Synthesis method of unprotected 1, 2-amino ester and oxazoline derivative

Abstract

The invention discloses a synthesis method of unprotected 1, 2-amino ester and oxazoline derivatives, which comprises the following steps: by taking aryl olefin as a raw material, carrying out selective oxidative amination on the aryl olefin in the presence of an amination reagent, an iron catalyst and alkali to obtain an unprotected 1, 2-amino ester compound; or aryl olefin is used as a raw material, and the oxazoline derivative is obtained through a one-pot two-step method in the presence of an amination reagent, an iron catalyst, alkali and acid. The method has the advantages of high efficiency, mild reaction conditions, convenience in operation, short reaction time, few byproducts and the like, and is suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing unprotected 1,2-amino ester and oxazoline derivatives. Background Art

[0002] As an important synthetic intermediate, 1,2-amino esters play a pivotal role in medicinal chemistry, materials science, and the synthesis of natural products. Similarly, as a five-membered heterocyclic compound, the oxazoline ring is widely used in the development of new drugs and functional materials due to its unique electronic properties and biological activity. For example, the oxazoline structure is an important component of the drug molecules Deflazacort and Tucatinib. At the same time, the oxazoline ring is also a chiral ligand widely used in the field of asymmetric synthesis and plays an important role in asymmetric catalytic transformations.

[0003] 1,2-amino esters are converted from 1,2-amino alcohols by chemical synthesis, which usually involves the use of suitable acylating agents to acylate 1,2-amino alcohols, thereby introducing ester groups into the molecule. However, this often requires the protection of the amino group first, and then the acylation of the hydroxyl group. Therefore, the synthesis of 1,2-amino ester compounds usually requires multiple steps, especially the synthesis of unprotected 1,2-amino ester compounds is particularly cumbersome. As for oxazoline, in general, the common synthesis methods of oxazoline include the reaction of carboxylic acid and its ester with β-amino alcohol, and the cyclization and dehydration reaction of β-hydroxyamide. For example, using carboxylic acid or carboxylic acid ester and chiral amino alcohol as raw materials, β-hydroxyamide is generated as an intermediate, and then intramolecular cyclization is performed to synthesize oxazoline compounds. However, these traditional synthesis methods usually require multiple steps, use excess reagents, produce difficult-to-handle byproducts, and have poor functional group compatibility. Therefore, developing a synthetic method with a wide source of raw materials, high atom economy, and good functional group compatibility to selectively, quickly and efficiently prepare unprotected 1,2-amino esters and oxazoline compounds remains one of the important issues facing synthetic chemistry. Summary of the invention

[0004] The present invention aims at the shortcomings of the existing synthetic routes and provides a method for synthesizing unprotected 1,2-amino esters and oxazoline derivatives. The present invention uses an iron catalyst and in the presence of an aminating agent to selectively oxidize an olefin and perform a cyclization reaction to generate unprotected 1,2-amino esters and oxazoline derivatives, respectively. The method of the present invention has the advantages of easy availability of raw materials, simple process, mild conditions, high yield, wide substrate range, and less by-products.

[0005] The method for synthesizing unprotected 1,2-amino esters of the present invention uses aromatic olefins as raw materials, performs reactions in the presence of an amination agent, an iron catalyst and a base, and obtains unprotected 1,2-amino ester compounds after separation and purification.

[0006] Specifically, the aromatic olefin is dissolved in a solvent under an air atmosphere, and reacted at room temperature in the presence of an amination reagent, an iron catalyst and a base. After the reaction, the unprotected 1,2-amino ester compound is separated and purified.

[0007] The structural formula of the aromatic olefin is shown below:

[0008] ;

[0009] Wherein: R1 is selected from alkyl, alkoxy, ester, halogen and other substituent groups.

[0010] For example: R1 is a substituent group such as tert-butyl group, acetoxy group or Br atom.

[0011] The reaction temperature of the synthesis method of the present invention is 10°C-40°C, preferably 28°C; the reaction time is 6-12 h, preferably 12 h.

[0012] The iron catalyst is selected from ferrous trifluoromethanesulfonate, ferrous acetate, ferrous sulfate, ferrous chloride or ferrous acetylacetonate, and the amount of the iron catalyst is 1 mol%-20 mol% (calculated on olefin).

[0013] The base is at least one of potassium fluoride, potassium carbonate, sodium carbonate and potassium phosphate, and the added amount is 1-5 times the equivalent (calculated as olefin).

[0014] The structural formula of the amination reagent is shown below:

[0015] ;

[0016] Wherein: R2 is a substituent group such as a hydrogen atom, a halogen, an alkoxy group (such as a methoxy group), an ester group, etc., - OTf is trifluoromethanesulfonate. The amount of the amination reagent added is 2.0-3.0 times equivalent (calculated as olefin).

[0017] The solvent is dichloromethane, ethyl acetate, 1,2-dichloroethane, chloroform or acetone.

[0018] The synthesis method of the unprotected 1,2-amino ester of the present invention, the synthesis route is as follows:

[0019] .

[0020] The synthesis method of the oxazoline derivative of the present invention uses aromatic olefin as raw material, performs reaction in the presence of an amination reagent, an iron catalyst, a base and an acid through a one-pot two-step method, and obtains the oxazoline derivative after separation and purification.

[0021] Specifically, the aromatic olefin is dissolved in a solvent under an air atmosphere, and the first step reaction is carried out at room temperature in the presence of an amination reagent, an iron catalyst and a base. After the reaction is completed, no post-treatment is required, and an acid is added to the system to carry out the second step reaction. After the reaction is completed, the oxazoline derivative is separated and purified to obtain the oxazoline derivative.

[0022] The structural formula of the aromatic olefin is shown below:

[0023] ;

[0024] Wherein: R1 is selected from alkyl, alkoxy, ester, halogen and other substituent groups.

[0025] For example: R1 is a substituent group such as tert-butyl group, acetoxy group or Br atom.

[0026] The reaction temperature of the synthesis method of the present invention is 10°C-40°C, preferably 28°C.

[0027] The reaction time of the first step reaction is 6-12 h, preferably 12 h; the reaction time of the second step reaction is 12 h.

[0028] The iron catalyst is selected from ferrous trifluoromethanesulfonate, ferrous acetate, ferrous sulfate, ferrous chloride or ferrous acetylacetonate, and the amount of the iron catalyst is 1 mol%-20 mol% (calculated on olefin).

[0029] The base is at least one of potassium fluoride, potassium carbonate, sodium carbonate and potassium phosphate, and the added amount is 1-5 times the equivalent (calculated as olefin).

[0030] The structural formula of the amination reagent is shown below:

[0031] ;

[0032] Wherein: R2 is a substituent group such as a hydrogen atom, a halogen, an alkoxy group (such as a methoxy group), an ester group, etc., - OTf is trifluoromethanesulfonate. The amount of the amination reagent added is 2.0-3.0 times equivalent (calculated as olefin).

[0033] The acid is a strong acid such as trifluoromethanesulfonic acid, hydrochloric acid or hypochlorous acid, and the amount used is 1-5 eq (calculated as olefin).

[0034] The solvent is dichloromethane, ethyl acetate, 1,2-dichloroethane, chloroform or acetone.

[0035] 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 to obtain the target product. The eluent for column chromatography separation and purification of non-protected 1,2-amino ester is petroleum ether: ethyl acetate = 2: 1, v / v; the eluent for column chromatography separation and purification of oxazoline derivatives is petroleum ether: ethyl acetate = 10: 1, v / v.

[0036] The synthetic method of the oxazoline derivative of the present invention, the synthetic route is as follows:

[0037]

[0038] The beneficial effects of the present invention are embodied in:

[0039] 1. The synthesis method of the present invention uses iron to catalyze the oxidative amination and cyclization reactions of aromatic olefins, and has the characteristics of low price, low toxicity, and green environmental protection.

[0040] 2. The synthesis method of the present invention has wide substrate applicability, high atom utilization rate, is compatible with a variety of functional groups, and is suitable for aromatic halides with a variety of substituents. DETAILED DESCRIPTION

[0041] 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.

[0042] During the synthesis process of the present invention, some reaction conditions were optimized and screened as follows:

[0043]

[0044]

[0045] For the above reaction, we used tert-butylstyrene (1a) and benzoylhydroxylamine amination reagent (2a) as model substrates, ferrous trifluoromethanesulfonate as catalyst, potassium carbonate as base, 1,10-phenanthroline as ligand, and used different solvents to achieve the synthesis of the target compound. Through the screening of different solvents, it was found that dichloromethane had the best reaction effect when used as solvent. Therefore, dichloromethane is the best solvent for this reaction.

[0046]

[0047]

[0048] For the above reaction, we used tert-butylstyrene (1a) and benzoylhydroxylamine amination reagent (2a) as model substrates, dichloromethane as solvent, ferrous trifluoromethanesulfonate as catalyst and 1,10-phenanthroline as ligand, and added different bases to achieve the synthesis of the target compound. Through the screening of different types of bases, potassium carbonate was found to have the best reaction effect when used as the base.

[0049]

[0050]

[0051] For the above reaction, we used tert-butylstyrene (1a) and benzoylhydroxylamine amination reagent (2a) as model substrates, dichloromethane as solvent, potassium carbonate as base, 1,10-phenanthroline as ligand, and added different metal catalysts to achieve the synthesis of the target compound. Through the screening of different catalysts, it was found that ferrous trifluoromethanesulfonate had the best reaction effect when used as a catalyst, so ferrous trifluoromethanesulfonate was the best catalyst for this reaction.

[0052]

[0053]

[0054] For the above reaction, we used tert-butylstyrene (1a) and benzoylhydroxylamine amination reagent (2a) as model substrates, ferrous trifluoromethanesulfonate as catalyst, dichloromethane as solvent, potassium carbonate as base, 1,10-phenanthroline as ligand to complete the first step of the reaction, and then added different acid additives to achieve the synthesis of the target compound. Through the screening of different types of acids, trifluoromethanesulfonic acid as an additive has the best reaction effect, so it is the best acid additive for this reaction.

[0055] The technical solution of the present invention is further described below through specific embodiments.

[0056] Embodiment 1:

[0057]

[0058] In a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, add the raw material 4-tert-butylstyrene (1a) (0.2 mmol), benzoylhydroxylamine amination reagent (2a) (0.5 mmol, 2.5 eq), potassium carbonate (0.4 mmol, 2 eq), ferrous trifluoromethanesulfonate catalyst (0.04 mmol, 20 mol%) and ligand 1,10-phenanthroline (0.04 mmol, 20 mol%). Add dichloromethane solvent (2 ml) under air atmosphere, fix the reaction tube on the stirrer, react at room temperature for 6-12 hours, extract with water 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 = 2:1) to obtain a white solid (3a) (47 mg, 80%). The NMR data of this compound are: 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.0 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.45 – 7.37 (m, 4H), 7.33 (d, J = 8.3 Hz, 2H), 6.69 (s, 1H), 4.92 (dd, J =8.2, 3.4 Hz, 1H), 3.91 (ddd, J = 14.0, 7.1, 3.4 Hz, 1H), 3.51 (ddd, J = 14.1,8.2, 4.7 Hz, 1H), 2.92 (s, 1H), 1.32 (s, 9H); 13 C NMR (101 MHz, Chloroform-d) δ168.58, 151.02, 138.74, 134.16, 131.69, 128.62, 127.03, 125.64, 125.55,73.55, 47.70, 34.59, 31.36.

[0059]

[0060] In a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, the raw material 4-tert-butylstyrene (1a) (0.2 mmol), benzoylhydroxylamine amination reagent (2a) (0.5 mmol, 2.5 eq), potassium carbonate (0.4 mmol, 2 eq), ferrous trifluoromethanesulfonate catalyst (0.04 mmol, 20 mol%) and ligand 1,10-phenanthroline (0.04 mmol, 20 mol%) were added. Dichloromethane solvent (2 ml) was added under air atmosphere, and the reaction tube was fixed on a stirrer. After reacting at room temperature for 6-12 hours, trifluoromethanesulfonic acid (0.4 mmol, 2.0 eq) was added to the reaction solution. After stirring at room temperature overnight, the reaction solution was extracted with water and ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow oily liquid (4a) (42 mg, 76%). The NMR data of the compound are: 1 H NMR (400 MHz, Chloroform-d) 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, 10.1 Hz, 1H), 4.45 (dd, J= 10.1, 14.8Hz, 1H), 4.01 (dd, J= 8.0, 14.8 Hz, 1H), 1.32 (s, 9H); 13 C NMR (100 MHz, Chloroform-d) 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.

[0061] Embodiment 2:

[0062]

[0063] Naphthylene (1b) 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 = 2:1) to obtain a light pink solid (3b) (35 mg, 60%). The NMR data of the compound are: 1HNMR (400 MHz, DMSO-d6) δ 8.57 (t, J = 5.7 Hz, 1H), 7.89 (d, J = 8.5 Hz, 4H), 7.83 (d, J = 7.4 Hz, 2H), 7.57 – 7.42 (m, 6H), 5.68 (d, J = 4.3 Hz, 1H), 4.96(dt, J = 8.7, 4.9 Hz, 1H), 3.69 – 3.53 (m, 1H), 3.49 – 3.38 (m, 1H). 13 C NMR(101 MHz, DMSO-d6) δ 166.99, 141.82, 134.97, 133.26, 132.85, 131.60, 128.71,128.22, 128.02, 127.97, 127.66, 126.50, 126.09, 125.10, 124.88, 71.77, 48.00.

[0064]

[0065] Naphthylene (1b) 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) to obtain a yellow oily liquid (4b) (30 mg, 55%). The NMR data of the compound are: 1 H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 8.0 Hz, 2H), 7.94 – 7.80 (m,4H), 7.58 – 7.40 (m, 6H), 5.84 (dd, J = 10.2, 8.0 Hz, 1H), 4.56 (dd, J =14.8, 10.2 Hz, 1H), 4.09 (dd, J = 14.8, 7.8 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 164.21, 138.24, 133.26, 133.19, 131.58, 129.06, 128.52,128.42, 128.06, 127.82, 127.66, 126.54, 126.36, 124.98, 123.39, 81.34, 63.15.

[0066] Embodiment 3:

[0067]

[0068] 4-Acetoxystyrene (1c) was used to replace 4-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 = 1:1) to obtain a light yellow solid (3c) (39 mg, 68%). The NMR data of the compound are: 1 H NMR (600 MHz, DMSO-d6) δ 8.53 (t, J = 5.7 Hz, 1H), 7.84 (d, J =7.0 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.40 (d, J =8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 5.57 (d, J = 4.4 Hz, 1H), 4.80 (dt, J= 7.8, 4.7 Hz, 1H), 3.49 (ddd, J = 13.2, 6.1, 4.9 Hz, 1H), 3.37 – 3.31 (m,1H), 2.26 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.77, 166.96, 149.91, 141.71,134.93, 131.60, 128.71, 127.66, 127.49, 121.86, 71.12, 48.00, 21.31.

[0069]

[0070] 4-Acetoxystyrene (1c) was used to replace 4-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 = 5:1) to obtain a yellow oily liquid (4c) (37 mg, 65%). The NMR data of the compound are: 1H NMR (400 MHz, Chloroform-d) 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, 14.8Hz, 1H), 2.29 (s, 3H); 13 CNMR (100 MHz, Chloroform-d) 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.

[0071] Embodiment 4:

[0072]

[0073] 3-Bromostyrene (1d) was used to replace 4-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 = 2:1) to obtain a white solid (3d) (33 mg, 52%). The NMR data of the compound are: 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.2 Hz, 2H), 7.59 (s, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 3H), 7.34 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 4.96 (dd, J = 7.7, 3.1 Hz, 1H), 3.91 (ddd, J = 14.3, 6.9, 3.1 Hz, 1H), 3.51 (ddd, J = 13.6, 7.7, 5.1 Hz, 1H). 13CNMR (101 MHz, Chloroform-d) δ 169.09, 144.36, 133.79, 131.92, 131.00, 130.19,129.01, 128.71, 127.01, 124.52, 122.78, 73.42, 48.03.

[0074]

[0075] 3-Bromostyrene (1d) was used to replace 4-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) to obtain a yellow oily liquid (4d) (30 mg, 50%). The NMR data of the compound are: 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 8.0 Hz, 2H), 7.54 (d, J= 7.7 Hz, 2H), 7.48 (t, J = 7.6 Hz, 3H), 7.30 (d, J = 14.6 Hz, 2H), 5.65 (dd,J = 10.2, 7.9 Hz, 1H), 4.52 (dd, J = 14.9, 10.2 Hz, 1H), 4.00 (dd, J = 14.8,7.8 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 163.93, 143.44, 131.66, 131.40,130.50, 128.77, 128.53, 128.38, 127.41, 124.28, 122.96, 80.11, 63.25.

[0076] Embodiment 5:

[0077]

[0078] The benzoylhydroxylamine amination reagent (2a) was replaced by 4-methoxy-benzoylhydroxylamine amination reagent (2b), 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 = 2:1) to obtain a white solid (3e) (51 mg, 79%). The NMR data of the compound are: 1H NMR (400 MHz, DMSO-d6) δ 8.39 (t, J = 5.6 Hz,1H), 7.84 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz,2H), 6.99 (d, J = 8.7 Hz, 2H), 5.43 (d, J = 4.2 Hz, 1H), 4.74 (dt, J = 8.5,4.5 Hz, 1H), 3.80 (s, 3H), 3.51 – 3.40 (m, 1H), 3.33 – 3.22 (m, 1H), 1.27 (s,9H). 13 C NMR (101 MHz, DMSO-d6) δ 166.40, 161.94, 149.76, 141.39, 129.51,127.22, 126.17, 125.24, 113.88, 71.48, 55.78, 48.18, 34.65, 31.67.

[0079]

[0080] The benzoylhydroxylamine amination reagent (2a) was replaced by 4-methoxy-benzoylhydroxylamine amination reagent (2b), 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) to obtain a yellow oily liquid (4e) (42 mg, 68%). The NMR data of the compound are: 1 H NMR (600 MHz, Chloroform-d) 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 (100 MHz, Chloroform-d) 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.

[0081] Embodiment 6:

[0082]

[0083] The benzoylhydroxylamine amination reagent (2a) was replaced with 4-chlorobenzoylhydroxylamine 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 = 2:1) to obtain a white solid (3f) (36 mg, 55%). The NMR data of the compound are: 1 H NMR (600 MHz, DMSO-d6) δ 8.63 (t, J = 5.7 Hz, 1H), 7.88(d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.29(d, J = 8.3 Hz, 2H), 5.43 (d, J = 4.3 Hz, 1H), 4.75 (dt, J = 8.5, 4.4 Hz,1H), 3.47 (ddd, J = 13.3, 6.0, 4.6 Hz, 1H), 3.30 (ddd, J = 13.4, 8.2, 5.3 Hz,1H), 1.27 (s, 9H). 13 C NMR (151 MHz, DMSO-d6) δ 170.59, 154.59, 146.00, 141.13,138.54, 134.41, 133.53, 130.94, 130.01, 76.04, 52.97, 39.40, 36.42.

[0084]

[0085] The benzoylhydroxylamine amination reagent (2a) was replaced by 4-chlorobenzoylhydroxylamine 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) to obtain a yellow oily liquid (4f) (31 mg, 50%). The NMR data of the compound are: 1H NMR (600 MHz, Chloroform-d) 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 (100 MHz, Chloroform-d) 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.

[0086] Embodiment 7:

[0087]

[0088] The benzoylhydroxylamine amination reagent (2a) was replaced by 4-ester benzoylhydroxylamine amination reagent (2d), and the other reactions were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (3 g) (41 mg, 57%). The NMR data of the compound are: 1 H NMR (600 MHz, Chloroform-d) δ 8.73 (t, J = 5.7 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 5.44 (d, J = 4.3 Hz, 1H), 4.76 (dt, J = 8.6, 4.5Hz, 1H), 3.88 (s, 3H), 3.51-3.44 (m, 1H), 3.36-3.30 (m, 1H), 1.27 (s,9H). 13C NMR (151 MHz, Chloroform-d) δ 170.97, 170.80, 154.61, 145.96, 143.94,136.89, 134.31, 132.87, 130.95, 130.03, 57.58, 52.97, 39.41, 36.42.

[0089]

[0090] The benzoylhydroxylamine amination reagent (2a) was replaced by 4-ester benzoylhydroxylamine amination reagent (2d), 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 = 5:1) to obtain a yellow oily liquid (4 g) (34 mg, 50%). The NMR data of the compound are: 1 H NMR (600 MHz, Chloroform-d) δ: 8.08 (d, J = 2.6Hz, 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, 8.2Hz, 1H), 3.94 (s, 3H), 1.32 (s, 9H); 13 C NMR (100 MHz, Chloroform-d) 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 unprotected 1,2-amino ester, characterized in that: The aromatic olefin 1 is dissolved in a solvent under air atmosphere, and reacted at room temperature in the presence of an amination reagent 2, an iron catalyst and a base. After the reaction is completed, the unprotected 1,2-amino ester compound 3 is separated and purified; The synthetic route is as follows: ； in: R1 is selected from alkyl, alkoxy, ester or halogen; R2 is a hydrogen atom, a halogen, an alkoxy group or an ester group, - OTf is trifluoromethanesulfonate.

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

3. The synthesis method according to claim 1, characterized in that: The base is at least one of potassium fluoride, potassium carbonate, sodium carbonate and potassium phosphate, and the added amount is 1-5 times the equivalent.

4. The synthesis method according to claim 1, characterized in that: The solvent is dichloromethane, ethyl acetate, 1,2-dichloroethane, chloroform or acetone.

5. A method for synthesizing an oxazoline derivative, characterized in that: The aromatic olefin 1 is dissolved in a solvent under air atmosphere, and the first step reaction is carried out at room temperature in the presence of an aminating agent 2, an iron catalyst and a base. After the reaction is completed, an acid is added to the system without post-treatment to carry out the second step reaction. After the reaction is completed, the oxazoline derivative 4 is separated and purified to obtain the oxazoline derivative 4. The synthetic route is as follows: ； in: R1 is selected from alkyl, alkoxy, ester or halogen; R2 is a hydrogen atom, a halogen, an alkoxy group or an ester group, - OTf is trifluoromethanesulfonate.

6. The synthesis method according to claim 5, characterized in that: The iron catalyst is selected from ferrous trifluoromethanesulfonate, ferrous acetate, ferrous sulfate, ferrous chloride or ferrous acetylacetonate, and the amount of the iron catalyst is 1 mol%-20 mol%.

7. The synthesis method according to claim 5, characterized in that: The base is at least one of potassium fluoride, potassium carbonate, sodium carbonate and potassium phosphate, and the added amount is 1-5 times the equivalent.

8. The synthesis method according to claim 5, characterized in that: The acid is trifluoromethanesulfonic acid, hydrochloric acid or hypochlorous acid, and the amount used is 1-5 eq.

9. The synthesis method according to claim 5, characterized in that: The solvent is dichloromethane, ethyl acetate, 1,2-dichloroethane, chloroform or acetone.

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