USOO684.1688B2 (12) United States Patent (10) Patent No.: US 6,841,688 B2 Hwang et al. (45) Date of Patent: Jan. 11, 2005

(54) METHOD OF PREPARING OPTICALLY FOREIGN PATENT DOCUMENTS PURE (R)- OR (S)- TETRAHYDROFURANYL KETONE WO WO 92/O1696 6/1992 (75) Inventors: Hee-Jun Hwang, Daejeon (KR); WO woO3O14106 : 2/2003 ...... 549/487 Jong-Ho Lim, Daejeon (KR) * cited by examiner (73) Assignee: SK Corporation, Seoul (KR) (*) Notice: Subject to any disclaimer, the term of this Primary Examiner Rita Desai patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Assistant Examiner Raymond Covington (74) Attorney, Agent, or Firm-Alston & Bird LLP (21) Appl. No.: 10/290,734 (57) ABSTRACT (22) Filed: Nov. 8, 2002 (65) Prior Publication Data Disclosed is a method of preparing an optically pure (R)- or (S)-tetrahydrofuranyl ketone. By such a method, (R)- or US 2003/0114693 A1 Jun. 19, 2003 (S)-2- amide is converted to (R)- or (S)-2- (30) Foreign Application Priority Data tetrahydrofuran nitrile through dehydration in the presence Dec. 4, 2001 (KR) ...... 2001-76279 of a dehydrating agent and an amine base. Then, thus (51) Int. Cl...... C07D 307/02 prepared (R)- or (S)-2-tetrahydrofuran nitrile is nucellophilic (52) U.S. Cl...... 549/474; 549/487 addition-reacted with a nucleophile, followed by (58) Field of Search ...... 549/487,474 hydrolyzing, thereby produce (R)- or (S)-tetrahydrofuranyl ketone having high optical purity, while minimizing pro (56) References Cited duction of other by-products. U.S. PATENT DOCUMENTS 3,125,584. A 3/1964 Weis et al...... 549/474 12 Claims, No Drawings US 6,841,688 B2 1 2 METHOD OF PREPARING OPTICALLY pure tetrahydrofuranyl ketone on an industrial Scale, race PURE (R)- OR (S)- TETRAHYDROFURANYL mization occurs. So, the resultant ketone is low in optical KETONE purity. Under these circumstances, there is proposed a prepara BACKGROUND OF THE INVENTION tion method in which carboxylic acid is converted, by use of N, O-dimethylhydroxyamine hydrochloride, to N, O 1. Field of the Invention dimethyl hydroxiamide, followed by reacting with an The present invention pertains to methods of preparing organic lithium compound or a to yield (R)- or (S)-tetrahydrofuranyl ketones. More specifically, the ketone. This method is advantageous in terms of Suppression present invention is directed to a method of preparing an of tertiary alcohols produced as a by-product, but is disad industrially applicable (R)- or (S)-tetrahydrofuranyl ketone Vantage ous due to use of expensive N, O having high optical purity by dehydration of (R)- or (S)-2- dimethylhydroxyamine hydrochloride. Therefore, it is dif tetrahydrofuran amide in the presence of a dehydrating agent ficult to industrially apply Such a method, in terms of and an amine base, to obtain (R)- or (S)-2-tetrahydrofuran 15 economic benefit. In particular, when this method is used for nitrile, after which nucellophilic addition-reaction with a preparation of an optically pure tetrahydrofuranylketone on nucleophile and hydrolysis are carried out in order. an industrial Scale, racemization occurs, thus the produced 2. Description of the Prior Art ketone has low optical purity. Generally, (R)- or (S)-tetrahydrofuranyl ketone com pounds are widely employed for preparation of antibiotics According to Tetrahedron Lett. 1984, 25(42), 4805, a which are used as antiviral medicines and of optically active method of preparing ketone is proposed, in which carboxylic chemicals, and also employed as important medicinal inter acid is activated with thionyl chloride and reacted with a mediates of optically active medicines and Veterinary medi Grignard reagent in the presence of iron (III) catalyst to CCS. produce ketone. But, when Such a method is also applied to However, most of the conventional techniques are 25 preparation of an optically pure tetrahydrofuranylketone on directed to the production of racemic tetrahydrofuranyl an industrial Scale, racemization is So unavoidable that the ketones, rather than of optically pure (R)- or (S)- resultant ketone is low in optical purity. tetrahydrofuranyl ketones. Meanwhile, WO92/01696 discloses a method for prepa SUMMARY OF THE INVENTION ration of (R)-2-acetyl-tetrahydrofuran bromide, in which a carboxylic acid moiety in (R)-2-tetrahydrofuroic acid used Leading to the present invention, the intensive and thor as a Starting material is activated by Oxalic acid chloride, and ough research into methods for preparation of (R)- or reacted with excessive diazomethane and then further with (S)-tetrahydrofuranyl ketone, carried out by the present 48% aqueous hydrogen bromide Solution, producing (R)-2- inventorS aiming to avoid the problems encountered in the acetyl-tetrahydrofuran bromide. Also, a preparation method 35 prior arts, resulted in the finding that, when (R)- or (S)-2- of 2-acetyl-tetrahydrofuran chlorides comprising reacting tetrahydrofuran amide is used a starting material, (R)- or racemic 2-tetrahydrofuroic acid used as a starting material (S)-2-tetrahydrofuran nitrile obtained from dehydration of with diazomethane according to the same manner as in the the above Starting material is nucleophilic addition-reacted above patent and further with hydrochloric acid, is described with a nucleophile, followed by hydrolyzing to yield (R)- or in J. Antibiot. 1994, 47(2), 253. But, the above methods 40 (S)-tetrahydrofuranyl ketone having high optical purity. cannot be applied on an industrial Scale due to use of Therefore, it is an object of the present invention to diazomethane being highly explosive. provide a method of preparing an industrially applicable In J. Heterocycl. Chem. 1995, 32(1), 109, a preparation (R)-tetrahydrofuranyl ketone having high optical purity. method of tetrahydrofuranyl ketone is disclosed by reaction of racemic 2-tetrahydrofuroic acid and phenylmagnesium 45 It is another object of the present invention to provide a bromide or phenyllithium. However, this method is disad method of preparing an industrially applicable (S)- vantageous Since even though (R)- or (S)-2-tetrahydrofuroic tetrahydrofuranyl ketone having high optical purity. acid is employed as a Starting material, the optical purity of In accordance with an embodiment of the present the resultant tetrahydrofuranyl ketone is lowered due to 50 invention, there is provided a method of preparing an racemization in the application on the industrial Scale. optically pure (R)-tetrahydrofuranyl ketone, which com Additionally, tertiary alcohols are produced in large amounts prises: as by-products, thus making it difficult to apply the above method to production on the large Scale. dehydrating (R)-2-tetrahydrofuran amide, represented by Further, it is well known in the art that Since ketones, 55 the following chemical formula 1a, in the presence of resulting from a nucleophilic addition reaction of carboxylic a dehydrating agent and an amine base at 50 to 100 C. acids, have higher activity for the nucleophilic addition than for 2 to 6 hours to obtain (R)-2-tetrahydrofuran nitrile carboxylic acids used as a starting material, tertiary alcohols represented by the following chemical formula 2a, are produced in large amounts through additional nucleo nucellophilic addition-reacting the (R)-2-tetrahydrofuran philic addition reaction of Said ketones, thus decreasing a 60 nitrile with a nucleophile in an organic Solvent at the reaction yield. Hence, diverse attempts have been conducted temperature range of from -80 to 100° C. for 10 to overcome Such problems. minutes to 4 hours, followed by hydrolyzing by use of For example, it is known that carboxylic acid and lithium aqueous acidic Solution to produce (R)- hydride are reacted at a molar ratio of 1:1, to produce lithium tetrahydrofuranyl ketone represented by the following carboxylate, which is then reacted with an organic lithium 65 chemical formula 3a; and compound or a Grignard reagent, to prepare ketone. But, recovering the resulting product obtained from the previ when this method is applied to preparation of an optically OuS Step: US 6,841,688 B2 4 Initially, (R)- or (S)-2-tetrahydrofuran amide is dehydrated Chemical Formula 1 a in the presence of a dehydrating agent and an amine base to produce (R)- or (S)-2-tetrahydrofuran nitrile. Thereafter, the (R)- or (S)-2-tetrahydrofuran nitrile is nucleophilic addition reacted with a nucleophile, followed by hydrolysis. As a result, (R)- or (S)-tetrahydrofuranylketone is produced with Chemical Formula 2a high optical purity. According to the present invention, (R)-2-tetrahydrofuran amide of chemical formula 1a or (S)-2-tetrahydrofuran amide of the following chemical formula 1b is used as a Chemical Formula 3a Starting material:

Chemical Formula 1 a

15

SP O wherein, R is a Straight-chained or branched, Saturated or unsaturated aliphatic alkyl group having 1-30 carbon Chemical Formula 1b atoms, a Saturated or unsaturated, Substituted or unsub Stituted cyclic alkyl group having 3–30 carbon atoms, NH2 or a Substituted or unsubstituted aryl group having 6-30 carbon atoms. O In accordance with another embodiment of the present invention, there is provided a method of preparing an In the present invention, the (R)- or (S)-2-tetrahydrofuran optically pure (S)-tetrahydrofuranyl ketone, which com 25 amide is preferably dehydrated in the presence of 1.0-1.5 prises: equivalents dehydrating agent and 1.0–7.0 equivalents dehydrating (S)-2-tetrahydrofuran amide represented by amine base under conditions of a reaction temperature the following chemical formula 1b, in the presence of ranging from 50 to 100° C. and a period of time required for a dehydrating agent and an amine base at 50 to 100 C. reaction ranging from 2 to 6 hours, to produce (R)-2- for 2 to 6 hours to obtain (S)-2-tetrahydrofuran nitrile tetrahydrofuran nitrile represented by the following chemi represented by the following chemical formula 2b, and cal formula 2a or (S)-2-tetrahydrofuran nitrile represented nucellophilic addition-reacting the (S)-2-tetrahydrofuran by the following chemical formula 2b: nitrile with a nucleophile in an organic Solvent at the Chemical Formula 2a temperature range of from -80 to 100° C. for 10 35 minutes to 4 hours, followed by hydrolyzing by use of aqueous acidic Solution to produce (S)- tetrahydrofuranyl ketone represented by the following chemical formula 3b; and Chemical Formula 2b recovering the resulting product obtained from the previ 40 ouS Step:

Chemical Formula 1b AS Such, it is noted that each using amount of the NH2 45 dehydrating agent and the amine base should be adjusted in O proper range. For example, in case of falling out of the range O as above, the dehydration may not Sufficiently performed or Chemical Formula 2b wastes may excessively generated. Furthermore, if the period of time required for reaction is shorter than 2 hours, 50 reaction conversion efficiency becomes low. On the other SOS, hand, if the reaction time is longer than 6 hours, economic Chemical Formula3b benefit is not realized due to insufficiently long reaction time. Also, when the reaction temperature is lower than 50 R C., a period of time required to obtain the reaction conver O 55 sion efficiency of 100% is lengthened. Meanwhile, the O temperature higher than 100° C. leads to generation of large amounts of by-products. wherein, R is a Straight-chained or branched, Saturated or The amine base of the present invention is Selected from unsaturated aliphatic alkyl group having 1-30 carbon atoms, the group consisting of primary amines, Such as a Saturated or unsaturated, Substituted or unsubstituted 60 methylamine, ethylamine, propylamine, butylamine, etc.; cyclic alkyl group having 3–30 carbon atoms, or a Substi Secondary amines, Such as dimethylamine, diethylamine, diisopropylamine, etc.; tertiary amines, Such as tuted or unsubstituted aryl group having 6-30 carbon atoms. trimethylamine, triethylamine, diethylisopropylamine, etc.; DETAILED DESCRIPTION OF THE and pyridine. Among them, pyridine is preferably used. INVENTION 65 The dehydrating agent of the present invention is Selected The present invention is directed to a preparation method from the group consisting of thionyl chloride, para of an optically pure (R)- or (S)-tetrahydrofuranyl ketone. toluenesulfone chloride, phosphorous pentoxide, phospho US 6,841,688 B2 S 6 rous oxytrichloride, a mixture of dimethylsulfoxide and The nucleophilic addition reaction is performed in the Oxalic acid chloride, trifluoroacetic anhydride, and a mixture temperature range of -80 to 100° C., preferably -20 to 50 of formaldehyde and formic acid. Among them, para C., and most preferably 0 to 30°C. The reaction temperature toluenesulfone chloride is preferably used. lower than -80 C. causes the reduction of economic ben Then, each of (R)- and (S)-2-tetrahydrofuran nitrile, efits due to the increased reaction time. Meanwhile, the resulting from the above dehydration, is nucleophilic temperature higher than 100° C. results in lowered optical addition-reacted with a nucleophile. Then, hydrolysis is purity due to racemization of the product. carried out to obtain (R)-tetrahydrofuranyl ketone repre In addition, the nucleophilic addition is conducted for 10 sented by the following chemical formula 3a, or (S)- minutes to 4 hours, preferably for 10 minutes to 2 hours, and tetrahydrofuranyl ketone represented by the following most preferably for 30 minutes to 1 hour. If the time is chemical formula 3b: Shorter than 10 minutes, the reaction conversion efficiency is reduced. On the other hand, if the time is longer than 4 Chemical Formula 3a hours, economic benefit is not realized due to excessively lengthened time. 15 After completion of the nucleophilic addition, hydrolysis is performed using an acidic aqueous Solution to effectively SP O prepare (R)- or (S)-tetrahydrofuranyl ketone, without any Chemical Formula3b change of optical purity. AS described above, the present invention is advantageous in that (R)- or (S)-tetrahydrofuran nitrile is used, instead of conventionally used (R)- or (S)-2-tetrahydrofuroic acid, O whereby the amount of the nucleophile to be used can be decreased by 1 equivalent or more, thus realizing economic wherein, R is a Straight-chained or branched, Saturated or benefits. As well, without any decrease of optical purity, (R)- unsaturated aliphatic alkyl group having 1-30 carbon atoms, 25 or (S)-tetrahydrofuranyl ketone can be obtained while pro a Saturated or unsaturated, Substituted or unsubstituted duction of tertiary alcohols as a by-product is minimized. cyclic alkyl group having 3–30 carbon atoms, or a Substi Having generally described this invention, a further tuted or unsubstituted aryl group having 6-30 carbon atoms. understanding can be obtained by reference to certain spe AS for the nucleophic addition reaction, (R)- or (S)-2- cific examples which are provided herein for purposes of tetrahydrofuran nitrile and the nucleophile are slowly intro illustration only and are not intended to be limiting unless duced in the presence of an organic Solvent. At this time, the otherwise Specified. (R)- or (S)-2-tetrahydrofuran nitrile and the nucleophile are introduced at an equivalent ratio of 1:1-1:3, preferably EXAMPLE 1. 1:1.1-1:2, and most preferably 1:1.1-1:1.3. When the ratio is less than 1:1, a part of the nucleophile is reacted with 195g of pyridine was introduced into a 1 L reactor and water and other impurities in the organic Solvent and thus the 35 stirred, to which 40.5 g of (S)-2-tetrahydrofuran amide reaction conversion efficiency is decreased. On the other having an optical purity of 99.1% ee was added together hand, when the ratio exceeds 1:3, large amounts of the with 73.8 g of para-toluene Sulfone chloride, and the reac nucleophile remain unreacted, thus not generating economic tion was conducted at 50° C. for 2 hours with stirring. benefit. Thereafter, most of the pyridine was removed through Examples of the nucleophile useful in the present inven 40 concentration under reduced pressure. The reactor was tion include, but are not limited to, Grignard reagents, Such placed into a water bath filled with ice water, and added with as methylmagnesium chloride, methylmagnesium bromide, dilute hydrochloric acid and stirred. Then, dichloromethane methylmagnesium iodide, ethylmagnesium chloride, ethyl was added thereto for extraction, followed by removing an magnesium bromide, ethylmagne Sium iodide, aqueous layer. Dichloromethane in the extracted organic n-propylmagnesium chloride, n-propylmagnesium bromide, 45 n-propylmagnesium iodide, iso-propylmagnesium chloride, layer was removed under reduced pressure and the iso-propylmagnesium bromide, iso-propylmagnesium dichloromethane-removed organic layer was distilled off iodide, cyclopentylmagnesium chloride, cyclohexylmagne under vacuum, yielding 25g of (S)-2-tetrahydrofuran nitrile. sium chloride, cyclopentylmagnesium bromide, cyclohexy A 0.5 L reactor at a temperature of 0°C. was added with lmagnesium bromide, cyclopentylmagnesium iodide, cyclo 50 0.1 L of 3 M methylmagnesium chloride in tetrahydrofuran, hexylmagnesium iodide, propargylmagnesium bromide, to which 25g of (S)-2-tetrahydrofuran nitrile as previously Vinylmagnesium chloride, Vinylmagnesium bromide, phe obtained, in 0.07 L of tetrahydrofuran was slowly added nylmagnesium chloride, and dropwise. AS Such, the reaction was carried out for 0.5 hours phenylmagnesium iodide, organic lithium compounds, Such with Stirring, while the temperature within the reactor was as , ethyllithium, propyllithium, iso 55 controlled below 15 C. Next, the resulting solution was propyllithium, n-butyllithium, iso-butyllithium, neobutyl added dropwise to 32 g of concentrated hydrochloric acid in lithium and phenylithium; organic Zinc compounds, Such as 0.2 L of water, while the temperature of the reaction was dimethylzinc and diethylzinc, and organic aluminum controlled below 25 C. Thereafter, the extraction was compounds, Such as trimethylaluminum and triethylalumi conducted by use of ethylacetate, followed by removing the U. 60 Solvent therein under reduced pressure, and the remainder AS the organic Solvent, Suitable is diethylether, di-n- was vacuum distilled off to produce 17.7 g of (S)-2-acetyl butyle ther, methylne obutyle ther, isopropyle ther, tetrahydrofuran having an optical purity of 99.1% ee. tetrahydrofuran, 1,4-dioxane, n-hexane, n-heptane, benzene, toluene, Xylene, or mixtures thereof. Preferably, the organic EXAMPLE 2 solvent is diethylether, dibutylether, methylneobutylether, 65 A 0.5 L reactor was added with 70 g of pyridine and isopropylether, tetrahydrofuran, 1,4-dioxane, or mixtures stirred, and then added with 20 g of (R)-2-tetrahydrofuran thereof. Most preferably, tetrahydrofuran is used. amide having an optical purity of 98.5% ee and 37 g of US 6,841,688 B2 7 8 para-toluenesulfone chloride, and stirred at 50 C. for 2 -continued hours. Thereafter, most of the pyridine was removed through Chemical Formula 3a concentration under reduced pressure. Then, the reactor was placed into a water bath filled with ice water, and added with dilute hydrochloric acid and stirred. Then, dichloromethane was added thereto for extraction, followed by removing an aqueous layer. Dichlo wherein, R is a Straight-chained or branched, Saturated or romethane in the extracted organic layer was removed under unsaturated aliphatic alkyl group having 1-30 carbon reduced pressure and the dichloromethane-removed organic atoms, a Saturated or unsaturated, Substituted or unsub layer was vacuum distilled off, yielding 13.5g of (R)-2- Stituted cyclic alkyl group having 3–30 carbon atoms, tetrahydrofuran nitrile. or a Substituted or unsubstituted aryl group having 6-30 carbon atoms. A1 L reactor at a temperature of 0°C. was added with 0.4 2. The method as defined in claim 1, wherein said L of 1.6 M n-butyllithium in n-hexane, to which 13.5g of 15 dehydrating agent is Selected from the group consisting of (R)-2-tetrahydrofuran nitrile as previously obtained, in 0.07 thionyl chloride, para-toluenesulfone chloride, phosphorous L of tetrahydrofuran was slowly added dropwise. AS Such, pentoxide, phosphorous Oxytrichloride, a mixture of dim ethylsulfoxide and Oxalic acid chloride, trifluoroacetic the reaction was carried out for 1 hour with Stirring, while anhydride, and a mixture of formaldehyde and formic acid. the temperature within the reactor was controlled below 15 3. The method as defined in claim 1, wherein said amine C. Next, the resulting Solution was added dropwise to 65 g base is Selected from the group consisting of methylamine, of concentrated hydrochloric acid in 0.4 L of water, while ethylamine, propylamine, butylamine, dimethylamine, the temperature of the reaction was controlled below 25 C. diethylamine, diisopropylamine, trimethylamine, Thereafter, the extraction was conducted by use of triethylamine, diethylisopropylamine, and pyridine. ethylacetate, followed by removing the Solvent therein under 25 4. The method as defined in claim 1, wherein said reduced preSSure, and the remainder was vacuum distilled nucleophile is Selected from the group consisting of Grig off to produce 19.6 g of (R)-1-(2-tetrahydrofuranyl)-1- nard reagent, organic lithium compound, organic Zinc com pentanone having an optical purity of 98.5% ee. pound and organic aluminum compound. 5. The method as defined in claim 4, wherein said The present invention has been described in an illustrative Grignard reagent is methylmagnesium chloride, methylmag manner, and it is to be understood that the terminology used nesium bromide, methylmagnesium iodide, ethylmagne is intended to be in the nature of description rather than of sium chloride, ethylmagnesium bromide, ethylmagnesium limitation. Many modifications and variations of the present iodide, n-propylmagnesium chloride, n-propylmagnesium invention are possible in light of the above teachings. bromide, n-propylmagnesium iodide, iso-propylmagnesium Therefore, it is to be understood that within the scope of the 35 chloride, iso-propylmagnesium bromide, iso appended claims, the invention may be practiced otherwise propylmagnesium iodide, cyclopentylmagnesium chloride, than as Specifically described. cyclohexylmagnesium chloride, cyclopentylmagnesium What is claimed is: bromide, cyclohexylmagnesium bromide, cyclopentylmag 1. A method of preparing an optically pure (R)- nesium iodide, cyclohexylmagnesium iodide, propargyl 40 magnesium bromide, Vinylmagnesium chloride, Vinylmag tetrahydrofuranyl ketone, which comprises the following nesium bromide, phenylmagne Sium chloride, Steps of: phenylmagnesium bromide or phenylmagnesium iodide, dehydrating (R)-2-tetrahydrofuran amide, represented by Said organic lithium compound is methyllithium, the following chemical formula 1a, in the presence of ethyllithium, propyllithium, iSo-propyllithium, a dehydrating agent and an amine base at 50 to 100 C. 45 n-butyllithium, iso-butyllithium, neobutyllithium or phenyl for 2 to 6 hours to obtain (R)-2-tetrahydrofuran nitrile lithium; Said organic Zinc compound is dimethylzinc or diethylzinc, and Said organic aluminum compound is trim represented by the following chemical formula 2a, ethylaluminum or triethylaluminum. nucellophilic addition-reacting (R)-2-tetrahydrofuran 6. The method as defined in claim 1, wherein Said organic nitrile with a nucleophile in an organic Solvent at the 50 Solvent is Selected from the group consisting of diethylether, temperature range of -80 to 100° C. for 10 minutes to di-n-butylether, methylneobutylether, isopropylether, 4 hours, followed by hydrolyzing by use of aqueous tetrahydrofuran, 1,4-dioxane, n-hexane, n-heptane, benzene, acidic Solution to produce (R)-tetrahydrofuranylketone toluene, Xylene and mixtures thereof. represented by the following chemical formula 3a; and 7. A method of preparing an optically pure (S)- recovering the resulting product obtained from the previ 55 tetrahydrofuranyl ketone, which comprises the following ouS Step: Steps of dehydrating (S)-2-tetrahydrofuran amide, represented by Chemical Formula 1 a the following chemical formula 1b, in the presence of a dehydrating agent and an amine base at 50 to 100 C. 60 for 2 to 6 hours to obtain (S)-2-tetrahydrofuran nitrile represented by the following chemical formula 2b; nucellophilic addition-reacting the (S)-2-tetrahydrofuran Chemical Formula 2a nitrile with a nucleophile in an organic Solvent at the temperature range of -80 to 100° C. for 10 minutes to 65 4 hours, followed by hydrolyzing by use of aqueous acidic Solution to produce (S)-tetrahydrofuranylketone represented by the following chemical formula3b; and US 6,841,688 B2 10 recovering the resulting product obtained from the previ 10. The method as defined in claim 7, wherein said ouS Step: nucleophile is Selected from the group consisting of Grig nard reagent, organic lithium compound, organic Zinc com Chemical Formula 1b pound and organic aluminum compound. NH2 11. The method as defined in claim 10, wherein said O Grignard reagent is methylmagnesium chloride, methylmag O nesium bromide, methylmagnesium iodide, ethylmagne Chemical Formula 2b sium chloride, ethylmagnesium bromide, ethylmagnesium iodide, n-propylmagnesium chloride, n-propylmagnesium bromide, n-propylmagnesium iodide, iso-propylmagnesium C. chloride, iso-propylmagnesium bromide, iso Chemical Formula3b propylmagnesium iodide, cyclopentylmagnesium chloride, cyclohexylmagnesium chloride, cyclopentylmagnesium R 15 bromide, cyclohexylmagnesium bromide, cyclopentylmag O nesium iodide, cyclohexylmagnesium iodide, propargyl O magnesium bromide, Vinylmagnesium chloride, Vinylmag nesium bromide, phenylmagne Sium chloride, wherein, R is a Straight-chained or branched, Saturated or unsaturated aliphatic alkyl group having 1-30 carbon phenylmagnesium bromide or phenylmagnesium iodide, atoms; Saturated or unsaturated, Substituted or unsub Said organic lithium compound is methyllithium, Stituted cyclic alkyl group having 3–30 carbon atoms, ethyllithium, propyllithium, iSo-propyllithium, or a Substituted or unsubstituted aryl group having 6-30 n-butyllithium, iso-butyllithium, neobutyllithium or phenyl carbon atoms. lithium; Said organic Zinc compound is dimethylzinc or 8. The method as defined in claim 7, wherein said 25 dehydrating agent is Selected from the group consisting of diethylzinc, and Said organic aluminum compound is trim thionyl chloride, para-toluenesulfone chloride, phosphorous ethylaluminum or triethylaluminum. pentoxide, phosphorous Oxytrichloride, a mixture of dim 12. The method as defined in claim 7, wherein said ethylsulfoxide and Oxalic acid chloride, trifluoroacetic organic Solvent is Selected from the group consisting of anhydride, and a mixture of formaldehyde and formic acid. diethylether, di-n-butyle ther, methylneobutyle ther, 9. The method as defined in claim 7, wherein said amine base is Selected from the group consisting of methylamine, isopropylether, tetrahydrofuran, 1,4-dioxane, n-hexane, ethylamine, propylamine, butylamine, dimethylamine, n-heptane, benzene, toluene, xylene and mixtures thereof. diethylamine, diisopropylamine, trimethylamine, triethylamine, diethylisopropylamine, and pyridine. k k k k k