DE10155209A1 - Process for the preparation of substituted aromatic compounds - Google Patents

Abstract

Process for the preparation of compounds of formula (II), DOLLAR F1 wherein substituents R · 1 · to R · 5 · independently of one another for H, CH¶3¶, straight-chain or branched C¶1¶-C¶8¶-alkyl, in particular C¶1¶-C¶4¶-Alkyl, CH (OC¶1¶-C¶5¶-Alkyl) ¶2¶, CH (C¶1¶-C¶5¶-Alkyl) (OC¶1¶- C¶5¶-alkyl), CH¶2¶ (OC¶1¶-C¶5¶-alkyl), CH (CH¶3¶) (OC¶1¶-C¶5¶-alkyl), C¶1 ¶-C¶8¶-alkoxy, especially C¶1¶-C¶4¶-alkoxy, N (C¶1¶-C¶5¶-alkyl) ¶2¶, phenyl, substituted phenyl, aryl, heteroaryl, S (C¶1¶-C¶5¶-alkyl) or a radical C¶Aryl, alkyl¶, and the symbols X · 1 to 5 · for carbon or a maximum of two adjacent X · 1-5 · for nitrogen or X · 1 · R · 1 · and X · 2 · R · 2 · together for O, NH, N (C¶1¶-C¶5¶-alkyl), N (C = OC¶1¶-C¶5¶-alkyl ), N (SiR¶3¶) ¶2¶ or S, DOLLAR A or where adjacent residues R · 1 · to R · 5 · form the following structural unit, DOLLAR F2 where X · 6 · to X · 9 · and R · 6 · to R · 9 · have the same meaning as X · 1 · to X · 5 · and R · 1 · to R · 5 · DOLLAR A and DOLLAR A the rest C¶Aryl, alkyl¶ for straight-chain or branched, substituted or unsubstituted C¶1¶-C¶8¶- Alkyl, 1-hydroxyalkyl with 1 to 8 carbon atoms, CN, 2-hydroxyalkyl with 2 to 5 carbon atoms, 3-hydroxyalkyl with 3 to 5 carbon atoms, 1-NHR-alkyl with 1 to 5 carbon atoms, CH (OC¶1¶-C¶5¶-Alkyl) ¶2¶, C (C¶1¶-C¶5¶-Alkyl) (OC¶1¶-C¶5¶-Alkyl), CH¶2¶ (OC¶1¶-C¶5¶-Alkyl), CH (CH¶3¶) (OC¶1¶-C¶5¶-Alkyl), C¶1¶-C¶5¶-Alkoxy, N (C ¶1¶-C¶5¶-alkyl) ¶2¶, phenyl, substituted phenyl, aryl, heteroaryl, CO¶2¶H, CO¶2¶alkyl, (C = O) ¶0.5¶, substituted .. ,

Description

The invention relates to a process for forming carbon-carbon bonds starting from chloro or fluoroaromatics by reaction with lithium metal and a carbon electrophile, whereby a wide range of alkyl- or aryl-substituted aromatics and heteroaromatics can be obtained.

From such conversions of chloro and fluoro aromatics to alkyl and Aryl-substituted aromatics and heteroaromatics, for example, can be a very wide range of versatile intermediates and active ingredients manufacture agrochemical and pharmaceutical industries to which a there is immense economic interest.

The conversion of halogen aromatics to alkyl or aryl substituted aromatics is described in countless publications in many different ways, for very many of these reactions even exist in general work regulations, according to which the respective target compounds can be obtained in good yields.

The most important and very widely applicable general approach is that Implementation of the halogen aromatics to Grignard compounds, which then subsequently with a wide range of C electrophiles to the target compounds have it implemented. The reaction of aromatics bromine or iodine to Grignard Connections succeed in the absence of the Grignard functionality reacting residues in aromatic halogen in almost all cases in good to very good good yields. It should be noted, however, that bromine and iodine aromatics almost always are significantly more expensive than the corresponding chloroaromatics, making it suitable for competitive technical manufacturing processes are a must to use the latter. Unfortunately, there are numerous cases in which, based on appropriate chlorine or Fluoroaromatics the Grignard compounds only in poor yields special, often expensive solvents or using more expensive Activation methods for the magnesium metal can be produced. this applies for example for 1-chloronaphthalene, in the example of a special and expensive work technique the use of Rieke-Magnesium is required to to be able to achieve any significant sales at all.

In these cases there is little alternative to using the bromine or Iodoaromatics, because the metallization with z. B. Butyllithium succeeds Not chloroaromatics, and also the reverse procedure, e.g. Legs Coupling of the aromatic halogen with a nucleophilic reagent such as. B. one Alkyl or aryl Grignard or a boronic acid usually only works with the more active ones Aromatic bromine or iodine. In the few coupling reactions described by Metallates with chlorobenzenes or fluorobenzenes are required, often in large quantities use specially developed and usually very expensive ligands, so this is mostly is not a serious alternative to consider.

Another significant disadvantage of the process mentioned is of an apparatus nature. From a procedural point of view, the production of Grignard connections is over Chlorinated or fluorinated aromatics are also problematic because the reaction is frequent initially not at all and then very suddenly and often uncontrollably. It will often observed that the time to start very much depends on the quality of the depends on the solvent used (e.g. water content, content of Radical formers and metal ions etc.). For a controlled technical process these are not optimal conditions.

The biggest problem and the biggest cost driver in the manufacture of alkyl and Aryl-substituted aromatics from chlorobenzenes and fluorobenzenes is the significant one apparatus expenditure. Since the aryl metallates available therefrom, such as, for example, the Arylgrignard compounds already mentioned several times only in very few cases and then commercially available at horrific prices, you have to be in one the first boiler, usually kept at the reflux temperature, the Grignard connection produce, after complete conversion cool in it, in a second Submit the appropriate C electrophile to the boiler, due to the high Cool the reactivity of the aryl metallates mostly to the lowest possible temperatures, then add the cooled Grignard compound, thaw, in hydrolyze a third boiler (boilers 1 and 2 must be absolutely water-free stay) and the work-up in this third or another boiler carry out. By simultaneously occupying several boilers and the necessary, lengthy heating and cooling phases for larger quantities only moderate space / time yields and overall high manufacturing costs are achieved.

The preparation of other organometallic reagents, e.g. B. based on the Metals zinc, aluminum, sodium, potassium or silicon are also none reasonable alternative since the metals are usually too unreactive to To be able to use chloroaromatics (Zn, Al, Si), or since the resulting metalates very easy to couple or to biarylene and other secondary products intramolecular rearrangements tend (K, Na, already tolyl sodium or potassium rearrange to benzyl metallates).

It would therefore be very desirable to have a process - while maintaining it the raw materials chlorinated or fluorinated aromatic and C-electrophile - ideally all of them Process steps at one and the same temperature or only slightly different temperature and therefore long Tempering phases can be avoided. But that would be even more important Possibility of producing the organometallic reagent in the same vessel how to carry out the implementation with the C electrophile. But there Production of the Grignard connection mostly at the reflux temperature of the used solvent, but the addition of the reactant Selectivity reasons must be carried out at temperatures <0 ° C appears this is not possible via a Grignard route.

Another common way to make alkyl or aryl substituted aromatics is the implementation of lithiated aromatics and Heteroaromatics with C electrophiles. The production of lithio aromatics can also take place in numerous ways. For example, the implementation of Bromine and iodine aromatics with butyllithium are a standard way to get lithio aromatics to generate. This exchange can be carried out at low temperatures, at which then carried out the reactions with C compounds highly selectively can be.

Unfortunately, this implementation cannot be carried out with chlorinated aromatics, because with very few exceptions, they do not react with butyllithium. Based on these The fact and the high price for butyllithium results despite the above Advantages in the overall balance no particularly economical procedure.

Various methods for producing are known from the prior art Lithium compounds known. So far, however, no overall process has been carried out Exchange of chlorine or fluorine for alkyl or aryl residues, all of the above described requirements are sufficient, described.

There was therefore a need for a method of making compounds of formula (I) to develop that of commercially available and inexpensive Chlorine or fluorine compounds, the required aryl or alkyl substituted aromatics and heteroaromatics in good yields and high Makes cleanliness accessible and at the same time process engineering works simply, efficiently and inexpensively. The latter also includes the Execution of all process steps excluding hydrolysis and workup one and the same temperature and if possible in one and the same Reaction vessel. Ideally, the method also enables direct Preparation of the target compounds by simply stirring chloroaromatic, metal and C electrophile in a suitable solvent.

The present invention achieves all of these objects and relates to a process for the preparation of compounds of the formula (II)


wherein the substituents R ¹ to R ⁵ independently of one another are H, CH ₃ , straight-chain or branched C ₁ -C ₈ alkyl, in particular C ₁ -C ₄ alkyl, CH (OC ₁ -C ₅ alkyl) ₂ , CH ( C ₁ -C ₅ alkyl) (OC ₁ -C ₅ alkyl), CH ₂ (OC ₁ -C ₅ alkyl), CH (CH ₃ ) (OC ₁ -C ₅ alkyl), C ₁ -C ₈ Alkoxy, in particular C ₁ -C ₄ alkoxy, N (C ₁ -C ₅ alkyl) ₂ , phenyl, substituted phenyl, aryl, heteroaryl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, naphthyl, substituted naphthyl, furanyl, substituted furanyl, benzofuranyl, substituted benzofuranyl, S (C ₁ -C ₅ alkyl) or a radical C _{aryl, alkyl} and
the symbols X ^{1 to 5} for carbon or a maximum of two adjacent X ^1-5 for nitrogen (N-six-membered heterocycles) or X ¹ R ¹ and X ² R ² together for O, NH, N (C ₁ -C ₅ - alkyl ), N (C = OC ₁ -C ₅ alkyl), N (SiR3) ₂ or S (five-membered heterocycles),
or where adjacent radicals R ¹ to R ^{5 form the} following structural unit,


where X ⁶ to X ⁹ and R ⁶ to R ^{9 have} the same meaning as X ¹ to X ⁵ and R ¹ to R ⁵ and
the radical C _{aryl, alkyl} for CH ₃ , straight-chain or branched, substituted or unsubstituted C ₁ -C ₈ alkyl, in particular C ₁ -C ₄ alkyl, 1-hydroxyalkyl having 1 to 8 C atoms, CN, 2-hydroxyalkyl with 2 to 5 carbon atoms, 3-hydroxyalkyl with 3 to 5 carbon atoms, 1-NHR-alkyl with 1 to 5 carbon atoms, CH (OC ₁ -C ₅ alkyl) ₂ , C (C ₁ -C ₅ -alkyl) (OC ₁ -C ₅ alkyl), CH ₂ (OC ₁ -C ₅ alkyl), CH (CH ₃ ) (OC ₁ -C ₅ alkyl), C ₁ -C ₅ alkoxy, in particular C ₁ -C ₄ alkoxy, N (C ₁ -C ₅ alkyl) ₂ , phenyl, substituted phenyl, aryl, heteroaryl, CO ₂ H, CO ₂ alkyl, (C = O) _0.5 (which corresponds to the structural unit Ar -CO-CO-Ar), substituted 1-vinylalkyl, CH ₃ -C (= O), RC (= O) or CHO,
by reacting chlorinated or fluorinated aromatics of the formula (I) with carbon electrophiles (C electrophile) and lithium metal.

The carbon electrophile comes in particular from one of the following categories:
Aryl or alkyl cyanates (C _{aryl, alkyl} = CN)
Oxirane, substituted oxiranes (C _{aryl, alkyl} = CH ₂ CH ₂ OH, CR ₂ CR ₂ OH) with R = R ¹ (identical or different)
Azomethine (C _{aryl, alkyl} = CR ¹ ₂ -NR'H)
Nitroenolates (C _{aryl, alkyl} = oximes)
Immonium salts (C _{aryl, alkyl} = amines)
Halogenaromatic, aryl triflates, other aryl sulfonates (C _{aryl, alkyl} = aryl, heteroaryl)
Carbon dioxide (C _{aryl, alkyl} = COOH)
Carbon monoxide (C _{aryl, alkyl} = (-CO-) _0.5 )
Aldehydes, ketones (C _{aryl, alkyl} = CHR ¹ -OH, CR ¹ ₂ -OH;
α, β-unsaturated aldehydes / ketones (C _{aryl, alkyl} = CH (OH) vinyl, CR ¹ (OH) vinyl)
Ketenes (C _{aryl, alkyl} = C (= O) CH ₃ for ketene, C (= O) -R ¹ for substituted ketenes)
Alkali and alkaline earth salts of carboxylic acids (C _{aryl, alkyl} = CHO for formates, COCH ₃ for acetates, R ¹ CO for R ¹ COOMet)
Aliphatic nitriles (C _{aryl, alkyl} = COCH ₃ for acetonitrile, R ¹ CO for R ¹ CN)
Aromatic nitriles (C _{aryl, alkyl} = COAr ')
Amides (C _{aryl, alkyl} = CHO at HCONR ₂ , C (= O) R at RCONR ' ₂ )
Ester (C _{aryl, alkyl} = [C (OH) R ¹ ] _0.5 ) or
Alkylating agent (C _{aryl, alkyl} = alkyl).

The method according to the invention opens up a method to reduce the cost and easily accessible chlorine and fluoroaromatics as ideal starting molecules in one convert a wide range of connections with high added value.

A preferred embodiment is the simultaneous stirring of C electrophile, Chlorinated or fluorinated aromatic and lithium metal in a suitable solvent (One-pot version), whereby after appropriate processing (usually hydrolysis) corresponding secondary products are often obtained in good yields. Provided no functional groups reacting even faster with lithium metal in the Reactants are present, this is a procedure that provides very high space / time yields and also only a single boiler requires. In some cases space / time yields up to 0.3 kg product / (L.h) can be achieved.

Another preferred embodiment is particularly advantageous if the One-pot version not used for the above or other reasons can be, and consists in the primary quantitative production of the Lithium compound and subsequent reaction with the C electrophile. In a particularly preferred embodiment, both stages are at the same or an only slightly different temperature, whereby here time-consuming and energy-consuming heating and cooling phases avoided become.

Suitable solvents for the method according to the invention for linking C, C- Bonds are aliphatic and aromatic ethers and hydrocarbons and Amines which do not carry hydrogen on nitrogen, preferably triethylamine, Diethyl ether, tetrahydrofuran, toluene, toluene / THF mixtures, anisole and Diisopropyl ether, particularly preferably toluene, THF or diisopropyl ether. Solutions in concentrations in the range from 1 to 60% by weight are preferred, in particular 5 to 40% by weight, particularly preferably 8 to 30% by weight.

The conversions of the invention are advantageous at temperatures carried out between -100 ° C and + 80 ° C, preferably at -80 ° C to + 20 ° C, particularly preferably between -65 ° C and -5 ° C.

In the present process, the lithium can be in the form of a dispersion, powder, chips, sand, Granules, pieces, bars or other forms are used, the size the lithium particle is not relevant to quality, but only the reaction times affected. Therefore smaller particle sizes are preferred, for example granules, Powders or dispersions. The amount of lithium added is per mole halogen to be reacted 1.95 to 2.5 mol, preferably 1.98 to 2.15 mol.

Working up is generally aqueous, with either water or aqueous mineral acids are added or the reaction mixture on water or aqueous mineral acids is metered. To get the best yields here each set the pH of the product to be isolated, i.e. usually one slightly acidic, in the case of N-heterocycles also slightly alkaline pH. The alkylated or arylated products are, for example, by extraction and Evaporation of the organic phases obtained, alternatively can also from the Hydrolysis mixture distilled off the organic solvent and then precipitating product can be obtained by filtration.

The purities of the products from the processes according to the invention are in the generally high, but for special applications (pharmaceutical intermediates) yet another purification step, for example by recrystallization from Addition of small amounts of activated carbon may be necessary. The yields on the Reaction products are between 70 and 99%, typical yields are in particular 85 to 95%.

The raw materials for the synthesis according to the invention (chloroaromatics and Fluoroaromatics) are generally very inexpensive commercially available, so that in combination with the aforementioned procedural advantages and thus associated high space / time yields and very high product purities extremely economical and very generally applicable process for Linkage of C, C bonds according to the invention was found.

The process according to the invention is illustrated by the examples below without restricting the invention to:

Examples 1 to 7 Production of p-methylacetophenone from chlorotoluene

A mixture of 126.5 g p-chlorotoluene (1 mol) and 45.1 g acetonitrile (freshly distilled, 1.1 mol) is added to a suspension of 13.8 g lithium granules (2.0 mol) in 350 ml THF -50 ° C added dropwise, 2 hours being selected as the dosing time. After a conversion determined by GC (dark color of the reaction mixture does not show the degree of Li consumption) of> 98% (7.5 h in total), the reaction mixture is added to 200 g of water, the pH to 37% HCl to 2.0 adjusted and the reaction mixture was refluxed for two hours. The organic phase is then separated off and the aqueous phase is extracted once more with 100 ml of petroleum ether. The combined organic phases are distilled. 132.7 g of 4-methylacetophenone (0.99 mol, 99%, boiling point 88 ° C./8 torr) are obtained as a colorless liquid, GC purity> 98% a / a, which gradually solidifies on standing at RT.

Example 8 Preparation of p-methylacetophenone from fluorotoluene

The preparation of p-methylacetophenone from p-fluorotoluene was carried out as in Example 1 described carried out, but here the response time had to Reaching the required turnover can be doubled. The hydrolysis was in a Teflon flask (HF). This gave 4-methylacetophenone in one Yield 88%.

Example 9 Preparation of 2- (4-isopropylphenyl) propene from 4-chloroisopropylbenzene

154.5 g of 4-chloroisopropylbenzene (1 mol) become a suspension of in 1 h 13.8 g of lithium granules (2.0 mol) in 400 ml of THF were added dropwise at -45 ° C. After one sales determined by GC of> 97% (total 9.5 h) Reaction mixture in 30 minutes to a solution of 60.9 g dry acetone (1.05 mol) in 120 ml of THF at -45 ° C and then 1 h at this Stirred temperature.

The reaction mixture is hydrolyzed in the manner described in Example 1 (150 ml of water, adjust to pH 1.0 with HCl). Then it becomes complete Elimination of water boiled at reflux for 6 h. Then at Separate the phases at room temperature and the aqueous phase again with Extract 100 ml of petroleum ether. The combined organic phases are with Dried sodium sulfate and then distilled from the remaining Free solvents. 152 g of 2- (4-isopropylphenyl) propene (0.95 mol, 95%) as a yellowish oil, GC purity 94.5% a / a.

Example 10 Preparation of 2- (4-isopropylphenyl) propene from 4-fluoroisopropylbenzene

Carried out as described in Example 3, the lithiation time again had to be carried out be doubled. Yield 95%, GC purity 93.1% a / a.

Example 11 Preparation of 4-octylbenzaldehyde from 4-chlorobenzaldehyde-ethylene glycol acetal

184.5 g of 4-chlorobenzaldehyde-ethylene glycol acetal (1 mol) become one in 2 h Suspension of 13.8 g lithium granules (2.0 mol) in 800 ml THF at -50 ° C dropwise. After a conversion determined by GC of> 97% (total 8.5 h) 193 g of n-octyl bromide (1.1 mol) are added dropwise at -50 ° C. in 60 minutes and then stirred for 1 h at this temperature.

After hydrolysis (220 ml of water, adjust to pH 2.0 with HCl) and boil for 2 hours on Reflux (to cleave the acetal), the organic phase is separated and the aqueous phase extracted again with 100 ml of petroleum ether. The United organic phases are dried with sodium sulfate and then Remaining solvents removed by distillation. There remain 198.4 g 4-octylbenzaldehyde (0.91 mol, 91%) as a slightly brownish oil, GC purity 98% a / a.

Example 12 Preparation of 4- (2-hydroxyethyl) phenetol from 4-chlorophenetol

In 400 ml of THF cooled to -60 ° C, 50 g of ethylene oxide (1.14 mol) condensed. Subsequently, 13.8 g are initially added under a nitrogen atmosphere Lithium powder (2.0 mol), then 156.5 g of 4-chlorophenetol added in 10 minutes. After reaching a conversion determined by GC of> 96% (total 5.5 h) the reaction mixture is hydrolyzed in the manner described in Example 1 (150 ml water, adjust to pH 4.0 with HCl). Then at Separate the phases at room temperature and the aqueous phase again with 100 ml Extracted dichloromethane. The combined organic phases are distilled freed from remaining solvents and water. There remain 152.7 g 4- (2-hydroxyethyl) phenetol (0.92 mol, 92%) as a highly viscous liquid.

Example 13 Preparation of 4-cyanobiphenyl

13.8 g of lithium powder (2.0 mol) in 225 ml of THF are added under a nitrogen atmosphere submitted. A solution of 188.5 g of 4-chlorobiphenyl and 119 g of phenyl isocyanate in 225 ml of THF is added dropwise at -65 ° C. over the course of an hour. After reaching one sales determined by HPLC of> 95% (total 8.5 h) Reaction mixture hydrolyzed in the manner described in Example 1 (150 ml Water, to separate off the by-product phenol, the pH is left here 12.4). The phases are then separated at room temperature and the aqueous phase extracted again with 100 ml dichloromethane. The United organic phases are washed again with 3% NaOH and then Remaining solvents and water residues are removed by distillation. There remain 166.5 g of 4-cyanobiphenyl (0.93 mol, 93%) as a colorless solid which can be recrystallized from ethanol if necessary.

Example 14 Preparation of 4-hydroxymethyl-N, N-dimethylaniline from 4-chloro-N, N-dimethylaniline

In a template cooled to -50 ° C with 400 ml of toluene and 13.8 g of lithium powder (2.0 mol) 155.5 g of 4-chloro-N, N-dimethylaniline are metered in over 60 minutes. To A conversion of> 98% (total 6.5 h) determined by GC is reached in the reaction mixture was blown in with gaseous formaldehyde until a total of 33 g were recorded. After stirring for 30 minutes, the described Hydrolyzed in a manner (200 ml of water, adjust to pH 7.0 with HCl). Subsequently the phases are separated at room temperature and the aqueous phase still extracted twice with 100 ml dichloromethane each time. The united organic Remaining solvents and water are removed from the phases by distillation. It 134.5 g of 4-hydroxymethyl-N, N-dimethylaniline (0.89 mol, 89%) remain as viscous, brownish liquid.

Example 15 Manufacture of acetophenone oxime

In a template cooled to -50 ° C with 400 ml THF and 13.8 g lithium powder (2.0 mol) 112.5 g of chlorobenzene are metered in over 60 minutes. After reaching a per GC determined sales of> 99% (total 8.5 h) becomes the greenish Reaction mixture metered into a suspension of nitroethane enolate in THF (Preparation: from 1 mol nitroethane, 1 mol n-BuLi in hexane and 300 ml THF -50 ° C). After stirring for 30 minutes, proceed as described hydrolyzed (200 ml water, carefully adjust to pH 6.0 with HCl). Subsequently the phases are separated at room temperature and the aqueous phase still extracted once with 100 ml dichloromethane. The combined organic phases Remaining solvents and water are removed by distillation. It 101 g of acetophenone oxime (0.75 mol, 75%) remain as a yellowish, highly viscous Oil.

Example 16 Preparation of 1,2-bis (4-methylthiophenyl) ethanedione

In a template cooled to -70 ° C with 400 ml THF and 13.8 g lithium powder (2.0 mol), 158.5 g of 4-chlorothioanisole are metered in over 60 minutes. After reaching one sales determined by GC of> 96% (7.5 h in total) is changed to reddish Blown reaction mixture at -75 ° C a strong stream of carbon monoxide. After the end of the uptake, hydrolyze in the manner described (200 ml Water, carefully adjust to pH 6.5 with HCl). Then at Separate the phases at room temperature and the aqueous phase twice with extracted 100 ml each of dichloromethane. The combined organic phases be as gentle as possible of remaining solvents and water freed. After crystallization from ethanol (96%), 83 g of 1,2-bis (4- methylthiophenyl) ethanedione (0.275 mol, 55%) as a brown, unpleasant smelling Solid.

Example 17 Preparation of bis (p-anisyl) carbinol

In a template cooled to -40 ° C with 370 ml THF and 13.8 g lithium pieces (1 cm × 1 cm × 0.5 cm, 2.0 mol), 158.5 g of 4-chlorothioanisole are metered in in 30 minutes (1.0 mol). After reaching a turnover determined by GC of> 97% (14.5 h in total), a solution of 58.8 g is added to the reaction mixture at -40 ° C. Formic acid methyl ester (0.98 mol) added dropwise in the same volume of THF. To one hour stirring at -40 ° C is in the manner described several times hydrolyzed (200 ml of water, adjust to pH 6.5 with HCl). Then be at room temperature separate the phases and the aqueous phase three more times extracted 100 ml each of dichloromethane. The combined organic phases Remaining solvents and water are removed by distillation. It 108.6 g of bis (p-anisyl) carbinol (0.445 mol, 89%) remain as a yellowish, viscous Product.

Example 18 Preparation of 4-methoxybiphenyl

142.5 g of 4-chloroanisole (1st.) Are metered into a template cooled to -50 ° C. with 370 ml of THF and 13.8 g of lithium pieces (1 cm × 1 cm × 0.5 cm, 2.0 mol) in 50 minutes , 0 mol). After a conversion determined by GC of> 97% (total 12.5 h), a solution of 0.05 g PdCl2 (dppf) in 20 ml THF and then a solution in 30 minutes is added to the reaction mixture at -50 ° C of 157 g of bromobenzene added in the same volume of THF (strongly exothermic). After stirring for one hour at -50 ° C., the mixture is allowed to thaw to room temperature and hydrolyzed in the manner described (200 ml of water, adjusted to pH 5.5 with HCl). The phases are then separated at room temperature and the aqueous phase is extracted again with 150 ml of toluene. The combined organic phases are freed from remaining solvents and water by distillation. 162 g of 4-methoxybiphenyl (0.88 mol, 88%) remain as a slightly yellowish solid which can be further purified by distillation.

Example 19 Preparation of 3-acetylpyridine from 3-chloropyridine

A mixture of 113.5 g 3-chloropyridine (1 mol) and 45.1 g acetonitrile (fresh distilled, 1.1 mol) becomes a suspension of 13.8 g of lithium granules (2.0 mol) in 350 ml of THF were added dropwise at -75 ° C, 2 hours being chosen as the dosing time. After a conversion of> 95% (total 17.5 h) determined by GC, the Reaction mixture worked up in the manner already described several times. After filtration of the remaining toluene solution over Primisil (high density Zeolite) and the solvents are condensed off to leave 110 g of 3-acetylpyridine (HPLC purity 93%) as an orange liquid.

Example 20 Preparation of 3-acetylfuran from 3-chlorofuran

By reacting 102.5 g of 3-chlorofuran (1 mol), 45.1 g of acetonitrile (fresh distilled, 1.1 mol) and 13.8 g of lithium granules (2.0 mol) according to the in The procedure given in Example 19 gives 98.5 g of 3-acetylfuran (HPLC purity 94%) as a light brown liquid.

Claims (7)

1. Process for the preparation of compounds of formula (II),


wherein the substituents R ¹ to R ⁵ independently of one another are H, CH ₃ , straight-chain or branched C ₁ -C ₈ alkyl, in particular C ₁ -C ₄ alkyl, CH (OC ₁ -C ₅ alkyl) ₂ , CH ( C ₁ -C ₅ alkyl) (OC ₁ -C ₅ alkyl), CH ₂ (OC ₁ -C ₅ alkyl), CH (CH ₃ ) (OC ₁ -C ₅ alkyl), C ₁ -C ₈ Alkoxy, in particular C ₁ -C ₄ alkoxy, N (C ₁ -C ₅ alkyl) ₂ , phenyl, substituted phenyl, aryl, heteroaryl, S (C ₁ -C ₅ alkyl) or for a radical C _aryl, Are _alkyl , and the symbols X ^{1 to 5} for carbon or a maximum of two adjacent X ^1-5 for nitrogen or X ¹ R ¹ and X ² R ² together for O, NH, N (C ₁ -C ₅ alkyl), N (C = OC ₁ -C ₅ alkyl), N (SiR ₃ ) ₂ or S,
or where adjacent radicals R ¹ to R ^{5 form the} following structural unit,


where X ⁶ to X ⁹ and R ⁶ to R ^{9 have} the same meaning as X ¹ to X ⁵ and R ¹ to R ⁵
and
the radical C _{aryl, alkyl} for straight-chain or branched, substituted or unsubstituted C ₁ -C ₈ -alkyl, 1-hydroxyalkyl with 1 to 8 C-atoms, CN, 2-hydroxyalkyl with 2 to 5 C-atoms, 3-hydroxyalkyl with 3 to 5 carbon atoms, 1-NHR alkyl with 1 to 5 carbon atoms, CH (OC ₁ -C ₅ alkyl) ₂ , C (C ₁ -C ₅ alkyl) (OC ₁ -C ₅ alkyl) ), CH ₂ (OC ₁ -C ₅ alkyl), CH (CH ₃ ) (OC ₁ -C ₅ alkyl), C ₁ -C ₅ alkoxy, N (C ₁ -C ₅ alkyl) ₂ , phenyl , substituted phenyl, aryl, heteroaryl, CO ₂ H, CO ₂ alkyl, (C = O) _0.5 , substituted 1-vinylalkyl, CH ₃ -C (= O), RC (= O) or CHO,
by reacting chlorinated or fluorinated aromatics of the formula (I) with carbon electrophiles (C electrophiles) and lithium metal. 2. The method according to claim 1, characterized in that the carbon electrophile is selected from the following group:
Aryl or alkyl cyanates (C _{aryl, alkyl} = CN)
Oxirane, substituted oxiranes (C _{aryl, alkyl} = CH ₂ CH ₂ OH, substituted CR ₂ CR ₂ OH)
Azomethine (C _{aryl, alkyl} = CR ¹ ₂ -NR'H)
Nitroenolates (C _{aryl, alkyl} = oximes)
Immonium salts (C _{aryl, alkyl} = amines)
Halogen aromatic, aryl triflates, other aryl sulfonates. (C _{aryl, alkyl} = aryl, heteroaryl)
Carbon dioxide (C _{aryl, alkyl} = COOH)
Carbon monoxide (C _{aryl, alkyl} = (-CO-) _0.5 )
Aldehydes, ketones (O _{aryl, alkyl} = CHR ¹ -OH, CR ¹ ₂ -OH,
α, β-unsaturated aldehydes / ketones (C _{aryl, alkyl} = CH (OH) vinyl, CR ¹ (OH) vinyl)
Ketenes (C _{aryl, alkyl} = C (= O) CH ₃ for ketene, C (= O) -R for substituted ketenes)
Alkali and alkaline earth salts of carboxylic acids (C _{aryl, alkyl} = CHO for formates, COCH ₃ for acetates, R ¹ CO for R ¹ COOMet)
Aliphatic nitriles (C _{aryl, alkyl} = COCH ₃ for acetonitrile, R ¹ CO for R ¹ CN)
Aromatic nitriles (C _{aryl, alkyl} = COAr ')
Amides (C _{aryl, alkyl} = CHO at HCONR ¹ ₂ , C (= O) R ¹ at R ¹ CONR'2)
Ester (C _{aryl, alkyl} = [C (OH) R ¹ ] _0.5 ) or
Alkylating agent (C _{aryl, alkyl} = alkyl). 3. The method according to claim 1 or 2, characterized in that the Implementation is carried out at a temperature in the range of -100 to + 80 ° C. 4. The method according to one or more of the preceding claims, characterized in that the lithium in the form of a dispersion, powder, chips, Sand, granules, pieces or in the form of bars are used. 5. The method according to one or more of the preceding claims, characterized in that aliphatic and aromatic solvents Ethers, hydrocarbons and amines that do not carry hydrogen on nitrogen, preferably triethylamine, diethyl ether, tetrahydrofuran, toluene, toluene / THF- Mixtures, anisole and diisopropyl ether, particularly preferably toluene, THF or Diisopropyl ether can be used. 6. The method according to one or more of the preceding claims, characterized in that the process is carried out as a one-pot process. 7. The method according to one or more of the preceding claims, characterized in that first generates the organolithium compound is and this at the same or a slightly different temperature the C electrophile is implemented.