Process for the preparation of an organozinc reagent

Details Process for the preparation of an organozinc reagent Process for the preparation of an organozinc reagent

1999-06-21

2001-07-10

Nazario-Gonzalez, Porfirio (Department: 1621)

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

Organic compounds

Heavy metal containing

C549S003000, C549S206000, C546S002000, C546S010000, C568S317000

Reexamination Certificate

active

06258967

ABSTRACT:

This invention relates to a process for the preparation of an organozinc reagent, more specifically to the preparation of organozinc reagents comprising an aromatic moiety, to compositions comprising organozinc reagents, and to processes for the use of such reagents and compositions.
Organozinc reagents may be made by reacting a zinc halide with an organic compound of another metal. The co-product of such a reaction is a halide of that other metal. To purify the organozinc compound, it has been proposed in the case of aromatic organozinc compounds, and when the other metal is magnesium, to precipitate its halide by adding 1,4-dioxan, (e.g. Nutzel in Houben-Weyls Methoden der organischen Chemie 1973, XIII/2a, 197-198, 592-599 and Soai et al. J. Chem. Soc. Perkin Trans. 1991. 1613-1615, based on Schlenk et al. Ber. 1929, LXII, 920-924). However, the organozinc compounds so produced have been found to be unsuitable for use in asymmetric synthesis.
We have now devised a simpler process for purifying aromatic organozinc compounds. Our process is applicable to a wider range of ‘other’ metals and to purifying aromatic organozinc reagents in which the organic groups are such that distillation would not be convenient. The organozinc reagents so produced are believed to be in a state different in point of purity from that resulting from the dioxan process, and in at least some aspects, are believed to be more suitable for enantioselective synthesis.
According to a first aspect of the present invention, there is provided a process for the preparation of an organozinc compound comprising an aromatic moiety by reaction between a zinc chloride, bromide or iodide and an organometallic compound of another metal comprising an aromatic moiety, thereby producing a reaction product comprising an organozinc compound and a halide salt of the other metal, the reaction product being contacted with a liquid in which the organozinc compound is soluble and the halide salt of the other metal is of low solubility, and separating the halide salt of the other metal from the liquid, characterised in that the liquid is a hydrocarbon.
The organozinc compound can be recovered from the liquid, or can be employed as a reagent as a solution in the liquid.
The hydrocarbon in which the organozinc compound is soluble and the co-product halide is of low solubility can be linear, branched or cyclic. Aliphatic and particularly aromatic hydrocarbons are most commonly employed. Examples of suitable aliphatic hydrocarbons include petroleum ethers; linear or branched alkanes, particularly those having from 5 to 22 carbon atoms, and preferably from 6 to 14 carbon atoms; kerosenes; and cyclic hydrocarbons, particularly those comprising a 5 to 8 membered alicyclic ring. Many suitable hydrocarbons have a boiling point at atmospheric pressure in the range of from 60 to 130° C. Examples of suitable aromatic hydrocarbons include those comprising from 6 to 10 carbon atoms, and include benzene and alkyl-substituted benzenes. Preferred hydrocarbons include hexane and cyclohexane, and particularly preferred hydrocarbons are toluene, xylene and mesitylene. The hydrocarbon need not itself be a liquid at ambient temperature, provided it forms a liquid system at processing temperatures in presence of other materials present, and so for example, butane may be employed under suitable pressure conditions. The liquid may be a mixture of one or more hydrocarbons. The liquid may also comprise one or more other compounds, providing that the solubility of the undesired metal halide in the liquid is not increased to an unacceptable level thereby.
If desired, the contact between the reaction product and the hydrocarbon may be preceded by a conventional dioxan addition and removal of the resulting metal halide precipitate as a first crude purification step, with the resultant dioxan-zinc solution being contacted with the hydrocarbon as a polishing step to precipitate further metal halide.
At least one of the organic groups in the organozinc compound prepared by the process of the present invention comprises an aromatic moiety. Examples of suitable aromatic moieties include particularly phenyl and naphthyl groups. The aromatic moiety may be a heteroaromatic group, especially a furyl, pyridyl, quinolyl or thienyl group; a metalloaromatic group such as ferrocenyl; or an araliphatic group, particularly a benzyl group. The second of the organic groups in the organozinc compound can be a second aromatic group, or may be a non-aromatic group. Where a non-aromatic group is present, the group can be an aliphatic group especially a C
1-20
, particularly a C
1-12
, aliphatic, and preferably alkyl, group and most preferably a methyl, trihalomethyl, such as trifluoromethyl, ethyl, pentahaloethyl, such as pentafluoroethyl, n- or iso-propyl, or n-, iso- or tert-butyl group; a cycloaliphatic, especially a C
3-8
cycloaliphatic group, preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, a carbonlinked heterocyclic group, or a hydrogenated derivative of an aromatic group. The non-aromatic groups may be saturated or unsaturated. The organic groups in the organozinc compound may carry one or more substituents. There may be present organic groups of more than one type, as the result for example of using a mixture of starting materials or mixing single-type reagents without or with disproportionation.
Organometallic compounds which can be reacted with zinc halides in the process according to the present invention include organic compounds of alkaline metals and alkaline earth metals, particularly organomagnesium compounds and organolithium compounds, organoaluminium, organoborane, organotin, organocuprate, organocerium organocadmium and organomercury compounds. The nature of the organic group(s) in the organometallic compound will be selected so as to introduce the desired organic groups into the organozinc compound. Accordingly, an organometallic compound comprising at least one aromatic moiety must be employed. Correspondingly, where an organozinc compound comprising a non-aromatic group is to be produced, an organometallic compound comprising such a group can also be employed. Example of suitable organomagnesium compounds include organomagnesium halides, particularly optionally substituted alkyl and aryl magnesium halide compounds, and particularly optionally substituted C
1-6
alkyl or optionally substituted phenyl magnesium halides. Examples of suitable organolithium compounds include optionally substituted alkyl and aryl lithium compounds, and particularly optionally substituted Con alkyl or optionally substituted phenyl lithium compounds. Further suitable organolithium compounds are organolithium halides, such as optionally substituted alkyl and aryl lithium halide compounds, especially optionally substituted C
1-4
alkyl or optionally substituted phenyl lithium halide compounds, and particularly organolithium chlorides and bromides. Preferred organolithium compounds include methyllithium, trifluoromethyllithium, ethyllithium, n- and iso-propyllithium, and n-, iso and tert-butyllithium, phenyllithium and the chlorides and bromides of methyllithium, trifluoromethyllithium, ethyllithium, n- and iso-propyllithium, and n-, iso- and tert-butyllithium and phenyllithium.
When the said ‘other’ metal is magnesium, the organometallic compound is conveniently a Grignard reagent, that is, introduced as an ethereal solution of a compound of stoichiometry R—Mg—X, where R is the required organic group and X is chlorine, bromine or iodine. The solvent is commonly an ether, such as a di(C
1-6
alkyl) ether, for example diethyl ether, dibutyl ether, diisoamyl ether and glyme. Asymmetric dialkyl ethers can also be employed, such as t-butylmethylether. Other ethers that may be employed include diglyme and tetrahydrofuran, THF being usually preferred because of its capacity to dissolve compounds having a greater range of groups R. The ether quantity may if desired be less than sufficient to dissolve the whole of the Grignard reactant.
In certain embodiments, a mixtu

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