CN102503872A - Method for preparing isothiocyanate - Google Patents

Abstract

The invention relates to a method for synthesizing isothiocyanate, belonging to the field of organic chemical industry. The method comprises the following steps: (1) synthesizing the isothiocyanate from a carbon sulfide reagent and primary amine used as raw materials, adding an alkali reagent used as the catalyst and the acid binding agent, and adding a solvent at the same time, wherein the organic reaction temperature is controlled at 300 DEG C below zero to 1,200 DEG C above zero, the reaction lasts for 1-30 hours, the molar ratio of the substituted phenoxy sulfuryl chloride to the alkyl primary amine is 1-3:1, and the molar ratio of the alkali reagent to the alkyl primary amine is 1-10:1; and (2) adding water and dichloromethane solution at the volume ratio of 2:3, extracting and separating organic phases, extracting the water phases by using dichloromethane, merging the organic phases, washing by using saturated salt water, drying by using nhydrous sodium sulfate, and separating by adopting chromatography to obtain the isothiocyanate. The method for synthesizing the isothiocyanate has the advantages of readily available reaction materials, low toxicity, mild reaction condition, short reaction time and convenience of separation and purification, thereby having high application value.

Description

A kind of method for preparing isothiocyanate

technical field

The invention relates to the field of organic chemical industry, in particular to a method for preparing isothiocyanate.

Background technique

Isothiocyanate is a class of organic synthesis intermediates and pharmaceutical intermediates with a wide range of uses. It is widely used in the preparation of medicines, pesticides, and dyes. Therefore, it plays an important role in both organic synthesis and chemical industry. , the research on the synthetic method of isothiocyanate has always been an important topic in organic chemistry.

Before the present invention was made, the preparation method of isothiocyanate mainly contained the following approaches:

Thiophosgene synthesis method: direct reaction of thiophosgene and amine compounds to generate isothiocyanate (T. R. Jr. Burke, B. S. Bajwa, A. E. Jacobson, K. C. Rice, R. A. Streaty, W. A. Klee, J. Med. Chem . 1984 , 27 , 1570-1574; Journal of Organic Synthesis , 1992 , 766 , 926.). But this reaction needs to use thiophosgene, and thiophosgene is a highly toxic volatile liquid, its production, transportation and use are not safe, and it is also more harmful to the environment.

Carbon disulfide method: first form dithioammonium salt by amine compound and carbon disulfide under the action of alkali, and then react with methyl chloroformate (Xie Bing, Zhou Guangming, Chemical Times , 2006 , 20 , 71-75.), p-toluene Sulfonyl chloride (R. Wong, S. J. Dolman, J. Org. Chem. 2007, 72, 3969-3971.), di-tert-butyl dicarbonate (H. Munch, J. S. Hansen, M. Pittelkow, J. B. Christensen, U. Boas , Tetrahedron Lett. 2008 , 49 , 3177-3199.), solid phosgene (A. C. Chaskar, S. Yewale, R. Bhagat, B. P. Langi, Synth. Commun. 2008 , 38 , 1972-1975.), elemental iodine (J . Nath, H. Ghosh, R. Yella, B. K. Patel, Eur. J. Org. Chem. 2009 , 1849-1851.), Clodronate (B. Kaboudin, E. Jafari, Synthesis 2008 , 2683-2685. ), dicyclohexylcarbodiimide (J. C. Jochims, A. Seeliger, Angew. Chem. Int. Ed. Engl. 1967 , 6 , 174-175.) or chlorosilane (CN 1880302A) to prepare the target compound. However, most of these reactions have harsh conditions, need to be carried out step by step, the reaction time is long, and the post-treatment is cumbersome.

Thiocyanate method: generate isothiocyanate by reacting halogenated hydrocarbon and thiocyanate (Yuan Lu, Zhong Hong, Liu Guangyi, Fine Chemical Intermediates , 2007 , 37 , 10-13.). However, there are still many defects in this method: the yield of the target product is low, the operation process is cumbersome, and the amount of solvent is large.

Isonitrile method: in an organic solvent, isothiocyanate is synthesized from isonitrile and sulfur powder or vulcanizing agent in the presence of a metal catalyst (US 3994924). However, the synthesis and purification of isonitriles are large-scale, and isonitriles are very toxic, which is not conducive to large-scale industrial production.

In addition, the patent CN 101759614 A reported a method for preparing isothiocyanate under base catalysis by using formamide, sulfonyl halide and elemental sulfur. However, the acquisition of formamide and sulfonyl halide is still inconvenient and uneconomical.

In short, it is still one of the important tasks for chemists to develop new synthetic methods of isothiocyanates with simple routes, mild reaction conditions, simple and safe operation, and environmental friendliness.

Contents of the invention

The technical problem solved by the invention is to provide a green and efficient method for synthesizing isothiocyanate. Using substituted phenoxysulfonyl chloride and aliphatic or aromatic primary amines as raw materials to synthesize isothiocyanate in the next step under the action of base. The reaction equation is as follows:

。

.

the

A method for synthesizing isothiocyanates, which is carried out according to the following steps: (1) synthesizing isothiocyanates with carbon vulcanization reagents and primary amines as raw materials, adding alkali reagents as catalysts and acid-binding agents; adding solvent simultaneously, The organic reaction temperature is -30 ⁰ C to +120 ⁰ C; the reaction time is 1~30 hours; the molar ratio of substituted phenoxysulfonyl chloride and alkyl primary amine is 1-3:1, the alkali reagent and alkyl primary amine The molar ratio is 1-10:1;

(2) After the reaction, add water and dichloromethane solution with a volume ratio of 2:3, extract and separate the organic phase, then extract the water phase with dichloromethane, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate ; Separation by column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain isothiocyanate.

；其中取代基R₁为1-6个碳原子的烷基、1-6个碳原子的烷氧基、卤素（氟，氯，溴或碘原子）、氨基、取代氨基、硝基；取代基R₁在苯氧基硫酰氯的邻位，间位或对位。 Wherein the carbon vulcanization reagent used in step (1) is phenoxysulfonyl chloride or substituted phenoxysulfonyl chloride, and the structural formula in substituted phenoxysulfonyl chloride is

; Wherein the substituent R ₁ is an alkyl group of 1-6 carbon atoms, an alkoxy group of 1-6 carbon atoms, a halogen (fluorine, chlorine, bromine or iodine atom), an amino group, a substituted amino group, a nitro group; a substituent R ₁ is in the ortho, meta or para position to phenoxysulfonyl chloride.

Wherein the primary amine described in step (1) is an aliphatic primary amine, an aromatic primary amine, an alkylamine containing a heteroatom or a heterocycle, an aromatic amine, benzylamine, a substituted benzylamine, a condensed cyclic amine; or a heteroatom Cyclic aromatic amines: aminopyridine derivatives, aminofuran derivatives, aminothiophene derivatives, aminopyrimidine derivatives, aminopyrazole derivatives or aminoimidazole derivatives.

Wherein the alkaline reagent used in the step (1) is an inorganic base: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, preferably sodium hydroxide; or an organic base: triethyl Amine, trimethylamine, diisopropylethylamine, pyridine, 4- N , N -lutidine, potassium tert-butoxide, sodium methoxide, sodium ethoxide, preferably triethylamine.

The solvent used in step (1) is dichloromethane, dichloroethane, chloroform, tetrahydrofuran, ether, 1,4-dioxane, toluene, xylene, chlorobenzene, N , N -dimethylformamide Or dimethyl sulfoxide; preferably dichloromethane or tetrahydrofuran; the amount of solvent used is primary amine: solvent is 1:6 (mmol/mL).

Among them, the reaction temperature in step (1) is preferably 0 ⁰ C to +30 ⁰ C; the reaction time is preferably 10 hours; the molar ratio of carbon vulcanization reagent to primary amine is preferably 1.2:1; the molar ratio of alkali to primary amine is preferably 3:1 .

Advantages of the present invention: Using substituted phenoxysulfuryl chloride and primary amine compounds to synthesize isothiocyanate in the next step under the action of alkali, compared with the preparation method in the literature, it has the advantages of easy availability of reaction raw materials, low toxicity, and mild reaction conditions , short reaction time, convenient separation and purification, and many other advantages, it has high application value.

the

Detailed ways:

The present invention is described in detail below in conjunction with examples, but the present invention is not limited to these examples.

Example 1

Phenoxysulfonyl chloride (1 mmol) and sodium hydroxide (1 mmol) were weighed, respectively added to a one-necked flask containing dichloromethane (5 mL), and stirred at -30 ⁰ C. Benzylamine (1 mmol) was then weighed and dissolved in dichloromethane (1 mL), added dropwise into the above flask, and stirred for 30 hours. Stop the reaction, add water (10 mL) and dichloromethane (15 mL), extract and separate the organic phase, then extract the water phase with dichloromethane (15 mL), combine the organic phases, wash with saturated brine (15 mL), Dry over anhydrous sodium sulfate. After separation by column chromatography (ethyl acetate:petroleum ether = 1:5), benzyl isothiocyanate was obtained with a yield of 80%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 7.39 (t, J = 7.0 Hz, 2H, ArH), 7.35 (d, J = 7.0 Hz, 1H, ArH), 7.31 (d, J = 7.0 Hz, 2H , ArH), 4.71 (s, 2H, NCH ₂ ). ¹³ C NMR (125 MHz, CDCl ₃ ) δ : 134.3, 129.0 (N=C=S), 128.4, 126.8, 48.7. GCMS m / z 149.

Example 2

Weigh phenoxysulfonyl chloride (3 mmol) and sodium hydroxide (10 mmol), add them to a single-necked flask filled with xylene (5 mL), and stir at room temperature. Benzylamine (1 mmol) was then weighed and dissolved in xylene (1 mL), and added dropwise to the above-mentioned flask. After the addition was complete, the reaction was stirred at +120 ⁰ C for 1 hour. Stop the reaction, distill off the solvent under reduced pressure, then add water (10 mL) and dichloromethane (15 mL), extract and separate the organic phase, extract the aqueous phase with dichloromethane (15 mL), combine the organic phases, wash with saturated salt Washed with water (15 mL), dried over anhydrous sodium sulfate. After separation by column chromatography (ethyl acetate:petroleum ether = 1:5), benzyl isothiocyanate was obtained with a yield of 86%.

Example 3

Weigh phenoxysulfonyl chloride (1.2 mmol) and sodium hydroxide (3 mmol), respectively add to a one-necked flask containing dichloromethane (5 mL), and stir in an ice bath. Then weigh benzylamine (1 mmol) and dissolve it in dichloromethane (1 mL), add it dropwise to the above flask, keep the temperature at 0~5°C; remove the ice bath after 1 hour, and stir the reaction at +30 ^° C 10 hours. Stop the reaction, add water (10 mL) and dichloromethane (15 mL), extract and separate the organic phase, then extract the water phase with dichloromethane (15 mL), combine the organic phases, wash with saturated brine (15 mL), Dry over anhydrous sodium sulfate. After separation by column chromatography (ethyl acetate:petroleum ether = 1:5), benzyl isothiocyanate was obtained with a yield of 95%.

Example 4

Referring to the method of Example 3, using p-fluorophenoxysulfonyl chloride as the carbon sulfide reagent, the yield of the target product was 92%.

Example 5

Referring to the method of Example 3, the molar ratio of phenoxysulfonyl chloride to benzylamine was 1:1, and the yield of the target product was 85%.

Example 6

Referring to the method of Example 3, the molar ratio of phenoxysulfonyl chloride to benzylamine was 3:1, and the yield of the target product was 95%.

Example 7

Referring to the method of Example 3, the molar ratio of sodium hydroxide to benzylamine was 1:1, and the yield of the target product was 88%.

Example 8

Referring to the method of Example 3, the molar ratio of sodium hydroxide to benzylamine was 10:1, and the yield of the target product was 94%.

Example 9

Referring to the method of Example 3, using triethylamine as the base, the yield of the target product was 87%.

Example 10

Referring to the method of Example 3, using tetrahydrofuran as a solvent, the yield of the target product was 94%.

Example 11

Referring to the method of Example 3, using aniline as a raw material, reacted for 12 hours, and the yield of the target product was 88%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 7.35 (t, J = 7.5 Hz, 2H, ArH), 7.28 (d, J = 7.5 Hz, 1H, ArH), 7.23 (d, J = 7.5 Hz, 2H , ArH).

Example 12

Referring to the method of Example 3, using p-methoxyaniline as a raw material, reacted for 8 hours, and the yield of the target product was 84%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 7.17 (d, J = 9.0 Hz, 2H, ArH), 6.85 (d, J = 9.0 Hz, 2H, ArH), 3.81 (s, 3H, OCH ₃ ).

Example 13

Referring to the method of Example 3, using p-methylaniline as a raw material, reacted for 10 hours, and the yield of the target product was 88%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 7.13 (d, J = 8.5 Hz, 2H, ArH), 7.10 (d, J = 8.5 Hz, 2H, ArH), 2.34 (s, 3H, CH ₃ ).

Example 14

Referring to the method in Example 3, using 4- N,N -dimethylaniline as a raw material, reacted for 6 hours, and the yield of the target product was 85%.

¹ H NMR (400 MHz, CDCl ₃ ) δ : 7.09 (d, J = 8.8 Hz, 2H, ArH), 6.59 (d, J = 8.8 Hz, 2H, ArH), 2.96 (s, 6H, CH ₃ ).

Example 15

Referring to the method of Example 3, using 3,5-dimethylaniline as a raw material, reacted for 8 hours, and the yield of the target product was 92%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 6.09 (s, 1H, ArH), 6.85 (s, 2H, ArH), 2.29 (s, 6H, CH ₃ ).

Example 16

Referring to the method of Example 3, using o-methylaniline as a raw material, reacted for 10 hours, and the yield of the target product was 86%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 7.23-7.16 (m, 4H, ArH), 2.38 (s, 3H, CH ₃ ).

Example 17

Referring to the method of Example 3, using m-methoxyaniline as a raw material, reacted for 10 hours, and the yield of the target product was 88%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 7.24 (t, J = 8.0 Hz, 1H, ArH), 6.83 (d, J = 2.0 Hz, 1H, ArH), 6.81 (d, J = 2.0 Hz, 1H , ArH), 6.74 (s, 1H, ArH), 3.80 (s, 3H, OCH ₃ ).

Example 18

With reference to the method of Example 3, using n-hexylamine as a raw material and triethylamine as a base, the reaction was carried out for 6 hours, and the yield of the target product was 91%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 3.52 (t, J = 7.0 Hz, 2H, NCH ₂ ), 1.73-1.67 (m, 2H, CH ₂ ), 1.45-1.39 (m, 2H, CH ₂ ) , 1.37-1.29 (m, 4H, CH ₂ ), 0.91 (t, J = 7.0 Hz, 3H, CH ₃ ).

Example 19

With reference to the method of Example 3, using cyclohexylamine as a raw material, triethylamine as a base, and reacting for 10 hours, the yield of the target product was 81%.

¹ H NMR (500 MHz, CDCl ₃ ) δ : 3.71-3.69 (m, 1H, NCH), 1.94-1.86 (m, 2H, CH ₂ ), 1.74-1.64 (m, 4H, CH ₂ ), 1.51-1.38 (m, 4H, CH ₂ ).

Claims (9)

1. the method for a synthetic lsothiocyanates is characterized in that carrying out according to following step: (1) is the synthetic lsothiocyanates of raw material with carbon sulfuration reagent and primary amine, and the interpolation alkali reagent is made catalyzer and acid binding agent; Add solvent simultaneously, the organic reaction temperature is-30 ⁰C is to+120 ⁰C; Reaction times is 1 ~ 30 hour; The mol ratio of substituent phenoxy sulfuryl chloride and kiber alkyl amine is 1-3:1, and the mol ratio of alkali reagent and kiber alkyl amine is 1-10:1;

(2) adding volume ratio after reaction finishes is water and the dichloromethane solution of 2:3, the extracting and separating organic phase, and water is used dichloromethane extraction again, merges organic phase, uses the saturated common salt water washing, anhydrous sodium sulfate drying; Through column chromatography for separation (ETHYLE ACETATE: sherwood oil=1:5), obtain lsothiocyanates.

2. the method for a kind of synthetic lsothiocyanates according to claim 1 is characterized in that wherein used carbon sulfuration reagent is phenoxy sulfuryl chloride or substituent phenoxy sulfuryl chloride in the step (1),

Structural formula in the wherein said substituent phenoxy sulfuryl chloride does

Substituent R wherein ₁Be the alkyl of 1-6 carbon atom, alkoxyl group, the fluorine of a 1-6 carbon atom, chlorine, bromine or iodine atom, amino, substituted-amino, nitro; Substituent R wherein ₁At the ortho position of phenoxy sulfuryl chloride, a position or contraposition.

3. the method for a kind of synthetic lsothiocyanates according to claim 1 is characterized in that wherein the primary amine described in the step (1) is fats primary amine, aromatics primary amine, contains heteroatoms or heterocyclic alkylamine, aromatic amine, benzylamine, alpha substituted benzylamine, condensed ring amine or heterocyclic aromatic amine.

4. the method for a kind of synthetic lsothiocyanates according to claim 1 is characterized in that wherein used alkali reagent is mineral alkali or organic bases in the step (1).

5. the method for a kind of synthetic lsothiocyanates according to claim 1 is characterized in that wherein solvent for use is methylene dichloride, ethylene dichloride, chloroform, THF, ether, 1 in the step (1), 4-dioxane, toluene, YLENE, chlorobenzene, N, N-N or DMSO 99.8MIN.; Wherein solvent load is a primary amine: solvent is 1: 6 (mmol/ mL).

6. the method for a kind of synthetic lsothiocyanates according to claim 3 is characterized in that wherein the heterocyclic aromatic amine described in the step (1) is aminopyrazole derivatives, amino furan derivatives, aminothiophene derivative, aminopyridine derivative, amino-pyrazol-derivatives or aminoimidazole derivative.

7. the method for a kind of synthetic lsothiocyanates according to claim 4 is characterized in that wherein used alkali reagent is that mineral alkali is sodium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, cesium carbonate in the step (1); Organic bases is triethylamine, Trimethylamine 99, diisopropylethylamine, pyridine, 4- N, N-lutidine, potassium tert.-butoxide, sodium methylate, sodium ethylate.

8. the method for a kind of synthetic lsothiocyanates according to claim 5 is characterized in that wherein the middle solvent for use of step (1) is methylene dichloride or THF.

9. the method for a kind of synthetic lsothiocyanates according to claim 1 is characterized in that wherein the middle temperature of reaction of step (1) is 0 ⁰C is to+30 ⁰C; Reaction times is 10 hours; The mol ratio of carbon sulfuration reagent and primary amine is 1.2:1; The mol ratio of alkali and primary amine is 3:1.