Polysubstituted benzoxazolizine compound, preparation method and application

Abstract

The invention relates to the technical field of organic synthesis, in particular to a polysubstituted benzoxazolizine compound as well as a preparation method and application thereof, the structural formula of the compound is as shown in formula I, # imgabs0 # R is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R1 is alkyl and substituted alkyl, R2 and R3 are hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, and R2 and R3 are hydrogen, alkyl and substituted alkyl, aryl and substituted aryl. R4, R5 and R6 are hydrogen, alkyl and substituted alkyl. The polysubstituted benzoxazolizine compound disclosed by the invention has certain biological activity and medicinal value, and can be used as a potential medicine or a candidate medicine; the preparation method disclosed by the invention is simple and convenient, easy to operate, concise in synthesis, economical and friendly in catalyst, environment-friendly and clean in solvent, simple and convenient in preparation method, simple in synthesis route, low in economic cost and relatively high in yield.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and specifically relates to polysubstituted benzoxazine compounds, a preparation method, and uses thereof. Background Art

[0002] Nitrogen- and oxygen-containing heterocyclic compounds are widely present in nature. In particular, bridged heterocyclic compounds containing an eight-membered ring are particularly attractive because these molecules with functional groups of a similar cleavage shape have recently become useful tools in molecular recognition research. Among the members of this family, benzoxazine compounds have received extensive attention due to their important pharmaceutical properties, including analgesic, antithrombotic, anticancer, and antioxidant activities. For example, nefopam has analgesic activity and acts on supraspinal and spinal sites. Marfey's reagent A has significant cytotoxicity against some cancer cell lines, especially the human colon cancer cell line HCT-116. The new 1,6-benzoxazolin-5-one alkaloids have significant antioxidant activity. In this regard, although benz[d][1,3]oxazine drugs contain tetrahydroquinoline and N,O-acetal moieties that are commonly present in natural products and drug molecules, their research is less. In addition, due to entropy reasons and ring strain, the construction of medium-sized heterocycles, especially eight-membered rings, remains an important synthetic challenge target in modern organic synthesis. Therefore, it is particularly important to seek an effective and convenient method for preparing benzoxazine compounds.

[0003] Currently, there are only a few reports on the synthesis of benzoxazine compounds. The Taheri group reported the dearomatization reaction of quinolinium salts with phenolic compounds to synthesize benzoxazine compounds (ARKIVOC, 2010, 11, 91; Helv. Chim. Acta, 2011, 94, 142.) (corresponding to 1 below). The Mondal group developed a tandem reaction of hydroxyquinoline / isoquinoline with quinolinium salts catalyzed by basic alumina under microwave conditions to construct bridged polycyclic quinoline / isoquinoline benzoxazine compounds, which provides a simple and effective route for the construction of multinuclear bridged oxazines (Tetrahedron Lett., 2011, 52, 4697) (corresponding to 2 below). The Xie Wenqing team developed the visible-light-driven synthesis of polycyclic benz[d][1,3]oxazine compounds from 2-aminobenzalacetophenone (RSC Adv. 2019, 9, 29005; Chem. Commun. 2020, 56, 6739) (corresponding to 3 below).

[0004]

[0005] In summary, the methods for synthesizing benzoxazine compounds are single, and the lack of substrate diversity and structural diversity limits their development. Therefore, the synthesis of polysubstituted benzoxazines still faces great challenges. Summary of the Invention

[0006] <Technical Problem Solved by the Invention>

[0007] In the current methods for synthesizing benzoxazine, there are problems such as low reaction yield, many reaction steps, long reaction time, and poor product diversity.

[0008] <Technical Solution Adopted by the Invention>

[0009] In view of the above technical problems, the present invention provides multi-substituted benzoxazine compounds, a preparation method, and uses thereof.

[0010] First, the present invention provides a multi-substituted benzoxazine compound, the structural formula of which is shown in Formula I,

[0011]

[0012] wherein, R is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 1 is alkyl and substituted alkyl, R 2 , R 3 is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 4 , R 5 , R 6 is hydrogen, alkyl and substituted alkyl.

[0013] Second, the present invention provides a preparation method of the aforementioned multi-substituted benzoxazine compound, comprising the following steps: mixing a quinoline quaternary ammonium salt derivative with allyl alcohol, a solvent, a catalyst, and a reducing agent, and reacting to obtain a multi-substituted benzoxazine compound; the synthesis route is,

[0014]

[0015] R is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 1 is alkyl and substituted alkyl, R 2 , R 3 is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 4 , R 5 , R 6 is hydrogen, alkyl and substituted alkyl.

[0016] Third, the use of the compound shown in Formula I, or its crystal form, or its pharmaceutically acceptable salt in anti-cancer, anti-malaria, anti-viral, anti-bacterial, anti-fungal, and anti-inflammatory applications.

[0017] <Beneficial Effects Achieved by the Invention>

[0018] (1) The multi-substituted benzoxazine compounds of the present invention have certain biological activities and can be used as potential drugs or drug candidates for anti-cancer, anti-malaria, anti-virus, anti-bacteria, anti-fungi, and anti-inflammatory novel multi-substituted benzoxazine compounds.

[0019] (2) The catalyst of the present invention is economically friendly, the solvent is environmentally friendly and clean, the preparation method is simple and convenient, the synthesis route is simple, the economic cost is low, and the yield is relatively high. Specific Embodiments

[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Those not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments not indicated by the manufacturer can be obtained as conventional products through commercial purchase.

[0021] First, the present invention provides a multi-substituted benzoxazine compound, characterized in that the structural formula of the compound is shown in Formula I,

[0022]

[0023] wherein, R is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 1 is alkyl and substituted alkyl, R 2 , R 3 are hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 4 , R 5 , R 6 are hydrogen or alkyl and substituted alkyl.

[0024] For the above R, R 1 -R 6 herein, the number of carbon atoms in "aryl" is not limited. Preferably, it can be an aryl of C6-C20, and more preferably, it can be an aryl of C6-C10. "Aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or polycyclic (i.e., fused-ring aryl) fused together or a covalently linked monocyclic or polycyclic.

[0025] For the above R, R 1 -R 6 herein, "alkyl" is a linear, branched or cyclic alkyl, and the number of carbon atoms is not limited. Preferably, it can be a linear, branched or cyclic alkyl of C1-C20, and more preferably, it can be a linear, branched or cyclic alkyl of C1-C12.

[0026] For the above R, R 1 -R 6In it, the "substituents in the substituted aryl" and the "substituents in the substituted alkyl" are selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, acyloxy, amino, nitro, and mercapto. Among them, the substitution in the "substituted aryl" or "substituted alkyl" can be mono-substitution or multi-substitution. "Substituted" means that one or more bonds of the hydrogen atoms contained in the aforementioned organic group are replaced by one or more bonds with non-hydrogen atoms.

[0027] For the substituent "alkyl", it can specifically be a linear, branched or cyclic alkyl having 1 to 20 carbon atoms. Preferably, it can be a linear, branched or cyclic alkyl having 2 to 15 carbon atoms. More preferably, it can be a linear, branched or cyclic alkyl having 2 to 12 carbon atoms.

[0028] For the substituent "haloalkyl", the halogen can be selected from fluorine, chlorine, bromine, and iodine; the alkyl can be selected from linear, branched or cyclic alkyl having 1 to 20 carbon atoms, preferably a linear, branched or cyclic alkyl having 2 to 15 carbon atoms. "Haloalkyl" can be a mono-haloalkyl, a multi-haloalkyl or a per-haloalkyl. For example, the term "halo(C1-C12)alkyl" includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0029] For the substituent "alkenyl", it can specifically be a linear or branched alkenyl having 2 to 12 carbon atoms. There is at least one double bond between two carbon atoms of the alkenyl. Examples include but are not limited to: vinyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, butadienyl, pentadienyl, and hexadienyl, etc.

[0030] For the substituent "alkynyl", it includes linear and branched alkynyl, and there is at least one triple bond between two carbon atoms. Examples include but are not limited to: -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc.

[0031] For the substituent "halogen", it is selected from fluorine, chlorine, bromine, and iodine.

[0032] For the substituent "alkoxy", it is selected from alkoxy having 1 to 12 carbon atoms.

[0033] For the substituent "amino", substituents in the form of -NH2, -NHR, -NR2, -NR3 + Specifically, it can be a primary, secondary, tertiary or quaternary amino group.

[0034] For each of the aforementioned substituents, it is further preferably that R is an alkyl or substituted alkyl having 1 to 10 carbon atoms, an aryl or substituted aryl having 6 to 10 carbon atoms, R 1 is an alkyl or substituted alkyl having 1 to 20 carbon atoms, R 2 、R 3 is an alkyl or substituted alkyl having 1 to 10 carbon atoms, an aryl or substituted aryl having 6 to 10 carbon atoms, R 4 、R 5 、R 6 is an alkyl or substituted alkyl having 1 to 10 carbon atoms.

[0035] For each of the aforementioned substituents, it is further preferably that R is hydrogen, an alkyl or substituted alkyl having 1 to 10 carbon atoms, an aryl or substituted aryl having 6 to 10 carbon atoms, R 1 is hydrogen, an alkyl or substituted alkyl having 1 to 20 carbon atoms, R 2 、R 3 is an alkyl or substituted alkyl having 1 to 10 carbon atoms, an aryl or substituted aryl having 6 to 10 carbon atoms, R 4 、R 5 、R 6 is an alkyl or substituted alkyl having 1 to 8 carbon atoms.

[0036] Second, the present invention provides a method for preparing the aforementioned multi-substituted benzoxazine compounds, comprising the following steps: mixing a quinoline quaternary ammonium salt derivative with allyl alcohol, a solvent, a catalyst, and a reducing agent, and reacting to obtain a multi-substituted benzoxazine compound; the reaction route is:

[0037]

[0038] R is hydrogen, an alkyl or substituted alkyl, an aryl or substituted aryl, R 1 is an alkyl or substituted alkyl, R 2 、R 3 is hydrogen, an alkyl or substituted alkyl, an aryl or substituted aryl, R 4 、R 5 、R 6 is hydrogen, an alkyl or substituted alkyl.

[0039] In the present invention, the molar ratio of the quinoline quaternary ammonium salt derivative to allyl alcohol is 1:0.1 to 10.

[0040] In the present invention, the molar ratio of the quinoline quaternary ammonium salt derivative to the catalyst is 1:0.01 to 5.

[0041] In the present invention, the molar ratio of the quinoline quaternary ammonium salt derivative to the reducing agent is 1:1 to 7.

[0042] In the present invention, the reaction time is 1 to 24 h; the reaction temperature ranges from room temperature to reflux; the product after the reaction is separated and purified to obtain the target product, and recrystallization or column chromatography separation methods are used for separation and purification.

[0043] In the present invention, the solvent includes at least one of toluene, 1,4-dioxane, benzene, ethylene glycol dimethyl ether, dichloromethane, ethanol, DMF, DMA, isopropanol, n-butanol, 1,2-dichloroethane, methanol, tetrahydrofuran, ether, acetonitrile, or DMSO. Further preferably, the solvent includes at least one of 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, ethanol, isopropanol, n-butanol, 1,2-dichloroethane, methanol, tetrahydrofuran, ether, acetonitrile.

[0044] In the present invention, the catalyst includes at least one of ZnCl2, Ni(acac)2, CuSO4, Zn(OTf)2, Pd(OAc)2, FeSO4, Fe(acac)3, FeCl3, Fe(ox)3·6H2O, FeBr3, Co(acac)2, Cu(acac)2, MnCl2·4H2O, or La(OTf)3. Further preferably, the catalyst includes at least one of Fe(acac)3, FeCl3, Fe(ox)3·6H2O, FeBr3, FeCl2·4H2O, Co(acac)2, Cu(acac)2, Fe(NO3)3·9H2O.

[0045] In the present invention, the reducing agent includes at least one of HCOOH, NaBH4, NaCNBH3, Ph2SiH2, HSiCl3, (EtO)3SiH, Et3SiH, PhSiH3, Ph3SiH, PhSiHMe, or PMHS. Further preferably, the reducing agent includes at least one of Et3SiH, (EtO)3SiH, NaBH4, PhSiHMe, HSiCl3, PhHSiCl2, PhSiH3, Ph2SiH2, PMHS.

[0046] Third, the use of the compound shown in Formula I, or its crystal form, or its pharmaceutically acceptable salt in anti-cancer, anti-malaria, anti-viral, anti-bacterial, anti-fungal, and anti-inflammatory applications.

[0047] "Pharmaceutically acceptable salt" refers to non-toxic inorganic acid or organic acid and / or base addition salts.

[0048] Among them, the "salt" can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0049] <Example>

[0050] Example 1

[0051] A preparation method of polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of a mixed solvent of ethanol and 1,2-dichloroethane (mixed in any ratio) is added, 2.1 g of 2-methylallyl alcohol and 2.3 g of phenylsilane are weighed, reacted at 50 °C for 4 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 2.2 g of a white solid with a yield of 82%.

[0052] The product is 1-benzyl-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo[d] [1,3]oxazocine (3a)

[0053]

[0054] White solid; m.p. 92-95 °C; R f = 0.50 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.37 - 7.31 (m, 2H), 7.27 (d, J = 8.11 Hz, 3H), 7.06 (t, J = 7.47 Hz, 1H), 6.99 (d, J = 6.92 Hz, 1H), 6.67 (t, J = 7.29 Hz, 1H), 6.57 (d, J = 8.17 Hz, 1H), 4.95 (s, 1H), 4.74 (d, J = 17.41 Hz, 1H), 4.59 (d, J = 17.41 Hz, 1H), 3.16 (s, 2H), 2.58 (s, 1H), 2.55 (s, 1H), 1.73 (d, J = 11.15 Hz, 1H), 1.30 (s, 3H), 0.70 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.3, 138.9, 130.3, 128.7, 127.6, 126.9, 126.3, 125.0, 116.4, 110.5, 81.3, 68.0, 51.9, 42.1, 34.0, 26.7, 25.4, 25.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 24 NO 294.1852; found 294.1856.

[0055] Example 2

[0056] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: sequentially add 2.5 g of quinoline quaternary salt and 1.1 g of iron acetylacetonate into a reaction flask, add 15 ml of ethanol, weigh 2.0 g of cyclopent-1-en-1-yl methanol and 1.1 g of polymethylhydrosiloxane, reflux and react for 3 h, quench with water, extract with ethyl acetate, and separate by column chromatography to obtain 2.3 g of white solid, with a yield of 75%.

[0057] The product is 1'-benzyl-1',6'-dihydro-2'H,4'H-spiro[cyclopentane-1,5'-[2,6] methanobenzo[d][1,3]oxazocine] (3b)

[0058]

[0059] White solid, m.p. 82 - 84 °C; R f = 0.63 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.37 - 7.28 (m, 2H), 7.24 (dd, J = 15.09, 7.67 Hz, 3H), 7.09 - 6.95 (m, 2H), 6.66 (t, J = 7.25 Hz, 1H), 6.55 (d, J = 8.06 Hz, 1H), 4.93 (s, 1H), 4.73 (d, J = 17.42 Hz, 1H), 4.58 (d, J = 17.39 Hz, 1H), 3.19 (s, 2H), 2.63 (s, 1H), 2.40 (d, J = 12.57 Hz, 1H), 2.11 (td, J = 7.81, 3.69 Hz, 1H), 1.78 (d, J = 11.47 Hz, 2H), 1.70 - 1.58 (m, 2H), 1.54 (dt, J = 16.17, 7.17 Hz, 3H), 0.85 - 0.71 (m, 1H). 13 13C NMR (101 MHz, CDCl3): δ 145.5, 139.0, 129.7, 128.7, 127.7, 126.9, 126.3, 125.6, 116.6, 110.4, 81.5, 66.3, 52.2, 46.8, 41.6, 36.0, 34.7, 28.0, 25.1, 24.3. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 22 H 26 NO 320.2008; found 320.2012.

[0060] Example 3

[0061] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of methanol is added, 2.2 g of cyclohex-1-en-1-yl methanol and 1.3 g of polymethylhydrosiloxane are weighed, and the mixture is refluxed for 5 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 2.4 g of a white solid with a yield of 86%.

[0062] The product is 1'-benzyl-1',6'-dihydro-2'H,4'H-spiro[cyclohexane-1,5'-[2,6] methanobenzo[d][1,3]oxazocine] (3c)

[0063]

[0064] White solid, m.p. 86 - 88 °C; R f = 0.61 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.38 - 7.26 (m, 2H), 7.22 (dd, J = 15.51, 7.30 Hz, 3H), 7.01 (t, J = 8.45 Hz, 2H), 6.63 (t, J = 7.26 Hz, 1H), 6.55 (d, J = 8.05 Hz, 1H), 4.90 (s, 1H), 4.70 (d, J = 17.41 Hz, 1H), 4.55 (d, J = 17.37 Hz, 1H), 3.49 (d, J = 11.76 Hz, 1H), 3.07 (d, J = 11.79 Hz, 1H), 2.71 (s, 1H), 2.53 (d, J = 12.76 Hz, 1H), 2.05 - 1.96 (m, 1H), 1.64 (d, J = 13.71 Hz, 2H), 1.58 - 1.47 (m, 4H), 1.41 - 1.31 (m, 1H), 1.16 (dq, J = 21.32, 9.98 Hz, 2H), 0.94 (d, J = 16.01 Hz, 1H). 13 13C NMR (101 MHz, CDCl3): δ 145.5, 139.0, 130.1, 128.8, 127.7, 127.0, 126.4, 124.6, 116.5, 110.6, 81.8, 65.5, 52.1, 36.2, 34.4, 32.4, 26.6, 26.1, 22.1, 21.6. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 23 H 28 NO 334.2165; found 334.2173.

[0065] Example 4

[0066] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.4 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.3 g of 2-methyl-1-phenylprop-2-en-1-ol and 2.1 g of diphenylsilane are weighed, and the reaction is carried out at 50 °C for 5 h. The reaction is quenched by adding water, extracted with ethyl acetate, and separated by column chromatography to obtain 1.8 g of a white solid with a yield of 75%.

[0067] The product is 1-benzyl-5,5-dimethyl-4-phenyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3d)

[0068]

[0069] White solid, m.p. 172 - 175 °C; R f = 0.44 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 7.27 Hz, 2H), 7.24 (s, 3H), 7.22 (s, 3H), 7.20 (s, 2H), 7.13 - 7.00 (m, 2H), 6.70 (t, J = 7.34 Hz, 1H), 6.59 (d, J = 8.16 Hz, 1H), 5.12 (s, 1H), 4.72 (d, J = 17.48 Hz, 1H), 4.56 (d, J = 17.46 Hz, 1H), 4.27 (s, 1H), 2.78 - 2.69 (m, 1H), 2.68 (s, 1H), 1.82 (d, J = 12.47 Hz, 1H), 1.01 (s, 3H), 0.73 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.6, 139.2, 138.9, 130.6, 128.7, 128.2, 127.9, 127.4, 127.2, 126.9, 126.4, 124.8, 116.6, 110.6, 82.7, 77.5, 52.2, 44.5, 37.4, 26.9, 26.2, 21.5. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 28 NO3 70.2165; found 370.2170.

[0070] Example 5

[0071] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.2 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 1.7 g of 1-(2-methylphenyl)-2-methylallyl-1-ol and 2.3 g of diphenylsilane are weighed, and the mixture is refluxed for 8 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 2.1 g of a white solid with a yield of 78%.

[0072] The product is 1-benzyl-5,5-dimethyl-4-(o-tolyl)-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3e)

[0073]

[0074] White solid, m.p. 145 - 147 °C; R f = 0.33 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 7.63 Hz, 1H), 7.32 (d, J = 7.67 Hz, 3H), 7.30 - 7.22 (m, 3H), 7.20 (t, J = 7.24 Hz, 1H), 7.15 (d, J = 7.47 Hz, 1H), 7.12 (d, J = 6.83 Hz, 1H), 7.08 (d, J = 7.01 Hz, 1H), 6.75 (t, J = 7.33 Hz, 1H), 6.67 (d, J = 8.16 Hz, 1H), 5.17 (s, 1H), 4.80 (d, J = 17.40 Hz, 1H), 4.74 (s, 1H), 4.62 (d, J = 17.39 Hz, 1H), 2.84 - 2.78 (m, 1H), 2.75 (s, 1H), 2.06 (s, 3H), 1.94 - 1.87 (m, 1H), 1.22 (s, 3H), 0.73 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.7, 139.0, 137.5, 135.9, 130.6, 130.0, 129.1, 128.7, 127.9, 127.1, 126.9, 126.4, 125.3, 124.8, 116.6, 110.5, 83.1, 72.0, 52.4, 44.8, 38.8, 26.9, 25.7, 22.1, 20.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 27 H 30 NO 384.2321; found 384.2329.

[0075] Example 6

[0076] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: sequentially add 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate into a reaction flask, add 15 ml of ethanol, weigh 3.0 g of 1-(2-chlorophenyl)-2-methylallyl-1-ol and 2.2 g of diphenylsilane, reflux and react for 5 h, quench with water, extract with ethyl acetate, and separate by column chromatography to obtain 2.6 g of a white solid with a yield of 82%.

[0077] The product is 1-benzyl-4-(2-chlorophenyl)-5,5-dimethyl-1,4,5,6-tetrahydro-2H- 2,6-methanobenzo[d][1,3]oxazocine (3f)

[0078]

[0079] White solid, m.p. 140 - 142 °C; R f = 0.31 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.01 Hz, 1H), 7.34 - 7.29 (m, 3H), 7.28 - 7.23 (m, 4H), 7.21 - 7.16 (m, 1H), 7.14 - 7.09 (m, 1H), 7.07 - 7.04 (m, 1H), 6.75 - 6.71 (m, 1H), 6.63 (d, J = 8.14 Hz, 1H), 5.13 (s, 1H), 5.01 (s, 1H), 4.75 (d, J = 17.51 Hz, 1H), 4.63 (d, J = 17.49 Hz, 1H), 2.80 - 2.74 (m, 1H), 2.72 (s, 1H), 1.90 - 1.85 (m, 1H), 1.16 (s, 3H), 0.79 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.6, 139.0, 137.1, 133.6, 130.7, 130.5, 129.1, 128.7, 128.4, 127.9, 126.8, 126.3, 126.1, 124.6, 116.8, 110.8, 83.1, 72.3, 52.4, 44.7, 38.8, 26.9, 25.7, 22.0. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 27 ClNO 404.1775; found 404.1775.

[0080] Example 7

[0081] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.5 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of isopropanol is added, 1.9 g of 1-(3-methylphenyl)-2-methylallyl-1-ol and 2.3 g of phenylsilane are weighed, the mixture is refluxed for 4 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 2.3 g of a white solid with a yield of 75%.

[0082] The product is 1-benzyl-5,5-dimethyl-4-(m-tolyl)-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3g)

[0083]

[0084] White solid, m.p. 148 - 150 °C; R f = 0.34 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 6.55 Hz, 2H), 7.30 (d, J = 6.69 Hz, 3H), 7.24 (t, J = 7.83 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.12 (d, J = 5.16 Hz, 3H), 7.08 (d, J = 7.64 Hz, 1H), 6.81 - 6.76 (m, 1H), 6.67 (d, J = 8.10 Hz, 1H), 5.20 (s, 1H), 4.81 (d, J = 17.60 Hz, 1H), 4.64 (d, J = 17.44 Hz, 1H), 4.32 (s, 1H), 2.84 - 2.79 (m, 1H), 2.77 (s, 1H), 2.40 (s, 3H), 2.03 - 1.73 (m, 1H), 1.11 (s, 3H), 0.81 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.6, 139.0, 138.9, 136.9, 130.5, 128.8, 128.6, 127.9, 127.8, 127.2, 126.8, 126.3, 125.4, 124.8, 116.5, 110.5, 82.6, 77.5, 52.1, 44.5, 37.3, 26.9, 26.2, 21.5, 21.5. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 27 H 30 NO384.2321; found 384.2320.

[0085] Example 8

[0086] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of isopropanol is added, 2.8 g of 1-(3-chlorophenyl)-2-methylallyl-1-ol and 2.5 g of phenylsilane are weighed, and the mixture is refluxed for 3 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 2.5 g of white solid with a yield of 82%.

[0087] The product is 1-benzyl-4-(3-chlorophenyl)-5,5-dimethyl-1,4,5,6-tetrahydro-2H- 2,6-methanobenzo[d][1,3]oxazocine (3h)

[0088]

[0089] White solid, m.p. 140 - 142 °C; R f = 0.34 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 7.11 Hz, 3H), 7.24 (d, J = 9.05 Hz, 4H), 7.19 (d, J = 7.85 Hz, 1H), 7.09 (dt, J = 17.74, 7.79 Hz, 3H), 6.72 (t, J = 7.26 Hz, 1H), 6.62 (d, J = 8.13 Hz, 1H), 5.14 (s, 1H), 4.73 (d, J = 17.43 Hz, 1H), 4.59 (d, J = 17.43 Hz, 1H), 4.26 (s, 1H), 2.75 (s, 1H), 2.71 (s, 1H), 1.84 (d, J = 11.61 Hz, 1H), 1.02 (s, 3H), 0.76 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.4, 141.3, 138.7, 133.4, 130.6, 128.7, 128.6, 128.2, 127.9, 127.3, 126.9, 126.3, 126.3, 124.5, 116.7, 110.6, 82.7, 77.0, 52.2, 44.4, 37.3, 26.8, 26.1, 21.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 27 ClNO 404.1775; found 404.1777.

[0090] Example 9

[0091] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 2.0 g of iron oxalate are successively added to a reaction flask, 15 ml of ethylene glycol dimethyl ether is added, 2.2 g of 1-(4-methylphenyl)-2-methylallyl-1-ol and 2.3 g of diphenylsilane are weighed, and the reaction is carried out at 75 °C for 10 h. The reaction is quenched by adding water, extracted with ethyl acetate, and recrystallized to obtain 2.1 g of a white solid with a yield of 72%.

[0092] The product is 1-benzyl-5,5-dimethyl-4-(p-tolyl)-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3i)

[0093]

[0094] White solid, m.p. 152 - 154 °C; R f = 0.36 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.39 - 7.31 (m, 2H), 7.29 (d, J = 7.34 Hz, 3H), 7.23 - 7.12 (m, 5H), 7.10 (d, J = 7.19 Hz, 1H), 6.77 (t, J = 7.32 Hz, 1H), 6.66 (d, J = 8.14 Hz, 1H), 5.18 (s, 1H), 4.79 (d, J = 17.49 Hz, 1H), 4.62 (d, J = 17.47 Hz, 1H), 4.32 (s, 1H), 2.77 (s, 1H), 2.75 (s, 1H), 2.39 (s, 3H), 1.94 - 1.82 (m, 1H), 1.09 (s, 3H), 0.79 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.7, 139.0, 136.7, 136.2, 130.6, 128.7, 128.1, 128.1, 127.8, 126.9, 126.4, 124.9, 116.6, 110.5, 82.6, 77.3, 52.2, 44.5, 37.4, 26.9, 26.2, 21.5, 21.2. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 27 H 30 NO 384.2321; found 384.2323.

[0095] Example 10

[0096] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 2.0 g of iron oxalate are successively added into a reaction flask, 15 ml of n-butanol is added, 2.2 g of 1-(4-methoxyphenyl)-2-methylallyl-1-ol and 2.4 g of diphenylsilane are weighed, and the reaction is carried out at 70 °C for 6 h. The reaction is quenched by adding water, extracted with ethyl acetate, and recrystallized to obtain 2.6 g of a white solid with a yield of 78%.

[0097] The product is 1-benzyl-4-(4-methoxyphenyl)-5,5-dimethyl-1,4,5,6-tetrahydro- 2H-2,6-methanobenzo[d][1,3]oxazocine(3j)

[0098]

[0099] White solid, m.p. 182 - 184 °C; R f = 0.47 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.34 - 7.26 (m, 2H), 7.24 (d, J = 7.24 Hz, 3H), 7.15 (d, J = 8.59 Hz, 2H), 7.13 - 7.07 (m, 1H), 7.05 (d, J = 7.30 Hz, 1H), 6.83 (d, J = 8.63 Hz, 2H), 6.71 (t, J = 7.29 Hz, 1H), 6.60 (d, J = 8.13 Hz, 1H), 5.12 (s, 1H), 4.74 (d, J = 17.48 Hz, 1H), 4.58 (d, J = 17.52 Hz, 1H), 4.24 (s, 1H), 3.80 (s, 3H), 2.77 - 2.71 (m, 1H), 2.70 (s, 1H), 1.89 - 1.75 (m, 1H), 1.03 (s, 3H), 0.72 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 158.7, 145.6, 138.9, 131.3, 130.5, 129.2, 128.6, 127.7, 126.8, 126.3, 124.8, 116.5, 112.8, 110.5, 82.7, 77.0, 55.2, 52.2, 44.4, 37.4, 26.8, 26.1, 21.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 27 H 30 NO2 400.2271; found 400.2277.

[0100] Example 11

[0101] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethylene glycol dimethyl ether is added, 2.7 g of 1-(4-chlorophenyl)-2-methylallyl-1-ol and 2.3 g of phenylsilane are weighed, and the mixture is refluxed for 10 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 2.6 g of a white solid with a yield of 76%.

[0102] The product is 1-benzyl-4-(4-chlorophenyl)-5,5-dimethyl-1,4,5,6-tetrahydro-2H- 2,6-methanobenzo[d][1,3]oxazocine(3k)

[0103]

[0104] White solid, m.p. 175 - 177 °C; R f = 0.38 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 7.50 Hz, 3H), 7.25 (d, J = 7.56 Hz, 4H), 7.17 (d, J = 8.35 Hz, 2H), 7.12 (t, J = 7.76 Hz, 1H), 7.08 - 7.02 (m, 1H), 6.73 (td, J = 7.36, 1.19 Hz, 1H), 6.63 (d, J = 8.17 Hz, 1H), 5.14 (dt, J = 3.44, 1.67 Hz, 1H), 4.73 (d, J = 17.44 Hz, 1H), 4.59 (d, J = 17.42 Hz, 1H), 4.27 (s, 1H), 2.75 (d, J = 2.94 Hz, 1H), 2.71 (s, 1H), 1.84 (d, J = 11.64 Hz, 1H), 1.01 (s, 3H), 0.74 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.5, 138.8, 137.7, 130.6, 129.5, 128.6, 127.9, 127.5, 126.9, 126.4, 124.6, 116.7, 110.6, 82.7, 76.9, 52.2, 44.4, 37.3, 26.8, 26.1, 21.3. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 27 ClNO 404.1775; found 404.1781.

[0105] Example 12

[0106] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.5 g of ferric chloride are successively added into a reaction flask, 15 ml of ethylene glycol dimethyl ether is added, 2.5 g of 1-(4-bromophenyl)-2-methylallyl-1-ol and 2.3 g of phenylsilane are weighed, and the mixture is refluxed for 7 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 2.8 g of a white solid with a yield of 82%.

[0107] The product is 1-benzyl-4-(4-bromophenyl)-5,5-dimethyl-1,4,5,6-tetrahydro-2H- 2,6-methanobenzo[d][1,3]oxazocine(3l)

[0108]

[0109] White solid, m.p. 190 - 192 °C; R f = 0.37 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.20 Hz, 2H), 7.37 - 7.30 (m, 2H), 7.27 (d, J = 7.19 Hz, 3H), 7.14 (d, J = 8.18 Hz, 3H), 7.08 (d, J = 7.15 Hz, 1H), 6.76 (t, J = 7.32 Hz, 1H), 6.65 (d, J = 8.15 Hz, 1H), 5.17 (s, 1H), 4.75 (d, J = 17.43 Hz, 1H), 4.62 (d, J = 17.41 Hz, 1H), 4.28 (s, 1H), 2.77 (s, 1H), 2.73 (s, 1H), 1.87 (d, J = 11.14 Hz, 1H), 1.03 (s, 3H), 0.77 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.5, 138.8, 138.3, 130.6, 130.5, 129.9, 128.7, 127.9, 126.9, 126.4, 124.6, 121.0, 116.7, 110.6, 82.7, 76.9, 52.3, 44.4, 37.3, 26.8, 26.1, 21.3. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 27 BrNO 448.1270; found 448.1277.

[0110] Example 13

[0111] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: sequentially add 2.5 g of quinoline quaternary ammonium salt and 1.3 g of ferric chloride into a reaction flask, add 15 ml of n-butanol, weigh 2.3 g of 1-(3,4-dimethylphenyl)-2-methylallyl-1-ol and 2.5 g of diphenylsilane, react at 70 °C for 8 h, quench with water, extract with ethyl acetate, and recrystallize to obtain 2.2 g of a white solid with a yield of 68%.

[0112] The product is 1-benzyl-4-(3,4-dimethylphenyl)-5,5-dimethyl-1,4,5,6- tetrahydro-2H-2,6-methanobenzo[d][1,3]oxazocine(3m)

[0113]

[0114] White solid, m.p. 158 - 160 °C; R f = 0.37 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.35 - 7.28 (m, 2H), 7.25 (d, J = 7.14 Hz, 3H), 7.16 - 7.09 (m, 1H), 7.09 - 7.02 (m, 3H), 6.97 (d, J = 7.75 Hz, 1H), 6.73 (t, J = 7.34 Hz, 1H), 6.62 (d, J = 8.14 Hz, 1H), 5.14 (s, 1H), 4.76 (d, J = 17.49 Hz, 1H), 4.58 (d, J = 17.49 Hz, 1H), 4.25 (s, 1H), 2.76 (dd, J = 12.59, 3.07 Hz, 1H), 2.71 (s, 1H), 2.26 (s, 6H), 1.89 - 1.80 (m, 1H), 1.07 (s, 3H), 0.75 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.7, 139.0, 136.5, 135.4, 135.3, 130.5, 129.4, 128.6, 127.8, 126.8, 126.3, 125.7, 124.9, 116.5, 110.5, 82.6, 77.4, 52.1, 44.5, 37.3, 26.9, 26.2, 21.5, 19.9, 19.5. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 28 H 32 NO 398.2478; found 398.2480.

[0115] Example 14

[0116] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.4 g of ferric trichloride are successively added into a reaction flask, 15 ml of n-butanol is added, 2.8 g of 1-(3,4-dichlorophenyl)-2-methylallyl-1-ol and 2.1 g of diphenylsilane are weighed, and the reaction is carried out at 75 °C for 3 h. The reaction is quenched by adding water, extracted with ethyl acetate, and recrystallized to obtain 2.5 g of a white solid with a yield of 68%.

[0117] The product is 1-benzyl-4-(3,4-dichlorophenyl)-5,5-dimethyl-1,4,5,6- tetrahydro-2H-2,6-methanobenzo[d][1,3]oxazocine(3n)

[0118]

[0119] White solid, m.p. 142 - 144 °C; R f = 0.36 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.36 (s, 1H), 7.32 (d, J = 8.68 Hz, 1H), 7.29 (d, J = 6.89 Hz, 2H), 7.24 (d, J = 7.48 Hz, 3H), 7.11 (t, J = 7.75 Hz, 1H), 7.06 - 7.02 (m, 2H), 6.72 (t, J = 7.35 Hz, 1H), 6.62 (d, J = 8.15 Hz, 1H), 5.13 (s, 1H), 4.71 (d, J = 17.38 Hz, 1H), 4.58 (d, J = 17.36 Hz, 1H), 4.23 (s, 1H), 2.72 (d, J = 3.05 Hz, 1H), 2.70 (s, 1H), 1.87 - 1.79 (m, 1H), 1.00 (s, 3H), 0.75 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.3, 139.6, 138.6, 131.6, 130.6, 130.0, 129.2, 128.7, 128.0, 127.5, 126.9, 126.4, 124.4, 116.8, 110.6, 82.8, 76.5, 52.2, 44.3, 37.3, 26.7, 26.0, 21.2. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 26 Cl2NO 438.1386; found 438.1383.

[0120] Example 15

[0121] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.3 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of a mixed solvent of acetonitrile and 1,2-dichloroethane (the two are mixed in any ratio) is added, 2.4 g of 1,3-benzodioxol-2-ylmethylprop-2-en-1-ol and 2.3 g of diphenylsilane are weighed, the mixture is refluxed for 4 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 2.4 g of a white solid with a yield of 63%.

[0122] The product is 4-(benzo[d][1,3]dioxol-5-yl)-1-benzyl-5,5-dimethyl-1,4,5,6- tetrahydro-2H-2,6-methanobenzo[d][1,3]oxazocine(3o)

[0123]

[0124] White solid, m.p. 146 - 148 °C; R f = 0.43 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.36 - 7.27 (m, 2H), 7.24 (d, J = 7.22 Hz, 3H), 7.10 (t, J = 7.75 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.81 (s, 1H), 6.71 (t, J = 6.70 Hz, 2H), 6.67 - 6.56 (m, 2H), 5.98 - 5.86 (m, 2H), 5.12 (s, 1H), 4.74 (d, J = 17.46 Hz, 1H), 4.59 (d, J = 17.46 Hz, 1H), 4.21 (s, 1H), 2.78 - 2.70 (m, 1H), 2.70 (s, 1H), 1.83 (d, J = 11.41 Hz, 1H), 1.04 (s, 3H), 0.74 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 146.9, 146.5, 145.5, 138.9, 133.0, 130.5, 128.6, 127.8, 126.8, 126.3, 124.7, 121.5, 116.6, 110.5, 108.8, 107.2, 100.8, 82.7, 77.3, 52.2, 44.4, 37.4, 26.8, 26.2, 21.6. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 27 H 28 NO3 414.2063; found 414.2067.

[0125] Example 16

[0126] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of a mixed solvent of tetrahydrofuran and 1,2-dichloroethane (the two are mixed in any ratio) is added, 3.6 g of 2-methyl-1-(naphthalen-2-yl) prop-2-en-1-ol and 2.2 g of diphenylsilane are weighed, and the mixture is refluxed for 10 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 3.1 g of a white solid with a yield of 86%.

[0127] The product is 1-benzyl-5,5-dimethyl-4-(naphthalen-2-yl)-1,4,5,6-tetrahydro- 2H-2,6-methanobenzo[d][1,3]oxazocine(3p)

[0128]

[0129] White solid, m.p. 150 - 152 °C; R f = 0.37 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.49 - 7.30 (m, 3H), 7.28 (s, 1H), 7.10 - 6.96 (m, 3H), 6.88 (d, J = 7.31 Hz, 2H), 6.87 - 6.78 (m, 3H), 6.77 - 6.66 (m, 2H), 6.35 (t, J = 7.34 Hz, 1H), 6.25 (d, J = 8.17 Hz, 1H), 4.81 (s, 1H), 4.37 (d, J = 17.47 Hz, 1H), 4.22 (d, J = 17.45 Hz, 1H), 4.08 (s, 1H), 2.41 (d, J = 12.65 Hz, 1H), 2.34 (s, 1H), 1.53 - 1.44 (m, 1H), 0.68 (s, 3H), 0.41 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.6, 138.9, 136.8, 132.8, 132.8, 130.6, 128.7, 128.0, 127.9, 127.6, 127.0, 126.9, 126.8, 126.6, 126.4, 125.8, 125.6, 124.8, 116.6, 110.6, 82.8, 77.6, 52.3, 44.6, 37.7, 26.9, 26.3, 21.6. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 30 H 30 NO 420.2321; found 420.2321.

[0130] Example 17

[0131] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.5 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of a mixed solvent of tetrahydrofuran and 1,2-dichloroethane (the two are mixed in any ratio) is added, 2.3 g of 1-(prop-1-en-2-yl)cyclohexyl-1-ol and 2.4 g of diphenylsilane are weighed, and the mixture is refluxed for 10 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 2.4 g of a white solid with a yield of 76%.

[0132] The product is 1'-benzyl-5',5'-dimethyl-1',2',5',6'-tetrahydrospiro [cyclohexane-1,4'-[2,6]methanobenzo[d][1,3]oxazocine](3q)

[0133]

[0134] White solid, m.p. 102 - 104 °C; R f = 0.44 (EtOAc / Petroleum ether 1:30). 1 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 7.46 Hz, 2H), 7.24 (t, J = 6.60 Hz, 3H), 7.10 - 6.95 (m, 2H), 6.62 (t, J = 7.29 Hz, 1H), 6.31 (d, J = 8.09 Hz, 1H), 5.19 - 5.05 (m, 1H), 4.91 (d, J = 17.54 Hz, 1H), 4.43 (d, J = 17.55 Hz, 1H), 2.57 (s, 1H), 2.53 (s, 1H), 1.78 - 1.73 (m, 1H), 1.72 - 1.59 (m, 4H), 1.52 - 1.40 (m, 2H), 1.26 (dd, J = 13.39, 4.75 Hz, 2H), 1.19 (s, 3H), 1.08 - 0.97 (m, 1H), 0.94 (s, 3H), 0.87 - 0.72 (m, 1H). 13 13C NMR (101 MHz, CDCl3): δ 144.3, 139.0, 130.3, 128.7, 127.7, 126.8, 126.3, 125.9, 115.8, 110.4, 81.1, 76.6, 53.1, 44.0, 39.3, 34.4, 32.2, 26.8, 26.8, 26.4, 25.5, 22.1, 21.7. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 25 H 32 NO 362.2478; found 362.2481.

[0135] Example 18

[0136] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of a mixed solvent of tetrahydrofuran and 1,2-dichloroethane (the two are mixed in any ratio) is added, 2.3 g of 1-(prop-1-en-2-yl)cycloheptyl-1-ol and 2.1 g of diphenylsilane are weighed, and the mixture is refluxed for 8 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 1.8 g of a white solid with a yield of 65%.

[0137] The product is 1'-benzyl-5',5'-dimethyl-1',2',5',6'-tetrahydrospiro [cycloheptane-1,4'-[2,6]methanobenzo[d][1,3]oxazocine](3r)

[0138]

[0139] White solid, m.p. 103 - 105 °C; R f = 0.43 (EtOAc / Petroleum ether 1:30). 1 1H NMR (400 MHz, CDCl3): δ 7.35 - 7.28 (m, 2H), 7.28 - 7.21 (m, 4H), 7.08 - 6.99 (m, 2H), 6.68 - 6.56 (m, 1H), 6.36 (d, J = 8.01 Hz, 1H), 5.07 (s, 1H), 4.80 (d, J = 17.31 Hz, 1H), 4.54 - 4.36 (m, 1H), 2.56 - 2.53 (m, 1H), 2.53 - 2.46 (m, 1H), 1.86 - 1.80 (m, 1H), 1.76 (s, 1H), 1.71 - 1.61 (m, 4H), 1.59 (d, J = 15.33 Hz, 3H), 1.48 - 1.39 (m, 2H), 1.29 (d, J = 10.67 Hz, 1H), 1.18 (s, 3H), 1.03 (dd, J = 21.35, 10.60 Hz, 1H), 0.97 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 144.5, 139.1, 129.8, 128.7, 127.8, 126.8, 126.2, 126.1, 115.9, 110.4, 80.7, 80.6, 52.6, 44.4, 40.0, 38.6, 35.7, 31.0, 30.0, 26.9, 26.6, 25.4, 23.7, 22.0. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 26 H 34 NO376.2634; found 376.2637.

[0140] Example 19

[0141] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of tetrahydrofuran is added, 2.2 g of 1-(prop-1-en-2-yl) cyclooctyl-1-ol and 2.2 g of diphenylsilane are weighed, and the mixture is refluxed for 5 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 19 g of a white solid with a yield of 75%.

[0142] The product is 1'-benzyl-5',5'-dimethyl-1',2',5',6'-tetrahydrospiro [cyclooctane-1,4'-[2,6]methanobenzo[d][1,3]oxazocine](3s)

[0143]

[0144] White solid, m.p. 110 - 112 °C; R f = 0.43 (EtOAc / Petroleum ether 1:30). 1 1H NMR (400 MHz, CDCl3): δ 7.31 (t, J = 7.19 Hz, 2H), 7.26 - 7.20 (m, 3H), 7.04 (ddd, J = 13.17, 7.34, 1.63 Hz, 2H), 6.64 (t, J = 7.31 Hz, 1H), 6.37 (d, J = 8.13 Hz, 1H), 5.05 (s, 1H), 4.80 (d, J = 17.64 Hz, 1H), 4.46 (d, J = 17.63 Hz, 1H), 2.51 (s, 1H), 2.51 - 2.43 (m, 1H), 1.87 - 1.76 (m, 1H), 1.75 - 1.63 (m, 4H), 1.59 (dd, J = 11.77, 3.73 Hz, 4H), 1.54 - 1.44 (m, 2H), 1.44 - 1.35 (m, 2H), 1.26 (s, 3H), 1.20 - 1.06 (m, 2H), 1.02 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 144.5, 139.1, 130.2, 128.6, 127.8, 126.7, 126.3, 126.0, 115.8, 110.3, 80.7, 79.6, 52.5, 44.7, 39.8, 34.0, 30.8, 29.5, 27.5, 27.2, 26.7, 26.1, 25.4, 22.8, 21.5. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 27 H 36 NO 390.2791; found 390.2794.

[0145] Example 20

[0146] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of N-methylquinoline quaternary ammonium salt and 1.2 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of a mixed solvent of tetrahydrofuran and ether (the two are mixed in any ratio) is added, 1.5 g of 2-methylallyl alcohol and 2.1 g of phenylsilane are weighed, and the mixture is refluxed for 6 h, quenched with water, extracted with ethyl acetate, and separated by column chromatography to obtain 1.8 g of a colorless liquid with a yield of 70%.

[0147] The product is 1,5,5-trimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo[d][1,3] oxazocine(3t)

[0148]

[0149] Colorless liquid, R f =0.48(EtOAc / Petroleum ether 1:15). 1 1H NMR(400MHz,CDCl3):δ7.23-7.13(m,1H),6.95(d,J=7.47Hz,1H),6.67(t,J=7.07Hz,2H),4.87-4.80(m,1H),3.10(s,1H),3.07(s,3H),3.01(d,J=11.60Hz,1H),2.51-2.44(m,2H),1.59(d,J=12.25Hz,1H),1.25(s,3H),0.62(s,3H). 13 13C NMR(101MHz,CDCl3):145.5,130.1,127.6,124.9,116.1,109.6,82.8,67.8,42.1,36.3,33.6,26.4,25.4,25.3.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 14 H 20 NO 218.1539;found 218.1541.

[0150] Example 21

[0151] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: sequentially add 2.1 g of N-allylquinoline quaternary ammonium salt and 1.2 g of iron acetylacetonate into a reaction flask, add 15 ml of a mixed solvent of tetrahydrofuran and ether (the two are mixed in any ratio), weigh 2.3 g of 2-methylallyl alcohol and 2.3 g of phenylsilane, reflux and react for 15 h, quench with water, extract with ethyl acetate, and separate by column chromatography to obtain 2.1 g of a colorless liquid with a yield of 70%.

[0152] The product is 1-allyl-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo[d] [1,3]oxazocine(3u)

[0153]

[0154] Colorless liquid, R f = 0.52 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.16 - 7.09 (m, 1H), 6.96 (d, J = 7.16 Hz, 1H), 6.66 (t, J = 7.47 Hz, 2H), 5.91 (ddt, J = 15.39, 9.65, 4.64 Hz, 1H), 5.22 (s, 1H), 5.16 (d, J = 11.55 Hz, 1H), 4.87 (s, 1H), 4.12 (dd, J = 17.59, 5.06 Hz, 1H), 3.95 (d, J = 17.51 Hz, 1H), 3.08 (s, 2H), 2.52 (s, 1H), 2.49 (s, 1H), 1.59 (d, J = 10.55 Hz, 1H), 1.27 (s, 3H), 0.66 (s, 3H).. 13 13C NMR (101 MHz, CDCl3): δ 144.8, 134.1, 130.3, 127.5, 124.9, 116.1, 115.6, 110.2, 81.0, 67.9, 50.8, 42.1, 34.0, 26.5, 25.4, 25.3. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 16 H 22 NO 244.1695; found 244.1698.

[0155] Example 22

[0156] A preparation method of polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of 1-(2-oxo-2-phenylethyl)quinoline quaternary ammonium salt and 2.0 g of iron oxalate are successively added into a reaction flask, 15 ml of a mixed solvent of acetonitrile and 1,2-dichloroethane (the two are mixed in any ratio) is added, 2.1 g of 2-methylallyl alcohol and 2.6 g of phenylsilane are weighed, and the reaction is carried out at 60 °C for 6 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 2.3 g of a colorless liquid, and the yield is 63%.

[0157] The product is 5,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[d][1,3]oxazocin-1 (4H)-yl)-1-phenylethan-1-one(3v)

[0158]

[0159] Colorless liquid, R f = 0.32 (EtOAc / Petroleum ether 1:7). 1 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.28 Hz, 2H), 7.63 (t, J = 7.40 Hz, 1H), 7.52 (t, J = 7.60 Hz, 2H), 7.05 (t, J = 7.74 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.67 (t, J = 7.23 Hz, 1H), 6.33 - 6.27 (m, 1H), 4.92 (d, J = 18.66 Hz, 1H), 4.84 (d, J = 18.54 Hz, 1H), 3.29 (d, J = 11.52 Hz, 1H), 3.12 (d, J = 11.51 Hz, 1H), 2.57 (s, 1H), 2.55 - 2.49 (m, 1H), 1.84 - 1.75 (m, 1H), 1.28 (s, 3H), 0.70 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 195.8, 144.4, 135.3, 133.6, 130.5, 128.9, 127.9, 127.6, 125.3, 116.8, 109.7, 82.4, 68.1, 54.9, 42.1, 34.0, 26.4, 25.5, 25.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 14 H 16 ClO2 C21H24NO2 322.1801; found 322.1805.

[0160] Example 23

[0161] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 1-(naphthalen-1-ylmethylene)quinolinium salt and 2.0 g of iron oxalate are successively added into a reaction flask, 15 ml of a mixed solvent of benzene and 1,2-dichloroethane (the two are mixed in any ratio) is added, 2.3 g of 2-methylallyl alcohol and 1.5 g of diphenylsilane are weighed, and the reaction is carried out at 80 °C for 5 h. The reaction is quenched by adding water, extracted with ethyl acetate, and recrystallized to obtain 1.8 g of a white solid with a yield of 73%.

[0162] The product is 5,5-dimethyl-1-(naphthalen-1-ylmethyl)-1,4,5,6-tetrahydro-2H-2, 6-methano-benzo[d][1,3]oxazocine(3w)

[0163]

[0164] White solid, m.p. 182 - 185 °C; R f = 0.47 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 8.10 - 8.01 (m, 1H), 8.00 - 7.87 (m, 1H), 7.80 (d, J = 8.16 Hz, 1H), 7.57 (tt, J = 8.51, 5.99 Hz, 2H), 7.49 - 7.27 (m, 2H), 7.04 (t, J = 7.46 Hz, 2H), 6.71 (t, J = 7.34 Hz, 1H), 6.51 (d, J = 8.10 Hz, 1H), 5.20 (d, J = 17.81 Hz, 1H), 5.07 (d, J = 17.76 Hz, 1H), 4.97 (s, 1H), 3.37 - 3.16 (m, 2H), 2.65 (s, 1H), 2.61 (d, J = 2.84 Hz, 1H), 1.86 (d, J = 11.66 Hz, 1H), 1.34 (s, 3H), 0.75 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.3, 133.9, 132.9, 130.3, 128.9, 127.7, 127.4, 126.1, 125.8, 125.7, 125.2, 122.9, 122.6, 116.6, 110.7, 81.0, 68.1, 49.6, 42.2, 34.1, 26.9, 25.5, 25.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 24 H 26 NO 344.2008; found 344.2015.

[0165] Example 24

[0166] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.5 g of 1-(4-methylbenzyl)quinoline quaternary ammonium salt and 1.5 g of ferric trichloride are successively added into a reaction flask, 15 ml of a mixed solvent of benzene and 1,2-dichloroethane (mixed in any ratio) is added, 1.8 g of 2-methylallyl alcohol and 2.2 g of diphenylsilane are weighed, and the reaction is carried out at 80 °C for 5 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 2.1 g of a white solid with a yield of 65%.

[0167] The product is 5,5-dimethyl-1-(4-methylbenzyl)-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine(3x)

[0168]

[0169] White solid, m.p. 104 - 106 °C; R f = 0.46 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.25 - 7.13 (m, 4H), 7.09 (t, J = 7.64 Hz, 1H), 7.02 (d, J = 7.06 Hz, 1H), 6.70 (t, J = 7.25 Hz, 1H), 6.62 (d, J = 8.14 Hz, 1H), 4.97 (s, 1H), 4.73 (d, J = 17.29 Hz, 1H), 4.59 (d, J = 17.26 Hz, 1H), 3.25 - 3.12 (m, 2H), 2.60 (s, 1H), 2.57 (s, 1H), 2.38 (s, 3H), 1.75 (d, J = 10.77 Hz, 1H), 1.33 (s, 3H), 0.73 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.3, 136.5, 135.8, 130.3, 129.4, 127.7, 126.3, 125.0, 116.4, 110.5, 81.3, 68.0, 51.7, 42.2, 34.1, 26.7, 25.5, 25.4, 21.1. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 21 H 26 NO 308.2008; found 308.2010.

[0170] Example 25

[0171] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: sequentially add 2.5 g of 1-(4-chlorobenzyl)quinoline quaternary ammonium salt and 2.2 g of iron tribromide into a reaction flask, add 15 ml of a mixed solvent of ethanol and 1,2-dichloroethane (the two are mixed in any ratio), weigh 2.1 g of 2-methylallyl alcohol, 1.8 g of triethylsilane, react at 80 °C for 7 h, quench with water, extract with ethyl acetate, and recrystallize to obtain 2.1 g of a white solid with a yield of 86%.

[0172] The product is 1-(4-chlorobenzyl)-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine(3y)

[0173]

[0174] White solid, m.p. 108 - 110 °C; R f = 0.61 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.15 Hz, 2H), 7.21 (d, J = 8.08 Hz, 2H), 7.07 (t, J = 7.68 Hz, 1H), 7.00 (d, J = 7.18 Hz, 1H), 6.69 (t, J = 7.27 Hz, 1H), 6.53 (d, J = 8.13 Hz, 1H), 4.92 (s, 1H), 4.70 (d, J = 17.47 Hz, 1H), 4.54 (d, J = 17.45 Hz, 1H), 3.15 (s, 2H), 2.58 (s, 1H), 2.56 (s, 1H), 1.72 (d, J = 11.06 Hz, 1H), 1.30 (s, 3H), 0.70 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.0, 137.5, 132.6, 130.4, 128.8, 127.7, 127.7, 125.1, 116.7, 110.4, 81.3, 68.0, 51.5, 42.0, 34.0, 26.7, 25.4, 25.3. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 23 ClNO 328.1462; found 328.1461.

[0175] Example 26

[0176] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.1 g of 2-methylquinoline quaternary ammonium salt and 1.3 g of iron tribromide are successively added to a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol, 1.8 g of triethoxysilane are weighed, and the reaction is carried out at 70 °C for 5 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 1.6 g of a white solid with a yield of 56%.

[0177] The product is 1-benzyl-2,5,5-trimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo [d][1,3]oxazocine(3z)

[0178]

[0179] White solid, m.p. 184 - 186 °C; R f = 0.50 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.31 (t, J = 7.53 Hz, 2H), 7.29 - 7.16 (m, 3H), 6.99 (t, J = 7.74 Hz, 1H), 6.93 (d, J = 7.32 Hz, 1H), 6.66 (t, J = 7.33 Hz, 1H), 6.50 (d, J = 8.20 Hz, 1H), 4.94 (d, J = 18.33 Hz, 1H), 4.28 (d, J = 18.33 Hz, 1H), 3.12 (q, J = 11.66 Hz, 2H), 2.51 (s, 1H), 2.39 (dd, J = 12.94, 2.29 Hz, 1H), 1.95 (dd, J = 12.90, 3.07 Hz, 1H), 1.37 (s, 3H), 1.26 (s, 3H), 0.65 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 147.8, 140.6, 129.8, 128.6, 127.6, 126.5, 126.0, 125.7, 117.0, 112.1, 83.7, 69.0, 49.7, 43.0, 34.5, 33.3, 27.2, 25.4, 24.9. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 21 H 26 NO 308.2008; found 308.2016.

[0180] Example 27

[0181] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 3-methylquinoline quaternary ammonium salt and 1.3 g of ferrous sulfate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol, 1.9 g of triethoxysilane are weighed, and the reaction is carried out at 60 °C for 5 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 1.9 g of a white solid with a yield of 65%.

[0182] The product is 1-benzyl-5,5,11-trimethyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine(3aa)

[0183]

[0184] White solid, m.p. 126 - 128 °C; R f = 0.50 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 6.39 Hz, 4H), 7.20 (td, J = 6.95, 6.15, 2.65 Hz, 1H), 7.05 - 6.95 (m, 1H), 6.96 - 6.87 (m, 1H), 6.63 (t, J = 7.33 Hz, 1H), 6.51 (d, J = 8.17 Hz, 1H), 4.65 (d, J = 17.37 Hz, 1H), 4.60 (s, 1H), 4.52 (d, J = 17.35 Hz, 1H), 3.09 - 3.01 (m, 2H), 2.58 (ddt, J = 9.91, 6.90, 4.22 Hz, 1H), 2.30 (s, 1H), 1.24 (s, 3H), 0.78 (d, J = 6.98 Hz, 3H), 0.62 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 144.8, 139.3, 131.7, 128.7, 127.6, 126.9, 126.3, 122.3, 116.7, 110.0, 86.1, 67.3, 52.1, 49.2, 35.0, 28.7, 25.9, 25.6, 15.9. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 21 H 26 NO 308.2008; found 308.2009.

[0185] Example 28

[0186] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: sequentially add 2.1 g of 4-methylquinoline quaternary ammonium salt and 1.7 g of ferrous sulfate into a reaction flask, add 15 ml of ethanol, weigh 2.1 g of 2-methylallyl alcohol and 1.7 g of triethoxysilane, react at 70 °C for 6 h, quench with water, extract with ethyl acetate, and separate to obtain 2.1 g of a white solid with a yield of 85%.

[0187] The product is 1-benzyl-5,5,6-trimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo [d][1,3]oxazocine(3ab)

[0188]

[0189] Colorless liquid, R f =0.50(EtOAc / Petroleum ether 1:7). 1 1H NMR(400MHz,CDCl3):δ7.37 - 7.34(m,1H),7.28(q,J=7.44Hz,2H),7.21(d,J=7.62Hz,3H),7.07 - 7.00(m,1H),6.72 - 6.55(m,1H),6.46(d,J=8.33Hz,1H),4.88(d,J=17.11Hz,1H),4.42(d,J=17.13Hz,1H),3.24(t,J=3.05Hz,1H),3.15(s,2H),2.27(dd,J=13.01,2.72Hz,1H),1.91(dd,J=13.00,3.81Hz,1H),1.67(s,3H),1.13(s,3H),0.90(s,3H). 13 13C NMR(101MHz,CDCl3):δ145.4,138.6,129.0,128.6,126.9,126.5,126.3,122.5,115.4,110.4,70.0,69.2,62.2,56.2,36.8,33.7,26.1,24.8,24.2.HRMS(ESI - TOF)m / z:[M + H] + Calcd for C 21 H 26 NO308.2008;found 308.2015.

[0190] Example 29

[0191] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 5-bromoquinoline quaternary ammonium salt and 1.2 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol and 1.4 g of diphenylsilane are weighed, and the reaction is carried out at 70 °C for 5 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 20. g of a white solid with a yield of 84%.

[0192] The product is 1-benzyl-7-bromo-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3ac)

[0193]

[0194] White solid, m.p. 122 - 124 °C; R f = 0.50 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.33 (t, J = 7.28 Hz, 2H), 7.29 - 7.18 (m, 3H), 6.95 (d, J = 7.83 Hz, 1H), 6.86 (t, J = 8.05 Hz, 1H), 6.52 (d, J = 8.16 Hz, 1H), 4.91 (s, 1H), 4.75 (d, J = 17.54 Hz, 1H), 4.58 (d, J = 17.51 Hz, 1H), 3.30 (s, 1H), 3.19 - 3.06 (m, 2H), 2.61 - 2.48 (m, 1H), 1.62 (d, J = 13.15 Hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 146.7, 138.2, 128.8, 128.2, 127.0, 126.1, 125.9, 124.3, 121.6, 110.0, 80.9, 67.9, 51.9, 39.9, 35.1, 26.2, 25.7, 24.3. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 23 BrNO 372.0957; found 372.0963.

[0195] Example 30

[0196] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 6-methylquinoline quaternary ammonium salt and 1.7 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol and 1.3 g of diphenylsilane are weighed, and the reaction is carried out at 75 °C for 6 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 2.1 g of a white solid with a yield of 85%.

[0197] The product is 1-benzyl-5,5,8-trimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo [d][1,3]oxazocine (3ad)

[0198]

[0199] White solid, m.p. 75 - 78 °C; R f = 0.50 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.39 - 7.30 (m, 2H), 7.29 (d, J = 7.23 Hz, 3H), 6.88 (d, J = 8.25 Hz, 1H), 6.83 (s, 1H), 6.50 (d, J = 8.22 Hz, 1H), 4.95 (s, 1H), 4.74 (d, J = 17.40 Hz, 1H), 4.57 (d, J = 17.39 Hz, 1H), 3.22 - 3.14 (m, 2H), 2.59 (s, 1H), 2.55 (s, 1H), 2.26 (s, 3H), 1.74 (d, J = 11.14 Hz, 1H), 1.31 (s, 3H), 0.72 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 143.1, 139.2, 131.0, 128.7, 128.1, 126.9, 126.3, 125.4, 125.0, 110.4, 81.3, 68.1, 52.0, 42.2, 34.0, 26.9, 25.5, 25.4, 20.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 21 H 26 NO 308.2008; found 308.2015.

[0200] Example 31

[0201] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 6-chloroquinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol and 2.2 g of diphenylsilane are weighed, and the reaction is carried out at 75 °C for 5 h. Water is added for quenching, and extraction is carried out with ethyl acetate. Recrystallization gives 2.1 g of a white solid with a yield of 75%.

[0202] The product is 1-benzyl-8-chloro-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3ae)

[0203]

[0204] White solid, m.p. 92 - 94 °C; R f = 0.50 (EtOAc / Petroleum ether 1:15). 1 1H NMR (400 MHz, CDCl3): δ 7.36 (t, J = 7.28 Hz, 2H), 7.27 (t, J = 9.09 Hz, 3H), 7.01 (d, J = 8.94 Hz, 1H), 6.99 (s, 1H), 6.49 (d, J = 8.56 Hz, 1H), 4.96 (s, 1H), 4.75 (d, J = 17.43 Hz, 1H), 4.56 (d, J = 17.41 Hz, 1H), 3.24 - 3.10 (m, 2H), 2.58 (d, J = 12.98 Hz, 2H), 1.71 (d, J = 10.63 Hz, 1H), 1.31 (s, 3H), 0.73 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 143.9, 138.4, 129.7, 128.8, 127.4, 127.1, 126.6, 126.2, 121.2, 111.6, 81.2, 68.0, 52.1, 42.1, 34.0, 26.6, 25.4, 25.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 23 ClNO 328.1462; found 328.1464.

[0205] Example 32

[0206] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 6-bromoquinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of methanol is added, 2.1 g of 2-methylallyl alcohol and 1.5 g of phenylsilane are weighed, the reaction is carried out at 70 °C for 5 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 1.9 g of white solid, with a yield of 75%.

[0207] The product is 1-benzyl-8-bromo-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3af)

[0208]

[0209] White solid, m.p. 100 - 102 °C; Rf = 0.50 (EtOAc / Petroleum ether 1:15). 1 H NMR (400 MHz, CDCl3): δ 7.34 (t, J = 7.23 Hz, 2H), 7.25 (dd, J = 16.27, 7.30 Hz, 3H), 7.17 - 7.03 (m, 2H), 6.42 (d, J = 8.62 Hz, 1H), 4.93 (s, 1H), 4.72 (d, J = 17.44 Hz, 1H), 4.53 (d, J = 17.43 Hz, 1H), 3.24 - 3.06 (m, 2H), 2.57 (s, 1H), 2.54 (s, 1H), 1.69 (d, J = 10.75 Hz, 1H), 1.28 (s, 3H), 0.71 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 144.3, 138.3, 132.4, 130.3, 128.8, 127.1, 127.1, 126.2, 112.1, 108.4, 81.2, 67.9, 52.0, 42.0, 34.0, 26.5, 25.4, 25.3. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 23 BrNO 372.0957; found 372.0957.

[0210] Example 33

[0211] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of 7-methylquinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol and 1.1 g of diphenylsilane are weighed, the reaction is carried out at 70 °C for 5 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 1.8 g of a white solid, with a yield of 85%.

[0212] The product is 1-benzyl-5,5,9-trimethyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo [d][1,3]oxazocine (3ag)

[0213]

[0214] White solid, m.p. 85 - 87 °C; R f = 0.51 (EtOAc / Petroleum ether 1:15). 11H NMR (400 MHz, CDCl3): δ 7.39 - 7.31 (m, 2H), 7.28 (dd, J = 12.88, 6.86 Hz, 3H), 6.89 (d, J = 7.45 Hz, 1H), 6.52 (d, J = 7.41 Hz, 1H), 6.44 (s, 1H), 4.93 (s, 1H), 4.73 (d, J = 17.39 Hz, 1H), 4.61 (d, J = 17.39 Hz, 1H), 3.22 - 3.12 (m, 2H), 2.56 (t, J = 6.34 Hz, 2H), 2.23 (s, 3H), 1.71 (d, J = 10.59 Hz, 1H), 1.30 (s, 3H), 0.71 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 145.3, 139.1, 137.3, 130.2, 128.7, 126.8, 126.4, 122.2, 117.3, 111.1, 81.1, 68.0, 51.7, 41.8, 34.0, 26.9, 25.4, 25.4, 21.6. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 21 H 26 NO 308.2008; found 308.2016.

[0215] Example 34

[0216] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: 2.1 g of 7-bromoquinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol and 1.7 g of diphenylsilane are weighed, the reaction is carried out at 70 °C for 5 h, quenched with water, extracted with ethyl acetate, and recrystallized to obtain 1.8 g of white solid, with a yield of 75%.

[0217] The product is 1-benzyl-9-bromo-5,5-dimethyl-1,4,5,6-tetrahydro-2H-2,6- methanobenzo[d][1,3]oxazocine (3ah)

[0218]

[0219] White solid, m.p. 106 - 108 °C; R f = 0.51 (EtOAc / Petroleum ether 1:15). 11H NMR (400 MHz, CDCl3): δ 7.34 (t, J = 7.26 Hz, 2H), 7.25 (dt, J = 12.17, 7.39 Hz, 3H), 6.80 (q, J = 7.91 Hz, 2H), 6.70 (s, 1H), 4.90 (s, 1H), 4.70 (d, J = 17.40 Hz, 1H), 4.54 (d, J = 17.39 Hz, 1H), 3.19 - 3.06 (m, 2H), 2.55 (s, 1H), 2.53 (s, 1H), 1.65 (d, J = 11.05 Hz, 1H), 1.26 (s, 3H), 0.67 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ. 146.5, 138.0, 131.4, 128.8, 127.1, 126.3, 123.9, 121.3, 119.3, 113.1, 80.7, 67.9, 51.8, 41.7, 33.9, 26.4, 25.3, 25.2. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 23 BrNO 372.0957; found 372.0961.

[0220] Example 35

[0221] A preparation method of a multi-substituted benzoxazine, the steps of which are as follows: sequentially add 2.1 g of phenanthroline quaternary ammonium salt and 1.1 g of iron acetylacetonate into a reaction flask, add 15 ml of ethanol, weigh 2.1 g of 2-methylallyl alcohol and 1.7 g of diphenylsilane, react at 70 °C for 5 h, quench with water, extract with ethyl acetate, and recrystallize to obtain 2.2 g of a white solid with a yield of 85%.

[0222] The product is 7-benzyl-11,11-dimethyl-7,10,11,12-tetrahydro-8H-8,12-methano [1,3]oxazocino[4,5-h]quinoline (3ai)

[0223]

[0224] White solid, m.p. 114 - 116 °C; R f = 0.51 (EtOAc / Petroleum ether 1:15). 11H NMR (400 MHz, CDCl3): δ 8.81 - 8.59 (m, 1H), 8.11 - 8.00 (m, 1H), 7.75 (d, J = 7.42 Hz, 2H), 7.38 (t, J = 7.40 Hz, 2H), 7.28 (dt, J = 9.58, 6.24 Hz, 2H), 7.19 (s, 2H), 6.33 (d, J = 14.36 Hz, 1H), 4.87 (s, 1H), 4.53 (d, J = 14.38 Hz, 1H), 3.23 (s, 2H), 2.65 (s, 1H), 2.54 (d, J = 12.88 Hz, 1H), 1.63 - 1.52 (m, 1H), 1.34 (s, 3H), 0.84 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ. 146.1, 142.6, 140.5, 139.7, 136.0, 130.0, 129.1, 129.0, 128.0, 126.6, 126.2, 120.1, 116.4, 78.9, 67.7, 52.2, 43.2, 33.4, 26.5, 25.6, 25.4. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 23 H 25 N2O3 45.1961; found 345.1964.

[0225] Example 36

[0226] A preparation method of a polysubstituted benzoxazine, the steps of which are as follows: 2.1 g of N-dodecyl quinoline quaternary ammonium salt and 1.1 g of iron acetylacetonate are successively added into a reaction flask, 15 ml of ethanol is added, 2.1 g of 2-methylallyl alcohol and 1.2 g of diphenylsilane are weighed, and the reaction is carried out at 70 °C for 5 h. The reaction is quenched by adding water, extracted with ethyl acetate, and recrystallized to obtain 2.0 g of a white solid with a yield of 60%.

[0227] The product is 5,5-dimethyl-1-tridecyl-1,4,5,6-tetrahydro-2H-2,6-methanobenzo [d][1,3]oxazocine (3aj)

[0228]

[0229] Colorless liquid, R f = 0.41 (EtOAc / Petroleum ether 1:30). 11H NMR (400 MHz, CDCl3): δ 7.17 (td, J = 7.77, 7.34, 1.63 Hz, 1H), 6.97 (dd, J = 7.36, 1.66 Hz, 1H), 6.76 - 6.57 (m, 2H), 4.92 (s, 1H), 3.54 (ddd, J = 15.32, 9.78, 6.06 Hz, 1H), 3.31 (ddd, J = 15.04, 9.71, 5.70 Hz, 1H), 3.09 (s, 2H), 2.51 (s, 1H), 2.51 - 2.45 (m, 1H), 1.71 (dq, J = 13.35, 5.67, 4.47 Hz, 2H), 1.61 - 1.54 (m, 1H), 1.38 (s, 4H), 1.35 (s, 4H), 1.32 (s, 6H), 1.29 (s, 3H), 0.94 (t, J = 6.71 Hz, 3H), 0.68 (s, 3H). 13 13C NMR (101 MHz, CDCl3): δ 130.5, 127.5, 115.7, 109.5, 81.8, 67.9, 49.2, 42.2, 34.0, 32.0, 29.7, 29.7, 29.7, 29.7, 29.6, 29.4, 27.8, 27.3, 26.4, 25.4, 25.4, 22.8, 14.2. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 25 H 42 NO 372.3260; found 372.3265.

[0230] All modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A multi-substituted benzoxazine compound, characterized in that, The structural formula of the compound is shown in Formula I, wherein, R is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 1 is alkyl and substituted alkyl, R 2 、R 3 are hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 4 , R 5 , R 6 are hydrogen, alkyl and substituted alkyl.

2. The polysubstituted benzoxazine compound according to claim 1, characterized in that R is C1-C10 alkyl and substituted alkyl, C6-C10 aryl and substituted aryl, R 1 is an alkyl or substituted alkyl group having 1 to 20 carbon atoms, R 2 、R 3 are C1-C10 alkyl and substituted alkyl, C6-C10 aryl and substituted aryl, R 4 、R 5 、R 6 are C1-C10 alkyl and substituted alkyl.

3. The polysubstituted benzoxazine compound according to claim 1, characterized in that R is hydrogen, C1-C10 alkyl and substituted alkyl, C6-C10 aryl and substituted aryl, R 1 is hydrogen, a C1-C20 alkyl or substituted alkyl, R 2 、R 3 are C1-C10 alkyl and substituted alkyl, C6-C10 aryl and substituted aryl, R 4 、R 5 、R 6 are C1-C8 alkyl and substituted alkyl.

4. A method for preparing a polysubstituted benzoxazine compound as described in any one of claims 1 to 3, characterized in that, comprising the following steps: Mix a quinoline quaternary ammonium salt derivative with allyl alcohol, a solvent, a catalyst, and a reducing agent, and obtain a polysubstituted benzoxazine compound through reaction; Its synthetic route is, R is hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 1 is alkyl and substituted alkyl, R 2 、R 3 are hydrogen, alkyl and substituted alkyl, aryl and substituted aryl, R 4 、R 5 、R 6 is hydrogen or an alkyl or substituted alkyl group.

5. The preparation method of the multi-substituted benzoxazine compound according to claim 4, characterized in that, The molar ratio of the quinoline quaternary ammonium salt derivative to allyl alcohol is 1:0.1 to 10.

6. The preparation method of the polysubstituted benzoxazine compound according to claim 4, characterized in that, The molar ratio of the quinoline quaternary ammonium salt derivative to the catalyst is 1:0.01 to 5.

7. The preparation method of the multi-substituted benzoxazine compound according to claim 4, characterized in that, The molar ratio of the quinoline quaternary ammonium salt derivative to the reducing agent is 1:1 to 7.

8. The preparation method of the multi-substituted benzoxazine compound according to any one of claims 4 to 7, characterized in that, The preparation method includes at least one of features (1) to (4): (1) The catalyst includes at least one of ZnCl2, Fe(NO3)3·9H2O, CuSO4, Zn(OTf)2, Pd(OAc)2, MnSO4·H2O, FeSO4, Fe(acac)3, FeCl3, Fe(ox)3·6H2O, FeBr3, FeCl2·4H2O, Co(acac)2, Cu(acac)2, MnCl2·4H2O, or La(OTf)3; (2) The reducing agent includes at least one of Et3SiH, (EtO)3SiH, Ph3SiH, NaBH4, NaCNBH3, PhSiHMe, HCOOH, HSiCl3, PhHSiCl2, PhSiH3, Ph2SiH2, or PMHS; (3) The solvent includes at least one of toluene, 1,4-dioxane, benzene, ethylene glycol dimethyl ether, dichloromethane, ethanol, DMF, DMA, isopropanol, n-butanol, 1,2-dichloroethane, methanol, tetrahydrofuran, ether, acetonitrile, or DMSO; (4) The reaction time is 1 to 24 h; the reaction temperature is from room temperature to reflux; the product after the reaction is separated and purified to obtain the target product, and the separation and purification are carried out by recrystallization or column chromatography.

9. The preparation method of the multi-substituted benzoxazine compound according to claim 8, characterized in that, The preparation method includes at least one of features (5) to (7): (5) The catalyst includes at least one of Fe(acac)3, FeCl3, Fe(ox)3·6H2O, FeBr3, FeCl2·4H2O, Co(acac)2, Cu(acac)2, Fe(NO3)3·9H2O; (6) The reducing agent includes at least one of Et3SiH, (EtO)3SiH, NaBH4, PhSiHMe, HSiCl3, PhHSiCl2, PhSiH3, Ph2SiH2, PMHS; (7) The solvent includes at least one of 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, ethanol, isopropanol, n-butanol, 1,2-dichloroethane, methanol, tetrahydrofuran, diethyl ether, and acetonitrile.

10. Use of the compound represented by formula I as described in any one of claims 1 to 3, or its crystal form, or its pharmaceutically acceptable salt, in anti-cancer, anti-malaria, anti-viral, anti-bacterial, anti-fungal, and anti-inflammatory applications.

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