Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-17
2001-03-27
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S241000, C549S374000, C556S012000, C568S640000, C568S641000, C568S643000, C568S645000, C568S660000, C568S807000
Reexamination Certificate
active
06207835
ABSTRACT:
The invention relates to a process for the preparation of arylmetal compounds by deprotonation of aromatics which have a hydrogen atom in the ortho position relative to a halogen atom or a trifluoromethoxy group, using a suitable base or by halogen-metal exchange of haloaromatics using a suitable metalating reagent and their reaction with electrophilic reagents, characterized in that the arylmetal compounds are prepared in a continuous-flow reactor.
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 highly 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 or a trifluoromethoxy group.
A variety of methods for the preparation of such compounds are described in the literature.
Thus, for example, the metalation, 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 trimnethyl 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.
Furthermore, the o-fluorophenyl derivatives can be prepared from the corresponding o-fluorobromobenzenes by reaction with magnesium to give o-fluorophenylmagnesium bromide and subsequent derivatization (e.g. EP 02 38 272). Here too, it is absolutely necessary to operate at low temperatures.
Analogously to the ortho-fluoroarylmetal compounds, other ortho-haloarylmetal compounds are also obtainable using ortho-position hydrogen with the help of a base at very low temperatures (e.g. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Vol. 13/1, 122-123, Stuttgart 1970).
According to DE 42 19 281, it is also possible to replace those hydrogen atoms which are in the ortho position relative to a trifluoromethoxy group. A pre-requisite for this process is likewise the maintenance of very low temperatures.
As well as the possibility of obtaining the arylmetal compounds by deprotonation, it is also possible to utilize halogen-metal exchange using a suitable metalating reagent to prepare the desired compounds (e.g. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Vol. 13/1, 152-156, Stuttgart 1970 and Vol. 13/2a, 172-173, Stuttgart 1973). Particularly when the arylmetal compounds are halogenated in the ortho position or are substituted in this position by the trimethoxy group, it is also necessary during halogen-metal exchange and during further reaction with electrophilic reagents to maintain very low temperatures.
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-benzyne 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 derivatives is still slow, but proceeds in an explosive manner at −25° C. (critical temperature −22.5° C.), the 2,3-difluorophenyllithium derivatives decomposing suddenly.
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 metalated 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 by-products.
For relatively large batches on a production scale, these processes for the preparation of ortho-halo- and ortho-trifluoromethoxyarylmetal compounds are not suitable since failure of the coolant would result in an increased risk of explosion.
Remedies are provided in this connection by processes described in EP 440 082 B1 and DE 42 01 308 C1, in which the electrophilic reagent and the aromatic are initially introduced and the base can be added at room temperature. In the process, the intermediate ortho-haloaryllithium compounds are immediately scavenged in situ by the respective electrophilic reagent, thus avoiding an accumulation of the unstable component and thus haza rdous secondary reactions.
However, these processes give unsatisfactory yields when a haloaromatic is reacted with an electrophilic reagent which reacts with the lithium base used at a similarly rapid rate to that of the haloaromatic to be metalated or even more rapidly than the latter. For example, drops in yield occur when, according to the processes described in EP 440 082 B1, a haloaromatic is to be reacted with a ketone in the presence of butyllithium or lithium diisopropylamide to give the corresponding lithium alkoxide. In this case, the addition of the base or the enolization of the ketone is at the fore, and the desired reaction does not take place (Scheme 3).
X′: F, Cl
Particularly for such reactions, the traditional processes are hitherto still unavoidable.
The very low temperatures which usually have to be maintained particularly in the case of the sensitive ortho-halometal compounds have proven to be a disadvantage if the intention is to deprotonate aromatics having only a very weakly acidic hydrogen atom. Higher rates of reaction and thus often also better yields, which can be achieved at relatively high temperatures, are excluded for the prior art processes with the exception of the processes described in EP 440 082 B1 and DE 42 01 308 C1.
Finally, the prior art processes, being typical batch processes, are time-consuming and costly to carry out, since cleaning, changeover and no-load times limit the optimum capacity of the plants used.
More recent developments in the electronics industry have resulted in a considerable demand for liquid crystals which have a mono- or polyfluorinated 1,4-phenylene radical, in particular a 2,3-difluoro- or 2,6-difluoro-1,4-phenylene radical. The object of the present invention was to find a preparation process for arylmetal compounds and in particular for ortho-haloarylmetal compounds which does not have the described disadvantages of the processes hitherto and it can be carried out safely on an industrial scale.
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 or a trifluoromethoxy group, using a suitable base or by halogen-metal exchange of haloaromatics using a suitable metalating reagent can be carried out safely even at relatively high temperatures and with a high yield if the arylmetal compounds are prepared in a continuous-flow reactor and are reacted immediately after their formation with a suitable electrophilic reagent.
Here, the reaction of the arylmetal compounds formed can be carried o
Reiffenrath Volker
Stiasny Hans Christian
Merck KGaA
Millen White Zelano & Branigan P.C.
Schroeder Ben
Shah Mukund J.
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