. The cold solution was treated with peracetic acid (32% w/w in dilute acetic acid, 1.24 g) over ten minutes. The resulting mixture was extracted with saturated sodium sulfite and brine. The organic phase was concentrated in vacuo . The residue was recrystallized from ethyl acetate/heptane to give 14.11 g of the title compound. Melting point 104°C (dec) . Analysis calculated for C 20 H 24 O 3 S: C, 69.74; H, 7.02; S, 9.31. Found: C, 69.47; H, 7.04; S, 9.54.
  • reaction mixture was treated with a solution of potassium t- butoxide in tetrahydrofuran (1.0 M, 12.0 mL) .
  • reaction was quenched by the addition of IN hydrochloric acid (12.0 mL) .
  • the organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to an oil (4.4 g) .
  • Example 2B The compound from Example 2B was converted to the title compound using the procedure substantially as described in Example IB.
  • the temperature of the reaction rose from about 20° to about 35°C upon addition of the methanesulfonyl chloride.
  • the mixture was cooled to about 25°C, then treated with potassium t- butoxide in tetrahydrofuran (1 M, 50.9 mL) .
  • the reaction was treated with IN hydrochloric acid (51.0 mL) .
  • the phases were separated; and the organic layer dried over magnesium sulfate, filtered, and concentrated to an oil (16.67 g) . This material was used in the next step without further purification.
  • the carbon and proton NMR spectra were similar to that obtained for the compound prepared as described in Examples 1 and 2.
  • Example 3B (3.0 g) in tetrahydrofuran (40 mL) was cooled to about -15°C. This cold solution was treated with n- butyllithium in cyclohexane (1.6 M, 8.3 mL) over 15 minutes. After stirring for ten minutes, the reaction mixture was warmed to 0°C, and treated with p-anisaldehyde (1.61 mL) .
  • reaction was monitored by thin layer chromatography (TLC) , using silica-gel plates and ethyl acetate/acetonitrile/triethylamine (10:6:1, v/v) . Additional portions of 1- (2-chloroethyl)piperidine hydrochloride are added until the starting 4-hydroxybenzoate ester is consumed. Upon complete reaction, the reaction mixture was treated with water (60 mL) and allowed to cool to room temperature. The aqueous layer was discarded and the organic layer concentrated in vacuo at 40°C and 40 mm Hg. The resulting oil was used in the next step without further purification.
  • TLC thin layer chromatography
  • Example 7A A solution of the compound prepared as described in Example 7A (about 13.87 g) in methanol (30 mL) was treated with 5 N sodium hydroxide (15 L) , and heated to 40°C. After 4 1/2 hours, water (40 mL) was added. The resulting mixture was cooled to 5-10°C, and concentrated hydrochloric acid (18 mL) was added slowly. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40-50°C to give 83% yield of the title compound. Melting point 270-271°C. C.
  • Boron trichloride gas was condensed into a cold graduated cylinder (2.8 mL) , and added to the cold mixture described above. After eight hours at 0°C, the reaction mixture was treated with additional boron trichloride (2.8 mL) . The resulting solution was heated to 35°C. After 16 hours, the reaction was complete.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP96918211A 1995-06-07 1996-06-04 VINYLSULFOXIDES AND METHOD FOR THEIR SYNTHESIS Ceased EP0830361A4 (en)

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US483130 1990-02-22
US08/483,130 US6372945B1 (en) 1995-06-07 1995-06-07 Process for the synthesis of vinyl sulfoxides
US478706 1995-06-07
US08/478,706 US5659087A (en) 1995-06-07 1995-06-07 Diarylvinyl sulfoxides
PCT/US1996/009163 WO1996040691A1 (en) 1995-06-07 1996-06-04 Vinyl sulfoxides and a process for their synthesis

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Title
P. A. T. W. PORSKAMP ET AL: "Synthesis and Reactions of Phosphoryl-Substituted Sulfines", JOURNAL OF ORGANIC CHEMISTRY., vol. 49, no. 2, 1984, EASTON US, pages 263 - 268, XP002068690 *
R. M. DODSON ET AL: "Thietanes. III. Rearrangement of 2,4-Diphenylthietane Dioxides to trans-1,2-Diphenylcyclopropanesulfinic Acid", JOURNAL OF ORGANIC CHEMISTRY., vol. 36, no. 18, 1971, EASTON US, pages 2698 - 2703, XP002068689 *
See also references of WO9640691A1 *

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EA000405B1 (ru) 1999-06-24
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AU697352B2 (en) 1998-10-01
JPH11507061A (ja) 1999-06-22
TR199801494T2 (xx) 1998-09-21
AU6092096A (en) 1996-12-30
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TR199801495T2 (xx) 1998-09-21
EP0830361A1 (en) 1998-03-25
HUP9900922A3 (en) 2000-06-28
EA199800028A1 (ru) 1998-08-27
TR199701510T1 (xx) 1998-03-21
CN1192741A (zh) 1998-09-09
NZ310179A (en) 1999-09-29

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