A method for synthesizing oxazoline compounds

Abstract

The application discloses a synthesis method of an oxazoline compound. The method is as follows: taking an olefin compound which is cheap and easy to obtain as a starting material, performing amine functionalization on the olefin in the presence of a catalyst, an amination reagent, a base and an additive, and then performing intramolecular cyclization to obtain the oxazoline compound in one step with high selectivity. The method has the characteristics of high atom economy, wide source of raw materials, avoidance of use of anhydrous and oxygen-free operation conditions, simple process and the like, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of an oxazoline compound, which is synthesized through functionalization of an olefin under catalysis of metal iron and further intramolecular cyclization, and belongs to the field of organic synthesis. BACKGROUND

[0002] Oxazoline compounds are widely used in the fields of pharmaceutical chemistry, material science and organic synthesis as nitrogen-containing heterocyclic compounds, and the synthesis method thereof is concerned. The compounds exist in some natural products with biological activity, and optically active oxazolines have been proved to be effective ligands in some asymmetric synthesis reactions. In the process of ring-opening polymerization, the oxazoline compounds can act as monomers, and can also act as a carboxyl protecting group in organic synthesis, so the oxazoline compounds are extremely valuable intermediates in organic synthesis.

[0003] At present, there are several methods for synthesizing oxazoline compounds. The most commonly used synthesis method is N-acyl amino alcohol dehydration cyclization. For acid-insensitive substrates, molybdenum oxide, BF3-Et2O and TsOH can be used as Lewis or Bronsted acid catalysts for the cyclization reaction. In addition, electrophilic reagents such as SOCl2, TsCl, PPh3 / CCl4, Vilsmeier reagent, DAST or Deoxo-Fluorand Burgess reagent are used to activate the hydroxyl group of the amino alcohol. However, the disadvantages of these synthesis methods are that they have poor functional group compatibility, and the reaction temperature and time need to be controlled, and the reaction conditions are harsh.

[0004] In recent years, in the field of synthesis of oxazoline compounds, new synthesis methods with the help of high-valence iodine reagents, amide reagents and electrochemical means have emerged. However, these methods are all based on the direct reaction of amides with olefins to obtain target oxazoline compounds, and there is still some limitation and space for improvement in the innovation of the synthesis path.

[0005] Therefore, it is necessary to develop a method for preparing oxazoline compounds with low cost of raw materials, high atom economy, and fast and high yield. We expect to provide a method for preparing oxazoline, which is simple in operation, can obtain compounds with high yield and high chemical selectivity, has short reaction time, mild reaction conditions and good functional group tolerance. SUMMARY

[0006] The present application provides a synthesis method of oxazoline compounds, which aims at the shortcomings of the existing synthesis route. The present application uses benzene acid-based amination reagent to couple with olefin under the catalysis of iron (II), so that the target product can be obtained in one step without the protection of inert gas. The present application has the advantages of easy-to-obtain raw materials, simple process, mild conditions, high atom economy, and wide substrate range.

[0007] The synthesis method of the oxazoline compounds of the present application is to react olefin as raw material in the presence of a catalyst, a base and an amination reagent, and then to obtain the oxazoline compounds after separation and purification.

[0008] Specifically, the olefin is dissolved in a solvent under an air atmosphere, and is reacted at room temperature in the presence of a catalyst, a base, an additive and an amination reagent. After the reaction is completed, the target product is obtained after separation and purification.

[0009] The structural formula of the olefin is as follows:

[0010] ;

[0011] Among them, R is selected from aryl, heteroaryl, alkyl, alkoxy, or a substituent of the above groups. The substituent includes heteroatom substitution, halogen substitution, etc.

[0012] The reaction temperature of the synthesis method of the present application is 10-40℃, preferably 26℃, and the reaction time is 6-24 h.

[0013] The catalyst is one of ferrous triflate, ferrous acetate, ferrous chloride, ferrous sulfate and iron phthalocyanine, and the addition amount of the catalyst is 1-20 mol% (based on the olefin).

[0014] The base is at least one of sodium ethoxide, potassium phosphate, dipotassium hydrogen phosphate, monopotassium phosphate, potassium methoxide, sodium carbonate and potassium tert-butoxide, and the addition amount is 1.5-3.0 times the equivalent amount (based on the olefin).

[0015] The structural formula of the amination reagent is as follows:

[0016] ;

[0017] Among them, R1 is H, halogen, methoxy, ester group, and OTf is triflate. The addition amount of the amination reagent is 2.0-4.0 times the equivalent amount (based on the olefin).

[0018] The additive is at least one of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N,N'-dicyclohexyl carbodiimide and N,N'-diisopropyl carbodiimide, and the addition amount is 0.3-1.2 times the equivalent amount (based on the olefin).

[0019] The solvent is dichloromethane, ethyl acetate, acetonitrile, 1,2-dichloroethane, 1,2-dibromoethane, tetrahydrofuran or chloroform.

[0020] The separation and purification is adding saturated sodium bicarbonate aqueous solution to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by rotary evaporation, and purifying by column chromatography, wherein the eluent for column chromatography is petroleum ether: ethyl acetate = 5:1 ~ 10:1, v / v, so that the target product can be obtained.

[0021] The reaction route of the present application is as shown below:

[0022]

[0023] The beneficial effects of the present application are embodied in:

[0024] 1、The synthetic method adopted in the present application catalyzes olefins and amination reagents by means of cheap metals, which can construct the target oxazoline compound in a single step. This method has the characteristics of low cost, high atom economy and green environmental protection concept, and shows unique advantages and application potential in the field of chemical synthesis.

[0025] 2、The synthetic method of the present application has wide substrate applicability and can be compatible with various functional groups. Whether it is a single functional group or a complex multi-functional group system, it will not obviously interfere with the reaction, and it is suitable for single-substituted and multi-substituted olefins. DETAILED DESCRIPTION

[0026] In order to further illustrate the characteristics and advantages of the present application, the technical solutions of the present application will be described below in combination with specific examples. However, the following examples are only for further illustrating the present application, but not limiting the present application.

[0027] In the synthesis process of the present application, part of the reaction conditions are optimized and screened as follows:

[0028]

[0029]

[0030] For the above reaction, we take p-tert-butyl styrene (1) and benzoyl amination reagent (2) as model substrates, dichloromethane as solvent, potassium tert-butoxide as base, and ferrous triflate as catalyst, and by adding different additives, the synthesis of target compounds is realized. Through the screening of different additives, only DCC, EDCI and DIC have target products generated, and the yield is 32%, 81% and 49% in turn, and no product is detected under other conditions. Therefore, EDCI is the best additive for the reaction.

[0031]

[0032]

[0033] After the target product was obtained by adding an additive to the reaction system, different types of bases were screened. 1.5 equivalents of potassium tert-butoxide can obtain 81% of the target product. When sodium salt is added to the reaction system, the yield is relatively low, and sodium ethoxide and sodium carbonate can only obtain 23% and 12% of the target product, while potassium salt can obtain a relatively good yield in the reaction system, and potassium phosphate and potassium methoxide can obtain 56% and 67% of the target product, respectively. After screening the potassium salt, potassium tert-butoxide is the best in the reaction system, and can obtain a yield of 81%.

[0034]

[0035]

[0036] Then, the types of solvents were screened. Dichloromethane, ethyl acetate and chloroform can obtain relatively high yields of 81%, 77% and 79%, respectively, but in 1,2-dichloroethane and carbon tetrachloride, the yield is relatively low, only 16% and trace amount of product, and in dimethyl sulfoxide and N,N'-dimethylformamide, only trace amount of product, which indicates that the reaction effect is poor in the large polarity solvent. Since when ethyl acetate is used as a solvent, ester exchange phenomenon will occur with potassium tert-butoxide in the system, so dichloromethane is the best solvent for the reaction.

[0037] The technical scheme of the present application is further illustrated by specific examples.

[0038] Example 1:

[0039]

[0040] A 25 mL Schlenk tube with a stirrer was taken, Fe(OTf)2 (0.04 mmol, 20 mol%) was added to the tube, and then p-tert-butylstyrene (1a) (0.2 mmol) and EDCI (0.1 mmol, 0.5 eq) were added. Finally, benzoyl amine reagent (2a) (0.4 mmol, 2.0 eq) and potassium tert-butoxide (0.3 mmol, 1.5 eq) were added in the glove box, and the reaction was carried out at room temperature for 12 h. After 12 h of reaction, saturated sodium bicarbonate solution and ethyl acetate were used for extraction, the organic phase was combined, dried with anhydrous sodium sulfate, and then concentrated under vacuum. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain yellow oily liquid (3a) (45 mg, 80%).

[0041] The compound's NMR data are as follows: 1 H NMR (CDC13, 400 MHz) δ: 8.03-8.00 (m, 2H), 7.51-7.47 (m, 1H), 7.44-7.39 (m, 4H), 7.31-7.28 (m, 2H), 5.63 (dd, J = 8.1, 10.1Hz, 1H), 4.45 (dd, J= 10.1, 14.8 Hz, 1H), 4.01 (dd, J = 8.0, 14.8 Hz, 1H),1.32 (s, 9H); 13 C NMR (CDC13, 100 MHz) δ: 164.0, 151.4, 137.8, 131.4, 128.3,128.3, 127.6, 125.69, 125.66, 81.0, 62.9, 34.6, 31.3.

[0042] Example 2:

[0043]

[0044] Example 1, except using p-fluorostyrene (1b) instead of p-t- butylstyrene (1a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to give a yellow oily liquid (3b) (32 mg, 66%). The compound's NMR data are as follows: 1 H NMR (CDC13, 400 MHz) δ: 8.02-7.99 (m, 2H), 7.53-7.48 (m,1H), 7.45-7.41 (m, 2H), 7.35-7.30 (m, 2H), 7.09-7.03 (m, 2H), 5.64 (dd, J=7.9, 10.1 Hz, 1H), 4.47 (dd, J= 10.1, 14.8 Hz, 1H), 3.96 (dd, J= 7.8, 14.8Hz, 1H); 13 CNMR (CDC13, 100 MHz) δ: 163.9, 162.6 (d, J= 245 Hz, 1C), 136.8 (d,J= 3.3 Hz, 1C), 131.5, 128.4, 128.2, 127.6 (d, J= 8.2 Hz, 1C), 127.5, 115.7(d, J= 21.6 Hz, 1C), 80.4, 63.1; 19F NMR (CDCl3, 376 MHz) δ: -113.7.

[0045] Example 3:

[0046]

[0047] Example 1, except that p-trifluoromethylstyrene (1c) was used instead of p-tert- butylstyrene (1a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to give yellow oily liquid (3d) (37.8 mg, 65%). The NMR data of this compound are as follows: 1 H NMR (CDCl3, 400 MHz) δ: 8.02-7.99 (m, 2H), 7.52-7.48 (m, 1H), 7.45-7.41 (m, 2H), 7.38-7.35 (m, 2H), 7.12-7.08 (m, 2H), 5.65(dd, J= 7.92, 10.1 Hz, 1H), 4.47 (dd, J= 10.1, 14.8 Hz, 1H), 3.98 (dd, J=7.9, 14.8 Hz, 1H), 2.29 (s, 3H); 13 CNMR (CDCl3, 100 MHz) δ: 169.3, 163.9,150.5, 138.6, 131.4, 128.4, 128.2, 127.5, 126.9, 121.9, 80.4, 63.1, 21.1.

[0048] Example 4:

[0049]

[0050] Example 1, except that p-trifluoromethylstyrene (1c) was used instead of p-tert- butylstyrene (1a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to give yellow oily liquid (3d) (37.8 mg, 65%). The NMR data of this compound are as follows: 1H NMR (CDC13, 400 MHz) δ: 8.04-8.01 (m, 2H), 7.64(d, J = 8.2 Hz, 2H), 7.55-7.50 (m, 1H), 7.47-7.43 (m, 4H), 5.71 (dd, J = 7.8,10.2 Hz, 1H), 4,53 (dd, J = 10.2, 14.8 Hz, 1H), 3.96 (dd, J = 7.7, 14.8 Hz,1H); 13 CNMR (CDC13, 100 MHz) δ: 163.9, 145.10, 145.09, 131.6, 130.5 (q, J= 3.2Hz, 1C), 128.5, 128.3, 127.3, 125.9, 125.8 (q, J= 3.7 Hz, 1C), 123.9 (q, J=270 Hz, 1C), 80.1, 63.2; 19 F NMR (CDC13, 376 MHz) δ: -62.6.

[0051] Example 5:

[0052]

[0053] Example 1 using octene (1e) instead of p-tert-butylstyrene (1a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to give a yellow oily liquid (3e) (20.8 mg, 45%). The NMR data of this compound are: 1 H NMR (CDC13, 600 MHz) δ: 7.94 (dd, J = 8.2, 1.4 Hz, 2H), 7.46(t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 4.75 – 4.65 (m, 1H), 4.11 (dd,J = 14.4, 9.5 Hz, 1H), 3.65 (dd, J = 14.4, 7.5 Hz, 1H), 1.80 – 1.72 (m, 1H),1.66 – 1.59 (m, 1H), 1.52 – 1.46 (m, 1H), 1.41 – 1.29 (m, 7H), 0.89 (t, J =6.8 Hz, 3H); 13C NMR (CDC13, 100 MHz) δ: 164.11, 131.24, 128.17, 128.08, 80.23, 60.01, 35.52, 31.76, 29.16, 25.15, 22.62, 14.10.

[0054] Example 6:

[0055]

[0056] Example 1, except that p-methoxybenzamidating reagent (2c) was used instead of benzamidating reagent (2a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to give yellow oily liquid (3g) (50 mg, 81%). The NMR data of this compound are: 1 H NMR (CDC13, 600 MHz) δ: 7.94 (d, J = 8.3 Hz, 2H), 7.40 (dd, J = 8.3, 5.9 Hz, 4H), 7.28 (d, J = 8.1 Hz, 2H), 5.63 (dd, J = 10.1, 8.0 Hz, 1H), 4.44 (dd, J = 14.9, 10.1 Hz, 1H), 4.01 (dd, J = 14.9, 8.1 Hz, 1H), 1.32 (s, 9H); 13 C NMR (CDC13, 100 MHz) δ: 163.18, 151.61, 137.71, 137.63, 129.70, 128.75, 126.30, 125.84, 125.77, 81.34, 34.68, 31.36.

[0057] Example 7:

[0058]

[0059] Example 1, except that p-methoxybenzamidating reagent (2c) was used instead of benzamidating reagent (2a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to give yellow oily liquid (3g) (50 mg, 81%). The NMR data of this compound are: 1H NMR (CDC13, 600 MHz) δ: 7.96 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.66 - 5.57 (m, 1H), 3.99 (dd, J = 14.6, 8.0 Hz, 1H), 3.85 (s, 3H), 1.32 (s, 9H); 13 C NMR (CDC13, 100 MHz) δ: 163.89, 162.18, 151.41, 138.08, 130.09, 125.77, 125.76, 120.25, 113.78, 81.00, 62.97, 55.41, 34.66, 31.36.

[0060] Example 8:

[0061]

[0062] Example 1 using p-methoxybenzoyl amidating reagent (2d) instead of benzoyl amidating reagent (2a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, V / V) to give yellow oily liquid (3h) (50.6 mg, 75%). The NMR data of this compound are: 1 H NMR (CDC13, 600 MHz) δ: 8.08 (d, J = 2.6 Hz, 4H), 7.41 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.66 (dd, J = 10.1, 8.2 Hz, 1H), 4.48 (dd, J = 15.1, 10.1 Hz, 1H), 4.05 (dd, J = 15.1, 8.2 Hz, 1H), 3.94 (s, 3H), 1.32 (s, 9H); 13 C NMR (CDC13, 100 MHz) δ: 166.52, 163.29, 151.66, 137.59, 132.56, 131.78, 129.65, 128.33, 125.85, 125.79, 81.42, 63.10, 52.39, 34.68, 31.34.

[0063] Example 9:

[0064]

[0065] Example 1 using p-methoxybenzamidating reagent (2) instead of benzamidating reagent (2a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, V / V) to give yellow oily liquid (3i) (41 mg, 72%). The NMR data of this compound are: 1 H NMR (CDC13, 600 MHz) δ: 8.08 (d, J = 2.6 Hz, 4H), 7.41 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.66 (dd, J = 10.1, 8.2 Hz, 1H), 4.48 (dd, J = 15.1, 10.1 Hz, 1H), 4.05 (dd, J = 15.1, 8.2 Hz, 1H), 3.94 (s, 3H), 1.32 (s, 9H); 13 C NMR (CDC13, 100 MHz) δ: 166.52, 163.29, 151.66, 137.59, 132.56, 131.78, 129.65, 128.33, 125.85, 125.79, 81.42, 63.10, 52.39, 34.68, 31.34.

Claims

1.A method for synthesizing oxazoline compounds, the method comprising: reacting an olefin in a solvent under an air atmosphere in the presence of a catalyst, a base, an additive, and an amination reagent at room temperature, and separating and purifying the reaction product to obtain an oxazoline compound; wherein the olefin has the following structure: wherein R is selected from an aryl group, a heteroaryl group, an alkyl group, or an alkoxy group; the catalyst is one of ferrous triflate, ferrous acetate, ferrous chloride, ferrous sulfate, and iron phthalocyanine; the additive is at least one of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-dicyclohexyl carbodiimide, and N, N'-diisopropyl carbodiimide; and the amination reagent has the following structure: wherein R1 is H, halogen, or methoxy, and OTf is triflate. 2.The method of claim 1, wherein: the catalyst is added in an amount of 1 mol% to 20 mol% based on the olefin. 3.The method of claim 1, wherein: the base is at least one of sodium ethoxide, potassium phosphate, dipotassium hydrogen phosphate, monopotassium phosphate, potassium methoxide, sodium carbonate, and potassium tert-butoxide, and is added in an amount of 1.5 to 3.0 equivalents based on the olefin. ； 4.The method of claim 1, wherein: the additive is added in an amount of 0.3 to 1.2 equivalents based on the olefin. 5.The method of claim 1, wherein: the solvent is dichloromethane, ethyl acetate, acetonitrile, 1, 2-dichloroethane, 1, 2-dibromoethane, tetrahydrofuran, or chloroform. 6.The method of claim 1, wherein: the reaction temperature is 10℃ to 40℃, and the reaction time is 6 to 24 hours. 7.The method of claim 1, wherein: the separation and purification is performed by adding saturated sodium bicarbonate aqueous solution to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and purifying by column chromatography. ； 8.The method of claim 7, wherein: the eluent used in the column chromatography is petroleum ether: ethyl acetate = 5: 1 to 10: 1, v / v. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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