EP1994037A1

EP1994037A1 - Organomagnesium synthesis agent

Info

Publication number: EP1994037A1
Application number: EP07712440A
Authority: EP
Inventors: Steffen Haber; Dieter Hauk; Ulrich Wietelmann; Dirk Dawidowski; Peter Rittmeyer; Jens RÖDER
Original assignee: Chemetall GmbH
Current assignee: Chemetall GmbH
Priority date: 2006-03-03
Filing date: 2007-03-05
Publication date: 2008-11-26
Also published as: CN101443337A; DE102007010953A1; WO2007099173A1; US9534001B2; US20090173914A1

Abstract

The invention provides an organomagnesium synthesis agent, a process for preparing this synthesis agent, and its use.

Description

Organomagnesium synthesizer

The invention relates to an organomagnesium synthesis agent, a process for the preparation of this synthesis agent and its use.

For the purposes of the invention, an organomagnesium synthesis agent is a mixture which contains an organomagnesium compound R-MgX and / or R-Mg-R with R = alkyl, aryl, and X = halide, triflate, tosylate in an organic solvent. An organomagnesium synthesis agent is used for the synthesis, in particular for organic synthesis.

In particular, the present invention relates to organomagnesium compounds in highly concentrated solution.

Organomagnesium compounds are known from the literature. Such compounds are synthesized, for example, by reacting mercury organyls with magnesium or by reacting aryl and alkyl halides with metallic magnesium. It is often necessary to use highly activated magnesium for synthesis, which is obtained, for example, by reduction of magnesium chloride by potassium (Ch Elschenbroich, A. Salzer, (1993), Organometallic Chemistry, 6.1 Alkaline earth metal organyls, 3rd edition, 1st corrected reprint, Teubner Studienbücher Chemistry, Stuttgart).

In preparative organic and organometallic chemistry (review: author collective, (1990), in Organikum, 18th, corrected edition, German Verlag der Wissenschaften, Berlin, page 495 ff.) Organomagnesium compounds are often used for deprotonation of acidic compounds (R'-AH , with A eg C, O, S, N, P):

R MgX + HAR ¹ ► RH + XMg-AR ¹

with R = alkyl, aryl, R '= alkyl, aryl, X = halide and A = C, O, S, N, P. These reagents also find use in halogen-metal exchange reactions in which an alkyl, alkenyl, alkynyl or aryl-bonded halogen X 'in an organohalide RX (with R' = alkyl, aryl) against a group MgX (with X = Cl, Br, I, triflate, tosylate, or alkyl or aryl). It is also known that such reagents can often be added in large quantities to an inorganic salt such as LiCl (Angew Chem et al., Ed., 2003, 42, 4302; Angew. Chem. Int. Ed. 2004, 43, 3333; Angew Chem. Int. Ed. 2005, 44, 1654, Chem. Commun. 2004, 2288, Organic Letters 2004, 6, 4215, EP-A-1582523) in order to accelerate the following reaction:

R MgX + X ¹ R "► RX ¹ + XMg - R '

It is also known that such organomagnesium compounds are used in CC cross-coupling reactions. For this purpose, transition metal catalysts, complexes of Cu, Fe, Ni, Pd and Pt salts, are often used. In addition to the catalyst, other salts such as ZnCl ₂ or ZnBr ₂ are also frequently added in amounts up to stoichiometric (LS Hegedus, Organic Synthesis with Transition Metals, translated, processed and updated by H.-G. Schmalz and Andre Majdalani, (1995), VCH, Weinheim, page 81 ff):

[Catalyst! R MgX + X ¹ R ' ^~ ^ - ^ R - R'

with R = alkyl, aryl, R '= alkyl, aryl, X = halide Addition reactions of organomagnesium compounds to electrophiles such as nitriles, carbonyls such as carboxylic acid esters, ketones, aldehydes and other groups such as> C = N-,> C = S, are also known. -N = O but also on CC double bonds C = C.

Also, organomagnesium compounds are used in transmetalation reactions with other metal salts MX _n (M = metal, X = halide, n = positive integer). Thus, the implementation of TiX ₄ , ZrX ₄ or HfX ₄ with suitable organomagnesium compounds to the corresponding metal alkyls or aryls TiR ₄ , ZrR ₄ or HfR ₄ , or in general to compounds of the type MR _n (R = with R = alkyl, aryl, R '= alkyl, aryl, n = positive integer) (Zucchini, E. Albizzati, U. Giannini, J. Organomet. Chem., 1971, 26, 357, P. Shao, RAL Gendron, DJ Berg, GW Bushneil, Organometallics 2000, 19, 509).

Organomagnesium compounds are also used in the synthesis of special boron compounds. By reacting boric acid esters such as trimethyl, triethyl or triisopropyl borate with organomagnesium compounds, alkyl or arylboranes, alkyl- or arylboronic acid esters or alkyl- or arylborinic acid esters are obtained. The two last-mentioned groups of substances form, after hydrolysis with water, alkyl- or arylboronic acids or alkyl- or arylborinic acids (R. Köster, Annalen der Chemie 1958, 618, 31, Synthesis and Use: DG Hall, (2005), Boronic Acids , Wiley-VCH Verlag, Weinheim).

Syntheses of organomagnesium compounds known to the expert skilled in the art and their reaction are further summarized in: K. Nützel,

(1973) Organomagnesium Compounds; in Eugen Müller, Houben Weyl, volume

13 / 2a, fourth edition, Georg Thieme Verlag, Stuttgart; F.R. Busch, D.M. De Antonis,

(2000), Grignard Reagents - Industrial Applications and Strategy, H.G. Richej, Jr.,

Grignard Reagents New Developments, Wiley, Weinheim; G. S. Silverman, P.E. Rakita, (1996), Handbook of Grignard Reagents, Marcel Dekker, Inc. New York.

It is known to carry out the synthesis of organomagnesium compounds in hydrocarbons, possibly with the addition of amines, or in solvents containing oxygen donors. A preferred laboratory-scale oxygen donor-containing solvent is diethyl ether. It is known from diethyl ether that organomagnesium compounds have a very high solubility therein and undesirable side reactions such as the coupling of aryl and alkyl halides with the organomagnesium compound (Wurtz coupling) occur only to a small extent (K. Nützel, (1973), Organomagnesium - A -

Compounds, in Eugen Müller, Houben Weyl, Volume 13 / 2a, fourth edition, Georg Thieme Verlag, Stuttgart).

But problematic in the use of diethyl ether on an industrial scale but its low boiling point (34.6 ⁰ C), the associated high vapor pressure (443 mm Hg at 20 ⁰ C), the low flash point (-4O ⁰ C), the low ignition temperature (16O ⁰ C) and the high explosiveness of steam / air mixtures (lower explosion limit 1, 8%, upper explosion limit 48%). In addition, it is known that diethyl ether is prone to form highly explosive peroxides. Therefore, the use of diethyl ether is usually omitted on an industrial scale (FR Busch, DM De Antonis, (2000), Grignard Reagents - Industrial Applications and Strategy, in HG Richej, Jr, Grignard Reagents New Developments, Wiley, Weinheim, page 167). ,

For the synthesis of organomagnesium compounds on an industrial scale, other oxygen donor-containing solvents such as, for example, tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), diethoxymethane (DEM), dimethoxyethane (DME) or dioxane are initially suitable. However, it is known from these solvents that the formation of the desired organomagnesium compounds from the corresponding aryl and alkyl halides and magnesium is significantly more difficult compared to the synthesis in diethyl ether. In these solvents accumulations of aryl and alkyl halides can occur during the synthesis, which can react at an uncontrollable rate. In many cases arise in these solvents due to the Schlenk equilibrium to a large extent unwanted Diorganomagnesiumverbindungen or higher coordination polymers. It is also known that these solvents tend to form insoluble complexes with magnesium salts. Due to the partially high aggregation of the organomagnesium compounds in these solvents, their reactivity with respect to addition reactions to electrophile or Ni, Pd, Pt or Fe complex-catalyzed cross-coupling reactions is greatly reduced. Side reactions such as the coupling of aryl and alkyl halides with the organomagnesium compound occur in these solvents to a high degree. Also, the solubility of the organomagnesium compound in these solvents is generally significantly lower compared to diethyl ether. The solubility of the organomagnesium compound can be partially increased in these solvents by admixing aromatic solvents such as benzene, toluene, xylenes, etc. (K. Nützel, (1973), Organomagnesium Compounds, in Eugen Müller, Houben Weyl, Volume 13 / 2a, fourth edition, Georg Thieme Verlag, Stuttgart).

Also known for the synthesis of specific organomagnesium compounds are specific cyclic ethers such as tetrahydro-2-methylfuran and tetrahydro-2,5-dimethylfuran. US-A-2838508 discloses the removal of these - undesirable - ethers of organomagnesium compounds. DE-C-19808570 discloses the peculiarities of the synthesis of benzyl and propen-3-yl magnesium halides in tetrahydro-2-methylfuran. Tetrahydro-2-methylfuran leads in the synthesis of benzyl and propen-3-ylmagnesiumhalogeniden, by shifting the Schlenk equilibrium, however, to the formation of high levels of dialkylmagnesium compounds such as (CeHs-CHb) ₂ Mg and (H ₂ C = CH-CHb ) ₂ Mg. This results in the unwanted deposition of larger amounts of the corresponding, insoluble magnesium halide during the synthesis. These insoluble magnesium halides must be separated with considerable product losses, consuming by filtration. The failure of the magnesium halides has the consequence that the desired Grignard compound is present only in reduced concentration, moreover, this can also have an unwanted change in reactivity result.

In order to achieve an optimal and economical space-time yield in reactions of organomagnesium compounds on an industrial scale, it is always interested to use the organomagnesium compounds in the highest possible concentration. The described substitution possibilities for diethyl ether are generally able to dissolve a significantly lower amount of the organomagnesium compounds at 20 ° C., and crystallization of magnesium halides or organomagnesium compounds also generally occurs upon cooling of these solutions, so that these solutions are usually under high energy expenditure, heated transported, stored and must be used. Diethyl ether surrogates having increased solvency for organomagnesium compounds are not disclosed in the prior art. Furthermore, most of the diethyl ether surrogates mentioned, with the exception of MTBE, have an increased miscibility with water. This has especially after the implementation of organomagnesium compounds and the aqueous work-up of the reaction products of importance and prolongs the production times, since the segregation is slow and incomplete. For example, tetrahydrofuran is indefinitely miscible with water at ambient temperature.

The object of the present invention is therefore to provide an organomagnesium synthesis agent which overcomes the disadvantages of the prior art. In particular, this synthesis agent should contain at least one organomagnesium compound in high concentration. The solvent used in the synthesis agent should have poor miscibility with water, and be used safely on an industrial scale. In addition, the preparation of the organomagnesium compound in this solvent should be possible, with no or only very minor side reactions during the production of organomagnesium compounds should occur.

Surprisingly, the object is achieved by the features of the main claim. Preferred embodiments can be found in the subclaims.

In particular, the object is surprisingly achieved by an organomagnesium synthesis agent containing in addition to at least one organomagnesium compound, a solvent containing at least one oxygen donor compound of the general formula 1 or consists of at least one oxygen donor compound of the general formula 1. The following is spoken of synthesis agent according to the invention and inventive solvent. Formula 1 :

wherein R ¹ and R ^{2 are} independently selected from: H (wherein: when R ¹ = H then R ² ≠ H), functionalized or unfunctionalized branched and / or unbranched alkyl, alkyloxy, cycloalkyl and / or cycloalkyloxy groups with 1 to 20 C atoms and / or functionalized and / or unfunctionalized aryl, hetaryl and / or aryloxy groups having 1 to 12 C atoms.

Examples of R ¹ and R ² are: H (wherein: when R ¹ = H then R ² ≠ H), methyl, methoxy, methylmethoxy, ethyl, ethoxy, methylethoxy, n-propyl, propoxy, methylpropoxy, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, hexyl, n-heptyl, iso-heptyl, n-octyl, iso-octyl, 2-ethyl-1-hexyl, 2,2,4-trimethylpentyl, nonyl, decyl, dodecyl, n-dodecyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, vinyl, 1-propenyl, 2-propenyl, naphthyl, anthranyl, phenanthryl, o-tolyl, p-tolyl, m-tolyl, xylyl, ethylphenyl, mesityl, phenyl, pentafluorophenyl, phenoxy, methoxyphenyl, benzyl, mesistyl, neophyl, thexyl, trimethylsilyl, triisopropylsilyl, tri (tert-butyl) silyl), dimethylthexylsilyl. Preferably, R ^{1 is} methyl and R ^{2 is} H (tetrahydro-2-methylfuran).

It has surprisingly been found that the solvent according to the invention dissolves very well other organomagnesium compounds than propen-3-yl and benzyl compounds, that this inventive solvent is poorly miscible with water and enables safe use. In particular, it was found in the synthesis of other organomagnesium compounds than propen-3-yl and benzyl compounds that even in tetrahydro-2-methylfuran as a solvent according to the invention, no shift in the Schlenk equilibrium occurs and thus no magnesium halides crystallize out of the solution. This is all the more surprising as DE-C-19808570 discloses that this shift in Schlenk equilibrium occurs. The solvent according to the invention is characterized by a high boiling point compared with diethyl ether. The risk of the formation of an explosive atmosphere is thus reduced on an industrial scale. For example, tetrahydro-2-methylfuran has a boiling point of 77-79X.

The synthesis agent according to the invention is prepared by reacting at least one compound of the general formula R-X with magnesium in the solvent according to the invention of formula 2 or 3, thereby obtaining the desired organomagnesium compounds in the solvent according to the invention:

Formula 2 R X + Mg ►R MgX

^{Formula 3} 2 RX + 2 Mg ►R Mg R + MgX ₂

where R-MgX and R-Mg-R are organomagnesium compounds, where R-X, R-MgX and R-Mg-R are:

R is selected from: functionalized and / or unfunctionalized branched and / or unbranched C 1 -C 20 -alkyl groups, C 1 -C 20 -haloalkyl groups with fluorine and / or chlorine as

Halogen atom, Ci-C ₂ o-Alkoxygruppen, Ci-C ₂ o-Halogenalk- oxygruppen with fluorine and / or chlorine as halogen atom, C ₂ - C ₂ o-Alkenylgruppen, C ₂ -C ₂ o-Alkinylgruppen, C ₃ -C _8- C 1 -C 10 -alkyl groups and / or functionalized and / or unfunctionalized phenyl, phenoxy, aryl and / or hetaryl groups having 3 to 12 C atoms, which in turn may carry one or more of the abovementioned substituents R; and

X is selected from: F and / or Cl and / or Br and / or I and / or triflate and / or tosylate, preferably from Cl and / or Br. Examples of R are: methyl, trimethylsilylmethyl, ethyl, ethenyl, ethynyl, trimethylsilylethynyl, dimethylthexylsilylethynyl, dimethylcyclohexylsilylethynyl, dimethyltertbutylsilylethynyl, triterbutylsilylethynyl, n-propyl, isopropyl, cyclopropyl, propyn-3-yl, n-butyl, cyclobutyl, 1-butene 4-yl, 1-but-4-yl, 2-buten-4-yl, crotyl, 2-butyn-4-yl, 2-butyl, iso-butyl, tert -butyl, n -pentyl, cyclopentyl, cyclopentadienyl iso-pentyl, neo-pentyl, tert-pentyl, cyclohexyl, hexyl, n-heptyl, isoheptyl, n-octyl, iso-octyl, 2-ethyl-1-hexyl, 2,2,4-trimethylpentyl , Nonyl, decyl, dodecyl, n-dodecyl, cyclohexyl, cyclohexenyl, cycloheptyl, methylcyclohexyl, vinyl, naphthyl, anthranyl, phenanthryl, o-tolyl, p-tolyl, m-tolyl, xylyl, ethylphenyl, phenyl, 2-fluorophenyl, 3 Fluorophenyl, 4-fluorophenyl, pentafluorophenyl, 2-chlorobenzyl, 2-methoxybenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 4-methylbenzyl, 2,5-dimethylbenzyl, naphth-2-ylmethyl, 5,6,7,8-tetrahydronaphth 2-ylmethyl, mesityl, neophyl, thexyl, T trimethylsilyl, triisopropylsilyl, tri (tert-butyl) silyl, dimethylthexylsilyl,

Trimethylsilylethynyl, dimethyltertbutylsilylethynyl, dimethylthexylsilylethynyl, triisopropylsilylethynyl, tritertbutylsilylethynyl, derivatives of substituted and unsubstituted aromatics such as fluorene, indene, indane, sterol, derivatives of substituted and unsubstituted heterocycles such as pyridine, pyrrole, pyrrolidine, pyrazole, imidazole, isoxazole, isothiazole, diazole, triazole, tetrazole, Thiophene, furan, dihydrofuran, tetrahydrofuran, pyrimidine, quinoline, isoquinoline, oxane, thian, piperidine, dioxane, dithiane, morpholine, piperazine, pyran, tetrahydropyran, dihydropyran, indole.

Preferred compounds of the formula R-MgX according to the invention are methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, ethynylmagnesium chloride, ethynylmagnesium bromide, vinylmagnesium chloride, vinylmagnesium bromide, n-propylmagnesium chloride, isopropylmagnesium chloride, cyclopropylmagnesium chloride, n-propylmagnesium bromide, isopropylmagnesium bromide, cyclopropylmagnesium bromide. Propyl magnesium bromide, n-butyl magnesium chloride, sec-butyl magnesium chloride, isobutyl magnesium chloride, tert-butyl magnesium chloride, n-butyl magnesium bromide, sec-butyl magnesium bromide, isobutyl magnesium bromide, tert-butyl magnesium bromide, phenyl magnesium chloride, phenyl magnesium bromide, magnesium bromide, 4-fluorophenylmagnesium chloride, 4-fluorophenylmagnesium bromide.

Exempted from the invention are, as compound of the formula R-MgX, benzyl MgX and propen-3-yl MgX and derivatives thereof of the general formula:

with one or more of the following substituents R ³ : H, fluorine, chlorine, Ci-Ce- alkyl groups, Ci-Cs-haloalkyl groups with fluorine and / or chlorine as the halogen atom, Ci-Cβ-alkoxy groups, Ci-Cβ-haloalkoxy groups with fluorine and / or chlorine as the halogen atom, C ₂ -C ₆ -alkenyl groups, Cs-Ce-cyclolyl groups, trimethylsilyl, phenyl and / or phenoxy groups, which in turn may carry one or more of the abovementioned substituents R ³ ; where X is selected from: F and / or Cl and / or Br and / or I and / or triflate and / or tosylate.

The solvent according to the invention is characterized by an excellent solubility, mostly over 20 wt .-%, sometimes up to about 30 wt .-%, in some cases to over 50 wt .-% of said organomagnesium compounds.

The synthesis agent according to the invention contains at least one of the organomagnesium compounds according to the invention in a concentration of 20 to 80 wt .-%, preferably from 30 to 70 wt .-%, particularly preferably from 35 to 60 wt .-%. According to the invention, the synthesis agent according to the invention can be prepared by synthesizing the organomagnesium compounds R-MgX and R-Mg-R, in particular compounds of the formula R-MgCl or R-MgBr, in the solvents according to the invention.

The solvent according to the invention may consist of at least one compound of the formula 1 or be present in a mixture with at least one aprotic solvent, the aprotic solvent (s) preferably being selected from benzene, toluene, m-xylene, p-xylene, Xylene, cyclohexane, methylcyclohexane. The total proportion of the aprotic solvent or of the aprotic solvents on the synthesis agent according to the invention is 0 to 60% by weight, preferably from 0.1 to 45% by weight, particularly preferably from 1 to 30% by weight, very particularly preferably from 5 to 20% by weight.

The synthesis agent according to the invention may additionally comprise one or more dissolved inorganic salts, for example LiCl, LiBr, MgCl ₂ , MgBr ₂ , FeCb, CuCl, CuCl ₂ , CuBr, CuBr ₂ , ZnCl ₂ or ZnBr ₂ . or mixtures of at least two of these salts.

The molar ratio of inorganic metal salt to the organomagnesium compounds according to the invention is 0.1 to 5, preferably 0.3 to 1.5.

According to the invention, the synthesis agent according to the invention can be used in the reaction of organomagnesium compounds with an electrophile or an aryl or alkyl halide or triflate or tosylate or a boric acid ester, in particular trimethyl-, triethyl-, triisopropylborate.

According to the invention, the synthesis agent according to the invention in a transition metal-catalyzed (Fe, Cu, Ni, Pd, or Pt complex with or without addition of zinc halides such as ZnCl ₂ or ZnBr ₂ ) cross-coupling reaction with an aryl or alkyl halide or triflate or tosylate be used. According to the invention, the synthesis agent according to the invention can be used for the reaction of organomagnesium compounds R-MgX or R-Mg-R in transmetalation reactions with other metal salts MX _n .

The subject of the invention is in detail:

an organomagnesium synthesis agent containing at least the following components:

a solvent containing at least one oxygen donor compound of the general formula:

wherein R ¹ and R ^{2 are} independently selected from:

H, functionalized or unfunctionalized branched and / or unbranched alkyl, alkyloxy, cycloalkyl and / or cycloalkyloxy groups having 1 to 20 C atoms and / or functionalized and / or unfunctionalized aryl, hetaryl and / or aryloxy groups having 1 to 12 C atoms, where: if R ¹ = H then R ² ≠ H;

- At least one organomagnesium compound of the general formula R-MgX or R-Mg-R, wherein R is selected from: functionalized and / or unfunctionalized branched and / or unbranched CrC ₂ o-alkyl groups, CrC ₂ o-haloalkyl groups with fluorine and / or chlorine as a halogen atom, C ₂ d- o-alkoxy, Ci-C ₂ o-haloalkoxy having fluorine and / or chlorine as the halogen atom, C ₂ -C ₂ o-alkenyl, C ₂ -C ₂ o-alkynyl, C ₃ -Cβ -Cycloalkyl groups and / or functionalized and / or unfunctionalized phenyl, phenoxy, aryl and / or hetaryl groups having 3 to 12 carbon atoms, which in turn may carry one or more of the abovementioned substituents R, and X is selected from: F and / or Cl and / or Br and / or I and / or triflate and / or tosylate,

with the proviso that the following compounds are excluded from the compounds of the formula R-MgX: compounds of the formulas benzyl-MgX and propen-3-yl-MgX and derivatives thereof of the general formula:

with one or more of the following substituents R ³ : H, fluorine, chlorine, Ci-Cs-alkyl groups, Ci-Cβ-haloalkyl groups with fluorine and / or chlorine as the halogen atom, Ci-Cs-alkoxy groups, Ci-Cβ-haloalkoxy groups with fluorine and / or chlorine as the halogen atom, C ₂ -C ₆ -alkenyl groups, C ₅ -C ₆ -

Cyclolkylgruppen, trimethylsilyl, phenyl and / or phenoxy groups, which in turn may carry one or more of the aforementioned substituents R ³ ;

an organomagnesium synthesis agent, wherein R ¹ and R ^{2 are} selected from: H, methyl, methoxy, methylmethoxy, ethyl, ethoxy, methylethoxy, n-propyl,

Propoxy, methylpropoxy, iso -propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, hexyl, n-heptyl, iso-heptyl, n -octyl, isooctyl, 2-ethyl-1-hexyl, 2,2,4-trimethylpentyl, nonyl, decyl, dodecyl, n-

Dodecyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, vinyl, 1-propenyl, 2-propenyl, naphthyl, anthranyl, phenanthryl, o-tolyl, p-tolyl, m-tolyl,

XyIyI, ethylphenyl, mesityl, phenyl, pentafluorophenyl, phenoxy, methoxyphenyl,

Benzyl, mesityl, neophyl, thexyl, trimethylsilyl, triisopropylsilyl,

Tri (tert-butyl) silyl), dimethylthexylsilyl, where: when R ¹ = H then R ² ≠ H; an organomagnesium synthesizing agent, wherein the oxygen donor-containing compound is tetrahydro-2-methylfuran;

- An organomagnesium synthesis agent, wherein the concentration of the organomagnesium compound or organomagnesium compounds from 20 to 80 wt .-%, preferably from 30 to 70 wt .-%, particularly preferably from 35 to 60 wt .-%. is;

- An organomagnesium synthesis agent, wherein the solvent in addition to the oxygen donor-containing compound or the compounds containing oxygen donor at least one aprotic solvent, preferably selected from benzene, toluene, m-xylene, p-xylene, o-xylene, cyclohexane and

methylcyclohexane;

- An organomagnesium synthesis agent, wherein the total proportion of the aprotic solvent or the aprotic solvent on the synthesis agent 0 to 60 wt .-%, preferably from 0.1 to 45 wt .-%, particularly preferably from 1 to 30 wt .-%, very particularly preferably from 5 to 20% by weight;

- an organomagnesium synthesis agent containing an inorganic salt, preferably selected from LiCl, LiBr, MgCl _2, Mg Br _2, FeCl _3, CuCl, CuCl _2, CuBr, CuBr _2, ZnCl _2, or ZnBr ₂ or mixtures of at least two of these salts ;

- An organomagnesium synthesis agent, wherein the molar ratio of inorganic metal salt for inventive organomagnesium

Compounds 0.1 to 5, preferably 0.3 to 1, 5;

a process for the preparation of the organomagnesium synthesis agent according to the invention, which is characterized by the following steps:

Preparation and dispersion of magnesium in the solvent according to the invention, activation of the magnesium,

Dosing a compound of general formula RX; - is kept to a method for producing the organomagnesium synthesis agent according to the invention, wherein the reaction temperature in the range of -10 to +100 ⁰ C, preferably in the range of 0 to +40 ⁰ C;

the use of the organomagnesium synthesis agent according to the invention in the synthesis, preferably in organic synthesis;

the use of the organomagnesium synthesis agent according to the invention, wherein the organomagnesium synthesizing agent is reacted with electrophiles, preferably carbonyls, nitriles, carboxylic esters, ketones, aldehydes, olefins, and / or nitro and / or nitroso compounds, oximes and the sulfur analogs of these compounds, preferably thione compounds, is implemented;

- The use of the organomagnesium synthesis agent according to the invention, wherein the organomagnesium synthesis agent is reacted with acidic compounds for their deprotonation;

the use of the organomagnesium synthesis agent according to the invention, wherein the organomagnesium synthesis agent is used in halogen-metal exchange reactions;

- The use of the organomagnesium synthesis agent according to the invention, wherein the organomagnesium synthesis agent is used in CC cross-coupling reactions, preferably involving a catalytically active compound, preferably selected from Fe, Cu, Ni, Pd, and Pt complexes, more preferably with addition of zinc halides, preferably selected from ZnCl ₂ and ZnBr ₂ ;

- The use of the organomagnesium synthesis agent according to the invention, wherein the organomagnesium synthesis agent with

Boric acid esters is reacted; - The use of the organomagnesium synthesis agent according to the invention, wherein the organomagnesium synthesis agent is used in Transmetallierungsreaktionen.

The following examples are intended to illustrate the invention without limiting it to:

Example 1 General Synthesis of Organomagnesium Compounds in the Solvents of the Invention

In an inertized, gas-tight apparatus, magnesium (chips according to Grignard, 1.1 equivalents) is initially introduced and dispersed in the solvent according to the invention. The magnesium is activated by the method known from the literature and then started with the dosage of a compound RX (at least 1 equivalent). The reaction temperature is at atmospheric pressure in the range of -10 to + 100 ° C, preferably in the range of 0 to +40 ⁰ C is maintained. The start of the reaction can be recognized by the fact that the reaction temperature rises. Should no increase in temperature take place, the dosage of the compound RX should be interrupted after a maximum of about 5% of the dosage and an activation of the magnesium with the reagents known from the literature (author collective, in Organikum, 18th, corrected edition, Deutscher Verlag der Wissenschaften, Berlin 1990, Page 499). After complete dosing of the compound RX is allowed to stir for an hour and filtered through a frit G3 from the excess of magnesium.

Example 2: Preparation and crystallization behavior of a solution of 40% by weight of ethylmagnesium chloride in tetrahydro-2-methylfuran

Magnesium turnings (37.9 g, 1.55 mol) and starter solution (EtMgCI 40 wt .-% in tetrahydro-2-methylfuran, 1 1, 43 g) are presented in 2-MeTHF (175.4 g) in the reactor. After reaching the reaction temperature (25 ° C) is started with the dosage of the ethyl chloride (88.00 g, 1, 36 mol). The ethyl chloride is within dosed for four hours. After completion of the addition, the reaction solution is stirred for a further two hours at the reaction temperature before being filtered through a frit D1.

When cold storage of the resulting solution to 0 ⁰ C no crystallization is observed.

Example 3: Preparation and crystallization behavior of a solution of 46% by weight of ethylmagnesium bromide in tetrahydro-2-methylfuran

The reaction is carried out analogously to Example 1. When cold storage of the resulting solution to -10 ° C no crystallization is observed.

Example 4 Preparation and Crystallization Behavior of a Solution of 40% by Weight of n-Propylmagnesium Chloride in Tetrahydro-2-methylfuran

The reaction is carried out analogously to Example 1. When cold storage of the resulting solution to 0 ⁰ C no crystallization is observed.

Example 5: Preparation and crystallization behavior of a solution of 35% by weight of methylmagnesium bromide in tetrahydro-2-methylfuran

Example 6 Production and Crystallization Behavior of a Solution of 39% by Weight of Methylmagnesium Bromide in Diethyl Ether (Comparative Example)

The reaction is carried out analogously to Example 1. When cold storage of the resulting solution to -15 ° C no crystallization is observed.

Example 7 Production and Crystallization Behavior of a Solution of 26% by Weight Methylmagnesium Bromide in Tetrahydrofuran (Comparative Example) The reaction is carried out analogously to Example 1. When storing the solution obtained from 15 ° C, a considerable crystallization can be observed.

Example 8 Comparative Example Preparation and Crystallization Behavior of a Solution of 26% by Weight of Ethylmagnesium Chloride in Tetrahydrofuran (Comparative Example)

The reaction is carried out analogously to Example 1. When cold storage of the resulting solution is carried out under 10 ⁰ C crystallization.

Example 9 Production and Crystallization Behavior of a Solution of 24% by Weight of Propylmagnesium Chloride in Tetrahydrofuran (Comparative Example)

Example 10 Preparation and Crystallization Behavior of a Solution of 40% by Weight of 3,4-Difluorophenylmagnesium Bromide in Tetrahydro-2-methylfuran (Comparative Example)

The reaction is carried out analogously to Example 1. When cold storage of the resulting solution is carried out at -10 ° C crystallization.

Table 1: Summary of the examples, crystallization behavior of organomagnesium compounds as a function of the solvent

* Comparative Example, ** Vergleichchsbeιspιel from DE-C-19808570 crystallization already during the synthesis

Examples 2 to 5 and Table 1 show that, when using the solvents according to the invention in Examples 2 to 5, synthesis agents according to the invention are obtained which contain organomagnesium compounds in high concentrations, that is to say in concentrations of more than 20% by weight. without cooling on cooling to 0 ° C, sometimes to -10 ⁰ C, crystallizate precipitates out of the solution. This result is all the more surprising since in DE-C-19808570 the formation of a magnesium halide crystal already during the synthesis of propen-3-yl and benzylmagnesium compounds is reported. The solvents according to the invention thus represent an ideal and safe diethyl ether surrogate for the preparation of other organomagnesium compounds than propen-3-yl or benzylmagnesium compounds.

Claims

claims

1 . Organomagnesium synthesizing agent, characterized in that it contains at least the following components:

a solvent containing at least one oxygen donor compound of the general formula:

wherein R ¹ and R ^{2 are} independently selected from: H, functionalized or unfunctionalized branched and / or unbranched alkyl, alkyloxy, cycloalkyl and / or cycloalkyloxy groups having 1 to 20 carbon atoms and / or functionalized and / or unfunctionalized aryl -, hetaryl and / or aryloxy groups having 1 to 12 carbon atoms, where: when R ¹ = H then R ² ≠ H;

at least one organomagnesium compound of the general formula R-MgX or R-Mg-R, where R is selected from: functionalized and / or unfunctionalized branched and / or unbranched C ₁ -C 20 -alkyl groups,

_{Ci-C2o-haloalkyl} having fluorine and / or chlorine as the halogen atom, Cr _C2o-alkoxy groups, Ci-C ₂ o-haloalkoxy having fluorine and / or chlorine as the halogen atom, C ₂ -C ₂ o-alkenyl, C ₂ C ₂ o-alkynyl groups, C ₃ -C ₈ -cycloalkyl groups and / or functionalized and / or unfunctionalized phenyl, phenoxy, aryl and / or hetaryl groups having 3 to 12 C atoms, which in turn contain one or more of the abovementioned substituents R, and

X is selected from: F and / or Cl and / or Br and / or I and / or triflate and / or tosylate, with the proviso that the following compounds are excluded from the compounds of the formula R-MgX: compounds of the formulas benzyl-MgX and propen-3-yl-MgX and derivatives thereof of the general formula:

with one or more of the following substituents R ³ : H, fluorine, chlorine, C 1 -C 6 -alkyl groups, C 1 -C 6 -haloalkyl groups with fluorine and / or chlorine as the halogen atom, C 1 -C 6 -alkoxy groups, C 1 -C 6 -haloalkoxy groups with fluorine and / or chlorine as the halogen atom, C ₂ -C 6 alkenyl, C _S -C _Θ - Cyclolkylgruppen, trimethylsilyl, phenyl and / or phenoxy which can carry one or more of the aforementioned substituents R ³ in turn.

2. organomagnesium synthesis agent according to claim 1, characterized in that R ¹ and R ^{2 are} selected from: H, methyl, methoxy, methyl methoxy, ethyl, ethoxy, methylethoxy, n-propyl, propoxy, methylpropoxy, iso-propyl, n-butyl , 2-butyl, iso-butyl, fe / t-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, hexyl, n-heptyl, iso-heptyl, n-octyl, isooctyl, 2 Ethyl-1 -hexyl, 2,2,4-trimethylpentyl, nonyl, decyl, dodecyl, n-dodecyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, vinyl, 1-propenyl, 2-propenyl, naphthyl, anthranyl, phenanthryl, o Tolyl, p-tolyl, m-tolyl, xylyl, ethylphenyl, mesityl, phenyl, pentafluorophenyl, phenoxy, methoxyphenyl, benzyl, mesityl, neophyl, thexyl, trimethylsilyl, triisopropylsilyl, tri (tert-butyl) silyl), dimethylthexylsilyl, where: when R ¹ = H then R ² ≠ H.

3. Organomagnesium synthesis agent according to claim 1 or 2, characterized in that the oxygen-donor compound is tetrahydro-2-methylfuran.

4. organomagnesium synthesis agent according to one or more of claims 1 to 3, characterized in that the concentration of the organomagnesium compound or organomagnesium compounds from 20 to 80 wt .-%, preferably from 30 to 70 wt .-%, particularly preferably from 35 to 60% by weight. is.

5. organomagnesium synthesis agent according to at least one of claims 1 to 4, characterized in that the solvent in addition to the oxygen donor compound or the oxygen donor-containing compounds contains at least one aprotic solvent, preferably selected from benzene, toluene, m-xylene, p-xylene, o Xylene, cyclohexane and methylcyclohexane.

6. organomagnesium synthesis agent according to at least one of claims 1 to 4, characterized in that the total proportion of the aprotic solvent or the aprotic solvent on the synthesis agent 0 to 60 wt .-%, preferably from 0.1 to 45 wt .-%, particularly preferably from 1 to 30% by weight, most preferably from 5 to 20% by weight.

7. organomagnesium synthesis agent according to at least one of claims 1 to 6, characterized in that it contains an inorganic salt, preferably selected from LiCl, LiBr, MgCl ₂ , Mg Br ₂ , FeCl ₃ , CuCl, CuCl ₂ , CuBr, CuBr ₂ , ZnCl ₂ or ZnBr ₂ or mixtures of at least two of these salts.

8. organomagnesium synthesis agent according to at least one of claims 1 to 7, characterized in that the molar ratio of inorganic

Metal salt for organomagnesium compounds according to the invention 0.1 to 5, preferably 0.3 to 1, 5.

9. A process for preparing an organomagnesium synthesis agent according to one or more of claims 1 to 8, characterized by the following steps:

- Dosing a compound of general formula R-X.

10. The method according to claim 9, characterized in that the reaction temperature in the range of -10 to +100 ⁰ C, preferably in the range of 0 to + 40 ° C is maintained.

1 1. Use of an organomagnesium synthesis agent according to at least one of claims 1 to 8 in the synthesis, preferably in organic synthesis.

12. Use according to claim 1 1, characterized in that the organomagnesium synthesis agent with electrophiles, preferably carbonyls, nitriles, carboxylic acid esters, ketones, aldehydes, olefins, and / or nitro and / or nitroso compounds, oximes and the sulfur analogues of these compounds, preferably Thione compounds, is implemented.

13. Use according to claim 1 1, characterized in that the organomagnesium synthesis agent is reacted with acidic compounds to their deprotonation.

14. Use according to claim 1 1, characterized in that the organomagnesium synthesis agent is used in halogen-metal exchange reactions.

15. Use according to claim 1 1, characterized in that the organomagnesium synthesis agent is used in CC cross-coupling reactions, preferably with the participation of a catalytically active compound, preferably selected from Fe, Cu, Ni, Pd, and Pt complexes, more preferably with addition of zinc halides, preferably selected from ZnCl ₂ and ZnBr ₂ .

16. Use according to claim 1 1, characterized in that the organomagnesium synthesis agent is reacted with boric acid esters.

17. Use according to claim 1 1, characterized in that the organomagnesium synthesis agent is used in transmetallation reactions.