CN110981745A - Preparation method of tertiary amide compound - Google Patents

Abstract

The invention discloses a preparation method of a tertiary amide compound, belonging to the field of organic synthesis. According to the invention, a ligand participation and high-temperature reaction system is not required, and the aryl formamide compound shown in the formula (II) and the p-toluenesulfonylhydrazone compound shown in the formula (III) are directly coupled under the action of a specific copper catalyst and an alkali reagent to prepare the tertiary amide compound shown in the formula (I). The method is green and simple, and the yield of the tertiary amide compound can reach about 82%.

Description

Preparation method of tertiary amide compound

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a tertiary amide compound.

Background

The tertiary amide compound is an important organic synthesis reagent and is a synthesis intermediate generally applied in multiple fields of drug synthesis, material research and development and the like. Since amide bonds are ubiquitous in biologically active compounds, improving an amide synthesis method or an amide bonding method to overcome the disadvantages of the conventional methods has been the most popular research field and the most important research target in the field of organic synthesis.

The existing method for preparing the tertiary amide compound is prepared by using secondary amide as a substrate for reaction, and a target compound cannot be obtained by directly coupling the primary amide. However, the secondary amide is expensive in raw material and is basically prepared from cheap and easily available primary amide. In addition, in the coupling process reported at present, expensive ligands are mostly used for participating in the reaction, so that the production cost is greatly increased; meanwhile, higher temperature is needed in the reaction process to promote the smooth reaction; harmful substances are generated even during the reaction. Therefore, the development of a simple and efficient method for preparing tertiary amide compounds is urgently needed.

Disclosure of Invention

In order to solve the problems, the invention directly prepares the tertiary amide from the primary amide by using C-N coupling reaction under the catalysis of cheap catalyst copper salt. The method not only solves the defect that expensive metal and ligand are needed in the traditional synthetic route, but also has the advantages of convenience and rapidness in the aspect of product separation because the harsh conditions of reaction involving high temperature are avoided.

The invention aims to provide a preparation method of a tertiary amide compound, which takes an aryl formamide compound shown in a formula (II) and a p-toluenesulfonylhydrazone compound shown in a formula (III) as substrates, and performs a coupling reaction under the action of a copper catalyst and an alkali reagent to prepare the tertiary amide compound shown in the formula (I);

wherein R is₁Selected from hydrogen, halogen, alkyl, alkoxy, cyano, alkyl ester, R₁At ortho, meta or para position; r₂Selected from halogen, hydrogen, halogen, alkyl,Alkoxy, cyano, alkyl ester, R₂In ortho, meta or para position.

In one embodiment of the present invention, the p-toluenesulfonylhydrazone compound is added in an amount of 3.0 to 6.0 molar equivalents based on the arylcarboxamide compound. Further preferably 4.0 to 5.5 molar equivalents.

In one embodiment of the invention, the copper catalyst is selected from the group consisting of CuI, CuBr₂，CuCl₂Or Cu (OAc)₂，CuSO₄，Cu(NO₃)₂，CuO，Cu(CH₃CN)₄BF₄Any one or more of them. The copper catalyst is further preferably CuI.

In one embodiment of the invention, the copper catalyst is added in an amount of 1 mol% to 20 mol% based on the arylcarboxamide compound. Preferably 5 mol% to 15 mol%.

In one embodiment of the present invention, the alkali agent is any one or a combination of more of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate, alkaline earth metal phosphate, alkali metal acetate, alkaline earth metal acetate, alkali metal alkoxide, and alkaline earth metal alkoxide.

In one embodiment of the invention, the base reagent is preferably an alkali metal tert-butoxide, including potassium tert-butoxide, sodium tert-butoxide, and the like.

In one embodiment of the invention, the basic agent is added in an amount of 1 to 9 molar equivalents based on the arylcarboxamide compound. Further preferably 6 molar equivalents.

In one embodiment of the invention, the coupling reaction is carried out in a solvent; the solvent is one or more of ethers, hydrocarbons, alcohols and amides. Wherein the ethers include tetrahydrofuran and dioxane; hydrocarbons include cyclohexane, benzene, toluene; alcohols include methanol, ethanol, 1-propanol; amides include dimethylformamide.

In one embodiment of the invention, the solvent is added in an amount of 1 to 20g per mole of the compound arylcarboxamide. Preferably 5-15 g.

In one embodiment of the invention, the method further comprises adding an additive, the additive being a phase transfer catalyst.

In one embodiment of the invention, the additive comprises one or more of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride. Tetrabutylammonium iodide is preferred.

In one embodiment of the invention, the additive is used in an amount of 1 mol% to 50 mol% based on the arylcarboxamide compound. Preferably 10 mol% to 30 mol%.

In one embodiment of the invention, the reaction temperature of the coupling reaction is from 0 ℃ to 150 ℃. Preferably 60 ℃ to 120 ℃.

In one embodiment of the invention, the reaction time of the coupling reaction is 1 to 24 hours. Preferably 2-12 h.

In one embodiment of the invention, the reaction of the process is as follows:

wherein R is₁Is hydrogen, halogen, alkyl, alkoxy, cyano, alkyl ester, R₁At ortho, meta and para positions, preferably benzamide; p-toluenesulfonylhydrazone compound III in which R is₂Is halogen, hydrogen, halogen, alkyl, alkoxy, cyano, alkyl ester, R₂In ortho-, meta-and para-positions, p-toluenesulfonylhydrazone is preferred.

The halogen related to the invention is fluorine, chlorine, bromine or iodine.

In an embodiment of the present invention, the method specifically includes the following steps:

adding aryl formamide compounds (formula II), p-toluenesulfonylhydrazone compounds (formula III), an alkali reagent, an additive and a catalytic amount of a copper catalyst into a reactor, vacuumizing, introducing nitrogen, stirring the mixture at 0-150 ℃ for 1-24 hours, after the reaction is finished, adding saturated salt water into the reaction solution, extracting with dichloromethane for three times, and then separating by a column to obtain a compound tertiary amide target compound (formula I).

The invention has the beneficial effects that:

the method avoids the participation of expensive ligand and the use of high temperature, and greatly reduces the production cost; in addition, no harmful substances are generated in the reaction process of the method, and the method is green and environment-friendly. Most importantly, the method can directly realize the preparation of the corresponding tertiary nitrogen substituted amide compound from the primary amide, is a cheap and efficient route method for synthesizing the tertiary amide, and has the yield of about 82 percent.

Drawings

FIG. 1 is a reaction scheme of a tertiary amide compound.

Detailed Description

Example 1: preparation of tertiary amide target compound (R)₁、R₂＝H)

In a nitrogen atmosphere, 61mg (0.5mmol) of benzamide, 616.5mg (2.25mmol) of p-toluenesulfonylhydrazone, 288mg (3.0mmol) of sodium tert-butoxide, 9.55mg (0.05mmol) of CuI and 18.5mg (0.05mmol) of tetrabutylammonium iodide were added to a reactor, 2.5mL of tetrahydrofuran was added, the reaction was carried out at 100 ℃ for 6 hours in a nitrogen atmosphere, the reaction was quenched with saturated brine, extracted with dichloromethane, dried, separated on silica gel, and the dichloromethane was distilled off to obtain 123mg of N, N-dibenzylbenzamide as a product, with a yield of 82%.

The yield is 82%; (column chromatography, eluent petroleum ether: ethyl acetate, v/v-10/1).¹H NMR(300MHz,CDCl₃)δ(ppm)7.95-7.90(m,2H,ArH),7.62-7.54(m,3H,ArH),7.36-7.29(m,10H,ArH),,4.91(s,4H,NCH₂)。

Example 2: preparation of tertiary amide target compound (R)₁＝CH₃、R₂＝CH₃)

Referring to example 1, the corresponding tertiary amide compound was prepared by replacing benzamide with equimolar p-methylbenzamide and p-toluenesulfonylhydrazone with equimolar (p-tolyl) p-toluenesulfonylhydrazone, and the other conditions were not changed.

The yield thereof was found to be 80%. (column chromatography, eluent petroleum ether: ethyl acetate, v/v-10/1).¹H NMR(300MHz,CDCl₃)δ(ppm)7.86-7.82(m,2H,ArH),7.34-7.30(m,2H,ArH),7.51-7.12(m,8H,ArH),4.89(s,4H,NCH₂),2.41(s,3H,CH₃),2.17(s,6H,CH₃)。

Example 3: preparation of tertiary amide target compound (R)₁＝Cl、R₂＝Br)

Referring to example 1, the corresponding tertiary amide compound was prepared by replacing benzamide with equimolar p-chlorobenzamide and p-toluenesulfonylhydrazone with equimolar (p-bromophenyl) p-toluenesulfonylhydrazone, and the other conditions were not changed.

The yield was 78% (column chromatography, eluent petroleum ether: ethyl acetate, v/v 10/1).¹H NMR(300MHz,CDCl₃)δ(ppm)7.90-7.85(m,4H,ArH),7.54-7.51(m,3H,ArH),7.46-7.43(m,1H,ArH),7.27-7.25(m,2H,ArH),7.19-7.15(m,2H,ArH),4.93(s,4H,NCH₂)。

Example 4: effect of copper catalyst on coupling reaction

Referring to example 1, CuI was replaced with CuBr₂、CuO、Cu(CH₃CN)₄BF₄Or Cu (OAc)₂And other conditions are not changed, and the coupling reaction is carried out. Specific results are shown in table 1.

TABLE 1 results of preparing tertiary amide compounds with different copper catalysts

Copper catalyst	Yield of tertiary amide compound
		CuBr2	20
CuO	21
		Cu(CH3CN)4BF4	40
Cu(OAc)2	35
		Without adding	<5

Example 5: effect of different base reagents on the coupling reaction

Referring to example 1, sodium tert-butoxide was replaced with NaOH and Cs, respectively₂CO₃And other conditions are not changed, and the coupling reaction is carried out. The specific results are shown in Table 2.

TABLE 2 results of preparing tertiary amide compounds with different basic reagents

Alkali reagent	Yield of tertiary amide compound
		Without adding	<5
NaOH	30
		Cs2CO3	21

Example 6:

referring to example 1, the additives were omitted and the other conditions were unchanged. As a result, it was found that the yield of the tertiary amide compound was 45% without adding an additive.

Comparative example 1:

0.5mmol (1eq) of benzamide, 0.75mmol (1.5eq) of p-toluenesulfonylhydrazone, and 1.5eq of sodium hydride were added to a reactor, 2.5mL of toluene was added thereto, and the reaction was carried out at room temperature for 24 hours. As a result, it was found that the yield of the tertiary amide obtained by the reaction system was only 10%.

Claims (10)

1. A preparation method of a tertiary amide compound is characterized in that an aryl formamide compound shown in a formula (II) and a p-toluenesulfonylhydrazone compound shown in a formula (III) are used as substrates, and a coupling reaction is carried out under the action of a copper catalyst and an alkali reagent to prepare the tertiary amide compound shown in the formula (I);

wherein R is₁Selected from hydrogen, halogen, alkyl, alkoxy, cyano, alkyl ester, R₁At ortho, meta or para position; r₂Selected from halogen, hydrogen, halogen, alkyl, alkoxy, cyano, alkyl ester, R₂In ortho, meta or para position.

2. The method of claim 1, wherein the p-toluenesulfonylhydrazone compound is added in an amount of 3.0 to 6.0 molar equivalents based on the arylcarboxamide compound.

3. The process according to claim 1 or 2, characterized in that the copper catalyst is selected from CuI, CuBr₂，CuCl₂Or Cu (OAc)₂，CuSO₄，Cu(NO₃)₂，CuO，Cu(CH₃CN)₄BF₄Any one or more of them.

4. The process of any of claims 1 to 3, wherein the copper catalyst is added in an amount of 1 mol% to 20 mol% based on the arylcarboxamide compound.

5. The process of any one of claims 1 to 4, wherein the alkali agent is any one or more of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate, alkaline earth metal phosphate, alkali metal acetate, alkaline earth metal acetate, alkali metal alkoxide and alkaline earth metal alkoxide.

6. The process of any of claims 1 to 5, wherein the basic agent is added in an amount of 1 to 9 molar equivalents based on the arylcarboxamide compound.

7. The process according to any one of claims 1 to 6, wherein the coupling reaction is carried out in a solvent, wherein the solvent is any one or more of ethers, hydrocarbons, alcohols and amides.

8. The process of claim 7 wherein the solvent is added in an amount of 1 to 20g per mole of the compound arylcarboxamide.

9. The method of any one of claims 1-8, further comprising adding an additive, wherein the additive is a phase transfer catalyst.

10. The method of claim 9 wherein the additive is present in an amount of from 1 mol% to 50 mol% based on the arylcarboxamide compound.

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