Method for preparing deuterated benzoxathiacyclohexadiene-4-ketone

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing deuterated benzoxathiacyclohexadiene-4-ketone. At present, a method for preparing the deuterated benzoxathiacyclohexadiene-4 ketone is not reported yet. In order to solve the problems, the invention provides the method for preparing the deuterated benzoxathiinecyclo-hexadiene-4-ketone, and the deuterated benzoxathiinecyclo-hexadiene-4-ketone is successfully synthesized by taking thiosalicylic acid, DABCO.CD2Cl2, a solvent, water and HI as reaction raw materials through a one-pot method. The method provided by the invention provides a new thought for the preparation of the deuterated benzoxathiacyclo-hexadiene-4-ketone derivative, and has a relatively good application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing deuterated benzothioxadiene-4-one. Background Art

[0002] Benzoxathiin-4-one and its derivatives are an important class of sulfur-containing oxygen heterocyclic compounds, which have broad application prospects and important research value in many fields such as medicinal chemistry, materials science, chemical synthesis, and optoelectronic materials.

[0003] Studies have shown that deuteration of benzothiophene-4-one and its derivatives can significantly improve the stability of the target product, change the interaction of the product, optimize the product kinetics, reduce the product toxicity and other properties.

[0004] At present, benzothiophene-4-one usually requires the use of transition metal catalysts such as iron or silver to participate in the reaction. After the reaction, there is a problem of transition metal residue in the obtained reaction product. Studies have shown that the use of 1,2-bis(diphenylphosphine)ethane as a key reagent to catalyze the reaction of benzodithiophene-3-one with paraformaldehyde can successfully prepare benzothiophene-4-one (Org. Chem. Front., 2024, 11, 4979). However, there is currently no report on the method of deuterated benzothiophene-4-one. Summary of the invention

[0005] The problem in the prior art is: how to prepare deuterated benzothioxanthene-4-one. In view of the above problem, the present invention provides a method for preparing deuterated benzothioxanthene-4-one, and the preparation method comprises the following steps:

[0006] Add thiosalicylic acid, 1-(chlorodideuteriomethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO·CD2Cl2), solvent, water and hydroiodic acid (HI) in the reactor in sequence, raise the temperature of the reaction system to the reaction temperature, and stir the reaction until deuterated benzothioxadiene-4-one is generated in the reaction system;

[0007] The chemical structural formula of the deuterated benzothioxadiene-4-one is as follows:

[0008]

[0009] Preferably, the solvent comprises acetonitrile or toluene.

[0010] Preferably, the reaction temperature is not less than 120°C.

[0011] Preferably, the reaction temperature is 120-160°C.

[0012] Preferably, the reaction temperature is 140-160°C.

[0013] Preferably, the reaction temperature is 140°C.

[0014] Preferably, the reaction time is 6-12 hours.

[0015] Preferably, the reaction time is 12 h.

[0016] Preferably, the usage ratio of thiosalicylic acid to DABCO·CD2Cl2, solvent, water and HI is 0.2mmol:0.2-0.6mmol:075-1.5mL:0.5-1.5mL:0.4-0.8mmol.

[0017] Preferably, the usage ratio of thiosalicylic acid to DABCO·CD2Cl2, solvent, water and HI is 0.2mmol:0.4mmol:1mL:1mL:0.6mmol.

[0018] The present invention has the following beneficial effects:

[0019] The present invention adopts thiosalicylic acid, DABCO·CD2Cl2, solvent, water and HI as reaction raw materials, and successfully synthesizes deuterated benzothioxan-4-one through a one-pot method. The method of the present invention provides a new idea for the preparation of deuterated benzothioxan-4-one derivatives and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 : is the hydrogen spectrum of deuterated benzothiohexacyclohexane-4-one obtained in Example 1 of the present invention.

[0021] Figure 2 : This is the hydrogen spectrum of benzothiophene-4-one. DETAILED DESCRIPTION

[0022] The present invention is described in detail below with reference to the examples. However, it should be understood that the following examples are only illustrative of the embodiments of the present invention, and are not intended to limit the scope of the present invention.

[0023] The preparation method of the benzothiophene-4-one in the present invention is as follows:

[0024] Thiosalicylic acid (0.2mmol, 30mg), DABCO·CH2Cl2 (0.4mmol, 79.8mg), acetonitrile (1.0mL), H2O (1.0mL), HI (0.6mmol, 71μL) were added to a 25mL sealed tube, and the mixture was stirred at 140°C for 12h. After the reaction, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain benzothiophene-4-one with a separation yield of 75%. The hydrogen spectrum of the obtained benzothiophene-4-one is shown in the attached manual. Figure 2 shown.

[0025] The DABCO·CD2Cl2 in the present invention can be prepared according to the literature (Guangke He, Yuan Li, Zilun Yu, Zhaoqiang Chen, et al. Selectfluor TM -catalyzed oxidative cyclization of ynamidesenables facile synthesis of oxazolidine-2,4-diones[J].Organic ChemistryFrontiers,2019,6,3644.DOI:10.1039 / c9qo00845d.) was prepared according to the following steps:

[0026] 1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1 mL of deuterated dichloromethane (CD2Cl2) were stirred and reacted at room temperature for 12 h. After filtration, a white solid product DABCO·CD2Cl2 was obtained.

[0027] The preparation method of DABCO·CH2Cl2 in the present invention is as follows:

[0028] 1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1 mL of dichloromethane (CH2Cl2) were stirred and reacted at room temperature for 12 h. After filtration, a solid product DABCO·CH2Cl2 was obtained.

[0029] Example 1

[0030] Thiosalicylic acid (0.2mmol, 30mg), DABCO·CD2Cl2 (0.4mmol, 79.8mg), acetonitrile (1.0mL), H2O (1.0mL), HI (0.6mmol, 71μL) were added to a 25mL sealed tube, and the mixture was stirred at 140°C for 12h. After the reaction, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain deuterated benzothiohexacyclohexene-4-one with a yield of 70%. The reaction process of the above reaction is as follows:

[0031]

[0032] The hydrogen spectrum of the obtained deuterated benzothiophene-4-one is as shown in the attached manual. Figure 1 The hydrogen spectrum data and mass spectrum data are as follows:

[0033] 1 H NMR (300MHz, CDCl3) δ8.20-8.15(m,1H),7.52-7.46(m,1H),7.37-7.30(m,2H).

[0034] MS(EI)=168.0[M] + .

[0035] Example 2 is the same as Example 1, except that the amount of DABCO·CD2Cl2 used in Example 2 is 0.2 mmol. The yield of deuterated benzothioxadiene-4-one is 62%.

[0036] Example 3 is the same as Example 1, except that the amount of DABCO·CD2Cl2 used in Example 3 is 0.6 mmol. The yield of deuterated benzothioxadiene-4-one obtained is 51%.

[0037] Example 4 is the same as Example 1, except that the amount of HI used in Example 4 is 0. The yield of deuterated benzothioxadiene-4-one obtained is 0.

[0038] Example 5 is the same as Example 1, except that the amount of HI used in Example 5 is 0.4 mmol. The yield of deuterated benzothioxadien-4-one is 40%.

[0039] Example 6 is the same as Example 1, except that the amount of HI used in Example 6 is 0.8 mmol. The yield of deuterated benzothioxadien-4-one is 55%.

[0040] Example 7 is the same as Example 1, except that the reaction time in Example 7 is 1 hour. The yield of deuterated benzothioxadien-4-one is 15%.

[0041] Example 8 is the same as Example 1, except that the reaction time in Example 8 is 6 hours. The yield of deuterated benzothioxadien-4-one is 60%.

[0042] Example 9 is the same as Example 1, except that the reaction time in Example 9 is 24 hours. The yield of deuterated benzothioxadien-4-one is 32%.

[0043] Example 10 is the same as Example 1, except that in Example 10, acetonitrile in Example 1 is replaced by an equal amount of ethyl acetate. The yield of deuterated benzothiin-4-one obtained is 0%.

[0044] Example 11 is the same as Example 1, except that in Example 11, an equal amount of tetrahydrofuran is used to replace the acetonitrile in Example 1. The yield of deuterated benzothioxadien-4-one is 0%.

[0045] Example 12 is the same as Example 1, except that in Example 12, an equal amount of toluene is used to replace the acetonitrile in Example 1. The yield of deuterated benzothioxadien-4-one is 54%.

[0046] Example 13 is the same as Example 1, except that in Example 13, an equal amount of N,N-dimethylformamide is used to replace the acetonitrile in Example 1. The yield of deuterated benzothioxan-4-one obtained is 0%.

[0047] Example 14 is the same as Example 1, except that in Example 14, an equal amount of dimethyl sulfoxide is used to replace the acetonitrile in Example 1. The yield of deuterated benzothioxan-4-one obtained is 0%.

[0048] Example 15 is the same as Example 1, except that in Example 15, an equal amount of methanol is used to replace the acetonitrile in Example 1. The yield of deuterated benzothioxan-4-one obtained is 0%.

[0049] Example 16 is the same as Example 1, except that in Example 16, an equal amount of dichloromethane is used to replace the acetonitrile in Example 1. The yield of deuterated benzothioxan-4-one obtained is 0%.

[0050] Example 17 is the same as Example 1, except that the amount of acetonitrile used in Example 17 is 0.5 mL, and the amount of water used is 1.5 mL. The yield of deuterated benzothioxadien-4-one obtained is 0%.

[0051] Example 18 is the same as Example 1, except that the amount of acetonitrile used in Example 18 is 0.75 mL, and the amount of water used is 1.25 mL. The yield of deuterated benzothioxadiene-4-one obtained is 39%.

[0052] Example 19 is the same as Example 1, except that the amount of acetonitrile used in Example 19 is 1.5 mL, and the amount of water used is 0.5 mL. The yield of deuterated benzothioxadiene-4-one obtained is 60%.

[0053] Example 20 is the same as Example 1, except that the reaction temperature in Example 20 is 100° C. The yield of deuterated benzothioxan-4-one is 0%.

[0054] Example 21 is the same as Example 1, except that the reaction temperature in Example 21 is 120° C. The yield of deuterated benzothioxadien-4-one is 54%.

[0055] Example 22 is the same as Example 1, except that the reaction temperature in Example 22 is 160° C. The yield of deuterated benzothioxadien-4-one is 60%.

[0056] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for preparing deuterated benzothioxadiene-4-one, characterized in that: The preparation method comprises the following steps: Add thiosalicylic acid, DABCO·CD2Cl2, solvent, water and HI in the reactor in sequence, raise the temperature of the reaction system to the reaction temperature, and stir the reaction until deuterated benzothioxadiene-4-one is generated in the reaction system; The chemical structural formula of the deuterated benzothioxadiene-4-one is as follows:

2. The method for preparing deuterated benzothioxan-4-one according to claim 1, characterized in that: The solvent includes acetonitrile or toluene.

3. The method for preparing deuterated benzothioxadiene-4-one according to claim 1, characterized in that: The reaction temperature is not less than 120°C.

4. The method for preparing deuterated benzothioxadiene-4-one according to claim 3, characterized in that: The reaction temperature is 120-160°C.

5. A method for preparing deuterated benzothioxadiene-4-one according to claim 4, characterized in that: The reaction temperature is 140-160°C.

6. A method for preparing deuterated benzothioxan-4-one according to claim 5, characterized in that: The reaction temperature was 140°C.

7. The method for preparing deuterated benzothioxan-4-one according to claim 1, characterized in that: The reaction time is 6-12h.

8. A method for preparing deuterated benzothioxan-4-one according to claim 7, characterized in that: The reaction time is 12h.

9. The method for preparing deuterated benzothioxadiene-4-one according to claim 1, characterized in that: The usage ratio of thiosalicylic acid to DABCO·CD2Cl2, solvent, water and HI is 0.2mmol:0.2-0.6mmol:075-1.5mL:0.5-1.5mL:0.4-0.8mmol.

10. The method for preparing deuterated benzothioxadien-4-one according to claim 1, characterized in that: The usage ratio of thiosalicylic acid to DABCO·CD2Cl2, solvent, water and HI is 0.2mmol:0.4mmol:1mL:1mL:0.6mmol.

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