Synthesis method of a thiophosphate compound

Abstract

The present invention discloses a method for synthesizing thiophosphate esters. After mixing a compound containing a mercapto group with a phosphorus oxide compound in a corresponding solvent, in the presence of a catalytic amount of a two-dimensional ene photoelectric reagent, the efficient construction of the P-S bond is achieved under mild light conditions, and then a series of thiophosphate esters are obtained. The present invention can efficiently synthesize thiophosphate esters. The catalyst used is simple to synthesize, low in dosage, and inexpensive, which not only reduces the cost of the reaction but also simplifies the post-treatment steps of the reaction. The synthesis reaction in the present invention can be carried out at normal temperature and pressure without a special gas protection atmosphere, with mild conditions, fast reaction, and high yield.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing thiophosphate compounds by using a light irradiation condition in the presence of a two-dimensional ene photoreagent. Background Art

[0002] Thiophosphate compounds containing S-P(O) bonds play important roles in the fields of organic synthesis and biomaterial science, such as being important reaction intermediates, flame retardant and fire-resistant materials, etc.; meanwhile, they also have extensive applications in medicinal chemistry and pesticides, etc., such as echothiophate for glaucoma, amifostine for adjuvant cancer therapy, and isoprothiolane, a fungicide.

[0003] The traditional synthesis of thiophosphate compounds usually utilizes the Atherton-Todd reaction, in which the in-situ generated phosphoryl chloride reacts with a mercapto group. Although the Atherton-Todd reaction still has a wide range of applications after being optimized in different ways, this type of reaction requires toxic carbon tetrachloride as a solvent or an excessive amount of base, catalyst, and additive to promote the reaction. However, these drawbacks need to be considered in practical applications.

[0004] In addition, 1) the synthesis of thiophosphate compounds can be achieved through an oxidation system: such as H 2 O 2(Hydrogen peroxide, see C. Min et al., Synlett 2018, 29, 2027 - 2030), TBPB (tert-Butyl peroxybenzoate, see J. Wang et al., Green Chem. 2015, 17, 314 - 319), DDQ (2,3-Dichloro-5,6-dicyanobenzoquinone, see N. Liu et al., Chem. Commun. 2014, 50, 10879 - 10882), etc. However, this type of reaction requires a large amount of oxides as additives, which limits the subsequent application of this type of reaction. 2) The synthesis of thiophosphates can be achieved through a reduction system: such as by using a multi-fold excess of phosphorus compound raw materials (see J. Bai et al., Chem. Commun. 2014, 50, 8860 - 8863, Chinese patents CN 106117266, CN 106565777) or by additionally adding triphenylphosphine (see Y. Moon et al., Green Chem. 2017, 19, 1005 - 1013) as a reducing agent. However, it is obvious that the excess raw materials or additives will make the reaction system complex and increase the synthesis cost. 3) Directly achieve the dehydrogenative coupling of P-H and S-H using transition metal catalysts, such as Pd (see Y. Zhu et al., J. Am. Chem. Soc. 2016, 138, 5825 - 5828), Ni (see J. W. Xue et al., J. Org. Chem. 2019, 84, 4179 - 4190), etc. However, the high temperature required for the reaction, the long reaction time, and the problem of transition metal residues limit the application of this type of reaction to a certain extent. 4) Activate thiols or thiol precursors using activating reagents, such as NCS (see Y. C. Liu et al., Green Chem. 2014, 16, 357 - 364), DCDMH (see X. Bi et al., Tetrahedron 2016, 72, 706 - 711), Tf 2O (see J. Shen et al., Org. Lett. 2021, 23, 1541 - 1547) and the use of disulfide compounds (see R. Choudhary et al., Org. Biomol. Chem. 2019, 17, 9757 - 9765), etc. However, these reactions require a large amount of additives or additional reaction steps, which also increases the cost to a certain extent. 5) Photo - promoted synthesis of thiophosphates: In the presence of photosensitizers, the construction of P - S bonds is achieved by light irradiation, such as rose bengal (see J. Sun et al., Org. Lett. 2016, 18, 5114 - 5117) and COF (covalent organic frameworks, see H. Qiao et al., Chem. Eur. J. 2022, 28, e202200600), etc. However, the amount of reaction catalyst used is relatively large, the cost is high, and the time is long, which also increases the economic cost and synthesis cost to a certain extent. Summary of the Invention

[0005] Object of the Invention: The object of the present invention is to provide a method for synthesizing thiophosphate compounds.

[0006] Technical Solution: A method for synthesizing thiophosphate compounds provided by the present invention realizes the efficient construction of P - S bonds under the conditions of the presence of compounds containing mercapto groups, phosphorus oxide compounds, two - dimensional ene photoelectric reagents, and corresponding solvents, and obtains thiophosphate compounds by using light irradiation conditions;

[0007] The specific operation steps are as follows: Add mercapto compounds, phosphorus oxide compounds, two - dimensional ene photoelectric reagents, and solvents into a reaction vessel, stir and react at room temperature while performing light irradiation. After the reaction is completed, remove the solvent, and obtain the target product lipid compounds through simple column chromatography separation;

[0008] The reaction route of this synthesis method is as follows:

[0009]

[0010] Among them, R is an alkyl group or a substituted or unsubstituted (hetero) aryl group, R 1 、R 2 are substituted or unsubstituted aryl groups or alkoxy groups;

[0011] The two - dimensional ene photoelectric reagent is elemental selenium (Se), tellurium (Te), bismuth (Bi), antimony (Sb), black phosphorus (P), and quantum dots or heterojunctions of graphdiyne;

[0012] The solvent is one or a mixture of several of tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, and toluene, preferably 1,4-dioxane.

[0013] Further, the mercapto compound is (hetero)arylthiol or alkylthiol.

[0014] Further, the phosphorus oxide compound is alkoxy or substituted or unsubstituted arylphosphorus oxide.

[0015] Further, the two-dimensional ene photoelectric reagent is bismuth (Bi) quantum dots.

[0016] Further, the molar ratio of the mercapto compound to the phosphorus oxide compound is 1:1.0 to 1:2.0, preferably 1:2.0.

[0017] Further, the dosage of the two-dimensional ene photoelectric reagent is 0.5 to 1.5 mol%, preferably 1.0 mol%.

[0018] Further, the light irradiation condition is visible light, sunlight, or a light source of 350 - 650 nm, preferably a 450 nm light source.

[0019] Further, the concentration of the mercapto compound is 0.2 - 0.5 M, preferably 0.2 M.

[0020] Further, the reaction temperature is 25 - 35 °C, preferably 25 °C.

[0021] Further, the reaction time is 1 - 4 hours, preferably 2 hours.

[0022] Advantageous effects: The specific advantages of the present invention are as follows:

[0023] 1. The present invention can achieve the efficient construction of P-S bonds under the existence of a trace amount of two-dimensional ene photoelectric reagent and light irradiation conditions, with mild conditions and without harsh conditions such as high temperature.

[0024] 2. The catalyst used in the present invention is simple to synthesize, has a low dosage, and is inexpensive. It not only reduces the cost of the reaction, but also simplifies the post-treatment steps of the reaction, and the reaction process is more environmentally friendly.

[0025] 3. The synthesis method of the present invention has a fast reaction rate, high yield, and simple operation. It can be carried out under normal temperature and pressure without a special gas protection atmosphere, and has certain application prospects and practical values. Brief description of the drawings

[0026] Figure 1 is the 1 H NMR spectrum of the structure of Example 1 prepared by the present invention;

[0027] Figure 2 13C NMR spectrum of the structure of Example 1 prepared according to the present invention 13 ;

[0028] Figure 3 31P NMR spectrum of the structure of Example 1 prepared according to the present invention 31 ;

[0029] Figure 4 19F NMR spectrum of the structure of Example 1 prepared according to the present invention 19 . Detailed implementation manners

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below, so that those skilled in the art can better understand the advantages and features of the present invention, and thus more clearly define the protection scope of the present invention. The described embodiments of the present invention are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the protection scope of the present invention.

[0031] Example 1

[0032]

[0033] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 4-fluorothiophenol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, it was irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 1H NMR (400 MHz, Chloroform-d) δ 7.83–7.70 (m, 4H), 7.48–7.41 (m, 2H), 7.40–7.29 (m, 6H), 6.86–6.77 (m, 2H). 13 13C NMR (101 MHz, CDCl 3 ) δ 164.66, 164.63, 162.17, 162.15, 137.51, 137.47, 137.42, 137.39, 132.48, 132.45, 131.66, 131.64, 131.59, 131.54, 128.69, 128.56, 121.16, 121.13, 121.11, 121.08, 116.48, 116.46, 116.26, 116.24. 31P NMR (162 MHz, CDCl 3 ) δ 41.69, 41.67。 19 F NMR (376 MHz, CDCl 3 ) δ -111.64, -111.65。

[0034] Example 2

[0035]

[0036] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 4-methylbenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 H NMR (400 MHz, Chloroform-d) δ 7.83–7.72 (m, 4H), 7.47–7.40 (m, 2H), 7.40–7.33 (m, 4H), 7.24 (dd, J = 8.2, 1.7 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 2.17 (d, J = 1.4 Hz, 3H).

[0037] Example 3

[0038]

[0039] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 2-methylbenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 H NMR (400 MHz, Chloroform-d) δ 7.90–7.79 (m, 4H), 7.54 (td, J = 7.3, 1.7 Hz, 2H), 7.46 (td, J = 7.6, 3.8 Hz, 5H), 7.23–7.13 (m, 2H), 7.03 (td, J = 7.4, 1.9 Hz, 1H), 2.36 (s, 3H).

[0040] Example 4

[0041]

[0042] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 2-methyl-3-mercaptofuran (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 HNMR(400MHz,Chloroform-d)δ7.91–7.84(m,4H),7.56(td,J=7.2,1.6Hz,2H),7.49(td,J=7.5,3.6Hz,4H),7.18(d,J=1.9Hz,1H),6.19(d,J=1.9Hz,1H),2.18(d,J=2.5Hz,3H).

[0043] Example 5

[0044]

[0045] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 3-methylbenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 H NMR(400MHz,Chloroform-d)δ7.78(ddt,J=12.8,6.9,1.4Hz,4H),7.44(td,J=7.2,1.7Hz,2H),7.36(ddd,J=10.7,6.6,2.8Hz,4H),7.16(dd,J=8.7,1.9Hz,2H),7.04–6.94(m,2H),2.14(s,3H).

[0046] Example 6

[0047]

[0048] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 2,4-dimethylbenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1HNMR (400 MHz, Chloroform-d) δ 7.89–7.81 (m, 4H), 7.55–7.50 (m, 2H), 7.45 (tdd, J=6.6, 3.5, 1.4 Hz, 4H), 7.32 (dd, J=7.9, 1.7 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.84 (dd, J=8.0, 1.9 Hz, 1H), 2.33 (s, 3H), 2.25 (d, J=1.5 Hz, 3H).

[0049] Example 7

[0050]

[0051] In a 10 mL reaction tube, diphenylphosphine oxide (0.4 mmol), 2-naphthalenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J=2.1 Hz, 1H), 7.94–7.86 (m, 4H), 7.78–7.71 (m, 2H), 7.68 (d, J=8.6 Hz, 1H), 7.49 (dddd, J=19.4, 7.1, 5.7, 3.8 Hz, 9H).

[0052] Example 8

[0053]

[0054] In a 10 mL reaction tube, bis(2,4-dimethyl)phenylphosphine oxide (0.4 mmol), 4-chlorobenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiated with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 HNMR (400 MHz, Chloroform-d) δ 7.39–7.32 (m, 4H), 7.32–7.28 (m, 2H), 7.13–7.09 (m, 2H), 7.06 (s, 2H), 2.25 (s, 12H).

[0055] Example 9

[0056]

[0057] In a 10 mL reaction tube, bis(4-methoxy)phenylphosphine oxide (0.4 mmol), 4-chlorobenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiation was carried out with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 HNMR(400MHz,Chloroform-d)δ7.80–7.72(m,4H),7.41–7.36(m,2H),7.21–7.15(m,2H),6.99–6.92(m,4H),3.84(s,6H).

[0058] Example 10

[0059]

[0060] In a 10 mL reaction tube, bis(2-methyl)phenylphosphine oxide (0.4 mmol), 4-chlorobenzenethiol (0.2 mmol) and a 1,4-dioxane solution of bismuth nanoquantum dots (1.0 mL, 1.0 M) were added. Under the condition of 25 °C, irradiation was carried out with a 450 - 460 nm light source and stirred for 2 hours. After the reaction was completed, the reaction system was concentrated and the target product was obtained by column chromatography separation. 1 HNMR(400MHz,Chloroform-d)δ7.78(ddd,J=15.2,7.7,1.3Hz,2H),7.47–7.39(m,4H),7.29–7.19(m,6H),2.42(s,6H).

Claims

1. A method for synthesizing thio-phosphate ester compounds, characterized in that: in the presence of a compound containing a mercapto group, a phosphorus oxide compound, a two-dimensional ene photoelectric reagent and a corresponding solvent, the efficient construction of the P-S bond is achieved under light conditions to obtain thio-phosphate ester compounds; The specific operation steps are as follows: Add a mercapto compound, a phosphorus oxide compound, a two-dimensional ene photoelectric reagent and a solvent into a reaction vessel, stir and react at room temperature while irradiating with light. After the reaction is completed, remove the solvent and obtain the target product lipid compound through simple column chromatography separation; The reaction route of this synthesis method is as follows: Wherein, R is an alkyl group or a substituted or unsubstituted heteroaryl group, R 1 , R 2 is a substituted or unsubstituted aryl group or alkoxy group; The two-dimensional ene photoelectric reagent is a quantum dot or a heterojunction of elemental selenium (Se), tellurium (Te), bismuth (Bi), antimony (Sb), black phosphorus (P) and graphdiyne; the solvent is one or a mixture of several of tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide and toluene; The compound containing a mercapto group is a heteroaryl thiol or an alkyl mercaptan; the phosphorus oxide compound is an alkoxy group or a substituted or unsubstituted aryl phosphorus oxide; The molar ratio of the mercapto compound to the phosphorus oxide compound is 1:1.0 to 1:2.0; The dosage of the two-dimensional ene photoelectric reagent is 0.5 to 1.5 mol%; The light condition is visible light, sunlight or a 350-650 nm light source; The concentration of the mercapto compound is 0.2 to 0.5 M; The reaction temperature is 25-35 °C; the reaction time is 1-4 hours.

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