A method for the removal of a tert-butylsulfinyl protecting group compatible with multiple functional groups

Abstract

This invention discloses a method compatible with multifunctional group deprotection of tert-butylsulfinyl groups. The method uses tert-butylsulfinyl compound 1 as a substrate and haloalkanes as solvents. Under a nitrogen or air atmosphere, N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide are used as deprotection reagents. The reaction is carried out at room temperature to 100°C with stirring for 0.1 to 5 hours. After quenching and purification, the target compound 2 is obtained. The molar ratio of substrate to reagent is 1:0.1 to 10.0, and the molar volume ratio of substrate to solvent is 1:1 to 10. The quenching reagent is selected from sodium thiosulfate solution, etc. This invention overcomes the shortcomings of existing methods, such as poor functional group compatibility and limited substrate applicability. It has advantages such as mild reaction conditions, high deprotection efficiency, wide substrate range, commercially available and inexpensive reagents, and safe and simple operation. It can be widely used in the synthesis of multifunctional and complex molecules and has good industrial application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for removing tert-butylsulfinyl protecting groups that is compatible with multifunctional groups. Background Technology

[0002] Protecting group chemistry is one of the core strategies for constructing complex molecules in synthetic chemistry. In the synthesis of multifunctional molecules such as natural products and drugs, protecting groups act as "molecular protecting units," specifically shielding sensitive functional groups such as hydroxyl and amino groups, ensuring that the reaction selectively occurs at the target site and effectively suppressing side reactions. Achieving precise introduction and selective removal of protecting groups is a key technological step in efficiently constructing complex molecular skeletons and shortening drug development cycles; it is also a core hub connecting chemical synthesis technology with life science applications.

[0003] Since Ellman introduced chiral tert-butylsulfinamides into asymmetric organic synthesis, this reagent has attracted widespread attention from synthetic chemists. It can be used to introduce chiral amine units into agrochemicals, pharmaceuticals, and natural products. In this process, the removal of the tert-butylsulfinyl group is often required to release the amine group. Therefore, chemists have developed a series of efficient methods for removing the tert-butylsulfinyl group, but most still require acidic conditions, leading to poor functional group compatibility. To date, only one example has successfully achieved the removal of the tert-butylsulfinyl group under neutral to weakly basic conditions using an iodine-mediated strategy that neutralizes the acid in the system with an inorganic base. However, the substrate applicability of this method remains limited, and the reaction efficiency and substrate universality do not yet meet the requirements for the synthesis of complex molecules.

[0004] Therefore, developing a novel method for removing tert-butyl sulfinyl groups under mild, highly selective, and widely applicable weakly basic conditions is of great promise for expanding synthetic pathways for multifunctional and complex molecules and reducing the risk of side reactions. It is also of great significance for solving the difficult problem of compatibility issues in the deprotection of sulfinyl protecting groups. Summary of the Invention

[0005] To overcome the problems in the prior art, the present invention provides a method for removing tert-butyl sulfinyl protecting groups that is compatible with multifunctional groups.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution: A method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups includes the following steps: (1) Dissolve tert-butylsulfinyl compound 1 in a haloalkane solvent. (2) Under a nitrogen or air atmosphere, the deprotecting agent is added to the system of step (1) at room temperature to 100°C for reaction, wherein the deprotecting agent is N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide; (3) React under stirring for 0.1 to 5 hours to obtain a reaction solution; (4) The reaction was quenched by adding a quenching agent to the reaction solution, and the compound 2 with the tert-butyl sulfinyl group removed was obtained by purification; The general structural formulas of compound 1 and compound 2 are as follows:

[0007] In the formula, R is selected from aryl, alkyl and allyl; R1 is selected from aryl, alkyl and allyl; R2 is selected from alkyl and hydrogen.

[0008] Preferably, the haloalkane solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, or trichloromethane.

[0009] Preferably, the deprotecting agent is N-chlorosuccinimide.

[0010] Preferably, the molar ratio of compound 1 to N-halosuccinimide is 1:0.1 to 10.0.

[0011] Preferably, the molar volume ratio of compound 1 to the haloalkane solvent is 1:1 to 10.

[0012] Preferably, the reaction temperature is 25℃~50℃.

[0013] Preferably, the quenching agent is selected from sodium thiosulfate solution, sodium bisulfite solution, sodium bicarbonate solution, sodium chloride solution, or water.

[0014] The substitution methods in the above preferred solutions include any permutation and combination of the above preferred solutions, but are not limited to this solution.

[0015] Compound 1 has any of the following structures, but is not limited to the following structures:

[0016]

[0017] Compound 2 has any of the following structures, but is not limited to the following structures:

[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) The solution provided by the present invention has a strong ability to remove tert-butyl sulfinyl protecting group, and at the same time solves the problem of poor compatibility of multifunctional groups; (2) The solution provided by the present invention has mild reaction conditions, broad functional group compatibility, and a wide range of applicable substrates.

[0019] (3) All reagents used in this invention are commercially available and inexpensive. They are low in cost, technically mature, easy to operate, and have low safety risks, and have certain potential for industrial application. Detailed Implementation

[0020] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0021] Example 1 Substrate 1 (128.2 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature. N -Chlorosuccinimide (73.4 mg, 0.55 mmol) was reacted in an oil bath at 40 °C for 1 h under air, quenched with 1 mL of saturated sodium thiosulfate, concentrated under reduced pressure to remove organic solvent, diluted with ethyl acetate and extracted, and the product was separated by silica gel column chromatography with dichloromethane / methanol (30:1 v / v) as eluent to give a pale yellow solid compound 2 (73 mg, 96%).

[0022] 1 H NMR (400 MHz, Methanol- d 4) δ 8.14 (d, J = 8.4 Hz, 2H), 7.55 (d, J =8.4 Hz, 2H), 4.76 (s, 2H), 3.91 (s, 2H). 13 C NMR (100 MHz, CD3OD) δ 151.58,148.18, 129.23, 124.55, 46.09. Example 2 Substrate 1 (208.8 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature. N-Chlorosuccinimide (73.4 mg, 0.55 mmol) was reacted in an oil bath at 40 °C for 1 h under air, quenched with 1 mL of saturated sodium thiosulfate, concentrated under reduced pressure to remove organic solvent, diluted with ethyl acetate and extracted, and the product was separated by silica gel column chromatography with dichloromethane / methanol (30:1 v / v) as eluent to give a pale yellow solid compound 2 (145.2 mg, 93%).

[0023] 1 H NMR (400 MHz, Chloroform- d ) δ 7.19 – 7.15 (m, 2H), 7.14 – 7.09 (m,2H), 7.05 – 7.00 (m, 3H), 6.61 – 6.58 (m, 2H), 4.95 (s, 1H), 1.66 (s, 2H), 0.80 (s, 9H), -0.00 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 154.57, 145.94, 138.41, 128.47, 127.98, 126.92, 119.96, 59.20, 25.75, 18.23, -4.35. Example 3 Substrate 1 (146.7 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature. N -Chlorosuccinimide (73.4 mg, 0.55 mmol) was reacted in an oil bath at 40 °C for 1 h under air, quenched with 1 mL of saturated sodium thiosulfate, concentrated under reduced pressure to remove organic solvent, diluted with ethyl acetate and extracted, and the product was separated by silica gel column chromatography with dichloromethane / methanol (v / v 50:1) as eluent to give a pale yellow solid compound 2 (82 mg, 87%).

[0024] 1 H NMR (400 MHz, Chloroform- d ) δ 7.34 – 7.27 (m, 4H), 7.24 – 7.19 (m,2H), 7.12 – 7.11 (m, 1H), 6.93 (dd, J = 5.2, 1.2 Hz, 1H), 5.18 (s, 1H), 2.21(s, 2H). 13C NMR (100 MHz, CDCl3) δ 146.68, 145.15, 128.58, 127.22, 126.89,126.87, 125.95, 120.69, 56.14. Example 4 Substrate 1 (195.3 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature. N -Chlorosuccinimide (73.4 mg, 0.55 mmol) was reacted in an oil bath at 40 °C for 1 h under air, quenched with 1 mL of saturated sodium thiosulfate, concentrated under reduced pressure to remove organic solvent, diluted with ethyl acetate and extracted, and the product was separated by silica gel column chromatography with dichloromethane / methanol (v / v 30:1) as eluent to give a pale yellow solid compound 2 (135.2 mg, 94%).

[0025] 1 H NMR (400 MHz, Chloroform- d ) δ 8.16 (d, J = 8.4 Hz, 1H), 7.62 (d, J =7.6 Hz, 1H), 7.52 (s, 1H), 7.33 – 7.29 (m, 1H), 7.26 – 7.21 (m, 1H), 5.89 –5.79 (m, 1H), 5.20 – 5.11 (m, 2H), 4.29 (dd, J = 8.2, 4.8 Hz, 1H), 2.72 – 2.66(m, 1H), 2.49 – 2.42 (m, 1H), 1.72 (brs, 2H), 1.66 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 149.88, 136.00, 135.41, 129.14, 125.36, 124.50, 122.49, 122.00,119.47, 118.00, 115.52, 83.61, 47.82, 42.54, 28.31. Example 5 Substrate 1 (195.7 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature. N-Chlorosuccinimide (73.4 mg, 0.55 mmol) was reacted in an oil bath at 40 °C for 1 h under air, quenched with 1 mL of saturated sodium thiosulfate, concentrated under reduced pressure to remove organic solvent, diluted with ethyl acetate and extracted, and the product was separated by silica gel column chromatography with dichloromethane / methanol (30:1 v / v) as eluent to give a pale yellow solid compound 2 (134.3 mg, 93%).

[0026] 1 H NMR (400 MHz, Chloroform- d ) δ 7.52 – 7.50 (m, 1H), 7.43 (d, J = 7.8Hz, 1H), δ 7.27 – 7.18 (m, 2H), 6.54 (s, 1H), 5.29 (s, 1H), 4.35 (dd, J = 8.0, 6.0 Hz, 1H), 2.81 (dd, J = 14.4, 5.8 Hz, 1H), 2.63 (dd, J = 14.4, 8.2 Hz, 1H), 1.76 (brs, 2H), 1.64 (s, 3H), 1.61 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.18,160.82, 159.64, 154.53, 127.91, 124.04, 122.76, 120.85, 110.92, 106.54,101.86, 95.18, 47.49, 40.40, 24.95, 24.82. Example 6 Substrate 1 (150.7 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature. N -Chlorosuccinimide (73.4 mg, 0.55 mmol) was reacted in an oil bath at 40 °C for 1 h under air, quenched with 1 mL of saturated sodium thiosulfate, concentrated under reduced pressure to remove organic solvent, diluted with ethyl acetate and extracted, and the product was separated by silica gel column chromatography with dichloromethane / methanol (v / v 20:1) as eluent to give a pale yellow solid compound 2 (94 mg, 95%).

[0027] 1H NMR (400 MHz, Chloroform- d ) δ 5.88 – 5.78 (m, 1H), 5.12 – 5.05 (m,2H), 3.93 – 3.89 (m, 4H), 2.14 (d, J = 7.6 Hz, 2H), 1.98 (s, 2H), 1.81 – 1.73(m, 2H), 1.65 – 1.55 (m, 4H), 1.52 – 1.45 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ133.79, 118.79, 108.78, 64.30, 64.28, 50.40, 46.61, 35.52, 30.80.

Claims

1. A method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups, characterized in that, Includes the following steps: (1) Dissolve tert-butylsulfinyl compound 1 in a haloalkane solvent. (2) Under a nitrogen or air atmosphere, the deprotecting agent is added to the system of step (1) at room temperature to 100°C for reaction, wherein the deprotecting agent is N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide; (3) React under stirring for 0.1 to 5 hours to obtain a reaction solution; (4) The reaction was quenched by adding a quenching agent to the reaction solution, and the compound 2 with the tert-butyl sulfinyl group removed was obtained by purification; The general structural formulas of compound 1 and compound 2 are as follows: In the formula, R is selected from aryl, alkyl and allyl; R1 is selected from aryl, alkyl and allyl; R2 is selected from alkyl and hydrogen.

2. The method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups according to claim 1, characterized in that, The haloalkane solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, or trichloromethane.

3. The method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups according to claim 2, characterized in that, The deprotecting agent is N-chlorosuccinimide.

4. The method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups according to claim 3, characterized in that, The molar ratio of compound 1 to N-halosuccinimide is 1:0.1 to 10.

0.

5. The method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups according to claim 4, characterized in that, The molar volume ratio of compound 1 to the haloalkane solvent is 1:1~10.

6. The method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups according to claim 5, characterized in that, The reaction temperature is 25℃~50℃.

7. The method for removing tert-butylsulfinyl protecting groups compatible with multifunctional groups according to claim 1, characterized in that, The quenching reagent is selected from sodium thiosulfate solution, sodium bisulfite solution, sodium bicarbonate solution, sodium chloride solution, or water.

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