US20030009029A1

US20030009029A1 - Catalytic titanium (IV) oxide, mediated geminal symmetric dialkylation of carboxamides

Info

Publication number: US20030009029A1
Application number: US10/162,257
Authority: US
Inventors: Herwig Buchholz; Urs Welz-Biermann
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1998-06-18
Filing date: 2002-06-05
Publication date: 2003-01-09
Also published as: JP2002518362A; DE19827164A1; KR20010052918A; EP1087928A1; WO1999065859A1; US6420302B1

Abstract

The present invention relates to a process preparing compounds of the general formula (I)

wherein R¹, R², R³and R⁴are defined herein.

Description

The present invention relates to a process for the symmetric disubstitution of carboxamides at the geminal carbonyl C atom using Grignard reagents in the presence of titanium dioxide, and to the compounds, prepared by this process, of the general formula (I)

in which

R ¹, R²and R³independently of one another are H, A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹or R¹and R²or R¹and R³or R⁸and R⁹can be attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to nitrogen, at least one further heteroatom selected from the group consisting of —S—, —O— and —NR⁶—,

R ⁴is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹, in which R⁸and R⁹are as defined above or R⁸and R⁹or two radicals R⁴can be attached to one another and together form a cyclic ring having 3 to 8 C atoms which can optionally contain, in addition to one nitrogen atom, at least one heteroatom selected from the group consisting of —S—, —O— and —NR⁶—,

R ⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

A is a straight-chain or branched alkyl radical having from 1 to 10 C atoms, a straight-chain or branched alkenyl radical having 2 to 10 C atoms, or a straight-chain or branched alkynyl radical having 2-10 C atoms or a substituted or unsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 C atoms, and

Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms.

In addition to monoalkylation, geminal dialkylations using various titanium reagents have been included in studies on titanium-mediated alkylation of carbonyl functions. The geminal dimethyl structure, which is frequently found as a component in terpenes and steroids, is particularly interesting here. It has been found that a large number of ketones can be methylated with the aid of (CH ₃)₂TiCl₂(M. T. Reetz, J. Westermann, R. Steinbach, J. Chem. Soc., Chem. Commun. (1981) 237; M. T. Reetz, J. Westerman, S. H. Kyung, Chem. Ber. (1985) 118, 1050). However, hitherto, no studies on the transfer of other alkyl building blocks with the aid of various titanium reagents are known.

Geminal symmetric dialkylations of amides have been known for a long time, on account of their reactions with Grignard reagents (F. Kuffner, S. Sattler-Dornbach, W. Seifried, Mh. Chem. (1962) 93, 469).

Hitherto, geminal dimethylations giving high yields have only been reported for pure ketones or aldehydes, the reactions being titanium-mediated alkylations. To this end, the reagents ZnMe ₂or AlMe₃are required for synthesising the required organotitanium compound TiMe₂Cl₂, since ethereal solutions of MeMgCl/TiCl₄only result in a simple addition of the methyl group to keto groups (M. T. Reetz, J. Westermann, R. Steinbach, J. Chem. Soc., Chem. Commun. (1981) 237; M. T. Reetz, J. Westerman, S. H. Kyung, Chem. Ber. (1985) 118, 1050).

In the hitherto known symmetric dialkylations of amides which are carried out with the aid of a Grignard reagent, the products are in most cases only obtained as byproducts. The yields that are obtained are in the range of a few percent, up to at most about 50%.

TABLE 1


Amide	Grignard	Yield	Lit.


		11%	M. Busch, M. Fleischmann, Chem. Ber. (1910), 43, 2553

		53%	R. Lukes, J. Langthaler, Collect Czech. Chem. Commun. (1959), 24, 110

		30%	R. Lukes, J. Langthaler, Collect Czech. Chem. Commun. (1959), 24, 110

		41%	R. Lukes, K. Smolek, Collect Czech. Chem. Commun. (1939), 11, 506

Accordingly, it is the object of the present invention to provide an inexpensive process which is easy to carry out and gives, from amides of the general formula (II)

in which R ¹, R²and R³have the meanings given above, compounds of the general formula (I) given above which are substituted symmetrically at the geminal carbonyl C atom, in high yield.

This object is achieved by a process for preparing compounds of the general formula (I)

in which

R ⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms,

from compounds of the formula (II)

in which R ¹, R²and R³have the meanings given above for formula (I), by reaction with a nucleophilic reagent of the general formula (IIIa) or a nucleophilic reagent of the general formula (IIIb)

Z-R⁴ (IIIa)

Z-R⁴-R⁴-Z (IIIb)

in which

R ⁴has the meaning given for the formula (I), and

Z is Li or MgX where

X is Hal and

Hal is Cl, Br or I,

where the latter is generated in situ or added directly.

According to the invention, the process is carried out in the presence of catalytic amounts of a metal oxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide.

The present invention also provides a corresponding process which is carried out in the presence of a cocatalyst. Accordingly, the present invention includes a process which is carried out using metal isopropoxides and alkylsilyl halides as cocatalysts; i.e. metal isopropoxides of the general formula (IV) and alkylsilyl halides of the general formula (V)

M′^(s+)(O-isopropyl)_s (IV)

R₃SiX (V)

or of the general formula (VI)

R₀—(X)_m—Si—Y—(Si)_p—(X)_q—R₀ (VI)

in which

M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,

s is an integer from 1 to 4 and is the oxidation state of the metal,

R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,

X is F, Cl, Br, CN,

m is 0, 1,

n is 1 to 10,

o is 0, 2, 3,

p is 0, 1 and

q is 0, 1,

with the proviso that o=3 and Y≠(CH ₂)_nif m=0.

Thus, the invention also provides a process, which is characterized in that

a) a carboxamide of the general formula (II), 1-15 mol %, based on the carboxamide, of a metal dioxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide and, if appropriate, a cocatalyst are initially charged at room temperature under an atmosphere of inert gas in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,

b) a solution comprising a nucleophilic reagent of the general formula (IIIa) or (IIIb) is added dropwise and

c) the mixture is allowed to react with stirring and, after the reaction has ended, worked up in a customary manner,

or in that, if Z=MgX,

a′) magnesium turnings, a carboxamide of the general formula (II), 1-15 mol %, based on the carboxamide, of a metal oxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide are initially charged at room temperature under an atmosphere of inert gas in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,

b′) an alkyl halide, dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, and of the general formula (IIIa′) or (IIIb′)

X—R⁴ (IIIa′)

or

X—R⁴—R⁴—X (IIIb′)

in which R ⁴and X have the meanings given for the formula (I), is added dropwise,

c′) the mixture is allowed to react with stirring and, after the reaction has ended, worked up in a customary manner.

Experiments have shown that, using a nucleophilic reagent of the general formula (IIIa) or (IIIb), which may be a Grignard reagent and which may either be generated in situ or added as such to the reaction mixture, it is possible to convert carboxamides of the general formula (II) in the presence of catalytic amounts of titanium dioxide, zirconium dioxide or hafnium dioxide in a simple manner into symmetrically substituted compounds of the general formula (I).

According to the invention, using the process described herein, it is possible to convert, with good yields, carboxamides of the general formula (II) in which R ¹, R²and R³independently of one another can have the following meanings:

H or

A i.e. branched or unbranched alkyl having 1-10 C atoms, such as methyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkyl having 3-8 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and corresponding methyl- or ethyl-substituted cycloalkyl groups, or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, or branched or unbranched alkenyl having 2 to 10 C atoms, such as allyl, vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2 to 10 C atoms, such as ethynyl, propynyl, or

aryl having 6 to 20 C atoms which is either unsubstituted or mono- or polysubstituted, such as phenyl, naphthyl, anthryl, phenanthryl, mono- or polysubstituted by substituents selected from the group consisting of NO ₂, F, Cl, Br, NH₂, NHA, NA₂, OH and OA, where A can have the meanings given above, can be mono-, poly-, or fully halogenated, preferably fluorinated, or

aralkenyl or aralkynyl, where the aryl, alkenyl and alkynyl groups can in each case have the given meanings, such as, for example, in phenylethynyl.

Good yields are in particular also obtained using carboxamides in which R ¹and R²or R¹and R³together form a cyclic ring having 3-8 C atoms which, in addition to nitrogen, contains further heteroatoms, such as —S—, —O— or —NR⁶—. Particular preference is given here to compounds in which R¹and R²or R¹and R³form a simple cyclic ring which includes the nitrogen of the carboxamide or in which R¹and R²or R¹and R³form a cyclic ring which contains, as further heteroatom, an oxygen atom.

Thus, high yields are obtained in this manner when the starting materials used are compounds such as, for example,

The nucleophilic reagent used can be a Grignard reagent or an organolithium compound of the general formulae (IIIa) or (IIIb), in which the radical

R ⁴is preferably an alkyl radical having 1 to 10 C atoms, such as methyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkyl having 3-8 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, or branched or unbranched alkenyl having 2 to 10 C atoms, such as allyl, vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2 to 10 C atoms, such as ethynyl, propynyl, or

is an aryl radical having 6 to 20 C atoms which is either unsubstituted or mono- or polysubstituted, such as phenyl, napthyl, anthryl, phenanthryl, mono- or polysubstituted by substituents selected from the group consisting of NO ₂, F, Cl, Br, NH₂, NHA, NA₂, OH and OA, where A can have the meanings given above, can be mono-, poly- or fully halogenated, preferably fluorinated, or

is an aralkyl radical having 7 to 20 C atoms, such as benzyl, optionally mono- or polysubstituted by substituents selected from the group consisting of NO ₂, F, Cl, Br, NH₂, NHA, NA₂, OH and OA, where A can have the meanings given above, can be mono-, poly- or fully halogenated, preferably fluorinated,

is an aralkenyl or aralkynyl radical, where the aryl, alkenyl and alkynyl group can in each case have the given meanings, such as, for example, in phenylethynyl.

Furthermore, the radicals R ⁴in the general formula (IIIa) or (IIIb) can be —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹, in which R⁶, R⁷, R⁸and R⁹independently of one another can have the abovementioned meanings or R⁸and R⁹are attached to one another and together form a cyclic ring having 3 to 8 C atoms which may optionally, in addition to a nitrogen atom, contain at least one heteroatom selected from the group consisting of —S—, —O— and —NR⁶—; or

two radicals R ⁴in the general formula (IIIb) can be an alkyl having 2-7 C atoms, so that, in the reaction according to the invention, a compound of the general formula (I) is formed in which two radicals R⁴form a cyclic ring having 3 to 8 atoms.

Particularly preferably, R ⁴has the meaning of an alkyl radical, such as, for example, methyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl, or of a cycloalkyl radical, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or of an aryl radical, such as, for example, phenyl, or of an aralkyl radical, such as, for example, benzyl.

The radical Z in the general formulae (IIIa) and (IIIb) preferably represents a radical MgX where X is Cl or Br, or the radical Z is lithium.

Particular preference according to the invention is given to using Grignard compounds such as: methylmagnesium bromide, ethylmagnesium bromide, n- or isopropylmagnesium bromide, iso-, sec- or tert-butylmagnesium bromide, n-hexylmagnesium bromide, cyclohexylmagnesium chloride, allylmagnesium bromide, vinylmagnesium bromide, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride, phenylmagnesium bromide, benzylmagnesium chloride, for the reaction.

Furthermore, it was found that only if a cocatalyst is added, the geminal symmetric dialkylation reactions according to the invention start even at room temperature and result in the complete conversion of the starting materials in a relatively short reaction time.

Suitable cocatalysts for this reaction are metal isopropoxides and alkylsilyl halides. Particularly suitable are metal isopropoxides of the general formula (IV) and alkylsilyl halides of the general formula (V)

M′^(s+)(O-isopropyl)_s (IV)

R₃SiX (V)

or of the general formula (VI)

R₀—(X)_m—Si—Y—(Si)_p—(X)_q—R₀ (VII)

in which

M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,

s is an integer from 1 to 4 and is the oxidation state of the metal,

R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,

X is F, Cl, Br, CN,

m is 0, 1,

n is 1 to 10,

o is 0, 2, 3,

p is 0, 1 and

q is 0, 1,

with the proviso that o=3 and Y≠(CH ₂)_nif m=0.

Preference is given to using metal isopropoxides in which s is an integer from 1 to 4 and is the oxidation state of the metal and M′ is Al, Ca, Na, K, Si or Mg. Particular preference is given to Mg or Na.

Preference is given to using alkylsilyl halides in which R is alkyl having 1 to 6 C atoms. Particular preference is given to those in which R is alkyl having 1 to 3 C atoms and X is chlorine.

Particularly suitable cocatalysts are, inter alia, the following silicon compounds:

(CH ₃)₃SiCl

(CH ₃)₂ClSi(CH₂)₂SiCl(CH₃)₂

(CH ₃)₂ClSi(CH₂)₃CN

[(CH ₃)₃Si]₂O

[(CH ₃)₃Si]₂NH and

[(CH ₃)₃Si]₂.

It has been found that the addition of from 0.7 to 1.2 mol, in particular from 0.9 and 1.1 mol, of a cocatalyst based on one mol of starting material leads to improved results such as, for example, higher yields, lower reaction temperature or shorter reaction times.

As can be demonstrated using examples, under favourable conditions a complete conversion of the carboxamide according to the general equation (Eq. 1) has taken place after just one hour:

For carrying out the process according to the invention, the catalyst used can be a commercial metal dioxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide. Preference is given to using pulverulent titanium(IV) dioxide. In the simplest case, this can be of technical grade. To ensure simple removal after the reaction has ended, it is advantageous to choose a quality which is not too fine. The metal dioxide, preferably titanium dioxide, which is pre-dried by heating, is employed as a suspension in a suitable pre-dried solvent. Suitable solvents are, for example aliphatic or aromatic hydrocarbons or ethers. Preference is given to using solvents selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, which are dried prior to the reaction by methods known to the person skilled in the art. Drying can be carried out with the aid of magnesium sulphate, calcium chloride, sodium, potassium hydroxide or by other methods.

A preferred embodiment of the process according to the invention comprises initially charging the titanium dioxide used as catalyst in an amount of from 1 to 15, preferably 1.5 to 14, in particular 2 to 10 and very particularly preferably from 3 to 6 mol %, based on one mol of the amide used as starting material, in the form of a suspension adjusted to a temperature of from 10 to 30° C., preferably 15-25° C., particularly preferably to a temperature of about 20° C. Under an atmosphere of inert gas (nitrogen or argon), the starting material, either as such in liquid form or dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, is slowly added dropwise with stirring. An amount of cocatalyst which corresponds to the amount to be reacted is then added dropwise, if required likewise in a solvent. The reaction mixture obtained is stirred for a short period, i.e. for a few minutes, at a constant temperature. Such an excess of the nucleophilic reagent of the general formula (IIIa) or (IIIb), in particular a Grignard reagent, is then slowly added to the resulting reaction mixture that substitution of the geminal carbonyl C atom by two identical substituents, i.e. a symmetric substitution of the geminal carbonyl C atom, can take place. The addition of a nucleophilic reagent according to the invention prepared by methods generally known to the person skilled in the art should take place at such a rate that the temperature of the reaction mixture does not exceed 50° C. It is advantageous to carry out the addition of the nucleophilic reagent, i.e. of the Grignard reagent or the lithium compound, with efficient mixing, preferably vigorous stirring. To shift the reaction equilibrium to the side of the desired symmetrically substituted product, the nucleophilic reagent used, preferably a Grignard reagent, is added in an amount of from 2.1 to 3 mol per mole of starting material that participates in the reaction. Preference is given to adding the Grignard reagent in an amount of from 2.2 to 2.6 mol, based on 1 mol of starting material. If a nucleophilic reagent or Grignard reagent of the general formula (IIIb) is used, only equimolar amounts, based on the starting material, are added to the reaction solution, corresponding to twice the number of reactive groups.

After the addition of the Grignard reagent has ended, the reaction mixture is stirred for some time at a constant temperature, until the reaction is brought to completion.

Another variant of the process according to the invention comprises preparing the Grignard reagent in situ by reacting magnesium with a compound of the general formula (IIIa′) or (IIIb′) in which R ⁴and X have the meanings given above. In the in situ preparation of the Grignard compounds, the amount of magnesium is preferably 2 to 5 times the molar amount, preferably 2.8 to 3.2 times the molar amount, based on the compounds of the general formula (II) used as starting material, and the amount of the compound of the general formula (IIIa′) or (IIIb′) is 2 to 3.8 times the molar amount, preferably 2.2 to 2.6 times the molar amount, based on the compound of the general formula (II).

Thus, by the synthesis according to the invention it is possible to prepare symmetrically substituted amino compounds of the general formula (I) with good or satisfactory yields within adequate reaction times. In an advantageous manner, it is possible, by adding one of the catalysts in combination with one of the cocatalyst compounds described of the general formulae (IV), (V) or (VI), to reduce the reaction times considerably, in the most favourable case to one hour, without this resulting in a reduction in the yields obtained.

Thus, the present invention also provides the use of a catalyst system comprising a metal dioxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide as catalyst and a compound of the general formulae (IV), (V) or (VI) with the meanings given above, and the use of this catalyst system for preparing the symmetrically substituted compounds of the general formula (I).

For example, 5 mmol of starting material are, at 20° C. and under an atmosphere of inert gas, added dropwise with stirring to a suspension of 3 mol % of titanium (IV) oxide in 40 ml of dried tetrahydrofuran. 5 mmol of cocatalyst, likewise taken up in dried tetrahydrofuran, are added slowly with stirring to this mixture. The mixture is stirred at 20° C. for 5 minutes, and 12 mmol of Grignard reagent are then added at such a rate that the temperature of the reaction mixture does not exceed 50° C. Stirring is continued for one hour, until the reaction has gone to completion.

After the reaction according to the invention, work-up of the reaction mixture can be carried out in a manner known to the person skilled in the art.

Here, the products can be precipitated as salts using solutions of hydrochloric acid, for example a 1 molar ethereal solution of hydrochloric acid, and be filtered off and, if required, purified by recrystallization.

To remove the Lewis acid, it is possible, for example, to add a suitable amount of saturated ammonium chloride solution and water, followed by further vigorous stirring for a plurality of hours (1-3 hours). The resulting precipitate is separated off and washed with a little ether, preferably diethyl ether. The filtrate is made alkaline (pH>10) by addition of a suitable base, such as an NaOH, KOH, sodium carbonate or potassium carbonate solution, preferably sodium hydroxide solution. The phases that are formed are then separated, and the aqueous phase is extracted repeatedly (for example in the special case given above three times with in each case 30 ml) with diethyl ether. The combined organic phases are washed with (for example 15 ml of) saturated sodium chloride solution and can be dried over potassium carbonate, magnesium sulphate or sodium sulphate and filtered.

The products can be purified by various routes using methods known to the person skilled in the art, such as, for example, in the following manner:

1. They are precipitated as hydrochlorides using 1 M ethereal hydrochloric acid solution and filtered off (the resulting product is, if required, purified by recrystallization).

2. The organic phase is extracted repeatedly with a 0.5 M acid solution, preferably an aqueous hydrochloric acid solution. The extract obtained is adjusted to pH>10 using bases, preferably 2 M aqueous sodium hydroxide solution, and extracted at least once, preferably repeatedly, with diethyl ether. The resulting organic phases, which contain the reaction product, can be dried, if appropriate, over potassium carbonate, magnesium sulphate or sodium sulphate and be freed from the organic solvent under reduced pressure.

3. Furthermore, it is possible to isolate the reaction product by removing the organic solvent under reduced pressure and separating the residue that remains by column chromatography, to isolate the reaction product.

In the general description of the process procedure given above, the Grignard reagents can also be replaced by the corresponding lithium compounds. The corresponding lithium compounds, like the Grignard reagents, can be prepared by methods generally known to the person skilled in the art, and they can be reacted according to the invention in the same manner as described above.

The compounds of the general formula (I) prepared according to the invention can be used, for example, as intermediates in the preparation of sulphur- or selenium-containing amines for the chiral catalysis of diethyl zinc syntheses (literature: Werth, Thomas; Tetrahydron Lett. 36; 1995, 7849-7852, Werth, Thomas et al. Helv. Chim. Acta 79, 1996, 1957-1966).

To illustrate and better understand the present invention, examples are given below. However, owing to the general validity of the described principle of the invention, they are not meant to reduce the scope of the present application to just these examples.

EXAMPLES

Titanium(IV)-oxide-induced Symmetric Dialkylation of Carboxamides Using Grignard Reagents

According to the reaction shown in Equation 1, the following reactions were carried out using one equivalent of (CH ₃)₃SiCl as cocatalyst:

TABLE 2


TiO₂-induced reaction of carboxamide with R₄MgX

				Reaction
Amide	Product	Yield	R⁴MgX	conditions


		95%^[6]	PhMgBr	1 h/RT/ 3 mol % TiO₂

		49%^[6]	Cyclopen tyl-MgCl	1 h/RT/ 13 mol % TiO₂

		94%^[6]	n-Hexyl-MgBr	1 h/RT/ 13 mol % TiO₂

Claims

1. A process for preparing compounds of the general formula (I)

in which

R¹, R²and R³independently of one another are H, A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹or R¹and R²or R¹and R³or R⁸and R⁹can be attached to one another and together form a cyclic ring having 3 to 8 C atoms which optionally contains, in addition to nitrogen, at least one further heteroatom selected from the group consisting of —S—, —O— and —NR⁶—,

R⁴is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹in which R⁸and R⁹are as defined above or R⁸and R⁹or two radicals R⁴can be attached to one another and together form a cyclic ring having 3 C atoms, R⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms, characterized in that a compound of the general formula (II)

in which

R¹, R²and R³have the meanings given above for the formula (I) is reacted with a reagent of the general formula (IIIa) or a nucleophilic reagent of the general formula (IIIb)

Z-R⁴ (IIIa)Z-R⁴—R⁴-Z (IIIb)

in which

R⁴has the meaning given for the formula (I), and

Z is Li or MgX where

X is Hal and

Hal is Cl, Br or I, which is/are generated in situ or added directly, and the process is carried out in the presence of catalytic amounts of a metal dioxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide.

2. A process according to claim 1, characterized in that it is carried out in the presence of a cocatalyst.

3. A process according to claim 1, characterized in that it is carried out in the presence of a metal isopropoxide or an alkylsilyl halide cocatalyst.

4. A process according to claim 2, characterized in that the cocatalyst used is a metal isopropoxide of the general formula (IV) or an alkylsilyl halide of the general formula (V)

M′^(s+)(O-isopropyl)_s (IV)R₃SiX (V)

in which

M′ is Al, Ca, Na, K, Si or Mg,

s is an integer from 1 to 4 and is the oxidation state of the metal,

R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,

X is F, Cl, Br, or CN.

5. A process according to claim 1, characterized in that the catalyst used is titanium dioxide.

6. A process according to claim 1, characterized in that

a) a carboxamide of the general formula (II), 1-15 mol %, based on the carboxamide, of a metal dioxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide and, if appropriate, the cocatalyst are initially charged at 10-30° C. under an atmosphere of inert gas in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,

b) a solution comprising a nucleophilic reagent of the general formula (IIIa) or (IIIb)

in which

R⁴is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹in which R⁸and R⁹are as defined above or R⁸and R⁹or two radicals R⁴can be attached to one another and together form a cyclic ring having 3 C atoms,

R⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms,

Z is Li or MgX where

X is Hal and

Hal is Cl, Br or I,

is added dropwise and

or in that, if Z=MgX,

a′) magnesium turnings, a carboxamide of the general formula (II), 1-15 mol %, based on the carboxamide, of a metal dioxide selected from the group consisting of titanium dioxide, zirconium dioxide and hafnium dioxide and, if appropriate, the cocatalyst are initially charged at 10-30° C. under an atmosphere of inert gas in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,

b′) an alkyl halide, dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, and of the general formula (IIIa′) of (IIIb′)

X—R⁴ (IIIa′)orX—R⁴—R⁴—X (IIIb′)

in which

R⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms,

X is Cl, Br, or I;

is added dropwise,

c′) the mixture is allowed to react with stirring and, after the reaction had ended, worked up in a customary manner.

7. A process according to claim 6, characterized in that the process step a) or a′) is carried out at a temperature of 15-25° C.

8. A process according to claim 6, characterized in that the process step a) or a′) is carried out at room temperature.

9. A process according to claim 1, characterized in that the nucleophilic reagent used is a lithium compound of the general formula (IIIa) or (IIIb) in which R⁴is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹in which R⁸and R⁹are as defined above or R⁸and R⁹or two radicals R⁴can be attached to one another and together form a cyclic ring having 3 C atoms,

R⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

Ar is a substituted or unsubstituted aryl radical having 6-20 C atoms.

10. A process according claim 1, characterized in that the compound that the nucleophilic reagent used is a compound of the general formula (IIIa) or (IIIb) in which R⁴is methyl, ethyl, n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, cyclopentyl, cyclohexyl, allyl, vinyl, phenyl or benzyl.

11. A process according to claim 1, characterized in that the compound that is reacted is a compound of the general formula (II) in which R¹, R²and R³independently of one another are H, methyl, ethyl, n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, phenyl or benzyl.

12. A process for preparing compounds of the general formula (I)

in which

R⁴is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹in which R⁸and R⁹are as defined above or R⁸and R⁹or two radicals R⁴can be attached to one another and together form a cyclic ring having 3 C atoms

R⁶, R⁷, R⁸and R⁹independently of one another are A or Ar,

A is a straight-chain or branched alkyl radical having from 1 to 10 C atoms, a straight-chain or branched alkenyl radical having 2 to 10 C atoms, or a straight-chain or branched alkynyl radical having 2-10 C atoms or a substituted or unsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 C atoms, by carrying out the process in the presence of a catalyst system, comprising a metal dioxide selected from the group consisting of titanium dioxide, and hafnium dioxide and a cocatalyst of the general formula (IV), (V)

M′^(s+)(O-isopropyl)_s (IV)R₃SiX (V)

in which

M′ is Al, Ca, Na, K, Si or Mg,

s is an integer from 1 to 4 and is the oxidation state of the metal,

R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,

X is F, Cl, Br, or CN,

or the general formulae

(CH₃)₂ClSi(CH₂)₂SiCl(CH₃)₂

(CH₃)₂ClSi(CH₂)₃CN

[(CH₃)₃Si]₂O

[(CH₃)₃Si]₂NH or

[(CH₃)₃Si]₂.

13. A process according to claim 4, wherein M¹is Mg or Na.

14. A process according to claim 12, wherein M¹is Mg or Na.