Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Reexamination Certificate
2000-07-13
2001-10-02
Vollano, Jean F. (Department: 1621)
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
Reexamination Certificate
active
06296788
ABSTRACT:
The present invention relates to a process for the preparation of Grignard reagents which contain a protected aldehyde function, and to novel Grignard reagents of this type.
Grignard reagents are important intermediates in organic synthesis, which enable various types of functional groups to be introduced into a molecule. Numerous active ingredients can be prepared in this way.
The conversion of a starting compound into a Grignard reagent is not, however, directly possible in every case. There are functional groups, e.g. the aldehyde function, which are incompatible with a grignardization. If such a functional group is present in the molecule and if it is to be retained during a Grignard synthesis step, then this group must be protected by suitable chemical derivatization. Then, following the Grignard synthesis step, this derivatization must be reversed and the original functional group restored. For this reason, prior to Grignard reactions, aldehyde groups are usually converted into acetals by reaction with alcohols or ortho esters, and these acetals are later cleaved again by acidic hydrolysis. Thus, 4-bromo-benzaldehyde, protected e.g. as diethyl acetal, is reacted, following conversion into the Grignard reagent by reaction with tributyl borate, to give 4-formyl-benzeneboronic acid (Chem. Ber. 123, 1841-1843 (1990)), which is of economic interest as the synthesis building block for constructing biaryl backbones for pharmaceutical active ingredients (EP-A 757 982).
Recently, a process has been described which can be used to convert chloroaromatics into Grignard reagents (WO 98/02443). However, chloroaromatics are less reactive than bromoaromatics, meaning that conversion of chloroaromatics into Grignard reagents is often not directly possible. In the process of WO 98/02443, an inorganic Grignard reagent of a transition metal is therefore additionally used as catalyst. This process is generally applied to chloroaromatics which are free from aldehyde groups.
Only in the document of WO 98/02443 (Example 16 therein) is a grignardization of 2-(4-chloro-phenyl)-1,3-imidazolidine described which has been prepared from p-chlorobenzaldehyde and N,N′dibenzylethylenediamine. The grignardization and the subsequent stage prepared therefrom were obtained in good yields. A disadvantage of this synthesis route is the use of a dialkylated ethylenediamine as protective group. Diamines of this type are very expensive compared with other protective groups and are not directly obtainable in industrial amounts. Also, the protective group remains in the molecule following the reaction and has to be removed in a further, complex reaction step.
Attempts have therefore been made to carry out this process using a customary protective group for the aldehyde function, where, firstly, p-chlorobenzaldehyde is reacted with triethyl orthoformate to give p-chlorobenzaldehyde diethyl acetal, and this was subjected to grignardization. However, only about 34% of the p-chlorobenzaldehyde diethyl acetal was converted into the Grignard reagent (see Comparative Example 1). The reaction of p-chlorobenzaldehyde with 1,3-propanediol to give 2-(4-chloro-phenyl)-1,3-dioxolane did not give a usable route to Grignard reagents of p-chlorobenzaldehyde either since the dioxolane proved to be incapable of undergoing a grignardization (see Comparative Example 2). From this it can be concluded that acetal protective groups are unsuitable for the conversion of chloroaromatics into Grignard reagents by the process of WO 98/02443.
There therefore continues to be a need for a process for the preparation of Grignard reagents which contain a protected aldehyde function in which it is possible to start from not only bromine-containing, but predominantly also from chlorine-containing, aldehydes, and in which protective groups can be used which are low cost, available in industrial amounts and can be cleaved off again in a simple manner.
We have now found a process for the preparation of Grignard reagents which contain a protected aldehyde function which is characterized in that, firstly, a halogenated aldehyde is reacted with a secondary monoamine to prepare an open-chain aminal, and the latter is converted into a Grignard reagent using metallic magnesium.
For the process according to the invention, suitable secondary monoamines are, for example, those of the formula (I)
in which
R
1
and R
2
are identical or different and are each a straight-chain or branched C
1
-C
10
-alkyl or alkylene, or a C
6
-C
10
-aryl which is optionally substituted by up to 3 C
1
-C
4
-alkyl radicals
and cyclic amines of the formula
in which
m and n independently of one another are zero, 1 or 2, and the sum m+n is at least 1, and
X is oxygen or a CH
2
group.
Preference is given to amines of the formula (I) in which R
1
and R
2
are identical and are a straight-chain C
1
-C
4
-alkyl or phenyl, and to cyclic amines of the formula (II) in which m and n are each 2.
Particularly preferred amines are dimethylamine and morpholine.
The secondary monoamine, in particular secondary alkylamines, can optionally be used as aqueous solution, preferably in concentrated aqueous solution.
For the process according to the invention, suitable halogenated aldehydes are, for example, straight-chain or branched C
2
-C
25
-alkyl aldehydes containing 1 to 3 halogen atoms, and C
6
-C
10
-aryl aldehydes containing 1 to 3 halogen atoms. The halogen atoms can, for example, be chlorine, bromine and/or iodine, preference being given to chlorine and/or bromine, particular preference being given to chlorine. Preferably, only one halogen atom is present in the halogenated aldehydes. As halogenated aldehydes, benzaldehydes are preferred, in particular chlorobenzaldehydes and very particularly p-chlorobenzaldehyde.
The preparation of the open-chain aminal from the halogenated aldehyde and the secondary monoamine can be carried out in a manner known per se (see e.g. J. Am. Chem. Soc. 77, 1114-1116 (1955) and 71, 2271-2272 (1949) and Synthesis 1993, 705-713) or analogously thereto. A possible procedure can, for example, involve using at least 2 mol, preferably 2.1 to 5 mol, of secondary monoamine per mole of halogenated aldehyde, and azeotropically distilling off the water of reaction formed either with a suitable solvent, or removing it using a water-abstracting agent (for example potassium carbonate or boric anhydride).
Suitable reaction temperatures are, for example, those in the range −30 to +150° C. The open-chain aminal prepared can be isolated in various ways, e.g. by extraction, distillation or crystallization.
For clarification, it is pointed out that the term “open-chain aminals” means aminals in which the two nitrogen atoms are not bridged to one another. For example, the formula (III) shows an open-chain aminal, whereas the formula (IV) shows a bridged aminal.
The conversion into the Grignard reagent is carried out by reacting the open-chain aminal with metallic magnesium. In the case of the more reactive open-chain aminals, in which the grignardization takes place at a bromine or iodine atom, it is possible to proceed by methods known per se for the preparation of Grignard reagents (see e.g. Organikum, 16
th
Edition, VEB Deutscher Verlag der Wissenschaften, Berlin 1986, p. 495 et seq.). In the process, the open-chain aminal can, for example, be reacted at a temperature of from −20° C. up to the boiling point of the solvent or solvent mixture, preferably between 0 and 100° C., with magnesium turnings or magnesium powder in an ether as solvent or in a mixture of an ether and a hydrocarbon as solvent. Suitable ethers are, for example, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether and dimethoxyethane, suitable hydrocarbons are, for example, toluene, cyclohexane, hexane and heptane. Preference is given to using tetrahydrofuran or tetrahydrofuran/toluene mixtures. In the case of open-chain aminals in which the grignardization takes place at a chlorine atom, it may be necessary to activate the magnesium catalytica
Giffels Guido
Steffan Guido
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Vollano Jean F.
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