A 1,4-benzoxazine spirocyclic derivative, its synthesis method and application

Abstract

The present invention provides a 1,4-benzoxazine spirocyclic derivative, a synthesis method and an application thereof, belonging to the technical field of organic synthetic chemistry. The structural general formula of the 1,4-benzoxazine spirocyclic derivative is: #imgabs0# wherein R is any one of H, Me, Ph, Cl or MeO; R 1 is any one of Me, Et, n Pr, n Am; R 2 is any one of H, Me, n Pr or n hexyl; Ar is a benzene ring, or a benzene ring substituted with Me, Cl or I. The present invention also discloses its synthesis method and application. Such compounds have certain antifungal activities and can be used for preventing and controlling plant diseases caused by fungi. Moreover, the operation is simple, the atom economy is high, the step economy is high, the chemical selectivity is high, the yield is high, and the functional group tolerance is good.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a 1,4-benzoxazine spirocyclic derivative, a synthesis method and an application thereof. Background Art

[0002] In 1955, Virtanen et al. first discovered the natural products 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one (DIBOA) and 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) (Acta Chem. Scand., 1955, 9, 1543-1544), and they have been proven to have the effect of inhibiting the spore germination of phytopathogenic fungi (Phytochemistry., 1973, 12, 347-352). Based on them, a large number of 1,4-benzoxazine derivatives have been synthesized, mainly showing antibacterial and herbicidal activities. For example, Alper-Hayta et al. synthesized a new type of benzoxazine derivative and demonstrated its inhibitory activity against C. krusei through experiments (Eur J Med Chem., 2006, 41, 1398-1404). In 1993, the 1,4-benzoxazine derivative flumioxazin developed by Sumitomo Chemical Company of Japan was put on the market and used to control gramineous weeds and broad-leaved weeds on crops such as soybeans and cotton. In China, the inhibition rate of 1-(((4-methoxyphenyl)carbamoyl)methyl)-2-(4-nitrophenyl)-3,1-benzoxazine synthesized by the research group of Tang Zilong against Sclerotinia sclerotiorum was as high as 71.9% (Fine Chemical Intermediates, 2020, 50, 21-24). On the other hand, spirocyclic compounds widely exist in many natural products and have important application values and biological activities (Chem. Rev., 1989, 89, 1617-1661; Chem. Rev., 2004, 104, 2751-2776). The spirotetramic acid derivative synthesized by Fischer et al. of Bayer CropScience AG has good herbicidal activity (Chem. Abstr, 2005, 143, 153282). Based on the above two aspects, the development of spirocyclic derivatives of benzoxazine compounds is of great significance for the prevention and control of diseases, insects and weeds. Summary of the Invention

[0003] In view of the above technical problems, the present invention provides a 1,4-benzoxazine spirocyclic derivative, a synthesis method and an application thereof. The method has the advantages of simple operation, atom economy, step economy, high chemical selectivity, high yield and good functional group tolerance.

[0004] In order to achieve the above object, the technical solution of the present invention is realized as follows:

[0005] A 1,4-benzoxazine spirocyclic derivative has the following structure:

[0006]

[0007] wherein R is any one of H, Me, Ph, Cl or MeO; R 1 is any one of Me, Et, n Pr, n Am; R 2 is any one of H, Me, n Pr or n hexyl; Ar is a benzene ring, or a benzene ring substituted with Me, Cl or I.

[0008] A method for synthesizing a 1,4-benzoxazine spirocyclic derivative, the method comprising the following steps: under an inert atmosphere, adding a benzoxazinone compound 1, an unsaturated ketone compound 2, a catalyst and an additive to a solvent to obtain a reaction solution for reaction to generate a 1,4-benzoxazine spirocyclic derivative; the reaction formula is as follows:

[0009]

[0010] wherein R is any one of H, Me, Ph, Cl or MeO; R 1 is any one of Me, Et, n Pr, n Am; R 2 is any one of H, Me, n Pr or n hexyl; Ar is a benzene ring, or a benzene ring substituted with Me, Cl or I; Rh(lll) is a catalyst.

[0011] The reaction temperature of the reaction is 80 - 120 °C, and the reaction time is 8 - 16 h.

[0012] The inert atmosphere is a gas atmosphere of nitrogen, argon or helium.

[0013] The catalyst includes a rhodium catalyst and a silver salt, and the molar ratio of the rhodium catalyst to the silver salt is 1:4. The rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium dimer or bis(hexafluorantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium dimer, and the silver salt is any one or combination of silver bis(trifluoromethanesulfonyl)imide, silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, silver trifluoroacetate.

[0014] The additive is sodium bicarbonate, acetic acid, adamantane formic acid, pivalic acid, mesitylenic acid, lithium acetate, lithium carbonate, sodium acetate or sodium carbonate.

[0015] The solvent is any one or a combination of 1,2-dichloroethane, tetrahydrofuran, cyclohexane, trifluorotoluene or toluene.

[0016] The molar ratio of the benzoxazinone compound 1, the unsaturated ketone compound 2, the catalyst and the additive is 1:(1.0-2.0):(0.02-0.1):(1-3).

[0017] The concentration of the benzoxazinone compound 1 in the reaction solution is 0.05M-0.2M.

[0018] Application of the above-mentioned 1,4-benzoxazine spirocyclized derivatives in the field of antibacterial and sterilization.

[0019] The reaction mode of the reaction process of the present invention is shown in the following formula:

[0020]

[0021] The compound 1 of the reaction generates a cyclometal intermediate a under the action of a catalyst, and then an unsaturated ketone is inserted to generate an intermediate b, followed by an intramolecular nucleophilic addition reaction and metal removal to generate a benzoxazine spirocyclized derivative c. (In fact, when the compound has two chiral centers, it includes two pairs of enantiomers (1'R, 2'R) and (1'S, 2'S), (1'R, 2'S) and (1'S, 2'R), wherein the ratio of the first pair of enantiomers to the second pair of enantiomers is greater than 20:1; when When this type of compound has three chiral centers, it includes four pairs of enantiomers (1'R, 2'R, 3'S) and (1'S, 2'S, 3'R), (1'R, 2'R, 3'R) and (1'S, 2'S, 3'S), (1'R, 2'S, 3'S) and (1'S, 2'R, 3'R), (1'S, 2'R, 3'S) and (1'R, 2'S, 3'R), wherein the ratio of the first pair of enantiomers to the other enantiomers is greater than 20:1:1:1; the specific structure is shown in the figure below. )

[0022]

[0023] Beneficial effects of the present invention: The present invention innovatively selects simple and easily available benzoxazine compounds and unsaturated ketone compounds as reactants, and synthesizes [5.4] spiro compounds in one step [3+2] under the action of metal rhodium catalyst, which provides a simple and effective method for the construction of complex spiro compounds, and the method has the advantages of good diastereoselectivity, simple operation, atom economy, step economy, high yield, good functional group tolerance, etc. The compounds show certain antibacterial effects on rapeseed sclerotinia, wheat take-all pathogen, and wheat sheath blight pathogen, especially its EC 50The value is 147.45, which has good antifungal properties and can be applied to the prevention and control of plant diseases caused by fungi. Description of the Drawings

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0025] Figure 1 is the 1H NMR spectrum of compound 3aa; 1 H spectrum; Figure 2 is the 13C NMR spectrum of compound 3aa; 13 C spectrum.

[0026] Figure 3 is the 1H NMR spectrum of compound 3ba; 1 H spectrum; Figure 4 is the 13C NMR spectrum of compound 3ba; 13 C spectrum.

[0027] Figure 5 is the 1H NMR spectrum of compound 3ca; 1 H spectrum; Figure 6 is the 13C NMR spectrum of compound 3ca; 13 C spectrum.

[0028] Figure 7 is the 1H NMR spectrum of compound 3da; 1 H spectrum; Figure 8 is the 13C NMR spectrum of compound 3da; 13 C spectrum.

[0029] Figure 9 is the 1H NMR spectrum of compound 3ea; 1 H spectrum; Figure 10 is the 13C NMR spectrum of compound 3ea; 13 C spectrum.

[0030] Figure 11 is the 1H NMR spectrum of compound 3fa; 1 H spectrum; Figure 12 is the 13C NMR spectrum of compound 3fa; 13 C spectrum.

[0031] Figure 13 is the 1H NMR spectrum of compound 3ga; 1 H spectrum; Figure 14 is the 13C NMR spectrum of compound 3ga; 13 C spectrum.

[0032] Figure 15 is the 1H NMR spectrum of compound 3ha;1 1H NMR spectrum; Figure 16 is the NMR of compound 3ha 13 13C NMR spectrum.

[0033] Figure 17 is the NMR of compound 3ia 1 1H NMR spectrum; Figure 18 is the NMR of compound 3ia 13 13C NMR spectrum.

[0034] Figure 19 is the NMR of compound 3ja 1 1H NMR spectrum; Figure 20 is the NMR of compound 3ja 13 13C NMR spectrum.

[0035] Figure 21 is the NMR of compound 3ka 1 1H NMR spectrum; Figure 22 is the NMR of compound 3ka 13 13C NMR spectrum.

[0036] Figure 23 is the NMR of compound 3la 1 1H NMR spectrum; Figure 24 is the NMR of compound 3la 13 13C NMR spectrum.

[0037] Figure 25 is the NMR of compound 3ab 1 1H NMR spectrum; Figure 26 is the NMR of compound 3ab 13 13C NMR spectrum.

[0038] Figure 27 is the NMR of compound 3ac 1 1H NMR spectrum; Figure 28 is the NMR of compound 3ac 13 13C NMR spectrum.

[0039] Figure 29 is the NMR of compound 3ad 1 1H NMR spectrum; Figure 30 is the NMR of compound 3ad 13 13C NMR spectrum.

[0040] Figure 31 is the NMR of compound 3ae 1 1H NMR spectrum; Figure 32 is the NMR of compound 3ae 13 13C NMR spectrum.

[0041] Figure 33 is the NMR of compound 3af 1 1H NMR spectrum; Figure 34 is the NMR of compound 3af13 C spectrum

[0042] Figure 35 It is the inhibition pictures of compound 3aa against Fusarium graminearum, Sclerotinia sclerotiorum, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis at different concentrations. Detailed implementation manners

[0043] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0044] Example 1

[0045] Taking the preparation of 2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3aa) with the following structural formula as an example, its preparation method is as follows:

[0046]

[0047] Under nitrogen conditions, 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol), and the solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube and reacted at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3aa) was separated by silica gel column. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 93% yield, dr value greater than 20:1, melting range: 207–209 °C. The nuclear magnetic resonance spectra are as Figure 1 and 2 shown. 1HNMR(400MHz,CDCl3)δ7.29–7.24(m,2H),7.15–7.06(m,2H),7.02–6.94(m,2H),6.90(td,J=7.7,1.6Hz,1H),6.61(dd,J=7.8,1.5Hz,1H),4.47(s,1H),4.46–4.42(m,1H),3.48(dd,J=16.6,7.5Hz,1H),3.18(dd,J=16.6,8.7Hz,1H),2.60–2.47(m,2H),0.99(t,J=7.2Hz,3H). 13 CNMR(101MHz,CDCl3)δ209.63,166.80,141.33,141.16,140.70,131.11,129.93,127.61,125.45,125.43,122.99,120.79,116.52,116.11,69.70,56.35,36.97,32.19,7.45.HRMS[M+H] + calculated for C 19 H 18 NO3 + =308.1281,found:308.1287.

[0048] Example 2

[0049] Taking the preparation of 7-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ba) with the following structural formula as an example, its preparation method is as follows:

[0050]

[0051] Under nitrogen atmosphere, 7-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added into a 35 mL sealed tube. The reaction was carried out at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure. The target product 7-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ba) was obtained by silica gel column chromatography. All eluents were prepared with petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 78% yield, dr value greater than 20:1, melting range: 142–144 °C. The nuclear magnetic resonance spectra are as shown in Figure 3 and 4 shown 1 1H NMR (400 MHz, CDCl3) δ 7.29–7.24 (m, 2H), 7.08 (td, J = 6.8, 5.8, 2.5 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.93 (s, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 7.9 Hz, 1H), 4.49–4.41 (m, 1H), 4.34 (s, 1H), 3.48 (dd, J = 16.6, 7.6 Hz, 1H), 3.16 (dd, J = 16.6, 8.7 Hz, 1H), 2.53 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 209.68, 167.11, 141.47, 141.15, 140.80, 130.83, 129.92, 128.57, 127.60, 126.01, 125.48, 123.07, 116.96, 116.02, 69.88, 56.44, 36.96, 32.10, 20.77, 7.52. HRMS [M+H] + calculated for C 20 H 20 NO3 + = 322.1438, found: 322.1439.

[0052] Example 3

[0053] Taking the preparation of 6-phenyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ca) with the following structural formula as an example, its preparation method is as follows:

[0054]

[0055] Under nitrogen atmosphere, 6-phenyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube and reacted at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 6-phenyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ca) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 66% yield, dr value greater than 20:1, melting range: 125–127 °C. The nuclear magnetic resonance spectra are as Figure 5 and 6 shown, 1 HNMR(400MHz,CDCl3)δ7.47(d,J=7.5Hz,2H),7.38(t,J=7.5Hz,2H),7.33–7.24(m,3H),7.18(d,J=8.4Hz,1H),7.15–7.04(m,3H),6.84(d,J=2.0Hz,1H),4.56(d,J=3.1Hz,1H),4.48(t,J=8.1Hz,1H),3.49(dd,J=16.7,7.5Hz,1H),3.20(dd,J=16.7,8.8Hz,1H),2.62–2.50(m,2H),1.00(t,J=7.2Hz,3H). 13 CNMR(101MHz,CDCl3)δ209.74,166.79,141.43,140.78,140.69,140.09,138.90,131.33,130.06,128.88,127.78,127.58,126.97,125.55,123.14,119.64,116.88,114.73,69.80,56.49,37.09,32.31,7.57.HRMS[M+H] + calculated for C25 H 22 NO3 + = 384.1594, found: 384.1596.

[0056] Example 4

[0057] Taking the preparation of 6-chloro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3da) with the following structural formula as an example, its preparation method is as follows:

[0058]

[0059] Under nitrogen atmosphere, 6-chloro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and the solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 6-chloro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3da) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 78% yield, dr value greater than 20:1, melting range: 193–195 °C. The nuclear magnetic resonance spectrum is as Figure 7 and 8 shown 1 HNMR(400MHz,CDCl3)δ7.32–7.24(m,2H),7.14–7.08(m,1H),7.06(s,2H),7.01(dd,J = 19.1,8.Hz,2H),6.85(dd,J = 8.6,2.3Hz,1H),6.65(d,J = 2.3Hz,1H),4.71(s,1H),4.49–4.40(m,1H),3.45(dd,J = 16.6,7.5Hz,1H),3.19(dd,J = 16.6,8.7Hz,1H),2.62–2.47(m,2H),1.00(t,J = 7.2Hz,3H). 13CNMR (101 MHz, CDCl3) δ 209.69, 166.19, 141.18, 140.67, 139.71, 132.22, 130.55, 130.19, 127.81, 125.62, 122.91, 120.56, 117.58, 115.95, 69.36, 56.47, 37.03, 32.28, 7.53. HRMS [M+H] + calculated for C 19 H 17 ClNO3 + =342.0891, found: 342.0897.

[0060] Example 5

[0061] Taking the preparation of 6-methoxy-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ea) with the following structural formula as an example, its preparation method is as follows:

[0062]

[0063] Under nitrogen atmosphere, 6-methoxy-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 6-methoxy-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ea) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 68% yield, dr value greater than 20:1, melting range: 154–156 °C. The NMR spectra are as Figure 9 and 10 shown 1HNMR (400 MHz, CDCl3) δ 7.29–7.23 (m, 2H), 7.12–7.06 (m, 1H), 7.05–6.98 (m, 2H), 6.42 (dd, J=8.9, 2.8 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.53–4.42 (m, 2H), 3.70 (s, 3H), 3.48 (dd, J=16.6, 7.6 Hz, 1H), 3.17 (dd, J=16.6, 8.7 Hz, 1H), 2.55 (qd, J=7.2, 1.4 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 209.75, 166.93, 157.27, 141.52, 140.73, 135.43, 131.88, 129.98, 127.70, 125.51, 123.07, 117.16, 105.97, 101.54, 69.59, 56.50, 55.62, 36.99, 32.17, 7.54. HRMS [M+H] + calculated for C 20 H 20 NO4 + =338.1387, found: 338.1389.

[0064] Example 6

[0065] Taking the preparation of 5-fluoro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3fa) with the following structural formula as an example, its preparation method is as follows:

[0066]

[0067] Under nitrogen atmosphere, 5-fluoro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonate) (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube. The reaction was carried out at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure. The target product 5-fluoro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3fa) was obtained by silica gel column chromatography. All eluents were prepared with petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 71% yield, dr value greater than 20:1, melting range: 170–172 °C. The nuclear magnetic resonance spectra are as Figure 11 and 12 shown 1 1H NMR (400 MHz, CDCl3) δ 7.31–7.25 (m, 2H), 7.15–6.98 (m, 3H), 6.59 (td, J = 8.5, 2.8 Hz, 1H), 6.37 (dd, J = 9.0, 2.8 Hz, 1H), 4.62 (s, 1H), 4.45 (dd, J = 8.8, 7.4 Hz, 1H), 3.46 (dd, J = 16.6, 7.4 Hz, 1H), 3.22 (dd, J = 16.6, 8.8 Hz, 1H), 2.64–2.47 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 209.77, 166.36, 161.21, 158.79, 141.26, 140.71, 137.34, 132.31 (d, J = 10.9 Hz), 130.22, 127.86, 125.65, 122.99, 117.55 (d, J = 9.9 Hz), 107.16 (d, J = 23.9 Hz), 103.21 (d, J = 27.3 Hz), 69.34, 56.45, 37.11, 32.45, 7.57. HRMS [M+H] + calculated for C 19 H 17 FNO3 + = 326.1187, found: 326.1188.

[0068] Example 7

[0069] Taking the preparation of 8,6-dichloro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ga) with the following structural formula as an example, its preparation method is as follows:

[0070]

[0071] Under nitrogen atmosphere, 8,6-dichloro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 8,6-dichloro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ga) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 65% yield, dr value greater than 20:1, melting range: 218–220 °C. The nuclear magnetic resonance spectra are as Figure 13 and 14 shown, 1 1H NMR (400 MHz, CDCl3) δ 7.33–7.26 (m, 2H), 7.18–7.12 (m, 1H), 7.02–6.93 (m, 2H), 6.57 (d, J = 2.3 Hz, 1H), 4.76 (s, 1H), 4.43 (dd, J = 8.7, 7.1 Hz, 1H), 3.44 (dd, J = 16.6, 7.2 Hz, 1H), 3.25 (dd, J = 16.6, 8.7 Hz, 1H), 2.64–2.48 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 209.71, 164.90, 140.76, 140.65, 136.05, 133.16, 130.44, 128.05, 125.75, 122.93, 122.37, 121.12, 114.38, 69.14, 56.33, 37.17, 32.62, 7.57 (one signal is missing due to overlap). HRMS [M+H] + calculated for C 19 H 16 Cl2NO3 += 376.0502, found: 376.0510.

[0072] Example 8

[0073] Taking the preparation of 5'-fluoro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ha) with the following structural formula as an example, its preparation method is as follows:

[0074]

[0075] Under nitrogen atmosphere, 5'-fluoro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 5'-fluoro-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ha) was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 94% yield, dr value greater than 20:1, melting range: 157–159 °C. The nuclear magnetic resonance spectrum is as Figure 15 and 16 shown, 1 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 7.8 Hz, 1H), 7.04–6.86 (m, 4H), 6.79 (td, J = 8.7, 2.5 Hz, 1H), 6.64 (dd, J = 7.8, 1.6 Hz, 1H), 4.51 (s, 1H), 4.43 (dd, J = 8.8, 7.1 Hz, 1H), 3.43 (dd, J = 16.9, 7.2 Hz, 1H), 3.17 (dd, J = 16.8, 8.7 Hz, 1H), 2.59–2.41 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13CNMR(101MHz,CDCl3)δ209.54,166.62,165.30,162.83,143.54(d,J=8.8Hz),141.19,137.12(d,J=2.6Hz),131.07,125.64,124.57(d,J=9.4Hz),121.07,116.45(d,J=39.7Hz),114.97(d,J=23.0Hz),112.58(d,J=22.8Hz),69.11,56.65,37.11,32.36(d,J=2.1Hz),7.49.HRMS[M+H] + calculated forC 19 H 17 FNO3 + =326.1187,found:326.1191.

[0076] Example 9

[0077] Taking the preparation of 5'-iodo-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ia) with the following structural formula as an example, its preparation method is as follows:

[0078]

[0079] Under nitrogen atmosphere, 5'-iodo-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube and reacted at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 5'-iodo-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ia) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 72% yield, dr value greater than 20:1, melting range: 152–154 °C. The nuclear magnetic resonance spectra are as Figure 17 and 18 shown 1HNMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.99 (td, J = 7.6, 1.5 Hz, 1H), 6.91 (td, J = 7.8, 1.5 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.63 (dd, J = 7.8, 1.5 Hz, 1H), 4.50 (s, 1H), 4.38 (dd, J = 8.7, 7.0 Hz, 1H), 3.41 (dd, J = 16.8, 7.1 Hz, 1H), 3.17 (dd, J = 16.8, 8.7 Hz, 1H), 2.61–2.39 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 209.44, 166.33, 143.31, 141.16, 141.02, 136.81, 134.73, 130.94, 125.68, 124.74, 121.15, 116.67, 116.24, 96.08, 69.50, 56.11, 37.10, 32.11, 7.51. HRMS [M+H] + calculated for C 19 H 17 INO3 + =434.0248, found: 434.0247.

[0080] Example 10

[0081] Taking the preparation of 5'-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ja) with the following structural formula as an example, its preparation method is as follows:

[0082]

[0083] Under nitrogen atmosphere, 5'-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonate) (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube. The reaction was carried out at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure. The target product 5'-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ja) was obtained by silica gel column chromatography. All eluents were prepared with petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 96% yield, dr value greater than 20:1, melting range: 180–182 °C. The nuclear magnetic resonance spectra are as Figure 19 and 20 shown 1 1H NMR (400 MHz, CDCl3) δ 7.14–7.06 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.93–6.84 (m, 3H), 6.61 (d, J = 7.8 Hz, 1H), 4.49–4.36 (m, 2H), 3.44 (dd, J = 16.6, 7.5 Hz, 1H), 3.13 (dd, J = 16.6, 8.7 Hz, 1H), 2.58–2.48 (m, 2H), 2.29 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 209.85, 167.03, 141.30, 140.97, 140.18, 138.65, 131.31, 128.53, 126.13, 125.50, 122.78, 120.85, 116.59, 116.21, 69.53, 56.59, 37.06, 32.12, 21.49, 7.54. HRMS [M+H] + calculated for C 20 H 20 NO3 + = 322.1438, found: 322.1439.

[0084] Example 11

[0085] Taking the preparation of 6'-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ka) with the following structural formula as an example, its preparation method is as follows:

[0086]

[0087] Under nitrogen atmosphere, 6'-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube. The reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure. The target product 6'-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3ka) was obtained by silica gel column chromatography. All eluents were prepared with petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 83% yield, dr value greater than 20:1, melting range: 155–157 °C. The NMR spectra are as Figure 21 and 22 shown, 1 1H NMR (400 MHz, CDCl3) δ 7.18–7.06 (m, 3H), 6.98 (t, J = 7.3 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.82 (s, 1H), 6.62 (d, J = 7.5 Hz, 1H), 4.43 (s, 1H), 4.41–4.35 (m, 1H), 3.40 (dd, J = 16.4, 7.2 Hz, 1H), 3.15 (dd, J = 16.4, 8.7 Hz, 1H), 2.59–2.41 (m, 2H), 2.20 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 209.83, 167.01, 141.60, 141.19, 137.78, 137.57, 131.24, 130.96, 125.53, 125.17, 123.63, 120.82, 116.63, 116.13, 69.86, 56.81, 37.07, 32.03, 21.40, 7.56. HRMS [M+H] + calculated for C 20 H 20 NO3 + = 322.1438, found: 322.1442.

[0088] Example 12

[0089] Taking the preparation of 5',6'-dichloro-2'-propanoyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3la) with the following structural formula as an example, its preparation method is as follows:

[0090]

[0091] Under nitrogen atmosphere, 5',6'-dichloro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-penten-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube and reacted at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 5',6'-dichloro-2'-propanoyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2-one (3la) was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 76% yield, dr value greater than 20:1, melting range: 188–190 °C. The nuclear magnetic resonance spectra are as Figure 23 and 24 shown, 1 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.21–7.09 (m, 2H), 7.02 (td, J = 7.7, 1.5 Hz, 1H), 6.94 (td, J = 7.7, 1.5 Hz, 1H), 6.66 (dd, J = 7.8, 1.5 Hz, 1H), 4.59 (s, 1H), 4.29 (dd, J = 8.6, 6.1 Hz, 1H), 3.31 (dd, J = 16.8, 6.2 Hz, 1H), 3.20 (dd, J = 16.8, 8.7 Hz, 1H), 2.56–2.32 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 209.44, 165.82, 141.21, 141.09, 141.02, 134.29, 131.82, 130.71, 127.25, 125.85, 125.20, 121.46, 116.83, 116.23, 69.45, 56.32, 37.20, 32.41, 7.51. HRMS [M+H] + calculated for C 19 H 16 Cl2NO3+ = 376.0502, found: 376.0507.

[0092] Example 13

[0093] Taking the preparation of 2'-butyryl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ab) with the following structural formula as an example, its preparation method is as follows:

[0094]

[0095] Under nitrogen atmosphere, 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-hexen-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 2'-butyryl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ab) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 68% yield, dr value greater than 20:1, melting range: 160–162 °C. The nuclear magnetic resonance spectrum is as Figure 25 and 26 shown, 1 HNMR(400 MHz, CDCl3) δ 7.29–7.23 (m, 2H), 7.15–7.05 (m, 2H), 7.05–6.95 (m, 2H), 6.90 (td, J = 7.7, 1.6 Hz, 1H), 6.62 (dd, J = 7.8, 1.6 Hz, 1H), 4.51 (s, 1H), 4.43 (dd, J = 8.7, 7.3 Hz, 1H), 3.46 (dd, J = 16.6, 7.4 Hz, 1H), 3.18 (dd, J = 16.6, 8.8 Hz, 1H), 2.56–2.40 (m, 2H), 1.62–1.46 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13CNMR (101 MHz, CDCl3) δ 209.28, 166.88, 141.45, 141.23, 140.76, 131.23, 129.98, 127.69, 125.53, 125.50, 123.05, 120.82, 116.59, 116.17, 69.77, 56.53, 45.65, 32.22, 16.90, 13.69. HRMS [M+H] + calculated for C 20 H 20 NO3 + =322.1438, found: 322.1439.

[0096] Example 14

[0097] Taking the preparation of 2'-hexanoyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ac) with the following structural formula as an example, its preparation method is as follows:

[0098]

[0099] Under nitrogen atmosphere, 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 1-octen-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonyl)imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 110 °C for 12 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 2'-hexanoyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ac) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 85% yield, dr value greater than 20:1, melting range: 96–98 °C. The nuclear magnetic resonance spectra are as Figure 27 and 28 shown, 1HNMR(400MHz,CDCl3)δ7.31–7.23(m,2H),7.14–7.05(m,2H),6.98(dd,J=17.1,7.9Hz,2H),6.89(t,J=7.6Hz,1H),6.62(d,J=7.6Hz,1H),4.54(s,1H),4.43(t,J=8.0Hz,1H),3.46(dd,J=16.6,7.3Hz,1H),3.18(dd,J=16.6,8.7Hz,1H),2.58–2.39(m,2H),1.60–1.39(m,2H),1.30–1.15(m,4H),0.83(t,J=6.9Hz,3H). 13 CNMR(101MHz,CDCl3)δ209.44,166.87,141.45,141.22,140.77,131.23,129.97,127.68,125.52,125.49,123.07,120.80,116.58,116.16,69.79,56.52,43.74,32.27,31.26,23.15,22.48,13.96.HRMS[M+H] + calculated for C 22 H 24 NO3 + =350.1751,found:350.1755.

[0100] Example 15

[0101] Taking the preparation of 3'-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ad) with the following structural formula as an example, its preparation method is as follows:

[0102]

[0103] Under nitrogen atmosphere, 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 4-hexen-3-one (0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), silver bis(trifluoromethanesulfonate) (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1,2-dichloroethane (2.0 mL) were added to a 35 mL sealed tube and reacted at 110 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3'-methyl-2'-propionyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ad) was obtained by silica gel column chromatography. All eluents were prepared with petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 87% yield, dr value greater than 20:1:1:1, melting range: 191–193 °C. The NMR spectra are as Figure 29 and 30 shown 1 1H NMR (400 MHz, CDCl3) δ 7.31–7.25 (m, 1H), 7.21–7.13 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.90 (t, J = 6.9 Hz, 1H), 6.81 (td, J = 7.8, 1.6 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 4.86 (s, 1H), 3.91 (d, J = 8.0 Hz, 1H), 3.70 (p, J = 7.4 Hz, 1H), 2.25 (dq, J = 18.4, 7.1 Hz, 1H), 1.89 (dq, J = 18.4, 7.2 Hz, 1H), 1.20 (d, J = 7.2 Hz, 3H), 0.74 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 210.64, 166.20, 145.89, 141.52, 140.67, 132.20, 129.84, 127.83, 125.26, 123.23, 123.20, 120.89, 116.58, 116.10, 69.59, 61.20, 40.18, 40.00, 14.84, 7.09. HRMS [M+H] + calculated for C 20 H 20 NO3 + = 322.1438, found: 322.1437.

[0104] Example 16

[0105] Taking the preparation of 3'-n-propyl-2'-acetyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ae) with the following structural formula as an example, its preparation method is as follows:

[0106]

[0107] Under nitrogen atmosphere, 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 3-hepten-2-one (0.20 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.002 mmol), silver bis(trifluoromethanesulfonyl)imide (0.008 mmol), sodium bicarbonate (0.6 mmol) and solvent 1,2-dichloroethane (1.0 mL) were added to a 35 mL sealed tube, and the reaction was carried out at 120 °C for 16 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 3'-n-propyl-2'-acetyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3ae) was obtained by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 60% yield, dr value greater than 20:1:1:1, melting range: 210–212 °C. The nuclear magnetic resonance spectra are as Figure 31 and 32 shown, 1 1H NMR (400 MHz, CDCl3) δ 7.38–7.32 (m, 1H), 7.27–7.23 (m, 3H), 7.11 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 4.74 (s, 1H), 4.12 (d, J = 7.4 Hz, 1H), 3.70–3.60 (m, 1H), 1.97 (s, 3H), 1.60–1.41 (m, 4H), 0.99 (t, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 208.40, 165.90, 145.72, 141.64, 140.60, 131.80, 129.87, 127.83, 125.38, 123.51, 123.43, 121.13, 116.78, 116.51, 69.44, 61.28, 46.16, 34.32, 32.38, 22.26, 14.39. HRMS [M+H] + calculated for C 21 H 22 NO3 += 336.1594, found: 336.1599.

[0108] Example 17

[0109] Taking the preparation of 3'-hexyl-2'-acetyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3af) with the following structural formula as an example, its preparation method is as follows:

[0110]

[0111] Under nitrogen atmosphere, 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (0.20 mmol), 3-decen-2-one (0.40 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.0008 mmol), silver bis(trifluoromethanesulfonyl)imide (0.0032 mmol), sodium bicarbonate (0.2 mmol) and solvent 1,2-dichloroethane (4.0 mL) were added to a 35 mL sealed tube and reacted at 80 °C for 8 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 3'-hexyl-2'-acetyl-2',3'-dihydro-2H,4H-spiro[benzo[b][1.4]oxazine-3,1'-indene]-2-one (3af) was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 20:1. Product data characterization: white solid, 27% yield, dr value greater than 20:1:1:1, melting range: 143–145 °C. The nuclear magnetic resonance spectrum is as Figure 33 and 34 shown, 1 1H NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 1H), 7.29–7.22 (m, 3H), 7.10 (d, J = 7.7 Hz, 1H), 7.00 (td, J = 7.6, 1.5 Hz, 1H), 6.92 (td, J = 7.7, 1.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 4.79 (s, 1H), 4.11 (d, J = 7.4 Hz, 1H), 3.70–3.55 (m, 1H), 1.95 (s, 3H), 1.54–1.24 (m, 10H), 0.89 (t, J = 6.6 Hz, 3H). 13CNMR (101 MHz, CDCl3) δ 208.38, 165.86, 145.77, 141.61, 140.57, 131.82, 129.84, 127.79, 125.35, 123.47, 123.42, 121.07, 116.76, 116.47, 69.45, 61.29, 46.40, 34.33, 31.80, 30.16, 29.82, 29.59, 29.04, 22.71, 14.17. HRMS [M+H] + calculated for C 24 H 28 NO3 + =378.2064, found: 378.2071.

[0112] Application Example 1

[0113] Antifungal Activity Test

[0114] Using the mycelial growth rate method, compound 3aa was dissolved in DMSO and diluted with an aqueous solution of Tween 80 to prepare medicaments with concentration gradients of 2000, 1000, and 500 μg / mL. 5 mL of the aqueous solution of Tween 80 was aspirated and injected into 45 mL of PDA medium and dispersed evenly. Then, the medicaments from low to high concentrations were injected into 45 mL of PDA medium at concentrations of 200, 100, and 50 μg / mL respectively. After cooling, Fusarium graminearum was inoculated. Then it was placed in an incubator at 25 °C until the mycelium on the blank medium was almost fully grown. After that, the colony diameter (subtracting the diameter of the inoculum disc) was measured using the cross-cross method. The inhibition rate of compound 3aa against Fusarium graminearum (Fg) at different concentrations was calculated according to the following formula.

[0115] Inhibition rate (%) = 100 × (colony diameter of the blank control group - colony diameter of the treatment group) / colony diameter of the blank control group. The inhibition rates of compound 3aa against Sclerotinia sclerotiorum (St), Gaeumannomyces graminis var. tritici (Ggt), and Rhizoctonia cerealis (Rc) at different concentrations were obtained using the same method as above, as Figure 35 shown. The leftmost in the figure is the blank medium, and the solutions of compound 3aa at concentrations of 200, 100, and 50 μg / mL are shown successively to the right; Figure 35 in the figure, the antifungal diagrams of Fusarium graminearum, Sclerotinia sclerotiorum, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis are shown from top to bottom in turn.

[0116] Table 1 Inhibition rates of compound 3aa against Fusarium graminearum, Sclerotinia sclerotiorum, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis

[0117] Fg St Ggt Rc 50 μg / mL 12.6％ 29.4％ 19.2％ 44.1％ 100 μg / mL 16.2％ 32.5％ 27.8％ 49.4％ 200 μg / mL 18.5％ 42.3％ 40.2％ 50.9％

[0118] The concentration coefficient is expressed in terms of logarithm x, the inhibition rate is converted into the probability value y, and then the virulence regression equation and R 2 value are calculated using an Excel spreadsheet, and simulated using spss software to obtain the EC 50 value.

[0119] Table 2 shows the virulence regression equations, R 2 values and EC 50 values (μg / mL) of compound 3aa against Fusarium graminearum, Sclerotinia sclerotiorum, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis

[0120] Toxicity regression equation <![CDATA[R 2 value]]> <![CDATA[EC 50 Value (μg / mL)]]> Fg y = 0.4006x + 3.1875 0.9755 >500.00 St y = 0.5773x + 3.4486 0.9282 480.93 Ggt y = 1.0289x + 2.3730 0.9969 355.81 Rc y = 0.2822x + 4.3879 0.8924 147.45

[0121] In summary, we can see that compound 3aa shows certain antibacterial effects against Sclerotinia sclerotiorum, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis. In particular, its EC 50 value is 147.45. Therefore, by using this synthesis method to construct structurally diverse spiro compounds and continue to conduct antibacterial activity tests on this pathogenic bacterium, it is expected to find more efficient fungicides.

[0122] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A 1,4-benzoxazine spirocyclic derivative, characterized in that, The structure is as follows: ， Wherein R is any one of H, Me, Ph, Cl or MeO; R 1 is Me, Et, n Pr, n Am; R 2 is H, Me, n Pr or n hexyl; Ar is a benzene ring, or a benzene ring substituted by Me, Cl or I.

2. A method for synthesizing a 1,4-benzoxazine spirocyclic derivative, characterized in that, The method comprises the following steps: under an inert atmosphere, adding a benzoxazinone compound 1, an unsaturated ketone compound 2, a catalyst and an additive into a solvent to obtain a reaction solution for reaction to generate a 1,4-benzoxazine spirocyclic derivative; the reaction formula is as follows: ， wherein R is any one of H, Me, Ph, Cl or MeO; R 1 is any one of Me, Et, n Pr, n Am; R 2 is any one of H, Me, n Pr or n hexyl; Ar is a benzene ring, or a benzene ring substituted by Me, Cl or I; Rh(III) refers to the catalyst; The catalyst is a rhodium catalyst and a silver salt, and the molar ratio of the rhodium catalyst to the silver salt is 1:

4. The rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium dimer or bis(acetonitrile)(pentamethylcyclopentadienyl)rhodium(III) bis(hexafluorantimonate). The silver salt is any one or a combination of silver bis(trifluoromethanesulfonyl)imide, silver hexafluoroantimonate, silver tetrafluoroborate, and silver trifluoroacetate; The additive is sodium bicarbonate, acetic acid, adamantane carboxylic acid, pivalic acid, mesitylenic acid, lithium acetate, lithium carbonate, sodium acetate or sodium carbonate; The solvent is any one or a combination of 1,2-dichloroethane, tetrahydrofuran, cyclohexane, trifluorotoluene or toluene.

3. The synthesis method of the 1,4-benzoxazine spirocyclic derivative according to claim 2, characterized in that, The reaction temperature of the reaction is 80 - 120 °C, and the reaction time is 8 - 16 h.

4. The synthesis method of the 1,4-benzoxazine spirocyclic derivative according to claim 2, wherein, The inert atmosphere is a gas atmosphere of nitrogen, argon or helium.

5. The synthesis method of the 1,4-benzoxazine spirocyclic derivative according to claim 2, characterized in that, The molar ratio of the benzoxazinone compound 1, the unsaturated ketone compound 2, the catalyst and the additive is 1:(1.0 - 2.0):(0.02 - 0.1):(1 - 3).

6. The method for synthesizing the 1,4-benzoxazine spirocyclic derivative according to claim 5, wherein, The concentration of the benzoxazinone compound 1 in the reaction solution is 0.05 M - 0.2 M.

7. Use of the 1,4-benzoxazine spirocyclic derivative according to claim 1 in the preparation of a fungicide for controlling plant diseases caused by fungi.

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