CN117003711A - 1, 4-benzoxazine spiro derivative and synthetic method and application thereof - Google Patents

1, 4-benzoxazine spiro derivative and synthetic method and application thereof Download PDF

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CN117003711A
CN117003711A CN202310697048.1A CN202310697048A CN117003711A CN 117003711 A CN117003711 A CN 117003711A CN 202310697048 A CN202310697048 A CN 202310697048A CN 117003711 A CN117003711 A CN 117003711A
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benzoxazine
mmol
spiro
compound
silver
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杨西发
李祥
耿月华
刘向阳
郝有武
李松
李宜越
辜凡
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Henan Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention provides a 1, 4-benzoxazine spiro derivative, a synthesis method and application thereof, belonging to the technical field of organic synthetic chemistry, wherein the structural general formula of the 1, 4-benzoxazine spiro derivative is as follows:wherein R is any one of H, me, ph, cl or MeO; r is R 1 Is Me, et, n Pr、 n Am; r is R 2 H, me is a, n Pr or n Any one of the hexyl groups; ar is benzene ring, or substituted benzene ring of Me, cl or I. The invention also discloses a synthesis method and application thereof. The compound has certain antifungal activity and can be used for preventing and treating plant diseases caused by fungi. And is combined withAnd the method has the advantages of simple operation, atom economy, step economy, high chemical selectivity, high yield and good functional group tolerance.

Description

1, 4-benzoxazine spiro derivative and synthetic method and application thereof
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a 1, 4-benzoxazine spiro derivative, a synthetic method and application thereof.
Background
In 1955, virtanen et al found for the first time that 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 (dimbo) (Acta chem.scand.,1955,9,1543-1544) and have been shown to have an effect of inhibiting spore germination of phytopathogenic fungi (phytochemistry, 1973,12,347-352). By taking the derivatives as a matrix, a large number of 1, 4-benzoxazine derivatives are synthesized and mainly show antibacterial and weeding activities. A novel class of benzoxazine derivatives was synthesized as by Alper-Hayta et al, and demonstrated inhibitory activity against C.krusei through experiments (Eur J Med chem.,2006,41,1398-1404). In 1993, 1, 4-benzoxazine derivative flumioxazin developed by Sumitomo chemical company was marketed and used for controlling grassy weeds and broadleaf weeds in crops such as soybeans and cotton. In China, the 1- (((4-methoxyphenyl) carbamoyl) methyl-2- (4-nitrophenyl) -3, 1-benzoxazine synthesized by the Tang Zilong subject has high inhibition rate of 71.9 percent on sclerotinia bacteria (fine chemical intermediate, 2020,50,21-24), on the other hand, spiro compounds widely exist in a plurality of natural products, have important application value and biological activity (chem.Rev., 1989,89,1617-1661; chem.Rev.,2004,104,2751-2776), and spiro-tetramic acid derivatives synthesized by Fischer and the like of Bayer crop science company have good herbicidal activity (chem.Abstr, 2005,143,153282), and the spiro-derivative of the benzoxazine compounds is developed based on the two aspects and has important significance on preventing and controlling diseases and insect pests.
Disclosure of Invention
Aiming at the technical problems, the invention provides a 1, 4-benzoxazine spiro derivative, a synthesis method and application thereof, and the method has the advantages of simple operation, atom economy, step economy, high chemical selectivity, high yield, good functional group tolerance and the like.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
1, 4-benzoxazine spiro derivative has the following structure:
wherein R is any one of H, me, ph, cl or MeO; r is R 1 Is Me, et, n Pr， n Am; r is R 2 H, me is a, n Pr or n Any one of the hexyl groups; ar is benzene ring, or substituted benzene ring of Me, cl or I.
A method for synthesizing 1, 4-benzoxazine spiro derivative, which comprises the following steps: under inert atmosphere, adding the benzoxazinone compound 1, the unsaturated ketone compound 2, a catalyst and an additive into a solvent to prepare a reaction solution for reaction to generate a 1, 4-benzoxazine spiro derivative; the reaction formula is as follows:
wherein R is any one of H, me, ph, cl or MeO; r is R 1 Is Me, et, n Pr、 n Am; r is R 2 H, me is a, n Pr or n Any one of the hexyl groups; ar is benzene ring, or substituted benzene ring of Me, cl or I; rh (lll) is a catalyst.
The reaction temperature of the reaction is 80-120 ℃ and the reaction time is 8-16h.
The inert atmosphere is a gas atmosphere of nitrogen, argon or helium.
The catalyst comprises a rhodium catalyst and silver salt, wherein the molar ratio of the rhodium catalyst to the silver salt is 1: the rhodium catalyst is dichloro (pentamethyl cyclopentadienyl) rhodium dimer or di (hexafluoroantimonic acid) triacetonitrile (pentamethyl cyclopentadienyl) rhodium dimer, and the silver salt is any one or combination of silver bis (trifluoromethanesulfonyl imide), silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate and silver trifluoroacetate.
The additive is sodium bicarbonate, acetic acid, adamantanecarboxylic acid, pivalic acid, mesitylene benzoic acid, lithium acetate, lithium carbonate, sodium acetate or sodium carbonate.
The solvent is any one or combination of 1, 2-dichloroethane, tetrahydrofuran, cyclohexane, benzotrifluoride or toluene.
The molar ratio of the benzoxazinone compound 1 to the unsaturated ketone compound 2 to the catalyst to the additive is 1: (1.0-2.0): (0.02-0.1): (1-3).
The concentration of the benzoxazinone compound 1 in the reaction liquid is 0.05M-0.2M.
The application of the 1, 4-benzoxazine spiro derivative in the field of antibiosis and sterilization.
The reaction mode of the reaction process of the invention is shown as the following formula:
the reacted compound 1 forms a cyclometallated intermediate a under the action of a catalyst, then an unsaturated ketone is inserted to form an intermediate b, and then nucleophilic addition reaction in a molecule and metal removal are carried out to form a benzoxazine spiro derivative c, (in practice, when the compound has two chiral centers, the compound comprises two enantiomers (1 'R,2' R) and (1 'S,2' S), (1 'R,2' S) and (1 'S,2' R), wherein the ratio of a first enantiomer to a second enantiomer is greater than 20:1; when the compound has three chiral centers, it includes four 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; specific structures are shown in the following figures
The invention has the beneficial effects that: the method creatively selects the benzoxazine compound and the unsaturated ketone compound which are easy to obtain as reactants, and adopts the method of [3+2 ] under the action of the metal rhodium catalyst]One-step synthesis of [5.4 ]]The spiro compound provides a simple and effective method for constructing complex spiro compounds, and the method has the advantages of good diastereoselectivity, simple operation, atom economy, step economy, high yield, good functional group tolerance and the like. The compounds show a certain antibacterial effect on sclerotinia rot of colza, total rot of wheat and sheath blight of wheat, in particular to EC of the compounds on sheath blight of wheat 50 The value is 147.45, has better antifungal performance, and can be applied to the prevention and treatment of plant diseases caused by fungi.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetism of Compound 3aa 1 H spectrogram; FIG. 2 is a nuclear magnetism of Compound 3aa 13 C spectrogram.
FIG. 3 is a nuclear magnetism of Compound 3ba 1 H spectrogram; FIG. 4 is a nuclear magnetism of Compound 3ba 13 C spectrogram.
FIG. 5 is a nuclear magnetism of Compound 3ca 1 H spectrogram; FIG. 6 is a nuclear magnetism of Compound 3ca 13 C spectrogram.
FIG. 7 is a nuclear magnetism of Compound 3da 1 H spectrogram; FIG. 8Is the nuclear magnetism of compound 3da 13 C spectrogram.
FIG. 9 is a nuclear magnetism of Compound 3ea 1 H spectrogram; FIG. 10 is a nuclear magnetism of Compound 3ea 13 C spectrogram.
FIG. 11 is a nuclear magnetism of Compound 3fa 1 H spectrogram; FIG. 12 is a nuclear magnetism of Compound 3fa 13 C spectrogram.
FIG. 13 is a nuclear magnetic resonance of Compound 3ga 1 H spectrogram; FIG. 14 is a nuclear magnetic resonance of Compound 3ga 13 C spectrogram.
FIG. 15 is a nuclear magnetism of Compound 3ha 1 H spectrogram; FIG. 16 is a nuclear magnetism of Compound 3ha 13 C spectrogram.
FIG. 17 is a nuclear magnetism of Compound 3ia 1 H spectrogram; FIG. 18 is a nuclear magnetism of Compound 3ia 13 C spectrogram.
FIG. 19 is a nuclear magnetism of Compound 3ja 1 H spectrogram; FIG. 20 is a nuclear magnetism of Compound 3ja 13 C spectrogram.
FIG. 21 is a nuclear magnetism of Compound 3ka 1 H spectrogram; FIG. 22 is a nuclear magnetism of Compound 3ka 13 C spectrogram.
FIG. 23 is a nuclear magnetism of Compound 3la 1 H spectrogram; FIG. 24 is a nuclear magnetism of Compound 3la 13 C spectrogram.
FIG. 25 is a nuclear magnetism of Compound 3ab 1 H spectrogram; FIG. 26 is a nuclear magnetism of Compound 3ab 13 C spectrogram.
FIG. 27 is a nuclear magnetism of Compound 3ac 1 H spectrogram; FIG. 28 is a nuclear magnetism of Compound 3ac 13 C spectrogram.
FIG. 29 is a nuclear magnetism of Compound 3ad 1 H spectrogram; FIG. 30 is a nuclear magnetism of Compound 3ad 13 C spectrogram.
FIG. 31 is a nuclear magnetism of Compound 3ae 1 H spectrogram; FIG. 32 is a nuclear magnetism of Compound 3ae 13 C spectrogram.
FIG. 33 is a nuclear magnetism of Compound 3af 1 H spectrogram; FIG. 34 is a nuclear magnetism of Compound 3af 13 C spectrogram.
FIG. 35 is a photograph showing the inhibition of Fusarium graminearum, sclerotinia sclerotiorum, rhizoctonia cerealis, and Rhizoctonia cerealis by Compound 3aa at various concentrations.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without any inventive effort, are intended to be within the scope of the invention.
Example 1
Taking the example of the preparation of 2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 aa) of the formula:
3-phenyl-2H-benzo [ b ] under nitrogen][1,4]Oxazin-2-one (0.20 mmol), 1-pentene-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 1, 2-dichloroethane (2.0 mL) as solvents were added into a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the reaction was completed, and the target product 2' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation on a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 aa), all eluents being petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 93% yield, dr value greater than 20:1, melting path: 207-209 ℃. The nuclear magnetic resonance spectrum is shown in figures 1 and 2, 1 HNMR(400MHz,CDCl 3 )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,CDCl 3 )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 NO 3 + ＝308.1281,found:308.1287.
example 2
Taking the example of the preparation of 7-methyl-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ba) of the formula:
under nitrogen, 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 dimer (0.004 mmol), silver bis (trifluoromethanesulfonyl imide) (0.016 mmo l), sodium bicarbonate (0.4 mmol) and 1, 2-dichloroethane (2.0 mL) as solvents were added into a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the completion of the reaction, and the target product of 7-methyl-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ba), all eluents being petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 78% yield, dr value greater than 20:1, melting path: 142-144 ℃. The nuclear magnetic resonance spectrum is shown in figures 3 and 4, 1 HNMR(400MHz,CDCl 3 )δ7.29–7.24(m,2H),7.08(td,J＝6.8,5.8,2.5Hz,1H),6.98(d,J＝7.7Hz,1H),6.93(s,1H),6.77(d,J＝7.8Hz,1H),6.50(d,J＝7.9Hz,1H),4.49–4.41(m,1H),4.34(s,1H),3.48(dd,J＝16.6,7.6Hz,1H),3.16(dd,J＝16.6,8.7Hz,1H),2.53(q,J＝7.2Hz,2H),2.30(s,3H),0.99(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.68,167.11,141.47,141.15,140.80,130.83,129.92,128.57,127.60,126.01,125.48,123.07,116.96,116.02,69.88,56.44,36.96,32.10,20.77,7.52.HRMS[M+H] + calculated for C 20 H 20 NO 3 + ＝322.1438,found:322.1439.
example 3
Taking 6-phenyl-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ca) of the formula as an example, the preparation method is as follows:
under nitrogen, 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 dimer (0.004 mmol), silver bistrifluoromethane sulfonyl imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2.0 mL) are added into a 35mL sealed tube, reacted for 12h at 110 ℃, after the reaction is finished, the solvent is removed under reduced pressure, and the target product 6-phenyl-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ca), all eluents being petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 66% yield, dr value greater than 20:1, melting path: 125-127 ℃. The nmr spectrum is shown in figures 5 and 6, 1 HNMR(400MHz,CDCl 3 )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,CDCl 3 )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 C 25 H 22 NO 3 + ＝384.1594,found:384.1596.
example 4
Taking 6-chloro-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 da) of the formula as an example, the preparation method is as follows:
under nitrogen, 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 bistrifluoromethane sulfonyl imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2.0 mL) are added into a 35mL sealed tube, reacted at 110 ℃ for 12h, after the reaction is finished, the solvent is removed under reduced pressure, and the target product 6-chloro-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 da), all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 20:1. Characterization of product data: white solid, 78% yield, dr value greater than 20:1, melting path: 193-195 ℃. The nmr spectrum is shown in figures 7 and 8, 1 HNMR(400MHz,CDCl 3 )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). 13 CNMR(101MHz,CDCl 3 )δ209.69,166.19,141.18,140.67,139.71,132.22,130.55,130.19,127.81,125.62,122.91,120.56,117.58,115.95,69.36,56.47,37.03,32.28,7.53.HRMS[M+H] + calculated for C 19 H 17 ClNO 3 + ＝342.0891,found:342.0897.
example 5
Taking 6-methoxy-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ea) of the following structural formula as an example, the preparation method is as follows:
6-methoxy-3-phenyl-2H-benzo [ b ] under nitrogen][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 1, 2-dichloroethane (2.0 mL) as solvents were added to a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the completion of the reaction, and the target product 6-methoxy-2' -propionyl-was obtained by separation on a silica gel column2',3' -dihydro-2H, 4H-spiro [ benzo [ b ]][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ea), all eluents are petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 68% yield, dr value greater than 20:1, melting path: 154-156 ℃. The nmr spectrum is shown in figures 9 and 10, 1 HNMR(400MHz,CDCl 3 )δ7.29–7.23(m,2H),7.12–7.06(m,1H),7.05–6.98(m,2H),6.42(dd,J＝8.9,2.8Hz,1H),6.15(d,J＝2.8Hz,1H),4.53–4.42(m,2H),3.70(s,3H),3.48(dd,J＝16.6,7.6Hz,1H),3.17(dd,J＝16.6,8.7Hz,1H),2.55(qd,J＝7.2,1.4Hz,2H),1.00(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.75,166.93,157.27,141.52,140.73,135.43,131.88,129.98,127.70,125.51,123.07,117.16,105.97,101.54,69.59,56.50,55.62,36.99,32.17,7.54.HRMS[M+H] + calculated for C 20 H 20 NO 4 + ＝338.1387,found:338.1389.
example 6
Taking the example of the preparation of 5-fluoro-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 fa) of the formula:
under nitrogen, 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 dimer (0.004 mmol), silver bistrifluoromethane sulfonyl imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2.0 mL) are added into a 35mL sealed tube, reacted for 12h at 110 ℃, after the reaction is finished, the solvent is removed under reduced pressure, and the target product 5-fluoro-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 fa), all eluents are petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 71% yield, dr value greater than 20:1, melting path: 170-172 ℃. The nmr spectrum is shown in figures 11 and 12, 1 HNMR(400MHz,CDCl 3 )δ7.31–7.25(m,2H),7.15–6.98(m,3H),6.59(td,J＝8.5,2.8Hz,1H),6.37(dd,J＝9.0,2.8Hz,1H),4.62(s,1H),4.45(dd,J＝8.8,7.4Hz,1H),3.46(dd,J＝16.6,7.4Hz,1H),3.22(dd,J＝16.6,8.8Hz,1H),2.64–2.47(m,2H),1.01(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.77,166.36,161.21,158.79,141.26,140.71,137.34,132.31(d,J＝10.9Hz),130.22,127.86,125.65,122.99,117.55(d,J＝9.9Hz),107.16(d,J＝23.9Hz),103.21(d,J＝27.3Hz),69.34,56.45,37.11,32.45,7.57.HRMS[M+H] + calculated for C 19 H 17 FNO 3 + ＝326.1187,found:326.1188.
example 7
Taking as an example the preparation of 8, 6-dichloro-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ga) of the formula:
under nitrogen, 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 1, 2-dichloroethane (2.0 mL) as solvents were added into a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the reaction was completed, and the target product 8, 6-dichloro-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation on a silica gel column][1.4]Oxazine-3, 1' -indene]-2-one (3 ga), all eluents were formulated as petroleum ether and ethyl acetate in a ratio of 20:1. Characterization of product data: white solid, 65% yield, dr value greater than 20:1, melting path: 218-220 ℃. The nmr spectrum is shown in figures 13 and 14, 1 HNMR(400MHz,CDCl 3 )δ7.33–7.26(m,2H),7.18–7.12(m,1H),7.02–6.93(m,2H),6.57(d,J＝2.3Hz,1H),4.76(s,1H),4.43(dd,J＝8.7,7.1Hz,1H),3.44(dd,J＝16.6,7.2Hz,1H),3.25(dd,J＝16.6,8.7Hz,1H),2.64–2.48(m,2H),1.02(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.71,164.90,140.76,140.65,136.05,133.16,130.44,128.05,125.75,122.93,122.37,121.12,114.38,69.14,56.33,37.17,32.62,7.57(onesignal is missing due to overlap).HRMS[M+H] + calculated for C 19 H 16 Cl 2 NO 3 + ＝376.0502,found:376.0510.
example 8
Taking the example of the preparation of 5' -fluoro-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ha) of the formula:
under nitrogen, 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 dimer (0.004 mmol), silver bistrifluoromethane sulfonyl imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2.0 mL) are added into a 35mL sealed tube, reacted for 12h at 110 ℃, after the reaction is finished, the solvent is removed under reduced pressure, and the target product 5 '-fluoro-2' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ha), all eluents are petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 94% yield, dr value greater than 20:1, melting path: 157-159 ℃. The nmr spectrum is shown in figures 15 and 16, 1 HNMR(400MHz,CDCl 3 )δ7.11(d,J＝7.8Hz,1H),7.04–6.86(m,4H),6.79(td,J＝8.7,2.5Hz,1H),6.64(dd,J＝7.8,1.6Hz,1H),4.51(s,1H),4.43(dd,J＝8.8,7.1Hz,1H),3.43(dd,J＝16.9,7.2Hz,1H),3.17(dd,J＝16.8,8.7Hz,1H),2.59–2.41(m,2H),0.97(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )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 for C 19 H 17 FNO 3 + ＝326.1187,found:326.1191.
example 9
Taking the example of the preparation of 5' -iodo-2 ' -propionyl-2 ',3' -dihydro-2 h,4 h-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ia) of the formula:
under nitrogen, 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 1, 2-dichloroethane (2.0 mL) as solvents were added into a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the reaction was completed, and the target product 5 '-iodo-2' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation on a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ia), all eluents being petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 72% yield, dr value greater than 20:1, melting path: 152-154 ℃. The nmr spectrum is shown in figures 17 and 18, 1 HNMR(400MHz,CDCl 3 )δ7.63(s,1H),7.43(d,J＝8.1Hz,1H),7.11(d,J＝7.9Hz,1H),6.99(td,J＝7.6,1.5Hz,1H),6.91(td,J＝7.8,1.5Hz,1H),6.75(d,J＝8.1Hz,1H),6.63(dd,J＝7.8,1.5Hz,1H),4.50(s,1H),4.38(dd,J＝8.7,7.0Hz,1H),3.41(dd,J＝16.8,7.1Hz,1H),3.17(dd,J＝16.8,8.7Hz,1H),2.61–2.39(m,2H),0.97(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.44,166.33,143.31,141.16,141.02,136.81,134.73,130.94,125.68,124.74,121.15,116.67,116.24,96.08,69.50,56.11,37.10,32.11,7.51.HRMS[M+H] + calculated for C 19 H 17 INO 3 + ＝434.0248,found:434.0247.
example 10
Taking the example of the preparation of 5' -methyl-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ja) of the following structural formula, the preparation method is as follows:
under nitrogen, 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 dimer (0.004 mmol), silver bistrifluoromethane sulfonyl imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2.0 mL) are added into a 35mL sealed tube, reacted for 12h at 110 ℃, after the reaction is finished, the solvent is removed under reduced pressure, and the target product 5 '-methyl-2' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ja), all eluents are petroleum ether and ethyl acetate according to the proportion of 20:1. Characterization of product data: white solid, 96% yield, dr value greater than 20:1, melting path: 180-182 ℃. The nmr spectrum is shown in figures 19 and 20, 1 HNMR(400MHz,CDCl 3 )δ7.14–7.06(m,2H),6.97(t,J＝7.6Hz,1H),6.93–6.84(m,3H),6.61(d,J＝7.8Hz,1H),4.49–4.36(m,2H),3.44(dd,J＝16.6,7.5Hz,1H),3.13(dd,J＝16.6,8.7Hz,1H),2.58–2.48(m,2H),2.29(s,3H),0.99(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.85,167.03,141.30,140.97,140.18,138.65,131.31,128.53,126.13,125.50,122.78,120.85,116.59,116.21,69.53,56.59,37.06,32.12,21.49,7.54.HRMS[M+H] + calculated for C 20 H 20 NO 3 + ＝322.1438,found:322.1439.
example 11
Taking the example of the preparation of 6' -methyl-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ka) of the formula:
under nitrogen, 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 dimer (0.004 mmol), silver bis (trifluoromethanesulfonyl) imide (0.016 mmo l), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2)0 mL) is added into a 35mL sealed tube, reacted for 12h at 110 ℃, the solvent is removed under reduced pressure after the reaction is finished, and the target product 6 '-methyl-2' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by silica gel column separation][1.4]Oxazine-3, 1' -indene]-2-one (3 ka), all eluents were formulated as petroleum ether and ethyl acetate in a ratio of 20:1. Characterization of product data: white solid, 83% yield, dr value greater than 20:1, melting path: 155-157 ℃. The nmr spectrum is shown in figures 21 and 22, 1 HNMR(400MHz,CDCl 3 )δ7.18–7.06(m,3H),6.98(t,J＝7.3Hz,1H),6.89(t,J＝7.4Hz,1H),6.82(s,1H),6.62(d,J＝7.5Hz,1H),4.43(s,1H),4.41–4.35(m,1H),3.40(dd,J＝16.4,7.2Hz,1H),3.15(dd,J＝16.4,8.7Hz,1H),2.59–2.41(m,2H),2.20(s,3H),0.97(t,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ209.83,167.01,141.60,141.19,137.78,137.57,131.24,130.96,125.53,125.17,123.63,120.82,116.63,116.13,69.86,56.81,37.07,32.03,21.40,7.56.HRMS[M+H] + calculated for C 20 H 20 NO 3 + ＝322.1438,found:322.1442.
example 12
Taking 5',6' -dichloro-2 '-propionyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 la) of the following structural formula as an example, the preparation method is as follows:
under nitrogen, 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 1, 2-dichloroethane (2.0 mL) as solvents were added into a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the reaction was completed, and the target product 5',6' -dichloro-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation on a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 la), all eluents were formulated as petroleum ether and ethyl acetate in a ratio of 20:1. Characterization of product data: white solid, 76%The dr value is greater than 20:1, the melting process: 188-190 ℃. The nmr spectrum is shown in figures 23 and 24, 1 HNMR(400MHz,CDCl 3 )δ7.36(s,1H),7.21–7.09(m,2H),7.02(td,J＝7.7,1.5Hz,1H),6.94(td,J＝7.7,1.5Hz,1H),6.66(dd,J＝7.8,1.5Hz,1H),4.59(s,1H),4.29(dd,J＝8.6,6.1Hz,1H),3.31(dd,J＝16.8,6.2Hz,1H),3.20(dd,J＝16.8,8.7Hz,1H),2.56–2.32(m,2H),0.95(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.44,165.82,141.21,141.09,141.02,134.29,131.82,130.71,127.25,125.85,125.20,121.46,116.83,116.23,69.45,56.32,37.20,32.41,7.51.HRMS[M+H] + calculated for C 19 H 16 Cl 2 NO 3 + ＝376.0502,found:376.0507.
example 13
Taking 2 '-butyryl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazine-3, 1' -indene ] -2-one (3 ab) with the following structural formula as an example, the preparation method is as follows:
3-phenyl-2H-benzo [ b ] under nitrogen][1,4]Oxazin-2-one (0.20 mmol), 1-hexene-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 1, 2-dichloroethane (2.0 mL) as solvents are added into a 35mL sealed tube, reacted for 12h at 110 ℃, after the reaction, the solvents are removed under reduced pressure, and the target product 2' -butyryl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by silica gel column separation][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ab), all eluents are petroleum ether and ethyl acetate which are prepared according to the proportion of 20:1. Characterization of product data: white solid, 68% yield, dr value greater than 20:1, melting path: 160-162 ℃. The nmr spectra are shown in figures 25 and 26, 1 HNMR(400MHz,CDCl 3 )δ7.29–7.23(m,2H),7.15–7.05(m,2H),7.05–6.95(m,2H),6.90(td,J＝7.7,1.6Hz,1H),6.62(dd,J＝7.8,1.6Hz,1H),4.51(s,1H),4.43(dd,J＝8.7,7.3Hz,1H),3.46(dd,J＝16.6,7.4Hz,1H),3.18(dd,J＝16.6,8.8Hz,1H),2.56–2.40(m,2H),1.62–1.46(m,2H),0.85(t,J＝7.4Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ209.28,166.88,141.45,141.23,140.76,131.23,129.98,127.69,125.53,125.50,123.05,120.82,116.59,116.17,69.77,56.53,45.65,32.22,16.90,13.69.HRMS[M+H] + calculated for C 20 H 20 NO 3 + ＝322.1438,found:322.1439.
example 14
Taking the example of the preparation of 2 '-hexanoyl-2', 3 '-dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ac) of the formula:
3-phenyl-2H-benzo [ b ] under nitrogen][1,4]Oxazin-2-one (0.20 mmol), 1-octen-3-one (0.24 mmol), dichloro (pentamethylcyclopentadienyl) rhodium dimer (0.004 mmol), silver bistrifluoromethane sulfonyl imide (0.016 mmol), sodium bicarbonate (0.4 mmol) and solvent 1, 2-dichloroethane (2.0 mL) are added into a 35mL sealed tube, reacted for 12h at 110 ℃, after the reaction, the solvent is removed under reduced pressure, and the target product 2' -hexanoyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ac), all eluents are petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 85% yield, dr value greater than 20:1, melting path: 96-98 ℃. The nmr spectrum is shown in figures 27 and 28, 1 HNMR(400MHz,CDCl 3 )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,CDCl 3 )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 NO 3 + ＝350.1751,found:350.1755.
example 15
Taking the example of the preparation of 3' -methyl-2 ' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ad) of the formula:
3-phenyl-2H-benzo [ b ] under nitrogen][1,4]Oxazin-2-one (0.20 mmol), 4-hexene-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 1, 2-dichloroethane (2.0 mL) as solvents were added into a 35mL sealed tube, reacted at 110℃for 12 hours, the solvents were removed under reduced pressure after the reaction was completed, and the target product 3 '-methyl-2' -propionyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation on a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ad), all eluents are petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 87% yield, dr value greater than 20:1:1:1, melting path: 191-193 ℃. The nmr spectrum is shown in figures 29 and 30, 1 HNMR(400MHz,CDCl 3 )δ7.31–7.25(m,1H),7.21–7.13(m,2H),7.10(d,J＝7.6Hz,1H),6.99(d,J＝7.9Hz,1H),6.90(t,J＝6.9Hz,1H),6.81(td,J＝7.8,1.6Hz,1H),6.59(d,J＝7.7Hz,1H),4.86(s,1H),3.91(d,J＝8.0Hz,1H),3.70(p,J＝7.4Hz,1H),2.25(dq,J＝18.4,7.1Hz,1H),1.89(dq,J＝18.4,7.2Hz,1H),1.20(d,J＝7.2Hz,3H),0.74(t,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ210.64,166.20,145.89,141.52,140.67,132.20,129.84,127.83,125.26,123.23,123.20,120.89,116.58,116.10,69.59,61.20,40.18,40.00,14.84,7.09.HRMS[M+H] + calculated for C 20 H 20 NO 3 + ＝322.1438,found:322.1437.
example 16
Taking the preparation of 3' -n-propyl-2 ' -acetyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 ae) of the following structural formula as an example, the preparation method is as follows:
3-phenyl-2H-benzo [ b ] under nitrogen][1,4]Oxazin-2-one (0.20 mmol), 3-hepten-2-one (0.20 mmol), dichloro (pentamethylcyclopentadienyl) rhodium dimer (0.002 mmol), silver bis (trifluoromethanesulfonyl) imide (0.008 mmol), sodium bicarbonate (0.6 mmol) and 1, 2-dichloroethane (1.0 mL) as solvents were added to a 35mL sealed tube, reacted at 120℃for 16 hours, the solvents were removed under reduced pressure after the completion of the reaction, and the target product 3 '-n-propyl-2' -acetyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] was obtained by separation with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 ae), all eluents are petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 60% yield, dr value greater than 20:1:1:1, melting path: 210-212 ℃. The nmr spectrum is shown in figures 31 and 32, 1 HNMR(400MHz,CDCl 3 )δ7.38–7.32(m,1H),7.27–7.23(m,3H),7.11(d,J＝7.9Hz,1H),7.01(t,J＝7.6Hz,1H),6.93(t,J＝7.7Hz,1H),6.72(d,J＝7.7Hz,1H),4.74(s,1H),4.12(d,J＝7.4Hz,1H),3.70–3.60(m,1H),1.97(s,3H),1.60–1.41(m,4H),0.99(t,J＝7.0Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ208.40,165.90,145.72,141.64,140.60,131.80,129.87,127.83,125.38,123.51,123.43,121.13,116.78,116.51,69.44,61.28,46.16,34.32,32.38,22.26,14.39.HRMS[M+H] + calculated for C 21 H 22 NO 3 + ＝336.1594,found:336.1599.
example 17
Taking the preparation of 3' -hexyl-2 ' -acetyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] [1.4] oxazin-3, 1' -indene ] -2-one (3 af) of the formula as follows as an example, the preparation method is as follows:
3-phenyl-2H-benzo [ b ] under nitrogen][1,4]Oxazin-2-one (0.20 mmol), 3-decen-2-one (0.40 mmol), dichloro (pentamethylcyclopentadienyl) rhodium dimer(0.0008 mmol), silver bis (trifluoromethanesulfonyl) imide (0.0032 mmol), sodium bicarbonate (0.2 mmol) and a solvent 1, 2-dichloroethane (4.0 mL) are added into a 35mL sealed tube, reacted for 8 hours at 80 ℃, the solvent is removed under reduced pressure after the reaction is finished, and the target product 3 '-hexyl-2' -acetyl-2 ',3' -dihydro-2H, 4H-spiro [ benzo [ b ] is obtained by separating with a silica gel column][1.4]Oxazine-3, 1' -indene]-2-ketone (3 af), all eluents being petroleum ether and ethyl acetate formulated in a ratio of 20:1. Characterization of product data: white solid, 27% yield, dr value greater than 20:1:1:1, melting path: 143-145 ℃. The nmr spectrum is shown in figures 33 and 34, 1 HNMR(400MHz,CDCl 3 )δ7.38–7.31(m,1H),7.29–7.22(m,3H),7.10(d,J＝7.7Hz,1H),7.00(td,J＝7.6,1.5Hz,1H),6.92(td,J＝7.7,1.5Hz,1H),6.69(d,J＝7.5Hz,1H),4.79(s,1H),4.11(d,J＝7.4Hz,1H),3.70–3.55(m,1H),1.95(s,3H),1.54–1.24(m,10H),0.89(t,J＝6.6Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ208.38,165.86,145.77,141.61,140.57,131.82,129.84,127.79,125.35,123.47,123.42,121.07,116.76,116.47,69.45,61.29,46.40,34.33,31.80,30.16,29.82,29.59,29.04,22.71,14.17.HRMS[M+H] + calculated for C 24 H 28 NO 3 + ＝378.2064,found:378.2071.
application example 1
Antifungal Activity test
Compound 3aa was dissolved in DMSO using hypha growth rate method, diluted with tween 80 aqueous solution, and formulated into a concentration gradient of 2000, 1000, 500 μg/mL. 5mL of Tween 80 aqueous solution was aspirated, and 45mL of the LPDA medium was injected and dispersed uniformly. Then, 45mL of PDA medium was injected with the low concentration to the high concentration of the drug, and the concentrations were 200, 100, and 50. Mu.g/mL, respectively. After cooling, fusarium graminearum is inoculated. Then culturing in a constant temperature box at 25 ℃ until hypha on the blank culture medium grows fully. Thereafter, colony diameters (minus cake diameters) were measured using the crisscross method. The inhibition of Fusarium graminearum (Fg) by compound 3aa at different concentrations was calculated according to the following formula.
Inhibition (%) = 100× (control colony diameter-treatment colony diameter)/control colony diameter. The inhibition rates of the compound 3aa on sclerotinia sclerotiorum (St), wheat take-all germ (Ggt) and Rhizoctonia cerealis (Rc) under different concentrations are obtained by adopting the same method, and as shown in a graph 35, a blank culture medium is arranged at the leftmost side of the graph, and compound 3aa solutions with concentrations of 200, 100 and 50 mug/mL are respectively arranged at the right side in sequence; in FIG. 35, the antibacterial patterns of Fusarium graminearum, sclerotinia sclerotiorum, rhizoctonia cerealis and Rhizoctonia cerealis are shown in sequence from top to bottom.
Inhibition ratio of Table 1 Compound 3aa to Fusarium graminearum, sclerotinia sclerotiorum, rhizoctonia cerealis
Fg St Ggt Rc
50μg/mL 12.6％ 29.4％ 19.2％ 44.1％
100μg/mL 16.2％ 32.5％ 27.8％ 49.4％
200μg/mL 18.5％ 42.3％ 40.2％ 50.9％
The concentration coefficient is expressed by the logarithm x, the inhibition rate is converted into the probability value y, and then the virulence regression equation and R are calculated by using an Excel table 2 Value, simulation with spss software, finding EC 50 Values.
Table 2 toxicity regression equation of 3aa on Fusarium graminearum, sclerotinia sclerotiorum, rhizoctonia cerealis, R 2 Value and EC 50 Value (μg/mL)
Toxicity regression equation R 2 Value of 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
In conclusion, we can see that the compound 3aa shows a certain antibacterial effect on sclerotinia sclerotiorum, total rot of wheat and sheath blight of wheat, especially EC on sheath blight of wheat 50 The value is 147.45, so that the spiro compound with various structures constructed by the synthetic method is expected to find a more efficient bactericide for continuously carrying out antibacterial activity test on the pathogenic bacteria.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (10)

1. 1, 4-benzoxazine spiro derivative is characterized by the following structure:
wherein R is any one of H, me, ph, cl or MeO; r is R 1 Is Me, et, n Pr、 n Am; r is R 2 H, me is a, n Pr or n Any one of the hexyl groups; ar is benzene ring, or substituted benzene ring of Me, cl or I.
2. The synthesis method of the 1, 4-benzoxazine spiro derivative is characterized by comprising the following steps: under inert atmosphere, adding the benzoxazinone compound 1, the unsaturated ketone compound 2, a catalyst and an additive into a solvent to prepare a reaction solution for reaction to generate a 1, 4-benzoxazine spiro derivative; the reaction formula is as follows:
wherein R is any one of H, me, ph, cl or MeO; r is R 1 Is Me, et, n Pr、 n Am; r is R 2 H, me is a, n Pr or n Any one of the hexyl groups; ar is benzene ring, or substituted benzene ring of Me, cl or I; rh (lll) is a catalyst.
3. The method for synthesizing 1, 4-benzoxazine spiro derivative according to claim 2, wherein the reaction temperature is 80-120 ℃ and the reaction time is 8-16h.
4. The method for synthesizing a 1, 4-benzoxazine-based spirocyclic derivative according to claim 2, wherein the inert atmosphere is a gas atmosphere of nitrogen, argon or helium.
5. The method for synthesizing 1, 4-benzoxazine spiro derivative according to claim 2, wherein the catalyst comprises rhodium catalyst and silver salt, and the molar ratio of the rhodium catalyst to the silver salt is 1: the rhodium catalyst is dichloro (pentamethyl cyclopentadienyl) rhodium dimer or di (hexafluoroantimonic acid) triacetonitrile (pentamethyl cyclopentadienyl) rhodium dimer, and the silver salt is any one or combination of silver bis (trifluoromethanesulfonyl imide), silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate and silver trifluoroacetate.
6. The method for synthesizing 1, 4-benzoxazine spiro derivative according to claim 2, wherein the additive is sodium bicarbonate, acetic acid, adamantanecarboxylic acid, pivalic acid, mesitylene benzoic acid, lithium acetate, lithium carbonate, sodium acetate or sodium carbonate.
7. The method for synthesizing a 1, 4-benzoxazine-based spirocyclic derivative according to claim 2, wherein the solvent is any one or a combination of 1, 2-dichloroethane, tetrahydrofuran, cyclohexane, benzotrifluoride and toluene.
8. The method for synthesizing 1, 4-benzoxazine spiro derivative according to any one of claims 2 to 7, wherein the molar ratio of benzoxazinone compound 1, unsaturated ketone compound 2, catalyst and additive is 1: (1.0-2.0): (0.02-0.1): (1-3).
9. The method for synthesizing a 1, 4-benzoxazine spiro derivative according to claim 8, wherein the concentration of the benzoxazinone compound 1 in the reaction solution is 0.05M to 0.2M.
10. The use of the 1, 4-benzoxazine spiro derivative according to claim 1 in the field of antibacterial and bactericidal.
CN202310697048.1A 2023-06-13 2023-06-13 1, 4-benzoxazine spiro derivative and synthetic method and application thereof Pending CN117003711A (en)

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