HRP940855A2 - Process for the production of acylated diketoic compounds - Google Patents

Description

The technical field to which the invention belongs

The invention belongs to the field of synthesis of aliphatic organic compounds and relates to the production of acylated diketone compounds by transferring the corresponding enol esters.

Technical problem

The types of compounds that will later be called acylated diketone compounds have the general formula:

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wherein R is a group as defined hereinafter (and may generally be an aromatic or aliphatic group). Compounds of this type are described in a number of references as useful, for example, as chemical intermediates and/or pesticides. The rest of the molecule, which includes the diketone group, has a mostly cyclic structure. the most preferred diketone group includes a 5- or 6-membered carbocyclic ring. Acylated diketone compounds of this type have the general structure:

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where R is as defined above and n is 2 or 3. The ring may be unsubstituted or substituted in one or more positions, for example, with alkyl, aryl, alkylene, etc., groups.

State of the art

One process for the production of acylated diketone compounds is described in European Patent Application. Publication No. 90262 and involves the reaction of an optionally substituted 1,3-cyclohexanedione with a substituted benzoyl cyanide. However, such a procedure has some disadvantages. Benzoyl cyanides are somewhat expensive reagents and hydrogen cyanide is produced in this reaction in amounts of about one mole for each mole of acylated ketone. Thus, it would be desirable to carry out the reaction using a less expensive and more readily available type of acylating agent that does not additionally produce such amounts of hydrogen cyanide. For example, benzoyl chlorides are relatively inexpensive and accessible forms of acylating agents. However, benzoyl chlorides are stronger acylating agents than benzoyl cyanide and, in the presence of common catalysts, will show a tendency not to perform acylation on the carbon atom between two carbonyl groups, but to directly attack one of the carbonyl groups themselves, forming an enol ester of the type:

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It is known from a number of references that acylated cyclic diketone compounds can be produced from the corresponding enol esters by moving:

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The references describe several different types of acylated diketone compounds and different catalysts or promoters for the transfer of enol esters to acylated diketones.

For example, Akhrem et al., Synthesis, pp. 925-927 (1978) describe the production of a number of acylated cyclohexanediones by reacting 1,3-cyclohexanedione with an acylating agent (especially an acyl halide) in two steps. In the first step, the acyl halide reacts with cyclohexanedione in the presence of pyridine to produce an enol ester, which is then converted to acylated cyclohexanedione by displacement in the presence of a two-molar excess of aluminum chloride. The acylating agents used in this work had the formula RCOCl where R was various alkyl (eg, methyl, ethyl, propyl), phenyl, substituted phenyl, benzyl, and substituted benzyl groups.

Tanabe et al., Chem. Letters, p. 53 (1982) describe work on the production of 3-acyl-4-hydroxy-2-pyrone by acylation of the pyrone with alkyl- or alkenyl-type acyl halides and displacement of the enol ester formed using a catalytic amount of 4-dimethylaminopyridine.

European Patent Application (Publication No.) 123001 discloses that other aminopyridine derivatives as well as certain N-alkylimidazole derivatives are suitable catalysts for the transfer of enol esters to acylated cyclohexanediones having a 5-carboxylate substituent.

USSR Patent 784,195 describes the transfer of enol esters to produce 2-oleoyl-cyclohexane-1,3-dione in the presence of molten sodium acetate at 160-170°C. European Patent Application, Publication No. 80301 describes the conversion of enol esters of 5-(polymethyl-phenyl)-1,3-cyclohexanedione to the corresponding acylated cyclohexanediones in the presence of some Lewis acid. Acylating agents used included anhydrides and acyl halides of the formula RCOCl where R is alkyl, fluoroalkyl, alkenyl, alkynyl or phenyl.

Description of the solution to the technical problem with implementation examples

This invention relates to a process for the production of an acylated cyclic diketone compound by displacement of an enol ester in which the displacement is carried out in the presence of a cyanide source.

This invention relates to a process for the production of an acylated diketone compound by transferring the enol ester according to the general reaction:

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where the transfer is done in the presence of a cyanide source.

More specifically, moving is done in the presence of or

(a) catalytic amounts of the cyanide source and a molar excess, relative to the enol ester, of some moderate base, for example, a tertiary amine, an alkali metal carbonate or an alkali metal phosphate; or

(b) stoichiometric amounts, relative to the enol ester, of calcium cyanide or lithium cyanide, and catalytic amounts of the cyclic Crown ether or its acyclic analogue.

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Wherein R can be various alkyl, alkenyl, aryl (for example, phenyl or substituted phenyl), phenalkyl (for example, optionally substituted benzyl, phenethyl, etc.), or other substituents, for example, those mentioned in the above described references.

The rest of the molecule includes a series of atoms that connect the carbon atoms of the two carbonyl groups so that the diketone is a cyclic compound. The diketone carbocyclic compound is most preferred. Preferred forms of diketones are cyclopentanediones and cyclohexanediones, which may be substituted in one or more positions on the ring with an alkyl, aryl or other substituent group. Most preferred are 1,3-cyclohexanediones, optionally substituted with one or more alkyl groups.

A particularly preferred class of products is that in which the diketone is cyclohexanedione and the acylating group is a substituted benzoyl group. That is, R is substituted phenyl. Basically, these compounds have the formula:

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in which:

R1, R2, R3, R4, R5 and R6 are independent hydrogen or C1-C6 (preferably C1-C4 alkyl) or

ON

║

R 1 , R 2 or R 3 is RaOC-where Ra is C 1 -C 4 alkyl, phenyl, optionally substituted with from 2 to 5 methyl groups;

or where R1 and R2, or R3 and R4, taken together are C3-C6 alkylene (such compounds have a spiro structure);

R 7 is halogen (chlorine, bromine, iodine or fluorine);

cyano;

C1-C4 alkyl;

C1-C4 haloalkyl (preferably trifluoromethyl);

RkS(O)n where Rk is C1-C4 alkyl and n is preferably 0, 1 or 2;

C1-C4 alkoxy (preferably methoxy) or nitro;

R 8 , R 9 and R 10 are independently hydrogen or substituents including halogen;

C1-C4 alkyl;

C1-C4 Alkoxy,

trifluoromethoxy;

cyano;

nitro;

C1-C4 haloalkyl;

C1-C4 alkylthio;

phenoxy; or

substituted phenoxy wherein the substituent is halogen or halomethyl or both;

RbS(O)n where n is 0, 1 or 2; and Rb is C1-C4 alkyl, C1-C4 haloalkyl, phenyl or benzyl,

ON

║

RcCHN - where Rc is C1-C4 alkyl,

-NRdRe where Rd and Re are independently hydrogen or C1-C4 alkyl;

RfC(O). Where Rf is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;

S=2NRgRh where Rg and Rh are independently hydrogen or C1-C4 alkyl;

or R8 and R9 taken together form a ring structure with two adjacent carbon atoms of the phenyl ring to which they are attached.

Compounds of this type have various substituents either on one, cyclohexane or on the phenyl ring are described in: European Patent Application, Publication No. 90262; next undecided u.s. patent applications, all the way to William J. Michaely et al., belonging to the present Applicant, and entitled: Certain 2-(2-Substituted Benzoyl)-1,3-Cyclohexanediones”: Serial No. 634, 408, filed July 31, 1984; Serial No. 640,791, filed July 31, 1984; Serial No. 752,702, filed July 8, 1985; and serial no. 722,593, filed September 5, 1985; the next U.S. patent applications belonging to the present Applicant, filed December 20, 1984; Serial No. 683,900, entitled “Certain 2-(2-nitrobenzoyl)-1,3-cyclohexanediones,” by Charles G. Carter; Serial No. 683,899, entitled “Certain 2-(2'-cyanobenzoyl)-1,3-cyclohexanediones” by Charles G. Carter; Serial No. 683,898, entitled “Certain 2-(2'-Substituted Benzoyl)-1,3-Cyclohexanediones” by Charles G. Carter et al.; and Serial No. 683,884 entitled “Certain 2-(2'-alkylbenzoyl)-1,3-cyclohexanediones” by Charles G. Carter; (all these patent applications relate to compounds that are herbicidal) and Japanese Patent Applications (Publication Nos.) 51/13750 and 51/13755 of Nippon Soda K.K., which describe some compounds of this type as herbicide intermediates. The descriptions of these documents are incorporated herein by reference.

Some other compounds to which this procedure can be applied are described in pending U.S. Pat. patent applications (usually indicated) Serial No. 764,110, filed Aug. 26, 1985 by David L. Lee et al., entitled “Certain 2-(2-Substituted Phenylacetyl 1,3-Cyclohexanediones”); and Serial No. 683,883, filed Dec. 20, 1984, by David L. Lee et al. L. Lee et al., entitled “Certain 2-(2'-Substituted Benzoyl)-1,3-Cyclohexanediones”, and compounds described in the literature and mentioned under the heading “Prior Art”. is in the presence of a cyanide source. The term "cyanide source" refers to a substance or substances which, under conditions of displacement, contain or generate hydrogen cyanide and/or cyanide anion. There are two primary embodiments.

In one embodiment, the process is carried out in the presence of a catalytic amount of a source of cyanide anion and/or hydrogen cyanide, together with a molar excess, relative to the enol ester, of some moderate base.

Preferred cyanide sources are alkali metal cyanides such as sodium and potassium cyanide; methylalkylketone cyanohydrins having from 1-4 carbon atoms in the alkyl groups, such as acetone or methylisobutylketone cyanohydrins; cyanohydrins of benzaldehyde or C2-C5 aliphatic aldehydes such as cyanohydride of acetaldehyde, propionaldehyde, etc.; zinc cyanide; three (lower alkyl) silicyanides, especially trimethylsilicyanide; 1 is hydrogen cyanide. Hydrogen cyanide is considered the most suitable since it produces a relatively fast reaction and is cheap. It can be used either in liquid or gaseous form; when used as a gas it can be purchased from a commercial supplier or generated in situ by reacting metal cyanide with an acid. Among cyanides, the preferred source of cyanide is acetone cyanohydrin.

In this embodiment, the cyanide source is used in an amount up to about 50 mole percent based on the enol ester. It can be used in as little as about 1 mole percent to provide an acceptable reaction rate at about 40°C on a small scale. Larger scale reactions give reproducible results with slightly higher catalyst levels of about 2 mole percent. Generally, about 1-10 mole % of the cyanide source is preferred.

In this embodiment, the procedure is carried out with a molar excess in relation to the enol ester, some moderate base. By the term "moderate base" here is meant a substance that acts as a base and whose strength or activity as a base lies between those having such strong bases as hydroxides (which can cause hydrolysis of enol esters) and those having such weak bases as bicarbonates ( (which will not function effectively). Moderate bases suitable for use in this embodiment include both 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 trisodium phosphate.

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

When the cyanide source is alkali metal cyanide, especially potassium cyanide, a phase transfer catalyst may be included in the reaction. Particularly preferred catalysts for phase transfer are crown ethers. A number of different solvents can 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 reactants or products, include toluene, acetonitrile, methylene chloride, ethyl acetate, dimethylformamide, and methylisobutyl ketone (MIBK).

Basically, depending on the nature of the reactants and the cyanide source, the transfer can be carried out at temperatures up to about 80°C. In some cases, for example, when excessive by-product formation is a possible problem (for example, when using orthocyanobenzoyl halide and alkali metal cyanide or acetone cyanohydrin as the cyanide source) the temperature should be kept at a maximum of about 40°C.

In another primary embodiment of this process, potassium or lithium cyanide serves as the cyanide source, but is used in a stoichiometric amount relative to the enol ester, without using a specific base. A cyanide source is used together with a catalytic amount of a phase transfer catalyst which is a crown ether or its acyclic analogue.

The preferred cyanide source in this embodiment is potassium cyanide. The preferred crown ether for this purpose is 18-crown-6. Other hexadentate compounds such as cyclohexoxy-18-Crown-6, dibenzo-18-Crown-6 and the acyclic compounds pentaethyledglycol dimethyl ether will also be suitable.

15-Kruna-5 is suitable for lithium cyanide.

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

This embodiment is suitable for the production of compounds of the general type but has been found to be particularly satisfactory for use when milder conditions are required or suitable to reduce the formation of a side product, as in the production of benzoylated cyclohexanediones having an ortho-cyano substituent on the phenyl ring. This implementation of the procedure can be carried out at room temperature. Similar solvents to the first embodiment can be used; acetonitrile is preferred.

The process according to any embodiment can be carried out using an enol ester as a starting material, or with the generation of an enol ester in situ, for example, by reacting an acylating agent with a diketone. The term “enol ester” as used herein refers to an enol ester of a carboxylic acid.

When an enol ester is used as a starting material in any embodiment of the process, it can be made by any of a number of known means, including alkylation of the diketone material with, for example, an acyl halide.

The production of acylated diketones according to this invention, starting with acylated agents and diketones (for example, with acyl halides and diketones such as cyclohexanediones) can conveniently be carried out with or without isolation of the intermediate enol ester. When carried out in two stages, the acyl halide or other acylating agent and the diketone are reacted in the presence of such a mild base as triethylamine. The enol ester can be isolated from the mixture of reaction products obtained by known techniques, for example, by washing the obtained solution with acid and base, and with saturated sodium chloride solution, and drying. Such a technique is suitable when a different solvent is desired for the second step - the transfer of the enol ester to the acylated di-ketone. The dried enol ester can then be mixed with such a suitable solvent as acetonitrile or 1,2-dichloroethane, and contacted with suitable amounts of a cyanide source and either a moderate base or a crown ether, depending on the embodiment used, at a suitable temperature, so that the final product is produced.

Alternatively, the enol ester can be retained in the reaction product and a second step can be performed (using the same solvent) by adding a cyanide source and additional base if necessary (in this embodiment) to produce the acylated diketone.

In another variation of the process, the acylated diketone product can be obtained in one step via in situ formation and transfer of the enol ester by reacting an acyl halide or other acylating agent with a diketone in the presence of an appropriate amount of cyanide source and a suitable amount of a moderate base or crown ether, depending on the embodiment used .

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

The acylated diketone product is obtained from this reaction in the form of its salt in the first described embodiment. The desired acylated diketone can be obtained by acidification and extraction with a suitable solvent, if necessary. In some cases, the product may be contaminated with small amounts of the carboxylic acid corresponding to the acyl halide; such side products can be separated by contacting the acidified solution of the product with dilute aqueous sodium hydroxide or with some other suitable base, so that the acid salt is formed. In another embodiment, the acylated diketone can be obtained by itself. The implementation of the process of this invention is illustrated by the following examples.

Example 1

Displacement of enol esters

A series of experiments was performed on the production of 2-(2', 3', 4'-trichlorobenzoyl)-1,3-cyclohexanedione by displacement of its enol ester using various sources of cyanide and solvents. The general procedure is as follows: 3.0 grams (g) (0.0094 mole) of the enol ester (made by reacting 2,3,4-trichlorobenzoyl chloride with 1,3-cyclohexanedione in the presence of triethylamine and isolated) is dissolved in 10 milliliters (ml) of the indicated solution and added se 10 mole percent of the designated catalyst and 140 mole percent of triethylamine (both amounts in relation to the enol ester).

The mixture is kept at room temperature and allowed to react for 4-18 hours. The reaction mixture is diluted with water and the solvent is separated by distillation under reduced pressure. The resulting aqueous mixture is acidified to a pH of about 1 by slowly adding 6N hydrochloric acid, with stirring. The resulting solids are collected by filtration and dried to a constant mass at 75°C.

The yield of the crude acylated diketone product, uncorrected for the purity of the starting materials, is shown in Table 1 below.

Table 1

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Example 2

Preparation of acylated diketone without isolation of enol ester

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

3.0 g (0.027 mol) of 1,3-cyclohexanedione, 15 ml of the specified solvent and 10 mole percent (relative to the intermediate enol ester) of sodium cyanide are placed in the flask. The reaction mixture is placed under a blanket of nitrogen and maintained at room temperature. Then it is kept at room temperature, since 300 mole percent of triethylamine (on the basis of enol ester) was previously added. Then 100 mole percent (relative to dione) of 2,3,4-trichlorobenzochloride is added to the mixture. The mixture is kept at room temperature and allowed to react for about 24 hours. The product is isolated as in Example 1, yielding 8.04 g of crude product (93.2% of theory, uncorrected for purity of starting materials).

Example 3-6

A series of experiments similar to those described in Example 2 were performed, but using different catalysts and solvents using the same reactants. All catalysts are used in an amount of 10 mole %, based on the intermediate enol ester. Table 2 contains the results of these experiments, where the yields are uncorrected for the purity of the starting materials.

Table 2

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Example 7

This example also represents carrying out the process without isolating the intermediate enol ester.

15 grams (0.13 mol) of 1,3-cyclohexanedione, 75 ml of 1,2-dichloroethane and 0.25 ml (2 mol percent based on enol ester) of acetone cyanohydrin are placed in the flask. The materials are placed under a blanket of nitrogen and the balloon is placed in an ice bath.

54.36 ml (34.96 g, 0.39 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 placed in the flask. When the addition of both amine and benzoyl chloride is complete, the temperature of the reaction mixture is brought up to 40°C and the mixture is allowed to react for 2 hours. At the end of this period, high pressure liquid chromatography monitoring showed an area of 84.6 percent of the desired product, with the major portion of the residue being unreacted cyclo-hexanedione.

The reaction mixture was then cooled and diluted with 100 ml of water, the pH, which was 9.8, was adjusted to 2.8 by the addition of 3 M sulfuric acid with an additional 100 ml of 1,2-dichloroethane added during this stage to redissolve the solids. substances that start to settle. The mixture is separated into aqueous and organic phases. The aqueous layer (about 200 ml) had a pH of 2.6.

The organic phases are washed with water and the phases are separated again (the aqueous phase had a pH of 4). The organic phase is then washed with 2 portions of 2.5 N aqueous sodium hydroxide and the phases are separated again after each wash. The organic phase is washed again with 100 ml of water.

All aqueous phases obtained from the above separation phases are combined and acidified with 3 M sulfuric acid. The pH value is reduced to 2.1. The combined aqueous phases are kept at low temperature in an ice bath. Solids that settle out of solution are collected by filtration. The solids are dried to a constant mass in a vacuum dryer. 39.19 grams of the desired product is obtained, m.p. 150-151°C. The structure of the product was confirmed by analysis with high pressure liquid chromatography and comparison with a known sample.

Example 8

Production of 2-propanoyl-1,3-cyclohexanedione

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

Examples 9 and 10

These examples illustrate the production of compounds that are described in U.S. Pat. Patent Application Serial No. 683,900 to Charles G. Carter, entitled “Certain 2-(2-nitrobenzoyl)-1,3-cyclohexanediones” filed Dec. 20, 1984.

Example 9

2-(2'-Nitrobenzoyl)-1,3-cyclohexanedione

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2-Nitrobenzoyl chloride (5.0 g, 0.027 mol) and cyclohexanedione (3.0 g, 0.027 mol) were dissolved in methylene chloride. Triethylamine (4.9 ml, 0.035 mol) was added dropwise and the resulting solution was stirred for one hour. The solution is washed with 2 N hydrochloric acid (2N HCL), with water, with 5% potassium carbonate solution and with saturated sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4) and concentrated in vacuo. The residue is dissolved in 20 ml of acetonitrile. Triethylamine (1 equivalent and potassium cyanide 40 mol%) are added and the solution is stirred for 1 hour at room temperature.

After dilution with ether, the solution is washed with 2N HCl and extracted with 5% potassium carbonate solution. The aqueous extract is acidified and ether is added. Filtration of the obtained mixture gives 3.2 g of the desired compound (m.p. 132-135°C), which was identified by nuclear magnetic resonance, infrared and mass spectroscopy.

Example 10

2-(2'-Nitrobenzoyl)-5,5-dimethyl-1,3-cyclohexanedione

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Triethylamine (3.4 ml, 0.025 mol) is added dropwise to a 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 for one hour at room temperature, more 3 equivalents of triethylamine and 0.4 ml of acetoncyanohydrin. The solution is stirred for 2.5 hours, then washed with 2N HCl and extracted with 5% potassium carbonate solution. The base extracts are acidified with 2N HCl and extracted with ether. The ethereal portion is washed with saturated sodium chloride solution, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give 2.0 g of the desired compound (m.p. 130-133°C) which was identified as such by nuclear magnetic resonance, infrared and mass spectroscopy.

Example 11

2-(2'-Cyanobenzoyl)-4,4-dimethyl-4,3-cyclohexanedione

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This example illustrates the production of a compound described in U.S. Pat. Patent Application Serial No. 683,899, by Charles G. Carter entitled “Certain 2-(2'-cyanobenzoyl)-4,4-cyclohexanediones,” filed Dec. 20, 1964.

2-Cyanobenzoic chloride (3.9 g, 0.024 mol) and 4,4-dimethyl-1,3-cyclohexanion (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 for one and a half hours at room temperature. The solution is washed with water, with 2N HCl, with 5% potassium carbonate solution (5% K2CO3) and with saturated sodium chloride solution (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated in vacuo. The residue is dissolved in 20 ml of acetonitrile. Triethylamine (4.4 ml, 0.032 mol) and acetone cyanohydrin (5 drops) were added and the solution was stirred for two hours. After dilution with ether, the solution is washed with 2N HCl and extracted with 5% K2CO3. The aqueous extract is acidified with concentrated hydrochloric acid and extracted with ether. The ether is washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel, so that 1.2 g of viscous oil was obtained, which was identified as the desired compound by nuclear magnetic resonance, infrared and mass spectroscopy.

Example 12

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

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This example illustrates the production of a compound described in U.S. Pat. Patent Application Serial No. 683,898, by Charles G. Carter et al., entitled “Certain 2-(2'-Substituted Benzoyl)-1,3-Cyclohexanediones”, which was filed concurrently with this application.

2-Methylthiobenzoyl chloride (7.2 g, 0.039 mol) and 4,4,6-tri-methylcyclohexanedione (5.0 g, 0.039 mol) were dissolved in methylene chloride. Triethylamine (7.0 ml, 0.050 mol) was added dropwise and the resulting solution was stirred for one hour at room temperature. The solution is washed with 2N HCl, with 5% K2CO3 and with brine, dried over MgSO4 and concentrated in vacuo. The residue is dissolved in 20 ml of acetonitrile. Triethylamine (2.5 equivalents) and acetone cyanohydrin (0.04 ml) were added and the solution was stirred for 45 minutes at room temperature. After dilution with ether, the solution is washed with 2N HCl and extracted with K2CO3. The aqueous solution is acidified with hydrochloric acid and extracted with ether. The ether is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by trituration with ether to give 5.0 g of a viscous oil which was identified as the desired compound by nuclear magnetic resonance, infrared and mass spectroscopy (ms).

Example 13

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

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This example illustrates the production of a compound described in U.S. Pat. Patent Application Serial No. 673,884, by Charles G. Carter, entitled “Certain 2-(2-alkylbenzoyl)-4,3-cyclohexadiones,” filed Dec. 20, 1984.

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 is cooled with an ice bath and reethylamine (2.1 ml, 0.015 mol) in 10 ml of methylene chloride is added dropwise. The ice bath is then separated and the resulting solution is stirred for 30 minutes at room temperature. The solution is washed with 2N hydrochloric acid (2N HCl), with 5% potassium carbonate solution (5% K2CO3) and with saturated sodium chloride solution (saline solution), dried over anhydrous magnesium sulfate (MgSO4) and concentrated in a vacuum. The residue (5.1 g) was dissolved in 20 ml of acetonitrile. Triethylamine (3.5 ml, 0.025 mol) and 0.4 ml of acetone cyanohydrin are added and the solution is stirred for two hours at room temperature while protected by a drying tube (potassium sulfate). After dilution with ether, the solution is washed with 2N HCl and extracted with 5% K2CO3. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. The ether was washed with brine, dried (MgSO4) and concentrated in vacuo. The obtained oil is purified on a silica gel column (80:20:1 hexane:ethyl acetate:acetic acid - eluent), so that 1.5 of viscous oil is obtained, which was identified by nuclear magnetic resonance, infrared and mass spectroscopy.

Example 14

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

This example illustrates the operation of the process using hydrogen cyanide (generated by the reaction of sodium cyanide with sulfuric acid) as the cyanide source.

5,5-Dimethylcyclohexane-1,3-dione (7.01 g 0.05 mol), acetonitrile (80 ml) and trimethylamine (21 ml, 0.15 mol) were combined in a flask and placed under a nitrogen atmosphere. A solution of 4-chlorobenzoyl chloride (6.4 ml, 0.05 mol) in acetonitrile (20 ml) was added during 15 minutes with stirring and cooling with a water bath at room temperature. A solution of sulfuric acid (0.25 g, 0.0025 mol) in water (10 ml) is added to a solution of sodium cyanide (0.25 g, 0.005 mol) in water ( 30 ml) at 85°C with stirring and gentle blowing of nitrogen through the secondary reactor and in the exemplary reactor. The primary reactor is then heated and stirred at 40°C for about 2 hours, after which the reaction is complete.

The reaction mixture is diluted with 60 ml of water and slightly acidified with 40 ml of 6 N HCl with precipitation of the product. After stirring for about 5 minutes, the solid product is collected by filtration, washed with water and dried so that 11.85 g (85.0% of the theoretical yield) of whitish solids are obtained: m.p. 134-134.5°C.

Example 15

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

This example illustrates the operation of a process using a tri-lower alkylsilicyanide as the cyanide source.

5,5-Dimethylcyclohexane-1,3-dione (7.01 g, 0.05 mol), acetonitrile (80 ml) and triethylamine (21 ml, 0.15 mol) were combined in a flask and placed under a nitrogen atmosphere. A solution of 4-chlorobenzoyl chloride (6.4 ml, 0.05 mol) in acetonitrile (20 ml) was added over 15 minutes with stirring and cooling with a water bath at room temperature. Trimethylsilylcyanide (0.33 ml, 2.55 mol) was added, and the reaction was heated and stirred at 40 °C for 3 hours, after which the reaction was complete.

The reaction mixture is diluted with 160 ml of water and acidified with 40 ml of 6N hydrochloric acid solution with precipitation of the product. After stirring for 10 minutes, the product is collected by filtration and washed with water and dried to give 13.2 g (95% of theoretical yield) of off-white solids: m.p. 135-134.5°C.

Example 16

2-(2'-Cyanobenzoyl)-1,3-cyclohexanedione

This example illustrates the implementation of another embodiment of the process, using stoichiometric amounts of potassium cyanide and crown ether.

1.2 g (0.005 mol) of enol ester, which was made by the reaction of 1,3-cyclohexanedione with 2-cyanobenzoyl chloride, potassium cyanide (0.3 g, 0.05 mol), 18-Kruna-6 (0.1 g, 0.0005 mol) are placed in the flask. and 10 ml of acetonitrile. The mixture is stirred at room temperature for 30 minutes, then poured into 300 ml of water. The pH is carefully adjusted to about 6 with concentrated hydrochloric acid; then the solution is extracted with 200 ml of ethyl acetate. Then it is extracted with 300 ml of saturated aqueous solution of sodium bicarbonate. The bicarbonate extract is acidified (to a pH of about 3) with concentrated hydrochloric acid and extracted with 200 ml of ethyl acetate. The resulting solution is dried over sodium sulfate and separated, so that 0.7 g (58% of the theoretical yield) of the desired product is obtained as an orange-brown oil. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectroscopy.

Example 17

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

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

5,5-Dimethylcyclohexane-1,3-dione (3.50 g, 0.025 mol), potassium carbonate (10 g), potassium cyanide (0.2 g) and dimethylformamide (40 ml) were combined in a flask and placed under a nitrogen atmosphere . p-chlorobenzoyl chloride (3.5 ml, 0.025 mol) is added dropwise. The mixture is stirred at 40°C for 3 hours and at 70°C for 2 hours.

The reaction mixture is diluted with methylene chloride and acidified with a 3N hydrochloric acid solution. The organic phase is washed with water and extracted with 2.5 N sodium hydroxide solution. The basic extract is acidified with a 3 N solution of hydrochloric acid. The settled product is collected by filtration, washed with water and dried to obtain 6.46 g (78.0% of the theoretical yield) of the crude product. Analysis of the product by HPLC (high performance liquid chromatography) showed 63% by mass of 2-(4'-chlorobenzoyl)-5 1,3-cyclohexanedione. p-Chlorobenzoic acid was only the main impurity.

Claims (15)

1. Process for the production of an acylated cyclic diketone compound by displacement of the corresponding enol ester, characterized in that the displacement is carried out in the presence or (a) catalytic amounts of cyanide source and molar excess, relative to enol ester, of moderate base; or (b) stoichiometric amounts, in relation to enol ester, potassium cyanide or lithium cyanide and catalytic amounts of cyclic crown ether or its acyclic analogue 2. The method according to claim 1, characterized in that the displacement is carried out in the presence of a source of cyanide, which is alkali metal cyanide, zinc cyanide, cyanohydrin methyl alkyl ketone with 1 to 4 carbon atoms in the alkyl group; benzaldehyde cyanohydrin; C2-C5 aliphatic aldehyde cyanohydrin; tri(lower alkyl)silyl cyanide or hydrogen cyano, and a molar excess, relative to the enol ester, of a moderate base. 3. The method according to claim 2, characterized in that the source of cyanide is hydrogen cyanide. 4. The method according to claim 2, characterized in that the source of cyanide is sodium cyanide. 5. The method according to claim 2, characterized in that the source of cyanide is potassium cyanide. 6. The method according to claim 2, characterized in that the source of cyanide is acetone cyanohydrin. 7. The method according to claim 2, characterized in that the source of cyanide is used in an amount of about 1 to about 10 molar percent, in relation to the enol ester. 8. The method according to claim 2, characterized in that the moderate base is a tertiary amine, an alkali metal carbonate or an alkali metal phosphate. 9. Process according to claims 2 to 8, characterized in that the moderate base is trialkylamine. 10. Process according to claims 2 to 9, characterized in that the moderate base is triethylamine. 11. Process according to claims 2 to 10, characterized in that the base is used in an amount of about 1 to 4 per mole of enol ester. 12. The process according to claim 1, characterized in that the displacement is carried out in the presence of a stoichiometric amount, in relation to the enol ester, potassium cyanide or lithium cyanide and a catalytic amount of cyclic Crown ether or its acyclic analogue. 13. The method according to claim 1, characterized in that the acylated diketone compound is a cyclohexanedione derivative. 14. The method according to claim 1, characterized in that the acylated diketone compound is a substituted benzoyl derivative of 1,3-cyclohexanedione. 15. The method according to claim 1, characterized in that the acylated diketone compound has the formula: [image] in which they are R1, R2, R3, R4, R5 and R6 are each independently hydrogen or C1-C6 alkyl or R1, R2 or R3 is [image] wherein Ra is C1-C4 alkyl, phenyl, optionally substituted with 2 to 5 methyl groups; or where R 1 and R 2 or R 3 and R 4 , taken together are C 1 -C 6 alkylene; R 7 is halogen; cyano; C1-C4 alkyl; C1-C4 haloalkyl; R k S (O) n where R k is C 1 -C 4 alkyl and n is 0, 1 or 2; C1-C4 alkoxy; R8, R9 and R10 are each independently hydrogen; halogen; C1-C4 alkyl; C1-C4 alkoxy, trifluoromethoxy; cyano; nitro; C1-C4 haloalkoxy; C1-C4 alkylthio; phenoxy; or substituted phenoxy wherein the substituent is halogen or halometal or both; RbS (O)n where n is 0, 1 or 2; and Rb is C1-C4 alkyl; C1-C4 haloaxyl, phenyl or benzyl, [image] where is Rc C1-C4 alkyl, -NrdRe where Rd and Re are each independently hydrogen or C1-C4 alkyl; RfC(O)- where Rf is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; SO2NRgRh wherein Rg and Rh are each independently hydrogen or C1-C4 alkyl; or R8 and R9 taken together form a ring structure of two adjacent carbon atoms of the phenyl ring to which they are attached.