EP1436301A1

EP1436301A1 - Method for producing, via organometallic compounds, organic intermediate products

Info

Publication number: EP1436301A1
Application number: EP02801306A
Authority: EP
Inventors: Detlef Wehle; Klaus Forstinger; Andreas Meudt
Original assignee: Clariant GmbH
Current assignee: Euticals GmbH
Priority date: 2001-10-12
Filing date: 2002-10-02
Publication date: 2004-07-14
Also published as: CN1568327A; DE10150614A1; WO2003033504A1; RU2004114272A; US20050001333A1; JP2005505629A

Abstract

The invention concerns a method for producing aryllithium compounds by reacting halogenaliphates (I) with metal lithium, to obtain a lithiumalkyl (II), then by subsequent reaction with aromatic halogen compounds (III) with halogen-metal exchange reaction resulting in corresponding lithium aromatic compounds (IV). Step 1: producing the base; step 2: halogen-metal exchange (equation I), formulae wherein: R represents methyl, primary, secondary or tertiary alkyl radical containing 2 to 12 carbon atoms, which are optionally substituted by a radical from the following groups: {phenyl, substituted phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio}, substituted alkyl, substituted or unsubstituted cycloalkyl containing 3 to 8 carbon atoms; Hal1 = fluorine, chlorine, bromine or iodine; Hal2 represents chlorine, bromine or iodine; X1-5 independently represent a carbon or one or several X1-5 R1-5 groups may represent together nitrogen, or two neighbouring X1-5 R1-5 may together represent O, S, NH or NR', wherein R' represents C1-C5 alkyl, SO2-phenyl, SO2-p-tolyl or benzoyl; the radicals R1-5 represent substituents from the group {hydrogen, methyl, cyclic or acyclic primary, secondary or tertiary alkyl radicals containing 2 to 12 carbon atoms, for which, as the case may be, one or several hydrogen atoms are substituted by fluorine, for example, CF3, substituted cyclic or acyclic alkyl groups, alkoxy, dialkylamino, alkylamino, arylamino, diaryalamino, phenyl, substituted phenyl, alkylthio, diarylphosphino, dialkylphosphino, dialkyl- or diarylaminocarbonyl, monoalkyl- or monoarylaminocarbonyl, CO2, hydroxyalkyl, alkoxyalkyl, fluorine or chlorine}, two neighbouring R1-4 radicals capable of representing an aromatic or aliphatic ring condensed on the chain.

Description

description

METHOD FOR THE METAL ORGANIC PRODUCTION OF ORGANIC INTERMEDIATE PRODUCTS

The invention relates to a process for the production of organic compounds by producing aryllithium compounds and reacting them with suitable electrophiles, a lithium alkyl being first generated by reacting haloaliphatics with lithium metal (step 1 in equation I), which is then carried out in a halogen-metal exchange reaction with aromatic

Halogen compounds are reacted to form the desired lithium aromatics (step 2 in equation I), these finally being reacted with an appropriate electrophile,

Step 1: creating the base lithium

R-Hal., ». R-Li

(I) (II)

Step 2: halogen-metal exchange

(II) (III) (IV)

(EQUATION I)

The boom in organometallic chemistry, especially that of the element lithium, in the production of compounds for the pharmaceutical and agrochemical industry and for numerous other applications is in the past years have been almost exponential if one plots the number of applications or the quantity of correspondingly manufactured products against a time axis. The main reasons for this are the increasingly complex structures of the required fine chemicals for the pharmaceutical and agro sectors on the one hand and the almost unlimited synthetic potential of the

Lithium organyle for the construction of complex organic structures on the other hand.

Almost every organolithium compound can be easily generated via the modern arsenal of organometallic chemistry and implemented with almost any electrophile to the desired product. Most of the lithium organyls are generated in one of the following ways:

(1) The most important way is undoubtedly the halogen-metal exchange, in which mostly bromoaromatics are reacted with n-butyllithium at low temperatures

(2) A large number of Li organyls can also be prepared by reacting bromine aromatics with lithium metal

(3) The deprotonation of sufficiently acidic organic compounds with lithium alkyls (e.g. BuLi), lithium amides (e.g. LDA or LiNSi) or the SCHLOSSER superbases is also very important

(RLi / KOtBu).

It follows from this that the use of commercially available alkyl lithium compounds is required for the majority of this chemistry, n-BuLi being used here mostly. The synthesis of n-BuLi and related lithium aliphates is technically complex and requires a great deal of know-how, as a result of which n-butyllithium, s-butyllithium, tert.-butyllithium and similar molecules are only offered at very high prices - measured by industrial standards. This is the most important, but by no means the only disadvantage of this otherwise very advantageous and widely usable reagent. Due to the extreme sensitivity and pyrophoric nature of such lithium aliphates in concentrated solutions, very complex logistical systems for transport, feeding into the dosing template and dosing have to be set up for the sizes sought in large industrial production (annual production quantities between 5 and 500 tons), the high investments in this Fixed assets correspond.

Furthermore, the reactions of n-, s- and tert-butyllithium produce either butanes (deprotonations), butyl halides (halogen-metal exchange, one equivalent of BuLi) or butene and butane (halogen-metal exchange, two equivalents of BuLi) are gaseous at room temperature and escape the reaction mixtures during the required hydrolytic work-ups. As a result, complex exhaust gas purification or corresponding combustion devices are also required to meet the strict legal immission regulations. As a way out, the specialized companies offer alternatives such as n-hexyllithium, which do not produce butanes, but are significantly more expensive than butyllithium.

Another disadvantage is that complex solvent mixtures occur after working up. Due to the high reactivity of alkyl lithium compounds towards ethers, which are almost always solvents for the subsequent reactions, alkyl lithium compounds can usually not be offered in these solvents. The manufacturers do offer a wide range of alkyl lithium compounds of different concentrations in different

Hydrocarbons, however, for example, halogen-metal exchanges do not take place in pure hydrocarbons, so that one necessarily has to work in mixtures of ethers and hydrocarbons. Therefore, after hydrolysis, water-containing mixtures of ethers and hydrocarbons are obtained, the separation of which is complex and in many cases cannot be carried out economically. For large-scale industrial production, however, recycling the solvents used is an essential requirement. For the reasons mentioned, it would therefore be very desirable to provide a process in which the alkyl lithium compound to be used is produced from the cheap raw materials haloalkane and lithium metal in an ether and is reacted simultaneously or subsequently with the halogen aromatic compound to be reacted, because by this procedure all the above-mentioned disadvantages of the "classic" production of lithium aromatics could be avoided.

The present invention achieves all of these objects and relates to a process for the preparation of aryllithium compounds by reacting haloaliphates with lithium metal to form a lithium alkyl and further reaction with aromatic halogen compounds (III) with a halogen-metal exchange reaction to give the corresponding lithium aromatics (IV), these optionally can be reacted in a further step with an appropriate electrophile (equation I),

Step 1: creating the base lithium

R-Hal., - R-Li

(I) (H)

Step 2: halogen-metal exchange

(II) (Hl) (IV)

(EQUATION 1)

wherein R is methyl, primary, secondary or tertiary alkyl radicals with two to 12 C atoms which are optionally substituted by a radical from the following group: {phenyl, substituted phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio}, substituted alkyl, substituted or unsubstituted cycloalkyl having 3 to 8 C atoms,

Hali = fluorine, chlorine, bromine or iodine, Hal _{2 represents} chlorine, bromine or iodine,

X-ι-5 independently of one another represent carbon or one or more groupings X ₁ . ₅ R ₁ -5 can denote nitrogen or two adjacent radicals X ₁ . ₅ R ₁ -5 can together represent O (furans), S (thiophenes), NH or NR '(pyrroles), where R' is Cι_ ₅ alkyl, SO _? -Phenyl, S0 ₂ -p-tolyl or benzoyl.

Preferred compounds of formula (III) which can be reacted by the process according to the invention are e.g. Benzenes, pyridines, pyrimidines,

Pyrazines, pyridazines, furans, thiophenes, pyrroles, any N-substituted pyrroles or naphthalenes. Examples include bromobenzene, 2-, 3- and 4-bromobenzotrifluoride, 2-, 3- and 4-chlorobenzotrifluoride, furan, 2-methylfuran, furfural acetals, thiophene, 2-methylthiophene, N-trimethylsilylpyrrole, 2,4-dichlorobromobenzene, Pentachlorobromobenzene and 4-bromo- or 4-iodobenzonitrile.

The residues R- |. ₅ represent substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 12 carbon atoms, in which one or more hydrogen atoms are optionally replaced by fluorine, for example CF ₃₎ substituted cyclic or acyclic

Alkyl groups, alkoxy, dialkylamino, alkylamino, arylamino, diarylamino, phenyl, substituted phenyl, alkylthio, diarylphosphino, dialkylphosphino, dialkyl- or diarylaminocarbonyl, monoalkyl- or monoarylaminocarbonyl, CO ₂ ^" , hydroxyalkyl, alkoxyalkyl, each can be fluorine or chlorine} or es two adjacent radicals R _1, ₄ together correspond to an aromatic or aliphatic fused ring. The lithium organyls prepared in this way can be reacted with any electrophilic compounds by methods of the prior art. For example, C, C linkages can be carried out by reaction with carbon electrophiles, boronic acids can be produced by reaction with boron compounds, and a very efficient route to organosilanes is opened up by reaction with halogen or alkoxysilanes.

All available fluorine, chlorine, bromine or iodine aliphates can be used as halogen aliphatics (I), since lithium metal in ethereal solvents reacts easily with all halogen aliphatics and in almost all cases with quantitative yields. Chlorine or bromoaliphatics are preferably used here, since iodine compounds are often expensive, fluorine compounds lead to the formation of LiF, which can lead to material problems in later aqueous work-ups as HF. In special cases, however, such halides can also be used advantageously.

Alkyl halides are preferably used which, after the halogen-metal exchange, are converted to liquid alkanes / alkenes (two equivalents of RLi) or alkyl halides (one equivalent of RLi). Chloro- or bromocyclohexane, benzyl chloride, chlorhexanes or chlorheptanes are particularly preferably used.

Suitable ethereal solvents are, for example, tetrahydrofuran, dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether or anisole; THF is preferably used.

Because of the high reactivity of alkyl and aryllithium compounds, in particular also towards the ethers used as solvents, the preferred reaction temperatures are between -100 and + 25 ° C, temperatures between -80 and -10 ° C are particularly preferred. In most cases, it is possible to work with very high concentrations of organolithium compounds. Concentrations of the aliphatic or aromatic intermediates (IV) of 5 to 30% by weight, in particular 12 to 25% by weight, are preferred.

In the two preferred embodiments, the haloalkane is first metered into the lithium metal in the ether, the lithium aliphatic (II) initially being formed. Then either the halogen aromatic (III) to be metallized is added first and then the electrophilic reactant, or in a one-pot variant halogen aromatic and electrophile are either added as a mixture or simultaneously.

Surprisingly, it was found that in the preferred embodiment as a stew, higher yields are observed in many cases than if RLi was first generated and then reacted with halogen aromatic and only then with the electrophile.

The lithium can be used in the present process as a dispersion, powder, chips, sand, granules, pieces, bars or in another form, the size of the lithium particles not being quality-relevant, but rather only influencing the reaction times. Smaller particle sizes are therefore preferred, for example granules, powders or dispersions. The amount of lithium added per mole of halogen to be reacted is 1.95 to 2.5 mol, preferably 1.98 to 2.15 mol.

In all cases, significant increases in reaction rates can be observed at the stage of the production of RLi by adding organic redox systems, for example biphenyl, 4,4'-di-tert-butylbiphenyl or anthracene. The addition of such systems proved to be particularly advantageous when the lithiation times were> 12 h without this catalysis. The concentrations of added organic catalyst are expediently between 0.01 and 1 mol%, preferably between 0.05 and 0.1 mol%.

Aromatics which can be used for halogen-metal exchange are initially all aromatic bromine and iodine compounds. For chlorine compounds it applies that those with activating, ie. H. strongly electron-withdrawing substituents such as CF3 residues, can be lithiated in good yields.

The lithium aromatics (IV) generated according to the invention can be reacted with electrophilic compounds by the methods familiar to the person skilled in the art, carbon and boron and silicon electrophiles in particular being of interest to the pharmaceutical and agrochemical industry with regard to the intermediate products required.

The reaction with the electrophile can either take place after the production of the lithiated compound (III) or, as already described above, in a one-pot process by simultaneous addition to the reaction mixture.

The carbon electrophiles come in particular from one of the following

Categories (the products in brackets):

Aryl or alkyl cyanates (benzonitriles) oxirane, substituted oxiranes (ArCH ₂ CH ₂ OH, ArCR ₂ CR ₂ OH) with R = R ¹ (identical or different)

Azomethine (ArCR ¹ ₂ -NR ^' H)

Nitroenolates (oximes)

Immonium salts (aromatic amines) halogen aromatics, aryl triflates, other aryl sulfonates (biaryls)

Carbon dioxide (ArCOOH)

Carbon monoxide (Ar-CO-CO-Ar)

Aldehydes, ketones (ArCHR ¹ -OH, ArCR ¹ ₂ -OH; α, β-unsaturated aldehydes / ketones (ArCH (OH) vinyl, CR ¹ (OH) vinyl) ketenes (ARC (= 0) CH ₃ for ketene , ArC (= 0) -R ¹ for substituted ketenes)

Alkali and alkaline earth salts of carboxylic acids (ArCHO for formates, ArCOCH3 for

Acetates, ArR ¹ CO at R ¹ COOMet) Aliphatic nitriles (ArCOCH ₃ for acetonitrile, ArR ¹ CO for R ¹ CN) Aromatic nitriles (ArCOAr ^' ) amides (ArCHO for HCONR ₂ , ArC (= 0) R for RCONR ^' ₂ ) esters (Ar ₂ C (OH) R ¹ ) or alkylating agent (Ar-alkyl).

Compounds of the formula BW ₃ are used as boron electrophiles, in which W is independently of one another for identical or different (Ci-Cβ-alkoxy), fluorine, chlorine, bromine, iodine, N (-C ₆ alkyl) ₂ or S ^ Cs Alkyl), trialkoxyboranes, BF ₃ * OR, BF ₃ * THF, BCI ₃ or BBr3 are preferred, trialkoxyboranes being particularly preferred.

Compounds of the formula SiW ₄ are used as silicon electrophiles, in which W independently of one another represents identical or different (Ci-Cβ-alkoxy), fluorine, chlorine, bromine, iodine, N (CrC ₆ -alkyl) ₂ or S (CC ₅ - Alkyl), tetraalkoxysilanes, tetrachlorosilanes or substituted alkyl or aryl halosilanes or substituted alkyl or aryl alkoxysilanes are preferred. The method according to the invention opens up a very economical method for carrying out the transformation of aromatic halogen into any residues in a very economical way.

The work-ups are generally aqueous, with either water or aqueous mineral acids being metered in or the reaction mixture being metered into water or aqueous mineral acids. In order to achieve the best yields, the pH of the product to be isolated is adjusted here, ie usually a slightly acidic, in the case of heterocycles also slightly alkaline pH. The reaction products are obtained, for example, by extraction and evaporation of the organic phases, alternatively the organic solvents can also be distilled off from the hydrolysis mixture and the product which then precipitates can be obtained by filtration. The purities of the products from the processes according to the invention are generally high, but a further purification step, for example by recrystallization with the addition of small amounts of activated carbon, may be required for special applications (pharmaceutical precursors). The yields of the reaction products are 70 to 99%, typical yields are in particular 85 to 95%.

The process according to the invention is to be illustrated by the following examples, without restricting the invention thereto:

example 1

Preparation of 4-trifluoromethyl acetophenone from 4-bromobenzotrifluoride

(2 equivalents of RLi)

41.6 g of chlorocyclohexane (0.35 mol) are added dropwise to a suspension of 4.65 g of lithium granules (0.68 mol) in 350 g of THF at -55 ° C., the metering time being chosen to be 2 hours. After a conversion of the chlorocyclohexane determined by GC of> 97% (10 h in total), 38.3 g of 4-bromobenzotrifluoride (0.170 mol) are added dropwise at the same temperature in 15 minutes. After stirring for a further 30 minutes at -50 ° C., the reaction mixture is metered onto 25.5 g of acetic anhydride (0.25 mol) in 50 g of THF at -30 ° C. (30 minutes). After stirring for 30 minutes, the reaction mixture is added to 120 g of water, the pH is adjusted to 6.3 with 37% HCl and the low boilers are distilled off at 45 ° C. under a slight vacuum. The organic phase is separated off and the aqueous phase is extracted twice with 70 mL toluene each time. After vacuum fractionation, 29.5 g of 4-trifluoromethylacetophenone are obtained from the combined organic phases as a colorless liquid (0.157 mol, 92.2%), GC purity> 98% a / a.

Example 2

Preparation of 4-trifluoromethylacetophenone from 4-bromobenzotrifluoride (1 equivalent of RLi)

The experiment was carried out as described in Example 1, but only half the amount of chlorocyclohexane and lithium metal was used here. After aqueous work-up and distillation, 4-trifluoromethylacetophenone was obtained in a yield of only 68%.

Example 3 Preparation of Benzoic Acid from Bromobenzene

A solution of 0.35 mol of cyclohexyllithium in THF was prepared in accordance with the procedure given in Example 1. At -55 ° C a solution of 31.4 g of bromobenzene (0.20 mol) in 50 g of THF were added dropwise in 1 h. After stirring for two hours at -55 ° C., the dark solution obtained was metered onto 200 g of crushed, anhydrous dry ice under nitrogen. After evaporation of the unreacted CO ₂ and the usual aqueous workup, benzoic acid was obtained in a yield of 91%.

Example 4: Implementation of a chloroaromatic

Preparation of 3-trifluoromethylbenzoic acid from 3-chlorobenzotrifluoride

At -78 ° C, a solution of tert-butyllithium in THF was first generated starting from 46.2 g tert-butyl chloride (0.50 mol), 7.0 g lithium granules, 20 mg biphenyl and 220 g THF (7 h ). 72.2 g of 3-chlorobenzotrifluoride were then added dropwise in 1 h and the mixture was stirred at -78 ° C. overnight and then at -45 ° C. for a further 4 h. The reaction with C0 ₂ and the workup were carried out analogously to Example 3. The yield of trifluoromethylbenzoic acid here was 86%, HPLC purity 98.3% a / a.

Example 5

Production of 4-trifluoromethylacetophenone from 4-bromoacetophenone (2 equivalents of RLi, "one-pot variant")

41.6 g of chlorocyclohexane (0.35 mol) are added dropwise to a suspension of 4.65 g of lithium granules (0.68 mol) in 350 g of THF at -55 ° C., the metering time being chosen to be 2 hours. After a conversion of the chlorocyclohexane determined by GC of> 97% (total 10 h), a mixture of 38.3 g of 4-bromobenzotrifluoride (0.170 mol) and 7.0 g of acetonitrile (0.170 mol) is added dropwise in 15 minutes at the same temperature , After stirring for a further 30 minutes at -50 ° C., the reaction mixture is slowly thawed to RT and worked up in the usual manner with water. The yield of 4-trifluoromethyl acetophenone is 81% after distillation.

Claims

claims

1. Process for the preparation of aryllithium compounds by reacting halogen aliphates (I) with lithium metal to form a lithium alkyl (II) and further reaction with aromatic halogen compounds (III) with a halogen-metal exchange reaction to give the corresponding lithium aromatics (IV),

Step 1: creating the base

lithium

R-Hal. R-Li (I) dl)

Step 2: halogen-metal exchange

(II) (III) (IV)

(EQUATION I)

wherein R is methyl, primary, secondary or tertiary alkyl radicals having two to 12 carbon atoms, which are optionally substituted by a radical from the following group: {phenyl, substituted phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio}, substituted alkyl , substituted or unsubstituted cycloalkyl having 3 to 8 carbon atoms,

Hali = fluorine, chlorine, bromine or iodine,

Have chlorine, bromine or iodine, X1.5 independently of one another represent carbon or one or more groupings X ₁ .5 R ₁ -5 can denote nitrogen or two adjacent radicals X ₁ -5 R ₁ - ₅ can together represent O, S, NH or NR ', where R 'is d-5-alkyl. S0 ₂ -phenyl, S0 ₂ -p-tolyl or benzoyl;

the radicals R ₁ . ₅ for substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 12 carbon atoms, in which one or more hydrogen atoms are optionally replaced by fluorine, for example CF ₃ , substituted cyclic or acyclic alkyl groups , Alkoxy, dialkylamino, alkylamino, arylamino, diarylamino, phenyl, substituted phenyl, alkylthio, diarylphosphino, dialkylphosphino, dialkyl- or diarylaminocarbonyl, monoalkyl- or monoarylaminocarbonyl, CO ₂ ^" , hydroxyalkyl, alkoxyalkyl, fluorine or chlorine} or neighboring radicals R ₁ -4 together can correspond to an aromatic or aliphatic fused ring.

2. The method according to claim 1, characterized in that the reaction is carried out at temperatures in the range of -100 to + 25 ° C.

3. The method according to claim 1 and / or 2, characterized in that chlorine or bromocyclohexane, benzyl chloride, chlorhexane or -heptane are used as compounds of formula (I).

4. The method according to at least one of the preceding claims, characterized in that the amount of lithium to be added per mole of halogen to be converted is in the range from 1.95 to 2.5 mol.

5. The method according to at least one of the preceding claims, characterized in that the reaction is carried out in an ethereal solvent.

6. The method according to at least one of the preceding claims, characterized in that organic redox systems are added in the reaction.

7. The method according to at least one of the preceding claims, characterized in that the compounds of the formulas (IV) are then reacted with an electrophile.

8. The method according to claim 7, characterized in that the reaction is carried out as a one-pot reaction and the electrophile simultaneously with the

Compound of formula (III) is added to the reaction mixture.

9. The method according to claim 7 and / or 8, characterized in that carbon, boron or silicon compounds are used as electrophiles.