Method for synthesizing aryl thiopyrano [3, 2-e] [1, 2] oxazine compound through photocatalysis

Abstract

The invention relates to a method for preparing an aryl thiopyrano [3, 2-e] [1, 2] oxazine compound. According to the method, an N-methyl aryl nitrone compound and an aryl thioether cyclopropane compound react through photocatalysis. Comprising the following steps: step 1, loading magnetons into a dried 10mL Schlenk tube, adding a photocatalyst C (solid) and a raw material A (solid), extracting and replacing nitrogen for three times, rapidly adding ultra-dry acetonitrile under nitrogen flow, rapidly adding the raw material A (liquid) by using a microsyringe, and tightening a cock to obtain a mixed solution; wherein the raw material A is N-methyl aryl nitrone, the raw material B is aryl thioether cyclopropane, and the photocatalyst C is Acr-Mes-tBu < + > (BF4 <->). And 2, stirring the mixed solution obtained in the step 1 at room temperature under the irradiation of 456nm blue light until the N-methyl aryl nitrone compound is completely reacted, and after the reaction is finished, carrying out silica gel column chromatography separation on the reaction solution to obtain the aryl thiopyrano [3, 2-e] [1, 2] oxazine compound. Compared with other methods for synthesizing the oxazine compounds, the preparation method disclosed by the invention has the advantages that the conditions are mild, the dosage of the used nonmetal catalyst is small, the cost is low, the substrate application range is wide, and the obtained aryl thiopyrano [3, 2-e] [1, 2] oxazine compounds have wide application prospects in research and development of medicines, agricultural chemicals and advanced materials.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to an arylthiopyrano[3,2-e][1,2]oxazine compound, a preparation method thereof, and an application thereof. Background Art

[0002] As a relatively special class of bicyclic heterocyclic compounds, pyrano[3,2-e][1,2]oxazine widely exists in natural products, advanced materials, and precursor compounds for drug research and development and agrochemical research and development. Because it can be used as an important structural building block or small molecule synthesis intermediate and has important value in the fields of organic synthetic chemistry research, antiviral drug research and development, advanced material preparation, etc., the preparation and application of pyrano[3,2-e][1,2]oxazine compounds are still being deeply explored.

[0003] Currently, the preparation of oxazine or pyrano[3,2-e][1,2]oxazine compounds mainly relies on the cycloaddition reaction of nitrones with alkenes or cyclopropanes. For example, in the method disclosed in Document 1 (Feng, C.; Xu, Y.; Gao, H-X. Angew. Chem. Int. Ed. 2023, 62, e20231067), the [3+3] cycloaddition of arylcyclopropane and nitrone can generate aryl oxazine compounds, and the specific reaction process is as follows:

[0004]

[0005] In the method disclosed in Document 2 (Knight, D.W.; Walton, J.M.; Bainbridge, N.P Tetrahedron Letters 48(2007)7782-7787), nucleophilic addition of 3-allyltetrahydrofuran-2-ol and hydroxylamine hydrochloride generates 5,6-dimethylhexahydro-2H-furo[2,3-b]pyrrole 6-oxide, and further Meisenheimer rearrangement can generate furo[3,2-e][1,2]oxazine compounds, and the specific reaction process is as follows:

[0006]

[0007] In the method disclosed in Document 3 (Chrystal, E.J.T.; Gilchrist, T.L.; Strech, W. J. Chem. Res. (S) 1987, 180-181; (M) 1563-1576), Diels-Alder addition cyclization of vinyl ether and ethyl bromopyruvate oxime can generate pyrano[3,2-e][1,2]oxazine compounds, and the specific reaction process is as follows:

[0008]

[0009] In the method disclosed in Document 4 (James, R. V.; Toshifumi, J. Dmitry. O. K. J. Org. Chem. 1998, 63, 13, 4485 - 4488), the Diels - Alder addition cyclization of vinyl ether and nitrone can be used to generate furoisoxazole compounds, and then pyrano[3,2 - e][1,2]oxazine compounds can be obtained through reduction and rearrangement. The specific reaction process is as follows:

[0010]

[0011] Although these disclosed research methods can efficiently synthesize oxazine compounds or pyrano[3,2 - e][1,2]oxazine compounds, there are some deficiencies in these strategies. For example, the structure is single, the applicability is not wide enough; the raw materials are not easily obtained, the reaction system is relatively complex, the cost is high, and the reaction selectivity is not specific enough, etc.

[0012] It is worth pointing out that the strategy proposed by this invention uses thioether cyclopropane and nitrone as starting materials, and the preparation of arylthio - substituted pyrano[3,2 - e][1,2]oxazine compounds through the ring - opening cyclization of cyclopropane is a mild, green and efficient mode, opening up a new synthetic route for pyrano[3,2 - e][1,2]oxazine compounds. Summary of the Invention

[0013] The purpose of the present invention is to provide a method for preparing arylthio - substituted pyrano[3,2 - e][1,2]oxazine compounds, aiming to solve the problems existing in the existing synthesis methods, such as the high activity and instability of the starting materials, harsh reaction conditions, poor selectivity, etc.

[0014] The present invention realizes an arylthio - substituted pyrano[3,2 - e][1,2]oxazine compound, and the chemical structural formula of this compound is shown as the following formula (I):

[0015]

[0017] In formula (I), R 1 is a group such as hydrogen, 4 - methyl, 4 - methoxy, 4 - fluoro, 4 - bromo,, 4 - trifluoromethyl, 3 - fluoro - 4 - methoxy, 4 - nitro, 3,5 - difluoro, 4 - phenyl, etc.;

[0018] R 2 is a group such as hydrogen, 4 - methyl, 4 - methoxy, 4 - chloro, 4 - bromo, 4 - trifluoromethyl, 2 - fluoro, 1 - methyl, etc.;

[0019] R3 are groups such as methyl, phenyl, benzyl, etc.

[0020] The present invention further discloses a preparation method of the above-mentioned arylthiopyrano[3,2-e][1,2]oxazines, and the method comprises the following steps:

[0021] (1) Under a nitrogen atmosphere, a photocatalyst C, a raw material A, and a raw material B are sequentially added to a reaction solvent according to a molar ratio of (0.003 - 0.1):1.0:(1.0 - 3.0) to obtain a mixed solution; wherein, the raw material A is N-methylaryl nitrone, the raw material B is arylthioether cyclopropane, and the photocatalyst C is Acr-Mes-tBu + (BF 4 - ).

[0022] (2) Under irradiation with 456 nm blue light, the mixed solution obtained in step (1) is stirred at room temperature until the reaction ends, and the reaction solution is separated by silica gel column chromatography to obtain arylthiopyrano[3,2-e][1,2]oxazine compounds.

[0023] Preferably, for the groups attached to the benzene ring in the structure of the raw material B (thioether cyclopropane): both electron-donating groups and electron-withdrawing groups attached to the para-position of the benzene ring are applicable, but the reaction effect is better when an electron-donating group is attached; the reaction effect of the groups attached to the benzene ring in the structure of the raw material A (nitrone) is similar to that of the raw material B (thioether cyclopropane); it is also applicable to replace the benzene ring in the structure of the raw material A (nitrone) with a heterocyclic compound or a straight-chain alkane, but the reaction effect is relatively general. In step (1), the arylthiopyrano[3,2-e][1,2]oxazine compounds are arylthiopyrano[3,2-e][1,2]oxazine compounds substituted by R 1 and / or R 2 and / or R 3 groups; wherein, R 1 is a group such as hydrogen, 4-methyl, 4-methoxy, 4-fluoro, 4-bromo,, 4-trifluoromethyl, 3-fluoro-4-methoxy, 4-nitro, 3,5-difluoro, 4-phenyl, etc.;

[0024] R 2 is a group such as hydrogen, 4-methyl, 4-methoxy, 4-chloro, 4-bromo, 4-trifluoromethyl, 2-fluoro, 1-methyl, etc.;

[0025] R 3 are groups such as methyl, phenyl, benzyl, etc.

[0026] Preferably, in step (1), the reaction solvent is acetonitrile; in step (2), the mixture is irradiated with 465 nm blue light and stirred at room temperature for 6 - 12 h.

[0027] The present invention further discloses the application of the above-mentioned arylthiopyrano[3,2-e][1,2]oxazine compounds in the research of drug molecule synthesis.

[0028] The present invention overcomes the deficiencies of the prior art and provides an arylthiopyrano[3,2-e][1,2]oxazine compound and a preparation method thereof. Under a nitrogen atmosphere, a photocatalyst C, a raw material A, and a raw material B are sequentially added to a reaction solvent according to a molar ratio of (0.003 - 0.1):1.0:(1.0 - 3.0) to obtain a mixed solution; wherein, the A is N-methylaryl nitrone, the raw material B is arylthioether cyclopropane, and the photocatalyst C is Acr-Mes-tBu + (BF 4 - ). The mixed solution is irradiated with 456 nm blue light and stirred at room temperature until the reaction is completed. After the reaction solution is separated by silica gel column chromatography, an arylthiopyrano[3,2-e][1,2]oxazine compound can be obtained.

[0029] In the preparation method of the present invention, when A is N-methylaryl nitrone and the raw material B is arylthioether cyclopropane, the reaction equation of the arylthiopyrano[3,2-e][1,2]oxazine compound is as follows:

[0030]

[0031] The arylthiopyrano[3,2-e][1,2]oxazine compound is a pyrano[3,2-e][1,2]oxazine compound containing easily activated carbon-sulfur bonds and nitrogen-oxygen bonds.

[0032] Compared with the disadvantages and deficiencies of the prior art, the present invention has the following advantageous effects:

[0033] (1) The preparation method of the present invention can occur at room temperature, has simple operation, wide sources of substrates used, low cost, and good functional group compatibility;

[0034] (2) The arylthiopyrano[3,2-e][1,2]oxazine compound of the present invention, as a kind of pyrano[3,2-e][1,2]oxazine structural unit compound containing easily activated carbon-sulfur bonds and nitrogen-oxygen bonds, has important application value in the synthesis of drug molecules and provides a new technical route for the synthesis of natural products. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is the hydrogen spectrum of Compound 1 in the examples of the present invention;

[0036] Figure 2 is the hydrogen spectrum of Compound 18 in the examples of the present invention;

[0037] Figure 3 is the hydrogen spectrum of Compound 22 in the embodiments of the present invention; Detailed implementation manners

[0038] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0039] Example 1

[0040] (1) Under a nitrogen atmosphere, the photocatalyst Acr-Mes-tBu + (BF 4 - )(0.002 mmol), N-methylphenyl nitrone (0.3 mmol), and 4-methoxyphenylthio cyclopropane (0.33 mmol) were successively added to acetonitrile (2.0 mL) to obtain a mixed solution;

[0041] (2) At room temperature, the mixed solution was irradiated with 456 nm blue light and stirred until the reaction ended. After separation by silica gel column chromatography of the reaction solution, the arylthio pyrano[3,2-e][1,2]oxazine compound 1 could be obtained;

[0042] Its structural formula is as follows:

[0043]

[0044] The hydrogen spectrum of this Compound 1 is as Figure 1 shown, and the nuclear magnetic resonance hydrogen spectrum data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.51 - 7.44 (m, 2H), 7.36 - 7.31 (m, 3H), 7.30 - 7.26 (m, 2H), 6.86 - 6.78 (m, 2H), 4.64 (d, J = 8.1 Hz, 1H), 4.15 (ddt, J = 11.6, 5.1, 1.6 Hz, 1H), 3.92 (d, J = 5.5 Hz, 1H), 3.80 (s, 3H), 3.68 (td, J = 12.2, 2.8 Hz, 1H), 3.57 (dd, J = 12.4, 5.5 Hz, 1H), 2.46 (s, 3H), 2.35 - 2.28 (m, 1H), 1.98 - 1.86 (m, 1H), 1.75 (qt, J = 12.7, 4.6 Hz, 1H), 1.66 - 1.58 (m, 1H), 1.23 - 1.12 (m, 1H).

[0045] Examples 2 to 17

[0046] Examples 2 to 17 are the same as Example 1, except for the substituent R in N-methylaryl nitrone 1 and R in cyclopropane 2 which are as follows respectively:

[0047] Table 1 Examples 2 to 17

[0048]

[0049] Example 18

[0050] (1) Under a nitrogen atmosphere, the photocatalyst Acr-Mes-tBu + (BF 4 - (0.002 mmol), N-phenylphenyl nitrone (0.3 mmol), and 4-methoxyphenylthio cyclopropane (0.33 mmol) were successively added to acetonitrile (2.0 ml) to obtain a mixed solution;

[0051] (2) The mixed solution was irradiated with 456 nm blue light and stirred at room temperature until the reaction was completed. After separation by silica gel column chromatography of the reaction solution, the arylthio pyrano[3,2-e][1,2]oxazine compound 18 could be obtained;

[0052] Its structural formula is as follows:

[0053]

[0054] The hydrogen spectrum of the compound 18 is as Figure 2 shown, and the nuclear magnetic resonance hydrogen spectrum data are as follows: δ 7.57 - 7.51 (m, 2H), 7.39 - 7.34 (m, 2H), 7.25 - 7.21 (m, 3H), 7.14 - 7.09 (m, 2H), 6.98 - 6.94 (m, 2H), 6.91 - 6.86 (m, 2H), 6.80 (tt, J = 7.4, 1.1 Hz, 1H), 4.89 (d, J = 5.5 Hz, 1H), 4.83 (d, J = 8.1 Hz, 1H), 4.23 (ddt, J = 11.6, 5.2, 1.6 Hz, 1H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 2.38 (dq, J = 13.2, 3.8, 3.1 Hz, 1H), 2.08 (tdd, J = 11.9, 8.1, 3.4 Hz, 1H), 1.89 - 1.73 (m, 1H), 1.71 - 1.63 (m, 1H), 1.27 - 1.20 (m, 1H).

[0055] Examples 19 to 21

[0056] Examples 19 to 21 are the same as Example 18, except for R in N-phenylphenyl nitrone1 Are as follows:

[0057] Table 2 Examples 19 - 21

[0058] Example No. <![CDATA[R 1 > <![CDATA[R 2 > <![CDATA[R 3 > Synthetic Compound No. 19 4-Methyl Methoxy Phenyl 19 20 4-Methoxy Methoxy Phenyl 20 21 3,5-Difluoro Methoxy Phenyl 21

[0059] Example 22

[0060] (1) Under a nitrogen atmosphere, the photocatalyst Acr-Mes-tBu + (BF 4 - )(0.002 mmol), N-benzyl-1-(4-(trifluoromethyl)phenyl)ethyl nitrone (0.3 mmol), and 4-methoxyphenylthio cyclopropane (0.33 mmol) were successively added to acetonitrile (2.0 ml) to obtain a mixed solution;

[0061] (2) At room temperature, the mixed solution was irradiated with 456 nm blue light and stirred until the reaction ended. After separation by silica gel column chromatography of the reaction solution, the arylthio pyrano[3,2-e][1,2]oxazine compound 22 could be obtained;

[0062] Its structural formula is as follows:

[0063]

[0064] The hydrogen spectrum of the compound 22 is as Figure 3 shown, and the nuclear magnetic resonance hydrogen spectrum data are as follows: δ 7.74 (d, J = 8.4 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.40 - 7.27 (m, 2H), 7.25 - 7.20 (m, 4H), 6.55 - 6.47 (m, 4H), 4.61 (d, J = 8.1 Hz, 1H), 4.08 (ddt, J = 11.7, 5.0, 1.7 Hz, 1H), 3.69 (s, 3H), 3.66 (d, J = 14.8 Hz, 1H), 3.57 (td, J = 12.0, 2.9 Hz, 1H), 3.42 (d, J = 14.7 Hz, 1H), 2.99 (d, J = 12.4 Hz, 1H), 2.64 - 2.57 (m, 1H), 1.84 (s, 3H), 1.80 - 1.65 (m, 3H), 1.26 - 1.15 (m, 1H).

[0065] Examples 23 - 25

[0066] Examples 23 - 25 are the same as Example 22, except that R in N-benzyl-1-(4-(trifluoromethyl)phenyl)ethyl nitrone 1 Are as follows:

[0067] Table 3 Examples 23 - 25

[0068] Example No. <![CDATA[R 1 > <![CDATA[R 2 > <![CDATA[R 3 > Synthetic Compound No. 23 (4-Phenyl)ethyl Methoxy Benzyl 23 24 3-Thienyl Methoxy Benzyl 24 25 2-Furyl Methoxy Benzyl 25

[0069] The reaction equation involved in the embodiment of the present invention is as follows:

[0070]

[0071] Among them, the hydrogen spectrum of Compound 1 is as Figure 1 shown.

[0072] The above are only the preferred embodiments of the present invention, and are 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 in the protection scope of the present invention.

Claims

1. An arylthiopyrano[3,2-e][1,2]oxazine compound, characterized in that: The chemical structure of the compound is shown in the following formula (I): In formula (I), R 1 is a group such as hydrogen, 4-methyl, 4-methoxy, 4-fluoro, 4-bromo, 4-trifluoromethyl, 3-fluoro-4-methoxy, 4-nitro, 3,5-difluoro, 4-phenyl, etc.; R 2 is a group such as hydrogen, 4-methyl, 4-methoxy, 4-chloro, 4-bromo, 4-trifluoromethyl, 2-fluoro, 1-methyl, etc.; R 3 It is a group such as methyl, phenyl, benzyl, etc.

2. The method for preparing the arylthiopyrano[3,2-e][1,2]oxazine compound according to claim 1, characterized in that: The method comprises the following steps: (1) Under a nitrogen atmosphere, photocatalyst C, raw material A, and raw material B are sequentially added to a reaction solvent in a molar ratio of (0.003-0.1):1.0:(1.0-3.0) to obtain a mixed solution; wherein the raw material A is N-methyl aryl nitrone, the raw material B is aryl sulfide cyclopropane, and the photocatalyst C is Acr-Mes-tBu + (BF4 - ). (2) Under 456 nm blue light irradiation, the mixed solution of step (1) is stirred at room temperature until the N-methylaryl nitrone compound is completely reacted. After the reaction is completed, the reaction solution is separated by silica gel column chromatography to obtain an arylthiopyrano[3,2-e][1,2]oxazine compound.

3. The method for preparing an arylthiopyrano[3,2-e][1,2]oxazine compound as claimed in claim 2, wherein in step (1), the raw material A (nitrone) is structurally characterized by the following substituent groups connected to the aromatic group: 4-hydrogen, 4-methyl, 4-methoxy, 4-fluoro, 4-bromo, 4-trifluoromethyl, 3-fluoro-4-methoxy, 4-nitro, 3,5-difluoro, 4-phenyl and the like; the raw material B (thioether cyclopropane) is structurally characterized by the following Substituent groups attached to the aromatic group: 4-hydrogen, 4-methyl, 4-methoxy, 4-chloro, 4-bromo, 4-trifluoromethyl, 2-fluoro, 1-methyl and the like.

4. The method for preparing an arylthiopyrano[3,2-e][1,2]oxazine compound according to claim 2, characterized in that: In step (1), the reaction solvent is acetonitrile; in step (2), the mixture is stirred and reacted at room temperature under 456 nm blue light irradiation for 6 to 12 hours.

5. Use of the arylthiopyrano[3,2-e][1,2]oxazine compounds and their derivatives as described in claim 1 in the research of synthesis of drug molecules, agricultural chemicals and advanced materials.

Images