CN109912475A - A kind of green preparation method of Z-3-thiocyanate-based acrylamide compound - Google Patents

Abstract

The invention discloses a green preparation method of Z-3-thiocyanate-based acrylamide compounds. Under the action of ultrasonic waves, lactic acid catalyzes a three-component addition reaction of propargyl amide compound, thiocyanate and water to generate Z-3-thiocyanate-based acrylamide compound; after the reaction, add water to the system to dilute , the high-purity Z-3-thiocyanate-based acrylamide product can be precipitated; the method has good product selectivity, high yield, simple separation process, low-cost catalyst, environmental friendliness, and is conducive to industrial production and application.

Description

A kind of green preparation method of Z-3-thiocyanate-based acrylamide compound

technical field

The present invention relates to a green preparation method of Z-3-thiocyanate-based acrylamide compound, in particular to a one-step addition reaction of propargyl amide compound, thiocyanate and water catalyzed by ultrasonic-assisted lactic acid to synthesize Z-3 -The method of thiocyanate-based acrylamide compound belongs to the technical field of organic intermediate synthesis.

Background technique

Z-3-thiocyanate-based acrylamide compounds not only have very important physiological activities, but also contain thiocyanate functional groups, alkenyl groups, and amide groups, which are all important modifiable functional groups, and are a very important class of drugs. And organic synthesis intermediate compounds. In the prior art, acidic ionic liquids catalyze the three-component reaction of propargyl amide, thiocyanate and water to obtain Z-3-thiocyanate-based acrylamide compounds, such as (Green Chem. 2018, 20, 3683) , but the reaction still has the following shortcomings, which limit its practical application:

1) The acidic ionic liquid is toxic, its preparation process is not environmentally friendly, and the cost is high, and there is no commercial product.

2) The yield of the Z-3-thiocyanate-based acrylamide compound is 81-83%, and there are E-form isomers and the decomposition product of propargyl amide, propynoic acid and unreacted propargyl amide raw materials in the reaction, The purity is not high.

3) The separation of the product needs to be extracted with a volatile organic solvent, and the purification of the product needs to be separated by silica gel column chromatography. The separation process is not only complicated and costly, but also produces environmental pollution.

4) The acidic ionic liquid is circulated 5 times, the efficiency is reduced by 13%, and the use cost is high.

Existing acidic ionic liquid catalyzes the three-component reaction of propargyl amide, thiocyanate and water to synthesize the method specific situation of Z-3-thiocyanate-based acrylamide compound as following table:

SUMMARY OF THE INVENTION

Aiming at the technical problems existing in the synthesis and separation of Z-3-thiocyanate-based acrylamide compounds in the prior art, the purpose of the present invention is to provide a non-toxic and cheap lactic acid-catalyzed propargyl amide compound, thiocyanate A method for synthesizing Z-3-thiocyanate-based acrylamide compound by one-pot reaction of acid salt and water, the method has good product selectivity, high yield, simple separation process, low cost, environmental friendliness, and is favorable for industrial production and application.

In order to achieve the above technical purpose, the present invention provides a green preparation method of Z-3-thiocyanate-based acrylamide compound. The method comprises the following steps: lactic acid catalyzes a propargylamide compound, thiocyanate and water under the action of ultrasonic waves. An addition reaction was performed to obtain a Z-3-thiocyanatoacrylamide compound.

In a preferred scheme, the propargyl amide compound has the structure of formula 1;

The Z-3-thiocyanate-based acrylamide compound has the structure of formula 2:

in,

R is selected from alkyl or aryl

In a preferred solution, R can be an alkyl group, such as a C ₁ -C ₁₀ alkyl group, such as a straight-chain alkyl group, or a branched alkyl group, or a C ₃ -C ₇ cycloalkyl group, such as Methyl, ethyl, isobutyl, cyclohexyl, etc. R can be an aryl group, specifically, an aryl group is a phenyl group or a substituted phenyl group containing a common substituent on the benzene ring, and a substituted phenyl group is a short chain containing a common substituent group on the benzene ring, such as C ₁ -C ₅ Alkyl, C ₁ -C ₅ alkoxy, halogen substituent (fluorine, chlorine, bromine, etc.), trifluoromethyl, nitro, cyano, amino, C ₂ -C ₅ ester group, hydroxyl. The position of the substituent is not limited, the number of the substituent may be one or more, and generally one substituent is contained.

In a preferred solution, the thiocyanate can be commonly soluble salts such as potassium thiocyanate and sodium thiocyanate. Most preferred is potassium thiocyanate.

In a preferred scheme, the molar ratio of propargyl amide compound, potassium thiocyanate, water and lactic acid is 1:1-2:1-2:2-5. The most preferred molar ratio is 1:1.2:1:4.

In a preferred solution, the conditions of the addition reaction are: at room temperature, the ultrasonic power is 25-45W, the ultrasonic frequency is 28KHz-60KHz, and the reaction time is 15-40min. A further preferred ultrasonic power is 35W. A still further preferred ultrasonic frequency is 40KHz. The addition reaction of lactic acid-catalyzed propargyl amide compound, thiocyanate and water under the aid of preferred ultrasonic conditions can not only shorten the reaction time, but also improve the conversion rate.

In a preferred solution, after the addition reaction is completed, water is added to the reaction system for dilution to precipitate the Z-3-thiocyanate-based acrylamide product, and separation of the product from the aqueous lactic acid solution is achieved by liquid separation or filtration to obtain Z-3 - Thiocyanate-based acrylamide compound products. The present invention adopts water to dilute the reaction mixture, so that high-purity Z-3-thiocyanate-based acrylamide compounds can be precipitated, and traditional organic solvent extraction and silica gel column chromatography separation methods are not required, and the volatile organic solvent is completely avoided. use.

In a preferred solution, the amount of water added is more than 5 times the mass of lactic acid. Water with a mass of more than 5 times is preferred, which can ensure the smooth precipitation of the Z-3-thiocyanatoacrylamide compound.

The lactic acid used in the present invention simultaneously serves as a catalyst and a reaction medium in the addition reaction.

The present invention carries out the addition reaction of propargyl amide compound, thiocyanate (taking potassium thiocyanate as an example) and water to synthesize the route of Z-3-thiocyanate-based acrylamide compound as follows:

The specific reaction principle is shown in the following reaction formula: lactic acid first activates the propargyl amide compound to obtain the allene intermediate IM2, and the thiocyanate nucleophilically attacks the β-carbon atom of the allene intermediate IM2 to form an intermolecular hydrogen bond with lactic acid to obtain Intermediate IM3; Intermediate IM3 captures the proton generated by the ionization of water molecules from the opposite direction of the hydrogen bond, and obtains the trans-addition product Z-3-thiocyanatoacrylamide compound.

Relative to the prior art, the beneficial technical effects brought by the technical solution of the present invention:

1) The present invention adopts lactic acid as the reaction medium and catalyst, which is easy to recycle, safe and non-toxic, environmentally friendly, easy to obtain, and low in price.

2) The present invention reacts at room temperature with mild conditions.

3) The present invention has wide selectivity to propargyl amide compounds, good functional group compatibility, and is easy to modify with various groups.

4) The present invention uses ultrasonic waves to promote the reaction, while shortening the reaction time, the raw material conversion rate is quantitative, the product selectivity is 100%, and no E-form isomer is generated in the reaction.

5) the present invention only needs to add the water of 5 times the amount of lactic acid quality in the reaction mixture, the product can be separated out in layers, and the pure product is obtained, avoiding the Z-3-thiocyanate-based propylene synthesized in the prior art The separation and purification process of amide compounds is a complex problem.

6) The lactic acid of the present invention can be recovered and recycled for 5 times, the efficiency is reduced by 3%, and the catalytic activity is kept relatively high, which has obvious advantages compared with the acidic ionic liquid.

7) The Z-3-thiocyanate-based acrylamide compound of the present invention has an important physiologically active thiocyanate functional group, a modifiable alkene group, an amide group, etc., and provides an important organic intermediate for the synthesis of drugs and organic compounds.

Detailed ways

The following specific examples are intended to further illustrate the content of the present invention, rather than limit the protection scope of the claims of the present invention.

Comparative Example:

The following control experimental groups 1 to 19 all responded according to the following reaction equation:

The specific operation steps are: in a 20mL reaction tube, N-phenylpropargylamide (1 equivalent, 10mmol), thiocyanate, water and biomass acid were added successively, and the obtained mixed solution was reacted in the ultrasonic reaction device of 30min. After the reaction, 18 ml of water was added to obtain the target product.

In the above table, experimental groups 1 to 3 investigated the influence of various thiocyanate sources on the addition reaction of N-phenylpropargylamide, potassium thiocyanate and water. It can be seen from the experimental data that cheap sulfur Compared with sodium thiocyanate or ammonium thiocyanate, potassium cyanate can obviously improve the efficiency of the three-component addition reaction.

In the above table, experimental groups 1 and 4 to 5 have investigated the effect of the amount of KSCN of the reaction raw material on the addition reaction of N-phenylpropynamide, potassium thiocyanate and water. The experiments show that the optimal molar amount of KSCN is: 1.2 equivalents; when the amount of KSCN is too low, the yield of the target product decreases, and if KSCN is further increased, the yield of the target product no longer increases.

In the above table, experimental groups 1 and 6-7 have investigated the influence of the amount of reaction raw material water on the addition reaction of N-phenylpropargyl amide, potassium thiocyanate and water. The experiments show that the optimal molar amount of KSCN is used. is 1 equivalent; when the amount of water is too low, the yield of the target product decreases, and if the amount of water is further increased, the yield of the target product no longer increases.

In the above table, experimental groups 8 to 13 investigated the influence of various reaction media on the addition reaction of N-phenylpropargylamide, potassium thiocyanate and water. It can be seen from the experimental data that the reaction in lactic acid medium Compared with other reaction media, the efficiency of the three-component addition reaction can be significantly improved, and the reaction has a single reaction addition selectivity.

In the above table, experimental groups 1 and 14-15 have investigated the influence of the lactic acid dosage on the addition reaction of N-phenylpropargyl amide, potassium thiocyanate and water. The experiments show that the optimal molar dosage of lactic acid is 4 equivalents. ; When the amount of lactic acid is higher than 4 equivalents, the reaction efficiency does not improve; when the amount of lactic acid is lower than 4 equivalents, the yield of the target product decreases.

In the above table, experimental groups 1 and 16 to 19 investigated the effect of ultrasonic assistance on the co-addition reaction of N-phenylpropynamide, potassium thiocyanate and water. Improve the reaction efficiency, especially when the ultrasonic power is 35W/frequency is 40KHz, the coaddition reaction effect is the best, and the best target product yield can be obtained in a relatively short time.

Cyclic experiment results

In a 20 mL reaction tube, N-phenylpropynamide (10 mmol), potassium thiocyanate (12 mmol, 1.16 g), water (10 mmol, 0.18 g), and lactic acid (40 mmol, 3.60 g) were sequentially added, and the resulting mixed solution React in a 35W/40KHz ultrasonic reaction device for 30 minutes. After the reaction, 18 ml of water and lactic acid were added to form an aqueous lactic acid solution, Z-3-thiocyanatoacrylamide was insoluble in the aqueous lactic acid solution, precipitated, separated, and vacuum-dried to calculate the weight. The water in the aqueous lactic acid solution was removed under reduced pressure and used directly in the next cycle experiment. The yield data obtained are as follows.

1 2 3 4 5 94% 94% 93% 92% 91%

Examples 1-2

Following examples 1～2 all react according to following reaction equation:

The specific operation steps are: in a 20 mL reaction tube, add propargyl amide (10 mmol), potassium thiocyanate (12 mmol, 1.16 g), water (10 mmol, 0.18 g), and lactic acid (40 mmol, 3.60 g) in turn, and the resulting mixed solution React in a 35W/40KHz ultrasonic reaction device for 30 minutes. After the reaction, 18 ml of water and lactic acid were added to form an aqueous lactic acid solution, Z-3-thiocyanatoacrylamide was insoluble in the aqueous lactic acid solution, precipitated, separated, and vacuum-dried to calculate the weight.

Example 1

raw material: Target product:

Z-N-octyl-3-thiocyanatoacrylamide:

Yield: 93%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16 (d, J=10.0 Hz, 1H), 6.33 (d, J=10.0 Hz, 1H), 5.82 (brs, 1H), 3.34 (q, J=6.8 Hz) ,2H),1.57–1.50(m,2H),1.33–1.27(m,2H),2.54 (t,J=6.8Hz,3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.1, 126.3, 125.9, 107.5, 39.9, 31.8, 29.5, 29.2, 29.0, 26.9, 22.7, 14.2.

Example 2

raw material: Target product:

Z-N-phenyl-3-thiocyanatoacrylamide:

Yield: 94%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J=6.4 Hz, 1H), 7.58-7.55 (m, 2H), 7.46-7.42 (m, 2H), 7.35-7.30 (m, 1H), 6.33(d,J=6.4Hz,1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.7, 139.6, 136.5, 129.4, 128.8, 127.6, 124.8, 114.8.

Claims (8)

1. a green preparation method of Z-3-thiocyanate-based acrylamide compound, is characterized in that: under ultrasonic effect, lactic acid catalyzed propargyl amide compound, thiocyanate and water carry out addition reaction, obtain Z -3-thiocyanatoacrylamide compound. 2. the green preparation method of a kind of Z-3-thiocyanate-based acrylamide compound according to claim 1, is characterized in that: The propargyl amide compound has the structure of formula 1; The Z-3-thiocyanate-based acrylamide compound has the structure of formula 2: in, R is alkyl or aryl. 3. the green preparation method of a kind of Z-3-thiocyanate-based acrylamide compound according to claim 2, is characterized in that: The alkyl group includes a C ₁ -C ₁₀ alkyl group; The aryl group includes phenyl, or includes C ₁ -C ₅ alkyl, halogen, nitro, cyano, amino, C ₂ -C ₅ ester, hydroxyl, trifluoromethyl, C ₁ -C ₅ The alkoxy group has at least one substituent in the phenyl group. 4. the green preparation method of a kind of Z-3-thiocyanate-based acrylamide compound according to claim 1, is characterized in that: described thiocyanate is potassium thiocyanate and/or sodium thiocyanate . 5. the green preparation method of a kind of Z-3-thiocyanate-based acrylamide compound according to claim 1, is characterized in that: the mol ratio of propargyl amide compound, thiocyanate, water and lactic acid is 1 :1～2:1～2:2～5. 6. The green preparation method of a Z-3-thiocyanate-based acrylamide compound according to any one of claims 1 to 5, characterized in that: the condition of the addition reaction is: at room temperature, The ultrasonic power is 25-45W, the ultrasonic frequency is 28KHz-60KHz, and the reaction time is 15-40min. 7. the green preparation method of a kind of Z-3-thiocyanate-based acrylamide compound according to any one of claim 1～5, it is characterized in that: after the addition reaction is completed, add water to the reaction system to dilute , the Z-3-thiocyanate-based acrylamide compound is precipitated, and the Z-3-thiocyanate-based acrylamide compound is obtained by filtration or liquid separation. 8. The green preparation method of a Z-3-thiocyanate-based acrylamide compound according to claim 7, wherein the water addition amount is more than 5 times of the lactic acid quality.