EP1744999A1

EP1744999A1 - Method for the production of aldehydes and ketones by oxidising primary and secondary alcohols with alkylphosphonic acid anhydrides

Info

Publication number: EP1744999A1
Application number: EP05737845A
Authority: EP
Inventors: Andreas Meudt; Stefan Scherer; Claudius BÖHM
Original assignee: Archimica GmbH
Current assignee: Euticals GmbH
Priority date: 2004-04-22
Filing date: 2005-04-18
Publication date: 2007-01-24
Also published as: JP2007533688A; DE102004020189A1; US20070191645A1; US7262328B1; WO2005102978A1

Abstract

The invention relates to a method for the production of a.) aldehydes of formula (II): R<1_> CHO and b.) aldehydes of formula (III): R<1_> C(O) <_> R<2> by reacting a.) primary alcohols (R<1>CH2-OH) or b.) secondary alcohols (R<1>-CH(OH)-R<2>) with cyclic phosphonic acid anhydrides in the presence of dialkyl-, diaryl- and/or alkyl-aryl sulphonic oxides at a temperature in the region of between -100 to + 120 DEG C, whereby R<1> and/or R<2> represent H, a substituted linear or branched C1-C12-alkyl radical, a substituted C3-C10 cycloalkyl-, alkenyl-, aryl- or heteroaryl radical. A cyclic phosphonic acid anhydride is used, preferably, as a 2,4,6-substituted 1,3,5,2,4,6-trioxatriphosphinane of formula (I), wherein R' independently represents allyl, aryl or open-chained or branched C1 - C12-alkyl-radicals. Optionally, the reaction can be carried out in the presence of a tertiary amine base NR<5>3.

Description

description

Process for the preparation of aldehydes and ketones by oxidation of primary and secondary alcohols with alkylphosphonic anhydrides

Aldehydes and ketones are important and extremely versatile intermediates in organic synthesis. Both classes of compounds show a high reactivity of the C, O double bond, which enables countless carbonyl reactions. The importance in modern organic synthesis is only limited by the accessibility of this

Connection classes restricted. Standard processes for the production of aldehydes and ketones are oxidations of corresponding alcohols, using countless methods such as catalytic vapor phase dehydrogenation or direct oxidation with molecular oxygen. In addition, reagents such as subhalogenous acids,

Heavy metal compounds such as silver carbonate, lead oxide, lead acetate, chromium oxides, ruthenates or even dimethyl sulfoxide can be used.

In modern organic synthesis, the importance of chemo-, regio- and stereoselective reagents is exploding. For example, if you want to convert a certain alcohol functionality into an aldehyde from a complex molecule with numerous functional groups, many of the methods mentioned, such as e.g. B. from the catalytic vapor phase dehydrogenation and direct oxidation with molecular oxygen from selectivity reasons. The use of subhalogenous acids is also restricted, since undesirable side reactions such as overoxidation, halogenation or esterification also occur, accompanied by sometimes low yields. In addition to the occurrence of by-products and overoxidation, the oxidation of primary alcohols to aldehydes or secondary alcohols to ketones with heavy metal compounds is always linked to the toxicity of the oxidizing agents. A highly selective problem solution for the conversion of primary and secondary alcohols into the corresponding aldehydes and ketones, which can also be used in complex multifunctional molecules, has hitherto been lacking. Although the known reagents can bring about the desired transformations, other groupings are often also influenced in the process. In many cases, the drastic conditions required even remote stereo centers are epimerized. Furthermore, the method to be developed should be free of heavy metals. In addition, the transformation should be applicable under very mild conditions and the separation of the secondary products of the reagent used should be very simple.

It would therefore be very desirable to have a process which can convert primary and secondary alcohols into the corresponding aldehydes or ketones by oxidation, but at the same time has very mild reaction conditions and simplified work-up, and can also be used in economically usable processes. The known reagents do not solve this problem, as will be demonstrated in a few examples: DMSO in combination with acetic anhydride can accomplish the reactions mentioned, but this method has only a limited application, since in most cases low yields are obtained. Often, by-products are produced in significant quantities primarily through a Pummerer rearrangement. The oxidation of primary alcohols to aldehydes with DMSO in combination with trifluoroacetic anhydride can lead to explosions and must therefore be carried out at low temperatures at which many complex molecules or natural products are often no longer sufficiently soluble. The oxidation of primary alcohols with DMSO and thionyl chloride or oxalyl chloride must also be carried out at low temperatures. However, these reagents can no longer be used if the molecules to be oxidized contain functional groups which can react with thionyl chloride or oxalyl chloride. DCC can also be used to carry out the desired transformation into aldehydes. However, the dicyclohexylurea formed as a secondary product can often hardly be separated from the product or can only be separated by increased cleaning effort. The use of water-soluble DCC derivatives is mostly characterized by their very high price, the instability of the intermediates in the oxidation and reduced effectiveness of the oxidizing agent.

Surprisingly, it was found that the combination of cyclic 2,4,6-substituted 1, 3,5,2,4,6-trioxatriphosphinanes and sulfoxides solves all of these problems. This combination is a highly selective oxidation method for the conversion of primary alcohols into the corresponding aldehydes as well as from secondary alcohols into the corresponding ketones, whereby the desired freedom from epimerization and maximum regio- and stereoselectivity are observed with at the same time almost quantitative yields.

The present invention thus relates to a highly selective process for the preparation of a.) Aldehydes of the formula (II) and b.) Ketones of the formula (III) R ¹ - CHO (II) R ¹ - C (O) - R ² (III )

by reaction of a.) primary alcohols (R ¹ CH ₂ - OH) or b.) secondary alcohols (R ¹ - CH (OH) - R ² )

with cyclic alkylphosphonic anhydrides in the presence of dialkyl, diaryl or alkyl aryl sulfoxides and optionally an amine base NR ₃ , in one

Temperature in the range of -100 to + 120 ° C, wherein R ¹ and / or R ² for an optionally substituted linear or branched C ₁ -C 2 -alkyl radical, substituted C3-C ₁ 0 cycloalkyl, alkenyl, aryl or

Heteroaryl remains.

In a preferred embodiment according to the invention, the cyclic phosphonic anhydride is a 2,4,6-substituted 1,3,5,2,4,6-trioxatriphosphinan of the formula (I)

(I)

wherein R 'independently of one another is allyl, aryl or open-chain or branched Ci to Ci ₂ alkyl radicals, in particular CrC ₈ alkyl radicals.

Particularly preferred are phosphonic anhydrides of formula (I) in which R 'is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, pentyl, hexyl, especially ethyl, propyl and / or butyl -Rest is there.

The oxidation to aldehydes (II) and ketones (III) can in general be carried out at temperatures in the range from -100 to + 120 ° C., temperatures in the range from -30 to + 30 ° C. are preferred, lower temperatures in general are correlated with higher selectivities. The reaction time depends on the temperature used and is generally 1 to 12 hours, in particular 3 to 6 hours.

Dialkyl, diaryl or alkyl aryl sulfoxides of the formula (IV) R ³ - S (O) - R ⁴ (IV) are generally used as sulfoxides

used, R ³ and R ⁴ independently of one another for al yi, aryl or open-chain, cyclic or branched Ci to C ^ alkyl radicals, aryloxy, allyloxy or alkoxy with open-chain, cyclic or branched Ci to C ₁₂ alkyl radicals or is a combination of the named substituents.

Sulfoxides of the formula (IV) in which R ³ or R ^{4 are} methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, pentyl, hexyl, Phenyl is in particular a methyl and / or phenyl or a combination of the substituents mentioned.

The addition of amines is generally not necessary, but may prove advantageous in individual cases. Amines of the formula (V) NR ⁵ ₃ (V) are generally used as amines, where R ⁵ for H, allyl, aryl or open-chain, cyclic or branched Ci to Ci ₂ alkyl radicals, aryloxy, allyloxy or alkoxy with open-chain , cyclic or branched Ci to C ₂ alkyl radicals or a combination of the substituents mentioned.

Amines of the formula (V) are particularly preferred in which R ^{5 is} an H, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, pentyl, hexyl, phenyl, in particular an H, ethyl, n- Propyl, isopropyl, n-butyl, 2-butyl, isobutyl or phenyl or a combination of the substituents mentioned.

The cyclic phosphonic anhydride can be added to the reaction medium either as a melt or as a liquid mixture dissolved in a solvent. Suitable solvents are those which do not give rise to any side reactions with the phosphonic anhydride; these are all aprotic organic solvents, e.g. Ligroin, butane, pentane, hexane, heptane, octane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, dichloromethane, i chloroform, carbon tetrachloride, 1,2-dichloroethane, 1, 1,2,2-tetrachloroethane, methyl acetate, ethyl acetate, propyl acetate , Butyl acetate, dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, diethyl ether, diisopropyl ether, tert-butyl methyl ether, THF, dioxane, acetonitrile or mixtures thereof, dichloromethane, chloroform, ethyl acetate are particularly preferred,

Propyl acetate, butyl acetate, dimethylformamide, diethylformamide,

Dimethylacetamide, diethylacetamide, diisopropyl ether, tert-butyl methyl ether, THF,

Dioxane, acetonitrile or mixtures of these, are very particularly preferred Dichloromethane, chloroform, ethyl acetate, butyl acetate, dimethylacetamide, tert-butyl methyl ether, THF, dioxane, acetonitrile or mixtures thereof, particularly preferred are THF, ethyl acetate or butyl acetate. The phosphonic anhydride is generally added at least three-stoichiometrically with respect to the starting compound, but can also be more than stoichiometric, for example in the ratio 1 alcohol: 1.2 T3P® (cyclic propanephosphonic anhydride). The reactions are preferably carried out in such a way that the corresponding alcohol is initially introduced in a solvent, then a dialkyl, diarylsulfoxide or alkyl-Ar 1-sulfoxide, for example DMSO (dimethyl sulfoxide), is added and the temperature is preferably brought to the reaction temperature before the addition of phosphonic anhydride , The alcohol is then converted into the desired aldehyde or the desired ketone by metering in the phosphonic anhydride as a melt or solution in one of the abovementioned solvents.

The reaction product is preferably isolated by hydrolysis and simple phase separation, since the secondary products of the phosphonic anhydrides are generally very readily water-soluble. Depending on the nature of the product to be isolated, subsequent extractions may also be necessary. The phosphonic anhydride secondary product formed often does not interfere with subsequent reactions, so that the direct use of the reaction solutions obtained often gives very good results. - - - -

All of the named procedures are distinguished by very good yields (typically 90-100%, in particular> 95%) with simultaneous absence of side reactions and epimerizations. The selectivities of the reaction according to the invention are in the range of 99-100%, in particular> 99.5%.

The process according to the invention is to be illustrated by the following examples, without restricting the invention thereto: Example 1: Oxidation of benzyl alcohol to benzaldehyde

1 mol of benzyl alcohol is placed in 50 ml of ethyl acetate and 50 ml of DMSO and cooled to 0 ° C. 1.2 mol of T3P solution in ethyl acetate (50% w / w) is metered in while maintaining the reaction temperature, and stirring is then continued for a further three hours at this temperature. At this time, the reaction GC showed 100% conversion. After warming to room temperature, 180 ml of water were added and the phases were separated. After the solvent had been condensed off, the benzaldehyde remained in a yield of 97%, HPLC purity 98% (a / a).

Example 2: Oxidation of 3-buten-1-ol to 3-butenal

0.1 mol of 3-buten-1-ol is placed in 50 ml of ethyl acetate and 50 ml of DMSO are introduced and cooled to 0 ° C. 0.12 mol of T3P solution in ethyl acetate (50% w / w) are metered in while maintaining the reaction temperature, followed by stirring at this temperature for a further two hours. At this time, the reaction GC showed> 99% conversion. After warming to room temperature, 25 mL water were added and the phases were separated. The organic phase was distilled. The isolated yield of this reaction was 96%.

Example 3: Oxidation of 2-butanol to 2-butanone

1 mol of 2-butanol is placed in 50 mL butyl acetate and 50 mL DMSO and cooled to 0 ° C. 1.2 mol of T3P solution in butyl acetate (50% w / w) are metered in while maintaining the reaction temperature, followed by stirring at this temperature for a further three hours. At this time, the reaction GC showed 100% conversion. After warming to room temperature, 180 ml of water were added and the phases were separated. The organic phase was distilled. The isolated yield was 97%. Example 4: Oxidation of N- (tert-butyloxycarbonyl) threonine methyl ester to Boc- (S) - o (-acetylg lyci n methyl ester

1 mol of N- (tert-butyloxycarbonyl) threonine methyl ester is placed in 50 ml of ethyl acetate and 50 ml of DMSO and cooled to 0 ° C. 1.2 mol of T3P solution in ethyl acetate (50% w / w) are metered in while maintaining the reaction temperature, and stirring is then continued for a further three hours at this temperature. At this time, the reaction GC showed 100% conversion. After warming to room temperature, 180 ml of water were added and the phases were separated. The aqueous phase was extracted twice with dichloromethane. After drying the combined organic phases over MgSO 4 and distilling off the solvents as gently as possible, the product remained in a yield of 97%.

Claims

claims:

1. Process for the preparation of a.) Aldehydes of the formula (II) and b.) Aldehydes of the formula (III)

R ¹ - CHO (II) R ¹ - C (O) - R ² (III)

by reacting a.) primary alcohols (R ¹ CH ₂ - OH) or b.) secondary alcohols (R ¹ - CH (OH) - R ² ) with cyclic phosphonic anhydrides in the presence of dialkyl, diaryl and / or alkyl aryl sulfoxides at a temperature in the range of -100 to + 120 ° C,

where R ¹ and / or R ^{2 represents} a substituted linear or branched C1-C ₁₂ alkyl radical, a substituted C ₃ -C ₁₀ cycloalkyl, alkenyl, aryl or heteroaryl radical.

2. The method according to claim 1, characterized in that the cyclic phosphonic anhydride is a 2,4,6-substituted 1,3,5,2,4,6-trioxatriphosphinane of the formula (I),

(I)

wherein R 'independently of one another is allyl, aryl or open-chain or branched Ci to C ₁₂ alkyl radicals.

3. The method according to claim 2, characterized in that R 'for a methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, pentyl, hexyl, in particular an ethyl, propyl and / or butyl -Rest is there.

4. The method according to at least one of the preceding claims, characterized in that the cyclic phosphonic anhydride is added either as a melt or dissolved in a solvent to the reaction solution.

5. The method according to claim 4, characterized in that the cyclic phosphonic anhydride is added in an aprotic solvent.

6. The method according to at least one of the preceding claims, characterized in that the reaction solution is heated to the reaction temperature before adding the phosphonic anhydride.

7. The method according to at least one of the preceding claims, characterized in that a sulfoxide of the formula (IV) is used R ³ - S (O) - R ⁴ (IV)

wherein R ³ and R ⁴ independently of one another for allyl, aryl or open-chain, cyclic or branched Ci to Ci ₂ -alkyl radicals, aryloxy, allyloxy or alkoxy with open-chain, cyclic or branched Ci to Cι ₂ -alkyl radicals or a combination of the named substituents. .

8. The method according to at least one of the preceding claims, characterized in that the reaction is carried out in the presence of an amine base of the formula (V) NR ⁵ ₃ (V)

used, wherein R ^{5 is} H, allyl, aryl or open-chain, cyclic or branched Ci to Ci ₂ alkyl radicals, aryloxy, allyloxy or alkoxy with open-chain, cyclic or branched Ci to Ci ₂ alkyl radicals or a combination of the substituents mentioned.

9. The method according to at least one of the preceding claims, characterized in that the phosphonic anhydride is used in relation to the starting compound third-stoichiometric to over-stoichiometric.