JP2008063239A - Method for preparing grignard reagent of oxygen-containing chlorobenzene compound using tetrahydropyran as solvent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve the lowness of reactivity of an oxygen-containing chlorobenzene compound to improve the length of the reaction time and the yield of the Gringard reagent in preparing the Grignard reagent with the use of an aromatic chloride, particularly an oxygen-containing chlorobenzene compound and magnesium. <P>SOLUTION: Tetrahydropyran is used as a solvent in the step of preparing a Grignard reagent using an oxygen-containing chlorobenzene compound as a raw material. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a Grignard reagent by reacting an oxygen-containing chlorobenzene compound and magnesium in tetrahydropyran, a composition comprising the Grignard reagent and tetrahydropyran produced by the method, and a method for producing a Grignard reaction product. .

The Grignard reaction is the most useful method for generating a carbon-carbon bond (Grignard Reactions of Non-Metallic Substances, Prentice Hall, Englewood, Cliffs, New Jersey (1954): Non-Patent Document 1).
The Grignard reaction is a reaction in which a carbon-carbon bond is formed by a highly reactive organometallic reagent (Grignard reagent), and the Grignard reagent is synthesized by reacting an organic halide and magnesium in an ether solvent.

（式中、Ｒは水素原子、アルキル基、アリール基、ビフェニル基、ベンジル基、アリル基またはシリル基を表し、ｎは１〜５の整数を表す。）で示されるグリニャール試薬は、有機合成上において重要な試薬であり、医農薬（特開平10-273475号公報：特許文献１）、触媒の配位子（特開2002-308892号公報：特許文献２）、電子材料などの合成に用いられている。 The following general formula (2)

(In the formula, R represents a hydrogen atom, an alkyl group, an aryl group, a biphenyl group, a benzyl group, an allyl group or a silyl group, and n represents an integer of 1 to 5). And is used for the synthesis of medicines and agricultural chemicals (JP-A-10-273475: Patent Document 1), catalyst ligands (JP-A 2002-308892: Patent Document 2), electronic materials and the like. ing.

As a method for synthesizing such an aromatic Grignard reagent, a method of synthesizing highly reactive aromatic bromide or aromatic iodide with magnesium in an ether solvent, and an aromatic chloride and magnesium with ether. There is a method of synthesis by reacting in a system solvent.
However, the method using aromatic bromide or aromatic iodide has a higher molecular weight than the method using aromatic chloride, so the amount of raw material used (mass) increases, and the unit cost of the raw material is high. There is a problem of becoming higher.

  On the other hand, the method using aromatic chloride has the advantages that the amount of raw material used is small and the unit price of the raw material is low compared with the method using aromatic bromide or aromatic iodide. Due to the low reactivity with magnesium, there are problems such as long reaction time and low yield of Grignard reagent.

  As a method for synthesizing a Grignard reagent from an aromatic chloride and magnesium, a method using activated magnesium obtained from magnesium chloride and potassium (JP-A-9-227575: Patent Document 3), an ether solvent and a hydrocarbon There is a method using a mixed solvent of solvents (Japanese Patent Laid-Open No. 2003-96082: Patent Document 4).

However, in the former method using activated magnesium, there is a problem in safety because potassium is used.
In the case of the latter method using a mixed solvent, the hydrocarbon solvent is added to the Grignard reagent produced only in the ether solvent, so that there are problems that the stability of the Grignard reagent is lowered and the concentration is lowered.

  Tetrahydrofuran is mainly used as the ether solvent, but in order to produce a Grignard reaction product from a Grignard reagent synthesized using a tetrahydrofuran solvent, a carbonyl compound or In the case of reacting with an ester or the like, if water is added to extract and separate the product, the solvent tetrahydrofuran and water are mixed, so that there is a problem that the product separation step becomes complicated and the yield decreases.

Grignard Reactions of Non-Metallic Substances, Prentice Hall, Englewood, Cliffs, New Jersey (1954) JP-A-10-273475 JP 2002-308892 A JP-A-9-227575 JP 2003-96082 A

  The present invention improves the low reactivity of an oxygen-containing chlorobenzene compound when producing a Grignard reagent using an aromatic chloride, particularly an oxygen-containing chlorobenzene compound and magnesium, and increases the reaction time and the Grignard reagent. It is to improve the yield.

As a result of diligent efforts in view of the above problems, the present inventors have completed the present invention by using tetrahydropyran as a solvent in a Grignard reagent production process using an oxygen-containing chlorobenzene compound as a raw material.
That is, the present invention relates to a method for producing the following Grignard reagent.

（式中、Ｒは水素原子、アルキル基、アリール基、ビフェニル基、ベンジル基、アリル基またはシリル基を表し、ｎは１〜５の整数を表す。）で示される含酸素クロロベンゼン化合物とマグネシウムをテトラヒドロピラン中で反応させて、下記式（２）

（式中、Ｒ及びｎは前記と同じ意味を表す。）で示されるグリニャール試薬を製造する方法。
［２］テトラヒドロピランと下記式（２）

（式中、Ｒ及びｎは前記と同じ意味を表す。）
からなることを特徴とするテトラヒドロピラン組成物。
［３］前記１に記載の方法で製造されたグリニャール試薬を用いて、テトラヒドロピラン中で求核付加反応を行うことを特徴とするグリニャール反応生成物の製造方法。
［４］グリニャール反応の後、水を加え、反応により生成した化合物をテトラヒドロピラン層へ抽出する前記３に記載のグリニャール反応生成物の製造方法。 [1] The following formula (1)

(Wherein R represents a hydrogen atom, an alkyl group, an aryl group, a biphenyl group, a benzyl group, an allyl group or a silyl group, and n represents an integer of 1 to 5) and magnesium. Reaction in tetrahydropyran gives the following formula (2)

(Wherein R and n represent the same meaning as described above).
[2] Tetrahydropyran and the following formula (2)

(In the formula, R and n have the same meaning as described above.)
A tetrahydropyran composition comprising:
[3] A method for producing a Grignard reaction product, wherein a nucleophilic addition reaction is carried out in tetrahydropyran using the Grignard reagent produced by the method described in 1 above.
[4] The method for producing a Grignard reaction product as described in 3 above, wherein water is added after the Grignard reaction, and a compound produced by the reaction is extracted into a tetrahydropyran layer.

  According to the present invention, when producing a Grignard reagent using an aromatic chloride, particularly an oxygen-containing chlorobenzene compound and magnesium, which has a low raw material cost, the reactivity of the aromatic chloride is improved and the reaction time is improved. And the yield of Grignard reagent can be improved.

（式中、Ｒは水素原子、アルキル基、アリール基、ビフェニル基、ベンジル基、アリル基またはシリル基を表し、ｎは１〜５の整数を表す。）で示される含酸素クロロベンゼン化合物とマグネシウムをテトラヒドロピラン中で反応させて、下記式（２）

（式中、Ｒは前記と同じ意味を表す。）で示されるグリニャール試薬を製造する方法に関する。 The specific contents of the present invention will be described in detail below.
1. The first aspect of the present invention is the following formula (1)

(Wherein R represents a hydrogen atom, an alkyl group, an aryl group, a biphenyl group, a benzyl group, an allyl group or a silyl group, and n represents an integer of 1 to 5) and magnesium. Reaction in tetrahydropyran gives the following formula (2)

(Wherein, R represents the same meaning as described above).

（式中、Ｒは水素原子、アルキル基、アリール基、ビフェニル基、ベンジル基、アリル基またはシリル基を表し、ｎは１〜５の整数を表す。）で示される化合物であり、具体的には、以下に示すようなクロロフェノール化合物、アルキルオキシクロロベンゼン化合物、アリールオキシクロロベンゼン化合物、ベンジルオキシクロロベンゼン化合物、アリルオキシクロロベンゼン化合物、シリルオキシクロロベンゼン化合物等を用いることができる。 [Oxygen-containing chlorobenzene compound]
The oxygen-containing chlorobenzene compound used in the present invention has the following formula (1):

(Wherein R represents a hydrogen atom, an alkyl group, an aryl group, a biphenyl group, a benzyl group, an allyl group or a silyl group, and n represents an integer of 1 to 5), specifically The following chlorophenol compounds, alkyloxychlorobenzene compounds, aryloxychlorobenzene compounds, benzyloxychlorobenzene compounds, allyloxychlorobenzene compounds, silyloxychlorobenzene compounds, and the like can be used.

  As chlorophenol compounds, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol, 2,3-dihydroxychlorobenzene, 2,4-dihydroxychlorobenzene, 2,5-dihydroxychlorobenzene, 2,6-dihydroxychlorobenzene, 3 , 4-dihydroxychlorobenzene, 3,5-dihydroxychlorobenzene, 2,4,6-trihydroxychlorobenzene, 3,4,5-trihydroxychlorobenzene, 2,3,5,6-tetrahydroxychlorobenzene, 2,3,4 , 5,6-pentahydroxychlorobenzene and the like can be used.

  Examples of the alkyloxychlorobenzene compound include 2-chloroanisole, 3-chloroanisole, 4-chloroanisole, 2,3-dimethoxychlorobenzene, 2,4-dimethoxychlorobenzene, 2,5-dimethoxychlorobenzene, 2,6-dimethoxychlorobenzene, 3,4-dimethoxychlorobenzene, 3,5-dimethoxychlorobenzene, 2,4,6-trimethoxychlorobenzene, 3,4,5-trimethoxychlorobenzene, 2,3,5,6-tetramethoxychlorobenzene, 2,3 4,5,6-pentamethoxychlorobenzene, 2-ethoxychlorobenzene, 3-ethoxychlorobenzene, 4-ethoxychlorobenzene, 2-isopropoxychlorobenzene, 3-isopropoxychlorobenzene, 4-isopropoxychloro , 2-t-butoxychlorobenzene, 3-t-butoxychlorobenzene, 4-t-butoxychlorobenzene, 4-methoxymethoxychlorobenzene, 4- (2-butoxyethoxy) chlorobenzene, 4- (1-butoxyethoxy) chlorobenzene, N, N-diethyl-2-phenoxychlorobenzene, 4- (tetrahydro-2H-pyran-2-yl) oxychlorobenzene, 2-methoxy-5-methylchlorobenzene, 4-trifluoromethoxychlorobenzene, 4-pentafluoroethoxychlorobenzene, 4- (2,2-dimethoxyethoxy) chlorobenzene or the like can be used.

  Examples of the aryloxychlorobenzene compound include 2-phenyloxychlorobenzene, 3-phenyloxychlorobenzene, 4-phenyloxychlorobenzene, 4- (2-methylphenoxy) chlorobenzene, 4- (3-methylphenoxy) chlorobenzene, 4- (4- Methylphenoxy) chlorobenzene, 4- (4-chlorophenoxy) chlorobenzene, 4- (4-fluorophenoxy) chlorobenzene, 4-pentafluorophenoxychlorobenzene and the like can be used.

  Benzyloxychlorobenzene compounds include 2-benzyloxychlorobenzene, 3-benzyloxychlorobenzene, 4-benzyloxychlorobenzene, 3,4-dibenzyloxychlorobenzene, 3,5-dibenzyloxychlorobenzene, 3,4,5-tri Benzyloxychlorobenzene and the like can be used.

  Examples of the allyloxychlorobenzene compound include 2- (2-propenyloxy) chlorobenzene, 3- (2-propenyloxy) chlorobenzene, 4- (2-propenyloxy) chlorobenzene, 2- (2-isopropenyloxy) chlorobenzene, 3- (2-Isopropenyloxy) chlorobenzene, 4- (2-isopropenyloxy) chlorobenzene and the like can be used.

  Examples of silyloxychlorobenzene compounds include 2-trimethylsilyloxychlorobenzene, 3-trimethylsilyloxychlorobenzene, 4-trimethylsilyloxychlorobenzene, 2-triethylsilyloxychlorobenzene, 3-triethylsilyloxychlorobenzene, 4-triethylsilyloxychlorobenzene, and 2-tripropyl. Silyloxychlorobenzene, 3-tripropylsilyloxychlorobenzene, 4-tripropylsilyloxychlorobenzene, 2-triisopropylsilyloxychlorobenzene, 3-triisopropylsilyloxychlorobenzene, 4-triisopropylsilyloxychlorobenzene, 2-t-butyldimethyl Silyloxychlorobenzene, 3-tert-butyldimethylsilyloxychlorobenzene, 4 t-butyldimethylsilyloxychlorobenzene, 2-t-butyldiphenylsilyloxychlorobenzene, 3-t-butyldiphenylsilyloxychlorobenzene, 4-t-butyldiphenylsilyloxychlorobenzene, 2-dimethylvinylsilyloxychlorobenzene, 3-dimethylvinyl Silyloxychlorobenzene, 4-dimethylvinylsilyloxychlorobenzene and the like can be used.

[magnesium]
The magnesium used in the present invention is preferably in the form of granular magnesium, specifically, magnesium chips, magnesium dust, magnesium powder and the like.
In the present invention, magnesium is used in excess relative to the oxygen-containing chlorobenzene compound.
When the amount of magnesium is equivalent to the oxygen-containing chlorobenzene compound, the reaction is not substantially completed, and when it is more than twice the amount, the advantage of accelerating the reaction is lost, and unreacted magnesium at the end of the reaction. There is a problem that must be removed. Magnesium is used in an amount of at least 1 mol equivalent to the oxygen-containing chlorobenzene compound.
Preferably, 1.01-1.5 mol equivalent is used with respect to the oxygen-containing chlorobenzene compound. More preferably, it is 1.05-1.35 mol equivalent.

[Reaction activator]
In this reaction, inorganic and organic halogen compounds can be used as reaction activators.
The reaction activator modifies the surface of magnesium and improves the reactivity of magnesium with the oxygen-containing chlorobenzene compound.
As such an inorganic halogen compound, for example, iodine, bromine, bromine iodide, chlorine iodide and the like can be used, and iodine is particularly preferable.

  Examples of organic halides include dibromomethane, diiodomethane, 1,2-dibromoethane, 1,2-diiodoethane, 1-chloro-2-bromoethane, 1-chloro-2-iodoethane, 1-bromo-2-iodoethane, and the like. Of which 1,2-dibromoethane is preferred.

  These halogen compounds are used in an amount of 0.01 to 0.3 mol equivalent to magnesium. Preferably it is 0.05-0.15 mol equivalent. If the amount of the halogen compound used is small, a sufficient reaction initiation effect cannot be obtained, and the production rate of the Grignard reagent will be slow. Further, if the amount of halide used is large, magnesium may be lost or a side reaction may occur, which is not preferable.

[solvent]
Tetrahydropyran is used as the reaction solvent.
A mixed solvent with an ether solvent such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether (diglyme), or a hydrocarbon solvent such as toluene or xylene can be used, but tetrahydropyran should be used alone from the viewpoint of recovery and reuse. Is desirable. Tetrahydropyran is usually used after being distilled and treated with a dehydrating agent, and is used in an amount of 2 to 50 times, preferably 5 to 30 times the weight of magnesium.

[Generation of Grignard reagent]
This reaction is usually carried out under an inert atmosphere such as nitrogen or argon.
Usually, after adding an organic dihalogen compound to a solution composed of tetrahydropyran and magnesium, an oxygen-containing chlorobenzene compound is added once or over time. An organic dihalogen compound and oxygen-containing chlorobenzene compound are added to a solution composed of tetrahydropyran and magnesium. There is a method of adding simultaneously, or a method of adding an organic dihalogen compound to a solution composed of tetrahydropyran, magnesium and an oxygen-containing chlorobenzene compound.
The reaction temperature is usually 0 ° C. or lower and below the reflux temperature of the reaction solution to be added, preferably 25 ° C. to the reflux temperature of the reaction solution.

2. TECHNICAL FIELD The present invention relates secondly to a method for producing a Grignard reaction product, which is used for subjecting the Grignard reagent thus obtained to a carbon increase reaction in the next step.

[Nucleophilic addition agent]
The Grignard reagent obtained in the present invention is reacted with the following nucleophilic adduct to give a Grignard product which is a carbon increase product.
Examples of such nucleophilic addition agents include formaldehyde, acetaldehyde, butyraldehyde, crotonaldehyde, 3-phenylpropionaldehyde, benzaldehyde, anisaldehyde, p-chlorobenzaldehyde, aldehyde compounds such as p-methylbenzaldehyde, terephthalaldehyde, acetone , Ketone compounds such as methyl ethyl ketone, diethyl ketone, cyclohexanone, acetophenone, benzophenone, ester compounds such as methyl formate, methyl acetate, ethyl benzoate, methyl anisate, carboxylic acid compounds such as formic acid, acetic acid, benzoic acid, anisic acid, Acid chloride compounds such as formic acid chloride, acetic acid chloride, benzoic acid chloride, anisic acid chloride, N, N′-dimethylacetamide, N, N′-diethylbenzene Amide compounds such as zamide, nitrile compounds such as acetonitrile, acrylonitrile, benzonitrile, terephthalonitrile, lactone compounds such as γ-butyrolactone, γ-valerolactone, ε-caprolactone, propylene oxide, butylene oxide, isobutylene oxide styrene oxide, bisphenol Epoxy compounds such as A and 4-membered cyclic compounds such as oxetane can be used. Also, C1 compounds such as carbon dioxide and carbon disulfide, molecular compounds such as oxygen and sulfur, sulfur-containing organic compounds such as dimethylsulfone, diethylsulfone, diphenylsulfone and other sulfone compounds, nitrogen-containing organic compounds such as methyl isocyanate, Isocyanate compounds such as phenyl esocyanate, nitroso compounds such as nitrosobenzene, p-dinitrobenzene, and p-nitrosotoluene can be used.

  Among the above, aldehyde compounds, ketone compounds, ester compounds, carboxylic acid compounds, chloride compounds, amide compounds, nitrile compounds, lactone compounds, and epoxy compounds are particularly useful industrially and can be suitably used in the present invention.

  Usually, the Grignard reagent produced in the preceding step is added to a tetrahydropyran solution of a reaction raw material such as an aldehyde or ketone, or an ester compound, and an alkyl group is introduced by a nucleophilic addition reaction. Conversely, reaction raw materials may be added to the Grignard reagent.

[solvent]
Also in this step, a mixed solvent of tetrahydropyran and an ether solvent such as tetrahydrofuran, dioxane or diglyme, or a hydrocarbon solvent such as toluene or xylene can be used as a solvent, but it is recovered and reused. From the viewpoint, it is desirable to use tetrahydropyran alone.

After completion of the reaction, water is added to the reaction solution, and the product is extracted and separated. Since tetrahydropyran separates from water, the product can be easily obtained.
Tetrahydropyran can be reused after dehydration after distillation recovery, thereby reducing the amount of solvent used.

  Summarizing the above, as an example of a reaction that can be applied in the present invention, an oxygen-containing chlorobenzene compound (wherein Ph represents a phenyl group substituted with an oxygen-containing substituent) is used as a Grignard reagent raw material. The reaction is shown in the following chemical formula.

なお、本発明の製造方法に従って合成したグリニャール化合物をアルコール類と反応させた場合、クロロ基を水素に置換した化合物を得ることができる。

In addition, when the Grignard compound synthesized according to the production method of the present invention is reacted with alcohols, a compound in which the chloro group is substituted with hydrogen can be obtained.

  Hereinafter, the present invention will be described in detail with typical examples, but the present invention is not limited thereto.

  In addition, the analysis of each component in an Example used the gas chromatograph apparatus (made by Agilent, 6890N), and used DB-1 column (length 30m, diameter 0.32mm, film thickness 1 micrometer) by J & W as an analysis column. In addition, a high performance liquid chromatograph apparatus (manufactured by SHIMADZU, LC-2010HT) was used for the analysis of hardly volatile substances, and RP-18 (ODS) and a full end cap treatment (manufactured by Kanto Chemical) were used as an analysis column.

[Example 1]
Under an argon atmosphere, a stirring bar, 2.91 g (120 mmol) of magnesium, and 20 ml of tetrahydropyran were added to a 300 ml eggplant flask and gently stirred at room temperature. Then, 1.13 g (6 mmol) of 1,2-dibromoethane was added and stirred with heating for 5 minutes. A solution of 14.3 g (100 mmol) of 2-chloroanisole in 80 ml of tetrahydropyran was added under reflux, and the mixture was stirred for 12 hours under reflux, then cooled to room temperature, and tetrahydro of 2-methoxyphenylmagnesium chloride (Grignard reagent). A pyran solution was obtained.
The 2-methoxyphenyl magnesium chloride produced by this reaction reacts with methanol to become anisole.
A part of the reaction solution was sampled, and the solution added in methanol was quantified by GC to find that 2-chloroanisole was 0.3% and anisole was 99.3%.

[Example 2]
Under argon atmosphere, a stirring flask, 0.29 g (12 mmol) of magnesium, 10 ml of tetrahydropyran, 0.11 g (0.6 mmol) of 1,2-dibromoethane, and 1.72 g of 3,4-dimethoxychlorobenzene were placed in a 50 ml eggplant flask. (10 mmol) was added at room temperature and then gently stirred. After stirring for 15 hours under reflux, the mixture was cooled to room temperature to obtain a tetrahydropyran solution of 3,4-dimethoxyphenylmagnesium chloride (Grignard reagent).
3,4-Dimethoxyphenylmagnesium chloride produced by this reaction reacts with methanol to become dimethoxybenzene.
A part of the reaction solution was sampled, and the solution added in methanol was quantified by GC to find that 3,4-dimethoxychlorobenzene was 1.1% and dimethoxybenzene was 98.4%.

[Example 3]
Under argon atmosphere, a stirring bar, magnesium 0.29 g (12 mmol), tetrahydropyran 10 ml, 1,2-dibromoethane 0.11 g (0.6 mmol), and 3-phenoxychlorobenzene 2.04 g (10 mmol) in a 50 ml eggplant flask. ) At room temperature and then gently stirred. After stirring for 10 hours under reflux, the mixture was cooled to room temperature to obtain a tetrahydropyran solution of 3-phenoxyphenylmagnesium chloride (Grignard reagent).
4-methoxyphenylmagnesium chloride produced by this reaction reacts with methanol to form diphenyl ether.
A part of the reaction solution was sampled, and the solution added in methanol was quantified by GC. As a result, it was 0.6% for 3-phenoxychlorobenzene and 99.0% diphenyl ether.

[Example 4]
Under argon atmosphere, a stirring bar, magnesium 0.29 g (12 mmol), tetrahydropyran 10 ml, 1,2-dibromoethane 0.11 g (0.6 mmol), and 4-benzyloxychlorobenzene 2.19 g 10 mmol) at room temperature and then gently stirred. After stirring for 12 hours under reflux, the mixture was cooled to room temperature to obtain a tetrahydropyran solution of 4-benzyloxyphenylmagnesium chloride (Grignard reagent).
4-Benzyloxyphenyl magnesium chloride produced by this reaction reacts with methanol to become benzyl phenyl ether.
A part of the reaction solution was sampled, and the solution added in methanol was quantified by GC.

[Example 5]
In a 50 ml eggplant flask under argon atmosphere, a stirrer, magnesium 0.29 g (12 mmol), tetrahydropyran 10 ml, 1,2-dibromoethane 0.11 g (0.6 mmol), and 4- (2-propenyloxy) chlorobenzene After 1.69 g (10 mmol) was added at room temperature, the mixture was gently stirred. After stirring for 10 hours under reflux, the mixture was cooled to room temperature to obtain a tetrahydropyran solution of 4- (2-propenyloxy) phenylmagnesium chloride (Grignard reagent).
4- (2-propenyloxy) chlorophenyl magnesium chloride produced by this reaction reacts with methanol to be allyloxybenzene.
A part of the reaction solution was sampled, and the solution added in methanol was quantified by GC. As a result, 4- (2-propenyloxy) chlorobenzene was 0.4% and allyloxybenzene was 99.2%.

[Example 6]
Under argon atmosphere, a stirring bar, magnesium 0.29 g (12 mmol), tetrahydropyran 10 ml, 1,2-dibromoethane 0.11 g (0.6 mmol), and 4-t-butyldiphenylsilyloxychlorobenzene 3.67 g (10 mmol) was added at room temperature and then gently stirred. After stirring for 8 hours under reflux, the mixture was cooled to room temperature to obtain a tetrahydropyran solution of 4-t-butyldiphenylsilyloxyphenyl magnesium chloride (Grignard reagent).
4-t-butyldiphenylsilyloxyphenyl magnesium chloride produced by this reaction reacts with methanol to form t-butyldiphenylsilyloxybenzene.
A part of the reaction solution was sampled, and the solution added in methanol was quantified by GC. As a result, it was 3.7% for 4-t-butyldiphenylsilyloxychlorobenzene and 94.2% for t-butyldiphenylsilyloxybenzene.

[Example 7: Preparation of Grignard reagent]
Under an argon atmosphere, a stirring bar, 2.91 g (120 mmol) of magnesium, and 20 ml of tetrahydropyran were added to a eggplant flask having a capacity of 300 ml, and gently stirred at room temperature. Next, 1.13 g (6 mmol) of 1,2-dibromoethane was added and stirred with heating for 5 minutes. Under reflux, a solution of 14.3 g (100 mmol) of 4-chloroanisole in 80 ml of tetrahydropyran was added. After stirring for 18 hours under reflux, the mixture was cooled to room temperature to obtain a tetrahydropyran solution of 4-methoxyphenylmagnesium chloride (Grignard reagent).
A part of the reaction solution was sampled, added to methanol, and quantified by GC. The yield of 4-methoxyphenylmagnesium chloride (quantified as anisole) was 99%.
In addition, this 4-methoxyphenyl magnesium chloride is used for Grignard reaction as 99 mmol conversion.

[Grignard reaction and product isolation]
Under an argon atmosphere, a stirring bar, 12.9 g (95 mmol) of 4-methoxybenzaldehyde, and 50 ml of tetrahydropyran were added to a 300 ml eggplant flask and stirred at room temperature. The previously prepared Grignard reagent was added over 10 minutes using a cannula under ice cooling, the reaction temperature was raised to room temperature, and the reaction was allowed to proceed for another 3 hours. 100 ml of water was added to this solution, and the pH of the solution was adjusted to around 4 with a 10% hydrochloric acid aqueous solution. The reaction solution was separated, and the tetrahydropyran layer was washed with 100 ml of water and then with saturated brine, and dried over magnesium sulfate. After drying overnight, the tetrahydropyran was distilled off and the remaining tetrahydropyran was removed with a vacuum pump. 21.4 g (crude yield 92%) of 4,4′-dimethoxybenzhydrol crude product was obtained.

[Example 8]
The tetrahydropyran solution (99 mmol equivalent) of 4-methoxyphenylmagnesium chloride prepared in Example 7 was added to aldehyde, ketone, and ester, reacted at room temperature for 3 hours, and then quantified by GC or HPLC. The results are shown in Table 1.

Claims (4)

Following formula (1)

(Wherein R represents a hydrogen atom, an alkyl group, an aryl group, a biphenyl group, a benzyl group, an allyl group or a silyl group, and n represents an integer of 1 to 5) and magnesium. Reaction in tetrahydropyran gives the following formula (2)

(Wherein R and n represent the same meaning as described above). Tetrahydropyran and the following formula (2)

(In the formula, R and n have the same meaning as described above.)
A tetrahydropyran composition comprising:   A method for producing a Grignard reaction product, comprising performing a nucleophilic addition reaction in tetrahydropyran using the Grignard reagent produced by the method according to claim 1.   The method for producing a Grignard reaction product according to claim 3, wherein water is added after the Grignard reaction, and a compound produced by the reaction is extracted into a tetrahydropyran layer.