MXPA98002592A - Procedure for preparing chlorine ketones, with the use of oxazoli - Google Patents

Abstract

This invention relates to a process for the preparation of an alpha-chloroketone compound, this process comprises the steps of: (i) subjecting an alkynyl amide to cyclization, to form a 5-methyleneoxazoline: (ii) subjecting to chlorination the 5-methylenexazoline, using the trichloroisocyanuric acid, to produce a chlorinated intermediate of oxazoline (iii) hydrolyze the chlorinated intermediate product of oxazoline, with an aqueous acid, to produce the desired monochloro ketone: wherein: Z is alkyl or substituted alkyl, aryl or aryl substituted, heteroaryl or substituted heteroaryl, or phenylene, R is a hydrogen atom or an alkyl group, and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they unite, form a cyclical structure. Additionally, when R is a hydrogen atom, a dichloro ketone can be formed conveniently by adjusting the reaction conditions.

Description

PROCEDURE FOR PREPARING CHLOROCETONS. WITH THE »USQ PE LAS QXAZQUNAS This invention relates to a novel, inexpensive process for preparing the 5-methylene oxazolines from the substituted alkynyl amides, followed by the subsequent conversion of the 5-methyleneoxazoline to an a-chloroketone, using a convenient chlorination agent, followed by hydrolysis. The resulting a-chloroketones are useful as fungicides. There are several problems in the existing field, which overcomes the present invention. Routes previously described for the desired 5-methylenexazoline, from the substituted alkynyl amides, required the use of strong and, consequently, expensive bases, such as sodium hydride or sodium amide. These bases require the use of scrupulously anhydrous conditions and are difficult to handle. Additionally, the yields of 5-methylene oxazoline from the alkynyl amide are unacceptably low for economic viability. Other routes described for the 5-methylenexazoline desired from the substituted alkynyl amides involve the treatment of the amide with silver ions in the N, N-dimethylformamide. This type of process uses a costly and environmentally toxic catalyst and a solvent that requires difficult processing and produces large volumes of aqueous waste loaded with organic substances. Still other disclosed routes employ water-soluble solvents in a method to form a 5-methylenexazoline, but such solvents are difficult to recover efficiently and result in a process that has an inconvenient cost. The subsequent preparation of an a-chloroketone from 5-methylenexazoline by known and customary methods, such as by the use of chlorine gas or N-chlorosuccinimide as the chlorinating agent, is also problematic, due to the lack of Selectivity of the monochlorination, forming both sub-chlorinated and overdosed ketones typically by addition to the desired monochloro ketone following the hydrolysis of 5-chloromethylene-oxazoline. Likewise, the use of chlorine presents dangers and a cost of equipment well known to experts in the field. We have discovered two convenient routes for -methylene oxazolines from substituted alkynyl amides. The first requires only the use of a cheap base, such as an aqueous solution of sodium hydroxide or sodium carbonate in the presence of an organic solvent and a phase transfer agent ("PTA"). The second requires only the use of a cheap, organic or mineral acid, such as oleum, an organosulfonic acid or a trihaloacetic acid, in the presence of an organic solvent.

We have also identified a novel chlorination reagent, trichloroisocyanuric acid (TCIA), which chlorinates the resulting 5-methyleneoxazoline selectively to give a monochlorinated intermediate, which, in acid-catalyzed hydrolysis, supplies a-monochloroacetone. desired, selectively and with high performance. TCIA has a high melting point, is an easily manageable solid that can be used in extremely precise quantities, in order to avoid under- or over-chlorination of the desired material. Although TCIA is a well-known, cheap and commercially available compound used in the chlorination of swimming pool water and in disinfecting drinking water, its use as a convenient and selective chlorinating agent for 5-methylenexazolines is not He has described above. A further feature of this invention provides a convenient process for the selective formation of a, a-dichloroketones, which are also useful as fungicides. WO 95/19351 discloses the formation of the aryl-5-methylenexazole derivatives, by the cyclization of an alkynyl amide, in the presence of a base. However, only the use of a large amount of strong base for cyclization is exemplified. Likewise, the use of a phase transfer agent to reduce cyclization is not suggested. The use of an acid for cyclization is also not suggested. Yih et al., In Weed Science, 18, 604-607 (1970) and J. Agr. Food Chem. , 19, 314-317 (1971) discloses the formation of an aryl-5-methylenexazoline from a substituted alkynyl amide, with the use of an acid, base or silver ions, in an aqueous alcohol solution, followed by hydrolysis to a ketone that does not possess an a-chloro group. The patents of E. ü. A., Nos. 4,822,902 and 5,304,572, disclose the formation of 5- (chloromethylene) oxazolines, which are obtained by the treatment of an alkynyl amide with chlorine. However, the use of TCIA as a chlorinating agent is not revealed or suggested. These references, either by themselves or taken together, do not suggest the process of the present invention. One embodiment of this invention provides a convenient process for preparing the a-chloroketones, which are useful as fungicides, comprising the steps of subjecting a substituted alkynyl amide to cyclization, with the use of a moderate aqueous base, in the presence of a organic solvent and a phase transfer agent, to form a 5-methylexaxazoline in a first step, chlorinate 5-methyleneoxazoline in a solvent using trichloroisocyanuric acid to produce a chlorinated oxazoline intermediate in a second step and, subsequently, hydrolyze the chlorinated oxazoline intermediate with an aqueous acid to produce the desired monochloro ketone in a third step. This ketone is typically isolated by the crystallization-filtration product. Specifically, this embodiment provides a process for the preparation of an a-chloroketone compound of the formula (I), which comprises the steps of: (i) cyclizing an alkynyl amide of the formula (II), using a moderate aqueous base, in the presence of an organic solvent and a phase transfer agent ("PTA"), to form a 5-methyleneoxazoline of the formula (III): (ii) chlorinating the 5-methylexaxazoline, of the formula (III), in a solvent, using the trichloroisocyanuric acid, to produce a chlorinated oxazoline intermediate of the formula (IV): and (iii) hydrolyzing the chlorinated oxazoline intermediate of the formula IV) with an aqueous acid to produce the desired monochloro ketone of the formula (I): wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure. In a preferred form of this embodiment, Z is an alkyl (C? -Cg), phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, (C1-C4) alkyl, alkoxy (C1-C4), (C2-C5) alkynyl, nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; R is a hydrogen atom or an alkyl group (C] _-C4), and R1 and Rz are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they join, form a cyclopentyl or cyclohexyl ring. In a more preferred form of this embodiment, Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C1-C4) -phenyl, 3,5-dihalophenyl, 3,5-dialkyl (C1-) C4) -phenyl, 4-alkyl (C? -C4) -3,5-dihalophenyl, 4-cyano-3,5-dihalo-phenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4- nitrophenyl, 2-naphthyl, 3-pyridyl or 1,4-phenylene; R is a hydrogen atom, a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring. In an even more preferred form of this embodiment, Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2- Naphyl, 3-pyridyl or 3-heptyl; R is a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl, A second embodiment of this invention provides a convenient process for preparing a-chloroketones, which are useful as fungicides, this process comprises the steps of When cyclizing an alkynyl amide, which uses an acid, in the presence of an organic solvent, under anhydrous conditions, to form a 5-methyleneoxazoline in a first step, chlorinate this 5-methyleneoxazoline in a solvent, which uses trichlorocyanuric acid to producing a chlorinated oxazoline intermediate, in a second step and then hydrolyzing the chlorinated oxazoline intermediate with an aqueous acid, to produce the desired monochloro ketone in a third step. This ketone is typically isolated by a crystallization-filtration method. Specifically, this embodiment provides a process for the preparation of an a-chloroketone compound of the formula (I), which comprises the steps of: (i) cyclizing an alkynyl amide of the formula (II), of the formula (III) (ii) chlorinating the 5-methyleneoxazoline, of the formula (III), in a solvent, using the trichloroisocyanuric acid, to produce a chlorinated oxazoline intermediate , of the formula (IV): (iii) hydrolyzing the chlorinated oxazoline intermediate of the formula IV) with an aqueous acid to produce the desired monochloro ketone of the formula (I): where : Z is alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and Rz are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure. In a preferred form of this embodiment, Z is an alkyl (C? -Cs), phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, (C1-C4) alkyl, alkoxy (C1-C4), (C2-C5) alkynyl, nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; R is a hydrogen atom or an alkyl group (C? ~ C4), and R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which join, form a cyclopentyl or cyclohexyl ring. In a more preferred form of this embodiment, Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C1-C4) -phenyl, 3,5-dihalophenyl, 3,5-dialkyl (C1-) C4) -phenyl, 4-alkyl (C-C4) -3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-alkoxy (C-C4) -3,5-dihalophenyl, 4-nitrophenyl, 2 -naphthyl, 3-pyridyl or 1,4-phenylene; R is a hydrogen atom, a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring. In an even more preferred form of this embodiment, Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2- Naphyl, 3-pyridyl or 3-heptyl; R is a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

In both embodiments of this invention, the amount of TCIA, which is employed in step (ii), can be advantageously increased, in order to form the 5- (dichloromethylene) oxazolines, which are subsequently hydrolysed to the a, a -Dichloroketones, which are useful as fungicides. Specifically, this feature of the invention provides a process for the preparation of an a, d-dichloroketone compound of the formula (IA), which comprises the steps of: (i) cyclizing an alkynyl amide of the formula ( IIA), to form a 5-methylenexazoline, of the formula (IIIA): R1 (ii) chlorinating the 5-methyleneoxazoline, of the formula (IIIA), in a solvent, using the trichloroisocyanuric acid, to produce a chlorinated oxazoline intermediate of the formula (IVA): and (ii) hydrolyzing the chlorinated oxazoline intermediate, of the formula IVA), with an aqueous acid, to produce the desired monochloro ketone, of the formula (IA): CHC12 (IA) wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure. In a preferred form of this embodiment, Z is an alkyl (C? -Cg), phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, (C1-C4) alkyl, alkoxy (C1-C4), alkynyl (C2 ~ Cg), nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; and R1 and R2 are each, independently, an (C-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring. In a more preferred form of this feature, Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C 1 -C 4) -phenyl, 3,5-dihalophenyl, 3,5-dialkyl (C-4) -phenyl, 4-alkyl ( C1-C4) -3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4-nitrophenyl, 2-naphthyl, 3-pyridyl or 1, 4-phenylene; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

In an even more preferred form of this feature, Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2- Naphyl, 3-pyridyl or 3-heptyl; R1 and R2 are each, independently, methyl or ethyl.

In this invention, alkyl means a straight chain alkyl (C? -Cg) or a branched chain (C3-C8) alkyl group, and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, secondary butyl, tertiary butyl, n-amyl, isoamyl, n-hexyl, isooctyl and the like. "Substituted alkyl" means an alkyl group substituted with one or more substituents, selected from the group consisting of alkoxy, halogen, alkylthio and cyano. "Alkoxy" means a straight-chain (C-C4) alkyl group or a branched-chain (C3-C4) alkyl group attached to an oxygen atom, for example, methoxy, ethoxy, isobutoxy and the like. "Alkylthio" means a straight-chain (C-C4) alkyl group or a branched-chain (C3-C4) alkyl group, attached to a sulfur atom, for example ethylthio, n-propylthio, sec. -butylthio and the like. Halogen means bromine, chlorine, fluorine and iodine.

Aryl means phenyl, naphthyl, or phenyl or naphthyl substituted with one to three substituents, independently selected from the group consisting of halogen, alkyl, alkynyl, alkoxy, nitro or cyano. Examples include, but are not limited to, phenyl, 2-naphthyl, 4-nitrophenyl, 4-chlorophenyl, 3,5-dimethylphenyl, 2,6-difluorophenyl, 3,5-dichloro-4-methylphenyl, 3,5-dichloroenyl , 3, 5-difluorophenyl, 3,5-dibromophenyl, 3-chloro-4-ethyl-5-fluorophenyl, 3,5-dichloro-4-cyanophenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-difluoro -4-propargylphenyl, 3,5-dibromo-4-methylphenyl and the like. Alkynyl means an alkynyl group (C2-Cg), for example, ethynyl, propargyl, 2-hexynyl, and the like. "Heteroaryl" means a 5-membered aromatic ring, which may contain an oxygen atom, a sulfur atom, 1, 2 or 3 nitrogen atoms, an oxygen atom with 1 or 2 nitrogen atoms, or a sulfur atom with 1 or 2 nitrogen atoms, or a 6-membered aromatic ring, containing 1, 2 or 3 nitrogen atoms, or a heteroaryl substituted with up to two substituents, selected from halogen, alkyl, haloalkyl or cyano. Examples include, but are not limited to 2-furyl, 2-thienyl, 4-chloro-2-thienyl, 2-oxazolyl, 2-imidazolyl, 1,2,4-triazolyl-1-yl, 2-imidazolyl, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl, 1, 3, 5-triazin-2-yl, 4-chloro-3-pyridyl and the like. Phenylene means 1,4-phenylene. Although a specific isomer is shown for the compound of the formula (IV), it will be understood that the formula (IV) actually represents a mixture of the cis and trans isomeric forms. In a first embodiment of this invention, the cyclization step (i) to form a 5-methyleneoxazoline from an alkynyl amide is carried out using a moderate aqueous base, in the presence of a phase transfer agent. Although the phase transfer agent ("PTA") is required, the selection thereof, which is employed, is not critical and may be non-ionic, cationic or amphoteric in nature. Examples of PTA include, but are not limited to, an alkylphenoxy-polyethoxy-ethanol, a quaternary ammonium halide, such as tetrabutylammonium bromide, benzyltributylammonium chloride, or tricaprylmethyl ammonium chloride, which are referred to by the trade name Aliquat® 336, and a quaternary phosphonium halide, such as an alkyl (C? G ~ C g) tributylphosphonium bromide, such as cetyltributyl phosphonium bromide. The amount of the PTA used is not too critical, and is generally in the range of 0.1 to 25% by weight, preferably approximately 0.1 to 10% by weight, based on the alkynyl amide starting material. The reaction temperature is usually from 25 ° C to the boiling point of the solvent / water system used. A preferred condition is a reaction temperature of at least 50 ° C up to the boiling point of the solvent / water system used. The pressure is not important, but the reaction is usually carried out at atmospheric pressure for convenience. The reaction time will depend on the temperature used, the substitution pattern of the starting alkynyl amide, the solvent used, the nature of the base and the PTA, and the size and design of the reactor. However, the reaction is usually carried out conveniently in a time of 24 hours or less and more usually of 10 hours or less. The majority of the common aqueous bases can be used for the formation of the oxazoline of the alkynyl amide. A basic ion exchange resin can be used. Preferred bases are sodium hydroxide (NaOH), and potassium hydroxide (KOH), or their mixtures, sodium carbonate (Na2C? 3), and potassium carbonate (K2CO3) or its mixtures, and the sodium bicarbonate (NaHC03) and the potassium bicarbonate (KHCO3), or their mixtures. More preferred are NaOH, KOH, NaHC 3 and Na 2 C 3. Even more preferred is NaOH. Several solvents can be used in this reaction. They may be non-polar, for example aliphatic hydrocarbons, such as heptane and isooctane or an aromatic hydrocarbon, such as toluene and a xylene, or polar, for example an ether. Generally, hydroxide-like bases are best used in the polar solvent, in order to avoid side reactions. The bicarbonate and carbonate bases can be used with any type of solvent, but are usually advantageously employed with the polar types. The amount of base employed is usually at least 0.05 equivalents per equivalent of alkynyl amide. A preferred amount is at least 0.1 equivalent of the base. A more preferred amount is at least 0.25 equivalent of the base. A representative reaction procedure typical for this first embodiment for step (i), alkynyl amide, solvent, base and chain transfer agent, are added together and heated to reflux until the starting material can no longer be removed. detect by gas chromatographic analysis ("GC"). After cooling, the lower aqueous layer is discarded and the organic solution is washed with brine, dried over a desiccant and filtered. If desired, the filtrate can be further treated with decolorizing and refiltered carbon. The solution is concentrated to remove most of the solvent and the resulting clear oil is distilled under vacuum to deliver the 5-methyleneoxazoline material.

In the second embodiment of this invention, the cyclization step (i), to form a 5-methyleneoxazoline from an alkynyl amide, is carried out using an acid, preferably an anhydrous acid, in the presence of an organic solvent . The acid can be mineral or organic. Examples of the acid include, but are not limited to, oleum, methanesulfonic acid, toluene sulfonic acid, trifluoroacetic acid and trichloroacetic acid. Preferred acids are methanesulfonic acid and trichloroacetic acid. A more preferred acid is methanesulfonic acid. The amount of acid employed can vary, but an amount of about 5 mole percent to 200 mole percent, based on the starting substituted amide material, is generally used. A preferred amount is from about 5 to 100 mole percent. A more preferred amount is about 5 to 20 mole percent. The solvent employed may be polar or non-polar and is preferably anhydrous in nature. Examples of polar solvents include, but are not limited to, esters, such as ethyl acetate and butyl acetate, ethers, such as methyl tert. -butyl ether, and nitriles, such as acetonitrile. Examples of non-polar solvents include, but are not limited to, aliphatic hydrocarbons, such as heptane, aromatic hydrocarbons, such as toluene, and haloaromatic hydrocarbons, such as chlorobenzene.

Preferred solvents are butyl acetate, chlorobenzene and heptane. The reaction temperature is usually from about 20 ° C to the reflux temperature of the solvent system employed. A preferred temperature is about 25 to 130 ° C. A more preferred temperature is about 80 to 120 ° C. The pressure is not important, but the reaction is usually carried out at atmospheric pressure for convenience. The reaction time will depend on the temperature used, the pattern of substituents of the starting alkynyl amide, the solvent used, the nature of the acid and the size and design of the reactor. However, the reaction is conveniently carried out in general in a time from about 2 hours to 5 days and more usually from 3 days or less. In a representative procedure typical of the reaction for stage (i) of this second embodiment, the starting amide is added to the reaction solvent, followed by the catalyst. The reaction is then brought to the temperature and stirred until complete, cooled to room temperature and quenched with saturated sodium bicarbonate. The layers are separated, the aqueous phase is extracted, the organic phases are combined, dried, filtered and evaporated to dryness to give the desired product. In both embodiments of this invention, the step (ii) of chlorination of the 5-methylexaxazoline using the TCIA can be carried out at a temperature of about -30 to 100 ° C. A preferred chlorination temperature is around 0 to 70 ° C. More preferred, in order to obtain the best chlorination selectivity, is a temperature of about 50 ° C or lower. An even more preferred temperature is from 0 to 30 ° C. The reaction is not dependent on pressure, but a pressure of 1 atmosphere is generally preferred for convenience. The stoichiometry of the reagents is extremely important. If less than 0.333 TCI equivalent per equivalent of 5-methyleneoxazoline is used, some of the 5-methylenexazoline starting material will remain unreacted. If more than 0.333 equivalent is used, an overcoated intermediate is formed, which leads to a dichloro ketone after hydrolysis. However, as mentioned previously, an added feature of this invention provides for the convenient formation of a 5- (dichloromethylene) oxazoline and the subsequent formation, in step (iii) of a, a-dichloro ketone when >; 0.667 equivalent of TCIA is used per equivalent of 5-methylenexazoline, in the situation where the methylene group of the oxazoline is not substituted with an alkyl group. The reaction time of the chlorination can vary from about 5 minutes to 1 hour, and is dependent on both the size and type of the reactor equipment employed and the solvent used. The chlorinating solvent is usually a polar solvent, such as, but not limited to, an ether, an ester or a ketone, for example ethyl acetate, butyl acetate and methyl t-butyl ether. Preferred solvents are ethyl acetate or butyl acetate. Non-polar solvents, such as an aromatic hydrocarbon, for example toluene, or an aliphatic hydrocarbon, for example heptane and isooctane, can also be employed when mixed with a polar-type miscible solvent or when heated to a temperature of one 40 ° C. After the chlorination reaction is carried out to the desired step, the by-product of cyanuric acid can be removed by filtration and / or by washing with a common base, such as sodium carbonate, sodium hydroxide and the like. The resulting solution, which contains the 5-chloromethylenexazoline, is then subjected to the hydrolysis step (iii). In the hydrolysis step (iii), a temperature of about 50 ° C or higher is required. Preferably, the hydrolysis is carried out at about 50 to 100 ° C. More preferably, the temperature employed is about 50 to 80 ° C. An aqueous acid or a non-aqueous acid may be used in admixture with some water. A common acid, such as, but not limited to, hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or toluene sulfonic acid is convenient in its use. Hydrochloric acid or sulfuric acid are preferred. An acid ion exchange resin can also be used. When hydrochloric acid or sulfuric acid is used, additional water is usually added to facilitate hydrolysis. It is preferred that about 0.05 to 0.5 equivalents of an aqueous acid be used per equivalent of 5-chloromethylenexazoline. More preferred is the use of about 0.1 to 0.25 equivalents of aqueous hydrochloric acid per equivalent of 5-chloromethylenexazoline. The hydrolysis step usually takes about 3 to 24 hours, over time depending on the nature of the Z group, the temperature and the size and nature of the equipment employed. The pressure used is not critical. However, the pressure of 1 atmosphere is generally preferred for convenience. In a representative procedure typical of the reaction for steps (ii) and (iii) of both embodiments, the oxazoline and the solvent are combined and the resulting solution is cooled to 0-5 ° C, using an ice bath. The TCIA is added gradually, keeping the reaction temperature below 30 ° C if possible. Once the TCIA has been added, the resulting aqueous paste is brought to room temperature and stirred until the reaction is complete, based on gas chromatographic analysis ("GC"). The by-product of cyanuric acid is removed by filtration and the solution is then washed with an appropriate base, such as a solution of sodium bicarbonate or sodium hydroxide, to remove some of the remaining cyanuric acid. The solution containing the 5-chloromethylene oxazoline is returned to the flask and heated to 60 ° C. The concentrated hydrochloric acid and water are added and the solution is stirred until hydrolysis is complete. The reaction mixture is cooled to room temperature and the desired a-chloroketone crystallizes on cooling. The solid obtained is filtered, washed and dried to give the product. A second crop is often obtained by the concentration and cooling of the filtered solution.

The following examples, tables and experimental procedures are provided to guide the practitioner and do not signify any limitation of the scope of the invention, which is defined in the claims.

TABLE I: EXAMPLES Bl A B4 Formation, Catalyzed With Bases, of the 5-Methylenexazolines, from Alkynyl Amides, in the Presence of a Phase Transfer Agent (PTA) "R1 Example Bl: Preparation of 4,4-dimethyl-5-methylene-2-phenyloxazoline To a round bottom flask equipped with a magnetic stir bar, heating jacket and reflux condenser was added N- (3-methylbuty- 3-yl) benzamide (25.00 g, 133.5 mmol), 200 ml of toluene, 27 ml of 0.5N aqueous sodium hydroxide and 2.00 g (4.95 mmol, 3.7 mol%) of Aliquat® 336. The resulting mixture was heated to reflux for 3 hours, at this time, no starting material could be detected by gas chromatographic (GC) analysis. After cooling, the mixture was transferred to a separatory funnel. The lower aqueous layer was discarded. The organic solution was washed with brine, dried over MgSO 4 and filtered. The filtrate was treated with 2.0 g of decolorizing carbon and filtered ag The solution was concentrated using a rotary evaporator to deliver 26.41 g of a clear oil. The product was distilled under vacuum (70-75 ° C, 0.6 mm Hg) to provide 23.65 g (95% yield) of a clear colorless liquid. This material, 4,4-dimethyl-5-methylene-2-phenyloxazoline, was found to be a simple component by gas chromatographic analysis: 1H NMR (400 MHz, CDC13) d 7.09 (d, J = 6.7 Hz, 2H ), 7.50-7.35 (m, 3H), 4.73 (d, J = 2.8 Hz, ÍH), 4.23 (d, J = 2.8 Hz, ÍH), 1.45 (s, 6H); 13c NMR (100 MHz, CDCl 3) d 167.8, 159.8, 131.6, 128.4, 126.0, 126.95, 82.3, 69.0, 29.7.

Example B2: Preparation of 4,4-dimethyl-5-methylene-2-phenyloxazoline In a similar manner to Example 1, 4,4-dimethyl-5-methylene-2- was obtd in 98% yield. phenyloxazoline, using methyl tertiary butyl ether in place of toluene and a reaction time of 4 hours.

Example B3: Preparation of 4,4-dimethyl-5-methylene-2-phenyloxazoline In a similar manner to Example 1, in a yield of 92%, 4,4-dimethyl-5-methylene-2-phenyloxazoline was obtd , using chlorobenzene instead of toluene, and a reaction time of 2.5 hours.

Example B4: Preparation of 2- (3,5-dimethylphenyl) -4,4-dimethyl-5-methyleneoxazoline To a round bottom flask, equipped with a magnetic stir bar, heating jacket and reflux condenser, was added the N- (3-methylbutyn-3-yl) -3,5-dimethylbenzamide (25.00 g, 116.1 mmol), 200 ml of toluene, 50 ml of 0.5 N aqueous sodium hydroxide and 1.74 g (4.31 mmol, 3.7 mol%) of Aliquat® 336. The resulting mixture was heated to reflux for 1.5 hours. After cooling, the mixture was transferred to a separatory funnel. The lower aqueous layer was discarded. The organic solution was washed with brine, dried over MgSO 4 and filtered. The solution was concentrated using a rotary evaporator to deliver a clear, colorless oil, which distilled (86-94 ° C, 0.4 mm Hg), to give 24.43 g (98%) of the 2- (3,5-dimethylphenyl) -4,4-dimethyl-5-methyleneoxazoline as a colorless liquid. 1 H NMR (400 MHz, CDC13) d 7.62 (s, 2H), 7.09 (s, ÍH), 4.73 (d, J = 3.2 Hz, ÍH), 4.22 (d, J = 3.2 Hz, ÍH), 2.30 ( s, 6H), 1.44 (s, 6H); 13 C NMR (100 MHz, CDCl 3) d 167.9, 160.1, 138.1, 133.3, 126.7, 125.8, 82.1, 68.9, 29.8, 21.1 Example B5: Preparation of 2- (3,5-dimethylphenyl) -4,4-dimethyl- 5-methyleneoxazoline In a manner similar to Example 4, in a 98% yield of 2- (3,5-dimethylphenyl) -4,4-dimethyl-5-methyleneoxazoline was obtd with the use of isooctane as the solvent , 2.95 g of hexadecyltributylphosphonium bromide as the phase transfer catalyst, and a reaction time of 2 hours.

Example B6: Preparation of 2- (4-chlorophenyl) -4-methyl-4-methyl-5-methylenexazoline In a manner similar to Example 4, with a 97% yield of 2- (4-chlorophenyl) -4 -ethyl-4-methyl-5-methylenexazoline was obtd using the isooctane as the solvent, 2.84 g of the octadecyltributylphosphonium bromide as the phase transfer catalyst, and a reaction time of 1.5 hours; boiling point (95 ° C, 0.6 mm); p.f. 55-57 ° C; XH NMR (400 MHz, CDC13) d 7.92 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 4.80 (d, J = 2.4 Hz, ÍH), 4.19 (d, J = 2.4 Hz, ÍH), 1.86 (dt, J = 20.8, 7.5 Hz, ÍH), 1.60 (dt, J = 20.8, 7.5 Hz, ÍH), 1.42 (s, 3H), 0.80 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) d 166.0, 159.0, 137.8, 129.4, 128.7, 125.4, 83.1, 72.9, 35.0, 28.6, 8.3.

Example B7: Preparation of 2- (2,6-difluorophenyl) -4,4-dimethyl-5-methylenexazoline In a manner similar to Example 4, with a 95% yield of 2- (2,6-difluorophenyl) -4,4-dimethyl-5-methylenexazoline was obtained using the isooctane as the solvent, 2.26 g of Aliquat® 336 as the phase transfer agent, and a reaction time of 1.25 hours; boiling point (80 ° C, 1.0 mm Hg); 1 H NMR (400 MHz, CDCl 3) d 7.42 (tt, J = 8.0 Hz, ÍH), 6.98 (t, J = 8.0 Hz, 2H), 4.74 (d, J = 3.2 Hz, ÍH), 4.30 (d, J = 3.2 Hz, ÍH), 1.45 (s, 6H); 13C NMR (100 MHz, CDCI3) d 167.1, 161.2 (of, J = 256.7, 5.7 Hz), 152.6, 132.8 (t, J = 10.3 Hz), 112.0 (d, J = 20.0 Hz), 106.7 (t, J = 17.1 Hz), 83.0, 69.5, 29.6.

Example B8: Preparation of 2- (2,6-difluorophenyl) -4,4- (pentamethylene) -oxazoline In a manner similar to Example 4, with a 96% yield of 2- (2,6-difluorophenyl) -4, 4- (pentamethylene) -oxazoline was obtained using toluene as the solvent, 2.41 g of hexadecyltributylphosphonium bromide as the phase transfer catalyst, and a reaction time of 6 hours; boiling point (110-112 ° C, 0.5 mm Hg); melting point: 43-46 ° C; XH NMR (400 MHz, CDCl 3) d 7. 38 (tt, J = 8.4, 6.0 Hz, ÍH), 6.94 (t, J = 8.8 Hz, 2H), 4. 72 (d, J = 3.2 Hz, ÍH), 4.26 (d, J = 3.2 Hz, ÍH), 2.0-1.3 (m, 10H); 13C NMR (100 MHz, CDCI3) d 167.6, 161.2 (de, J = 256. 3, 6.0 Hz), 151.9, 12.6 (t, J = 10.3 Hz), 111.9 (of, J = 20.2, 5.4 Hz), 107.2 (t, J = 18.3 Hz), 83.2, 72.6, 39.3, . 6, 22.2.

Example B9: Preparation of 2- (3,5-dichloro-4-methylphenyl) -4-ethyl-4-methyl-5-methylenexazoline In a manner similar to Example 4, with an 87% yield of 2- ( 3, 5-dichloro-4-methylphenyl) -4-ethyl-4-methyl-5-methylenexazoline was obtained using heptane as the solvent, 1.08 g of Aliquat® 336 as the phase transfer catalyst, a solution of 102 g of sodium carbonate in 80 ml of water and a reaction time of 1.5 hours; boiling point (128 ° C, 1.0 mm Hg); 13C NMR (100 MHz, CDCI3) d 165.1, 156.5, 137.6, 135.0, 126.5, 83.9, 72. 7, 34.0, 28.0, 17.4, 8.1.

Example B10: Preparation of 2- (4-nitrophenyl) -4,4-dimethyl-5-methylenexazoline In a manner similar to Example 4, with 90% yield of 2- (4-nitrophenyl) -4, -dimethyl-4-methylenexazoline was obtained using the isooctane as the solvent, 2.25 g of Aliquat® 336 as the phase transfer catalyst, and a reaction time of 1.25 hours. The crude product was recrystallized from hexane to give 22.61 g of a light orange solid; melting point of 91-94 ° C; 1 H NMR (400 MHz, CDCl 3) d 8.29 (d, J = 8.8 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H), 4.80 (d, J = 3.2 Hz, ÍH), 4.33 (d, J = 3.2 Hz, ÍH), 1.48 (s, 6H); 13C NMR (100 MHz, CDC13) d 167.3, 158.1, 149.6, 132.8, 129.1, 123.6, 83.5, 69.7, 29.6.

Example Bll: Preparation of bis (4,4-diethyl-5-methylene-oxazolin-2-yl) -1,4-phenylene In a manner similar to Example 4, with a yield of 87% of bis (4, 4- diethyl-5-methylenexazolin-2-yl) -1,4-phenylene was obtained using toluene as the solvent, 2.00 g of Aliquat® 336 as the phase transfer catalyst, 50 ml of an IN NaOH solution and a time reaction time 2 hours; The crude product was recrystallized from hexane to give 21.81 g of a white solid; melting point 143-144 ° C; XH NMR (400 MHz, CDCI3) d 8.09 (s, 4H), 4.90 (d, J = 3.2 Hz, 2H), 4.17 (d, J = 3.2 Hz, 2H), 1. 92 (dt, J = 21.2, 7.4 Hz, 4H), 1.58 (dt, J = 21.2, 7.4 Hz, 4H), 8.81 (t, J = 7.4 Hz, 12H); 13C NMR (100 MHz, CDCI3) d 164.0, 159.5, 129.6, 128.2, 83.6m 77.2, 34.0, 8.1 Example B12: Preparation of 4,4-dimethyl-5-methylene-2- (2-naph il) oxazoline In a manner similar to Example 4, with 95% yield of 4,4-dimethyl-5-methylene -2- (2-naphthyl) -oxazoline was obtained using toluene as the solvent, 1.00 g of Aliquat® 336 as the phase transfer catalyst, 50 ml of INOH NaOH and a reaction time of 1.5 hours.; boiling point (132-137 ° C, 0.5 mm Hg); 1 ti NMR (400 MHz, CDCI3) d 8.46 (s, ÍH), 8.04 (of, J = 8.8, 2.0 Hz, ÍH), 7.84 (of, J = 6.4, 2.4 Hz, ÍH), 7.79 (d, J = 8.4 Hz, HH), 7.75 (of, J = 6.8, 2.8 Hz, ÍH), 7.48-7.40 (m, 2H), 4.78 (d, J = 2.9 Hz, HH), 4.25 (d, J = 2.8 Hz , ÍH), 1.48 (s, 6H); 13C NMR (100 MHz, CDCI3) d 167.8, 159.9, 134.7, 132.6, 128.8, 128.7, 128.2, 127.7, 127.6, 126.5, 124.3, 124.1, 82.3, 69.1, 29.8.

Example B13: Preparation of 4,4-dimethyl-5-methylene-2- (3-pyridyl) oxazoline In a manner similar to Example 4, with a yield of 96% of 4,4-dimethyl-5-methylene- 2- (3-pyridyl) oxazoline was obtained using isooctane as the solvent, 2.00 g of stearyltributylphosphonium bromide as the phase transfer catalyst, 50 ml of a 0.5N NaOH solution and a reaction time of 1 hour; boiling point 80 ° -87C (0.6 mm Hg); XH NMR (400 MHz, CDCl 3) d 164.9, 152.0, 148.0, 135.2, 123.4, 86.8, 69.7, 48.2, 29.0.

Example B14: Preparation of 2-heptan-3-yl-4,4-dimethyl-5-methylenexazoline In a manner similar to Example 4, with a yield of 98% of 2-heptan-3-yl-4, 4 -dimethyl-5-methylenexazoline was obtained using heptane as the solvent, 4.81 g of Aliquat® 336 as the phase transfer catalyst, and a reaction time of 2 hours; boiling point (62 ° C, 1.0 mm Hg); 1 H NMR (400 MHz, CDC13) d 168.2, 165.8, 81.4, 68.1, 41.0, 31.8, 29.8, 29.5, 25.4, 22.6, 14.0, 11.7.

Comparative Examples Cyclization Catalyzed with Bases, Without the Presence of a PTA To demonstrate the utility of the present invention, 5-methyleneoxazoline was formed from a substituted amide, using a base in the presence of a PTA, the following comparative examples without a PTA present.

Comparative Example Bl When an experiment was condu in a manner similar to Example B4, but in the absence of any base transfer catalyst, only 21% of 2- (3,5-dimethylphenyl) -4,4-dimethyl- 5-Methyleneoxazoline was obtained using heptane as the solvent and a reaction time of 8 hours. The other 79% of the recovered material consisted of the unrea N- (3-methylbut-3-yl) -3,5-dimethylbenzamide.

Comparative Example B-2 When an experiment was condu in a manner similar to Example B4, using toluene as the solvent, but in the absence of any phase transfer catalyst, N- (3-methylpentin-3-yl) was recovered. -3, 5-dichloro-4-methylbenzamide without change, after a reaction time of 8 hours.

The following procedure for the acid-catalyzed formation of 5-methyleneoxazoline, from a substituted amide, was used for all examples Al to A18, shown in Table II: To 2 g of aminoalkyne in 10 ml of solvent, they added 5 to 200 mole% of acid catalyst. The mixture was then heated to the desired temperature. Anhydrous starting materials were used. The reaction was stirred until the gas chromatography analysis indicated that all of the starting material had been consumed or the reaction was no longer consuming more starting material. It was then cooled to room temperature and the reaction was quenched with 15 ml of an aqueous saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was extra with ethyl acetate (15 mL), the organic materials were combined, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give the desired product in the yields shown in Table II. The products were identified by comparison with a known standard and by 1 H NMR (Magnetic Resonance-Nuclear) spectroscopy.

TABLE II: EXAMPLES Al A Al8 (next page) Acid Catalyzed Formation of the 5-methylene oxazolines from Alkynyl Amides In Table II, the weight refers to the aggregate of the desired product of 5-methylenexazoline, a ketone having the formula: and the substituted amide starting material.

Examples Cl-Cll illustrate the experimental conditions used in the preparation of the desired a-monochloroketones from 5-methyleneoxazoline, prepared by subjecting cyclization catalyzed by a base, in the presence of PTA or cyclization catalysed by an acid of the material starting of substituted amide, with the use of TCIA and followed by hydrolysis with the use of an aqueous acid.

TABLE II: Formation, catalysed with acid, of the 5-methyleneoxazolines, from the acetylenic amides Example Cl: Preparation of N- (1-chloro-3-methyl-2-oxobut-3-yl) -4-nitrobenzamide A solution of 4,4-dimethyl-5-methylene- (2- (4-nitrophenyl) Oxazolin (10.0 g, 43.1 mmol) and ethyl acetate (35 mL) was cooled to 5 ° C using an ice bath, trichlorocyanuric acid (3.33 g, 14.3 mmol) was added in several portions in 15 minutes, with the In order to keep the reaction temperature below 40 ° C. When the addition was complete, the reaction mixture was cooled to 20 ° C. and the ice bath was removed.The reaction was monitored by GC analysis for the disappearance of the material After 1.5 hours, an additional 0.25 g (1.07 mmol) of the chlorinating agent was added in order to complete this chlorination.When the reaction was complete, the mixture was filtered and the filtrate was washed with ethyl acetate ( 15 ml) The filtrate was transferred to a round-bottomed flask and heated to 60 ° C and hydrochloric acid (0.85 g of an 37%) and water (2.8 ml) The reaction mixture was stirred at 60 ° C for 5 hours, then cooled to room temperature. The resulting aqueous paste was stored in a hard refrigerator overnight. The mixture was filtered and the solids were rinsed with a cold filtering solution. The filtrate was concentrated to about half of its original volume by evaporation, under reduced pressure. Hexane was added gradually until the solution became turbid; The flask was cooled in a refrigerator at 8 ° C overnight, then the aqueous slurry was filtered to obtain a second crop of crystals. Both harvests were dried at 60 ° C under vacuum, yielding N- (1-chloro-3-methyl-2-oxobut-3-yl) -4-nitrobenzamide (10.78g, 88%) as a white solid. , (melting point of 181-182 ° C). Following substantially the same procedure, the compounds of Examples C2-C11 were prepared, as shown in Table III.

TABLE III: Preparation of the a-chloroketones from a 5-methyleneoxazoline and TCIA, followed by hydrolysis 12 To better illustrate the benefits of the present invention, using TCIA as a chlorinating agent for the 5-methylene oxazolines, the following comparative examples were carried out with other conventional chlorinating agents.

Comparative Example Cl: Use of Chlorine Gas A solution of 2- (3,5-dichloro-4-methylphenyl) -4- ethyl-4-methyl-5-methylenexazoline (20.0 g, 70.4 mmol) and methanol (100 ml) ) was cooled to 0 ° C. Chlorine gas was bubbled into the solution; the reaction was monitored by gas chromatography1. The chlorine feed was stopped when the starting material disappeared (1.5 hours). The solution was purged with nitrogen to remove any remaining chlorine, then the solution was heated to 50 ° C. Water (20 ml) was added and the reaction was stirred until the hydrolysis was complete. The reaction mixture was cooled to room temperature and the aqueous paste was filtered. The wet mass was washed with a cold solution of 10% water in methanol and dried in a vacuum oven to give 15.89 g of a white solid. The product contained 71% of the N- (1-chloro-3-methyl-2-oxopent-3-yl) -3,5-dichloro-4-methyl-benzamide, 16% of the N- (1, 1- dichloro-3-methyl-2-oxopent-3-yl) -3,5-dichloro-4-methylbenzamide and 0.8% of the N- (3-methyl-2-oxopent-3-yl) -3,5-dichloro -4-methylbenzamide. The yield of the desired monochloro ketone was estimated at 48%. { Compare to Example C6). 1 OBSERVATION: Mixtures of chlorine gas and methanol can form methyl hypochlorite, which is explosive and sensitive to shocks.

Comparative Example C2: Use of N-Chlorosuccinimide A solution of 2- (3,5-dichloro-4-methylphenyl) -4-ethyl-4-methyl-5-methylenexazoline (5.0 g, 17.6 mmol) and ethyl acetate (20 ml) was treated with N-chlorosuccinimide (2.35 g, 17.6 mmol). The solution was stirred at room temperature for 70 hours. The reaction mixture contained 50% of the unreacted starting material and 50% of the desired 5-chloromethylene-2- (3,5-dichloro-4-methylphenyl) -4-ethyl-4-methyl-oxazoline. (Compare to Example C6).

It will be understood that changes and variations may be made in this invention, without departing from the spirit and scope of this invention, as defined by the appended claims.

Claims (39)

1. A process for the preparation of an a-chloroketone compound of the formula (I), which comprises the steps of: (i) subjecting an alkynyl amide of the formula (II) to cyclization using a moderate aqueous base , in the presence of an organic solvent and a phase transfer agent, to form a 5-methylenexazoline of the formula (III): R1 (ii) subjecting to chlorination 5-methylexaxazoline, of the formula (III), in a solvent, using the trichloroisocyanuric acid, to produce a chlorinated oxazoline intermediate of the formula (IV): (iii) hydrolyze the chlorinated oxazoline intermediate, of formula IV), with an aqueous acid, to produce the desired monochloro ketone of the formula (I): wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure.

2. A process for the preparation of an a chloroketone of the formula (I), which comprises the steps of: (i) cyclizing an alkynyl amide of the formula (II), with the use of an acid, to form a 5-methylenexazoline of the formula (III) R1 (ii) subjecting 5-methylexaxazoline of the formula (III) to chlorination in a solvent using trichloroisocyanuric acid to produce a chlorinated oxazoline intermediate of the formula (IV): (iii) hydrolyze the chlorinated oxazoline intermediate, of formula IV), with an aqueous acid, to produce the desired monochloro ketone of the formula (I): wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure.

3. A process, according to claims 1 or 2, wherein: Z is an alkyl (C] -Cg), phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, alkyl (C ^ -Cj), alkoxy (C ^ -Cj), alkynyl (C2-C5), nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; R is a hydrogen atom or an alkyl group (C] -C4) R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached , form a cyclopentyl or cyclohexyl ring.

4. The process of claim 3, wherein: Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C 1 -C 4) -phenyl, 3,5-dihalophenyl, 3, 5-dialkyl (C1 -C4) -phenyl, 4-alkyl (C-C4) -3,5-dihalophenyl, 4-cyano-3,5-dihalo-phenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4- nitrophenyl, 2-naphthyl, 3-pyridyl or 1,4-phenylene; R is a hydrogen atom, a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

5. The process of claim 4, wherein: Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2- Naphyl, 3-pyridyl or 3-heptyl; R is a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

6. The process of claim 1, wherein the phase transfer agent, in step (i) is non-ionic, cationic, anionic or amphoteric in nature.

7. The process of claim 6, wherein the phase transfer agent is selected from an alkylphenoxy polyethoxy ethanol, a quaternary ammonium halide and a quaternary phosphonium halide.

8. The process of claim 1, wherein the base, in step (i), is selected from the sodium hydroxide and potassium hydroxide or mixtures thereof, the sodium carbonate and the potassium carbonate or mixtures thereof, the sodium bicarbonate and potassium bicarbonate or its mixtures, and a basic ion exchange resin.

9. The process of claim 8, wherein the base is sodium hydroxide, potassium hydroxide, sodium bicarbonate or sodium carbonate.

10. The method of claim 8, wherein the amount of the base employed is at least 0.05 equivalents per equivalent of the alkynyl amide.

11. The process of claim 1, wherein the solvent used in step (i) is an aliphatic hydrocarbon, an aromatic hydrocarbon, an ester, an ether or a ketone.

12. The process of claim 2, wherein the acid used in step (i) is a mineral acid or an organic acid.

13. The process of claim 12, wherein the acid is oleum, methanesulfonic acid, toluene sulfonic acid, trifluoroacetic acid or trichloroacetic acid.

14. The process of claim 12, wherein the amount of the acid employed is from 5 to 200 mole percent, based on the substituted measure.

15. The process of claim 2, wherein the solvent used, in step (i) is an ester, an ether, a nitrile, an aliphatic hydrocarbon, an aromatic hydrocarbon or a haloaromatic hydrocarbon.

16. The process of claim 12, wherein the acid is anhydrous.

17. The process of claim 15, wherein the solvent is anhydrous.

18. The use of trichloroisocyanuric acid as a chlorinating agent, for a 5-methylenexazoline, to form a 5- (chloromethylene) oxazoline or a 5,5- (dichloromethylene) oxazoline.

19. The use of trichloroisocyanuric acid according to claim 18, in which the product is a 5- (chloromethylene) oxazoline.

20. A process, according to claims 1 or 2, wherein the chlorination step (ii) of the 5-methylenexazoline is carried out at a temperature of -30 to 100 ° C.

21. The method of claim 20, wherein the temperature is from 0 to 70 ° C.

22. A method, according to claims 1 or 2, wherein the solvent of the chlorination step (ii) is a polar solvent, a mixture of a miscible polar solvent and a non-polar solvent, or a mixture of a polar solvent and a non-polar solvent, at a temperature of about 40 ° C.

23. The process of claim 22, wherein the polar solvent is an ether, an ester or a ketone, and the non-polar solvent is an aromatic hydrocarbon or an aliphatic hydrocarbon.

24. The process of claim 23, wherein the solvent is ethyl acetate or butyl acetate.

25. The process of claim 24, wherein the temperature in the hydrolysis step (iii) is 50 ° C or higher.

26. The process of claim 24, wherein the acid used in the hydrolysis step (iii) is aqueous or non-aqueous.

27. The process of claim 26, wherein the acid is hydrochloric acid, sulfuric acid, "trifluoroacetic acid, methanesulfonic acid, toluene sulfonic acid or an acid ion exchange resin.

28. The process of claim 27, wherein the acid is hydrochloric acid or sulfuric acid.

29. The process of claim 26, wherein 0.05 to 0.5 equivalents of acid are used per equivalent of 5-chloromethylenexazoline.

30. A process for the preparation of a 5-methylenexazoline compound of the formula (III), this process comprises subjecting to cyclization an alkynyl amide of the formula (II), which uses a moderate aqueous base, in the presence of a organic solvent and a phase transfer agent R1 wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure.

31. A process for the preparation of a 5-methylenexazoline compound of the formula (III), which comprises subjecting an alkynyl amide of the formula (II) to cyclization, with the use of an acid R 1 wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure.

32. A process for the preparation of a chlorinated oxazoline compound, of the formula (IV), which comprises chlorinating a 5-methylexaxazoline, of the formula (III), in a solvent, with the use of trichloroisocyanuric acid. Cl where: Z is alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure.

33. A process, according to claims 30, 31 or 32, wherein Z is an alkyl group (C? -Cg), phenyl or substituted phenyl, with up to three substituents, independently selected from the group consisting of: halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 2 -Cg) alkynyl, nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; R is a hydrogen atom or an alkyl group (C? ~ C4), and R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring.

34. The process of claim 33, wherein: Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C 1 -C 4) -phenyl, 3,5-dihalophenyl, 3, 5-dialkyl (C1 -C4) -phenyl, 4-alkyl (C? -C4) -3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4-nitrophenyl , 2-naphthyl, 3-pyridyl or 1,4-phenylene; R is a hydrogen atom, a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

35. The process of claim 34, wherein: Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2- Naphyl, 3-pyridyl or 3-heptyl; R is a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

36. A process for the preparation of an a, d-dichloro ketone compound of the formula (IA), this process comprises the steps of: (i) cyclizing an alkynyl amide of the formula (IIA), to form a 5-methyleneoxazoline of the formula (IIIA): R1 (ii) chlorinating the 5-methyleneoxazoline, of the formula (IIIA), in a solvent, using the trichloroisocyanuric acid, to produce a chlorinated oxazoline intermediate of the formula (IVA): (iii) hydrolyze the chlorinated oxazoline intermediate, of the formula IVA), with an aqueous acid, to produce the desired monochloro ketone, of the formula (IA): wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure.

37. The process of claim 36, wherein: Z is an alkyl (C] -Cg), phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, (C1-C4) alkyl ), (C 1 -C 4) alkoxy, (C 2 -Cg) alkynyl, nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; and R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring.

38. The process of claim 37, wherein: Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C 1 -C 4) -phenyl, 3,5-dihalophenyl, 3, 5-dialkyl (C1 -C4) -phenyl, 4-alkyl (C 1 -C 4) -3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4-nitrophenyl, 2-naphthyl, 3-pyridyl or 1,4-phenylene; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

39. The process of claim 38, wherein Z is 4-rophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-diro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2-naphyl. , 3-pyridyl or 3-heptyl; R1 and R2 are each, independently, methyl or ethyl. SUMMARY OF THE INVENTION This invention relates to a process for the preparation of an a-roketone compound, this process comprises the steps of: (i) subjecting an alkynyl amide to cyclization to form a 5-methyleneoxazoline: (ii) rination of 5-methylexaxazoline, using triroisocyanuric acid, to produce a rinated oxazoline intermediate (ii) hydrolyze the rinated intermediate of oxazoline, with an aqueous acid, to produce the desired monoro ketone: wherein: Z is alkyl or substituted alkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl, or phenylene; R is a hydrogen atom or an alkyl group; and R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure. Additionally, when R is a hydrogen atom, a diroketone can conveniently be formed by adjusting the reaction conditions.