Method for preparing 3,6-dihydro-1,2-oxazine derivatives in aqueous phase by iodine catalysis

Abstract

The invention discloses a method for preparing 3,6-dihydro-1,2-oxazine derivatives by iodine catalysis in an aqueous phase. Substituted hydroxylamine and conjugated diene are used as substrates, gemini quaternary ammonium iodide salt is used as a catalyst and a surfactant, peroxide is used as an oxidant, and water is used as a solvent. The 3,6-dihydro-1,2-oxazine derivatives are obtained by stirring reaction; the structural formula of the substituted hydroxylamine is #imgabs0#, R 1 is an aryl acyl group, an alkyl acyl group, an alkoxy acyl group, an amino acyl group or a benzene ring; the structural formula of the conjugated diene is #imgabs1#, R 2 is an alkyl or phenyl group, x is #imgabs2#, and n≥1. The present invention has the characteristics of cheap and readily available raw materials, low catalyst loading, mild reaction conditions, simple operation, wide application range of substrates, easy expansion of reaction scale, good cyclicity of reaction medium (aqueous solution containing catalyst), etc., and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 3,6-dihydro-1,2-oxazine derivatives in an aqueous phase by iodine catalysis. Background Art

[0002] 3,6-Dihydro-1,2-oxazine is widely present in the skeleton of biologically active molecules and has rich biological and pharmaceutical activities. In addition, this type of substance can also be used as a key intermediate for the synthesis of natural products. For example, in the synthesis of marine tricyclic alkaloids fasicularin and lepadiformine, the key step is to construct an intermediate containing a 3,6-dihydro-1,2-oxazine unit through an intramolecular hetero-Diels-Alder reaction. Therefore, its synthesis method has attracted widespread attention from scientists. Among them, the hetero-Diels-Alder reaction based on nitroso compounds is undoubtedly one of the most powerful methods for preparing such heterocyclic compounds. However, since nitroso compounds are very unstable and have certain toxicity and explosion risks, they usually participate in the reaction in the form of in-situ preparation, that is, using substituted hydroxylamine as a raw material, the nitroso intermediate is generated in situ under oxidative conditions and a hetero-Diels-Alder reaction with the diene is carried out to achieve the preparation of 3,6-dihydro-1,2-oxazine derivatives.

[0003] To date, a variety of oxidation strategies have been used for the in situ generation of nitroso intermediates and tandem Diels-Alder reactions. Among them, iodine-mediated or catalyzed oxidation reactions have attracted widespread attention from chemists and pharmacists as a metal-free strategy. This is mainly because the methods involved usually have many advantages such as mild reaction conditions and simple experimental operations, providing a common and effective means for the green and efficient construction of some pharmaceutical intermediates and bioactive molecular skeletons. At present, the iodine oxidants used for the in situ conversion reactions of nitroso intermediates mainly include periodates, aromatic trivalent iodine and Dess-Martin oxidants. However, the above methods all rely on the use of stoichiometric iodine reagents, and the economy of iodine atoms needs to be improved. Akio Saito's group first used tetrabutylammonium iodide as a catalyst, tert-butyl hydroperoxide or hydrogen peroxide as a terminal oxidant, and dichloromethane as a solvent to achieve an in situ hetero Diels-Alder reaction of nitroso intermediates and prepared a series of 3,6-dihydro-1,2-oxazine derivatives. However, the substrate applicability and yield of this method were not ideal (Uraoka S, Shinohara I, Shimizu H, et al. Hetero Diels–Alder Reaction and EneReaction of Acylnitroso Species in situ Generated by Hypoiodite Catalysis[J]. European Journal of Organic Chemistry, 2018, 2018(45): 6199-6203).

[0004] In summary, the iodine-mediated or catalyzed tandem hetero-Diels-Alder reaction of nitroso intermediates with dienes is one of the most powerful methods for preparing 3,6-dihydro-1,2-oxazine compounds. Although there have been many reports on its synthesis methods, most of the existing preparation methods require the use of stoichiometric high-valent iodine reagents and rely on organic solvents as reaction media. There are also problems such as narrow substrate applicability or low product yield. Water, as a non-toxic and economical solvent, is considered to be an ideal solvent in laboratories and industrial processes. Therefore, there is an urgent need for a method that uses water as a reaction medium, has an excellent substrate applicability range and high iodine atom economy to synthesize 3,6-dihydro-1,2-oxazine derivatives in a greener and more efficient way. Summary of the invention

[0005] In view of the above-mentioned prior art, the purpose of the present invention is to provide a method for preparing 3,6-dihydro-1,2-oxazine derivatives by iodine catalysis in an aqueous phase. The present invention uses substituted hydroxylamine and conjugated diene as substrates, gemini quaternary ammonium iodide salt as catalyst and surfactant, peroxide as oxidant, and water as solvent, and forms a nitroso intermediate by in-situ oxidation of substituted hydroxylamine, and then undergoes a hetero-Diels-Alder reaction with a conjugated diene to prepare a 3,6-dihydro-1,2-oxazine derivative.

[0006] To achieve the above object, the present invention adopts the following technical solution:

[0007] In a first aspect of the present invention, a method for preparing 3,6-dihydro-1,2-oxazine derivatives by iodine catalysis in an aqueous phase is provided, wherein:

[0008] Using substituted hydroxylamine and conjugated diene as substrates, gemini quaternary ammonium iodide salt as catalyst and surfactant, peroxide as oxidant, and water as solvent, a 3,6-dihydro-1,2-oxazine derivative is obtained by stirring reaction;

[0009] The structural formula of the substituted hydroxylamine is , R 1 is an aryl acyl group, an alkyl acyl group, an alkoxy acyl group, an amino acyl group or a benzene ring;

[0010] The structural formula of the conjugated diene is , R 2 is an alkyl group or a phenyl group, and x is , n≥1.

[0011] Preferably, the substituted hydroxylamine is selected from benzohydroxamic acid, 3-bromo- N -Hydroxybenzamide, N -Hydroxy-4-methoxybenzamide, N -Hydroxy-4-(trifluoromethyl)benzamide, 2-amino- N -Hydroxybenzamide, N , 2-dihydroxybenzamide, N -Hydroxy-4-nitrobenzamide, acetohydroxamic acid, N -Hydroxypivalamide, N -Hydroxycyclohexanecarboxamide, hydroxy benzyl carbamate, 1-hydroxyurea, N -Hydroxythiophene-2-carboxamide, N -Hydroxyfuran-3-carboxamide, N -Hydroxy-2-naphthylamide or N -phenylhydroxylamine.

[0012] Preferably, the conjugated diene is selected from 1,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene, 1,3-butadiene, 1,3-cyclooctadiene or (E )-1-phenyl-1,3-butadiene.

[0013] Preferably, the structural formula of the gemini quaternary ammonium iodide salt is:

[0014]

[0015] Among them, y and z are , y and z are both ≥ 1.

[0016] More preferably, y=1 or 2, z=10 or 16.

[0017] Preferably, the peroxide is cumene hydroperoxide or a hydrogen peroxide solution; the mass concentration of the hydrogen peroxide solution is 30%.

[0018] More preferably, the peroxide is cumene hydroperoxide.

[0019] Preferably, the molar ratio of the substituted hydroxylamine, the conjugated diene and the oxidant is 1:2:1.5; and the amount of the gemini quaternary ammonium iodide salt is 0.5-5% of the molar amount of the substituted hydroxylamine.

[0020] Preferably, the ratio of the added amount of the substituted hydroxylamine to the solvent is 1 mmol: 5 mL.

[0021] More preferably, the amount of the gemini quaternary ammonium iodide salt is 2.5% of the molar amount of substituted hydroxylamine.

[0022] Preferably, the stirring reaction temperature is 20-40° C., and the stirring reaction time is 6-24 h.

[0023] More preferably, the stirring reaction temperature is 30° C., and the stirring reaction time is 12 h.

[0024] In a second aspect of the present invention, a 3,6-dihydro-1,2-oxazine derivative prepared by the above method is provided, wherein the structural formula of the 3,6-dihydro-1,2-oxazine derivative is

[0025] ;

[0026] Among them, R 1 is an aryl acyl group, an alkyl acyl group, an alkoxy acyl group, an amino acyl group or a benzene ring, R 2 is an alkyl group or a phenyl group, and x is , n≥1.

[0027] Preferably, the 3,6-dihydro-1,2-oxazine derivative is (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(phenyl)methanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(3-bromophenyl)methanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-methoxyphenyl)methanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-(trifluoromethyl)phenyl)methanone, (2-aminophenyl)(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-(trifluoromethyl)phenyl)methanone, 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)ethanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(2-hydroxyphenyl)methanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-nitrophenyl)methanone, 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)ethanone, 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)ethanone, azabicyclo[2.2.2]oct-5-en-3-yl)-2,2-dimethylpropan-1-one, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(cyclohexyl)methanone, 2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxylic acid benzyl ester, 2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxamide, (2-oxa-3-azabicyclo[2.2 .2] oct-5-en-3-yl)(thiophene-2-yl)methanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(furan-3-yl)methanone, (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(naphthalen-2-yl)methanone, 3-phenyl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene, (4,5-dimethyl-3,6-dihydro-2 H -1,2-oxazin-2-yl) (phenyl)methanone, (3,6-dihydro-2 H -1,2-oxazin-2-yl)(phenyl)methanone, (7-oxa-8-azabicyclo[4.2.2]dec-9-en-8-yl)(phenyl)methanone or phenyl(6-phenyl-3,6-dihydro-2 H -1,2-oxazin-2-yl)methanone.

[0028] Beneficial effects of the present invention:

[0029] (1) The present invention uses substituted hydroxylamine and conjugated diene as substrates, gemini quaternary ammonium iodide salt as catalyst and surfactant, peroxide as oxidant, and water as solvent, and reacts under stirring at 30°C to obtain 3,6-dihydro-1,2-oxazine derivatives. The starting materials involved in the preparation method are all industrial products, which are easy to obtain and have a wide range of sources.

[0030] (2) The method provided by the present invention does not require the use of transition metal catalysts and stoichiometric iodine reagents, and can completely avoid the addition of any organic solvent during the reaction. It has the characteristics of cheap and readily available raw materials, low catalyst loading, mild reaction conditions, simple operation, wide range of substrate applicability, easy expansion of reaction scale, good recyclability of the reaction medium (aqueous solution containing the catalyst), etc., and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 1;

[0032] Figure 2 The carbon NMR spectrum of the target product obtained in Example 1;

[0033] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 5;

[0034] Figure 4 This is the carbon NMR spectrum of the target product obtained in Example 5;

[0035] Figure 5 is the carbon NMR spectrum of the target product obtained in Example 9;

[0036] Figure 6 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 12;

[0037] Figure 7 is the carbon NMR spectrum of the target product obtained in Example 12;

[0038] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 13;

[0039] Fig. 9 is the carbon NMR spectrum of the target product obtained in Example 13;

[0040] Fig.10 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 15;

[0041] Fig.11 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 16;

[0042] Fig.12 is the carbon NMR spectrum of the target product obtained in Example 16;

[0043] Fig.13 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 18;

[0044] Fig.14 is the carbon NMR spectrum of the target product obtained in Example 18;

[0045] Fig.15 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 20;

[0046] Fig.16 This is the carbon NMR spectrum of the target product obtained in Example 20. DETAILED DESCRIPTION

[0047] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0048] As introduced in the background technology section, the iodine-mediated or catalyzed tandem hetero-Diels-Alder reaction of nitroso intermediates with dienes is one of the most powerful methods for preparing 3,6-dihydro-1,2-oxazines. However, most of these methods currently require the use of stoichiometric high-valent iodine reagents and rely on organic solvents as reaction media. In addition, they also have the problems of narrow substrate applicability or low product yields.

[0049] Based on this, the purpose of the present invention is to provide a method for preparing 3,6-dihydro-1,2-oxazine derivatives by iodine catalysis in an aqueous phase. The present invention uses substituted hydroxylamine and conjugated diene as substrates, gemini quaternary ammonium iodide salt as catalyst and surfactant, cumene hydroperoxide (CHP) or hydrogen peroxide (mass concentration 30%) as oxidant, and water as solvent, and stirs the reaction at 30°C to obtain 3,6-dihydro-1,2-oxazine derivatives. The general reaction formula is as follows:

[0050] .

[0051] The possible reaction mechanism of the present invention is: the catalyst generates a high-valent iodine species (IO - or IO2 - ), the high-valent iodine species oxidatively replaces the hydroxylamine substrate to form a nitroso intermediate in situ, and then undergoes a hetero-Diels-Alder reaction with a conjugated diene to prepare a 3,6-dihydro-1,2-oxazine derivative. The present invention incorporates a gemini-type amphiphilic structure into the design of iodine salt catalysts. When the number of these catalysts exceeds their critical micelle concentration (CMC), they will self-assemble in water to form a micelle array, which not only helps to increase the solubility of lipophilic substrates in water, but also can regulate the reactivity caused by the micelle effect, and promote the smooth operation of the reaction in the aqueous phase.

[0052] In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments.

[0053] Note: The water used in the examples is distilled water, and the effect of other water on the reaction has not been tested.

[0054] The CAS number of benzohydroxamic acid used in the examples is 495-18-1,3-bromo- N -Hydroxybenzamide CAS number is 2593-28-4, N The CAS number of -hydroxy-4-methoxybenzamide is 10507-69-4, 2-amino- N The CAS number of -hydroxybenzamide is 5623-04-1, N , the CAS number of 2-dihydroxybenzamide is 89-73-6, N The CAS number of 4-hydroxy-nitrobenzamide is 1613-76-9, the CAS number of acetohydroxamic acid is 546-88-3, the CAS number of 1-hydroxyurea is 127-07-1, and the CAS number of hydroxybenzyl carbamate is 3426-71-9. N The CAS number of -hydroxythiophene-2-carboxamide is 17698-15-6, N The CAS number of -hydroxyfuran-3-carboxamide is 1016794-31-2, N The CAS number of -phenylhydroxylamine is 100-65-2.

[0055] The test materials used in the examples of the present invention are all conventional test materials in the art and can be purchased through commercial channels.

[0056] Example 1: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl) (phenyl)methanone

[0057] The specific synthetic route is:

[0058] .

[0059] The specific preparation method is:

[0060] Benzohydroxamic acid (0.4 mmol, 54.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added to a reaction tube equipped with a magnetic bar, followed by cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30 °C for 6 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0061] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl) (phenyl)methanone, with a yield of 99%. Its H NMR spectrum is as follows Figure 1 As shown, the carbon NMR spectrum is Figure 2 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0062] 1 H NMR (400 MHz, rotameric mixture) δ 7.62 (s, 2H), 7.45 – 7.31 (m,3H), 6.62 (s, 0.6H), 6.51 (s, 1.4H), 5.36 (s, 0.6H), 4.77 (s, 1.4H), 2.33 –2.14 (m, 2H), 1.55 – 1.44 (m, 2H).

[0063] 13 C NMR (101 MHz, rotameric mixture) δ 168.8 (s), 134.3 (s), 133.0(s), 131.7 (s), 130.7 (s), 128.5 (s), 127.9 (s), 71.9 (s), 47.2 (s), 23.5(s), 21.2(s).

[0064] Example 2: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(3-bromophenyl)methanone

[0065] The specific synthetic route is:

[0066] .

[0067] The specific preparation method is:

[0068] Add 3-bromo- N-Hydroxybenzamide (0.4 mmol, 86.0 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0069] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(3-bromophenyl)methanone, with a yield of 95%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0070] 1 H NMR (600 MHz, rotameric mixture) δ 7.81 (s, 1H), 7.66 – 7.39 (m,2H), 7.24 (t, J = 7.6 Hz, 1H), 6.70 (s, 0.8H), 6.54 (s, 1.2H), 5.40 (s, 0.8H), 4.77 (s, 1.2H), 2.38 – 2.24 (m, 1H), 2.24 – 2.19 (m, 1H), 1.58 – 1.47 (m,2H).

[0071] 13 C NMR (101 MHz, rotameric mixture) δ 167.1 (s), 136.2 (s), 133.8(s), 131.9 (s), 129.6 (s), 127.5 (s), 122.0 (s), 72.3 (s), 47.2 (s), 23.6(s), 21.0(s).

[0072] Example 3: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-methoxyphenyl)methanone

[0073] The specific synthetic route is:

[0074] .

[0075] The specific preparation method is:

[0076] Add the following to the reaction tube equipped with a magnet: N -Hydroxy-4-methoxybenzamide (0.4 mmol, 66.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0077] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-methoxyphenyl)methanone, with a yield of 98%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0078] 1H NMR (600 MHz, rotameric mixture) δ 7.68 (s, 2H), 6.87 (d, J = 8.7Hz, 2H), 6.64 (s, 0.9H), 6.56 – 6.45 (m, 1.1H), 5.21 (s, 0.9H), 4.78 (s,1.1H), 3.81 (s, 3H), 2.32 – 2.25 (m, 1H), 2.25 – 2.19 (m, 1H), 1.56 – 1.46 (m, 2H).

[0079] 13 C NMR (101 MHz, rotameric mixture) δ 169.5 (s), 161.8 (s), 131.7 (s), 130.9 (s), 126.5 (s), 113.3 (s), 72.0 (s), 55.4 (s), 23.7 (s), 21.2 (s).

[0080] Example 4: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-(trifluoromethyl)phenyl)methanone

[0081] The specific synthetic route is:

[0082] .

[0083] The specific preparation method is:

[0084] (1) At room temperature, add hydroxylamine hydrochloride (7.5 mmol, 517.5 mg) to a 250 mL flask equipped with a magnetic rod and dissolve it in 100 mL of isopropyl ether, then add 15 mL of water. Stir the mixture rapidly for 20 min, add 4-trifluoromethylbenzoyl chloride (7.5 mmol, 1.57 g, dissolved in 5 mL of isopropyl ether) dropwise, then stir vigorously at room temperature for 45 min, and monitor the reaction progress by thin layer chromatography. After the conversion of the raw materials is completed, filter under reduced pressure, wash with isopropyl ether to obtain the crude product, and finally recrystallize from ethanol to obtain the pure target compound. N -Hydroxy-4-(trifluoromethyl)benzamide.

[0085] (2) Add the following into the reaction tube equipped with a magnet: N- Hydroxy-4-(trifluoromethyl)benzamide (0.4 mmol, 82.0 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0086] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-(trifluoromethyl)phenyl)methanone, with a yield of 95%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0087] 1 H NMR (400 MHz, rotameric mixture) δ 7.77 (s, 2H), 7.63 (d, J= 7.4Hz, 2H), 6.73 (s, 0.8H), 6.54 (s, 1.2H), 5.43 (s, 0.8H), 4.75 (s, 1.2H), 2.37– 2.16 (m, 2H), 1.62 – 1.45 (m, 2H).

[0088] 13 C NMR (101 MHz, rotameric mixture) δ 167.1 (s), 137.5 (s), 133.2 (s), 132.3 (q, J = 32.3 Hz), 131.8 (s), 129.3 (s), 124.7 (s), 123.8 (q, J = 272.9Hz), 72.3 (s), 47.0 (s), 23.4 (s), 20.8 (s).

[0089] 19 F NMR (565 MHz, CDCl3) δ -62.97 (s).

[0090] Example 5: Preparation of (2-aminophenyl)(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)methanone

[0091] The specific synthetic route is:

[0092] .

[0093] The specific preparation method is:

[0094] Add 2-amino- N -Hydroxybenzamide (0.4 mmol, 60.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0095] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-aminophenyl)(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)methanone, with a yield of 71%. Its H NMR spectrum is as follows Figure 3 As shown, the carbon NMR spectrum is Figure 4 The decomposition data of hydrogen spectrum and carbon spectrum are as follows:

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.6 Hz, 1H), 7.21 – 7.13 (m, 1H), 6.70 – 6.64 (m, 2H), 6.63 – 6.51 (m, 2H), 5.00 (s, 1H), 4.85 (s, 1H), 4.67(s, 2H), 2.38 – 2.28 (m, 1H), 2.25 – 2.17 (m, 1H), 1.56 – 1.46 (m, 2H).

[0097] 13 C NMR (101 MHz, CDCl3) δ 169.3 (s), 147.0 (s), 131.9 (s), 131.7 (s), 129.7 (s), 117.5 (s), 116.9 (s), 116.7 (s), 72.0 (s), 49.9 (s), 23.6(s),21.5(s).

[0098] Example 6: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(2-hydroxyphenyl)methanone

[0099] The specific synthetic route is:

[0100] .

[0101] The specific preparation method is:

[0102] Add the following to the reaction tube equipped with a magnet: N,2-dihydroxybenzamide (0.4 mmol, 61.2 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0103] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(2-hydroxyphenyl)methanone, with a yield of 92%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0104] 1 H NMR (400 MHz, CDCl3) δ 11.33 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.37– 7.30 (m, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.68 (t, J =6.8 Hz, 1H), 6.59 – 6.53 (m, 1H), 5.47 – 5.38 (m, 1H), 4.91 – 4.85 (m, 1H), 2.37 – 2.28 (m, 1H), 2.26 – 2.17 (m, 1H), 1.61 – 1.51 (m, 2H).

[0105] 13 C NMR (101 MHz, CDCl3) δ 169.0 (s), 161.0 (s), 133.7 (s), 132.7 (s), 132.1 (s), 130.5 (s), 118.2 (s), 117.7 (s), 115.0 (s), 72.7 (s), 47.8 (s), 23.4 (s), 21.0 (s).

[0106] Example 7: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-nitrophenyl)methanone

[0107] The specific synthetic route is:

[0108] .

[0109] The specific preparation method is:

[0110] Add the following to the reaction tube equipped with a magnet: N -Hydroxy-4-nitrobenzamide (0.4 mmol, 72.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0111] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(4-nitrophenyl)methanone, with a yield of 81%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0112] 1 H NMR (400 MHz, rotameric mixture) δ 8.09 – 7.45 (m, 4H), 6.69 (s, 0.8H), 6.50 (s, 1.2H), 5.40 (s, 0.8H), 4.71 (s, 1.2H), 2.31 – 2.13 (m, 2H),1.63 – 1.40 (m, 2H).

[0113] 13 C NMR (101 MHz, rotameric mixture) δ 168.9 (s), 134.4 (s), 133.1 (s), 131.8 (s), 130.8 (s), 128.6 (s), 128.1 (s), 72.0 (s), 47.3 (s), 23.6 (s), 21.2 (s).

[0114] Example 8: Preparation of 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)ethan-1-one

[0115] The specific synthetic route is:

[0116] .

[0117] The specific preparation method is:

[0118] To a reaction tube equipped with a magnetic bar, acetohydroxamic acid (0.4 mmol, 30.0 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added in sequence, followed by cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1).

[0119] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a yellow oily product, namely 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)ethan-1-one, with a yield of 64%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0120] 1 H NMR (600 MHz, CDCl3) δ 6.55 – 6.50 (m, 1H), 6.45 – 6.36 (m, 1H), 5.16 (s, 1H), 4.66 (s, 1H), 2.14 – 2.08 (m, 1H), 2.00 – 1.95 (m, 1H), 1.85 (s, 3H), 1.42 – 1.37 (m, 2H).

[0121] 13 C NMR (101 MHz, CDCl3) δ 170.1 (s), 132.8 (s), 131.2 (s), 71.7 (s), 46.1 (s), 23.4 (s), 21.0 (s), 20.8 (s).

[0122] Example 9: Preparation of 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-2,2-dimethylpropan-1-one

[0123] The specific synthetic route is:

[0124] .

[0125] The specific preparation method is:

[0126] (1) Using trimethylacetyl chloride as raw material, N -Synthesis method of hydroxy-4-(trifluoromethyl)benzamide N- Hydroxypivalamide.

[0127] (2) Add the following into the reaction tube equipped with a magnet: N- Hydroxypivalamide (0.4 mmol, 46.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely 1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-2,2-dimethylpropan-1-one, with a yield of 73%. Its carbon NMR spectrum is shown in Figure 5 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0128] 1 H NMR (400 MHz, CDCl3) δ 6.70 – 6.58 (m, 1H), 6.57 – 6.44 (m, 1H), 5.34 – 5.25 (m, 1H), 4.81 – 4.67 (m, 1H), 2.23 – 2.16 (m, 1H), 2.11 – 2.03 (m, 1H), 1.51 – 1.39 (m, 2H), 1.16 (s, 9H).

[0129] 13C NMR (101 MHz, CDCl3) δ 177.9 (s), 133.7 (s), 131.2 (s), 71.7 (s), 47.3 (s), 39.1 (s), 26.4 (s), 23.8 (s), 20.8 (s).

[0130] Example 10: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(cyclohexyl)methanone

[0131] The specific synthetic route is:

[0132] .

[0133] The specific preparation method is:

[0134] (1) Using cyclohexanecarbonyl chloride as raw material, according to Example 4 N -Synthesis method of hydroxy-4-(trifluoromethyl)benzamide N -Hydroxycyclohexanecarboxamide.

[0135] (2) Add the following into the reaction tube equipped with a magnet: N -Hydroxycyclohexanecarboxamide (0.4 mmol, 57.2 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(cyclohexyl)methanone, with a yield of 98%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0136] 1 H NMR (400 MHz, CDCl3) δ 6.60 (t, J = 6.9 Hz, 1H), 6.48 (t, J = 6.6 Hz,1H), 5.31 – 5.16 (m, 1H), 4.82 – 4.69 (m, 1H), 2.49 (t,J = 11.0 Hz, 1H), 2.25– 2.14 (m, 1H), 2.09 – 2.01 (m, 1H), 1.79 – 1.68 (m, 3H), 1.67 – 1.59 (m,2H), 1.51 – 1.38 (m, 3H), 1.29 – 1.16 (m, 4H).

[0137] 13 C NMR (101 MHz, CDCl3) δ 175.9 (s), 133.4 (s), 131.2 (s), 71.8 (s), 46.3 (s), 40.6 (s), 28.8 (s), 27.5 (s), 26.0 (s), 25.9 (s), 25.8 (s), 23.7(s), 21.1(s).

[0138] Example 11: Preparation of 2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxylic acid benzyl ester

[0139] The specific synthetic route is:

[0140] .

[0141] The specific preparation method is:

[0142] Benzyl hydroxycarbamate (0.4 mmol, 66.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added to a reaction tube equipped with a magnetic bar. Subsequently, cumene hydroperoxide (0.6 mmol, 108.5 μL) was added and stirred at 30 °C for 6 h. The reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely 2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxylic acid benzyl ester, with a yield of 98%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0143] 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 6.57 – 6.48 (m, 2H), 5.19 (d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 4.83 – 4.78 (m, 1H), 4.77 –4.72 (m, 1H), 2.23 – 2.16 (m, 1H), 2.15 – 2.08 (m, 1H), 1.52 – 1.43 (m, 1H),1.40 – 1.33 (m, 1H).

[0144] 13 C NMR (101 MHz, CDCl3) δ 158.1 (s), 136.0 (s), 132.0 (s), 131.7 (s), 128.5 (s), 128.2 (s), 128.1 (s), 71.1 (s), 67.7 (s), 50.2 (s), 23.5 (s), 20.6(s).

[0145] Example 12: Preparation of 2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxamide

[0146] The specific synthetic route is:

[0147] .

[0148] The specific preparation method is:

[0149] To a reaction tube equipped with a magnetic bar, 1-hydroxyurea (0.4 mmol, 30.4 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added in sequence, followed by cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely 2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxamide, with a yield of 92%. Its H NMR spectrum is as follows Figure 6 As shown, the carbon NMR spectrum is Figure 7 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0150] 1 H NMR (400 MHz, CDCl3) δ 6.59 – 6.53 (m, 1H), 6.53 – 6.45 (m, 1H), 5.34 (s, 2H), 4.93 – 4.87 (m, 1H), 4.72 – 4.63 (m, 1H), 2.20 – 2.07 (m, 2H), 1.56 – 1.47 (m, 1H), 1.39 – 1.31 (m, 1H).

[0151] 13 C NMR (101 MHz, CDCl3) δ 163.4 (s), 132.5 (s), 130.6 (s), 70.9 (s), 49.8 (s), 23.9 (s), 20.2 (s).

[0152] Example 13: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(thiophen-2-yl)methanone

[0153] The specific synthetic route is:

[0154] .

[0155] The specific preparation method is:

[0156] Add the following to the reaction tube equipped with a magnet: N-Hydroxythiophene-2-carboxamide (0.4 mmol, 57.2 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), geminal quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide or hydrogen peroxide (30%) (0.6 mmol, 108.5 μL), stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-yl)(thiophene-2-yl)methanone, with a yield of 99%. Its H NMR spectrum is as follows Figure 8 As shown, the carbon NMR spectrum is Fig. 9 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0157] 1 H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 3.2 Hz, 1H), 7.51 (dd, J = 5.0, 1.1Hz, 1H), 7.06 (dd, J = 4.9, 4.0 Hz, 1H), 6.70 (t, J = 7.1 Hz, 1H), 6.57 – 6.50(m, 1H), 5.42 (s, 1H), 4.97 – 4.89 (m, 1H), 2.32 – 2.27 (m, 1H), 2.23 – 2.18(m, 1H), 1.59 – 1.50 (m, 2H).

[0158] 13 C NMR (101 MHz, CDCl3) δ 162.1 (s), 135.2 (s), 133.7 (s), 133.4 (s), 132.1 (s), 131.5 (s), 126.8 (s), 72.5 (s), 47.8 (s), 23.7 (s), 20.8 (s).

[0159] Example 14: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(furan-3-yl)methanone

[0160] The specific synthetic route is:

[0161] .

[0162] The specific preparation method is:

[0163] Add the following to the reaction tube equipped with a magnet: N -Hydroxyfuran-3-carboxamide (0.4 mmol, 50.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirred at 30 °C for 6 hours, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-yl)(furan-3-yl)methanone, with a yield of 99%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0164] 1 H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.35 (t, J = 1.6 Hz, 1H), 6.83(s, 1H), 6.68 (t, J = 6.7 Hz, 1H), 6.56 – 6.51 (m, 1H), 5.40 (s, 1H), 4.88 –4.83 (m, 1H), 2.31 – 2.24 (m, 1H), 2.20 – 2.14 (m, 1H), 1.58 – 1.50 (m, 2H).

[0165] 13 C NMR (101 MHz, CDCl3) δ 162.5 (s), 147.1 (s), 142.3 (s), 133.2 (s), 131.5 (s), 120.4 (s), 111.2 (s), 72.3 (s), 47.2 (s), 23.7 (s), 21.0 (s).

[0166] Example 15: Preparation of (2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)(naphthalen-2-yl)methanone

[0167] The specific synthetic route is:

[0168] .

[0169] The specific preparation method is:

[0170] (1) Using 2-naphthoyl chloride as raw material, N -Synthesis method of hydroxy-4-(trifluoromethyl)benzamide N- Hydroxy-2-naphthamide.

[0171] (2) Add the following into the reaction tube equipped with a magnet: N- Hydroxy-2-naphthamide (0.4 mmol, 72.8 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely (2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-yl)(naphthalene-2-yl)methanone, with a yield of 89%. Its H NMR spectrum is as follows Fig.10 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0172] 1 H NMR (400 MHz, rotameric mixture) δ 8.19 (s, 1H), 7.94 – 7.87 (m,1H), 7.83 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.59 – 7.42 (m, 2H), 6.67 (s,0.7H), 6.55 (s, 1.3H), 5.42 (s, 0.7H), 4.81 (s, 1.3H), 2.46 – 2.22 (m, 2H), 1.64 – 1.45 (m, 2H).

[0173] 13 C NMR (101 MHz, rotameric mixture) δ 169.3 (s), 134.4 (s), 132.5(s), 131.9 (s), 131.7 (s), 129.2 (s), 129.0 (s), 127.8 (s), 127.5 (s), 126.5(s), 125.4 (s), 72.1 (s), 47.7 (s), 23.6 (s), 21.3 (s).

[0174] Example 16: Preparation of 3-phenyl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene

[0175] The specific synthetic route is:

[0176] .

[0177] The specific preparation method is:

[0178] Add the following to the reaction tube equipped with a magnet: N -phenylhydroxylamine (0.4 mmol, 43.6 mg), 1,3-cyclohexadiene (0.8 mmol, 76.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of hydrogen peroxide (30%) (0.6 mmol, 46.5 μL), stirred at 30 ° C for 12 hours, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the reaction was completed, the reaction was quenched with saturated Na2S2O3 solution, then extracted with ethyl acetate (5 mL*3), the organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio) to obtain a white solid product, namely 3-phenyl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene, with a yield of 76%. Its H NMR spectrum is Fig.11 As shown, the carbon NMR spectrum is Fig.12 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0179] 1 H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.9 Hz, 2H), 7.02 (d, J = 7.7 Hz,2H), 6.93 (t, J= 7.3 Hz, 1H), 6.63 – 6.53 (m, 1H), 6.20 – 6.09 (m, 1H), 4.75 –4.67 (m, 1H), 4.48 – 4.41 (m, 1H), 2.34 – 2.20 (m, 2H), 1.63 – 1.54 (m, 1H),1.42 – 1.34 (m, 1H).

[0180] 13 C NMR (101 MHz, CDCl3) δ 152.4 (s), 131.7 (s), 130.1 (s), 128.4 (s), 122.0 (s), 117.5 (s), 69.2 (s), 56.6 (s), 24.1 (s), 21.5 (s).

[0181] Example 17: (4,5-dimethyl-3,6-dihydro-2 H Preparation of 1,2-oxazin-2-yl) (phenyl)methanone

[0182] The specific synthetic route is:

[0183] .

[0184] The specific preparation method is:

[0185] Benzohydroxamic acid (0.4 mmol, 54.8 mg), 2,3-dimethyl-1,3-butadiene (0.8 mmol, 90.5 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added to a reaction tube equipped with a magnetic bar, followed by adding cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30°C for 12 hours, and the reaction progress was monitored by thin layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluent: petroleum ether: ethyl acetate = 10:1) to obtain a colorless oily product, namely (4,5-dimethyl-3,6-dihydro-2 H -1,2-oxazine-2-yl) (phenyl) ketone, the yield is 90%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0186] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d,J = 7.1 Hz, 2H), 7.48 – 7.44 (m, 1H), 7.40 (t, J = 7.3 Hz, 2H), 4.17 (s, 2H), 4.13 (s, 2H), 1.70 (s, 3H), 1.58 (s, 3H).

[0187] 13 C NMR (151 MHz, CDCl3) δ 169.6 (s), 133.8 (s), 130.9 (s), 128.5 (s), 128.0 (s), 122.8 (s), 121.9 (s), 72.8 (s), 46.6 (s), 15.5 (s), 13.8 (s).

[0188] Example 18: (3,6-dihydro-2 H Preparation of 1,2-oxazin-2-yl)(phenyl)methanone

[0189] The specific synthetic route is:

[0190] .

[0191] The specific preparation method is:

[0192] Benzohydroxamic acid (0.4 mmol, 54.8 mg), 1,3-butadiene (1.9 mol / L n-hexane) (0.8 mmol, 421.1 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added to a reaction tube equipped with a magnetic bar, followed by adding cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30°C for 12 hours, and the reaction progress was monitored by thin layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluent: petroleum ether: ethyl acetate = 4:1) to obtain a yellow oily product, namely (3,6-dihydro-2 H -1,2-oxazine-2-yl)(phenyl)methanone, the yield is 73%. Its nuclear magnetic resonance hydrogen spectrum is as follows Fig.13 As shown, the carbon NMR spectrum is Fig.14 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0193] 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2 Hz,1H), 7.41 (t, J = 7.4 Hz, 2H), 5.94 – 5.85 (m, 2H), 4.41 – 4.34 (m, 4H).

[0194] 13 C NMR (151 MHz, CDCl3) δ 170.0 (s), 133.8 (s), 131.1 (s), 128.5 (s), 128.1 (s), 124.0 (s), 122.6 (s), 70.0 (s), 43.7 (s).

[0195] Example 19: Preparation of (7-oxa-8-azabicyclo[4.2.2]dec-9-en-8-yl)(phenyl)methanone

[0196] The specific synthetic route is:

[0197] .

[0198] The specific preparation method is:

[0199] Benzohydroxamic acid (0.4 mmol, 54.8 mg), 1,3-cyclooctadiene (0.8 mmol, 114.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added to a reaction tube equipped with a magnetic bar, followed by cumene hydroperoxide (0.6 mmol, 108.5 μL). The mixture was stirred at 30 °C for 12 h, and the reaction progress was monitored by thin layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5mL*3). The organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluent: petroleum ether: ethyl acetate = 10:1) to obtain a yellow oily product, namely (7-oxa-8-azabicyclo[4.2.2]dec-9-en-8-yl)(phenyl)methanone, with a yield of 84%. The decomposition data of its hydrogen spectrum and carbon spectrum are:

[0200] 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.48 (m, 2H), 7.48 – 7.31 (m, 3H), 6.44 – 6.08 (m, 1H), 5.92 (s, 1H), 5.26 (s, 1H), 4,78 – 4.30 (m, 1H), 2.42 –1.57 (m, 8H).

[0201] 13 C NMR (101 MHz, CDCl3) δ 167.9 (s), 134.8 (s), 130.9 (s), 130.4 (s), 128.6 (s), 127.8 (s), 127.1 (s), 77.3 (s), 51.0 (s), 34.7 (s), 31.4 (s), 25.0(s), 22.9(s).

[0202] Example 20: Phenyl (6-phenyl-3,6-dihydro-2 H Preparation of 1,2-oxazin-2-yl)methanone

[0203] The specific synthetic route is:

[0204] .

[0205] The specific preparation method is:

[0206] To a reaction tube equipped with a magnetic bar, benzohydroxamic acid (0.4 mmol, 54.8 mg), ( E )-1-phenyl-1,3-butadiene (0.8 mmol, 119.0 μL), gemini quaternary ammonium iodide (2.5 mol%, 7.2 mg) and 2 mL of water were added, followed by the addition of cumene hydroperoxide (0.6 mmol, 108.5 μL), stirring at 30°C for 12 hours, and the reaction progress was monitored by thin layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (5 mL*3), the organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluent: petroleum ether: ethyl acetate = 10:1) to obtain a light yellow oily product, namely phenyl (6-phenyl-3,6-dihydro-2 H -1,2-oxazine-2-yl)methanone, the yield is 72%. Its nuclear magnetic resonance hydrogen spectrum is as follows Fig.15 As shown, the carbon NMR spectrum is Fig.16 The decomposition data of its hydrogen spectrum and carbon spectrum are as follows:

[0207] 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz,1H), 7.31 – 7.20 (m, 5H), 7.14 (d, J = 6.9 Hz, 2H), 6.07 (d, J = 10.3 Hz, 1H),5.95 (d, J = 10.4 Hz, 1H), 5.36 (s, 1H), 4.56 (d, J = 17.8 Hz, 1H), 4.37 (d, J =17.8 Hz, 1H).

[0208] 13 C NMR (101 MHz, CDCl3) δ 170.0 (s), 136.1 (s), 133.5 (s), 130.5 (s), 129.2 (s), 128.7 (s), 128.5 (s), 128.5 (s), 127.6 (s), 126.4 (s), 123.4 (s), 80.9 (s), 42.8 (s).

[0209] Example 21: Amplification experiment of Example 1 at different dosages of gemini quaternary ammonium iodide salts

[0210] The specific synthetic route is:

[0211] .

[0212] The specific preparation method is:

[0213] Benzohydroxamic acid (4 mmol, 548 mg), 1,3-cyclohexadiene (8 mmol, 760 μL), gemini quaternary ammonium iodide (0.5%~2.5 mol%) and 20 ml of water were added to a round-bottom flask equipped with a magnetic rod, followed by adding cumene hydroperoxide (6 mmol, 1085 μL), stirring at 30°C, and monitoring the reaction progress by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 1:1). After the complete conversion of benzohydroxamic acid, the reaction was quenched with a saturated Na2S2O3 solution, and then extracted with ethyl acetate (20 mL*3), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 1:1 volume ratio). The characterization of hydrogen and carbon nuclear magnetic resonance spectra was the same as in Example 1. The relationship between reaction time and yield at different catalyst loadings is shown in Table 1 below.

[0214] Table 1 Relationship between reaction time and yield at different catalyst loadings

[0215]

[0216] As can be seen from Table 1, after the reaction scale is enlarged, even if the catalyst loading is reduced to 0.5 mol%, the target product can be obtained with excellent yield after the reaction time is appropriately extended to 12 hours. This fully proves the high efficiency of the catalytic oxidation system of the present invention and is suitable for industrial production.

[0217] Comparative Example 1

[0218] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide and cumene hydroperoxide is replaced by 0.6 mmol NaIO4.

[0219] Comparative Example 2

[0220] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide salt and cumene hydroperoxide is replaced by 0.6 mmol PhI(OCOCF3)2.

[0221] Comparative Example 3

[0222] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide and cumene hydroperoxide is replaced by 0.6 mmol I2.

[0223] Comparative Example 4

[0224] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide and cumene hydroperoxide is replaced by 0.6 mmol CHP.

[0225] Comparative Example 5

[0226] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide and cumene hydroperoxide is replaced by 0.6 mmol H2O2.

[0227] Comparative Example 6

[0228] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide and cumene hydroperoxide is replaced by 0.6 mmol m -CPBA.

[0229] Comparative Example 7

[0230] The difference from Example 1 is that the combination of gemini quaternary ammonium iodide and cumene hydroperoxide is replaced by 0.6 mmol Na2S2O8.

[0231] Comparative Example 8

[0232] The difference from Example 1 is that the gemini quaternary ammonium iodide salt is replaced by an equimolar amount of KI.

[0233] Comparative Example 9

[0234] The difference from Example 1 is that the gemini quaternary ammonium iodide salt is replaced with an equimolar amount of dodecyltrimethylammonium iodide (TMDAI).

[0235] Comparative Example 10

[0236] The difference from Example 1 is that the gemini quaternary ammonium iodide salt is replaced by an equimolar amount of dodecyltrimethylammonium bromide (TMDAB).

[0237] The product yields of Comparative Examples 1 to 10 are shown in Table 2.

[0238] Table 2 Yield of each comparative example

[0239]

[0240] As can be seen from Table 2, Comparative Examples 1 to 3 use some common inorganic or organic high-valent iodine reagents and iodine (including NaIO4, PhI(OCOCF3)2, I2) to replace the catalytic oxidation system composed of iodine salt and peroxide in the present invention, and it is found that only when PhI(OCOCF3)2 is used as an oxidant, a medium yield is obtained. Relatively speaking, when inorganic high-valent iodine or iodine is used as an oxidant, only a trace yield is obtained.

[0241] In Comparative Examples 4 to 7, some common organic or inorganic peroxides (including CHP, H2O2, m-CPBA and Na2S2O8) were used to replace the catalytic oxidation system composed of iodine salt and CHP in the present invention, but no product was obtained. This shows that it is difficult to achieve the oxidation of substituted hydroxylamine in the aqueous phase by peroxide alone. Only when iodine salt and peroxide are combined, the reaction can proceed smoothly.

[0242] In addition, Comparative Examples 8 to 10 show the results when KI, TMDAI or TMDAB are used as catalysts, and the product yield obtained is much lower than that of Example 1. Therefore, the use of gemini quaternary ammonium iodide salts as catalysts is the key to obtaining 3,6-dihydro-1,2-oxazine compounds in high yield. This may be attributed to the lower critical micelle concentration and higher surface activity of gemini quaternary ammonium iodide salts, which can better play the role of micelle catalysis.

[0243] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing 3,6-dihydro-1,2-oxazine derivatives by iodine catalysis in aqueous phase, characterized in that: The method is: Using substituted hydroxylamine and conjugated diene as substrates, gemini quaternary ammonium iodide salt as catalyst and surfactant, peroxide as oxidant, and water as solvent, a 3,6-dihydro-1,2-oxazine derivative is obtained by stirring reaction; The substituted hydroxylamine is selected from benzohydroxamic acid, 3-bromo- N -Hydroxybenzamide, N -Hydroxy-4-methoxybenzamide, N -Hydroxy-4-(trifluoromethyl)benzamide, 2-amino- N -Hydroxybenzamide, N , 2-dihydroxybenzamide, N -Hydroxy-4-nitrobenzamide, acetohydroxamic acid, N -Hydroxypivalamide, N -Hydroxycyclohexanecarboxamide, hydroxy benzyl carbamate, 1-hydroxyurea, N -Hydroxythiophene-2-carboxamide, N -Hydroxyfuran-3-carboxamide, N -Hydroxy-2-naphthylamide or N -phenylhydroxylamine; The conjugated diene is selected from 1,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene, 1,3-butadiene, 1,3-cyclooctadiene, ( E )-1-phenyl-1,3-butadiene; The structural formula of the gemini quaternary ammonium iodide salt is: Among them, y=1 or 2, z=10 or 16.

2. The method according to claim 1, characterized in that The peroxide is cumene hydroperoxide or a hydrogen peroxide solution; the mass concentration of the hydrogen peroxide solution is 30%.

3. The method according to claim 1, characterized in that The molar ratio of the substituted hydroxylamine, the conjugated diene and the oxidant is 1:2:1.5; the amount of the gemini quaternary ammonium iodide salt is 0.5-5.0% of the molar amount of the substituted hydroxylamine.

4. The method according to claim 1, characterized in that: The stirring reaction is carried out at a temperature of 20 to 40° C. and for a time of 6 to 24 hours.

Images