JP4825969B2 - Method for producing tertiary alcohol - Google Patents

Description

  The present invention relates to a method for producing a tertiary alcohol.

  The Grignard reaction is known as a typical alkylation reaction widely used for pharmaceutical synthesis, functional material synthesis, and the like. In the Grignard reaction, a Grignard reagent is prepared in advance from a metal such as magnesium and an alkyl halide, and the reagent is reacted with a carbonyl compound to introduce an alkyl group into the carbonyl group.

  However, the Grignard reaction is not suitable as an industrial production method because it is difficult to prepare a Grignard reagent and the reagent is ignitable.

  Barbier type reaction is known as a simple method of Grignard reaction. This reaction is a technique for introducing an alkyl group into a carbonyl group by simultaneously mixing a metal, an alkyl halide, and a carbonyl compound in the reaction system, performing a Grignard reaction while forming a Grignard reagent in the reaction system.

  However, in this Barbier type reaction, the reactivity of the ester is very low among carbonyl compounds. For this reason, almost no Barbier-type reaction is applied to the method for producing an alcohol using an ester as a carbonyl compound, and only Non-Patent Documents 1 and 2 have been reported.

Non-Patent Document 1 discloses a method for producing a tertiary alcohol from a halogenated alkyl and an ester by a Barbier reaction using SmI ₂ (samarium diiodide) as a metal.

However, the method described in Non-Patent Document 1 requires that a reaction catalyst such as NiI ₂ be present in the reaction system together with SmI ₂ . The reaction catalyst such as NiI ₂ used in the reaction is very disadvantageous industrially because the reaction operation becomes complicated because it is necessary to separate it from the reaction mixture after completion of the reaction. Furthermore, reaction catalysts such as SmI ₂ and NiI ₂ are relatively expensive compounds, and SmI ₂ is poorly soluble in solvents such as tetrahydrofuran, so it is used only at a low concentration of about 0.1 mol / liter. However, when SmI ₂ is used at a low concentration, a large amount of solvent is required, which is not suitable for mass synthesis.

  Non-Patent Document 2 discloses a method for producing a tertiary alcohol from an allyl halide and an ester by a Barbier-type reaction using Al (aluminium) as a metal.

However, the method described in Non-Patent Document 2 requires that a reaction catalyst such as PbBr ₂ be present in the reaction system together with Al. The reaction catalyst such as PbBr ₂ used in the reaction has a strict drainage standard and requires a separation from the reaction mixture after completion of the reaction, which makes the reaction operation complicated and is extremely disadvantageous industrially. In addition, this method has a problem that it cannot be applied to alkyl halides.
Henri B. Kagan et.al., SYNLETT, 633, July 1996 Hideo Tanaka et.al., Inorganica Chimica Acta, 296, 204-207, 1999

  An object of the present invention is to provide a method for industrially advantageously producing a tertiary alcohol from an alkyl halide and an ester by a Barbier-type reaction.

  In order to solve the above problems, the present inventors have conducted various studies on Barbier-type reactions using metal strontium. In the course of the research, metal strontium, benzoic acid ethyl ester and tert-butyl iodide can be reacted in tetrahydrofuran at −20 ° C. to selectively introduce a tert-butyl group at the para position of benzoic acid ethyl ester. It has been found that tert-butylbenzoic acid ethyl ester can be produced.

  In the above reaction, a tertiary alcohol could not be produced, but the present inventors changed the reaction conditions such as the type of alkyl iodide to be used, the reaction temperature, etc. When a Barbier-type reaction is performed under specific reaction conditions, two alkyl groups are selectively added to the ester portion of benzoic acid ethyl ester without introducing a primary alkyl iodide group at the para position of benzoic acid ethyl ester. It was found that a tertiary alcohol can be produced as a result.

  Further, the present inventors can produce a tertiary alcohol in the same manner as described above even when a ketone such as propiophenone and a carboxylic acid such as 3-phenylpropionic acid are used in place of ethyl benzoate. I found out.

  The present invention has been completed based on such findings.

This invention provides the manufacturing method of the tertiary alcohol shown to the following 1-7.
1. General formula (1)

［式中、Ｒ^１は有機基を示す。Ｒ^２はアルキル基、アルコキシ基、アリールオキシ基又は水酸基を示す。］
で表される化合物と一般式（２）
Ｒ^３Ｘ （２）
［式中、Ｒ^３は第１級アルキル基を示す。Ｘはハロゲン原子を示す。］
で表されるハロゲン化アルキルとを、金属ストロンチウムの存在下に反応させて、一般式（３）

[Wherein R ¹ represents an organic group. R ² represents an alkyl group, an alkoxy group, an aryloxy group or a hydroxyl group. ]
And a compound represented by the general formula (2)
R ³ X (2)
[Wherein R ³ represents a primary alkyl group. X represents a halogen atom. ]
Is reacted with an alkyl halide represented by the general formula (3) in the presence of metal strontium.

［式中、Ｒ^１及びＲ^３は前記に同じ。一般式（１）におけるＲ^２がアルキル基を示す場合には、Ｒ^４はＲ^２を示し、また、一般式（１）におけるＲ^２がアルコキシ基、アリールオキシ基又は水酸基を示す場合には、Ｒ^４はＲ^３を示すものとする。］
で表される第３級アルコールを得る、
第３級アルコールの製造方法。
２．一般式（１）において、Ｒ^１で示される有機基が、置換基を有することのあるアリール基、置換基を有することのあるアリールアルキル基、置換基を有することのあるアルキル基又は置換基を有することのあるアルケニル基である上記１に記載の方法。
３．一般式（１）において、Ｒ^２が、アルコキシ基又はアリールオキシ基である上記１に記載の方法。
４．一般式（１）の化合物に対して、２〜３当量程度の一般式（２）の化合物を使用する上記３に記載の方法。
５．一般式（１）の化合物に対して、２〜３当量程度の金属ストロンチウムを使用する上記３に記載の方法。
６．反応をテトラヒドロフラン中で行う上記１に記載の方法。
７．反応を室温付近で行う上記１に記載の方法。

[Wherein, R ¹ and R ³ are the same as above. If the R ² represents an alkyl group in the general formula (1), when R ⁴ represents a R ^2, also showing R ² in the general formula (1) is an alkoxy group, an aryloxy group or a hydroxyl group, R ⁴ represents R ³ . ]
To obtain a tertiary alcohol represented by
A method for producing tertiary alcohol.
2. In the general formula (1), the organic group represented by R ¹ is an aryl group that may have a substituent, an arylalkyl group that may have a substituent, an alkyl group that may have a substituent, or a substituent. 2. The method according to 1 above, which is an alkenyl group which may have.
3. ^2. The method according to 1 above, wherein, in the general formula (1), R ² is an alkoxy group or an aryloxy group.
4). 4. The method according to 3 above, wherein about 2 to 3 equivalents of the compound of the general formula (2) are used with respect to the compound of the general formula (1).
5). 4. The method according to 3 above, wherein about 2 to 3 equivalents of metal strontium is used relative to the compound of general formula (1).
6). The process according to 1 above, wherein the reaction is carried out in tetrahydrofuran.
7). 2. The method according to 1 above, wherein the reaction is performed at around room temperature.

In the general formula (1), examples of the organic group represented by R ¹ include an aryl group that may have a substituent, an arylalkyl group that may have a substituent, an alkyl group that may have a substituent, Examples thereof include an alkenyl group which may have a substituent.

  Examples of the aryl group that may have a substituent include a phenyl group, a naphthyl group, a phenyl group having a substituent, and a naphthyl group having a substituent.

  The substituent on the phenyl ring or naphthyl ring is preferably an electron withdrawing group. Examples of the electron withdrawing group include a halogen atom (chlorine atom, bromine atom, etc.), a carbonyl group, a nitro group, a sulfonyl group, a nitrile group, and the like.

  The substituent may be an electron donating group depending on the substitution position of the substituent substituted on the phenyl ring or naphthyl ring. Examples of the electron donating group include an alkyl group, an amino group, an alkylamino group (such as a methylamino group, an ethylamino group, a dimethylamino group, and a diethylamino group) and an alkoxy group (such as a methoxy group and an ethoxy group).

  The number of substituents substituted on the phenyl ring or naphthyl ring is 1 to 5, preferably 1 to 3.

  Examples of the arylalkyl group that may have a substituent include a phenylalkyl group, a naphthylalkyl group, a phenylalkyl group having a substituent, and a naphthylalkyl group having a substituent. The substituent on the phenyl ring or naphthyl ring may be the same as the substituent of the phenyl group and naphthyl group described above.

Examples of the alkyl group constituting the arylalkyl group include C _1-8 linear or branched alkyl groups.

  Specific examples of the phenylalkyl group include benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl, 3-phenylpropyl group and the like. Specific examples of the naphthylalkyl group include a naphthylmethyl group, a 1-naphthylethyl group, a 2-naphthylethyl group, a 1-naphthylpropyl group, a 2-naphthylpropyl group, and a 3-naphthylpropyl group.

Examples of the alkyl group which may have a substituent include a C _1-30 linear or branched alkyl group, and a C _1-30 linear or branched alkyl group having a substituent. It is done. The substituent on the alkyl group may be the same as the substituent of the phenyl group and naphthyl group described above.

Specific examples of the C _1-30 linear or branched alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- Butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n- A tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group and the like can be exemplified.

_Examples of the alkenyl group which may have a substituent include a C _2-30 linear or branched alkenyl group and a C _2-30 linear or branched alkenyl group having a substituent. It is done. The substituent on the alkenyl group may be the same as the substituent of the phenyl group and naphthyl group described above.

Specific examples of the C _2-30 linear or branched alkenyl group include a vinyl group, an allyl group, a 2-butenyl group, a 3-butenyl group, a 1-methylallyl group, a 2-pentenyl group, and 2-hexenyl. Examples include groups. The number of double bonds in the alkenyl group is about 1 to 3.

In the general formula (1), examples of the alkyl group represented by R ² include a C _1-8 linear or branched alkyl group, and specific examples thereof include a methyl group, an ethyl group, and the like. Group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, etc. it can.

In the general formula (1), examples of the alkoxy group represented by R ² include a C _1-8 linear or branched alkoxy group, and specific examples thereof include a methoxy group and an ethoxy group. Group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, n-heptyloxy group, n-octyl An oxy group etc. can be illustrated.

In the general formula (1), examples of the aryloxy group represented by R ² include a phenyloxy group, a naphthyloxy group, a phenyloxy group having a substituent, and a naphthyloxy group having a substituent. Examples of the substituent on the phenyl ring or naphthyl ring include a halogen atom (chlorine atom, bromine atom, etc.), carbonyl group, nitro group, sulfonyl group, nitrile group, alkyl group, amino group, alkylamino group (methylamino). Group, ethylamino group, dimethylamino group, diethylamino group, etc.), alkoxy group (methoxy group, ethoxy group, etc.) and the like. The number of substituents substituted on the phenyl ring or naphthyl ring is 1 to 5, preferably 1 to 3.

In the general formula (2), examples of the primary alkyl group represented by R ³ include a C _1-20, more preferably a C _1-8 linear or branched primary alkyl group. Specific examples thereof include methyl group, ethyl group, n-propyl group, n-butyl group, isobutyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like. It can be illustrated.

  In the general formula (2), examples of the halogen atom represented by X include a chlorine atom, a bromine atom, and an iodine atom.

  In the method of the present invention, the amount of the compound of the general formula (2) and the metal strontium used with respect to the compound of the general formula (1) varies depending on the type of the compound of the general formula (1).

For example, when a compound of the general formula (1) in which R ² represents an alkyloxy group or an aryloxy group is used, the compound of the general formula (2) is usually 1. About 8 to 4 equivalents, preferably about 2 to 3 equivalents, more preferably about 2.5 equivalents. Moreover, metal strontium is normally used in a ratio of about 1.8 to 4 equivalents, preferably about 2 to 3 equivalents, and more preferably about 2.5 equivalents with respect to the compound of the general formula (1).

When the compound of the general formula (1) in which R ² represents an alkyl group is used, the compound of the general formula (2) is usually about 1 to 3 equivalents, preferably 1 with respect to the compound of the general formula (1). About 1.5 equivalents, more preferably about 1 to 1.2 equivalents. Further, the metal strontium is usually used at a ratio of about 1 to 3 equivalents, preferably about 1 to 1.5 equivalents, more preferably about 1 to 1.2 equivalents with respect to the compound of the general formula (1). .

When the compound of the general formula (1) in which R ² represents a hydroxyl group is used, the compound of the general formula (2) is usually about 2 to 5 equivalents, preferably 2 to 2 with respect to the compound of the general formula (1). It is used at a ratio of about 3.5 equivalents, more preferably about 2 to 2.5 equivalents. Further, the metal strontium is usually used at a ratio of about 2 to 5 equivalents, preferably about 2 to 3.5 equivalents, more preferably about 2 to 2.5 equivalents with respect to the compound of the general formula (1). .

  The reaction of the present invention is carried out in a suitable solvent. As the solvent, known solvents can be widely used as long as they are inert to the reaction of the present invention and do not adversely affect the reaction. Examples of such a solvent include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, 1,3-dioxolane, diethyl ether, n-hexane, benzene and the like. Among these, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and 1,3-dioxolane are preferable, and tetrahydrofuran is more preferable. The usage-amount of a solvent is about 0.5-2 ml normally with respect to 1 mmol of compounds of General formula (2), Preferably it is about 0.8-1.2 ml.

  The reaction of the present invention proceeds under heating, at room temperature or under cooling, but is preferably about -40 to 40 ° C, preferably 5 ° C to around room temperature. The reaction time varies depending on reaction conditions such as reaction temperature, but is usually about 0.1 to 2 hours, preferably about 0.5 hours.

  The tertiary alcohol of the general formula (3) obtained by the method of the present invention is easily isolated and purified from the reaction mixture by known isolation and purification means.

  By the method of the present invention, the tertiary alcohol represented by the general formula (3) can be produced with high yield and high purity.

  The raw materials such as metal strontium used in the method of the present invention are all easily available and inexpensive compounds. Metal strontium has no particular waste liquid treatment criteria and does not need to be separated from the reaction mixture after completion of the reaction. Therefore, the post-treatment operation after the reaction is extremely simple. Further, metal strontium does not have the problem of being easily ignited in air like metal sodium.

In the method of the present invention does not require the use of a reaction catalyst such as NiI _2.

  Further, in the method of the present invention, unlike the Grignard method, it is not necessary to prepare an ignitable organic metal in advance. In addition, since the amount of solvent is small and the reaction is possible even at a high concentration as compared with the Grignard method, there is an advantage suitable for mass production in a plant.

Furthermore, the versatility of the substrate that can be used is much greater than the methods described in the prior art, such as compounds having halogen in the molecule that cannot be used with SmI ₂ can also be used as the substrate.

  Therefore, the method of the present invention is industrially extremely advantageous as a method for producing a tertiary alcohol to which a Barbier-type reaction is applied.

  The present invention will be further clarified by the following examples.

  In the following examples, metal strontium is used by washing a lump that is stored in liquid paraffin with n-hexane and then finely chopping with a sword. did. THF (tetrahydrofuran) used as a solvent was distilled from sodium-benzophenone immediately before use. Other reagents were used as they were without purifying commercially available products.

  Wakogel-B5F (silica gel) was used for thin layer chromatography, and Silica Gel 60 (230-400 mesh) (nacalai tesque) was used for column chromatography.

Various analysis values were measured using the following analyzers.
¹ H-nuclear magnetic resonance spectrum ( ¹ H-NMR spectrum)
400 MHz; JEOL EX-400 (JEOL)
90 MHz; JEOL EX-90A (JEOL)
Infrared absorption spectrum (IR spectrum)
FT-IR; HORIBA FT-210

Example 1
A metal stir bar was placed in a 30 ml side tube flask with a rubber septum and a three-way cock was attached. An argon balloon was attached to one of them. A vacuum pump was connected to the other side, and the reaction flask was well dried using a heat gun under reduced pressure. Subsequently, after replacing with argon, metal strontium (3.09 mmol, 271.0 mg) was added, and drying under reduced pressure was performed again. After sufficiently substituting the inside of the reaction flask with argon, the flask was allowed to cool at room temperature. When the reaction container returned to room temperature, anhydrous THF (5 ml) as a solvent, methyl benzoate (1.16 mmol, 158.3 mg) as a substrate, methyl iodide (3.52 mmol, 499.8 mg) in this order using a syringe. It was dripped. The reaction was allowed to proceed at room temperature for 30 minutes, and the reaction was stopped with 0.2N hydrochloric acid (20 ml). The reaction solution was extracted with diethyl ether (15 ml × 3), washed with 5% aqueous sodium hydrogen sulfite solution (15 ml), dehydrated with sodium sulfate and filtered, and then the solvent was distilled off. Isolation was performed by TLC (n-hexane: ethyl acetate = 4: 1), and 2-phenyl-2-propanol (yellow oily substance) was obtained in a yield of 79% (125.7 mg). It was.
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 1.56 (s, 6H), 2.01 (brs, 1H), 7.25-7.44 (m, 5H)
IR (neat); 3392, 3060, 3028, 2976, 2929, 1495, 1446, 1365, 1257, 1174, 1155, 1142, 1074, 1030, 910, 862, 764, 734, 700 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 2-phenyl-2-propanol.

Example 2
Using metal strontium (2.50 mmol, 219.4 mg), anhydrous THF (5 ml), methyl benzoate (1.01 mmol, 138.4 mg) and methyl iodide (2.78 mmol, 395.7 mg), The reaction was conducted in the same manner for 30 minutes, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 96% of 2-phenyl-2-propanol (yellow oily substance). Obtained in a yield of (132.6 mg).

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance.

Example 3
Example 1 with metal strontium (2.08 mmol, 182.9 mg), anhydrous THF (5 ml), methyl benzoate (1.02 mmol, 139.3 mg) and methyl iodide (2.11 mmol, 299.9 mg) The reaction was conducted in the same manner for 30 minutes, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 78% of 2-phenyl-2-propanol (yellow oily substance). Obtained in a yield of (109.3 mg).

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance.

Example 4
Using metal strontium (2.50 mmol, 218.5 mg), anhydrous THF (5 ml), ethyl benzoate (1.02 mmol, 153.5 mg) and methyl iodide (2.68 mmol, 381.6 mg) and Example 1 The reaction was conducted in the same manner for 30 minutes, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 96% of 2-phenyl-2-propanol (yellow oily substance). Obtained in a yield of (133.7 mg).

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance.

Example 5
Using metal strontium (3.06 mmol, 268.5 mg), anhydrous THF (5 ml), i-propyl benzoate (1.03 mmol, 170.6 mg) and methyl iodide (3.12 mmol, 443.2 mg) The reaction was carried out for 30 minutes in the same manner as in Example 1, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 2-phenyl-2-propanol (yellow oily substance). Was obtained in a yield of 91% (127.9 mg).

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance.

Example 6
Examples using metal strontium (3.14 mmol, 274.4 mg), anhydrous THF (5 ml), t-butyl benzoate (1.00 mmol, 179.4 mg) and methyl iodide (3.09 mmol, 438.7 mg) The reaction was carried out for 30 minutes in the same manner as in Example 1, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 2-phenyl-2-propanol (yellow oily substance). Obtained in 74% (103.6 mg) yield.

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance.

Example 7
Example 1 with metal strontium (2.53 mmol, 222.2 mg), anhydrous THF (5 ml), methyl benzoate (0.99 mmol, 135.8 mg) and ethyl iodide (2.50 mmol, 390.5 mg) The reaction was carried out in the same manner for 30 minutes, and the same post-treatment and isolation operation as in Example 1 (n-hexane: ethyl acetate = 4: 1) was performed to give 1-ethyl-1-phenyl-1-propanol (yellow oily substance). ) Was obtained in a yield of 85% (139.8 mg).
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 0.76 (t, J = 7.5 Hz, 6H), 1.74 (brs, 1H), 1.85 (q, J = 7.5 Hz, 4H) ), 7.23-7.40 (m, 5H)
IR (neat); 3446, 3060, 3028, 2970, 2937, 2879, 1494, 1446, 1377, 1155, 1052, 1030, 962, 894, 758, 702 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 1-ethyl-1-phenyl-1-propanol.

Example 8
Examples using metal strontium (3.12 mmol, 273.7 mg), anhydrous THF (5 ml), methyl benzoate (1.03 mmol, 140.9 mg) and n-butyl iodide (3.07 mmol, 566.5 mg) The reaction was carried out for 30 minutes in the same manner as in Example 1, and the same post-treatment and isolation operation as in Example 1 (n-hexane: ethyl acetate = 9: 1) was performed to give 1-n-butyl-1-phenyl-1-pen. Tanol (yellow oil) was obtained in 84% (191.1 mg) yield.
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 0.78-1.90 (m, 19H), 7.21-7.45 (m, 5H)
IR (neat); 3475, 3060, 3028, 2935, 2871, 1494, 1468, 1446, 1379, 1149, 1049, 1034, 910, 766, 735, 702 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 1-n-butyl-1-phenyl-1-pentanol.

Example 9
Using metal strontium (3.08 mmol, 270.3 mg), anhydrous THF (5 ml), methyl benzoate (1.01 mmol, 138.7 mg) and isobutyl iodide (3.00 mmol, 553.0 mg), The reaction was conducted in the same manner for 30 minutes, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 9: 1) was performed in the same manner as in Example 1 to obtain 1-isobutyl-3-methyl-1-phenyl-1-butanol. (Yellow oily substance) was obtained in a yield of 96% (212.8 mg).
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 0.65 (d, J = 6.1 Hz, 6H), 0.90 (d, J = 6.2 Hz, 6H), 1.47-1.79. (M, 7H), 7.22-7.36 (m, 5H)
IR (neat); 3504, 3060, 3028, 2952, 2867, 1602, 1496, 1468, 1446, 1365, 1160, 1031, 910, 769, 735, 702 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 1-isobutyl-3-methyl-1-phenyl-1-butanol.

Example 10
Using metal strontium (3.07 mmol, 269.2 mg), anhydrous THF (5 ml), methyl 4-chloro-benzoate (1.00 mmol, 171.6 mg) and methyl iodide (3.11 mmol, 442.8 mg), The reaction was carried out for 30 minutes in the same manner as in Example 1, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 2- (4-chlorophenyl) -2-propanol. (Yellow oily substance) was obtained in a yield of 90% (154.5 mg).
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 1.55 (s, 6H), 1.90 (brs, 1H), 7.27 (d, J = 9.0 Hz, 2H), 7.43 ( d, J = 9.0 Hz, 2H)
IR (neat); 3354, 2976, 2930, 2872, 1599, 1487, 1400, 1364, 1168, 1141, 1097, 1013, 957, 862, 829 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 2- (4-chlorophenyl) -2-propanol.

Example 11
Using metal strontium (2.53 mmol, 221.7 mg), anhydrous THF (5 ml), methyl phenylacetate (1.03 mmol, 155.1 mg) and methyl iodide (2.60 mmol, 370.0 mg), The reaction was conducted in the same manner for 30 minutes, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 2-methyl-3-phenyl-2-propanol (yellow oily substance). ) Was obtained in 81% (124.6 mg) yield.
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 1.14 (s, 6H), 1.53 (brs, 1H), 2.69 (s, 2H), 7.19 (brs, 5H)
IR (neat); 3400, 3028, 2972, 2931, 1492, 1452, 1375, 1151, 1126, 901, 727, 712, 700 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 2-methyl-3-phenyl-2-propanol.

Example 12
Using metal strontium (3.19 mmol, 280.0 mg), anhydrous THF (5 ml), ethyl 3-phenylpropionate (1.01 mmol, 180.8 mg) and methyl iodide (3.15 mmol, 448.5 mg) The reaction was carried out for 30 minutes in the same manner as in Example 1, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 9: 1) was performed in the same manner as in Example 1 to obtain 2-methyl-4-phenyl-2-butanol ( Yellow oily substance) was obtained in a yield of 90% (157.6 mg).
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 1.28 (s, 6H), 1.50-1.88 (m, 3H), 2.60-2.80 (m, 2H), 7. 22 (m, 5H)
IR (neat); 3384, 3026, 2970, 2864, 1604, 1495, 1468, 1377, 1213, 1151, 1126, 928, 914, 740, 698 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 2-methyl-4-phenyl-2-butanol.

Example 13
Examples using metal strontium (3.26 mmol, 286.5 mg), anhydrous THF (5 ml), methyl 10-undecenoate (1.05 mmol, 208.7 mg) and methyl iodide (3.04 mmol, 432.5 mg) The reaction was performed for 30 minutes in the same manner as in Example 1, and the same post-treatment operation as in Example 1 was performed. The product was isolated by column chromatography (n-hexane: ethyl acetate = 9: 1), and 87% (181.8 mg) of 2-methyl-11-dodecen-2-ol (colorless oil) was obtained. Obtained in yield.
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 1.20 (s, 6H), 1.28-1.60 (m, 14H), 1.95-2.15 (m, 2H), 4. 87-5.10 (m, 2H), 5.59-5.98 (m, 1H)
IR (neat); 3352, 2926, 2855, 1641, 1468, 1377, 1151, 991, 908, 735 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 2-methyl-11-dodecen-2-ol.

Example 14
Example 1 with metal strontium (3.04 mmol, 267.2 mg), anhydrous THF (5 ml), methyl palmitate (1.14 mmol, 308.8 mg) and methyl iodide (3.12 mmol, 443.6 mg) Similarly, the reaction was carried out for 30 minutes, and the same post-treatment operation as in Example 1 was performed. The product was isolated by column chromatography (n-hexane: ethyl acetate = 9: 1), and 2-methyl-2-heptadodecanol (white solid) was obtained in a yield of 84% (258.2 mg). Obtained.
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 0.85 (m, 3H), 1.17 (s, 6H), 1.20-1.90 (m, 29H)
IR (KBr); 3460, 2966, 2920, 2848, 1471, 1466, 1379, 1157, 1149, 910, 727, 721 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 2-methyl-2-heptadodecanol.

Example 15
Using metal strontium (3.03 mmol, 265.6 mg), anhydrous THF (5 ml), ethyl 6-bromohexanoate (1.01 mmol, 226.3 mg) and methyl iodide (3.02 mmol, 428.3 mg) The reaction was carried out for 30 minutes in the same manner as in Example 1, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 4: 1) was performed in the same manner as in Example 1 to obtain 7-bromo-2-methyl-2-heptanol ( A colorless oily substance) was obtained in a yield of 90% (157.6 mg).
¹ H-NMR (90 MHz, CDCl ₃ ); δ ppm = 1.25 (s, 6H), 1.29-2.09 (m, 9H), 3.46 (t, J = 6.7 Hz, 2H)
IR (neat); 3383, 2968, 2936, 2862, 1466, 1377, 1238, 1150, 908, 733 cm ⁻¹
The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 7-bromo-2-methyl-2-heptanol.

Example 16
A metal stir bar was placed in a 30 ml side tube flask with a rubber septum and a three-way cock was attached. An argon balloon was attached to one of them, and a vacuum pump was connected to the other. First, the reaction flask was well dried using a heat gun under reduced pressure. Subsequently, after purging with argon, metal strontium (1.22 mmol, 107.6 mg) was added, and drying was again performed under reduced pressure. After sufficiently substituting the inside of the reaction flask with argon, the flask was allowed to cool at room temperature. When the reaction vessel returned to room temperature, anhydrous THF (1.5 ml) as a solvent, propiophenone (1.04 mmol, 140.4 mg) as a substrate, methyl iodide (1.68 mmol, 239.7 mg) using a syringe In the order of. The reaction was allowed to proceed at room temperature for 20 minutes, and the reaction was stopped with 0.2N hydrochloric acid. The reaction solution was extracted with diethyl ether, washed with 5% aqueous sodium hydrogen sulfite solution, dehydrated with sodium sulfate, filtered, and then the solvent was distilled off. Isolation was performed by TLC (thin layer chromatography) (n-hexane: ethyl acetate = 4: 1), and 39% (61.5 mg) of 1-methyl-1-phenyl-1-propanol (yellow oily substance) was obtained. Obtained in yield.

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 1-methyl-1-phenyl-1-propanol.

Example 17
Example 16 using metal strontium (1.18 mmol, 103.7 mg), anhydrous THF (5 ml), propiophenone (1.00 mmol, 135.5 mg) and methyl iodide (3.38 mmol, 480.0 mg). In the same manner as in Example 16, the mixture was reacted at 5 ° C. for 60 minutes, and subjected to the same post-treatment and isolation operation as in Example 16 (n-hexane: ethyl acetate = 4: 1) to give 1-methyl-1-phenyl-1- Propanol (yellow oil) was obtained in 29% (44.1 mg) yield.

The ¹ H-NMR spectrum and IR spectrum of the product were in good agreement with those of the standard substance. Therefore, it was confirmed that the obtained compound was 1-methyl-1-phenyl-1-propanol.

Example 18
A metal stir bar was placed in a 30 ml side tube flask with a rubber septum and a three-way cock was attached. An argon balloon was attached to one of them. A vacuum pump was connected to the other side, and the reaction flask was well dried using a heat gun under reduced pressure. Subsequently, after purging with argon, metal strontium (3.05 mmol, 267.0 mg) was added, and drying was performed again under reduced pressure. After sufficiently substituting the inside of the reaction flask with argon, the flask was allowed to cool at room temperature. When the reaction vessel returned to room temperature, benzoic acid (1.00 mmol, 122.3 mg) as a substrate was added, and anhydrous THF (10 ml) and methyl iodide (3.15 mmol, 448.0 g) were used in this order using a syringe. It was dripped. The reaction was allowed to proceed at room temperature for 30 minutes, and the reaction was stopped with 0.2N hydrochloric acid (20 ml). The reaction solution was extracted with diethyl ether (15 ml × 3), washed with 5% aqueous sodium hydrogen sulfite solution (15 ml), 2N aqueous sodium hydroxide solution (15 ml) and saturated brine (15 ml), dehydrated with sodium sulfate, After filtration, the solvent was distilled off. Isolation was performed by TLC (n-hexane: ethyl acetate = 8: 1) to obtain 2-phenyl-2-propanol (yellow oily substance) in a yield of 18% (24.3 mg). It was.

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard material. Therefore, it was confirmed that the obtained compound was 2-phenyl-2-propanol.

Example 19
Example 18 using metal strontium (3.05 mmol, 267.5 mg), anhydrous THF (10 ml), p-toluic acid (1.05 mmol, 143.8 mg) and methyl iodide (3.22 mmol, 457.3 mg) The mixture was reacted for 30 minutes in the same manner as described above, and subjected to the same post-treatment and isolation operation as in Example 18 (n-hexane: ethyl acetate = 8: 1) to give 2- (4-methylphenyl) -2-propanol (yellow Oil) was obtained in a yield of 16% (24.3 mg).

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard. Therefore, it was confirmed that the obtained compound was 2- (4-methylphenyl) -2-propanol.

Example 20
Examples using metal strontium (3.16 mmol, 276.5 mg), anhydrous THF (10 ml), p-chlorobenzoic acid (1.03 mmol, 162.2 mg) and methyl iodide (3.21 mmol, 455.7 mg) The reaction was carried out for 30 minutes in the same manner as in Example 18, and the post-treatment and isolation operation (n-hexane: ethyl acetate = 8: 1) was performed in the same manner as in Example 1 to give 2- (4-chlorophenyl) -2-propanol (colorless) Oily substance) was obtained in a yield of 17% (30.6 mg).

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard. Therefore, it was confirmed that the obtained compound was 2- (4-chlorophenyl) -2-propanol.

Example 21
Examples using metal strontium (3.04 mmol, 267.0 mg), anhydrous THF (10 ml), 3-phenylpropionic acid (1.02 mmol, 153.3 mg) and methyl iodide (3.13 mmol, 444.9 mg) The reaction was allowed to proceed for 30 minutes in the same manner as in Example 18, followed by the same post-treatment and isolation procedure as in Example 18 (n-hexane: ethyl acetate = 8: 1), and 2-methyl-4-phenyl-2-butanol (yellow) Oily substance) was obtained in a yield of 21% (35.0 mg).

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard. Therefore, it was confirmed that the obtained compound was 2-methyl-4-phenyl-2-butanol.

Example 22
Examples using metal strontium (3.04 mmol, 266.7 mg), anhydrous THF (10 ml), n-decanoic acid (1.02 mmol, 175.9 mg) and methyl iodide (3.15 mmol, 447.2 mg) The mixture was reacted for 30 minutes in the same manner as in Example 18, and subjected to the same post-treatment and isolation operation as in Example 18 (n-hexane: ethyl acetate = 10: 1) to give 2-methyl-2-undecanol (yellow oily substance). Obtained in 19% (36.8 mg) yield.

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard. Therefore, it was confirmed that the obtained compound was 2-methyl-2-undecanol.

Example 23
Example 1 using metal strontium (3.01 mmol, 263.9 mg), anhydrous THF (10 ml), 10-undecenoic acid (1.02 mmol, 188.2 mg) and methyl iodide (3.08 mmol, 436.9 mg) The mixture was reacted for 30 minutes in the same manner as described above, and subjected to the same post-treatment and isolation operation as in Example 18 (n-hexane: ethyl acetate = 10: 1) to give 2-methyl-11-dodecen-2-ol (yellow oil). Material) was obtained in a yield of 22% (43.6 mg).

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard. Therefore, it was confirmed that the obtained compound was 2-methyl-11-dodecen-2-ol.

Example 24
Examples using metal strontium (3.08 mmol, 269.6 mg), anhydrous THF (10 ml), 6-bromohexanoic acid (1.03 mmol, 201.7 mg) and methyl iodide (3.33 mmol, 473.8 mg) The reaction was carried out for 30 minutes in the same manner as in Example 18, and the same post-treatment and isolation operation as in Example 18 (n-hexane: ethyl acetate = 8: 1) was performed to obtain 7-bromo-2-methyl-2-heptanol (yellow Oil) was obtained in a yield of 17% (36.0 mg).

The ¹ H-NMR spectrum of the product was in good agreement with that of the standard. Therefore, it was confirmed that the obtained compound was 7-bromo-2-methyl-2-heptanol.

Claims (5)

General formula (1)

[Wherein R 1 represents an aryl group that may have an electron withdrawing group, an arylalkyl group that may have an electron withdrawing group, an alkyl group that may have an electron withdrawing group, or an alkenyl that may have an electron withdrawing group Indicates a group . R2 represents an alkyl group, an alkoxy group, an aryloxy group or a hydroxyl group. ]
And a compound represented by the general formula (2)
R3X (2)
[Wherein R 3 represents a primary alkyl group. X represents a halogen atom. ]
Is reacted with an alkyl halide represented by the general formula (3) in the presence of metal strontium at room temperature.

[Wherein, R 1 and R 3 are the same as above. When R2 in the general formula (1) represents an alkyl group, R4 represents R2, and when R2 in the general formula (1) represents an alkoxy group, an aryloxy group or a hydroxyl group, R4 represents R3. Shall be shown. ]
The manufacturing method of the tertiary alcohol which obtains the tertiary alcohol represented by these. The method according to claim 1, wherein R2 in the general formula (1) is an alkoxy group or an aryloxy group. The method according to claim 2 , wherein 2 to 3 equivalents of the compound of the general formula (2) are used with respect to the compound of the general formula (1). The method according to claim 2 , wherein 2 to 3 equivalents of metal strontium are used with respect to the compound of the general formula (1). The process according to claim 1, wherein the reaction is carried out in tetrahydrofuran.