Synthesis method of oxazoline compound

Abstract

The invention discloses a synthesis method of an oxazoline compound, which comprises the following steps: by taking a cheap and easily available olefin compound as an initial raw material, carrying out amination functionalization on olefin in the presence of a catalyst, an amination reagent, alkali and an additive, and then carrying out intramolecular cyclization to obtain the oxazoline compound in one step with high selectivity. The method has the characteristics of high atom economy, wide raw material sources, avoidance of use of anhydrous and anaerobic operation conditions, simple process and the like, and is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing oxazoline compounds, which belongs to the field of organic synthesis and realizes the synthesis of oxazoline compounds by functionalizing olefins under the catalysis of metallic iron and further performing intramolecular cyclization. Background Art

[0002] Oxazoline compounds, as nitrogen-containing heterocyclic compounds, are widely used in the fields of medicinal chemistry, materials science, organic synthesis, etc., and their synthesis methods have attracted much attention. This type of compound exists in some natural products with biological activity, among which optically active oxazolines have been proven to be effective ligands in some asymmetric synthesis reactions. At the same time, in the process of ring-opening polymerization, oxazoline compounds can act as monomers, and can also serve as carboxyl protecting groups in organic synthesis, so it is a very valuable intermediate in organic synthesis.

[0003] Several methods for synthesizing oxazoline compounds are currently available. The most commonly used synthetic method is the dehydration cyclization of N-acylamino alcohols. 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 amino alcohols. However, the shortcoming of these synthetic methods is that their functional group compatibility is bad, and the reaction temperature and time must be controlled at all times, and the reaction conditions are harsh.

[0004] In recent years, in the field of synthetic research on oxazoline compounds, new synthetic methods using high-valent iodine reagents, amide reagents and electrochemical methods have emerged one after another. However, these methods are all based on the direct reaction of amides and alkenes to obtain the target oxazoline compounds, and there are still certain limitations and room for improvement in the innovative expansion of synthetic routes.

[0005] Therefore, it is necessary to develop a method for preparing oxazoline compounds with low raw materials, high atom economy, and rapid and high yield. We hope to provide a method for preparing oxazoline, which is simple to operate, can obtain compounds with high yield and high chemical selectivity, and has a short reaction time, mild conditions, and the process exhibits good functional group tolerance. Summary of the invention

[0006] The present invention aims at the shortcomings of the existing synthetic route and provides a method for synthesizing oxazoline compounds. The present invention uses a benzoic acid-based amination reagent to couple with an olefin under the catalysis of iron (II) to obtain the target product in one step, and does not require inert gas protection, and has the advantages of easy raw material availability, simple process, mild conditions, high atom economy, and a wide range of substrates.

[0007] The synthesis method of the oxazoline compound of the present invention is to use olefin as raw material, react in the presence of a catalyst, a base and an aminating agent, and obtain the oxazoline compound after separation and purification.

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

[0009] The structural formula of the olefin is:

[0010] ;

[0011] Wherein: R is selected from aryl, heteroaryl, alkyl, alkoxy, or a substituent of the above groups, including heteroatom substitution, halogen substitution, etc.

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

[0013] The catalyst is one of ferrous trifluoromethanesulfonate, ferrous acetate, ferrous chloride, ferrous sulfate and iron phthalocyanine, and the added amount of the catalyst is 1 mol%-20 mol% (calculated as olefin).

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

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

[0016] ;

[0017] Wherein: R1 is H, halogen, methoxy, ester group, OTf is trifluoromethanesulfonate. The amount of the amination reagent added is 2.0-4.0 times equivalent (calculated as olefin).

[0018] The additive is at least one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide and N,N'-diisopropylcarbodiimide, and the additive amount is 0.3-1.2 times the equivalent (calculated as olefin).

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

[0020] The separation and purification is to add a saturated sodium bicarbonate aqueous solution to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and finally remove the solvent by rotary evaporation, and separate and purify by column chromatography, wherein the eluent during the column chromatography separation and purification is petroleum ether: ethyl acetate = 5:1 ~ 10:1, v / v, to obtain the target product.

[0021] The reaction scheme of the present invention is as follows:

[0022]

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

[0024] 1. The synthesis method adopted by the present invention uses cheap metals to catalyze olefins and amination reagents, and can construct the target oxazoline compounds in a single step. This method has the remarkable characteristics of low cost, high atom economy and conformity with the concept of green environmental protection, showing unique advantages and application potential in the field of chemical synthesis.

[0025] 2. The synthetic method of the present invention has a wide range of substrate applicability and is compatible with a variety of functional groups. Whether it is a single functional group or a complex multi-functional group system, it will not significantly interfere with the reaction, and is applicable to mono-substituted and multi-substituted olefins. DETAILED DESCRIPTION

[0026] To further illustrate the features and advantages of the present invention, the technical solution of the present invention is described below in conjunction with specific embodiments. However, the following embodiments are only for further illustrating the present invention, rather than limiting the present invention.

[0027] During the synthesis process of the present invention, some reaction conditions were optimized and screened as follows:

[0028]

[0029]

[0030] For the above reaction, we used p-tert-butylstyrene (1) and benzoyl amination reagent (2) as model substrates, dichloromethane as solvent, potassium tert-butoxide as base, ferrous trifluoromethanesulfonate as catalyst, and added different additives to achieve the synthesis of the target compound. Through the screening of different additives, only three structures, DCC, EDCI and DIC, produced the target product, with yields of 32%, 81% and 49% respectively, while no product was detected under the other conditions. Therefore, EDCI is the best additive for this reaction.

[0031]

[0032]

[0033] After adding additives to the reaction system to obtain the target product, different types of bases were screened. 1.5 times the equivalent of potassium tert-butoxide can obtain 81% of the target product. When sodium salts were added to the reaction system, the yields were low. Sodium ethoxide and sodium carbonate could only obtain 23% and 12% of the target product, while potassium salts could obtain a better yield in the reaction system. Potassium phosphate and potassium methoxide could obtain 56% and 67% of the target product, respectively. In summary, after screening potassium salts, potassium tert-butoxide was the best in the reaction system, and a yield of 81% could be obtained.

[0034]

[0035]

[0036] Next, we screened the types of solvents. Dichloromethane, ethyl acetate, and chloroform gave high yields of 81%, 77%, and 79%, respectively, but the yields were lower in 1,2-dichloroethane and carbon tetrachloride, only 16% and trace products, and only trace products in dimethyl sulfoxide and N,N'-dimethylformamide, indicating that the reaction effect in highly polar solvents was very poor. Since ethyl acetate would undergo ester exchange with potassium tert-butoxide in the system when used as a solvent, dichloromethane was the optimal solvent for this reaction.

[0037] The technical solution of the present invention is further described below through specific embodiments.

[0038] Embodiment 1:

[0039]

[0040] Take a 25 mL Schlenk tube with a stirrer, add Fe(OTf)2 (0.04 mmol, 20mol%), p-tert-butylstyrene (1a) (0.2 mmol) and EDCI (0.1 mmol, 0.5 eq) in the tube, and finally add benzoyl amination reagent (2a) (0.4 mmol, 2.0 eq) and potassium tert-butoxide (0.3 mmol, 1.5 eq) in a glove box, and react at room temperature for 12 h. After reacting for 12 h, extract with saturated sodium bicarbonate solution and ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and then concentrate in vacuo. The product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3a) (45 mg, 80%).

[0041] The NMR data of this compound are: 1 H NMR (CDCl3, 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 (CDCl3, 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] Embodiment 2:

[0043]

[0044] p-Fluorostyrene (1b) was used to replace p-tert-butylstyrene (1a), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3b) (32 mg, 66%). The NMR data of the compound are: 1 H NMR (CDCl3, 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 (CDCl3, 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] Embodiment 3:

[0046]

[0047] p-Acetoxystyrene (1c) was used to replace p-tert-butylstyrene (1a), and the other conditions were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3c) (26.4 mg, 47%). The NMR data of the compound are: 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] Embodiment 4:

[0049]

[0050] 4-Trifluoromethylstyrene (1c) was used to replace 4-tert-butylstyrene (1a), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3d) (37.8 mg, 65%). The NMR data of the compound are: 1H NMR (CDCl3, 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 (CDCl3, 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 (CDCl3, 376 MHz) δ: -62.6.

[0051] Embodiment 5:

[0052]

[0053] p-Octene (1e) was used to replace p-tert-butylstyrene (1a), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3e) (20.8 mg, 45%). The NMR data of the compound are: 1 H NMR (CDCl3, 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 (CDCl3, 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] Embodiment 6:

[0055]

[0056] The benzoyl amination reagent (2a) was replaced by p-chlorobenzoyl amination reagent (2b), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3f) (50.7 mg, 81%). The NMR data of the compound are: 1 H NMR (CDCl3, 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, 8.1Hz, 1H), 1.32 (s, 9H); 13 C NMR (CDCl3, 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] Embodiment 7:

[0058]

[0059] The benzoyl amination reagent (2a) was replaced by p-methoxybenzoyl amination reagent (2c), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, V / V) to obtain a yellow oily liquid (3 g) (50 mg, 81%). The NMR data of the compound are: 1H NMR (CDCl3, 600 MHz) δ: 7.96 (d, J = 8.7Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.8Hz, 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 (CDCl3, 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] Embodiment 8:

[0061]

[0062] The benzoyl amination reagent (2a) was replaced by p-methoxybenzoyl amination reagent (2d), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, V / V) to obtain a yellow oily liquid (3h) (50.6 mg, 75%). The NMR data of the compound are: 1 H NMR (CDCl3, 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 (CDCl3, 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] Embodiment 9:

[0064]

[0065] The p-methoxybenzoyl amination reagent (2) was used to replace the benzoyl amination reagent (2a), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, V / V) to obtain a yellow oily liquid (3i) (41 mg, 72%). The NMR data of the compound are: 1 H NMR (CDCl3, 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 (CDCl3, 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 an oxazoline compound, characterized in that: The olefin is dissolved in a solvent under air atmosphere, and reacted at room temperature in the presence of a catalyst, a base, an additive and an amination agent, and after the reaction is completed, the oxazoline compound is separated and purified to obtain the oxazoline compound; The structural formula of the olefin is: ； Wherein: R is selected from aryl, heteroaryl, alkyl, alkoxy, or a substituent of the above groups.

2. The synthesis method according to claim 1, characterized in that: The catalyst is one of ferrous trifluoromethanesulfonate, ferrous acetate, ferrous chloride, ferrous sulfate and iron phthalocyanine, and the added amount of the catalyst is 1 mol%-20 mol%.

3. The synthesis method according to claim 1, characterized in that: The base is at least one of sodium ethoxide, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium methoxide, sodium carbonate, and potassium tert-butoxide, and the added amount is 1.5-3.0 times the equivalent.

4. The synthesis method according to claim 1, characterized in that: The structural formula of the amination reagent is: ； Wherein: R1 is H, halogen, methoxy, ester group, and OTf is trifluoromethanesulfonate.

5. The synthesis method according to claim 1, characterized in that: The additive is at least one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide and N,N'-diisopropylcarbodiimide, and the additive amount is 0.3-1.2 times the equivalent.

6. The synthesis method according to claim 1, characterized in that: The solvent is dichloromethane, ethyl acetate, acetonitrile, 1,2-dichloroethane, 1,2-dibromoethane, tetrahydrofuran or chloroform.

7. The synthesis method according to claim 1, characterized in that: The reaction temperature is 10℃~40℃, and the reaction time is 6-24 h.

8. The synthesis method according to claim 1, characterized in that: The separation and purification is to add saturated sodium bicarbonate aqueous solution to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, separate and purify by column chromatography, and obtain the target product.

9. The synthesis method according to claim 8, characterized in that: The eluent for column chromatography separation and purification is petroleum ether:ethyl acetate = 5:1 ~ 10:1, v / v.

Images