Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
1999-12-17
2002-07-16
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S419000, C556S467000, C556S402000, C556S403000, C556S052000, C556S121000, C260S66500B
Reexamination Certificate
active
06420584
ABSTRACT:
The invention relates to a process for the preparation of ortho-substituted arylmetal compounds by deprotonation of aromatics which have a hydrogen atom in the ortho position relative to at least one halogen atom, one trifluoromethoxy group, one dialkylamino group, one nitrilo group, one alkoxy group or one dialkylamido group, and their reaction with electrophilic reagents, characterized in that the deprotonation of the aromatics is carried out using alkyl- or arylmetal compounds or metal hydrides in the presence of a catalytic amount of a secondary metal amide.
Substituted aromatics are useful intermediates for the synthesis of high-value-added end products or are themselves such end products for the electronics industry, such as, for example, liquid crystals, for crop protection, such as, for example, pesticides or for the preparation of pharmaceutically high-active substances, such as, for example, dopamine receptor blockers, antiemetics or antipsychotics.
This is true in particular of aromatics which are substituted in the ortho position relative to a halogen atom, a trifluoromethoxy group, a dialkylamino group, a nitrile group, an alkoxy group or a dialkylamido group.
A variety of methods for the preparation of such compounds are described in the literature.
Thus, for example, the metallation, described by D. L. Ladd in J. Org. Chem. 46, 203 (1981), of 1,4-difluorobenzene with butyllithium at <−65° C. gives 1-lithium-2,5-difluorobenzene, which is reacted at the same (low) temperature with trimethyl borate to give dimethyl 2,5-difluorobenzeneboronate (Scheme 1).
The boronate is oxidized with hydrogen peroxide to give the corresponding phenol.
This reaction sequence is also described in WO 89/2425 for the preparation of 2,3-difluorophenol, the reaction temperatures being unchanged and the reaction conditions being changed only slightly (Scheme 2).
WO 89/2425 further describes the preparation of liquid-crystalline 2,3- or 2′,3′-difluoro-p-terphenylene starting from 1,2-difluorobenzene. WO 89/8629 describes the synthesis of other liquid-crystalline compounds which have a 2,3-difluoro-1,4-phenylene group. In the processes described therein, the 1,2-difluorobenzene or 1-substituted 2,3-difluorobenzene is deprotonated using a strong base, normally using n-butyllithium, and the resulting 2,3-difluorophenyllithium compound is reacted with an electrophilic reagent.
The reason for the low reaction temperatures is the poor stability of the ortho-haloarylmetal compounds. For example, 2,3-difluorophenyllithium derivatives eliminate lithium fluoride above −50° C., forming 1-fluoro-2,3-benzene derivatives, which further react in an uncontrolled manner to give unknown secondary products. At −50° C. the rate of the decomposition reaction of the 2,3-difluorophenyllithium derivative is still slight, but proceeds in an explosive manner at −25° C. (critical temperature −22.5° C.), the 2,3-difluorophenyllithium derivatives decomposing suddenly.
Analogously to the ortho-fluoroarylmetal compounds, other ortho-haloarylmetal compounds are also obtainable using ortho position hydrogen with the help of a base (e.g. Houben-Weyl, Methoden der organischen Chemie, [Methods of Organic Chemistry], vol. 13/1, 122-123, Stuttgart 1970).
However, other ortho-haloarylmetal compounds usually have an even lower stability than the ortho-fluoroarylmetal compounds, meaning that the decomposition reactions occur at considerably lower temperatures. For example, from Bull. Soc. Chim. France 1986 No. 6, 925-929, it is known that chloroaryl compounds metallated in the ortho position readily eliminate chloride in an exothermic reaction, as a result of which arynes are formed, which give rise to the formation of undesired byproducts.
According to DE 42 19 281, it is also possible to replace those hydrogen atoms of an aromatic which are in the ortho position relative to a trifluoromethoxy group. Furthermore, deprotonations in the ortho position to other groups such as, for example, alkoxy groups, cyano groups, amines and amides have been described (S. Patai (ed.) The Chemistry of the functional groups, Vol. 4, John Wiley & Sons 1987, pages 59-67). In the case of these groups too, it is usually necessary to maintain low temperatures in order to avoid secondary reactions.
Very low temperatures are required particularly when the aromatic to be deprotonated contains reactive groups, such as ester or cyano groups, which would react with the arylmetal compound already formed or with the base used at relatively high temperatures.
Many of said aromatics which, because of their reactive groups, can also react as electrophilic reagents, such as, for example, benzonitriles, are therefore preferably deprotonated using a lithium amide, which is prepared from secondary amines, in order to avoid an addition of alkyllithium compounds to the electrophilic groups (e.g. J. Org. Chem. 47, 2681, 1982). However, for industrial processes deprotonations using such lithium-amides are unsuitable because of the high costs of the parent amine.
The very low temperatures which must generally be observed for the sensitive ortho-substituted arylmetal compounds have proven to be a disadvantage particularly when aromatics with only a very slightly acidic hydrogen atom are to be deprotonated. Such aromatics frequently require very long reaction times, but produce only poor yields, or often cannot be deprotonated at all at low temperatures, whilst at higher temperatures secondary reactions occur. Higher rates of deprotonation and thus also better yields of arylmetal compound can frequently not be achieved for the processes of the prior art if low temperatures are maintained.
An object of the present invention is to provide a process for the preparation of ortho-substituted arylmetal compounds and their reaction with electrophilic reagents and in particular a process for the preparation of ortho-haloarylmetal compounds and their reaction with electrophilic reagents, which does not have the described disadvantages of the processes to date and can be carried out at favorable cost on an industrial scale.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
It has now been found that the preparation of arylmetal compounds by deprotonation of aromatics which have a hydrogen atom in the ortho position relative to a halogen atom, a trifluoromethoxy group, a dialkylamino group, a nitrile group, an alkoxy group or a dialkylamido group can be carried out safely and with high yield if the corresponding aromatics are treated with alkyl- or arylmetal compounds or metal hydrides in the presence of a catalytic amount of a secondary metal amide. The ortho-substituted arylmetal compounds formed can be reacted with electrophilic reagents in the usual manner.
In the process according to the invention, catalytic amounts of a secondary amine are converted into the corresponding metal amide using an alkyl- or arylmetal compound or a metal hydride. Following deprotonation of the respective aromatic by this metal amide, the amine reformed during the reaction is again converted into the metal amide by alkylmetal or arylmetal compound present or a metal hydride. Surprisingly, the use of catalytic amounts of the secondary amine increases the rate of deprotonation and the yield of arylmetal compound, although metal amides generally have lower basicity than, for example, alkyllithium compounds.
According to the process of the invention, it is surprisingly possible to prepare lithiated aromatics, which can be used as useful intermediates, for example for liquid crystals, auxiliaries, plant-protection compositions and pharmaceuticals, in a simple and cost-effective manner in high yields. The use of only catalytic amounts of the secondary amine reduces the costs and simplifies work-up of the reaction mixtures since only small amounts of the amine have to be removed and, if necessary, disposed of.
The invention thus provides a pro
Reiffenrath Volker
Stiasny Hans Christian
Merck Patent GmbH
Shaver Paul F.
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