JPH06157454A - Production of isothiocyanates - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a raw material for thiourea and a synthetic intermediate for pharmaceuticals and agricultural chemicals in high efficiency by reacting a dithiocarbamic acid amine salt with a haloiminium salt as a dehydrosulf idization agent. CONSTITUTION:The isothiocyanates can be produced by reacting a haloiminium salt of formula I (R<1> and R<2> are lower alkyl; X is halogen; (n) is 2 or 3) with a dithiocarbamic acid amine salt of formula II (R<3> is organic group; B is amine). The use of the haloiminium salt of formula I as the dehydrosulfidization agent enables the reaction at nearly neutral pH under moderate condition. The produced isothiocyanate can be used as a raw material for thiourea compound without purification.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing isothiocyanates, and more particularly to a method for producing isothiocyanates from amine salts of dithiocarbamic acid using a haloiminium salt which is a novel desulfurizing agent. .

[0002]

2. Description of the Related Art Isothiocyanates can be easily converted into compounds such as thiourea and thiocarbamic acid derivatives by easily reacting with nucleophiles such as amines and alcohols.
It is an important intermediate in organic synthesis. In addition, isothiocyanates are important synthetic intermediates for pharmaceuticals, agricultural chemicals, etc., because they are used as building blocks in the construction of heterocycles via the cycloaddition reaction.

On the other hand, as a conventional method for producing isothiocyanates, a method of synthesizing an amine and thiophosgene, a method of thermally decomposing thiourea in an appropriate organic solvent, an amine and carbon disulfide are used. There are known methods such as thermal decomposition or decomposition with a metal salt of a product obtained by reacting carboxylic acid in the presence of a base, and a method of causing carbon disulfide to act on a phosphoramidate ester anion.

[0004]

However, the synthetic method from amine and thiophosgene requires strong handling because thiophosgene has strong toxicity and bad odor, and cannot be applied to the production of naphthalene-based compounds. . The method of decomposing thiourea has a drawback that the reaction temperature must be raised to the reflux temperature of chlorobenzene used in the reaction. In addition, the method of decomposing the product obtained by reacting an amine with carbon disulfide in the presence of a base has a problem of environmental pollution because it uses a metal such as copper sulfate or lead nitrate, and is therefore not suitable for implementation on an industrial scale. Is not suitable. Furthermore, the method of synthesizing from phosphoramidate has the disadvantage that dangerous reagents such as sodium hydride have to be used for the preparation of phosphoramidate anion.

Therefore, there has been a demand for the development of a method for producing isothiocyanates which is industrially advantageous without being affected by the properties of the raw materials and requiring no high temperature heating during the reaction.

[0006]

Under such circumstances, the present inventor has conducted diligent research and, as a result, reacted the amine salt of dithiocarbamic acid with a haloiminium salt represented by the following general formula (1) as a desulfurizing agent. If so, the reaction can be carried out at about neutral pH and under mild conditions,
Moreover, they have found that isothiocyanates can be obtained in high yield, and have completed the present invention.

The production method of the present invention is shown by the following reaction formula.

[0008]

[Chemical 2]

[Wherein R ¹ and R ² are the same or different and each is a lower alkyl group, X is a halogen atom, n is 2 or 3, R ³ is an organic group, B is an amine and B ' Indicates a base]

That is, the present invention provides a process for producing isothiocyanates (4), which comprises reacting a dithiocarbamic acid amine salt (2) with a haloiminium salt (1).

In the present invention, the haloiminium salt used as the desulfurizing agent is represented by the general formula (1), and in the formula (1), the lower alkyl group represented by R ¹ and R ² is: Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom is particularly preferable. Further, preferred specific examples of the haloiminium salt (1) include 2-chloro-1,3-dimethylimidazolinium chloride, 2-chloro-1,3-dimethyl-3,4.
5,6-tetrahydropyrimidinium chloride and the like can be mentioned.

The haloiminium salt (1) is represented by the following general formula (8), which is known as an easily available solvent.

[0013]

[Chemical 3]

In the compound represented by the formula [wherein R ¹ and R ² have the same meanings as described above], an oxalyl halogenide,
It can be easily obtained by reacting a halogenating agent known per se, such as phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, phosgene, trichloromethyl chloroformate and the like. In this reaction, one of the compound (8) and the halogenating agent is dissolved in a suitable solvent such as carbon tetrachloride, and the other is added little by little to room temperature to 7
It is carried out by reacting at 0 ° C. for several hours to several tens of hours. The haloiminium salt (1) thus obtained can be isolated, but the reaction solution can also be used in the reaction of the present invention without isolation.

The dithiocarbamic acid amine salt (2) which is the starting material compound of the method of the present invention is not particularly limited, and the group represented by R ³ in the general formula (2) may be an alkyl which may have a substituent. Group, alkenyl group, aromatic group, heterocyclic group and the like. In the present invention, the substituent that R ³ has may be a substituent containing an ether bond, a double bond, or the like. Examples of the amine represented by B include triethylamine, tributylamine, N, N-dimethylaniline, pyridine and the like.

This amine salt of dithiocarbamic acid (2)
Is an amine in the presence of a base according to a conventionally known method,
It can be produced by reacting carbon disulfide, and in the production method of the present invention, the reaction liquid thus obtained can be used as it is as a raw material without purification.

To carry out the present invention, about 1 mol of the haloiminium salt (1) and about 1 mol of the base (3) are added to 1 mol of the dithiocarbamic acid amine salt (2), and the mixture is allowed to react at room temperature. Good. As the base, pyridine, triethylamine, tributylamine and the like can be used, but it is preferable to use an amine corresponding to the amine salt of the starting dithiocarbamic acid amine salt. The reaction solvent does not have to be used, but a solvent that does not participate in the reaction, such as a halogenated hydrocarbon such as dichloromethane or dichloroethane, a hydrocarbon, an ether, an aromatic hydrocarbon, or the like can be used. Further, as the reaction apparatus, even when it is carried out on an industrial scale, it is possible to use an ordinary stainless steel reaction kettle instead of a special reaction kettle such as glass lining.

The method of the present invention has the advantage that no environmental problems are caused because no heavy metal is used in the oxidation reaction, and since the haloiminium salt (1) is converted into the water-soluble compound (8), it can be easily separated and purified. is there. Therefore, the desired ketones can be isolated from the reaction mixture by a conventional method such as distillation or recrystallization.

Further, when the thioureas are produced using the isothiocyanates obtained by the production method of the present invention as a raw material, it is not necessary to isolate the produced isothiocyanates (4). To the reaction solution containing the isothiocyanates (4) before purification obtained as described above, an amine was added, and the mixture was stirred and mixed according to a known method to cause a reaction, whereby thioureas were easily obtained in one step. Can be obtained.

[0020]

According to the production method of the present invention, almost neutral
It is possible to industrially and efficiently produce isothiocyanates from an amine salt of dithiocarbamic acid at pH and under mild conditions. The isothiocyanates obtained by the method of the present invention can be used as a raw material for thioureas without purification.

[0021]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 Preparation of Phenylisothiocyanate: Methylene chloride 25
5.0 g (19 mmol) of triethylammonium phenyldithiocarbamate and 1.
9 g (26 mmol) were added and 2-chloro-1,3 was added to it.
-Dimethyl imidazolinium chloride 3.8 g (22
(10 mmol) methylene chloride solution (10 ml) was slowly added dropwise. After completion of dropping, the mixture was further stirred at room temperature for 18 hours, then the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (solvent: n-hexane / ethyl acetate).
2.3 g of the title compound which is a pale yellow oily substance.
(Yield 92%) was obtained. IR ν _max ^neat cm ^-1 : 2070, 920

Example 2 Preparation of cyclohexyl isothiocyanate: In 20 ml of methylene chloride, 2.5 g (9 mmol) of triethylammonium cyclohexyldithiocarbamate and 1.3 g (13 mmol) of triethylamine are added, into which 2-chloro-1, 3-Dimethylimidazolinium chloride 1.
A solution of 8 g (11 mmol) in 10 ml of methylene chloride was slowly added dropwise. After the dropping is completed, the mixture is further stirred at room temperature for 13 hours,
Then, the same operation as in Example 1 was carried out to obtain 1.2 g (yield: 92%) of the title compound as a slightly yellow oily substance. IR ν _max ^neat cm ^-1 : 2170, 2090, 2050, 695

Example 3 Preparation of 2-phenylethylisothiocyanate: To 25 ml of methylene chloride, 5.0 g (17 mmol) of triethylammonium 2-phenylethyldithiocarbamate and 2.4 g (23 mmol) of triethylamine are added. A solution of 3.4 g (20 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in 10 ml of methylene chloride was slowly added dropwise. Then, after stirring at room temperature for 17 hours, the same operation as in Example 1 was performed to obtain 2.1 g (yield 76%) of the title compound as a yellow oily substance. IR ν _max ^neat cm ^-1 : 2190, 2100, 700

Example 4 Preparation of diphenylthiourea: (1) 2.0 g of aniline (2 g) in 25 ml of methylene chloride.
1 mmol) and 5.2 g (51 mmol) of triethylamine were dissolved and cooled with water. 1.6 g of carbon disulfide (21
mmol) was added dropwise, and after completion, stirring was continued at room temperature for another 30 minutes. Then 2-chloro-1,3-dimethylimidazolinium chloride 4.3 g (26 mmol) methylene chloride 3
The 0 ml solution was slowly added dropwise while cooling with ice, and after completion, stirring was continued at room temperature for 4 hours. (2) 2.0 g (21 mmol) of aniline was added dropwise to the reaction liquid containing phenylisothiocyanate obtained in (1), and after completion of the dropwise addition, the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, the organic layer was separated, and the organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. Next, 5.5 g of a crystalline residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (solvent: n-hexane / ethyl acetate) to obtain 4.2 g (yield 88%) of the title compound. It was IRν _max ^KBr cm ^-1 : 3190, 1540, 1240

Claims (1)

[Claims] 1. A dithiocarbamic acid amine salt is added to the following general formula (1): [Wherein R ¹ and R ² are the same or different and each represents a lower alkyl group, X represents a halogen atom, and n represents 2 or 3], and isothiocyanate characterized by reacting Manufacturing method.