Process for preparing vinylaromatic compounds

Details Process for preparing vinylaromatic compounds Process for preparing vinylaromatic compounds

2002-06-04

2003-08-19

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C585S427000, C568S630000, C568S631000, C568S633000, C558S132000

Reexamination Certificate

active

06608212

ABSTRACT:

CROSS-REFERENCES TO RELATED APPLICATIONS
Not Applicable.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
Not Applicable.
FIELD OF THE INVENTION
This invention relates generally to preparing vinylaromatic compounds. More specifically, it relates to preparing vinylaromatic compounds wherein the vinyl group is derived from an enolizable aldehyde or ketone and the aromatic group is derived from an arylmetal reagent. The invention also relates to preparing vinylphosphates from enolizable ketones for use in coupling reactions to prepare vinyl compounds. Vinylaromatic compounds are valuable as fine chemical intermediates and pharmaceutically active compounds. For example, nafoxidine, a vinylaromatic compound, is an estrogen receptor modulator which can be converted, via hydrogenation of the vinylic double bond, to lasofoxifene, another estrogen receptor modulator.
BACKGROUND OF THE INVENTION
A classical method for the preparation of vinylaromatic compounds is the reaction of an aldehyde or ketone bearing a hydrogen on a carbon adjacent to the carbonyl group with an arylmetal reagent to form, on acidic hydrolysis, first an alcohol then a vinylaromatic compound by acid catalyzed dehydration. This is diagrammed in the top route in Scheme 1 in which the arylmetal reagent is an aryl Grignard reagent and where R, R′, R″ are each hydrogen or a hydrocarbyl group, Ar is an aromatic group, and X is a halide. An alternative mode of reaction that can occur between the aldehyde or ketone and the arylmetallic reagent reactants is simple &agr;-deprotonation of the aldehyde or ketone to form the enolate and the protonated aromatic group. On hydrolysis, the enolate returns the aldehyde or ketone starting material. This is diagramed in the bottom route in Scheme 1.
The alternative mode of reaction to form the enolate can cause not only chemical yield loss, but also recovery yield loss due to problematic separations of the desired product from the alternative products. For certain combinations of aldehydes or ketones (certain R, R′, R″) and aryl Grignard reagents (certain Ar), the enolization reaction so dominates as to make this method practically useless for the preparation of the desired vinylaromatic compound.
Lednicer et al.,
J. Med. Chem. Soc
., vol. 9 (1966), pp. 172-176 and Lednicer et al.,
J. Med. Chem. Soc
., vol. 10 (1967), pp. 78-84 disclose preparations of certain 1,2-diaryl-3,4-dihydronaphthalene compounds, including nafoxidine, via reactions of corresponding 2-aryl-1-tetralone compounds with aryl Grignard reagents. Lednicer et al., in
J. Med. Chem. Soc
., vol. 12 (1969), pp. 881-885, later state, “The nucleus of this system [1,2-diaryl-3,4-dihydronaphthalenes] has usually been prepared by condensation of the appropriate 2-aryl-1-tetralone with the Grignard reagent of the aryl group that is to appear at the 1 position. Yields in this reaction have tended to be poor due to extensive enolization of the ketone by the Grignard reagent; large amounts of unreacted ketone are characteristically recovered.”
U.S. Pat. No. 5,552,412 discloses preparations of nafoxidine (1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-6-methoxy-2-phenyl-3,4-dihydronaphthalene) from 1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene, a 1-aryl-3,4-dihydronaphthalene compound. (In the patent it is designated by the alternative name 1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl)pyrrolidine.) The 1-{4-[2-(pyrrolidin-N-yl)-ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene was prepared by reacting an excess of a 4-[2-(pyrrolidin-N-yl)ethoxy]phenyl cerium reagent (prepared from the corresponding aryl bromide by treating sequentially with n-butyl lithium and cerium chloride) with 6-methoxy-1-tetralone, combined at −78° C. and allowed to warm to room temperature, and subsequently acidifying the product mixture. In the ensuing workup, 34% of the 6-methoxy-1-tetralone was recovered prior to isolation of the desired 1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-5 6-methoxy-3,4-dihydronaphthalene in 57% yield (See Step A in column 21).
Aldehydes and ketones can be converted to vinylphosphates by phosphorylation of their enolates. Bases that have typically been used to generate the enolates for phosphorylation include amines (e.g. triethylamine), amides (e.g. lithium diisopropylamide), alkoxides (e.g. potassium t-butoxide), and basic salts (e.g. potassium carbonate).
Vinyl phosphates have been used as reagents in coupling reactions to prepare vinyl compounds. Fugami et al.,
Chem. Lett
. (1987), pp. 2203-2206 disclose reactions of certain vinylphosphates with triphenylmanganate reagent, preformed from phenyl lithium or phenyl Grignard reagent and Li
2
MnCl
4
, in the presence of a palladium catalyst provided by Pd(PPh
3
)
4
to afford vinylbenzene compounds. Nan et al.,
Tetrahedron Letters
, vol. 40 (1999), pp. 3321-3324 discloses reactions of cyclohexenylphosphate with arylboronic acid reagents in the presence of a palladium or nickel catalyst to afford cyclohexenyl aromatic compounds. Sahlberg et al.,
Tetrahedron Letters
, vol. 24 (1983), pp. 5137-5138 and Sofia et al.,
J. Org. Chem
., vol. 64 (1999), pp. 1745-1749 each disclose reactions of certain 1,3-dien-2-ol phosphates with phenyl Grignard reagent in the presence of certain phosphine ligated nickel catalysts to afford 2-phenyl-1,3-diene compounds (&agr;-vinyl-vinylbenzene compounds). Wu et al.,
J. Org. Chem
., vol. 66 (2001), pp. 7875-7878 discloses reactions of 4-diethyl-phosphonooxycoumarins with alkyl or aryl zinc reagents in the presence of a nickel or palladium catalyst to afford 4-alkyl or 4-aryl substituted coumarins.
Takai et al.,
Tetrahedron Letters
, vol. 21 (1980), pp. 2531-2534; Takai et al.,
Bull. Chem. Soc. Jpn
., vol. 57 (1984), pp. 108-115; Fukarniya et al.,
Chem. Ind
. (London), vol. 17 (1981), pp. 606-607; Sato et al.,
Tetrahedron Letters
, vol. 22 (1981), pp. 1609-1612; Asao et al.,
Synthesis
(1990), pp. 382-386; and Alderdice et al.,
Can. J. Chem
., vol. 71 (1993), pp. 1955-1963 disclose, in all, reactions of certain vinylphosphates with trialkyl-, trialkenyl-, or trialkynyl-aluminum reagents in the presence of a palladium, nickel, or copper catalyst to afford vinyl-alkyl, -alkenyl, or -alkynyl compounds. Hayashi et al.,
Synthesis
(1981), pp. 1001-1003; Armstrong et al.,
Can. J. Chem
., vol. 60 (1982), pp. 673-675; and Danishefsky et al.,
J. Am. Chem. Soc
., vol. 110 (1988), pp.8129-8133 disclose, in all, reactions of certain vinylphosphates with trimethylsilylmethylmagnesium halide reagents in the presence of a palladium or nickel catalyst to afford allyltrimethylsilane compounds. Okuda et al.
Tetrahedron Letters
, vol. 24 (1983), pp. 2015-2018 discloses reactions of certain vinyl-phosphates with phenyldimethylsilyl-aluminum and -magnesium reagents in the presence of a palladium catalyst to afford vinylsilane compounds.
Hayashi et al.,
Tetrahedron Letters
, vol. 22 (1981), pp. 4449-4452 discloses reactions of aryl phosphates with alkyl or aryl Grignard reagents in the presence of a nickel catalyst to afford alkyl-aryl compounds and biaryl compounds, respectively.
OBJECTS OF THE INVENTION
The object of this invention is to provide an effective and efficient process for the preparation of vinylaromatic compounds. A further object of this invention is to provide such a process capable of using enolizable aldehydes and ketones to provide the vinyl group in combination with using arylmetal reagents selected from arylmagnesium reagents and aryllithium reagents to provide the aromatic group. Another object of this invention is to provide a process for preparing vinylphosphates from enolizable ketones for use in coupling reactions to prepare vinyl compounds.
A further object of this invention is to provide an

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