Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Reexamination Certificate
1995-06-07
2002-04-16
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
C568S037000, C564S440000
Reexamination Certificate
active
06372945
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to a new process for the synthesis of vinyl sulfoxides, 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. 3-Substituted benzo[b]thiophenes are prepared by acid-catalyzed cyclization of arylthiomethyl ketones; however, this route is limited to the preparation of 3-alkylbenzo[b]thiophenes. See Campaigne, “Thiophenes and their Benzo Derivatives: (iii) Synthesis and Applications,” in Comprehensive Heterocyclic Chemistry (Katritzky and Rees, eds.), Volume IV, Part III, 863-934 (1984). 3-Chloro-2-phenylbenzo[b]thiophene is prepared by the reaction of diphenylacetylene with sulfur dichloride. Barton and Zika,
J. Org. Chem
., 35, 1729-1733 (1970). Benzo[b]thiophenes have also been prepared by pyrolysis of styryl sulfoxides. However, low yields and extremely high temperatures make this route unsuitable for production-scale syntheses. See Ando,
J. Chem. Soc
., Chem. Comm., 704-705 (1975).
The preparation of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophenes was described in U.S. Pat. Nos. 4,133,814 and 4,380,635. One process described in these patents is the acid-catalyzed intramolecular cyclization/rearrangement of &agr;-(3-methoxyphenylthio)-4-methoxyacetophenone. The reaction of this starting compound in neat polyphosphoric acid at about 85° C. to about 90° C. gives an approximate 3:1 mixture of two regioisomeric products: 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 4-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. These isomeric benzo[b]thiophenes co-precipitate from the reaction mixture, producing a mixture containing both compounds. To obtain a single regioisomer, the regioisomers must be separated, such as by chromatography or fractional crystallization. Therefore, there currently exists a need for an efficient and regiospecific synthesis of 2-arylbenzo[b]thiophenes from readily available starting materials. The products of the present invention are useful for the efficient and regiospecific synthesis of 2-arylbenzo[b]thiophenes from readily available starting materials.
SUMMARY OF THE INVENTION
The present invention is directed to a new process for the synthesis of vinyl sulfoxides, in particular diarylvinyl sulfoxides. Specifically, the present invention is directed to a process for preparing a compound of the formula
wherein:
R
1
is hydrogen, C
1
-C
4
alkoxy, arylalkoxy, halo, or amino;
R
2
is hydrogen, C
1
-C
4
alkoxy, arylalkoxy, halo, or amino; and
R
3
is a thermally-labile or acid-labile C
2
-C
10
alkyl, C
4
-C
10
alkenyl, or aryl(C
1
-C
10
alkyl) group having a tertiary carbon atom adjacent to the sulfur atom;
comprising the steps of:
(1) oxidizing a benzyl sulfide of the formula:
wherein R
2
and R
3
are as defined above; with an oxidizing agent to produce a benzyl sulfoxide of the formula:
wherein R
2
and R
3
are as defined above;
(2) reacting said benzyl sulfoxide with a strong base to form a benzylic anion;
(3) condensing said benzylic anion with a benzaldehyde of the formula
wherein R
1
is as defined above;
(4) reacting the condensation product from step 3 with an acid chloride to produce an ester of the formula
wherein:
R
1
, R
2
, and R
3
are as defined above; and
R
4
is CO(C
1
-C
6
alkyl), CO(aryl), CO(arylalkyl), SO
2
(C
1
-C
6
alkyl), SO
2
(aryl), SO
2
(aryalkyl) CO
2
(C
1
-C
6
alkyl) CO
2
(aryl), CO
2
(arylalkyl), or CON(C
1
-C
6
alkyl)
2
; and
(5) treating said ester with a second strong base. The E and Z regioisomers the formula II compounds are represented by the following structures:
Another aspect of the present invention is a process for the regioselective synthesis of the Z isomer of the formula II compounds. In particular, the present invention relates to a process for preparing a compound of the formula
wherein:
R
1
is hydrogen, C
1
-C
4
alkoxy, arylalkoxy, halo, or amino;
R
2
is hydrogen, C
1
-C
4
alkoxy, arylalkoxy, halo, or amino; and
R
3
is a thermally-labile or acid-labile C
2
-C
10
alkyl, C
4
-C
10
alkenyl, or aryl(C
1
-C
10
alkyl) group having a tertiary carbon atom adjacent to the sulfur atom;
comprising the steps of:
(1) reacting a benzyl sulfide of the formula:
wherein 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
wherein R
1
is as defined above;
(3) reacting the condensation product from step 2 with an acid chloride to produce an ester of the formula
wherein:
R
1
, R
2
, and R
3
are as defined above; and
R
4
is CO(C
1
-C
6
alkyl), CO(aryl), CO(arylalkyl), SO
2
(C
1
-C
6
alkyl), SO
2
(aryl), SO
2
(arylalkyl), CO
2
(C
1
-C
6
alkyl), CO
2
(aryl), CO
2
(arylalkyl), or CON(C
1
-C
6
alkyl)
2
;
(4) treating said ester with a second strong base to produce a styryl sulfide of the formula
wherein R
1
, R
2
, and R
3
are as defined above; and
(5) oxidizing said styryl sulfide with an oxidizing agent.
DETAILED DESCRIPTION OF THE INVENTION
The term “C
1
-C
6
alkyl” represents a straight or branched alkyl chain having from one to six carbon atoms. Typical C
1
-C
6
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. The term “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.
The term “C
1
-C
4
alkoxy” represents groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and like groups. The term “halo” refers to fluoro, chloro, bromo, or iodo groups.
The term “aryl” represents groups such as phenyl and substituted phenyl. The term “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-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl, 2-trifluoro-methylphenyl, 2-chloro-5-trifluoromethylphenyl, 3,5-bis-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl, 4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitro-phenyl, and the like.
The term “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)methyl, (4-hydroxyphenyl)methyl, (2,4-dinitrophenyl)methyl, diphenylmethyl, triphenylmethyl, (p-methoxyphenyl)-diphenylmethyl, bis(p-methoxyphenyl)methyl, bis(2-nitrophenyl)methyl, and the like.
The term “arylalkoxyl” represents a C
1
-C
4
alkoxy group bearing one or mor
Aikins James A.
Miller Randal Scot
Zhang Tony Y.
Birch Gary M.
Eli Lilly and Company
Leeds James P.
Rotman Alan L.
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