JP5950255B2 - Process for producing 1,2-bis (trimethylsilyl) benzene or its related compounds - Google Patents

Description

  The present invention belongs to the technical field of organic synthesis, and particularly relates to a novel process for producing 1,2-bis (trimethylsilyl) benzene or an analogous compound thereof.

  Aromatic compounds having substituents at positions 1 and 2 of the benzene ring often play an important role in the field of organic synthesis (for example, as precursors and intermediates for various synthetic reactions), but are adjacent to each other. Many of them are difficult to synthesize due to the steric hindrance caused by the substituents.

  As such an aromatic compound, there is 1,2-bis (trimethylsilyl) benzene or an analogous compound thereof. 1,2-bis (trimethylsilyl) benzene or its related compounds are many important compounds required for various organic syntheses, and in particular, 1,2-bis (trimethylsilyl) benzene is a synthetic reaction through benzyne and various other compounds. As an excellent precursor used in a metal exchange reaction, it is an important compound with extremely high needs.

  Currently, as a method for producing 1,2-bis (trimethylsilyl) benzene or its related compounds, a method using hexamethylphosphoric triamide (HMPA) as a solvent is the most established method with high yield. For example, 1,2-bis (trimethylsilyl) benzene can be obtained by adding metal magnesium and chlorotrimethylsilane using 1,2-dichlorobenzene as a starting material and hexamethylphosphoric triamide (HMPA) as a solvent. A method obtained at a rate of 70 to 85% is known (see Non-Patent Documents 1 and 2).

  However, in this production method, there is a big problem in terms of safety that the toxicity of hexamethylphosphoric triamide (HMPA) required as a solvent is extremely high. In addition, it is required to react at a temperature of 100 ° C. for 2 days, and the reaction conditions are severe. Therefore, there is a demand for a method for producing 1,2-bis (trimethylsilyl) benzene or its related compounds that can be substituted for this production method.

  Under such circumstances, various attempts have been made to produce 1,2-bis (trimethylsilyl) benzene or its related compounds that avoid the use of hexamethylphosphoric triamide (HMPA).

  For example, the starting material is 1,2-dibromobenzene, tetrahydrofuran (THF) is used as a solvent, tert-butyllithium (t-BuLi) and trimethylsilyl triflate (TMSOTf) are added, and Br-Li exchange is performed. There is a method for obtaining 2-bis (trimethylsilyl) benzene (see Non-Patent Document 3). However, in order to cause Br—Li exchange, an extremely low temperature of −120 ° C. is required. Further, tert-butyllithium (t-BuLi) is a very reactive reagent, and as a reaction time proceeds, a yellow mixture as a by-product is generated. In order to suppress the formation of the yellow mixture, a special operation is required in which trimethylsilyl triflate (TMSOTf) is added in excess and then immediately cooled under concentrated hydrochloric acid and ethanol. Furthermore, as a result of the reaction, trimethylsilylbenzene is obtained together with 1,2-bis (trimethylsilyl) benzene, but since trimethylsilylbenzene is obtained in a three-dimensional structure, the yield of 1,2-bis (trimethylsilyl) benzene is obtained. Will be low.

  Also, for example, using 1,2-dibromobenzene as a starting material and tetrahydrofuran (THF) as a solvent, chlorotrimethylsilane (TMSCl), metal magnesium [activated with diisobutylaluminum hydride (DEBAL-H)] , Tetramethylethylenediamine (TMEDA) and iron chloride are added to obtain 1,2-bis (trimethylsilyl) benzene (see Non-Patent Document 4). However, this method requires a low temperature condition of reacting at −10 ° C. for 18 hours, and the yield is only 41% at most.

  Also, for example, Rieke magnesium carefully prepared from chlorotrimethylsilane (TMSCl), metal potassium in anhydrous tetrahydrofuran (THF) and anhydrous magnesium chloride using 1,2-dibromobenzene as a starting material and tetrahydrofuran (THF) as a solvent. There is a method in which 1,2-bis (trimethylsilyl) benzene is obtained by reacting at a temperature of 0 ° C. (see Non-Patent Document 5). However, with this method, the yield is at most 65%. Further, even if 1,2-dibromoethane is added to a tetrahydrofuran (THF) solvent of shaved metal magnesium, 1,2-dibromobenzene, excess chlorotrimethylsilane (TMSCl) and reacted at 20 ° C., 1, Although 2-bis (trimethylsilyl) benzene can be obtained (see Non-Patent Document 5), this method requires strict inert gas atmosphere conditions and a moderate yield of 52%.

  As described above, the conventional method for producing 1,2-bis (trimethylsilyl) benzene that avoids the use of hexamethylphosphoric triamide (HMPA) uses 1,2-dibromobenzene as a starting material, Although hexamethylphosphoric triamide (HMPA) can be replaced with tetrahydrofuran (THF), severe reaction conditions are still required, and the yield of 1,2-bis (trimethylsilyl) benzene, which is the target product, is low. Furthermore, the cost of obtaining the starting material 1,2-dibromobenzene is about 120 times higher than that of 1,2-dichlorobenzene.

  Thus, the conventional method for producing 1,2-bis (trimethylsilyl) benzene that avoids the use of hexamethylphosphoric triamide (HMPA) is expensive and low in yield, and is far from practical use. is there.

Journal of Organometallic Chemistry, vol. 84, page 165-175, 1975. Organic Synthesis, Coll. vol. 10, page 653 (2004); vol. 78, page 104 (2002) Journal of Organic Chemistry, vol. 72, page 9750-9752, 2007. Synthesis, No. 16, page 2759-2762, 2010. Advanced Synthesis & Catalysis, vol. 352, page 3443-3449, 2010.

  The object of the present invention has been proposed to solve the above-mentioned problems, and it is possible to reduce the cost of 1,2-bis (trimethylsilyl) benzene or a related compound thereof under a mild reaction condition using a safe solvent. Another object of the present invention is to provide a process for producing a new type of 1,2-bis (trimethylsilyl) benzene or its related compounds that can be produced in high yield.

  As a result of intensive studies, the present inventors have newly found reaction conditions to which a safer solvent can be applied when synthesizing 1,2-bis (trimethylsilyl) benzene or its related compounds, and under the use of the solvent. And found that cheaper starting materials can be applied. Furthermore, the present inventors have made such a novel synthesis reaction sufficiently proceeding under milder reaction conditions, and furthermore, 1,2-bis (trimethylsilyl) benzene or its related compound can be obtained in a high yield. Newly found to be.

Thus, according to the present invention, 1,3-dialkyl-2-imidazolidinone represented by the following general formula (I) is used as a solvent,

  1,2-bis (characteristically characterized in that it comprises a step of reacting a benzene derivative having at least two adjacent chlorine atoms as substituents with chlorotrimethylsilane in the presence of metallic magnesium, a copper salt and lithium chloride. A process for producing trimethylsilyl) benzene or related compounds thereof is provided.

In the above formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms. That is, 1,3-dialkyl-2-imidazolidinone represented by the above general formula (I) includes 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-diethyl-2- It can be selected from either imidazolidinone, 1,3-dipropyl-2-imidazolidinone, 1,3-diisopropyl-2-imidazolidinone, or 1,3-dibutyl-2-imidazolidinone, In particular, 1,3-dimethyl-2-imidazolidinone (DMI) is preferably used because it is easily available and easy to handle.

  The benzene derivative having at least two adjacent chlorine atoms as a substituent used in the present invention is the one in which at least two adjacent hydrogen atoms of the benzene ring of an aromatic compound having a benzene ring are substituted with chlorine atoms. The presence or absence of a substituent other than a chlorine atom is not particularly limited. The aromatic compound having such a benzene ring can be selected from the group consisting of benzene, toluene, fluorobenzene and anisole, for example.

  Accordingly, examples of the benzene derivative having at least two adjacent chlorine atoms as substituents used in the present invention include 1,2-dichlorobenzene, 3,4-dichlorotoluene, 3,4-dichlorofluorobenzene, 1,2 , 4,5-tetrachlorobenzene, 1,2-dichloroanisole.

  According to the production method of the present invention, 1,2-bis (trimethylsilyl) benzene or an analogous compound thereof can be obtained. Here, the 1,2-bis (trimethylsilyl) benzene analogue referred to in the present invention is substituted on the benzene ring (substitutes at least two adjacent chlorine atoms as raw materials) in the same manner as 1,2-bis (trimethylsilyl) benzene. Means a compound having at least two adjacent trimethylsilyl groups (corresponding to the position of the chlorine atom substituent in the benzene derivative in the group), and examples of such 1,2-bis (trimethylsilyl) benzene analogues Includes 1,2-bis (trimethylsilyl) benzene, 3,4-bis (trimethylsilyl) toluene, 1,2,4,5-tetrakis (trimethylsilyl) benzene, 3,4-bis (trimethylsilyl) fluorobenzene, etc. Can do.

  As the chlorotrimethylsilane used in the present invention, commercially available chlorotrimethylsilane (TMSCl) can be used.

  As the magnesium metal used in the present invention, a machined or powdered one can be used. From the viewpoint of promoting the reaction, it is preferable to use a powdery one having a large surface area. As such powdery metal magnesium, for example, those having a particle size of 212 to 600 μm can be used, and it is particularly preferable to use powdery 99% pure metal magnesium.

  As the copper salt used in the present invention, copper chloride, copper bromide, copper iodide, or metallic copper can be used. Of these, copper chloride or copper iodide is preferably used because of easy handling.

  Commercially available lithium chloride can be used for the present invention.

  Such a method for producing 1,2-bis (trimethylsilyl) benzene or an analogous compound thereof according to the present invention is represented, for example, by the following reaction formula (1). That is, 1,2-dichlorobenzene represented by the formula (1a) as the benzene derivative as the above starting material, and 1,3-dimethyl-2-imidazolidinone as the above 1,3-dialkyl-2-imidazolidinone. By using (DMI) and copper chloride as the above-described copper salts, 1,2-bis (trimethylsilyl) benzene represented by the formula (1b) can be obtained.

  The reaction for producing 1,2-bis (trimethylsilyl) benzene or its related compound as shown in the above reaction formula (1) takes about a day or night at room temperature and normal pressure, that is, 10 to 20 hours (for example, 17 hours). Proceed well. In addition, about reaction temperature, although reaction progresses sufficiently also at normal temperature, Preferably it is normal temperature-90 degreeC, More preferably, it is 50 degreeC-90 degreeC, for example, can be 50 degreeC.

  The method for producing 1,2-bis (trimethylsilyl) benzene or its related compound according to the present invention can sufficiently react at normal temperature to 90 ° C under normal pressure without using highly toxic hexamethylphosphoric triamide (HMPA). Thus, 1,2-bis (trimethylsilyl) benzene or an analogous compound thereof can be obtained in a high yield exceeding 90% at maximum (see Examples described later).

  Some conventional methods for producing 1,2-bis (trimethylsilyl) benzene or its related compounds have improved safety by not using hexamethylphosphoric triamide (HMPA), which is extremely toxic, as a solvent. On the other hand, expensive starting materials [for example, 1,2-dibromobenzene in the case of 1,2-bis (trimethylsilyl) benzene] are required, which not only increases the production cost but also requires the required temperature conditions. It becomes severe and the yield is low. On the other hand, according to the present invention, not only hexamethylphosphoric triamide (HMPA) is not used as a solvent, but also inexpensive 1,2-dichlorobenzene can be used as a starting material [for example, 1,2 In the case of -bis (trimethylsilyl) benzene, 1,2-dichlorobenzene having a cost of about 1/120 compared to 1,2-dibromobenzene is used], so that the production cost can be reduced and normal temperature to 90 ° C. under normal pressure. Thus, a completely new and excellent reaction without a conventional example that the reaction proceeds sufficiently and a higher yield can be realized.

  In another aspect, the method for producing 1,2-bis (trimethylsilyl) benzene or a related compound thereof according to the present invention does not require special equipment or skilled techniques, and the reaction operation is simple. It is a very excellent synthesis method that can be easily applied to industrial mass synthesis methods.

  Although the detailed mechanism by which such an excellent synthesis reaction of the present invention is obtained has not yet been elucidated, a mixture of magnesium metal and copper salt (also referred to as “hybrid Grignard reagent”), In the presence of lithium chloride, the activity is remarkably enhanced in a 1,3-dialkyl-2-imidazolidinone (eg, 1,3-dimethyl-2-imidazolidinone (DMI)) solvent, whereby the above reaction formula ( It is presumed that the trimethylsilylation reaction shown in 1) is strongly promoted.

  The 1,2-bis (trimethylsilyl) benzene and related compounds according to the present invention thus obtained can be used in a wide range of applications as precursors and intermediates for various synthetic reactions including benzyne synthesis. it can.

  In the above description, 1,2-bis (trimethylsilyl) benzene or a related compound thereof is mainly described for the sake of convenience mainly for the case of 1,2-bis (trimethylsilyl) benzene, but it is obtained by the production method of the present invention. The 1,2-bis (trimethylsilyl) benzene and its related compounds to be obtained are not limited to this, and various 1,2-bis (trimethylsilyl) benzene and its related compounds can be selected by selecting a starting benzene derivative. The compound is obtained analogously. That is, 1,2-bis (trimethylsilyl) benzene and related compounds obtained by the production method of the present invention include, for example, 1,2-bis (trimethylsilyl) benzene, 3,4-bis (trimethylsilyl) as shown below. ) Toluene, 1,2,4,5-tetrakis (trimethylsilyl) benzene, 3,4-bis (trimethylsilyl) fluorobenzene and the like.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited only to these Examples.

Example 1
Production of 1,2-bis (trimethylsilyl) benzene

Magnesium, copper (I) chloride, lithium chloride, and 1,3-dimethyl-2-imidazolidinone are those manufactured by Wako Pure Chemical Industries, Ltd., and chlorotrimethylsilane and 1,2-dichlorobenzene are The thing made by Tokyo Chemical Industry Co., Ltd. was used. ¹ H and ¹³ C NMR were measured using a JEOL AL-300 apparatus.

A 100 ml three-necked round bottom flask, a reflux tube and a cock were placed in a dryer at 130 ° C. for 1 hour to dry the apparatus. The dried instrument was removed from the dryer and assembled. At this time, a drying tube was attached to the upper part of the reflux tube, and a star rubber was put into a 100 ml three-necked round bottom flask. A cock was attached to one of the three-necked round bottom flasks, and argon gas was flowed for 5 minutes to fill the reactor with argon gas. 10 ml of 1,3-dimethyl-2-imidazolidinone dried with magnesium (8 mmol), copper (I) chloride (1 mmol), lithium chloride (8 mmol) and molecular sieves 4A from the other end of the three-necked round bottom flask (DMI) and distilled chlorotrimethylsilane (TMSCl) (16 mmol) were added and stirred at room temperature for 15 minutes. Then, according to the following reaction formula (1), 1,2-dichlorobenzene (1 mmol) which is a starting material represented by the formula (1a) was added and stirred at 55 ° C. After confirming the completion of the reaction, the solution was neutralized with saturated sodium bicarbonate. After confirming the completion of neutralization, debris such as magnesium was removed by suction filtration, put into a separatory funnel and extracted three times with hexane (the aqueous layer was poured from the bottom of the separatory funnel, and the hexane layer was taken out from above ). The hexane layer was washed with saturated brine, and the hexane layer was taken out and dried by adding sodium sulfate. A powder funnel was filled with cotton, sodium sulfate was removed, and the solution was concentrated with an evaporator. The concentrated solution was placed in a desiccator and dried overnight. When 0.1 mmol of an internal standard substance (1,4-dimethoxybenzene) was added to the dried and concentrated solution and the yield was determined by ¹ H NMR, 1,2-bis (trimethylsilyl) benzene represented by the formula (1b) ( Yield 93%) was obtained. Note that 1,2-bis (trimethylsilyl) benzene (yield 80%) was also obtained when copper iodide (CuI) was used as the copper salt. It was also confirmed that 1,2-bis (trimethylsilyl) benzene was obtained when metal copper (copper powder) was used as the copper salt. In addition, by the same procedure as described above, the scale was increased, and 1,2-dichlorobenzene (50 mmol) was added with magnesium (400 mmol), copper (I) chloride (50 mmol), lithium chloride (400 mmol), and molecular sieves. When 300 ml of 1,3-dimethyl-2-imidazolidinone (DMI) and distilled chlorotrimethylsilane (TMSCl) (800 mmol) were added and reacted, 1,2-bis (trimethylsilyl) benzene (yield 87 %)was gotten. From this, it was found that even if the scale was increased for 1,2-dichlorobenzene (even in the case of 50 mmol scale), a yield equivalent to the 1 mmol scale described above was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.37 (s, 18H, Me), 7.31-7.34 (m, 2H, ArH), 7.65-7.68 (m, 2H, ArH ).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 2.48, 128.21, 135.57, 146.10.

(Example 2)
Production of 3,4-bis (trimethylsilyl) toluene According to the following reaction formula (2), the starting material is 3,4-dichlorotoluene (1 mmol) represented by formula (2a) in the same procedure as in Example 1 above. ), 3,4-bis (trimethylsilyl) toluene (92% yield) represented by the formula (2b) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.35 (s, 9H, Me), 0.36 (s, 9H, Me), 2.34 (s, 3H, Me), 7, 16 (d, J = 7.5 Hz, ArH), 7, 49 (s, 1H, ArH), 7.58 (d, J = 7.5 Hz, ArH).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 1.96, 2.02, 21, 42, 128.57, 135.42, 136.16, 137.11, 142.20, 145, 89.

Example 3
Production of 1,2,4,5-tetrakis (trimethylsilyl) benzene In the same procedure as in Example 1 described above, the starting material is represented by the formula (3a) according to the following reaction formula (3). As 1,2,4,5-tetrachlorobenzene (1 mmol), 1,2,4,5-tetrakis (trimethylsilyl) benzene represented by the formula (3b) (yield 77%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.37 (s, 36H, Me), 7.96 (s, 2H, ArH).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 1.83, 141.52, 144, 76.

Example 4
Production of 3,4-bis (trimethylsilyl) fluorobenzene In the same procedure as in Example 1, the starting material is 3,4-dichlorofluorobenzene represented by the formula (4a) according to the following reaction formula (4). As (1 mmol), 3,4-bis (trimethylsilyl) fluorobenzene (yield 88%) represented by the formula (4b) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.37 (s, 9H, Me), 3.38 (s, 9H, Me), 7.00 (dt, J = 3.0, 8.4 Hz, 1H, ArH), 7.37 (dd, J = 3.0, 10.8 Hz, 1H, ArH), 7.65 (dd, J = 6.6, 8.4 Hz, 1H, ArH).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 1.70, 2.00, 114.32 (d, J = 18.6 Hz), 121.97 (d, J = 17.3 Hz), 137.30 (D, J = 6.2 Hz), 141.33, 149.72, 173.64.

Claims (5)

1,2-bis (trimethylsilyl) benzene, or a related compound thereof, wherein a hydrogen atom contained in a benzene ring constituting 1,2-bis (trimethylsilyl) benzene is a fluorine atom, a methyl group, or at least two trimethylsilyl groups A method for producing an analogous compound substituted with any of the following:
1,3-dialkyl-2-imidazolidinone represented by the following general formula (I) as a solvent,

(In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms.)
1,2-bis (characteristically characterized in that it comprises a step of reacting a benzene derivative having at least two adjacent chlorine atoms as substituents with chlorotrimethylsilane in the presence of metallic magnesium, a copper salt and lithium chloride. A method for producing trimethylsilyl) benzene or its related compounds.   The 1,2-bis (trimethylsilyl) benzene according to claim 1, wherein the 1,3-dialkyl-2-imidazolidinone is 1,3-dimethyl-2-imidazolidinone (DMI). A method for producing the related compound.   A benzene derivative having at least two adjacent chlorine atoms as substituents is 1,2-dichlorobenzene, 3,4-dichlorotoluene, 3,4-dichlorofluorobenzene, 1,2,4,5-tetrachlorobenzene, 1 The process for producing 1,2-bis (trimethylsilyl) benzene or an analogous compound thereof according to claim 1 or 2, wherein the compound is any one of 1,2-dichloroanisole.   The copper salt is copper chloride, copper bromide, copper iodide, or metallic copper, 1,2-bis (trimethylsilyl) benzene according to any one of claims 1 to 3, or its A method for producing an analogous compound. 1,3-dialkyl-2-imidazolidinone is 1,3-dimethyl-2-imidazolidinone (DMI), and a benzene derivative having at least two adjacent chlorine atoms as substituents is 1,2-dichlorobenzene The method for producing 1,2-bis (trimethylsilyl) benzene according to any one of claims 1 to 4, wherein the copper salt is copper chloride.