WO2004002980A2

WO2004002980A2 - Method for synthesizing coumarin and the derivatives thereof

Info

Publication number: WO2004002980A2
Application number: PCT/EP2003/006987
Authority: WO
Inventors: Wolfgang Hölderich; Monika Cornelia WISSLER
Original assignee: Grünenthal GmbH
Priority date: 2002-07-01
Filing date: 2003-07-01
Publication date: 2004-01-08
Also published as: AU2003246651A1; DE10229462A1; WO2004002980A3

Abstract

The invention relates to an environmentally friendly, heterocatalytic method for synthesizing coumarins based on phenols and carboxylic acids/carboxylic acid derivatives or ß-keto carboxylic acids/carboxylic acid derivatives. Alkylation of the aromatic phenol ring is assisted by an additional functional group of the carboxylic acids/carboxylic acid derivatives while the coumarin unit is formed. High yields can be obtained by using Nafion-silica composite materials. Particularly silica composites that are loaded with 20 to 80 percent of Nafion have a very high activity (compared with pure Nafion resin) due to the high number of acidic cores in connection with the improved active surface thereof. An efficient Pechmann reaction can be carried out by simple preparation in toluene, the catalyst being recyclable and/or regenerable.

Description

Patent application of Grünenthal GmbH, D-52078 Aachen (own sign: GRA 3206)

Process for the synthesis of coumarin and its derivatives

The present application relates to the synthesis of coumarins by reacting various phenols with carboxylic acids / carboxylic acid derivatives or y #-keto-carboxylic acids / carboxylic acid derivatives in the presence of Nafion-silica composite materials, deloxane and narrow-pore zeolites as heterogeneous catalysts.

State of the art

Coumarin and its derivatives are widely used in the perfume, dye, pharmaceutical and agro industries. At the end of the 19th century, numerous synthetic methods for their production were developed, which differ in different starting reagents and mechanisms. Syntheses based on phenols and y # keto esters (Pechmann reaction) [H. von Pechmann, C. Duisberg, Chem. Ber., 1883, 16, 2119; H. von Pechmann, Chem. Ber., 1884, 17, 929], from o-Cresol (Raschig reaction) [F. Raschig, Ger. Pat, 1909, 223, 684] and salicylaldehyde (Perkin Reaction / Knoevenagel) [W. H. Perkin, J. Chem. Soc, 1887, 31, 388; E. Knoevenagel, Chem Ber., 1896, 29, 172] have proven themselves. These methods are based on the use of classic acids, such as. B. sulfuric acid, phosphorus pentoxide, trifluoroacetic acid, aluminum chloride, zinc chloride and alcoholic HCI solutions. The replacement of these non-regenerable homogeneous catalysts with heterogeneous acids is necessary with regard to environmental protection and reduces processing steps while at the same time small amounts of the by-products and waste products. In contrast, heterogeneous catalysts can often be regenerated and recycled.

The increasing demand for important fluorescent coumarin derivatives is more and more in line. with the development of new biological processes based on the use of such coumarin derivatives. For example, hydroxy-substituted coumarins are used for the production of fluorescent colorants and enzyme substrates. Particularly noteworthy is 7-hydroxy-4-methylcoumarin, also known as 4-methylumbelliferone, an important starting material for the synthesis of numerous fluorine-containing enzyme substrates. Phosphorilation of the 7-hydroxy function leads to phosphoric acid monoester (MUP) [US 5,830,912], which is used for the detection of enzymes. Furthermore, sulfonates of hydroxycu marines, which can be synthesized ^" by reaction of the latter with sulfonic acid derivatives [US 4,618,622], are used as active ingredients for the treatment of psychological disorders. 7-Hydroxy-4-rhethylcoumarin is also an important starting product for the preparation of the insecticide" hymecromone ". , ,

Carrying out the Pechmann reaction with conventional acids, such as. B. sulfuric acid, which is often used in excess, is known from a number of previous publications [H. Appel, J. Chem. Soc, 1935, 1031; L. L Woods and J. Sapp, J. Org. Chem., 1961, 26, 240]. The replacement of such catalyst systems with heterogeneous acids is important for economic and ecological reasons. First applications of solid acids in the Pechmann reaction include the use of pure Nafion resins [DD Chaudhari, Chem. Ind., 1983, 568] or Amberlyst 15 [AJ Hoefnagel, EA Gunnewegh, RS Downing, H. van Bekkum, J Chem. Soc. Chem. Commun., 1995, 225-226] as an acidic ion exchanger. Chaudhari reported a 90% yield of 7-hydroxy-4-methylcoumarin after a reaction time of 3.5 hours, which is not always a reproducible result. H. van Bekkum et al. further achieved yields of coumarins of up to 81% with H-beta zeolites [EA Gunnewegh, AJ Hoefnagel, RS Downing, H. van Bekkum, Recl. Trav. Chim. Pays-Bas, 1996, 115, 226-230]. With the first use of zeolites, the question of possible regenerability and traceability of the catalyst in the synthesis of coumarins was initiated. Zeolites can be regenerated by calcining and they also have higher TON (TON = turnover number) - compared to Amberlyst 15. Disadvantages when using zeolites are the relatively high amounts of catalyst (1.0 gram for 10 mmol substrate) and long contact times of at least 4 hours and the high production costs, combined with a high retail price. Further developments both in the homogeneous system with dilute sulfuric acid [V. Singh, J. Singh, KP Kaur, GL Kad, J. Chem. Research, 1996, 58-59] as well as with Amberlyst 15 in the solvent-free system [A. de la Hoz, A. Moreno, E. Vazquez, Synlett, 1999, 5, 608-610], which are associated with a reduction in the necessary contact time to up to 5 minutes, also use microwave radiation. The disadvantage of this method is the associated high process and investment costs.

Even with the use of montmorillonite in toluene, very high yields of coumarins were achieved (96%) [T.-S. Li, Z.-H. Zhang, F. Yang, C.-G. Fu, J. Chem. Research (S), 1998, 38-39], however, the disadvantage of longer reaction times and poor long-term stability also remain here.

Jacobs et al. [Y. V. Subba Rao, D.E. De Vos, P.A. Jacobs, Angew. Chem., 1997, 109, 2776] reported the synthesis of 3-cyanocoumarin in moderate yield (58%) with 1, 5,7-triazabicyclo [4,4,0] dec-5-ene, which can be found in MCM-41 is immobilized. The base-catalyzed synthesis of coumarins according to Knoevenagel with calcined, basic Mg-Al hydrotalcite led to very good yields of over 85% [A. Ramani, B.M. Chanda, S. Velu, S. Sivasanker, Green Chemistry, 1999, 1, 163]. Recently, Tanaka et al. [T. Sugino, K. Tanaka, Chem. Lett., 2001, 110-111] the synthesis of coumarins via Pechmann and Knoevenagel in a solvent-free system with p-toluenesulfonic acid and piperidine in catalytic amounts. They also achieved high yields of up to 98%. Disadvantages of this process are the strong tendency of p-toluenesulfonic acid to corrode and the environmental pollution caused by the formation of salts which are difficult to separate.

The object of the invention was therefore to find a new, inexpensive process for the preparation of coumarins.

The invention therefore relates to a process for the synthesis of coumarins from

Phenols and carboxylic acids and / or carboxylic acid derivatives and / or /? - keto-carboxylic acids and / or / 2-keto-carboxylic acid derivatives, in which the reactions are carried out in the presence of Nafion-silica composite materials and / or deloxane and / or narrow-pore zeolites , In a preferred embodiment of the process according to the invention, several reaction steps (transesterification / esterification, alkylation / hydroxyalkylation, dehydration) are carried out in one reaction step on Nafion-silica composite materials and / or narrow-pore zeolites as catalysts.

In a further preferred embodiment of the process according to the invention, the use of substituted phenols of the general formulas I and II

Formula I.

wherein R Rβ are independently selected from

H, OH; -Cι..ιo-alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; -OC- o-alky !, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; Aryl, aralkyl radicals or -O-aryl, each substituted or unsubstituted.

For the purposes of this invention, alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. C _{2 is} alkyl for C1 or C2 alkyl, C _1-3 alkyl for C1, C2 or C3 alkyl, C _1-4 alkyl for C1, C2, C3 or C4 alkyl , Cι _-5 alkyl of C1, C2, C3, C4 or C5-alkyl, Cι _-6 alkyl of C1, C2, C3, C4, C5 or C6 alkyl, C _{1 -7-} alkyl for C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, Cι _-8 -alkyl for C1-, C2-, C3-, C4-, C5-, C6- , C7- or C8-alkyl, Cι-1 ₀ alkyl for C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8, - C9- or C10- alkyl and C -, _ ι ₈ alkyl for C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16 -, C17 or C18 alkyl! _C3-4 -Cycloalkyl further stands for C3- or C4-cycloalkyl, C ₃ . _5- cycloalkyl for C3-, C4- or C5-cycloalkyl, C _3-6 -cycloalkyl for C3-, C4-, C5- or Cβ-cycloalkyl, C _3-7 -cycloalkyl for C3-, C4-, C5-, C6 or C7 cycloalkyl, C _3-8 cycloalkyl for C3, C4, C5, C6, C7 or C ^β cycloalkyl, C _4-5 cycloalkyl for C4 or C5 cycloalkyl, C _{4 -6-} Cycloalkyl for C4-, C5- or C6-cycloalkyl, C ₄ . _7- cycloalkyl for C4-, C5-, C6- or C7-cycloalkyl, C _5-6 -cycloalkyl for C5- or C6-cycloalkyl and C _5-7 -cycloalkyl for C5-, C6- or C7-cycloalkyl. With regard to cycloalkyl, the term also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O. The term cycloalkyl also includes, in particular, one or more, preferably mono, unsaturated cycloalkyls without a hetero atom in the ring, as long as the cycloalkyl is not an aromatic system. The alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, Pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF2, CF ₃ or CH2OH as well as pyrazolinone, oxopyrazolinone, [1, 4] dioxane or dioxolane.

In connection with alkyl and cycloalkyl - as long as this is not expressly defined otherwise - is understood by the term substituted in the sense of this

Invention the substitution of at least one (possibly also several)

Hydrogen residues (s) by F, Cl, Br, I, NH ₂ , SH or OH, where “multiply substituted” or “substituted” is to be understood in the case of multiple substitution that

Substitution takes place both on different and on the same atom several times with the same or different substituents, for example three times on the same C atom as in the case of CF ₃ or at different points as in the case of -CH (OH) -CH = CH-CHCI ₂ , Particularly preferred substituents here are F, Cl and OH. With regard to cycloalkyl, the hydrogen radical can also be substituted by OCι _-3- alkyl or C-ι-3-alkyl (each one or more times substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF ₃ , methoxy or ethoxy.

The term (CH ₂ ) ₃ - ₆ is -CH ₂ -CH ₂ -CH2-, -CH2-CH2-CH2-CH2-, -CH ₂ -CH ₂ -CH ₂ - CH ₂ -CH2- and CH ₂ - CH ₂ -CH ₂ -CH ₂ -CH2-CH2- to understand, under (CH ₂ ) ι _-4 is -CH ₂ -, - CH2-CH2-, -CH2-CH2-CH2- and -CH2-CH ₂ -CH ₂ -CH ₂ - to be understood as (CH ₂₎ ₄ - ₅ - CH2-CH2-CH2-CH2- and -CH2- To understand CH2-CH2-CH2-CH2-, etc.

An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.

A heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring, which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and can also be substituted once or more than once. Examples from the group of the heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1, 2.5] thiadiazole, benzothiazole, indole,

Benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline are listed.

In connection with aryl and heteroaryl, substituted is understood to mean the substitution of aryl or heteroaryl with R ²² , OR ²² a halogen, preferably

F and / or Cl, a CF3, a CN, a N0 ₂ , an NR ²³ R ²⁴ , a

Alkyl (saturated), a C-i.g-alkoxy, a C .g-cycloalkoxy, a C .s-cycloaikyl or a C2_g-alkylene.

The radical R ^{22 here stands} for H, a C- _j _ • ₎ r _j alkyl, preferably a C- ₎ _ρ alkyl, an aryl or heteroaryl or for a via C - ^ - alkyl, saturated or unsaturated, or a C - ^ - alkylene group-bonded aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,

The radicals R ²³ and R ^4, is H, a C _j same or different.-Jo alkyl, preferably a C ^ g alkyl, an aryl, a heteroaryl or a C ^ over _y Alkyl, saturated or unsaturated, or a C- _| , ₃ -AlkyJen group bound aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,

or the radicals R ²³ and R ²⁴ together represent CH2CH20CH ₂ CH ₂ ,

CH ₂ CH ₂ NR ²⁵ CH2CH2 or (CH ₂ ) ₃ . ₆ , and

the Rest.R ²⁵ is H, a C ^. ^ alkyl, preferably a C _j .g-alkyl, an aryl or heteroaryl radical or a C over _j. -Alkyl, saturated or unsaturated, or a C- _j . -Alkylene group-bound aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals.

In a further preferred embodiment of the process according to the invention it applies that in the substituted phenols of the general formula I and II R1-R4 and R5-R8 are identical or different and are identical to H and / or hydroxyl groups and / or AI koxy radicals with 1-10 C- Atoms, e.g. B.

Methoxy, ethoxy, propyloxy, butyloxy, 2-ethylbutyloxy, isobutyloxy / τ-butyl, pentyloxy and / or aralkyloxy radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B.

Benzyloxy, 1-phenylethyloxy, 2-methyl-phenylmethoxy, p-sulfobenzyloxy, p-nitrobenzyloxy, p-fluorobenzyloxy and / or alkyl radicals with 1-10 carbon atoms and / or haloalkyl radicals, e.g. B.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tetτ-butyl, pentyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl and / or alkenyl radicals with 1-10 C atoms, e.g. B.

Ethenyl, n-propenyl, isopropenyl, hexenyl, 3-methylpentenyl, 3-ethylbutenyl and / or aryl radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on aromatic ring, e.g. B. Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl,

Naphthyl, p-nitrophenyl, hydroxylphenyl and / or aralkyl radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B. benzyl, 1-phenylethyl, 2-phenylethyl, cumylmethyl, mesitylmethyl,

Fluorine, chlorine, bromine, cyano groups mean.

In a further preferred embodiment of the process according to the invention, carboxylic acids and / or carboxylic acid derivatives of the general formula III-V are used,

Formula III Formula IV

wherein R ₉ H; -C-Mo-alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; or aryl, substituted or unsubstituted; and Rio are an ethynyl group,

and Ri- _δ H; -Cι „ιo-alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; or aryl, substituted or unsubstituted;

mean.

In a further preferred embodiment of the process according to the invention, the following applies in the carboxylic acids and / or carboxylic acid derivatives of the general formula III -V,

R ₉ is H or an alkyl radical with 1 -10 C atoms, for example Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ter-butyl, pentyl or an aryl radical, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl,

Naphthyl and Rio an ethinyl residue and Rn. ₁₅ equal to H and / or alkyl radicals with 1-10 C atoms and / or haloalkyl radicals, for. B.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tetτ-butyl, pentyl,

Trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl and / or aryl radicals with alkyl and / or halogen and / or nitro and / or

Sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl,

Naphthyl, p-nitrophenyl, hydroxyphenyl, p-fluorophenyl groups

mean.

In a further preferred embodiment of the process according to the invention, Nafion-silica composite materials are used as acidic heterogeneous catalysts.

In a further preferred embodiment of the method according to the invention it is true that Nafion-silica composite materials with different proportions between 3% -98% of Nafion are used in the silica.

In a further preferred embodiment of the method according to the invention, the proportion of Nafion in the Nafion silica composite materials is preferably between 40% and 80%.

In a further preferred embodiment of the process according to the invention, the Nafion-silica composite materials used are synthesized in an “in situ” gel process by co-precipitation of Nafion particles with silica. In a further preferred embodiment of the process according to the invention, the catalysis is carried out in the liquid phase, in the reactants and / or in an organic solvent.

In a further preferred embodiment of the process according to the invention, the reaction is carried out with the addition of narrow-pore zeolites.

In a further preferred embodiment of the process according to the invention, the reaction is carried out with the addition of A zeolites.

In a further preferred embodiment of the method according to the invention, molecular sieves of the general formula K _n Na ₂ - _n [(lθ ₂ ) i ₂ (Siθ ₂ ) i ₂ ] .xH ₂ θ are used.

In a further preferred embodiment of the process according to the invention, molecular sieves with different pore diameters, such as 3A and / or 4 Å and / or 5 A, act as catalysts.

In a further preferred embodiment of the method according to the invention applies that the catalysis in organic solvents such as. B. toluene, cumene, xylene, sulfolane, dichloromethane, ethanol is carried out.

In a further preferred embodiment of the process according to the invention, the catalysis is preferably carried out in an aromatic solvent such as, for. B. toluene, cumene, xylene is carried out.

In a further preferred embodiment of the process according to the invention, the heterogeneous catalyst can be regenerated and recycled, or is recycled directly without regeneration.

method The present application describes the preparation of coumarins by heterogeneous catalysis based on phenols and

Carboxylic acids / carboxylic acid derivatives or? Keto carboxylic acids / carboxylic acid derivatives.

The carboxylic acids / carboxylic acid derivatives have a further functional group, so that alkylation on the phenol ring is supported with the formation of the cümarine unit.

Phenols of the general formula I and II are used,

Formula I Formula II

where R1-R4 and Rs-Rs are the same or different and are the same as H and / or hydroxyl groups and / or alkoxy radicals with 1-10 C atoms, e.g. B.

Benzyloxy, 1-phenylethyloxy, 2-methylphenylmethoxy, p-sulfobenzyloxy, p-nitrobenzyloxy, p-fluorobenzyloxy. and / or alkyl radicals with 1-10 C atoms and / or haloalkyl radicals, for. B.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te / τ-butyl, pentyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl and / or alkenyl radicals with 1-10 C atoms, e.g.

Ethenyl, n-propenyl, isopropenyl, hexenyl, 3-methylpentenyl, 3-ethylbutenyl. and / or aryl radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl,

Naphthyl, p-nitrophenyl, hydroxylphenyl and / or aralkyl radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B.

Benzyl, 1-phenylethyl, 2-phenylethyl, cumylmethyl, mesitylmethyl,

Fluorine-chlorine, bromine, cyano groups mean.

Carboxylic acids / carboxylic acid derivatives of the general formula III-V are used,

Formula Formula IV Formula V

where R ₉ is H or an alkyl radical having 1-10 C atoms, for example

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fetτ-butyl, pentyl or an aryl radical, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl, naphthyl and R o is an ethynyl radical and R11-15 is H and / or alkyl radicals having 1-10 C atoms and / or haloalkyl radicals, for. B.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ferf-butyl, pentyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl and / or aryl radicals with alkyl and / or halogen and / or nitro and / or

Sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl, naphthyl, p-nitrophenyl, hydroxyphenyl, p-fluorophenyl groups and / or R = CH ₂ CO ₂ CH ₂ CH ₃ .

The coumarin derivatives are prepared by reaction of the previously described phenols of the general formula I and II and the carboxylic acids / carboxylic acid derivatives according to formula III-V by acid catalysis. In a first step, the carboxylic acids are esterified with phenols or the carboxylic acid esters are transesterified. This is followed by alkylation of the aromatic phenol ring to form the cümarine unit (formula VI).

Formula VI (coumarin)

This cümarine unit can carry substituents at various points in accordance with the phenols and carboxylic acids / carboxylic acid derivatives used. If> 9-keto-carboxylic acid derivatives of the formula V are used, as in the Pechmann reaction (equation I), a further step follows, dehydration.

equation

The reactions are carried out in the presence of heterogeneous catalysts in the liquid phase. The temperature limits are determined by the boiling points and melting points of the reactants or by the boiling point of the solvent used. The reactions are carried out batchwise, in a “slurry” reactor, in a fixed bed reactor and / or continuously. The temperatures set are between 20-250 ° C., preferably between 40 and 120 ° C. or the boiling point temperature of the particular solvent and particularly preferably between 60-100 ° C. The reactions can be carried out at ambient pressure, at elevated pressure up to 100 bar or at reduced pressure up to 0.01 bar become. Aliphatic, cycloaliphatic, halogen-containing or aromatic solvents such as. B. xylene, cumene, dichloromethane, chlorobenzene, sulfolane can be used. Aromatic solvents such as toluene, cumene, xylene are the most suitable.

Nafion silica composite materials provide surprisingly excellent results as acidic heterogeneous catalysts. These materials are very reactive, can be easily separated and recycled. They can be easily regenerated if coking occurs, e.g. B. by treatment with organic solvents and / or by treatment with acids.

Nafion is a registered trademark of DuPont. It is a perfluorinated polymer, which receives highly acidic terminal SO ₃ H groups by sulfonation. By co-precipitation of Nafion with silica gel, materials with changing Nafion content are obtained. BET surface measurements showed 100-120 (m ² / g) for the SAG 40 and 10-20 (m ² / g) for the SAG 80. The BET surface area of pure Nafion is <0.02 (m ² / G). Results of the ICP-AES analyzes after ion exchange of the protons by Cu ²⁺ , Zn ²⁺ , Fe ³⁺ and Al ³⁺ ions gave 0.25 meqH ⁺ / g for SAG 40 and 0.43 meqH for the number of acidic centers ^" 7g for SAG 80 [meqH ⁺ / g = mol equivalent H ⁺ per gram of sample].

The Nafion silica composite materials, a further development of the Nafion resin, were developed by M. A. Harmer et al .. [M. A. Harmer, Q. Sun, W.E. Farneth, J. Am. Chem. Soc, 1996, 118, 7708-7715; M. A. Harmer, Q. Sun, A. J. Vega, A. Heidekum, W. E. Farneth and W. F. Hoelderich, Green Chem., 2000, 2, 7-14]. In order to avoid the problem of the low active surface area of the pure Nafion resin, nanoparticles (20-60 nm diameter) of the Nafion resin were distributed and fixed in a silica matrix. The interaction of the high catalytic properties of the hydrated Nafion copolymer with the surface of the silica opens up new avenues in heterogeneous catalysis. It has been shown that a number of important reactions are catalyzed by Nafion silica composites [A.

Heidekum, M.A. Harmer, W.F. Hoelderich, Catal. Leti., 1997, 47, 243; A. Heidekum,

Harmer, M.A., Hoelderich, W.F., ACS Polym. Prepr., 1997, 763; A. Heidekum, M. A.

Harmer, W.F. Hoelderich, J. Catal., 1998, 260, 176; A Heidekum, M.A. Harmer, W.

^' F. Hoelderich, J. Catal., 1999, 217, 181]. Active catalysts in the Pechmann reaction are surprisingly silica composite materials loaded with 40% and / or 80% Nafion. The Nafion silica composite materials are further characterized by the fact that they are not sensitive to water and that precisely this property can be exploited in the Pechmann reaction (water formation). Carrying out the reaction with the composite materials does not require azeotropic removal of the water formed. Thus, only a simple apparatus is necessary, which consists of a reaction flask, a megnat stirrer and a reflux condenser. There is no need for an additional water separator.

Deloxan can also be successfully used as a catalyst in the Pechmann reaction. It is a registered trademark of Degussa. It is a polysiloxane resin, which like Nafion contains the highly acidic, terminal sulfonic acid groups. Deloxan has a high thermal stability [C. Boix, M. Poliakoff, Tetrahedron Lett., 1999, 40, 4433-4436],

Best results in toluene solvent. Should the catalyst deactivate, it can be regenerated before recycling. The regeneration is carried out by washing with solvents such as acetone, toluene, THF, ethanol or by treatment with organic and / or inorganic acids. In particular acids with oxidation properties such as nitric acid, sulfuric acid, inorganic and organic peroxides are preferred.

If the ^ keto carboxylic acid derivatives carry a fluoroalkyl group as a substituent (for example Rι ₄ = CF ₃ ), they are preferably in the enol form according to equation II [V. Bayer, R. Pastor, A. Cambon, J. Fluorine Chem., 1982, 20, 187-202] and have an increased reactivity.

Equation II 7-Hydroxycoumarins with fluorine-containing substituents are used due to their particularly sensitive UV activity in the production of valuable, fluorescent colorants and in the synthesis of enzyme substrates.

The Pechmann reaction with fluoro-alkyl - # - keto-carboxylic acid derivatives takes place most simply in the solvent-free reaction environment, with weakly acidic catalysts being efficient. Mol sieves of the ^' general form K _n Naι ₂ - _n [(Alθ ₂ ) i ₂ (Siθ ₂ ) i ₂ ] .xH ₂ θ with different pore diameters are sufficient as the driving force of the Pechmann reaction with fluoroalkyl-ß-keto-carboxylic acid derivatives out. The results with molecular sieves compete with those observed with liquid trifluoroacetic acid or with sulfuric acid. In this case, simple, narrow-pore zeolites with a pore diameter of 3A, 4 A or 5 A and erionite, chabazite, ferierite are both the liquid and the other heterogeneous acids (H-BEA, Nafion-Composites or Amberlyst 15) not only because of the higher selectivities to the desired coumarin, but also preferred because of their relatively low price. No waste problems, such as when using trifluoroacetic acid or other homogeneous Bronsted acids, need to be taken into account.

The invention is explained in more detail below with the aid of three exemplary embodiments.

Examples of Nafion silica composite materials

Catalyst A = Nafion SAG 40, i.e. H. Nafion silica composite material with a Nafion content of 40%;

Catalyst B = Nafion SAG 80 d. H. Nafion silica composite material with a Nafion content of 80%;

Example 1: Pechmann reaction according to equation III:

Equation III

A mixture of 10 mmoles (1.1 g) of resorcinol, 10 mmoles (1.3 g) of ethyl acetoacetate, 10 ml of toluene and 0.5 g of SAC 80 is initially introduced at room temperature and stirred under reflux with a magnetic stirring bar for two hours. The 7-hydroxy-4-methylcoumarin 1 formed precipitates in toluene during the reaction at the reaction temperature (reflux). In order to bring the product into solution, acetone and / or tetrahydrofuran is added to the still hot solution at the end of the reaction. After filtering off the still warm reaction solution, the catalyst is washed again with acetone, air-dried and used again. A sample is taken from the filtrate and analyzed by gas chromatography using a 50m SE-54 column from Chrompack.

The product is analyzed by GC-MS, ¹ H and ¹³ C NMR measurements.

Result: conversion of resorcinol (> 98%), selectivity to 7-hydroxy-4-methylcoumarin (> 98%), yield of 7-hydroxy-4-methylcoumarin (> 96%).

Table 1 lists the results achieved with SAC 40 and SAC 80 compared to Amberlyst 15 and the pure Nafion NR 50 in 10 ml toluene.

Table 1

^* Yield after qualitative and quantitative GC analysis of the reaction mixture, SAC 40, SAC 80 = 40% or δ0% Nafion on silica, NR-50 = pure Nafion resin. The catalyst (SAC 80) can be recycled; with repeated use, the conversion of resorcinol drops to a constant value of 89% with the same selectivity to 7-hydroxy-4-methylcoumarin of over 98%. It is also possible to regenerate the catalyst in such a way that maximum resorcinol conversion is again achieved. For this, the used catalyst is stirred with 30% nitric acid at 80 ° C for 2-4 hours, washed with distilled water and dried at 130 ° C in a high vacuum.

The compared examples show the superiority of the claimed catalysts.

Example 2:

Reaction of resorcinol with acrylic acid (equation IV):

Equation IV

A mix of 10mm _. ol (1.1 g) resorcinol, 10 mmole (0.7 g) acrylic acid, 10 ml or 50 ml toluene and 0.5 g SAC 80 are initially charged at room temperature and stirred under reflux with a magnetic stirring bar for two hours. In addition to the desired 7-hydroxy-3,4-dihydrocoumarin 2 of resorcinol is formed after esterification with two hydroxyl functions, the byproduct 3. From the reaction solution, a sample is taken and analyzed by gas chromatography using a 50m SE-54 column Chrompack ^'■.

The products are analyzed using GC-MS, ¹ H and ¹³ C NMR. Result: 100% conversion of resorcinol, selectivity to 7-hydroxy-3,4-dihydrocumarin (86% in 10 ml, 93% in 50 ml toluene), yield of 7-hydroxy-3,4-dihydrocumarin (86% in 10 ml , 93% in 50ml toluene).

Table 2 lists the results obtained with SAC 40 and SAC 80 compared to Amberlyst 15 and the pure Nafion NR 50 in 10 ml toluene.

Table 2

* Yield after qualitative and quantitative GC analysis of the reaction mixture, SAC 40, SAC 80 = 40% or 80% Nafion on silica, NR-50 = pure Nafion resin.

As shown in Example 1, the catalysts of the invention can be regenerated.

Example 3:

Conversion of resorcinol and ethyl trifluoroacetoacetate according to equation V:

Equation V

A mixture of 10mmol (1.1g) resorcinol, 10mmol (1.8g) trifluoroacetoacetic acid ethyl ester is warmed to 120 ° C. The resulting melt (melting point of resorcinol: 109-111 ° C) is stirred over 0.5 g molecular sieve (3A) at 120 ° C until the melt completely forms the higher-melting end product (melting point of 4- (trifluoromethyl) umelliferone 4: 180-180 ° C) has solidified. The resulting solid mass is brought into solution with acetone and the catalyst is filtered off. After removing the solvent, the crude product is recrystallized from ethanol / water in a 1: 1 ratio. In several experiments, pure, colorless, crystalline 4- (trifluoromethyl) umelliferone 4 is obtained in a high yield of 80% and sometimes a little bit more. The products are analyzed using GC, ¹ H and ¹³ C NMR.

Table 3 lists the results that are achieved with other catalysts compared to molecular sieve (3A) in the molten resorcinol phase.

Table 3

^* Yield of the purely isolated F-coumarin 4 after recrystallization in ethanol / water 1: 1; TFA = trifluoroacetic acid, SAC 13; SAC 40 = 13% or 40% Nafion on silica, H-BEA = ß-

Zeolite in the H ⁺ form

The low yield with the more acidic, heterogeneous catalysts may be due to increased formation of by-product 5 (Eq. V). The A-mole sieves can be regenerated, i.e. Drying at approx. 200 ° C in

Fine vacuum, can be used again. Carrying out the reactions in organic solvents, such as toluene or o-xylene, leads to longer reaction times. As can easily be seen from Table 3, the A zeolite is superior to the other catalysts. A similar yield can only be achieved with TFA, but the associated disadvantages, in particular severe corrosion and the high price for TFA, must be taken into account.

Claims

claims:

\

1. A process for the synthesis of coumarins from phenols and carboxylic acids and / or carboxylic acid derivatives and / or ^ keto-carboxylic acids and / or β-keto-carboxylic acid derivatives, characterized in that the reactions in the presence of Nafion-silica composite materials and / or deloxane and / or narrow-pore zeolites.

Process according to Claim 1, characterized in that several reaction steps (transesterification / esterification, alkylation / hydroxyalkylation, dehydration) are carried out in one reaction step on Nafion-silica composite materials and / or narrow-pore zeolites as catalysts.

Process according to Claim 1, characterized in that substituted phenols of the general formula I and II are used,

Formula Formula I

wherein R Rβ are independently selected from

H, OH; -Ci.io-alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; -OCι-ι ₀ alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; Aryl, aralkyl radicals or -O-aryl, each substituted or unsubstituted.

, A method according to claim 3, characterized in that in the substituted phenols of the general formula I and II R1-R4 and R5-R8 are the same or different and are the same as H and / or hydroxyl groups and / or alkoxy radicals with 1-10 C atoms, e.g. , B.

Methoxy, ethoxy, propyloxy, butyloxy, 2-ethylbutyloxy, isobutyloxy, / butyl, pentyloxy and / or aralkyloxy radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B. benzyloxy, 1-phenylethyloxy, 2-methylphenylmethoxy, p-

Sulfobenzyloxy- p-nitrobenzyloxy, p-fluorobenzyloxy and / or alkyl radicals with 1-10 C atoms and / or haloalkyl radicals, e.g. B.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fe / τ-butyl, pentyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl and / or alkenyl radicals with 1-10 C atoms, z. B.

Ethenyl, π-propenyl, isopropenyl, hexenyl, 3-methylpentenyl, 3-ethylbutenyl and / or aryl radicals with alkyl and / or halogen and / or nitro and / or sulfonyl and / or hydroxyl groups on aromatic ring, e.g. B. phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl,

Benzyl, 1-phenylethyl, 2-phenylethyl, cumylmethyl, mesitylmethyl, fluorine, chlorine, bromine, cyano groups.

5. The method according to claim 1, characterized in that carboxylic acids and / or carboxylic acid derivatives of the general formula III -V are used

become,

Formula III Formula IV Formula V where Rg H; -Cι.ι ₀ alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; or aryl, substituted or unsubstituted; and Rio are an ethynyl group,

and R11-15 H; -Cι. ₁₀ -alkyl, substituted or unsubstituted, saturated or unsaturated, branched or unbranched; or aryl, substituted or unsubstituted;

mean. _

6. The method according to claim 5, characterized in that in the

Carboxylic acids and / or carboxylic acid derivatives of the general formula III -V, R ₉ is H or an alkyl radical with 1-10 C atoms, for example

Methyl, ethyl, propyl, isopropyl ,. Butyl, isobutyl, ferf-butyl, pentyl or an aryl radical, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl, naphthyl and R1 ₀ an ethynyl radical and R11-15 are H and / or alkyl radicals with 1-10 C atoms and / or haloalkyl radicals, for. B.

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ferf-butyl, pentyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl and / or aryl radicals with alkyl and / or halogen and / / or nitro and / or sulfonyl and / or hydroxyl groups on the aromatic ring, e.g. B.

Phenyl, methylphenyl, ethylphenyl, mesithyl, cumyl, xylyl, naphthyl, p-nitrophenyl, hydroxyphenyl, p-fluorophenyl groups and / or R ₁₄ = CH ₂ C0 ₂ CH ₂ CH ₃ .

7. The method according to any one of claims 1 to 6, characterized in that Nafion-silica composite materials are used as acidic heterogeneous catalysts.

8. The method according to claim 7, characterized in that Nafion-silica composite materials with different proportions between 3% -98% of Nafion are used in the silica.

9. The method according to claim 8, characterized in that in the Nafion silica composite materials the proportion of Nafion is preferably between 40% and 80%.

10. The method according to any one of claims 7 to 9, characterized in that the Nafion-silica composite materials used are synthesized in an "in situ" gel process by co-precipitation of Nafion particles with silica.

11. The method according to any one of claims 1 to 10, characterized in that the catalysis is carried out in the liquid phase, in the reactants and / or in an organic solvent.

12. The method according to any one of claims 1 to 6, characterized in that the reaction is carried out with the addition of narrow-pore zeolites.

13. The method according to any one of claims 1 to 6, characterized in that the reaction is carried out with the addition of A zeolites.

14. The method according to claim 13, characterized in that molecular sieves of the general formula K _n Nai ₂ -n [(AI0 ₂ ) i ₂ (Siθ ₂ ) i ₂ ] -xH ₂ θ are used.

15. The method according to claim 13, characterized in that molecular sieves with different pore diameters such as 3 A and / or 4 A and / or 5 A act as catalysts.

16. The method according to any one of claims 1 to 15, characterized in that the catalysis in organic solvents such as. B. toluene, cumene, xylene, sulfolane, dichloromethane, ethanol is carried out.

17. The method according to any one of claims 1 to 15, characterized in that the catalysis preferably in an aromatic solvent such as. B. toluene, cumene, xylene is carried out.

18. A process for the synthesis of coumarins according to claims 1 to 17, characterized in that the heterogeneous catalyst can be regenerated and recycled, or is recycled directly without regeneration.