EP1537125A1

EP1537125A1 - Method for the organometallic production of organic intermediate products comprising carbon-heteroatom bonds achieved by the deprotonation of heteroatoms

Info

Publication number: EP1537125A1
Application number: EP03794905A
Authority: EP
Inventors: Andreas Meudt; Bernd Lehnemann; Michael Erbes; Klaus Forstinger
Original assignee: Archimica GmbH; Clariant GmbH
Current assignee: Euticals GmbH
Priority date: 2002-08-31
Filing date: 2003-08-21
Publication date: 2005-06-08
Also published as: US20050258553A1; JP2005537331A; DE10240260A1; WO2004024737A1

Abstract

The invention relates to a method for binding heteroatom-carbon bonds. According to said method, a lithium compound (II) is first generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, said compound is then used for the deprotonation of the compounds (III) or (V). The lithium salts of formulas (IV) or (VI) obtained by said deprotonation are subsequently reacted with suitable carbon electrophiles (equation I), said process binding the heteroatom-carbon bond and forming the products (VIII) or (VIII), (equation I).

Description

description

Process for organometallic production of organic intermediates with carbon-heteroatom bonds via the deprotonation of heteroatoms

The invention relates to a process for the preparation of organic compounds having carbon-heteroatom bonds, a lithium compound (II) being first generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, which compound is then used to deprotonate the compounds (III) or ( V) is used, and the resulting lithium salts of the formulas (IV) or (VI) are finally reacted with suitable carbon electrophiles to form the lower bond of the heteroatom-carbon bond and form the products (VIII) or (VIII). (EQUATION 1).

Step 1: creating the base

Lithium R-Hal * - R-LI

I II

Step 2: deprotonation of the substrate

R-Li + R1 - XH ^ R1 - X _r ü

II III IV

R1 R1

\

R— Li x ₂ -HX -Li

R2 R2

V VI

Step 3: implementation with an electrophile

R1-X Li ^{ElΘktrθ h} ₁ ^il R1-X _r Ei

IV VII

R1 R1

X ₂ - Li ^Elektr ° P ^hil X ₂ - El

R2 R2

VI VIII

(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 has been almost exponential in recent years, given the number of applications and the quantity of products manufactured accordingly plots against a timeline. 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 lithium organyls for the construction of complex organic structures on the other. A large part of this development is the use of organolithium compounds and alkali metal hydrides as strong, less nucleophilic bases for the deprotonation of alcohols, phenols, thiols, amines etc., ie the generation of heteroatom anions, for the conversion with electrophiles.

The majority of this chemistry requires the use of commercially available alkyl or aryllithium compounds, n-butyllithium, methyllithium or phenyllithium mostly being used here. The synthesis of such lithium aromatics and lithium aliphatics is technically complex and requires a great deal of know-how, as a result of which methyl lithium, n-butyllithium, s-butyllithium, tert-butyllithium, phenyllithium and similar molecules are only offered at very high prices - measured on an industrial scale. This is the most important, but by no means the only disadvantage of these otherwise very advantageous and widely usable strong bases. Alkali metal hydrides are cheaper, but because of their considerably lower basicity they have the disadvantage of a considerably smaller range of applications.

Due to the extreme sensitivity and pyrophoric nature of lithium organyls in concentrated solutions, very large logistical systems for transport, feeding into the dosing template and dosing are required for the sizes desired in large industrial production (annual production quantities between 5 and 500 tons). The same applies to the alkali metal hydrides, which are also pyrophoric in their pure form and are frequently phlegmatized with mineral oil. The processing of these solids, which are very poorly soluble in organic solvents, under the corresponding conditions is a problem that is hardly technically solved.

Furthermore, the deprotonation of H-acidic compounds with methyllithium methane gas and the use of n-, s- and tert-butyllithium butanes, which are also gaseous at room temperature and escape the reaction mixtures during the reaction or during the required hydrolytic work-ups. As a result, complex exhaust gas purifications or corresponding are also required Combustion devices 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. The use of phenyllithium, on the other hand, leads to the development of human carcinogenic benzene, which often precludes technical use. Alternatives such as 4-tolyllithium are hardly available on the market, especially not in the volume required for production tasks.

Working with alkali metal hydrides is even more difficult than with the lower alkyl lithium compounds, since their use produces hydrogen, which in addition to the exhaust air problem (risk of oxyhydrogen gas formation) leads to material damage, especially at high temperatures. Embrittlement of metals due to diffusion and storage.

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

Hydrocarbons and ether-hydrocarbon mixtures. 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. This also applies to the mineral oil in which the alkali metal hydrides are usually supplied. For large-scale industrial production, however, the recycling of the solvents used is an essential requirement.

For the reasons mentioned, it would therefore be very desirable to have a process in which an alkyl lithium compound to be used for deprotonation, which avoids the disadvantages mentioned as far as possible, is produced in an ether from the cheap raw materials haloalkane or haloaromatic and lithium metal and at the same time or subsequently with the one to be deprotonated Substrate is implemented because this procedure could avoid all of the above-mentioned disadvantages of the "classic" production of the lithium compounds mentioned.

The present invention solves all of these problems and relates to a method for forming heteroatom-carbon bonds, a lithium compound (II) being first generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, which compound is then used to deprotonate the compounds (III ) or (V) is used, and the resulting lithium salts of the formulas (IV) or (VI) are finally linked with suitable carbon electrophiles to form the heteroatom-carbon bond and form the products (VIII) or (VIII) for the reaction brought (equation I).

Step 1: creating the base lithium

R-Ha! R - Li I II

Step 2: deprotonation of the substrate

R - Li R1 - Xr-H R1 - X - Li

IN IV

R1

^R1 \

R - Li XM - H X

/ ² /, ² - Li

R2 R2 VI

Step 3: implementation with an electrophile

electrophile

R1 - X - Li R1 - X-El

IV VII

^R1 \ R1

XM - Li electrophile

/ ² X— El

R2 R2

VI VIII

(EQUATION I)

R stands for methyl, primary, secondary or tertiary branched and unbranched alkyl radicals having 1 to 20 carbon atoms, phenyl, aryl and heteroaryl radicals, substituted by a radical from the group {methyl, primary, secondary or tertiary alkyl, phenyl Phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio} substituted alkyl, substituted or unsubstituted cycloalkyl having 3 to 8 C atoms,

Shark = fluorine, chlorine, bromine or iodine, Xi represents an oxygen or sulfur bound by a single bond to R1 or an sp2-hybridized nitrogen bound by a double bond to R1, and X _{2 represents} an sp3-hybridized nitrogen,

the R 1 and R ₂ radicals independently of one another represent substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl, alkenyl or alkynyl radicals having 1 to 20 C atoms, substituted cyclic or acyclic alkyl groups, acyl groups , Alkoxy, aryloxy, dialkylamino, alkylamino, arylamino, diarylamino, alkylarylamino, imino, sulfone, sulfonyl, phenyl, substituted phenyl, alkylthio, diarylphosphino,

Dialkylphosphino, alkylarylphosphino, dialkyl- or diarylaminocarbonyl, monoalkyl- or monoarylaminocarbonyl, alkylarylaminocarbonyl, alkoxyalkyl, carboxylate, alkyl carboxylate, CN or CHO, heteroaryl}, where two adjacent radicals R 1 and R ₂ together can correspond to an aromatic or aliphatic ring.

Preferred compounds of formula (III) which can be reacted by the process according to the invention are e.g. Alcohols, thiols, phenols, thiophenols, oximes, hydrazones, preferred compounds of formula (V) are e.g. Amines, carboxamides, sulfonamides and hydrazines, to name but a few.

The lithium organyls prepared in this way can be reacted with any electrophilic compounds by methods of the prior art. By reaction with carbon electrophiles, for example, alkylations to ethers, thioethers, secondary and tertiary amines etc. can be carried out or semi-acetals and their secondary products as well as esters, acid amides and carbonyl derivatives can be prepared by carbonyl additions.

The carbon electrophiles come in particular from one of the following categories (the product groups in brackets):

Aryl or alkyl cyanates, isocyanates (carbonic acid derivatives) Oxirane, substituted oxiranes (2-hydroxyethers, amines, thioethers, etc.) aziridines, substituted aziridines (2-aminoethers, amines, thioethers, etc.) imines, aldehydes, ketones (hemiacetals, aminals, thioacetals, etc.) organic halogen compounds, triflates, other sulfonates, sulfates (substitution products / alkylation products) ketenes (carboxylic acid derivatives) carboxylic acid chlorides (carboxylic acid derivatives) carboxylic acid esters, thioesters and amides (carboxylic acid derivatives) carbonic acid esters and phosgene derivatives (carboxylic acid derivatives)

All available or producible fluorine, chlorine, bromine or iodine compounds can be used as halogen aliphates or aromatics, since lithium metal in ethereal solvents reacts easily and in almost all cases with quantitative yields with all halogen aromatics and aliphates. 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 workups as HF. In special cases, however, such halides can also be used advantageously.

In the process according to the invention, preference is given to using alkyl or aryl halides which can be converted to liquid alkanes or aromatics after deprotonation. Chloro- or bromocyclohexane, benzyl chloride, tert-butyl chloride, chlorhexanes, chlorheptanes or chloroctanes as well as chloro- and bromobenzenes, -toluenes and -xylenes are particularly preferably used.

The reaction is carried out in a suitable organic solvent; ethereal solvents, for example tetrahydrofuran, dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether, glyme, diglyme, dibutyl diglyme or anisole are preferred, tetrahydrofuran is particularly preferably used.

Another advantage of the method according to the invention is that it is possible to work with organolithium compounds at very high concentrations. Concentrations of the aliphatic or aromatic intermediates of formula (II) of 5 to 30% by weight, in particular 12 to 25% by weight, are preferred.

In the preferred embodiment, halogen compound (R-Hal) and substrate to be deprotonated (III or IV) are metered in simultaneously or as a mixture to lithium metal in the ether. In this one-pot variant, the organolithium compound first forms, which then immediately deprotonates the substrate. However, it is also possible (particularly useful if the substrate can undergo side reactions with metallic lithium) to first generate the organolithium compound in ether by reaction of the halogen compound and lithium and only then to add the substrate.

Because of the high reactivity of alkyl and aryllithium compounds, in particular also towards the ethers used as solvents, the preferred reaction temperatures are in the range from -100 to +70 ° C, and temperatures from -80 to -25 ° C are particularly preferred when deprotonation not at the same time as the lithiation, but in a second step. In the variant of simultaneous lithiation and deprotonation, the particularly preferred temperature range is between -40 and +40 ° C.

Surprisingly, we have found that in the preferred embodiment as a one-pot, significantly higher yields and shorter reaction times are observed in many cases than when RLi is first generated and only then is the substrate to be deprotonated added.

In the present process, the lithium can be used as a dispersion, powder, chips, sand, granules, pieces, bars or in some other form, the size of the lithium particles not being quality-relevant but merely influencing the reaction times. Smaller particle sizes are therefore preferred, for example granules, powders or dispersions. The amount of lithium added is 1.95 to 2.5 mol, preferably 1.98 to 2.15 mol, per mole of halogen to be reacted. In all cases, organic redox systems by adding, for example biphenyl, 4,4 ^{'-di-tert-butylbiphenyl} or anthracene, substantial increases in reaction rates are observed. The addition of such systems proved to be particularly advantageous when the lithiation times were> 12 h without this catalysis.

Substrates that can be used for deprotonation are initially all oxygen, sulfur and nitrogen compounds which carry a sufficiently acidic hydrogen atom on the corresponding heteroatom in order to be deprotonated under the reaction conditions.

All alcohols, thiols and non-tertiary amines are to be mentioned here first. The basicity of the organolithium compound formed is sufficient in almost every case to deprotonate these compounds. Compounds (III) or (V) are particularly easy to deprotonate if they have groups R1 and R2 which are able to stabilize the resulting negative charge through mesomeric and / or inductive effects. This affects e.g. Carboxamides, arylamines, phenols, thiophenols, naphthols and conjugated oximes, hydrazones etc.

The lithium compounds generated according to the invention can be converted using the methods familiar to the person skilled in the art with electrophilic carbon compounds (electrophilic) to give products with newly formed heteroatom-carbon bonds which are of great interest for the pharmaceutical and agrochemical industry.

The workups 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. To achieve the best yields, the pH of the product to be isolated is adjusted here. 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 between 70 and 99%, typical yields are in particular 80 to 95%.

The method according to the invention opens up a very economical method for the transformation of acidic hydrogen into any residues in a highly selective, economical way.

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

example 1

Production of 2-furylmethyl propargyl ether from furylmethanol and

Propargyl bromide (two-step procedure)

A suspension of 1.45 g (0.210 mol) lithium granules in 170 ml

Tetrahydrofuran is cooled to -35 ° C and 13.29 g (0.105 mol) of 4-chlorotoluene are slowly added. The mixture is stirred at this temperature until the conversion of the 4-chlorotoluene is at least 97% a / a It. GC (approx. 8 h). 9.81 g (0.100 mol) of 2-furylmethanol are added, the mixture is allowed to warm to room temperature, 14.28 g (0.120 mol) of propargyl bromide are added and the mixture is boiled under reflux for 2 h. To

Cooling, the reaction mixture is shaken with 100 ml of 2N hydrochloric acid and the phases are separated. The aqueous phase is re-extracted twice with 50 ml of toluene, the combined organic phases are concentrated and the crude product in vacuo at max. Distilled 70 ° C over a Vigreux column. 12.66 g (0.093 mol, 93%) of 2-prop-2-ylyloxymethyl-furan are obtained in an HPLC purity of> 97% a / a.

Example 2

Preparation of N'-benzylidene-N-phenylhydrazinecarboxylic acid methyl ester (acylation of benzaldehyde-phenylhydrazone, one-pot variant)

A suspension of 1.45 g (0.210 mol) of lithium granules in 150 ml of tetrahydrofuran and 19.63 g (0.100 mol) of benzaldehyde phenylhydrazone is mixed with 15.61 g (0.105 mol) of octyl chloride at -40 ° C. and at - 30 ° C stirred until the conversion of the octyl chloride It. GC at min. 97% a / a is (approx. 8 h). Then 11.34 g (0.120 mol) of methyl chloroformate are added dropwise and the reaction mixture is stirred at 0 ° C. for 30 minutes. The reaction mixture is hydrolyzed with 100 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml of toluene. The combined organic phases are concentrated and the crude product is recrystallized from ethanol. The product is obtained in the form of colorless, flake-like crystals with a yield of 20.85 g (0.082 mol, 82%) and an HPLC purity of> 98.5% a / a. Example 3

Production of N, N-diphenyl-carbamic acid methyl ester from diphenylamine

(One-pot version, catalyzed lithiation)

16.92 g (0.100 mol) of diphenylamine, 25 mg of biphenyl as redox catalyst and 1.45 g (0.105 mol) of lithium granules are added to 150 ml of tetrahydrofuran and the resulting suspension is cooled to -25 ° C. 13.29 g (0.105 mol) of 4-chlorotoluene are added dropwise over 60 min. The mixture is stirred until the GC conversion control indicates a conversion of> 97% a / a (approx. 4 h), and 11.34 g (0.120 mol) are then added dropwise to the reaction mixture.

Methyl chloroformate. The reaction mixture is warmed to room temperature, the solvent and unreacted chloroformate are distilled off and the residue is fractionated through a short column. 19.77 g (0.087 mol, 87%) of the N, N-diphenylcarbamic acid methyl ester are obtained.

Example 4

Production of dihexyl thioether from hexanethiol and bromhexane

1.45 g (0.105 mol) of lithium granules are suspended in a solution of 50 mg of biphenyl in 150 ml of tetrahydrofuran. 13.29 g (0.105 mol) of the technical isomer mixture of the monochlorotoluenes are added dropwise at -30 ° C. and the reaction mixture is stirred at this temperature until the lithium granules have largely dissolved (about 6 h). Then 11.82 g (0.100 mol) of hexanethiol are added dropwise, the reaction mixture is warmed to 0 ° C., 16.51 g (0.100 mol)

Bromohexane added and boiled under reflux until GC conversion control shows complete conversion. The cooled reaction mixture is extracted with 50 ml of water, the aqueous phase is re-extracted with 50 ml of toluene and the combined organic phases are concentrated. The residue is distilled in vacuo. 17.81 g (0.085 mol, 85%) of the dihexylthioether are obtained with a GC purity of> 98%. Example 5

Production of benzyl N-benzyl-N-benzenesulfonylcarbamate from

N-Benzylbenzolsulfonamid

A suspension of 1.45 g (0.210 mol) lithium granules in 150 ml

Tetrahydrofuran and 24.73 g (0.100 mol) of N-benzylbenzoisulfonamide are added dropwise at -40 ° C. with 13.29 g (0.105 mol) of 4-chlorotoluene and stirred at this temperature until the conversion of the tolyl chloride according to GC minute 97% a / a lies (approx. 6 h). Then 11.34 g (0.120 mol) of benzyl chloroformate are added dropwise and the reaction mixture is stirred overnight at room temperature. The reaction mixture is hydrolyzed with 100 ml of water, the phases are separated and the aqueous phase is re-extracted with 100 ml of toluene. The combined organic phases are concentrated and the residue is purified by flash chromatography. 26.30 g (0.069 mol, 69%) of the product with an HPLC purity of> 96% are obtained.

Claims

claims:

1. A process for forming heteroatom-carbon bonds, a lithium compound (II) initially being generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, which is then used to deprotonate the compounds (III) or (V), and the resulting lithium salts of the formulas (IV) or (VI) are finally reacted with suitable carbon electrophiles by forming the heteroatom-carbon bond and forming the products (VIII) or (VIII) (equation I).

Step 1: creating the base

Lithium R-Hal * - R— Li

I II

Step 2: deprotonation of the substrate

R - Li + R1 - X _r H ^ R1 - X Li II III IV

R1 R1

\ \

R— Li + X -j2 - H ■ ■> - X Λ ₂ - L l_il

R2 R2

II V VI

Step 3: Implementation I with an electrophile

electrophile

R1 - X - Li R1 - X _r EI

IV VII

R1 R1 X— Li electrophile X— El

R2 R2

VI VIII

(EQUATION I) R stands for methyl, primary, secondary or tertiary branched and unbranched alkyl radicals having 1 to 20 carbon atoms, phenyl, aryl and heteroaryl radicals, substituted by a radical from the group {methyl, primary, secondary or tertiary alkyl, phenyl Phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio} substituted alkyl, substituted or unsubstituted cycloalkyl having 3 to 8 C atoms;

Shark = fluorine, chlorine, bromine or iodine,

Xi stands for an oxygen or sulfur bound by a single bond to R1 or an sp2-hybridized nitrogen bound by a double bond to R1, and X ₂ for an sp3-hybridized nitrogen;

the R 1 and R ₂ radicals independently of one another represent substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl, alkenyl or alkynyl radicals having 1 to 20 C atoms, substituted cyclic or acyclic alkyl groups, acyl groups , Alkoxy, aryloxy, dialkylamino, alkylamino, arylamino, diarylamino, alkylarylamino, imino, sulfone, sulfonyl, phenyl, substituted phenyl, alkylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, dialkyl- or diarylaminocarbonyl,

Monoalkyl or monoarylaminocarbonyl, alkylarylaminocarbonyl, alkoxyalkyl, carboxylate, alkyl carboxylate, CN or CHO, heteroaryl}, where two adjacent radicals R 1 and R ₂ together can correspond to an aromatic or aliphatic ring.

2. The method according to claim 1, characterized in that as compounds of the formula (III), preferably alcohols, thiols, phenols, thiophenols, oximes, hydrazones, and as compounds of the formula (V) preferably amines, carboxamides, sulfonamides and hydrazines become.

3. The method according to claim 1 or 2, characterized in that a compound from the following group is used as an electrophile: or Alkyl cyanates, isocyanates, oxirane, substituted oxiranes, aziridines, substituted aziridines, imines, aldehydes, ketones, organic halogen compounds, triflates, other sulfonates, sulfates, ketenes, carboxylic acid chlorides, carboxylic acid esters, thioesters and amides, carbonic acid esters and phosgene derivatives.

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

5. The method according to at least one of the preceding claims, characterized in that the reaction temperature is in the range of -100 to + 70 ° C.

6. The method according to at least one of the preceding claims, characterized in that the concentrations of the aliphatic or aromatic

Intermediates of formula (II) is in the range of 5 to 30% by weight.

7. The method according to at least one of the preceding claims, characterized in that the amount of lithium added per mole of converted halogen is 1.95 to 2.5 moles.

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