Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Patent
1998-11-04
2000-01-11
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
568 22, 568 24, 568 25, 568 42, C07C31914
Patent
active
060138394
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for preparing certain 2-thiosubstituted acetophenone derivatives, which are useful as intermediates in the preparation of herbicidally active compounds.
Cooper et al, Synthetic Communications, Vol. 25(6), pages 899-906 (1995) describe the preparation of 2-ethylthio-4-chlorobenzamides and 2-ethylthio-3,4-dichlorobenzamides by reacting the corresponding 2,4-dichloro- and 2,3,4-trichlorobenzamides respectively with ethanethiol in N,N-dimethyl formamide (DMF) in the presence of potassium carbonate. These reactions were reported as proceeding with ortho-selectivity, except where the benzamide was a tertiary amide. Fink et al, Tetrahedron Letters. Vol. 34(41) pages 6525-6528 (1993) describe the preparation of 4-fluoro-2-(phenylmethylthio)acetophenone from 2,4-difluoroacetophenone. The reaction is performed in tetrahydrofuran (THF) with benzyl mercaptan and potassium t-butoxide. This is described as proceeding in a yield of 63% with a ratio of ortho/para products of 8.6:1 (i.e. 89% ortho, 11% para). It is however desirable to provide intermediates which are used in multi-step reaction schemes in high yields and with high isomeric purity.
It is therefore an object of this invention to provide a process for preparing 2-thiosubstituted acetophenones proceeding in high yield.
It is a further object of this invention to provide an improved process for preparing 2-thiosubstituted acetophenones with a greater ortho selectivity.
Surprisingly, the present invention allows these objects to be met in whole or in part.
Thus, the present invention provides a process for preparing a 2-(thiosubstituted)-4-(halo)acetophenone which comprises reacting a 2,4-(dihalo)acetophenone with a thiolating agent under substantially anhydrous conditions, optionally in the presence of a base.
Surprisingly, it has been found that the reaction proceeds in good yield and with high regioselectivity under such conditions.
It will be understood that the halogen atoms in the 2,4-(dihalo)acetophenone may be the same or different, and that the acetophenone may be optionally substituted by from one to three groups in the 3- and/or 5- and/or 6-positions of the benzene ring.
By the term "substantially anhydrous" is meant that water not deliberately introduced into the reaction mixture (e.g. the thiolating agent used is not provided in an aqueous solution or suspension). Generally the reaction takes place with less than about 5% by volume water content, preferably less than about 2%, even more preferably less than about 1%, typically from about 0.01 to about 0.5%. It will however be understood that in certain cases slightly more or less water may be tolerated, depending on the nature of the solvents used, the 2-thiosubstituted acetophenone derivative to be prepared and other reaction conditions.
The reaction is preferably performed in an ether solvent such as THF, diisopropyl ether, tert-butyl methyl ether (MTBE), diglyme and diethyl ether. Preferred solvents are THF, diisopropyl ether and MTBE, the latter two being preferred when the process is performed on a large scale, for reasons of cost and availability.
Preferably the 2-(thiosubstituted)-4-haloacetophenone is a compound of formula (I): ##STR2## wherein R.sup.1 is lower alkyl, or phenyl optionally substituted by from one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy and --S(O).sub.n R.sup.5 ; lower haloalkoxy or --S(O).sub.n R.sup.5 ; groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkyl and --S(O).sub.n -alkyl; ##STR3## where R.sup.2 and R.sup.3 are as defined above and R.sup.4 is halogen; and the thiolating agent is a compound of formula (III):
By the term `lower` is meant radicals comprising at least one hydrocarbon chain, it being understood that such radicals contain from one to six carbon atoms linked together in a straight- or branched-carbon chain.
In a preferred aspect of the invention each of R.sup.
REFERENCES:
CA:109:170526 by Anderson, J Org Chem, 53(13), pp. 3125-3127, 1988.
CA:114:122954 by Marriott, Tetrahedron Lett. 31(51), 7485-8, 1990.
CA:125:10525 by Hoepping, Phosphorus, Sulfur Silicon Rela Elements 107(1-4) pp. 285-288, 1995.
WPI/Derwent Abstract No. 96-318910--abstract of JP 08 143534 (1996).
Cooper et al, Synthetic Communications, 25(6), pp. 899-906 (1995).
Fink et al, Tetrahedron Letters, 34(41), pp. 6525-6528 (1993).
March, Advanced Organic Chemistry, fourth edition, pp. 250-251 (1992).
March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, New York, New York, pp. 576-578 (1985).
Hoepping et al, Phosphorous, Sulfur, and Silicon, vol. 107, pp. 285-288 (1995).
Geist Gary
Rhone-Poulenc Agriculture Limited
Vollano Jean F
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