CN104557759A - Method for preparing 5-sulfonyl methyl oxazole derivative - Google Patents

Abstract

The present invention relates to a method for preparing 5-sulfonylmethyloxazole derivatives under simple and mild conditions by N-sulfonyl propargyl amide, specifically by substituted N-sulfonyl propargyl amide only Under the catalysis of 10mol% organic base, 5-sulfonylmethyloxazole derivatives are generated almost quantitatively. This method allows the synthesis of trisubstituted oxazoles under mild conditions. Whether the substituent is alkyl or aryl, the electron-withdrawing group or the electron-donating group can be well compatible with this reaction.

Description

A method for preparing 5-sulfonylmethyloxazole derivatives

technical field

The invention relates to a method for preparing 5-sulfonylmethyloxazole derivatives from N-sulfonyl propargyl amide derivatives.

Background technique

Oxazoles are a class of important heterocycles, which widely exist in natural products and molecules with physiological activity as important structural units (Document 1: (a) Yeh, V.S.C. Tetrahedron 2004, 60, 11995. (b) Jin, Z .Nat.Prod.Rep.2006,23,464.(c)Wipf,P.Chem.Rev.1995,95,2115.). 5-sulfonylmethyloxazole has been known to selectively inhibit a specific biological link of arthropod insects, and may be used to make the next generation of environmentally friendly insecticides (Document 2: Kumamoto, K.; Miyazaki, H. .Int.Appl.WO2009028727A1, 2009.). However, such compounds lack ready-made preparation methods (Reference 3: Sakamoto, K.; Kondo, Y.; Suginome, T.; Ohba, S.; Yamanaka, H. Synthesis 1992, 552). This synthesis patent provides a convenient and quick method for synthesizing 5-sulfonyloxazole, without metal catalysis, the 5-sulfonylmethyloxazole product can be obtained at room temperature under the condition of oxygen and moisture.

Contents of the invention

The object of the present invention is to provide a new method for synthesizing 5-sulfonylmethyloxazole derivatives.

Reaction equation 1. is synthesized oxazole derivative by propargyl amide

The specific operation steps are as follows (reaction equation 1):

Carry out the reaction in the reactor, add propargyl amide (1) in the air, then add the solvent and 10mol% alkali, and react at room temperature for 7-24 hours; after the reaction, use the rotary evaporator to remove the solvent, solid Dissolved in dichloromethane and applied to silica gel column chromatography to obtain oxazole derivative (2). The yields of substrates with different substituents ranged from 56-99%.

Wherein ^R is phenyl, substituted phenyl, 2-pyridyl, 2-furyl, 4-oxazolyl, and the substituents on the benzene ring can be C1-C6 alkyl, C1-C6 alkoxy, One, or two, or three of F, Cl, Br, I, NO ₂ , OH, NH ₂ , and the number of substituents on the benzene ring of the substituted phenyl group is 1-5.

R ² , R ³ , and R ⁴ are hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, 2-pyridyl, 2-furyl, 4-oxazolyl, and the substituents on the benzene ring can be One, or two, or three of C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br, I, NO ₂ , OH, NH ₂ , substituents on the benzene ring of substituted phenyl The number is 1-5.

The solvents are N,N-dimethylformamide, N,N-dimethylacetamide, anisole, toluene, 1,4-dioxane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, One or both of methanol, acetone, and dichloromethane; the amount of solvent used is 5–20 ml of solvent per millimole of reactant N-sulfonyl propargyl amide derivative (1); react in air, and the temperature is room temperature.

The reaction formula and steps for the synthesis of reactant 3-aza-1,5-enyne 1 are as follows:

Wherein ^R is phenyl, substituted phenyl, 2-pyridyl, 2-furyl, 4-oxazolyl, and the substituents on the benzene ring can be C1-C6 alkyl, C1-C6 alkoxy, One, or two, or three of F, Cl, Br, I, NO ₂ , OH, and NH ₂ .

R ² , R ³ , and R ⁴ are hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, 2-pyridyl, 2-furyl, 4-oxazolyl, and the substituents on the benzene ring can be One, two, or three of C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br, I, NO ₂ , OH, and NH ₂ .

The specific operation steps are as follows:

Carry out the reaction in the reactor, after the reactor is evacuated and replaced with argon, add 40ml of newly steamed THF or dichloromethane or toluene; then add 5mmol of N-sulfonyl-allylamine of formula 3 and 5mmol of NaH; finally add 6mmol Formula 4, stirred at 0°C-room temperature for 1-24 hours; after the reaction, part of the solvent was evaporated until the volume of the solution was 1/4-1/5 of the volume of the solution before evaporation, and the sample was subjected to silica gel column chromatography to obtain the formula 1 N-sulfonylpropargylamide.

The molar ratio of N-sulfonyl-allylamine 3 to alkyne 4 is 1:1-1.5; the reaction is carried out in tetrahydrofuran, dichloromethane, or toluene.

The present invention has the following advantages:

1. The reactant propargyl amide 1 is obtained from cheap and easy-to-obtain raw materials aldehyde, sulfonamide and acid chloride through simple reaction steps, and the raw materials are conveniently prepared.

2. The reaction operation is simple; no transition metal catalyst is used, the environment is friendly, and the yield is high.

3. It is difficult to prepare such trisubstituted oxazole products by other existing synthetic methods.

Detailed ways

In order to understand the present invention better, illustrate by following examples.

Example 1

The reaction was carried out in a reactor. In the air, 0.2 mmol (93 mg) of propargyl amide 1a and DBU (10 mol%, 3 mg) were added to 2 mL of acetonitrile, and the reaction was stirred at room temperature for 7 hours. After the reaction was finished, the solvent was removed under vacuum, and then the sample was dissolved in dichloromethane and loaded for silica gel column chromatography. The eluent was a mixed solvent of sherwood oil: ethyl acetate=20:1 to obtain 91mg of oxazole 2a. The isolated yield was 98%.

The characterization data of compound 1a are as follows:

N-(1,3-diphenylprop-2-ynyl)-N-tosylbenzamide(1a).White solid,52%yield,mp139–140C; ¹ H NMR(400MHz,CDCl ₃ )δ7.75(d,J=7.8 Hz,2H),7.53(d,J=6.7Hz,2H),7.38(dd,J=29.1,10.9Hz,8H),7.28–7.13(m,7H),6.53(s,1H),2.30(s ,3H).; ¹³ C NMR(100MHz,CDCl ₃ )δ171.1,144.8,136.1,136.0,135.1,131.8,131.7,129.3,128.8,128.4,128.2,127.9,122.3,87.4,84.7,54.4,21.5; HRMS( ESI-TOF) m/z: Calcdfor C ₂₉ H ₂₃ NO ₃ SNa(M+Na) ⁺ :488.1296,found:488.1295.

The characterization numbers of compound 2a are as follows:

2,4-Diphenyl-5-(phenyl(tosyl)methyl)oxazole(2a).White solid,91mg,98%yield,mp156-157C; ¹ H NMR(500MHz,CDCl ₃ )δ8.12(ddd,J= 5.6,3.0,1.5Hz,2H),7.70–7.62(m,2H),7.55–7.49(m,3H),7.49–7.35(m,10H),7.13(d,J=8.0Hz,2H),5.70 (s,1H),2.39(s,3H); ¹³ C NMR(126MHz,CDCl ₃ )δ161.9,145.2,142.4,138.5,134.5,131.0,130.9,130.8,130.4,129.5,129.5,129.3,129.0,129.0, 128.8,128.8,127.9,127.1,126.9,68.7,21.8; HRMS(ESI-TOF)m/z: Calcd for C ₂₉ H ₂₃ NO ₃ SNa(M+Na) ⁺ :488.1296,found:488.1288.

Example 2

The reaction was carried out in a reactor, and 0.2 mmol (81 mg) of propargyl amide 1b and DBU (10 mol%, 3 mg) were added to 2 mL of acetonitrile in the air, and the reaction was stirred at room temperature for 7 hours. After the reaction was finished, the solvent was removed under vacuum, and then the sample was dissolved in dichloromethane and loaded for silica gel column chromatography. The eluent was petroleum ether: a mixed solvent of ethyl acetate=20:1 to obtain 72mg of oxazole 2b. The isolated yield was 89%.

The characterization data of compound 1b are as follows:

N-(1,3-Diphenylprop-2-ynyl)-N-tosylacetamide(1b).White crystal,55%yield,mp146-147C; ¹ H NMR(500MHz,CDCl ₃ )δ7.98(d,J=8.4 Hz,2H),7.70(dd,J=8.4,1.0Hz,2H),7.48–7.30(m,10H),7.04(s,1H),2.44(s,3H),2.12(s,3H); ¹³ C NMR (126MHz, CDCl ₃ )δ170.2, 145.0, 137.0, 136.8, 131.9, 129.8, 129.1, 128.9, 128.6, 128.4, 128.3, 127.0, 122.2, 87.5, 84.7, 52.5, 25.7, 21.8; HRMS (ESI-TOF) m/z: Calcd for C ₂₄ H ₂₁ NO ₃ SNa(M+Na) ⁺ :426.1140,found426.1147.

The characterization numbers of compound 2b are as follows:

2-Methyl-4-phenyl-5-(phenyl(tosyl)methyl)oxazole(2b).White solid,72mg,89%yield,mp168-169C; ¹ H NMR(500MHz,CDCl ₃ )δ7.57(dd, J=7.9,1.6Hz,2H),7.41–7.29(m,10H),7.11(d,J=7.9Hz,2H),5.57(s,1H),2.56(s,3H),2.36(s,3H ); ¹³ CNMR (126MHz, CDCl ₃ ) δ162.1, 145.1, 141.1, 138.0, 134.5, 130.9, 130.7, 130.4, 129.5, 129.4, 129.1, 128.9, 128.8, 128.6, 127.7, 68.4, 21.7, 14.3; TOF) m/z: Calcdfor C ₂₄ H ₂₁ NO ₃ SNa(M+Na) ⁺ :426.1140,found426.1136.

Example 3

The reaction was carried out in a reactor, and 0.2 mmol (65 mg) of propargyl amide 1c and DBU (10 mol%, 3 mg) were added to 2 mL of acetonitrile in the air, and the reaction was stirred at room temperature for 7 hours. After the reaction was finished, the solvent was removed under vacuum, and then the sample was dissolved in dichloromethane and loaded for silica gel column chromatography. The eluent was sherwood oil: a mixed solvent of ethyl acetate=20:1 to obtain 53mg of oxazole 2c. The isolated yield was 81%.

The characterization data of compound 1c are as follows:

N-(1,3-Diphenylprop-2-ynyl)-N-(methylsulfonyl)acetamide(1c).White solid,21%yield,mp102-103C; ¹ H NMR(500MHz,CDCl ₃ )δ7.68–7.62( m,2H),7.54(dt,J=4.0,2.3Hz,2H),7.46–7.33(m,6H),6.90(s,1H),3.45(s,3H),2.23(s,3H) ^; C NMR (126MHz, CDCl ₃ ) δ171.9, 136.7, 132.0, 129.3, 129.0, 128.6, 128.4, 126.8, 121.7, 87.8, 84.1, 51.6, 43.0, 25.7; HRMS (ESI-TOF) m/z: Calcd for C ₁₈ H ₁₇ NO ₃ SNa(M+Na) ⁺ :350.0827,found:350.0836.

The characterization numbers of compound 2c are as follows:

2-Methyl-5-(methylsulfonyl(phenyl)methyl)-4-phenyloxazole(2c).White solid,53mg,81%yield,mp168-169C; ¹ H NMR(500MHz,CDCl ₃ )δ7.74–7.67(m ,2H),7.63–7.57(m,2H),7.50–7.43(m,5H),7.40(ddd,J=7.4,3.7,1.3Hz,1H),5.59(s,1H),2.79(s,3H ),2.61(s,3H); ¹³ C NMR(126MHz,CDCl ₃ )δ162.3,141.3,137.7,130.9,130.9,130.1,129.8,129.4,129.1,129.0,127.9,67.3,39.1,14.4; HRMS(ESI- TOF) m/z: Calcd for C ₁₈ H ₁₇ NO ₃ SNa(M+Na) ⁺ :350.0827,found:350.0837.

Biological test application example 1——Test on Spodoptera litura larvae

Solvent: 3 parts by weight dimethylformamide

Emulsifier: 1 part by weight polyoxyethylene alkylphenyl ether

To prepare a suitable active compound preparation, 1 part by weight of the active compound (product prepared in Example 1) is mixed with a solvent containing the above-mentioned amount of emulsifier, and the mixture is diluted with water to a concentration of 50, 100, 200 ppm.

The sweet potato leaves were soaked in the test agent diluted to the specified concentration with water, air-dried, and put into a dish with a diameter of 9 cm. Ten third-instar Spodoptera litura larvae were put into the dish and stored in a room with a constant temperature of 25°C. After 2 and 4 days, more sweet potato leaves were added and after 7 days the number of dead larvae was counted to calculate the mortality. In this experiment, the results of each set of experiments are the average of the results of two dishes.

The compounds of the invention showed a 100% mortality at a concentration of 100 ppm active compound.

Biological Test Application Example 2—Test against Tetranychus urticae (spray test)

Solvent: 3 parts by weight dimethylformamide

Emulsifier: 1 part by weight polyoxyethylene alkylphenyl ether

To prepare a suitable active compound preparation, 1 part by weight of the active compound (product prepared in Example 2) is mixed with a solvent containing the above-mentioned amount of emulsifier, and the mixture is diluted with water to the indicated concentration.

50-100 adults of Tetranychus urticae were inoculated onto leaves of second-leaf stage beans planted in pots with a diameter of 6 cm. After 1 day, a sufficient amount of a diluted aqueous solution of the active compound of the indicated concentration is sprayed with a spray gun. After spraying, the pot was stored at room temperature for 7 days, and the acaricidal rate was calculated.

The compound of the present invention exhibits acaricidal rate greater than 98% at a compound concentration of 100 ppm.

Claims (6)

1. A method for preparing 5-sulfonylmethyloxazole derivatives, characterized in that: The N-sulfonyl propargyl amide derivative (1) shown in the following formula is used as a raw material to generate an oxazole derivative (2), and the reaction formula is as follows: Wherein ^R is phenyl, substituted phenyl, 2-pyridyl, 2-furyl or 4-oxazolyl, and the substituent on the phenyl ring of substituted phenyl is C1-C6 alkyl, C1-C6 alkoxy One, or two, or three of , F, Cl, Br, I, NO ₂ , OH, NH ₂ , the number of substituents on the benzene ring of the substituted phenyl group is 1-5; R ² , R ³ , and R ⁴ are hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, 2-pyridyl, 2-furyl or 4-oxazolyl, and the substituent on the benzene ring of the substituted phenyl is One, or two, or three of C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br, I, NO ₂ , OH, NH ₂ , substituents on the benzene ring of substituted phenyl The number is 1-5. 2. according to the described method of claim 1, it is characterized in that: The solvents are N,N-dimethylformamide, N,N-dimethylacetamide, anisole, toluene, 1,4-dioxane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, One or more of methanol, acetone, and dichloromethane; the amount of solvent used is 5–20 ml of solvent per millimole of reactant N-sulfonyl propargyl amide derivative (1); react in air, temperature for room temperature. 3. according to the described method of claim 1 or 2, it is characterized in that: The specific operation steps are as follows: Carry out the reaction in the reactor, in the air, add N-sulfonyl propargyl amide (1), then add 1-10mol% alkali catalyst and solvent, and react at room temperature for 7 to 24 hours; after the reaction, use a rotary evaporator The solvent was removed, and the solid was dissolved in dichloromethane and subjected to silica gel column chromatography to obtain oxazole (2). 4. according to the described method of claim 1, it is characterized in that: the reaction formula and the steps of synthetic reactant 3-aza-1,5-enyne 1 are as follows: Wherein ^R is phenyl, substituted phenyl, 2-pyridyl, 2-furyl or 4-oxazolyl, and the substituents on the benzene ring can be C1-C6 alkyl, C1-C6 alkoxy, One, or two, or three of F, Cl, Br, I, NO ₂ , OH, NH ₂ , the number of substituents on the benzene ring of the substituted phenyl group is 1-5; R ² , R ³ , R ⁴ are hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, 2-pyridyl, 2-furyl or 4-oxazolyl, and the substituents on the benzene ring can be One, or two, or three of C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br, I, NO ₂ , OH, NH ₂ , substituents on the benzene ring of substituted phenyl The number is 1-5; The specific operation steps are as follows: Carry out the reaction in the reactor, after the reactor is evacuated and replaced with argon, add 40ml of newly steamed THF or dichloromethane or toluene; then add 5mmol of N-sulfonyl-allylamine of formula 3 and 5mmol of NaH; finally add 6mmol Formula 4, stirred at 0°C-room temperature for 1-24 hours; after the reaction, part of the solvent was evaporated until the volume of the solution was 1/4-1/5 of the volume of the solution before evaporation, and the sample was subjected to silica gel column chromatography to obtain the formula 1 N-sulfonylpropargylamide. 5. according to the described method of claim 4, it is characterized in that: The molar ratio of N-sulfonyl-allylamine 3 to alkyne 4 is 1:1-1.5; the reaction is carried out in tetrahydrofuran, dichloromethane, or toluene. 6. according to the described method of claim 1, it is characterized in that: All substrates afforded products in high yields ranging from 56-99%.