Method for the synthesis of an aromatic derivative ortho-disubst

Details Method for the synthesis of an aromatic derivative ortho-disubst Method for the synthesis of an aromatic derivative ortho-disubst

1998-09-15

2000-12-05

Tsang, Cecilia

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

Organic compounds

Nitriles

C07C25300

Patent

active

061569224

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a method for the synthesis of an aromatic compound exhibiting an aromatic nucleus comprising at least one C--C unit substituted on a carbon atom by a cyano group and on the other carbon atom by a halogen atom other than fluorine.
The cyanation of halogenated aromatic compounds is known, the most widely used reaction being the Rosenmund-von Braun reaction, which achieves the cyanation of chlorinated or brominated aromatics in the presence of a stoichiometric amount of cuprous ions.
However, the industrial application of this reaction is very awkward and expensive because it requires effluent treatment operations for the purpose of separating copper salts and of possible recycling of the transition metal.
Furthermore, when the intended product is an aromatic compound carrying a cyano group ortho to a halogen substituent, the reaction to be carried out is a monocyanation of the corresponding orthodihalogenated aromatic. Now, the grafting of a nitrile functional group ortho to a halogen has a tendency to promote a second substitution to result in a dicyano, which is unfavourable to the reaction yield.
In addition, the copper-catalysed Rosenmund-von Braun reaction is generally not regioselective with respect to a specific halogen atom. However, a regioselective substitution of a halogen is often observed when the latter is ortho to an electron-withdrawing substituent with a predominant mesomeric effect, such as NO.sub.2. In contrast, in the case of aromatic compounds with a nucleus depleted in electrons by an electron-withdrawing functional group with a predominant inductive effect, the orientation of the substitution is not very marked, much less than for nuclei depleted by an electron-withdrawing functional group by a mesomeric effect, and problems of regioselectivity can be posed.
The aim of the present invention is to overcome these disadvantages and to provide a method for the synthesis of such an aromatic derivative, disubstituted by a cyano group and a halogen atom arranged in the ortho position, which makes use of simple and inexpensive reactants, which does not require an effluent treatment operation and which results in the desired product with a good yield and good selectivity.
Surprisingly, the present Inventors have found that this aim, and others which will become apparent subsequently, can be achieved by a two-step method with great success, both from the yield viewpoint and from the viewpoint of selectivity, in comparison with the conventional single-step method.
In this respect, the subject-matter of the invention is a method for the synthesis of a compound of formula (I) ##STR1## in which ##STR2## is an optionally substituted aromatic nucleus depleted in electrons containing at least five carbon-comprising ring members, least the steps consisting in ##STR3## in which ##STR4## has the above meaning and the X substituents, which are identical or different, are selected from Cl, Br and I, with a fluoride-based halogen/fluorine exchange reactant, in order predominantly to form a compound of formula (III) ##STR5## and (b) reacting the reaction product of the step (a) with a cyanide-based fluorine/cyanide exchange reactant, in order selectively to form the compound of formula (I).
The reaction of the step (a) generally results in a major isomer of formula (III) and possibly in a minor isomer of formula (IIIb), ##STR6## by monosubstitution by a fluorine atom. It is even possible to observe very good regioselectivity depending on the nature of the compound of formula (II), in particular as a function of other possible substituents of the aromatic nucleus and of the position of the latter. This will be described in detail subsequently.
The reaction product of the step (a) can, however, comprise a mixture of isomers, the separation of which is technically very difficult and expensive to implement on an industrial scale.
Surprisingly, the reaction of the step (b) shows very high chemoselectivity which enhances the selectivity of the overall synthetic sequence in favour of

REFERENCES:
Chemistry and Industry, Jan. 21, 1978, pp. 56-63, XP000601110, William Prescott, "The halogen exchange process for the production of fluoro-aromatics".
Journal of Fluorine Chemistry, vol. 61, 1993, pp. 193-216, XP000601952, V.M. Vlasov, "Flouride ion as a nucleophile and a leaving group in aromatic nucleophilic substitution reactions".

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