JP5083753B2 - Novel process for producing 4,5-dimethyl- [1,3] diselenol-2-thelone - Google Patents

Description

  The present invention relates to a novel process for producing 4,5-dimethyl- [1,3] diselenol-2-thelone.

  Tetramethyltetraselenafulvalene (TMTSF) is the first organic molecule to give a superconductor. In 1980, the organic donor of an organic superconductor having a superconducting critical temperature (Tc) of 0.9K. It was found to be a molecule. Subsequent research has led to the synthesis of TMTSF complexes coordinated with certain anions, which have been improved to superconductors with maximum Tc of 1.4K (normal pressure) and 3K (5 kbar) (non-patented). Reference 1).

  TMTSF is known to be synthesized from the intermediate raw material 4,5-dimethyl- [1,3] diselenol-2-thelone by the action of trialkoxyphosphine according to the following scheme. To date, 4,5-dimethyl- [1,3] diselenol-2-thelone is the only synthetic raw material.

Conventionally, 4,5-dimethyl- [1,3] diselenol-2-selone is synthesized using carbon diselenide (CSe ₂ ) or hydrogen selenide gas (H ₂ Se) as a starting material.

  Non-patent documents 2 to 4 disclose methods for synthesizing 4,5-dimethyl- [1,3] diselenol-2-selone using carbon diselenide. Here, carbon diselenide can be synthesized by heating methylene chloride and selenium to 550 ° C. (Non-patent Document 4). Synthesis of 4,5-dimethyl- [1,3] diselenol-2-selone using carbon diselenide is performed, for example, by the following reaction (Non-patent Document 3).

  However, carbon diselenide is highly toxic and cannot be stored at room temperature, and is not available as a commercially available reagent. To synthesize it, as described above, reaction at a high temperature of 500 ° C. or higher is required. Need to do.

  On the other hand, methods for synthesizing 4,5-dimethyl- [1,3] diselenol-2-selone using hydrogen selenide gas are disclosed in Non-Patent Documents 5 to 8.

によって合成されうる（非特許文献６）。 For example, the following scheme:

(Non-patent Document 6).

  However, hydrogen selenide gas is extremely toxic and needs to be reported for its handling. In Japan, it is designated as a special high-pressure gas by the High-Pressure Gas Safety Law.

で表される反応に置き換えることができる（非特許文献８）。しかし、当該反応では、二段目のイミニウム塩の純度などに大きく左右され、収率の再現性に乏しいこと、および実際の反応では容器中でセレン化水素ガスが副生物として生成するため、合成にあたってはセレン化水素ガスを使用した合成法と全く同じ安全策を講じる必要がある。 The first and second stages of the above scheme are

(Non-patent Document 8). However, in this reaction, it depends greatly on the purity of the second stage iminium salt, etc., and the reproducibility of the yield is poor, and in the actual reaction, hydrogen selenide gas is generated as a by-product in the vessel. It is necessary to take the same safety measures as the synthesis method using hydrogen selenide gas.

  Until the 1980s, carbon diselenide or hydrogen selenide gas was used in a relatively large number of research groups. From the viewpoint of environmental protection and toxic reagent management, which have been rapidly increasing in recent years, these are newly introduced in the future. It is difficult to synthesize 4,5-dimethyl- [1,3] diselenol-2-thelone by a conventional method using the above chemical substance as a starting material.

  By the way, 4,5-bis-hydroxymethyl- [1,3] dithiol-2-thione, 4,5-bis, which is similar in structure to 4,5-dimethyl- [1,3] diselenol-2-thelone. Non-Patent Documents 9 and 10 disclose methods for synthesizing -bromomethyl- [1,3] dithiol-2-thione, respectively.

で表される反応で合成される（非特許文献９）。 4,5-bis-hydroxymethyl- [1,3] dithiol-2-thione is

(Non-Patent Document 9).

で表される反応で合成される（非特許文献１０）。 Also, 4,5-bis-bromomethyl- [1,3] dithiol-2-thione is

(Non-Patent Document 10).

Written by Gunji Saito, Chemistry of Organic Conductors, Maruzen (2003) K. Bechgaard, D.C. O. Cowan and A.M. N. Bloch, Chem. Commun. , 937-938 (1974) K. Bechgaard, D.C. O. Cowan and A.M. N. Bloch, J.M. Org. Chem. , 40, 746-749 (1975) F. Ogura and K.K. Takimiya, Organoselenium Chemistry: A Practical Approach, T .; G. Back Ed. , Ch. 14, Preparation of organic conductors, Protocol 4, pp. 263-266, Ixford University Press, Oxford (1999) F. Wudl, D.W. Nalawayjek, J .; Chem. Soc. , Chem. Commun. , 866-866 (1980) L. Chiang, T.A. O. Poehler, A.M. N. Bloch, D.D. O. Cowan, J .; Chem. . Soc. , Chem. Commun. , 866-867 (1980) J. et al. M.M. Braam, C.I. D. Carlson, D.C. A. Stephens, A.M. E. Rehan, S.M. J. et al. Compton, J.A. M.M. Williams, Inorganic Syntheses, 24, 131-134 (1986). A. Moradpour, V.M. Peyrussan, I.D. Johansen, K. et al. Bechgaard, J.A. Org. Chem. , 48, 388-389 (1983) M.M. A. Fox, H.M. -L. Pang, J. et al. Org. Chem. , 59, 6519-6527 (1994) J. et al. O. Jeppesen, K. et al. Takimiya, F.A. Jensen, T.W. Brimert, K.M. Nielsen, N.M. Thorup, J.A. Becher, J.A. Org. Chem. , 65, 5794-5805 (2000)

  The object of the present invention is to provide 4,5-dimethyl- [1 which can be synthesized under safer, milder conditions and easy to industrialize, which is an alternative to conventional synthesis methods using carbon diselenide or hydrogen selenide. , 3] It is to provide a novel method for producing diselenol-2-thelone.

As a result of intensive studies on the synthesis route in order to solve the above problems, the present inventors have found that 4-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester is used as a starting material under mild conditions. , 5-dimethyl- [1,3] diselenol-2-thelone was discovered and the present invention was completed.
The features of the present invention are as follows.

で表される４，５−ジメチル−［１，３］ジセレノール−２−チオンの製造方法を提供する。この方法は、下記の（ａ）〜（ｃ）の工程： In the first aspect, the present invention provides the following formula (4):

A process for producing 4,5-dimethyl- [1,3] diselenol-2-thione represented by the formula: This method includes the following steps (a) to (c):

（式中、Ｒ^１およびＲ^２は独立に、同じまたは異なるアルキル基を表わす）で表される２−チオキソ−［１，３］ジセレノール−４，５−ジカルボン酸ジアルキルエステルを、アルカリハライドの存在下、還元剤と反応させて、式（２）： (A) Formula (1):

(Wherein R ¹ and R ² independently represent the same or different alkyl group) 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester represented by the presence of an alkali halide Under reaction with a reducing agent, formula (2):

で表される４，５−ビス−ヒドロキシメチル−［１，３］ジセレノール−２−チオンを合成する工程、

A step of synthesizing 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione represented by:

（式中、Ｘはハロゲン原子を表わす）で表される４，５−ビス−ハロメチル−［１，３］ジセレノール−２−チオンを合成する工程、および、 (B) reacting the compound of formula (2) with a halogenating agent to give formula (3):

(Wherein X represents a halogen atom), a step of synthesizing 4,5-bis-halomethyl- [1,3] diselenol-2-thione, and

(C) A step of reacting a compound of the formula (3) with a reducing agent to synthesize a compound of the formula (4) is characterized.

  In the embodiment of the present invention, the reducing agent used in the step (a) and the step (c) is a hydride reducing agent.

で表される４，５−ジメチル−[１，３]ジセレノール−２−セロンの製造方法を提供し、この方法は、下記の工程（ｄ）および（ｅ）： The present invention also provides, in the second aspect, the following formula (6):

A process for producing 4,5-dimethyl- [1,3] diselenol-2-thelone represented by the following steps (d) and (e):

で表される４，５−ジメチル−［１，３］ジセレノール−２−チオンを、メチル化剤ＭｅＬ（ここで、Ｍｅはメチル基を表わし、Ｌはアニオン性脱離基を表わす）と反応させ、次いで脂肪族または環状二級アミンＲ^３-ＮＨ-Ｒ^４（ここで、Ｒ^３およびＲ^４は独立に、同じまたは異なるアルキル基を表わすか、あるいは、Ｒ^３とＲ^４は一緒になって、１もしくは複数の酸素原子、窒素原子または硫黄原子を含んでもよい飽和または不飽和の５員〜７員環状二級アミンを形成する）と反応させて、式（５）： (D) Formula (4):

4,5-dimethyl- [1,3] diselenol-2-thione represented by the following formula is reacted with a methylating agent MeL (wherein Me represents a methyl group and L represents an anionic leaving group). And then an aliphatic or cyclic secondary amine R ³ —NH—R ⁴ where R ³ and R ⁴ independently represent the same or different alkyl groups, or R ³ and R ⁴ together To form a saturated or unsaturated 5- to 7-membered cyclic secondary amine, which may contain one or more oxygen, nitrogen or sulfur atoms, to give a compound of formula (5):

で表される化合物を合成する工程、および、

A step of synthesizing a compound represented by:

(E) A step of reacting a compound of formula (5) with hydrogen selenide or a salt thereof to synthesize a compound of formula (6) is characterized.

  In the third aspect, the present invention further provides 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione, which is a novel compound represented by the above formula (2).

  The present invention further provides, in the fourth aspect, a novel compound comprising 4,5-bis-halomethyl- [1,3] diselenol-2-thione represented by the above formula (3).

  According to an embodiment of the present invention, in the above formula (3), X is a chlorine atom, a bromine atom or an iodine atom, preferably a bromine atom.

  According to the method of the present invention, 4,5-dimethyl- [1,3] diselenol-2-thelone can be synthesized under safe and mild conditions, and industrialization becomes easy.

[1] Method for producing 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester The starting material, 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester is Known methods such as C.I. M.M. It can be derived from simple selenium powder using the following scheme described in the document of Bolinger et al. (CM Bolinger, TB Rauchfuss, Inorg. Chem., 21, 3947-3954 (1982)).

2-Thioxo- [1,3] diselenol-4,5-dicarboxylic acid dimethyl ester ( 1 ) is synthesized using titanocene pentaselenide easily derived from simple selenium powder as a starting material.

Compound ( 1 ) can be converted to a free dicarboxylic acid by hydrolysis under acidic conditions such as hydrochloric acid-acetic acid. This is further esterified with an alcohol such as an aliphatic alcohol such as ethanol, propanol or butanol, an alicyclic alcohol such as cyclopentanol or cyclohexanol, or an aromatic alcohol such as benzyl alcohol under an acidic catalyst. By carrying out the reaction, 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester of general formula (1) can be produced.

  Alternatively, in the above scheme, when DEAD (diethyl acetylenedicarboxylate) is used instead of DMAD (dimethyl acetylenedicarboxylate), diethyl ester, diethyl 2-thioxo- [1,3] diselenol-4,5-dicarboxylate Esters can be synthesized.

  In the compound of the above general formula (1), the alkyl group is a substituted or unsubstituted alkyl group, preferably a linear or branched C1-C8 alkyl group, more preferably an unsubstituted linear C1-C4 alkyl group; Substituted or unsubstituted 5- to 7-membered cycloalkynyl groups such as cyclopentyl, cyclohexyl and the like; including but not limited to substituted or unsubstituted phenylalkenyl groups such as benzyl, phenethyl and the like.

[2] Method for producing 4,5-dimethyl- [1,3] diselenol-2-thione 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid of general formula (1) synthesized by the above method Starting from a dialkyl ester, 4,5-dimethyl- [1,3] diselenol-2-thione ( 4 ) is synthesized according to the following scheme.

(I) Synthesis of Compound ( 2 ) from Compound of General Formula (1) From 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester of general formula (1) to 4,5-bis- The reduction reaction to hydroxymethyl- [1,3] diselenol-2-thione ( 2 ) can be performed using an appropriate reducing agent in the presence of an alkali halide.

  Alkali halide is a reaction accelerator, and an alkali halide other than lithium halide, such as sodium halide or potassium halide, can be preferably used.

The reducing agent is not particularly limited as long as it is an agent that selectively reduces only an ester group to an alcohol without reducing existing double bonds. Examples of such reducing agents are hydride reducing agents, diborane and the like. Hydrogen of the hydride reducing agent acts as a highly nucleophilic hydride ion, has the ability to nucleophilically attack the ester carbonyl group and reduce it to alcohol, and the ability to replace halogen atoms with hydrogen Also have. Examples of hydride reducing agents are borohydride reducing agents such as sodium borohydride, sodium cyanoborohydride (NaBH ₃ CN), tetraalkylammonium tetrahydroborate (eg, the alkyl group is butyl, etc.), Lithium borohydride, lithium trialkylborohydride (eg, alkyl group is ethyl, sec-butyl, etc.), potassium trialkylborohydride (eg, alkyl group is sec-butyl, etc.), borohydride Including, but not limited to zinc. However, an aluminum reducing agent is not preferred as the reducing agent.

  The solvent is preferably a liquid for mixing ether and alcohol, particularly preferably a mixed solution of tetrahydrofuran and dehydrated ethanol. As the ether, for example, an aliphatic ether or a cyclic ether can be preferably used, and examples of the aliphatic ether include diethyl ether, diisopropyl ether, dimethoxyethane, and methyl-t-butyl ether, and examples of the cyclic ether. , Tetrahydrofuran (THF), dioxane, and 2-methyltetrahydrofuran. The alcohol may be any alcohol as long as it can dissolve the alkali halide, but a primary or secondary alcohol can be suitably used. Examples of the alcohol include methanol, ethanol, isopropanol, 2-propanol, and 2-butanol, and ethanol is particularly preferable.

  A suitable amount of 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester and alkali halide is dissolved in a solvent, and the reducing agent is 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid. 2 to 10 equivalents are added to the acid dialkyl ester and reacted with stirring. The reaction temperature is preferably about -20 to 10 ° C, such as 0 ± 5 ° C. Further, the end point of the reaction can be grasped by monitoring the decrease in the raw material by, for example, high performance liquid chromatography (HPLC) or thin layer chromatography.

Purification of the product ( 2 ) can be performed, for example, as follows. The reaction is stopped by adding water, the product is extracted with a solvent such as ethyl acetate, and the organic layer is washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent is removed. The crude product can be further purified using conventional techniques such as chromatography such as silica gel chromatography, HPLC, thin layer chromatography, and crystallization. Furthermore, the purified product can be identified by spectrum analysis such as NMR, IR, and mass, elemental analysis and the like.

In addition, 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione ( 2 ) synthesized by the above method is a novel compound and is included in the scope of the present invention.

(Ii) Synthesis of compound ( 3 ) from compound ( 2 ) 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione ( 2 ) to 4,5-bis-halomethyl- [1,3 In the reaction for synthesizing diselenol-2-thione ( 3 ), a halogenating agent for converting a hydroxyl group to a halogen (particularly Cl, Br, or I) is used. Halogenating agents include, but are not limited to, for example _{PBr 3, HBr, BBr 3,} PCl 3, PCl 5, HCl, HI, potassium iodide - containing phosphoric acid.

  The solvent is preferably ether, and includes, for example, tetrahydrofuran, diethyl ether, * diisopropyl ether, dimethoxyethane, methyl-t-butyl ether, dioxane, 2-methyltetrahydrofuran and the like.

4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione ( 2 ) is dissolved in a solvent and cooled, and a halogenating agent is added in an amount of 2 to 3 equivalents with respect to the compound ( 2 ) and stirred. While reacting. The reaction temperature is preferably about 0 ± 5 ° C. Further, the end point of the reaction can be grasped by monitoring the decrease of the raw material by, for example, HPLC or thin layer chromatography.

Purification of the product ( 3 ) can be performed, for example, as follows. The solvent is distilled off, the residue is dissolved in a solvent such as methylene chloride, the organic layer is washed with water, dried using, for example, anhydrous magnesium sulfate as a desiccant, then concentrated by removing the desiccant and silica gel Purification can be performed using conventional techniques such as chromatography, chromatography such as HPLC, thin layer chromatography, and crystallization. Furthermore, the purified product can be identified by spectrum analysis such as NMR, IR, and mass, elemental analysis and the like.

In addition, 4,5-bis-halomethyl- [1,3] diselenol-2-thione ( 3 ) (wherein the halogen is Cl, Br, or I) synthesized by the above method is a novel compound, Included in the present invention.

(Iii) Synthesis of compound ( 4 ) from compound ( 3 ) 4,5-bis-halomethyl- [1,3] diselenol-2-thione ( 3 ) to 4,5-dimethyl- [1,3] diselenol- The synthesis of 2-thione ( 4 ) can be carried out using a reducing agent similar to the above, preferably a hydride reducing agent. The use of a hydride reducing agent that is soluble in an ether solvent system is preferred, and in this respect, the preferred hydride reducing agent is tetraalkylammonium tetrahydroborate (where the preferred alkyl group is a C1-C4 alkyl group), more preferably is tetrahydroborate tetrabutylammonium (TBA-BH _4).

  As the solvent, aliphatic or cyclic ether is preferable, and examples thereof include aliphatic ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, and methyl-t-butyl ether, and cyclic ethers such as tetrahydrofuran, dioxane, and 2-methyltetrahydrofuran.

4,5-bis-halomethyl- [1,3] diselenol-2-thione ( 3 ) was dissolved in a solvent and cooled, and a solution obtained by dissolving a reducing agent in the solvent was added to the compound ( 3 ) with 2 to 3 Add equivalent amount and allow to react with stirring. The reaction temperature is preferably about 0 ± 5 ° C. Further, the end point of the reaction can be grasped by monitoring the decrease of the raw material by, for example, HPLC or thin layer chromatography.

Purification of the product ( 4 ) can be performed, for example, as follows. Hydrochloric acid is added to stop the reaction, an alkaline solution such as aqueous sodium hydrogen carbonate solution is added to neutralize the reaction mixture, and the solvent is distilled off, followed by extraction with a halogenated hydrocarbon solvent such as methylene chloride. The obtained organic layer is washed with water and dried using, for example, anhydrous magnesium sulfate as a drying agent. The desiccant is removed and concentrated, followed by purification using conventional techniques such as silica gel chromatography, HPLC, chromatography such as thin layer chromatography, and crystallization. Furthermore, the purified product can be identified by spectrum analysis such as NMR, IR, and mass, elemental analysis and the like.

[3] Method for producing 4,5-dimethyl- [1,3] diselenol-2-thelone 4,5-dimethyl- [1,3] diselenol-2-thione ( 4 ) synthesized by the above method as a starting material 4,5-dimethyl- [1,3] diselenol-2-thelone ( 6 ) is synthesized according to the following scheme.

(Iv) Synthesis of Compound ( 5 ) from Compound ( 4 ) 4,5-Dimethyl- [1,3] diselenol-2-thione ( 4 ) to 4- (4,5-dimethyl- [1] trifluoromethanesulfonate , 3] diselenol-2-ylidene) -morpholine-4-ium ( 5 ) is treated by reacting with a methylating agent represented by CF ₃ SO ₃ Me and then reacting with morpholine. The methylating agent may be any methylating agent as long as it forms the methylsulfonium salt of the compound ( 4 ), and in addition to CF ₃ SO ₃ Me, for example, FSO ₃ Me, RfSO ₃ Me ( Here, Rf represents a perfluoroalkyl group), methyl iodide, dimethyl sulfate, trimethyloxonium tetrafluoroborate, and the like.

  In the above method, morpholine was used as the secondary amine, but other secondary amines such as aliphatic amines or cyclic amines may be used, such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine. Piperidine, pyrrolidine, thiomorpholine and the like can also be used. In this case, the following general formula (5):

（式中、Ｌは、アニオン性脱離基を表わし、Ｒ^３およびＲ^４は独立に、同じまたは異なるアルキル基を表わすか、あるいは、Ｒ^３とＲ^４は一緒になって、１もしくは複数の酸素原子、窒素原子または硫黄原子を含んでもよい飽和または不飽和の５員〜７員環状二級アミンを形成する）で表わされる化合物が生成する。

(Wherein L represents an anionic leaving group and R ³ and R ⁴ independently represent the same or different alkyl groups, or R ³ and R ⁴ together represent one or more A saturated or unsaturated 5- to 7-membered cyclic secondary amine which may contain oxygen, nitrogen or sulfur atoms is formed.

That is, when the above reaction formula is generally represented, the compound ( 4 ) is reacted with a methylating agent MeL (where Me represents a methyl group and L represents an anionic leaving group), and then aliphatic or Cyclic secondary amine R ³ —NH—R ⁴ (wherein R ³ and R ⁴ independently represent the same or different alkyl groups, or R ³ and R ⁴ together represent one or more By reacting with a saturated or unsaturated 5- to 7-membered cyclic secondary amine which may contain an oxygen atom, a nitrogen atom or a sulfur atom, the compound of the above general formula ( 5 ) can be obtained.

4,5-Dimethyl- [1,3] diselenol-2-thione ( 4 ) is dissolved in a halogenated hydrocarbon solvent such as methylene chloride and cooled. The methylating agent is added in an amount of 1 to 3 equivalents relative to the compound ( 4 ), and is reacted with stirring. The reaction temperature is preferably about 0 ± 5 ° C. Diethyl ether is added to precipitate the methylsulfonium salt, and the mixture is further stirred at about 0 ± 5 ° C. for about 30 minutes, for example, and then heated to room temperature. Further diethyl ether is added to complete the formation of the precipitate, the supernatant is removed, the precipitate is washed, dried, dissolved in acetonitrile and cooled to about 0 ± 5 ° C. A secondary amine is added in an amount of 1 to 1.5 equivalents to 4,5-dimethyl- [1,3] diselenol-2-thione ( 4 ), and the mixture is allowed to react with stirring. The reaction temperature is preferably about 0 ± 5 ° C. The temperature is raised to room temperature, and methanethiol gas is generated at this time, and the generation is completed. The solvent is distilled off, the resulting liquid is dissolved in acetonitrile, and diethyl ether is added to obtain a precipitate of the compound of general formula ( 5 ). The product can be purified using recrystallization. Furthermore, the purified product can be identified by spectrum analysis such as NMR, IR, and mass, elemental analysis and the like.

(V) Compound of the compound from (5) (6) Synthesis of trifluoromethanesulfonic acid 4- (4,5-dimethyl - [1,3] Jiserenoru-2-ylidene) - morpholin-4-ium (5), such as Synthesis of 4,5-dimethyl- [1,3] diselenol-2-thelone ( 6 ) from the compound of general formula (5) can be performed using hydrogen selenide (H ₂ Se) or a salt thereof. The use of an alkali salt of hydrogen selenide is preferable, for example, using sodium hydrogen selenide (NaSeH), potassium hydrogen selenide (KSeH), sodium selenide (Na ₂ Se), potassium selenide (K ₂ Se), etc. It can be carried out.

  A preferred solvent is a mixed solution of alcohol and acetic acid. The alcohol is preferably ethanol. For example, n-propanol, isopropanol, and n-butanol can also be used. Further, in place of acetic acid, for example, organic acids such as propionic acid and butyric acid can be used.

The compound of general formula (5) is suspended in a solvent and cooled to about −30 ° C. to about −20 ° C. Prepare an ethanol solution of sodium hydrogen selenide synthesized from selenium powder, sodium borohydride and ethanol, and add sodium selenide to about 1 to 1.2 equivalents to the compound of general formula (5). And react. The reaction temperature is preferably about −30 ° C. to about −20 ° C. The progress of the reaction can be confirmed using the color change of the suspension (for example, yellow orange to red orange) as an index. After raising the temperature to room temperature, the reaction mixture is poured into water, the product is extracted using a halogenated hydrocarbon solvent, for example, a solvent such as methylene chloride, and the resulting organic layer is washed with water, for example, anhydrous Dry with magnesium sulfate. When the solvent is removed, 4,5-dimethyl- [1,3] diselenol-2-thelone ( 6 ) having a purity sufficient for analysis is obtained as red crystals, spectrum analysis such as NMR, IR, Mass, elemental analysis, etc. Can be identified. Further, it can be further purified by recrystallization using an appropriate solvent.

The following examples further illustrate the present invention, but the scope of the present invention is not limited by these examples.
<Synthesis of 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione ( 2 )>
Under an inert gas atmosphere, 80 ml of 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dimethyl ester ( 1 ) (4.01 g, 11.6 mmol) and lithium chloride (888 mg, 2.09 mmol) were added. After dissolving in a mixed solution of tetrahydrofuran and 40 ml of dehydrated ethanol, it was cooled to 0 ° C. 4.48 g of sodium borohydride (110 mmol) was added in portions at 0 ° C. over 10 minutes. After stirring at 0 ° C. for 1.5 hours, the reaction was stopped by adding 180 ml of cold water at 5 ° C., and the product was extracted with ethyl acetate (150 ml × 3 times). The extracted organic layer was washed with saturated brine (150 ml × 2 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The obtained crude product was purified using silica gel chromatography (diameter 70 mmφ, length 365 mm). As a developing solvent, a mixed solvent of ethyl acetate-methylene chloride (9: 1) was used at the start of development, and then development was performed using only ethyl acetate. When the second yellow band flowing out was collected and the solvent was distilled off under reduced pressure, 1.52 g of the desired product 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione ( 2 ) was obtained. This was obtained as a bright yellow crystal (5.28 mmol, yield 46%, the yield relative to the immediately preceding raw material compound. The same applies hereinafter).
2 : Yamabuki crystals, mp 146 ° C .; m / z (EI, 70 eV): 290 (M ⁺ 290 for C ₅ H ₆ O ₂ S ⁸⁰ Se ₂ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 4.64 (d, 4H, J = 5.6 Hz), 5.07 (t, 2H, J = 5.6 Hz); ¹³ C-NMR (100 MHz) 60.86, 147.79, 219.83; IR (neat) ν (cm ^-1 ) 791 (m ), 947 (m), 976 (m), 1024 (s), 1157 (s), 1221 (m), 1296 (m), 1341 (m), 1345 (m), 1472 (m), 2842 (m ), 2896 (m), 3156 (br s); elemental analysis: calculated for C ₅ H ₆ O ₂ SSe ₂ : C, 20.85; H, 2.10. Experimental values: C, 20.91; H, 2.13%. X-ray Crystal structure analysis data: Crystalline system: monoclinic, space group: C2 / c, lattice constant: a = 13.883 (4) 4, b = 9.024 (2) Å, c = 13.165 (3) Å, β = 100.781 (4) °, V = 1620.1 (7) Å ³ .

<Synthesis of 4,5-bis-bromomethyl- [1,3] diselenol-2-thione ( 3 )>
Under an inert gas atmosphere, 1.11 g (3.84 mmol) of 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione ( 2 ) was dissolved in 20 ml of tetrahydrofuran and cooled to 0 ° C. . 0.81 ml of phosphorus tribromide (8.5 mmol) was added dropwise at 0 ° C. over 5 minutes. After completion of dropping, the mixture was stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 90 minutes. After distilling off the solvent under reduced pressure, the residue was dissolved in 250 ml of methylene chloride and transferred to a separatory funnel. The organic layer was washed with 48 ml of dilute hydrochloric acid (2M) and subsequently with water (200 ml × 2 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified using silica gel chromatography (diameter 45 mmφ, length 105 mm). Using methylene chloride as a developing solvent, the first yellow-orange band flowing out was collected, and the solvent was distilled off under reduced pressure to obtain 1.27 g of the desired product 4,5-bis-bromomethyl- [1,3] diselenol. -2-thione ( 3 ) was obtained as yellow-orange crystals (3.06 mmol, 80% yield).
3 : Yellow-orange crystal, mp 134 ° C; m / z (EI, 70 eV): 414 (M ⁺ 414 for C ₅ H ₄ Br ₂ S ⁸⁰ Se ₂ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 4.40 (s, 4H); ¹³ C-NMR (100 MHz) 23.18, 145.55, 211.23; IR (neat) ν (cm ^-1 ) 685 (s), 770 (s), 912 (m), 1026 (s), 1132 (s), 1194 (s), 1416 (m), 1439 (m), 1566 (m), 1676 (m), 2961 (m), 3023 (m); Elemental analysis: C ₅ H ₄ Br ₂ SSe Calculated values for ₂ : C, 14.51; H, 0.97. Experimental values: C, 14.50; H, 1.01%. X-ray crystal structure analysis data: Crystalline: monoclinic, Space group: C2 / c, a = 7.464 (3) Å, b = 17.638 (6) Å, c = 7.846 (3) Å, β = 113.241 (7) °, V = 949.2 (6) Å ³ .

<Synthesis of 4,5-dimethyl- [1,3] diselenol-2-thione ( 4 )>
Under an inert gas atmosphere, 2.02 g (4.89 mmol) of 4,5-bis-bromomethyl- [1,3] diselenol-2-thione ( 3 ) was dissolved in 150 ml of tetrahydrofuran and cooled to 0 ° C. A solution prepared by dissolving 3.09 g (11.8 mmol) of tetrabutylammonium tetrahydroborate in 50 ml of tetrahydrofuran was added dropwise at 0 ° C. over 20 minutes. After stirring at 0 ° C. for 50 minutes, 100 ml of diluted hydrochloric acid (1.0 M) was added at 0 ° C. to stop the reaction. An aqueous sodium hydrogen carbonate solution prepared with 8.6 g of sodium hydrogen carbonate and 150 ml of water was added to neutralize the reaction solution, and then tetrahydrofuran was distilled off under reduced pressure. After adding 600 ml of methylene chloride to the obtained suspension, it was transferred to a separatory funnel. The organic layer was washed with water (500 ml × 2 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified using silica gel chromatography (diameter 60 mmφ, length 180 mm). As a developing solvent, a mixed solution of carbon disulfide-hexane (9: 1) was used at the start of development, and then development was performed using only carbon disulfide. The yellow band that flows out first was collected, and the solvent was distilled off under reduced pressure. As a result, 1.07 g of the desired product 4,5-dimethyl- [1,3] diselenol-2-thione ( 4 ) was converted into yellow fine crystals. Obtained (4.17 mmol, 85% yield).
4 : Yellow crystals, mp 103 ° C .; m / z (EI, 70 eV): 258 (M ⁺ 258 for C ₅ H ₆ S ⁸⁰ Se ₂ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 2.23 (s, 6H); ¹³ C-NMR (100 MHz) 15.63, 139.72, 216.63; IR (neat) ν (cm ^-1 ) 698 (w), 725 (w), 774 (s), 814 (w), 1007 (br s), 1161 (w), 1435 (m), 1593 (w), 2043 (w), 2907 (w); elemental analysis: calculated for C ₅ H ₆ SSe ₂ : C, 23.45; H, 2.36. Values: C, 23.43; H, 2.39%. X-ray crystallography data: Crystalline system: orthorhombic, space group: Pnma, a = 11.861 (4) Å, b = 10.827 (3) Å, c = 6.0210 (19) Å, V = 773.2 (4) Å ³ .

<Synthesis of trifluoromethanesulfonic acid 4- (4,5-dimethyl- [1,3] diselenol-2-ylidene) -morpholine-4-ium ( 5 )>
Under an inert gas atmosphere, 1.54 g (6.00 mmol) of 4,5-dimethyl- [1,3] diselenol-2-thione ( 4 ) was dissolved in 8 ml of methylene chloride and cooled to 0 ° C. Using a syringe, 1.33 ml (12.0 mmol) of methyl trifluorosulfonate was added at 0 ° C. over 5 minutes. The resulting yellow-orange solution was stirred at 0 ° C. for 1 hour, and then 90 ml of diethyl ether was added to precipitate a yellow methylsulfonium salt. The resulting yellow suspension was stirred at 0 ° C. for 30 minutes and then warmed to room temperature. After completion of precipitation by adding 60 ml of diethyl ether, the supernatant solution portion was removed by decantation. The yellow precipitate was washed with diethyl ether (60 ml × 3 times by decantation) and then dried under reduced pressure. The obtained yellow crystals were dissolved in 8 ml of acetonitrile in a flask equipped with a calcium chloride drying tube, cooled to 0 ° C., and 0.52 ml (6.4 mmol) of morpholine was added over 3 minutes using a syringe. It was. The reaction solution was stirred at 0 ° C. for 1.5 hours and then warmed to room temperature. During this time, generation of methanethiol gas was observed. The calcium chloride drying tube was replaced with a two-way cock connected to a vacuum line, and the reaction solution was slowly depressurized to complete the generation of methanethiol gas. Finally, the solvent was completely distilled off under reduced pressure, and the obtained light brown liquid was dissolved in 5 ml of acetonitrile. By adding 300 ml of diethyl ether to this solution, a white precipitate of 5 as the target product was formed. The precipitate was collected by filtration and dried under reduced pressure to give 2.09 g of trifluoromethanesulfonic acid 4- (4,5-dimethyl- [1,3] diselenol-2-ylidene) -morpholine-4-ium ( 5 ). Was obtained as white crystals (4.54 mmol, 76% yield).
5 : White crystal, mp 132 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ) 2.33 (s, 6H), 3.75 (m, 4H), 3.87 (m, 4H); ¹³ C-NMR (100 MHz) 15.77 , 57.00, 64.46, 120.67 (q, J _CF = 32 Hz), 133.12, 191.39; IR (neat) ν (cm ^-1 ) 633 (s), 756 (m), 804 (w), 876 (m), 1026 (s), 1107 (s), 1157 (s), 1225 (s), 1244 (s), 1306 (w), 1370 (w), 1395 (w), 1468 (w), 1426 (m), 1437 (m), 1510 (m), 1526 (m), 1605 (w); elemental analysis: calculated for C ₁₀ H ₁₄ F ₃ NO ₄ SSe ₂ : C, 26.16; H, 3.07; N, 3.05. Values: C, 26.04; H, 3.00; N, 3.09%.

<Synthesis of 4,5-dimethyl- [1,3] diselenol-2-thelone ( 6 )>
52 ml of 2.04 g (4.45 mmol) of trifluoromethanesulfonic acid 4- (4,5-dimethyl- [1,3] diselenol-2-ylidene) -morpholin-4-ium ( 5 ) under an inert gas atmosphere In ethanol-acetic acid (1: 1) mixed solution and cooled to -30 ° C. 4.9 ml of an ethanol solution of sodium hydride prepared from 804 mg of selenium powder and 407 mg of sodium borohydride and 10 ml of dehydrated ethanol was added at −30 ° C. over 12 minutes. As the reaction progressed, the color of the suspension changed from yellow-orange to red-orange. After raising the temperature to room temperature over 2 hours, the reaction solution was poured into 300 ml of water. After transferring the solution to a separatory funnel, the product was extracted with methylene chloride (250 ml × 1 time, 150 ml × 1 time). The obtained organic layer was washed with water (300 ml × 3 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated and dried under reduced pressure to obtain 1.29 g of 4,5-dimethyl- [1,3] diselenol-2-thelone ( 6 ) as red crystals ( 4.25 mmol, yield 95%). mp 151 ° C. (reference: values described in the literature (K. Beckgaard, D. O. Cowan and A. N. Bloch, J. Org. Chem., 40, 746-749 (1975)) ).

  The method of the present invention is for the production of 4,5-dimethyl- [1,3] diselenol-2-thelone, which is a raw material for the synthesis of tetramethyltetraselenafulvalene (TMTSF) and related asymmetric tetraselenafulvalene derivatives. Can be used for.

Claims (5)

Equation (4) below:

A process for producing 4,5-dimethyl- [1,3] diselenol-2-thione represented by the formula:
(A) Formula (1):

(Wherein R ¹ and R ² independently represent the same or different alkyl group) 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester represented by the presence of an alkali halide Under reaction with a borohydride reducing agent, formula (2):

A step of synthesizing 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione represented by:
(B) reacting a compound of formula (2) with PBr ₃ , PCl ₃ , PCl ₅ , HCl or HBr to give a compound of formula (3):

(Wherein X represents a halogen atom), a step of synthesizing 4,5-bis-halomethyl- [1,3] diselenol-2-thione, and
(C) The method as described above, which comprises a step of reacting a compound of formula (3) with a borohydride reducing agent to synthesize a compound of formula (4). Equation (6) below:

A process for producing 4,5-dimethyl- [1,3] diselenol-2-thelone represented by:
(A) Formula (1):

(Wherein R ¹ and R ² independently represent the same or different alkyl group) 2-thioxo- [1,3] diselenol-4,5-dicarboxylic acid dialkyl ester represented by the presence of an alkali halide Under reaction with a borohydride reducing agent, formula (2):

A step of synthesizing 4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione represented by:
(B) reacting a compound of formula (2) with PBr ₃ , PCl ₃ , PCl ₅ , HCl or HBr to give a compound of formula (3):

(Wherein X represents a halogen atom), a step of synthesizing 4,5-bis-halomethyl- [1,3] diselenol-2-thione,
(C) reacting the compound of formula (3) with a borohydride reducing agent to give formula (4):

A step of synthesizing 4,5-dimethyl- [1,3] diselenol-2-thione represented by:
(D) Formula (4):

4,5-dimethyl- [1,3] diselenol-2-thione represented by the following formula is reacted with a methylating agent MeL (wherein Me represents a methyl group and L represents an anionic leaving group). And then an aliphatic or cyclic secondary amine R ³ —NH—R ⁴ where R ³ and R ⁴ independently represent the same or different alkyl groups, or R ³ and R ⁴ together To form a saturated or unsaturated 5- to 7-membered cyclic secondary amine, which may contain one or more oxygen, nitrogen or sulfur atoms, to give a compound of formula (5):

A step of synthesizing a compound represented by:
(E) reacting the compound of formula (5) with hydrogen selenide or a salt thereof to synthesize the compound of formula (6). Formula (2) :

4,5-bis-hydroxymethyl- [1,3] diselenol-2-thione represented by Formula (3) :

A compound comprising 4,5-bis-halomethyl- [1,3] diselenol-2-thione represented by the formula (where X is a chlorine atom, a bromine atom or an iodine atom). The compound of Claim 4 whose X is a bromine atom in Formula (3).