Organic compounds -- part of the class 532-570 series – Organic compounds – Halogen containing
Reexamination Certificate
2000-02-17
2002-03-12
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Halogen containing
C570S127000, C570S147000, C570S171000, C564S355000
Reexamination Certificate
active
06355849
ABSTRACT:
The subject matter of the present invention is a process of use in perfluoroalkylation and a reactant for making use of this process. The invention more particularly relates to a reactant and a process for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic functional group. It more particularly relates to a technique for perfluoroalkylating different compounds by addition or nucleophilic substitution reactions typically carried out with organometallic derivatives.
Perfluoroalkylation techniques, or equivalent techniques, generally use derivatives of the perfluoroalkyl iodide type, in the presence of zinc. This technique is thus expensive, while requiring plants for the treatment of the metal wastes which it is advisable to treat, as zinc is a significant pollutant of water courses.
Other techniques, where the perfluoroalkyl radical does not form a stabilized reactive intermediate of the organometallic type, are generally difficult to employ because of the very low stability of the free perfluoro anions in the reaction mixtures. The latter generally result in products of the carbene type, which, when they react, have lost one of their substituents.
This is why one of the aims of the present invention is to provide a reactant which makes possible perfluoroalkylation according to a mechanism of the type involving a carbanion, without resorting to organometallic derivatives of transition metals, such as zinc.
Attempts have often been made to use perfluorocarboxylic acids as source of perfluoroalkyl radicals, more generally of trifluoromethyl radicals, by employing decomposition reactions targeted at removing the carboxyl fragment from the said acids with release of carbon dioxide. However, the successes which had been achieved were very mixed and used particularly complicated catalytic systems. The perfluoroalkyl radicals or their equivalents generated by the decomposition of the said perfluorocarboxylic acids were, in addition, unstable in the reaction mixture and required the use of stabilizing agents.
More recently, Shono, in an article entitled “A Novel Trifluoromethylation of Aldehydes and Ketones Promoted by an Electrogenerated Base” and published in J. Org. Chem., 1991, 56, 2-4, attempted to carry out perfluoromethylation reactions from fluoroform and showed that it was very difficult to obtain positive results in the absence of the base, composed of the pyrrolidonyl anion in combination with a quaternary ammonium cation, this being under the express condition that this base was generated by electrolysis.
During this comparative study, taking, as test reaction, the trifluoromethylation of benzaldehyde according to the so-called Barbier technique (which will be given in detail hereinbelow), this writer concluded that the results obtained from other bases gave zero or poor yields and that the side reactions, and in particular the Cannizzaro reaction (disproportionation of benzaldehyde to benzoic acid and benzyl alcohol), predominated [but the procedures relating to the usual bases (potassium tert-butoxide, sodium hydride, and the like) are not described therein].
However, the techniques using the electrogenerated bases described by this writer require, on the one hand, complex equipment and, on the other hand, a dexterity such that they are problematic to reproduce and extremely difficult to extrapolate to industrial scales. Finally, the use of quaternary ammonium compounds, which are very hygroscopic, implies great care.
The present invention provides a remedy for the disadvantages of the existing processes by providing a reactant which is non-toxic to the environment and which is capable of resulting in the desired products with a satisfactory yield. These aims and others which will appear subsequently are achieved by means of a process which comprises a stage in which a material of formula RfH and a base (or a species capable of generating a strong base in the presence of a compound containing mobile hydrogen, such as, for example, toluene; mention may be made, as example of such a species, of alkali metals or even alkaline earth metals) are brought into contact, in a polar and non-protic or only slightly protic medium, with a substrate carrying at least one electrophilic functional group, provided that, when the substrate is base-sensitive, the addition of the substrate is not carried out last,
either by carrying out the addition, then optionally continuing the reaction after the addition, so that, on the one hand, at least 90% of the addition of the final component is carried out and that, on the other hand, the reaction mixture has been maintained for at least ½ hour (including the duration of the addition) at a temperature at most equal to −20° C., advantageously to −30° C.;
or by meeting at least one of the, preferably both, conditions hereinbelow:
the water content is limited to a value at most equal to 200 ppm (two significant figures), advantageously to 100 ppm (two significant figures), preferably to 50 ppm (one significant figure);
or the amount of base is at most equal to 1.3 times the stoichiometric amount with respect to the substrate with a temperature at most equal to 0° C. or else the base is at most equal to 1.1 times the stoichiometric amount with a temperature at most equal to 20° C.
It should be pointed out that the above conditions are favourable even when the substrate is not base-sensitive. However, it can sometimes be advantageous to carry out reactions by departing somewhat from the optimum conditions when the economic conditions are it.
(cf. the preferred ranges of anhydrousness).
In the present description, H-Rf is understood to mean radicals of formula:
H-(CX
2
)
p
-EWG (II)
where the X, which are alike or different, represent a fluorine or a radical of formula C
nF
2n+l
with n an integer at most equal to 5, preferably to 2, or a chlorine;
where p represents an integer at least equal to 1 and at most equal to 2;
where EWG represents an electron-withdrawing group, the possible functional groups of which are inert under the reaction conditions, advantageously fluorine or a perfluoro residue of formula C
nF
2n+1
with n an integer at most equal to 8, advantageously to 5;
with the condition that X can only be chlorine once on the same carbon. The case where the carbon carrying the hydrogen atom exhibits two X other than chlorine is particularly advantageous.
It is also desirable that, among the X and EWG, at least one, advantageously 2, are atoms (of chlorine or of fluorine).
The total carbon number of Rf is advantageously between 1 and 15, preferably between 1 and 10.
In the material RfH of the reactant of the invention, the EWG entity which exerts an electron-withdrawing effect on the difluoro carbon atom is preferably chosen from functional groups with a Hammett constant &sgr;
p
at least equal to 0.1. In addition, it is preferable for the inductive component of &sgr;
p
, &sgr;
i
, to be at least equal to 0.2, advantageously to 0.3. In this respect, reference will be made to the work by March, “Advanced Organic Chemistry”, third edition, John Wiley and Son, pages 242 to 250, and in particular to Table 4 in this section.
More particularly, the electron-withdrawing entity can be chosen from halogen atoms, preferably light halogen atoms [in particular chlorine and fluorine]. The corresponding material RfH is, when p is equal to 1, a haloform. EWG can also be advantageously chosen from nitrile, carbonyl-containing, sulphonated and perfluoroalkyl-containing groups. Preferred materials of formula RfH of this type which can be used correspond to the formula R-G-CF
2
-H
where G represents a divalent group of formula -Z-G′- in which
the divalent Z represents a single bond, a chalcogen atom, or a divalent residue -Y(R′)-, where R′ is a hydrocarbon-comprising radical of at most ten atoms, advantageously of at most six atoms, advantageously of at most two atoms, of carbon and where Y is a semimetallic atom from column V (nitrogen, p
Roques Nicolas
Russel James
Parsa J.
Rhodia Chimie
Richter Johann
Seugnet Jean-Louis
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