3, 6-dihydro-1, 2-oxazine compound and synthesis method thereof

Abstract

According to the 3, 6-dihydro-1, 2-oxazine compound and the synthesis method thereof, 1, 4, 2-dioxazole-5-ketone and 1, 3-conjugated diene are used as raw materials, commercially available cuprous thiocyanate is used as a catalyst, no additional oxidizing agent needs to be added in the reaction process, and 1, 4, 2-dioxazole-5-ketone, 1, 3-conjugated diene and 1, 4, 2-dioxazole-5-ketone are used as raw materials. 2, 2-dioxazole-5-ketone and a copper catalyst form a metal nitrogen-based intermediate which can be used as a self-oxidant to promote the reaction, so that the problems of poor substrate adaptability, low reaction activity, more byproducts and the like of a traditional cyclization method are solved; compared with harmful by-products (such as sulfur / nitrogen-containing compounds or heavy metal residues) generated by a traditional process, the environment friendliness of the method is remarkably improved, and meanwhile, the waste treatment cost is reduced, so that the comprehensive benefits of industrial production are effectively improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of fine chemical industry, and particularly relates to a 3,6-dihydro-1,2-oxazine compound and a synthesis method thereof. BACKGROUND

[0002] 1,2-oxazines, especially 3,6-dihydro-1,2-oxazines, are nitrogen-oxa-heterocycles of important synthetic utility and biological interest. They can serve as versatile intermediates in organic synthesis. Their structure provides multiple functionalization sites - such as the N-O bond, the endocyclic double bond, and various substituents - that can be transformed into a wide range of nitrogen-containing compounds. Notably, they are key precursors to δ-amino phosphonic acids, pyrrolidines, oxaphosphonates, and polyhydroxylamines, structural units that are widely present in biologically active natural products (such as rhizoxins and phosphomycin) and pharmacologically active analogs.

[0003] The use of 1,4,2-oxazol-5-ones to achieve C-N bond coupling has become an effective strategy to obtain nitrogen-containing compounds. As a new type of amination reagent, 1,4,2-oxazol-5-ones have the characteristics of easy availability, stability, and convenient use compared with traditional organic azides and iminoiodobenzene amination reagents. The current general method for synthesizing 1,2-oxazine compounds is the Diels-Alder (DA) cycloaddition method, catalytic cyclization method, etc. For example, Radomir Jasiński et al. reported in Chemistry of Heterocyclic Compounds the use of the Diels-Alder (DA) cycloaddition method to prepare 1,2-oxazine N-oxides, but this method has the disadvantages of long reaction time, multiple by-products, etc. In addition, the team of Mo Dongliang reported in Chinese Journal of Chemistry the use of ytterbium to catalyze the asymmetric [3+3] cycloaddition of n-vinyl nitroketone and activated cyclopropane to prepare 1,2-oxazine compounds, but this method also has certain limitations, such as high catalyst dosage, harsh conditions (need to be anhydrous), and limited substrates, etc. SUMMARY

[0004] In order to overcome the shortcomings of the prior art, the purpose of the present application is to provide a 3,6-dihydro-1,2-oxazine compound and a synthesis method thereof, which uses 1,4,2-oxazol-5-ones and 1,3-conjugated dienes as raw materials, and commercially available cuprous thiocyanate as a catalyst. The reaction process does not require the addition of an additional oxidizing agent. The 1,4,2-oxazol-5-ones form a metal nitrene intermediate with the copper catalyst, which can act as an oxidizing agent to promote the reaction, solving the problems of poor substrate adaptability, low reaction activity, and multiple by-products of the traditional cyclization method.

[0005] In order to achieve the above object, the technical scheme of the present application is: A 3,6-dihydro-1,2-oxazine compound is synthesized by taking 1,4,2-dioxazol-5-one and 1,3-conjugated diene as raw materials and cuprous thiocyanate as catalyst, and the compound has a molecular formula of: , R is aryl or alkyl.

[0006] A synthesis method of a 3,6-dihydro-1,2-oxazine compound, specifically comprising the following steps: (A) Dry the reaction tube and add a stirring rod, add 1,4,2-dioxazol-5-one and cuprous thiocyanate catalyst under a nitrogen atmosphere, backfill with nitrogen, then add 1,3-conjugated diene into the reaction tube, and then add reaction solvent N-methyl pyrrolidone, ensure that the total concentration of the reactant 1,3-conjugated diene is in the range of 0.1 M-0.2 M, and stir at 40-100 DEG C for 8-16 hours, and the reaction is completed; (B) After the reaction is completed, add enough water to extract the reaction solvent N-methyl pyrrolidone, wash with saturated brine, extract and separate the organic phase and dry with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to remove the solvent; (C) The organic phase is subjected to column chromatography to obtain the target product.

[0007] The molar ratio of the 1,4,2-dioxazol-5-one, cuprous thiocyanate and 1,3-conjugated diene is (2.5-3):(0.05-0.1):1.

[0008] The column chromatography conditions are as follows: the silica gel used is of 200-300 mesh size, the mass ratio of the silica gel to the purified material is (50-100):1, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixture is (10-5):1.

[0009] Compared with the prior art, the present application has the following advantages and characteristics: 1. In the present application, 1,4,2-dioxazol-5-one is used as an amination reagent to form a metal nitrene intermediate as an oxidant to promote the reaction, so that the amination and cyclization reactions are realized at the same time, and the problems of poor substrate adaptability, low reaction activity and many by-products in the traditional cyclization method are solved.

[0010] 2. In the present application, 1,4,2-dioxazol-5-one and 1,3-conjugated diene are used as raw materials, the raw materials are cheap and easy to obtain, the catalyst cuprous thiocyanate is cheap, the reaction conditions are simple, and the substrate is widely applicable.

[0011] 3. The by-product of the reaction in the present application is carbon dioxide, which has little environmental pollution and meets the concept of green environmental protection.

[0012] In summary, the present application uses 1,4,2-dioxazol-5-one as an inexpensive and easily prepared aminating reagent, and inexpensive copper as a catalyst to achieve efficient synthesis of 3,6-dihydro-1,2-oxazine compounds. The by-product generated in the reaction is mainly carbon dioxide, which is more environmentally friendly than the harmful by-products (such as sulfur / nitrogen compounds or heavy metal residues) generated by traditional processes. At the same time, the cost of waste disposal is reduced, thereby effectively improving the overall benefits of industrial production, and solving the problems of poor substrate adaptability, low reaction activity and multiple by-products of traditional synthesis of 1,2-oxazine compounds. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 is the nuclear magnetic hydrogen spectrum of (6-phenyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (phenyl) methanone.

[0014] Figure 2 is the nuclear magnetic carbon spectrum of (6-phenyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (phenyl) methanone.

[0015] Figure 3 is the nuclear magnetic hydrogen spectrum of (6-phenyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (p-tolyl) methanone.

[0016] Figure 4 is the nuclear magnetic carbon spectrum of (6-phenyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (p-tolyl) methanone.

[0017] Figure 5 is the nuclear magnetic hydrogen spectrum of (6-phenyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (naphthalene-2-yl) methanone.

[0018] Figure 6 is the nuclear magnetic carbon spectrum of (6-phenyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (naphthalene-2-yl) methanone.

[0019] Figure 7 is the nuclear magnetic hydrogen spectrum of (6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazol-2-yl) (phenyl) methanone.

[0020] Figure 8 is the nuclear magnetic carbon spectrum of (6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazol-2-yl) (phenyl) methanone.

[0021] Figure 9 is the nuclear magnetic hydrogen spectrum of (6-heptyl-3,6-dihydro-2H-1,2-oxazol-2-yl) (phenyl) methanone.

[0022] Figure 10 The NMR carbon spectrum of (6-heptyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl) methanone.

[0023] Figure 11 is a universal expansion of the 1,4,2-oxadiazol-5-one substrate of the reaction of the present application.

[0024] Figure 12 is a universal expansion of the 1,3-conjugated diene substrate of the reaction of the present application. DETAILED DESCRIPTION

[0025] The present application will be described in detail below with specific examples.

[0026] Example 1 The method of the present example for synthesizing 3,6-dihydro-1,2-oxazine compounds, specifically the method for preparing (6-phenyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl) methanone, comprises the following steps: adding 3-phenyl-1,4,2-oxadiazol-5-one (48.9 mg, 0.3 mmol), cuprous thiocyanate (1.2 mg, 0.01 mmol) into a Schlenk reaction bottle, filling with nitrogen 3 times, adding 1-phenyl-1,3-butadiene (13.0 mg, 0.1 mmol) and N-methylpyrrolidone (1 mL). Reacting at 60 degrees Celsius for 12 hours; after the reaction is completed, extracting with water (10 mL), washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using silica gel with a mesh size of 200-300, the mass ratio of silica gel to the product to be purified is 50:1-100:1, and the eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate in the mixture is 10:1) to obtain colorless oily liquid (6-phenyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl) methanone (24.9 mg, 94%), and the nuclear magnetic spectrum, high-resolution mass spectrum, and infrared spectrum of the product all prove that the product is pure.

[0027] The reaction equation is as follows: The product structure is as follows: Reference Figure 1 , Figure 2 The hydrogen spectrum and carbon spectrum data of the product are as follows: 1H NMR (400 MHz, CDCl3) δ 7.51 - 7.48 (m, 2H), 7.40 - 7.36 (m, 1H), 7.30 - 7.23 (m, 5H), 7.17 - 7.14 (m, 2H), 6.13 - 6.10 (m, 1H), 6.00 - 5.97 (m, 1H), 5.37 (t, J = 2.6 Hz, 1H), 4.62 - 4.56 (m, 1H), 4.42 - 4.37 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 170.1, 136.2, 133.6, 130.6, 129.3, 128.8, 128.7, 128.6, 127.7, 126.5, 123.6, 81.1, 42.9. Example Two The method of the present example synthesizes 3,6-dihydro-1,2-oxazine compounds, specifically (6-phenyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(p-tolyl)methanone, including the following steps: adding 3-(p-tolyl)-1,4,2-dioxazol-5-one (38.4 mg, 0.3 mmol), cuprous thiocyanate (1.2 mg, 0.01 mmol) into a Schlenk reaction flask, filling with nitrogen 3 times, adding 1-phenyl-1,3-butadiene (13.0 mg, 0.1 mmol) and N-methylpyrrolidone (1 mL). Reacting at 60 degrees Celsius for 8 hours; after the reaction is completed, extracting with water (10 mL), washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using silica gel with a mesh size of 200-300, a mass ratio of silica gel to the product to be purified of 50:1-100:1, and a mixture of petroleum ether and ethyl acetate as the eluent, with a volume ratio of petroleum ether to ethyl acetate of 10:1) to obtain colorless oily liquid (6-phenyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(p-tolyl)methanone (24.3 mg, 87%), which is confirmed to be pure by nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and infrared spectroscopy.

[0028] The reaction equation is as follows: The structure of the product is as follows: Reference Figure 3 , Figure 4, the proton and carbon spectra of the product and the high resolution mass spectrum data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.2 Hz, 2H), 7.32 – 7.26 (m,3H), 7.23 – 7.20 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.13 – 6.09 (m, 1H), 6.01– 5.97 (m, 1H), 5.41 (t, J = 2.5 Hz, 1H), 4.65 – 4.59 (m, 1H), 4.37 – 4.32 (m,1H), 2.36 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 170.2, 141.1, 136.5, 130.7, 129.3, 128.9,128.7, 128.7, 128.5, 126.7, 123.6, 81.1, 43.1, 21.6. HRMS (APCI) calcd forC 18 H 18 NO2[M+H] + 280.1332, found 280.1335. Example Three The method for synthesizing 3,6-dihydro-1,2-oxazine compounds, specifically preparing (6-phenyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(naphthalen-2-yl)methanone, comprises the following steps: adding 3-(2-naphthyl)-1,4,2-dioxazol-5-one (64.0 mg, 0.3 mmol), cuprous thiocyanate (1.2 mg, 0.01 mmol) into a Schlenk reaction bottle, filling with nitrogen for 3 times, adding 1-phenyl-1,3-butadiene (13.0 mg, 0.1 mmol) and N-methylpyrrolidone (1 mL). Reacting at 80 degrees Celsius for 12 hours; after the reaction is completed, extracting with water (10 mL), washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using silica gel with a mesh size of 200-300, the mass ratio of silica gel to the product to be purified is 50:1-100:1, and the eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate in the mixture is 10:1) to obtain a colorless oily liquid, (6-phenyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(naphthalen-2-yl)methanone (25.9 mg, 82%), and the nuclear magnetic resonance spectrum, high resolution mass spectrum and infrared spectrum of the product prove that the product is pure.

[0029] The reaction equation is as follows: The product structure is as follows: Reference Figure 5 , Figure 6 The hydrogen spectrum and carbon spectrum and high resolution mass spectrum data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.99 – 7.98 (m, 1H), 7.82 – 7.72 (m, 3H),7.58 (dd, J = 8.6, 1H), 7.52 – 7.47 (m, 2H), 7.24 (d, J = 1.7 Hz, 1H), 7.24 –7.13 (m, 4H), 6.14 – 6.13 (m, 1H), 6.00 (dd, J = 10.4, 1H), 5.42 – 5.41 (m,1H), 4.66 – 4.58 (m, 1H), 4.51 – 4.43 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 170.2, 136.3, 134.4, 132.5, 131.0, 129.4,129.4, 129.0, 128.9, 128.6, 127.7, 127.4, 127.2, 126.5, 126.4, 125.5, 123.6,81.2, 43.1. HRMS (APCI) calcd for C 21 H 18 NO2[M+H] + 316.1332, found 316.1335. Example Four The method of the present example for synthesizing 3,6-dihydro-1,2-oxazine compounds, in particular, the method for preparing (6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl)methanone, comprises the following steps: adding 3-phenyl-1,4,2-dioxazol-5-one (48.9 mg, 0.3 mmol), cuprous thiocyanate (1.2 mg, 0.01 mmol) into a Schlenk reaction flask, filling with nitrogen for 3 times, adding 4-methoxyphenyl-1,3-butadiene (16.0 mg, 0.1 mmol) and N-methylpyrrolidone (1 mL). Reacting at 40 degrees Celsius for 10 hours; after the reaction is completed, extracting with water (10 mL), washing with saturated brine (10 mL), drying over anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using silica gel with a mesh size of 200-300, a mass ratio of silica gel to the product to be purified of 50:1-100:1, and a mixture of petroleum ether and ethyl acetate as the eluent, with a volume ratio of petroleum ether to ethyl acetate of 10:1) to obtain colorless oily liquid (6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl)methanone (19.2 mg, 65%), which is proved to be pure by nuclear magnetic resonance spectroscopy, high resolution mass spectrometry and infrared spectroscopy.

[0030] The reaction equation is as follows: The structure of the product is as follows: Reference Figure 7 , Figure 8 The hydrogen spectrum and carbon spectrum of the product and the high resolution mass spectrometry data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.48 (m, 2H), 7.39 – 7.35 (m, 1H),7.30 – 7.26 (m, 2H), 7.07 – 7.05 (m, 2H), 6.76 (d, J = 8.7 Hz, 2H), 6.12 –6.08 (m, 1H), 5.99 – 5.95 (m, 1H), 5.32 (t, J = 2.5 Hz, 1H), 4.58 – 4.52 (m,1H), 4.45 – 4.39 (m, 1H), 3.77 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 170.0, 160.3, 133.7, 130.5, 130.2, 128.6,128.3, 127.6, 126.6, 123.5, 113.9, 80.6, 55.3, 42.7. HRMS (APCI) calcd forC 18 H 18 NO3[M+H] + 296.1281, found 296.1285. Example Five The method of the present example for synthesizing 3,6-dihydro-1,2-oxazine compounds, in particular, the method for preparing (6-heptyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl)methanone, comprises the following steps: A Schlenk reaction bottle was added with 3-phenyl-1,4,2-dioxazol-5-one (48.9 mg, 0.3 mmol), cuprous thiocyanate (1.2 mg, 0.01 mmol), filled with nitrogen for 3 times, 1,3-undecadiene (15.2 mg, 0.1 mmol) and N-methylpyrrolidone (1 mL), and reacted at 60 degrees Celsius for 16 hours; after the reaction was completed, water (10 mL) was used for extraction, saturated brine (10 mL) was used for washing, anhydrous sodium sulfate was used for drying, the organic phase was concentrated under reduced pressure, and column chromatography (using silica gel with a mesh size of 200-300, a mass ratio of silica gel to the product to be purified of 50:1-100:1, and a mixture of petroleum ether and ethyl acetate as the eluent, a volume ratio of petroleum ether to ethyl acetate in the mixture being 10:1) was used for purifying the product, to obtain colorless oily liquid (6-heptyl-3,6-dihydro-2H-1,2-oxazin-2-yl)(phenyl)methanone (16.7 mg, 58%), and the nuclear magnetic resonance spectrum, high resolution mass spectrum and infrared spectrum of the product proved that the product was pure.

[0031] The reaction equation is as follows: The product structure is as follows: Referring to Figure 9 , Figure 10 The hydrogen spectrum and carbon spectrum data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.68 (m, 2H), 7.45 – 7.37 (m, 3H),5.88 – 5.84 (m, 1H), 5.77 – 5.73 (m, 1H), 4.64 (d, J = 17.7 Hz, 1H), 4.35 (d, J = 8.2 Hz, 1H), 4.10 – 4.04 (m, 1H), 1.44 – 1.40 (m, 2H), 1.28 – 1.22 (m, 2H),1.17 – 1.07 (m, 8H), 0.86 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 169.8, 134.0, 130.8, 128.7, 128.3, 127.9,122.4, 79.4, 42.9, 33.4, 31.8, 29.3, 29.2, 25.0, 22.8, 14.2. HRMS (APCI)calcd for C 18 H 26 NO2[M+H] + 288.1958, found 288.1961. The present application also evaluates the substrate universality of this cyclization reaction.

[0032] As Figure 11 , Figure 12, various 1,4,2-dioxazol-5-ones in this C-N coupling reaction, all can get moderate to good yield. The effect of substituents on the aromatic ring on the yield is not obvious. In the aromatic ring 4, 3, 2 substituted 1, 4, 2-dioxazol-5-one is also applicable (3i, 3j, 3k), the yield is between 76%-87%. Alkyl substituted 1, 4, 2-dioxazol-5-one also obtained the desired product (3q, 3r, 3s), the yield is between 45%-54%. In addition, N-Boc substituted 1, 4, 2-dioxazol-5-one also obtained the desired product, the yield is 60%. Different 1, 3-conjugated diene, also can get moderate to good yield. 1-Thiophenyl substituted 1, 3-conjugated diene is also applicable (4l), the yield is 68%. Alkyl substituted 1, 3-conjugated diene also obtained the desired product (4o), the yield is 58%.

Claims

1. A 3,6-dihydro-l,2-oxazine compound, characterized by, The 3,6-dihydro-1,2-oxazine compound is synthesized by using 1,4,2-dioxol-5-one and 1,3-conjugated diene as raw materials and cuprous thiocyanate as catalyst, and the molecular formula of the compound is: R is aryl or alkyl.

2. A method for synthesizing 3,6-dihydro-l,2-oxazines, characterized by, Specifically comprising the following steps: (A) Dry the reaction tube and add a stirring rod, add 1,4,2-dioxol-5-one and cuprous thiocyanate catalyst under a nitrogen atmosphere, backfill nitrogen, then add 1,3-conjugated diene into the reaction tube, add reaction solvent N-methyl pyrrolidone, ensure the total concentration of the reactant 1,3-conjugated diene is between 0.1 M-0.2 M, stir at 40-100 degrees Celsius for 8-16 hours, and the reaction is completed; (B) After the reaction is completed, add enough water to extract the reaction solvent N-methyl pyrrolidone, wash with saturated brine, extract and separate the organic phase and dry with anhydrous sodium sulfate, reduce the pressure to concentrate the organic phase, and remove the solvent; (C) Perform column chromatography on the organic phase to obtain the target product.

3. The 3,6-dihydro-1,2-oxazine compound according to claim 2, characterized in that, The molar ratio of the 1,4,2-dioxol-5-one, cuprous thiocyanate and 1,3-conjugated diene is (2.5-3):(0.05-0.1):

1.

4. The 3,6-dihydro-1,2-oxazine compound according to claim 2, characterized by, The column chromatography conditions are: use silica gel with a size of 200-300 mesh, the mass ratio of silica gel to the purified material is (50-100):1, the eluent is a mixture of excess petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixture is (10-5):1.

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