CS270553B2 - Method of acylated cyclic diketone compound production - Google Patents

Abstract

In the prodn. of an acylated cyclical diketonic cpd. (I) by rearrangement of the corresp. enol ester (II), the rearrangement is conducted in the presence of a cyanide source. Pref. either a catalytic amt. of cyanide source and a molar excess, w.r.t. (II) of a moderate base or a stoichiometric amt., w.r.t. (II) of KCN or LiCN, and a catalytic amt. of cyclical crown ether or acyclic analogue, is employed. (I) are pref. of formula (Ia), where R1 - R6 = H or 1-6C alkyl; or R1, R2 or R3 = RaOCO; or R1 + R2 or R3 + R4 = 3-6C alkylene; Ra = 1-4C alkyl or phenyl (opt. substd. by 2-5 Me gps.); R7 = halo, CN, 1-4C alkyl, 1-4C haloalkyl, RkD(O)n, 1-4C alkoxy or NO2; Rk = 1-4C alkyl; n = 0-2; R8-R10 = H, halo, 1-4C alkyl, 1-4C alkoxy, trifluoromethoxy, CN, NO2, 1-4C haloalkyl, 1-4C alkylthio, phenoxy or substd. phenoxy (substd. by halo and/or halomethyl), RbS(O)n, RcCONH, NRdRe, RfC(O) or SO2NRgRh; Rb = 1-4C alkyl, 1-4C haloalkyl, phenyl or benzyl; Rc = 1-4C alkyl; Rd, Re = H or 1-4C alkyl; Rf + H, 1-4C alkyl, 1-4C haloalkyl or 1-4C alkoxy; Rg and Rh = H or 1-4C alkyl; or R8 + R9 = a ring strcture with 2 adjacent C atoms of the phenyl ring to which they are attached.

Description

The invention relates to a process for the preparation of an acylated cyclic diketone compound by rearrangement of the corresponding enol ester.

They're known compounds containing the group: -----CH-CR / ^x 0

wherein R is an aromatic or aliphatic group. Compounds of this type are described in numerous references as useful, for example, chemical intermediates and / or pesticides. The remainder of the molecule, which comprises a diketone group, generally has a cyclic structure. Most preferably, the diketone group comprises a 5- to 6-membered carbocyclic ring. Acylated diketone compounds of this type have a general structure

wherein R is as defined above and n is 2 or 3. The ring may be unsubstituted or substituted at one or more positions by, for example, alkyl, aryl, alkylene, aid.

One method for producing acyl diketone compounds is disclosed in European Patent Application No. 90262 and involves the reaction of an optionally substituted 1,3-cyclohexanedione 6 with a substituted benzoyl cyanide. The reaction is carried out in the presence of zinc chloride and triethylamine. However, this method has some disadvantages. Benzoyl cyanides are somewhat expensive reagents and in this reaction hydrogen cyanide is produced in an amount of one mole per mole of acylated diketones. It would therefore be desirable to carry out the reaction using a less expensive and readily available acylating agent, and in addition with less hydrogen cyanide formed. For example, benzoyl chloride is a relatively less expensive and available form of acylating agent. However, benzoyl chloride is a stronger acylating agent than benzoyl cyanide and, in the presence of a conventional catalyst, does not tend to acylate at a carbon atom between two carbonyl groups, but directly attacks one of the carbonyl groups to form an enol ester of the type

It is known from numerous references that acylated cyclic diketone compounds can be prepared from the corresponding enol esters by rearrangement: and ^ OCR 0 // ------C 0 - 4 ----> \ II _c z CH / - CR ^c \ 0 -----C 0

The references disclose some different types of acylated diketone compounds and various catalysts or promoters for rearrangement of enol esters to acylated diketones.

For example, Akhrem et. al., Synthesis, pp. 925-927 (1978) discloses the preparation of numerous acylated cyclohexanediones by reacting 1,3-cyclohexanedione with an acylating agent (particularly acyl halide) in two steps. In the first step, the acyl halide is reacted with cyclohexanedione in the presence of pyridine to give the enol ester, which is converted to the acylated cyclohexanedione by rearrangement in the presence of a two molar excess of aluminum chloride. The acylating agent used in this reaction has the formula RCOCl wherein R is various alkyl (e.g., methyl, ethyl, propyl), phenyl, substituted phenyl, benzyl, and substituted benzyl.

Tanabe et al., Chem. Letters, p. 53 (1982) describes the preparation of 3-acyl-4-hydroxy-2-pyrone by acylating the pyrone with an alkyl or alkenyl type acyl halide and rearrangement of the enol ester formed using a catalytic amount of 4-dimethylaminopyridine.

European Patent Application No. 123001 discloses that other aminopyridine derivatives and certain N-alkylimidazole derivatives are suitable catalysts for the rearrangement of enol esters n and acylated cyclohexanediones having a 5-carboxylate substituent.

USSR patent 784,195 discloses an enol ester rearrangement for the preparation of 2-oleoyl-cyclohexane-1,5-dione in the presence of molten sodium acetate at a temperature of 160-170 ° C.

European Patent Application No. 80301 discloses the rearrangement of 5- (polymethylphenyl) -1,3-cyclohexanedione enol esters to the corresponding acylated cyclohexanedione in the presence of a Lewis acid. The acylating agents used include anhydrides and acyl halides of the formula RCOC1, wherein R is alkyl, fluoroalkyl, alkenyl, alkynyl and phenyl.

The present invention provides a process for the preparation of an acylated cyclic diketone compound of formula I wherein Rp

are independently hydrogen or alkyl of 1 to 6 carbon atoms.

₽ ₇ is hydrogen, halogen, cyano, (C 1 -C 4) alkyl, (C 1 -C 4) haloalkyl, nitro or R 1 S / O / _n , wherein R 1 is C 1 -C 4 alkyl and _n is 0, 1 or 2, R q and R 4 are independently hydrogen, halogen, C 1 -C 4 alkoxy or R 2 S / O / R 1 where R 5 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; 0, 1 or 2, by rearranging the corresponding enol ester containing a group of formula II

II

OCR

^ CH

wherein R is an appropriately substituted phenyl group, characterized in that the rearrangement is carried out in the presence of a catalytic amount of a cyanide source comprising alkali metal cyanides, cyanohydrins of C 1-4 alkylalkyl ketone, benzaldehyde cyanohydrin, cyanohydrins of aliphatic aldehydes of 2 to 5 atoms and a molar excess of the weak base relative to the enol ester or in the presence of a stoichiomatic amount of alkali metal cyanide relative to the enol ester and a catalytic amount of the cyclic Crown ¹ ether or an acyclic analog thereof.

Compounds of this type with different substituents on one or both rings of cyclohexane or phenyl are disclosed in European Patent Application No. 96262, U.S. Pat. Nos. 270206 and 51/13750 and 51/13755, which disclose certain compounds of this type as intermediates for herbicides.

The rearrangement according to the invention is carried out in the presence of a cyanide source. The term cyanide source refers to a substance or substances which liberate hydrogen cyanide and / or a cyanide anion under rearrangement conditions. There are two basic designs.

In one embodiment, the process is performed from the presence of a catalytic amount of a cyanide anion source and / or hydrogen cyanide together with a molar excess relative to the enol ester of the mild base.

A preferred cyanide source is an alkali metal cyanide such as sodium and potassium cyanide; cyanohydrins of a methyl alkyl ketone having 1-4 carbon atoms in the alkyl group such as acetone or methyl isobutyl ketone cyanohydrin; cyanohydrins of benzaldehyde or aliphatic aldehydes having 2 to 5 carbon atoms such as acetaldehyde, propionaldehyde, zinc cyanide, trimethylsilyl cyanide and hydrogen cyanide. Hydrogen cyanide is believed to be most advantageous because it utilizes a relatively rapid reaction and is not costly. It can be used in either liquid or gaseous form; when used as a gas, it may be obtained from a commercial supplier or released in situ by reaction of a metal cyanide with an acid. Of the cyanohydrin, the preferred cyanide source is acetone cyanohydrin.

In this embodiment, the cyanide source is used in an amount of up to 50 moles based on the enol ester. Only 1 mol% can be used to achieve a suitable reaction rate at 40 ° C on a small scale. With larger scale reactions, reproducible results are obtained with a slightly higher catalyst level, 2 mol%.

CS 270553 82

The catalyst used is preferably cyanate, sodium cyanide, potassium cyanide or acetone cyanohydrin in an amount of 1 to 10 µl based on the enol ester.

In this embodiment, the process is performed with a molar excess of the mild phase relative to the enol ester. The term mild base refers to a substance that acts as a base whose strength or potency as the base lies between a strong base such as hydroxide (which could cause hydrolysis of the enol ester) and the effect of a weak base such as bicarbonate (which would not work effectively). Moderate bases suitable for use in this embodiment include organic bases such as tertiary amines and inorganic bases such as alkali metal carbonates and phosphates. Suitable tertiary amines include trialkylamines such as triethylamine, trialkanolamines such as triethanolamine and pyridine. Suitable inorganic bases include potassium carbonate and sodium phosphate.

The base used is preferably a tertiary amine, an alkali metal carbonate or an alkali metal phosphate, in particular triethylamine.

The base is used in an amount of 1 to 4 moles per mole of enol ester, preferably 2 moles per mole.

When the cyanide source is an alkali metal cyanide, especially potassium cyanide, a phase transfer catalyst may be used in the reaction. A particularly suitable phase transfer catalyst is Crown ether.

Various solvents may be used in this process, depending on the nature of the acid chloride or the acylated product.

The preferred solvent for this reaction is 1,2-dichloroethane. Other solvents that may be used depending on the reagents or products include toluene, acetonitrile, methylene chloride, ethyl acetate, dimethylformamide and methyl isobutyl ketone.

In general, the rearrangement may be carried out depending on the nature of the reactants and the cyanide source at a temperature of up to 80 ° C. In some cases, for example, when the problem of excess by-product formation is possible (for example using orthocyanobenzoyl halide and alkali metal cyanide or aoetone cyanohydrin as a cyanide source), the temperature is maintained at most * at 40 ° C.

In a second basic embodiment of the process, potassium or lithium cyanide is used as the cyanide source, but is used in stoichiometric amounts relative to the enol ester without the use of a separate base. The cyanide source is used together with a catalytic amount of a phase transfer catalyst such as Crown ether or an acyclic analog thereof.

A preferred cyanide source in this embodiment is potassium cyanide. The preferred Crown Ether for this source is 18-Crown-6. Other hexadentate compounds such as cyclohexy-10-Crown-6, dibenzo-18-Crown-6 and the acyclic pentaethylene glycol dimethyl ether are also suitable.

15-Crown-5 is suitable for lithium cyanide.

In this embodiment, a separate base is not required and is therefore not used.

This embodiment is suitable for the preparation of compounds of the general type, but has been found to be particularly satisfactory for use where milder conditions are preferred or the need to reduce by-product formation such as in the preparation of benzoylated cyclohexanedione having an ortho-cyano substituent on the phenyl ring. This embodiment of the method can be carried out at room temperature. The same solvents as in the first embodiment may be used;

acetonitrile is preferred.

The process of both embodiments can be carried out using the enol ester as a starting material or releasing the enol ester in situ, for example by reacting an acylating agent with a diketone. The term enol ester ¹ 'as used herein refers to an enol carboxylic acid ester.

When an enol ester is used as the starting material in both embodiments of the process, it can be prepared by any known method, including acylation of the diketone substance with, for example, an acyl halide. .

The preparation of the acylated diketones of the invention using an acylating agent and a diketone (for example, an acyl halide as a substituted benzoyl halide and a diketone as a cyclohexanedione) can preferably be carried out by isolation or without isolation of the enol ester intermediate. When carried out in two steps, an acyl halide or other acylating agent and a diketone are reacted in the presence of a mild base such as triethylamine. The enol ester can be isolated from the resulting product mixture in a known manner, for example by washing the resulting solution with acid and base, and saturated sodium chloride solution, and drying. This technique is advantageous when a different solvent is used for the second step, rearrangement of the enol ester to the acylated diketone. The dry enol ester may then be mixed with a suitable solvent such as acetonitrile or 1,2-dichloroethane and contacted with an appropriate amount of a cyanide source and either a mild base or a Crown ether according to the embodiment used, at a suitable temperature to prepare the final. product.

Alternatively, the enol ester may be left in the reaction product and the second step may be carried out (using the same solvent) with the addition of a cyanide source and optionally a base (according to the embodiment) to prepare the acylated diketone. .

In another variation, the acylated diketone product can be obtained in one step by forming an in situ and rearrangement of the enol ester by reacting an acyl halide or other acylating agent with the diketone in the presence of an appropriate amount of cyanide source and an appropriate amount of mild base or Crown ether.

Comparable yields can be obtained either with or without isolation of the enol ester.

The acylated diketone product is obtained from this reaction as a salt in the first embodiment described. The desired acylated diketone can be obtained by acidification and extraction with an appropriate solvent. In some cases, the product may be contaminated with a small amount of an acyl halide carboxylic acid; this by-product can be removed by contacting the acidified product solution with a dilute aqueous sodium hydroxide solution or other suitable base to form an acid salt. In a second embodiment, the acylated diketone can be obtained per se. *

The process of the invention is illustrated in the following examples.

He did

Rearrangement of enol ester

A series of experiments are carried out in the preparation of 2- (2 ', 3', 4'-trichlorobenzoyl) -1,3-cyclohexanedione by rearrangement of the enol ester using a different cyanide source and solvent. The general procedure was as follows: 3.0 g (0.0094 mol) of the enol ester (prepared by reaction of 2,3,4-trichlorobenzoyl chloride with 1,3-cyclohexanedione in the presence of triethylamine and isolation) was dissolved in 10 ml of the solvent and mol% of the catalyst

CS 270553 82 and 140 mol% of triethylamine) the amounts indicated refer to the enol ester). The mixture is kept at ambient temperature and the reaction is allowed to proceed for 4-18 hours. The reaction mixture was diluted with water and the solvent was removed by distillation under reduced pressure. The resulting aqueous mixture was acidified with stirring by slowly adding 6N hydrochloric acid to pH 1. The resulting material was filtered off and dried to constant weight at 75 ° C.

The yield of the crude acylated diketone product without correcting the purity of the starting materials is shown in Table 1.

Tabulkal

Catalyst Solvent Theoretical yield% Product purity KCN acetonitrile 91.3 82.8 KCN _ acetonitrile 91.0 81.9 KCN acetonitrile 95.3 84.6 KCN 1,2-dichloroethane 87.3 76.0 KCN 90% 1,2-dichloroethane / 10% dimethylformamide 86.0 75.7 NaCN 1,2-dichloroethane 78.7 80.3 acetone cyanohydrin acetonitrile 92.0 80.1

Example 2

Preparation of acylated diketone without isolation of enol ester

This example illustrates the process of starting an acyl halide and diketone in one step without isolating the enol ester intermediate. The procedure was as follows:

To the flask was charged 3.0 g (0.027 mol) of 1,3-cyclohexanedione, 15 ml of the solvent and 10 mol% (relative to the enol ester) of sodium cyanide. The reaction mixture was purged with nitrogen and maintained at room temperature. Then, 300 mol% of triethylamine (based on the enol ester) is added and the mixture is kept at room temperature. 2,3,4-Trichlorobenzoyl chloride was then added to the mixture at 100 mole% (based on dione). The mixture is maintained at ambient temperature and the reaction is allowed to proceed for 24 hours. The product is obtained as in Example 1 and 8.04 g of crude product are obtained (93.2% of the theoretical yield, uncorrected for the purity of the starting materials). '

Example 3-6 ·

A series of experiments were carried out as described in Example 2, but using different catalysts and solvents. The same reactants were used. All catalysts were used in an amount of 10 mol% based on the enol ester. Table 2 shows the results of these experiments, yields are not corrected for the purity of the starting materials.

Table 2

Ex. C. Catalyst Solvent Theoretical yield% Product purity 3 KCN methylene chloride 81.1 80.5 4 KCN 1,2-dichloroethane 87.5 69.9 5 acetone cyanohydrin 1,2-dichloroethane 90.7 82.6 6 acetone cyanohydrin toluene 90.4 79.3

Example 7.

In this example, the process is also carried out without isolating the enol ester.

15 g (0.13 mol) of 1,3-cyclohexanedione, 75 ml of 1,2-dichloroethane and 0.24 ml (2 mol% based on enol ester) of acetone cyanohydrin are placed in a flask. The substances were placed under a nitrogen layer and the flask was placed in an ice bath. '

Then, 54.36 ml (34.96 g, 9.39 mol) of triethylamine and 32.86 g (0.13 mol) of 2,3,4-trichlorobenzoyl chloride dissolved in 125 ml of 1,2-dichloroethane are added sequentially. When the amine and benzoyl chloride were added, the temperature of the reaction mixture was raised to 40 ° C and allowed to react for 2 hours. At the end of this time, 84.6% of the desired product was identified by HPLC, the remainder being mainly unreacted cyclohexanedione.

The reaction mixture was then cooled and diluted with 100 mL of water. The pH of 9.8 is adjusted to 2.8 by the addition of 3M sulfuric acid and an additional 100 ml of 1,2-dichloroethane is added during this step to dissolve the substance which has begun to precipitate. The mixture was separated into an aqueous and an organic phase. The aqueous phase (about 200 mL) had a pH of 2.6.

The organic phase was washed with water and the phases were separated again (the aqueous phase had a pH of 4). The organic phase is then washed with two portions of a 2.5N aqueous sodium hydroxide solution and the phases are separated after washing. The aqueous phases had pH values of 10.7 and 12.8. The organic phase is washed again with 100 ml of water.

All aqueous phases obtained above were combined and acidified with 3M sulfuric acid. The pH is lowered to 2.1. The combined aqueous phases are kept in an ice bath at a low temperature. The solution precipitated from the solution and was filtered off. Dry in a vacuum oven to constant weight. 39.19 g of the desired product is obtained, m.p. Mp 150-151 ° C. The structure of the product was confirmed by high pressure liquid chromatography and comparison with a known sample.

Example 8

Production of 2-propanoyl-1,3-cyclohexanedione.

To a mixture of 3.0 g (0.027 mol) of 1,3-cyclohexanedione and 3.8 ml (0.027 mol) of triethylamine in 15 ml of methylene chloride was added dropwise with stirring and cooling in a water bath at room temperature of 2.3 ml (0.027 mol). propionyl chloride). After stirring at ambient temperature for 4 hours, an additional 7.5 ml (0.054 mol) of triethylamine and 0.25 ml (10 mol% relative to the enol ester) of acetone cyanohydrin are added. The mixture was stirred overnight at ambient temperature and then diluted with water and acidified with 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and the ken centrated under reduced pressure to give 4.68 g of crude product as a mixture of solid and liquid. The crude product was dissolved in methylene chloride and extracted with 2.5N sodium hydroxide solution and water. The combined aqueous phases were acidified with 6N hydrochloric acid and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.83 g of an oily product (84% of theory). The structure of the product was confirmed by infrared, nuclear magnetic resonance and mass spectroscopy.

Example

2- (2'-nitrobenzoyl) -1,3-cyclohexanedione.

2-Nitrobenzoyl chloride (5.0 g, 0.027 mol) and cyclohexanedione (3.0 g, 0.027 mol) were dissolved in methylene chloride. Triethythylamine (4.9 mL, 0.035 mol) was added dropwise and the resulting solution was stirred for 1 hour. The solution was washed with 2N hydrochloric acid (2N HCD, water, 5¾ potassium carbonate solution and saturated sodium chloride solution), dried over anhydrous magnesium sulfate (MgSO 4) and concentrated in vacuo. The residue was dissolved in 20 mL acetonitrile. The solution was stirred at room temperature for 1 hour, diluted with ether, washed with 2N HCl and extracted with 5% potassium carbonate solution, the aqueous extract was acidified and ether was added. 2 g of the title compound (mp 132-135 ° C), which was identified by nuclear magnetic resonance, infrared and mass spectroscopy.

Example 9

2- (2-nitrobenzoyl) -5,5-dimethyl-1,3-cyclohexanedione

Triethylamine (3.4 ml, 0.025 mol) was added dropwise to methylene chloride solution of 2-nitrobenzoyl chloride (3.5 g, 0.019 mol) and 5,5-dimethylcyclohexanedione (2.4 g, 0.019 mol). After stirring at room temperature for 1 hour, an additional 3 equivalents of triethylamine and 0.4 ml of acetone cyanohydrin are added. The solution is stirred for 2.5 hours, then washed with 2N HCl and extracted with 5¾ potassium carbonate solution. The basic extracts were acidified with 2N HCl and extracted with ether. The ether portion was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was lysed Recrystallization from ethyl acetate yielding 2 g of the desired compound (mp 130-133 C ^Q), identified by nuclear magnetic resonance, infrared and mass spectroscopy.

Example 10

2- (2'-cyanobenzoyl) -4,4-dimethyl-1,3-cyclohexanedione

This example illustrates the preparation of a compound described in U.S. Patent Application No. 6,883,899 entitled certain 2- (2'-cyanobenzoyl) -1,3-cyclohexanediones.

2-Cyanobenzoyl chloride (3.9 g, 0.024 mol) and 4,4-dimethyl-1,3-cyclohexanedione (3.3 g, 0.024 mol) were dissolved in 75 ml of methylene chloride. Triethylamine (5.0 mL, 0.036 mol) was added dropwise and the resulting solution was stirred at room temperature for one and a half hours. The solution was washed with water, 2N HCl, 5% potassium carbonate solution (5% K ₂ CO 3), saturated sodium chloride solution (brine), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dissolved in 20 ml of acetonitrile. Triethylamine (4.4 mL, 0.032 mol) and 5 drops of acetone cyanohydrin were added and the solution was stirred for 2 hours. After dilution with ether, the solution was washed with 2N HCl and extracted with 54 L-003. The aqueous extract was acidified with concentrated hydrochloric acid and extracted with ether. The ether was washed with water and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1.2 g of a viscous oil, which was identified as the desired compound by nuclear magnetic resonance, infrared, and mass spectroscopy.

Example 11

2- (2'-Methylthiobenzoyl) 4,4,6-trimethyl-1,3-cyclohexanedione

CH *

CH

This example illustrates the preparation of a compound described in U.S. Patent Application No. 683,898 entitled certain 2- (2'-substituted benzoyl) -1,3-cyclohexanediones.

2-Methylthiobenzoyl chloride (7.2 g, 0.039 mol) and 4,4,6-trimethylcyclohexanedione (5.0 g, 0.039 mol) were dissolved in methylene chloride. Triethylamine (7p mL, 0.050 mol) was added dropwise and the resulting solution was stirred at room temperature for 1 hour. The solution was washed with 2N HCl, 5% potassium carbonate and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in 20 ml of acetonitrile. Triethylamine (2.5 equivalents) and acetone cyanohydrin (0.4 mL) were added and the solution was stirred at room temperature for 45 minutes. After dilution with ether, the solution was washed with 2N hydrochloric acid and extracted with 54 carbonate potassium. The aqueous extract was acidified with hydrochloric acid and extracted with ether. The ether was washed with brine, dried with magnesium sulfate and concentrated in vacuo. The residue was purified by trituration with ether to give 5.9 g of a viscous oil which was ideitified as the desired compound by nuclear magnetic resonance, infrared, and mass spectroscopy.

Example 12

2- (4'-bromo-2-trifluoromethylbenzoyl) -4,4,6-trimethyl-1,3-cyclohexanedione

CH ₃ CF ₃

This example illustrates the preparation of a compound described in U.S. Patent Application No. 673,884 entitled Certain 2- (2-alkylbenzoyl) -1,3-cyclohexanediones.

4-Bromo-2-trifluoromethylbenzoyl chloride (4.3 g, 0.015 mol) and 4,4,6-trimethyl-1,3-cyclohexanedione (2.3 g, 0.015 mol) were dissolved in 100 ml of methylene chloride. The solution was cooled in an ice bath and triethylamine (2.1 mL, 0.015 mol) in 10 mL of methylene chloride was added dropwise. The ice bath was then removed and the resulting solution was stirred at room temperature for 30 minutes. Wash the solution with 2N hydrochloric acid (2 N HCl), 5¾ potassium carbonate solution and saturated sodium chloride solution, dry over anhydrous magnesium sulfate, and concentrate in vacuo. The residue (5.1 g) was dissolved in 20 ml of acetonitrile. Triethylamine (3.5 mL, 0.025 mol) and 0.4 mL acetone cyanohydrin were added and the solution was stirred at room temperature for 2 hours using a drying tube (calcium sulfate). After dilution with ether, the solution was washed with 2N hydrochloric acid and extracted with 5% potassium carbonate. The aqueous extract was acidified with concentrated hydrochloric acid and extracted with ether. The ether was washed with brine, dried with magnesium sulfate and concentrated in vacuo. The resulting oil was purified on a silica gel column (hexane: ethyl acetate: acetic acid 80: 20: 1 - eluent) to give 1.5 g of a viscous oil which was identified by nuclear magnetic resonance, infrared, and mass spectroscopy.

Example 13

2- (4-chlorobenzoyl) -5,5-dimethyl-1,3-cyclohexanedione

This case illustrates carrying out the process using hydrogen cyanide (liberated by the reaction of sodium cyanide with sulfuric acid) as a cyanide source.

To a flask under nitrogen was charged 5,5-dimethylcyclohexane-1,3-dione (7.01 g, 0.05 mol), acetonitrile (80 mL) and trimethylamine (21 mL, 0.15 mol). A solution of 4-chlorobenzoyl chloride (6.4 mL, 0.05 mol) in 20 mL acetonitrile was added over 15 minutes with stirring and cooled in a water bath at ambient temperature. In a separate reaction flask connected by a subsurface gas inlet tube, a solution of sulfuric acid (0.25 g, 0.0025 mol) in 30 mL of water at 85 ° C was added over 10 minutes with stirring and slow nitrogen flow through the secondary reactor and to the primary reactor. reactor. The primary reactor was then heated and stirred at 40 ° C for 2 hours, after which the reaction was complete.

The reaction mixture was diluted with 60 mL of water and slowly acidified with 40 mL of 6H NC1 to precipitate the product. After stirring for 5 minutes, the product is filtered off, washed with water and dried to give 11.85 g (85.0% of theory) of an off-white substance; m.p. Mp 134-134.5 ° C.

Example 14

2- (4-chlorobenzoyl) 5,5-dimethyl-1,3-cyclohexanedione

This example illustrates carrying out the process using a tri-lower alkyl silyl cyanide as a cyanide source.

In a flask under nitrogen atmosphere, 5,5-dimethylcyclohexane-1,3-dione (7.01 g, 0.05 mol), 80 mL acetonitrile and triethylamine (21 mL, 0.15 mol) were mixed. A solution of 4-chlorobenzyl chloride (6.4 mL, 0.05 mol) in 20 mL of acetonitrile was added over 15 minutes with stirring and cooling on a water bath at ambient temperature. Trimethylsilyl cyanide (0.33 mL, 2.55 mol) was added and heated and stirred at 40 ° C for 3 hours, after which the reaction was complete.

The reaction mixture was diluted with 160 mL of water and acidified with 40 mL of 6N hydrochloric acid to precipitate the product. After stirring for 10 minutes, the product was filtered off and washed with water, dried to give 13.2 g (95.0% of theory) of an off-white solid: m.p. Mp 135-134.5 ° C.

Example 15

2- (2-cyanobenzoyl) -1,3-cyclohexanedione

This example illustrates the implementation of the second embodiment of the method using a stoichiometric amount of potassium cyanide and Crown ether.

The flask was charged with 1.2 g (0.005 mol) of the enol ester prepared by reaction of 1,3-cyclohexanedione with 2-cyanob enzoyl chloride, potassium cyanide (0.3 g, 0.005 mol), 18-Crown-6 (0.1 g, 0.005 mol) and 10 ml of acetonitrile. The mixture was stirred at room temperature for 30 minutes, then poured into 300 ml of water. The pH is adjusted to 6 with carefully concentrated hydrochloric acid, then the solution is extracted with 200 ml of ethyl acetate. It is then extracted with 300 ml of saturated aqueous sodium bicarbonate solution. The bicarbonate extract was acidified (to pH 3) with concentrated hydrochloric acid and extracted with 200 ml ethyl acetate. The resulting solution was dried over sodium sulfate and distilled to give 0.7 g (58%) of the desired product, an orange-brown oil. The structure was confirmed by infrared (irvonuum, nucleation), by means of massive opuclopoulos.

Example 16

2,4,4-chlorobenzoyl) -5,5-dimethyl-1,3-cyclohexanedione

This example illustrates carrying out the process using a metal carbonate base.

5,5-dimethylcyclohexane-1,3-dione (3.50 g, 0.025 mol), potassium carbonate (10 g), potassium cyanide (0.2 g) and 40 ml of dimethylformamide are placed in a flask and placed under a nitrogen atmosphere. Add p-chlorobenzoyl chloride (3.5 µL, 0.025 eol) dropwise. The mixture was stirred at 40 ° C for 3 hours and at 70 ° C for 2 hours.

The reaction mixture was diluted with methylene chloride and acidified with 3N hydrochloric acid solution. The organic phase was washed with water and extracted with 2.5N sodium hydroxide solution. The basic extract was acidified with a 3N hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried to give 5.46 g (78.0% of theory) of the crude product. HPLC analysis of the product indicated 63% wt. 2- (4-chlorobenzoyl) -5,5-dimethyl-l-1,3-cyclohexanedione. The greatest impurity was only p-chlorobenzoic acid.

Example 17

2- (2-chloro-4-methanesulfonylbenzoyl) -1,3-cyclohexanedione

0.376 mol of 1,3-cyclohexanedione, 1.0 mol of triethylamine, 0.026 mol of acetone cyanohydrin and 1.5 mol of toluene are added to the flask. The temperature is kept below 20 ° C. Then, 2-chloro-4-methanesulfonylbenzoyl chloride (0.3666 mol) was added via a dropping funnel, which was then washed with toluene. The temperature is maintained at 60 ° C. Water is added to the reaction product, neutralized with caustic, and the aqueous phase is treated with 20% by weight of hydrochloric acid. The product is regenerated, filtered and analyzed by structure-compatible infrared, nuclear magnetic resonance and mass spectroscopy.

Example 18

2- (2-chloro-3-ethoxy-4-ethanesulfonylbenzoyl) -1,3-cyclohexanedione

355 g (3.07 mol) of 1,3-cyclohexanedione, 2,7 + 1,2-dichloroethane and 1.29 l (9.21 mol) of triethylamine are charged to the reactor. The mixture is cooled to 3 ° C and then 1003 · g (3.00 moles) of crude 2-chloro-4-ethanesulfonyl-3-ethoxybenzoyl chloride in 900 ml of 1.2 is added over 76 minutes while maintaining the reaction temperature at 0 ° C. -dichloroethane. Analysis of an aliquot part of the mixture by gas chromatography at the end of this section shows the complete formation of the enol ester with at most a trace of the remaining acid chloride.

25.0 g (0.252 mol) of triethylsilyl cyanide are then added in one portion and the temperature is allowed to rise. After 4.5 hours, gas chromatography analysis showed no unreacted residual enol ester. The mixture was allowed to stand overnight and then hydrochloric acid, water, sodium hydroxide and dichloromethane were added. 952 g (7θ> 3% of theory) of the desired product is obtained, the structure of which is confirmed by spectroscopic methods as described above.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of an acylated cyclic diketone compound of formula (I) / 1 0 Λ in %. -h E (AND) ^r 4 \ = ^ Rg v ⁰ 6 where Rj> ^ 2 ' ^R 4' ^R 5 ^{and R} 6 ^{are Sou} independently hydrogen or alkyl having 1 up to 6 carbon atoms, R? is hydrogen, halogen , cyano , alkyl s 1-4 carbon atoms, haloalkyl of 1 to 2 4 alkoxy, nitro or R ^{5/0-R 'wherein R} to ^{а1к У!} with 1 to 4 carbon atoms and n is 0,1 or 2, R 8 and R 6 are independently hydrogen, halogen, C 1 -C 4 alkoxy or R _b S / O / _n , where R _b is C 1 -C 4 alkyl 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms and n is 0, 1 or 2, the rearrangement of the corresponding enol ester containing a group of formula II (11) С \ н / wherein R is an appropriately substituted phenyl group, characterized in that the rearrangement is carried out in the presence of a catalytic amount of a cyanide source comprising alkali metal cyanides, cyanohydrins of C 1-4 alkyl alkyl ketone, benzaldehyde cyanohydrin, cyanohydrins of aliphatic C 2 -C 5 aldehydes, trimethylsilyl cyanide and hydrogen cyanide, and a molar excess of the weak base relative to the enol ester or in the presence of a stoichiometric amount of alkali metal cyanide relative to the enol ester and a catalytic amount of the cyclic Crown Ether or its acyclic analog.