Process for the preparation of alkenyl sulfoximines

Abstract

The application discloses a preparation method of alkenyl sulfoximine, which comprises the following steps: reacting a compound of formula 3 with a compound of formula 2 in the presence of a fluorine source, a base, an electrolyte and a solvent by constant current electrolysis to obtain an alkenyl sulfoximine compound of formula 1. The method has the advantages of mild reaction conditions, safety, controllability, environmental protection and low cost.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a method for preparing alkenylsulfenyl imine. Background Art

[0002] Sulfenyl imine compounds are bioisosteres of sulfonamide and sulfone groups. Due to the introduction of a mildly basic nitrogen atom on the sulfur, they are very stable in chemical structure and spatial configuration. Moreover, sulfenyl imines have unique hydrogen donating / accepting abilities: the sulfur-hetero-double bond connected to the sulfur is a hydrogen bond acceptor, and the nitrogen on the sulfur-nitrogen double bond, if unsubstituted, is a good hydrogen bond donor. Sulfenyl imines have better solubility in protic solvents than the corresponding sulfones. These properties indicate that sulfenyl imines, as small, hydrophilic, and stable functional groups, have great medicinal potential in drug development. Therefore, developing efficient and convenient methods to enrich the sulfenyl imine compound library will help accelerate the drug development rate of this type of compound. Among them, alkenyl-substituted sulfenyl imines are an important component of this type of structure. Currently, there are several main methods for their synthesis:

[0003] The literature Eur. J. Org. Chem., 2000, 3973-4009 reports a method in which a pre-prepared N-methyl-substituted methyl arylsulfenyl imine is subjected to hydrogen extraction with n-butyl lithium under ultra-low temperature conditions and then reacts with the corresponding alkyl aldehyde to produce a β-hydroxy-substituted sulfenyl imine. Subsequently, a protecting group and a base are added to undergo an elimination reaction to produce an alkenylsulfenyl imine:

[0004]

[0005] This two-step method for synthesizing olefin sulfenyl imines has the following disadvantages: (1) The synthetic route is long, requiring two steps, and the starting materials are not easily available. (2) The N-methyl group on the final product is difficult to remove, which increases the difficulty of subsequent N-functionalization reactions and limits the subsequent structural modification of this type of compound.

[0006] In order to make up for the above shortcomings, Nat. Commun., 2023, 14, 5168-5178 used fluorinated sulfenyl imine as a substrate to generate thiol radicals under light, which then attacked olefins to generate free radical addition, and then eliminated them to return to the olefin structure:

[0007]

[0008] Although this photocatalytic synthesis method for alkenylsulfenyl imines can shorten the reaction steps to one step and the N-protecting group is also easy to remove, the synthesis of the substrate requires the use of dangerous and highly toxic tert-butyl hypochlorite and potassium bifluoride. In addition, the core step also requires the use of expensive photosensitizers, which is relatively costly.

[0009] Based on the above research background, it is of great research significance to develop a safer, greener, more efficient, low-cost and shorter-step method to prepare alkenylsulfenyl imines. Summary of the Invention

[0010] One or more embodiments of the present application provide a method for preparing alkenylsulfenyl imine, which comprises reacting a compound of formula 3 with a compound of formula 2 in the presence of a fluorine source, a base, an electrolyte, and a solvent by constant current electrolysis to obtain an alkenylsulfenyl imine compound of formula 1.

[0011]

[0012] R 1 、R 2 、R 3 Each independently selected from C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkynyl, halogen, -C(O)H, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, -OC(O)C 1-8 Alkyl, -OC(O)OC 1-8 Alkyl, -C(O)NH2, -C(O)NHC 1-8 Alkyl, -C(O)N(C 1-8 alkyl)2 and cyano.

[0013] In one or more embodiments, the compound of Formula 3, the compound of Formula 2, a fluorine source, a base, and an electrolyte are dissolved in the solvent, and current is passed through to react to obtain the alkenylsulfenyl imide compound of Formula 1.

[0014] In one or more embodiments, the positive and negative electrodes used in the electrolysis are respectively selected from graphite felt, platinum sheet, nickel sheet, stainless steel and carbon sheet.

[0015] In one or more embodiments, the graphite felt is the anode and the platinum sheet is the cathode.

[0016] In one or more embodiments, the fluorine source is selected from the group consisting of potassium fluoride, sodium fluoride, cesium fluoride, triethylamine hydrogen fluoride, pyridine hydrogen fluoride, and tetrabutylammonium fluoride.

[0017] In one or more embodiments, the molar ratio of the fluorine source to the compound of Formula 3 is 1-5:1, for example 2:1, 3:1, 4:1.

[0018] In one or more embodiments, the electrolyte is selected from tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, and tetrabutylammonium fluoride.

[0019] In one or more embodiments, the molar ratio of the electrolyte to the compound of Formula 3 is 0.5-3:1, for example 1:1, 1.5:1, 2:1, 2.5:1.

[0020] In one or more embodiments, the base is selected from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD).

[0021] In one or more embodiments, the molar ratio of the base to the compound of Formula 3 is 1-5:1, such as 2:1, 3:1, 4:1.

[0022] In one or more embodiments, the solvent is selected from the group consisting of acetonitrile, 1,2-dichloroethane, acetone, butanone, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

[0023] In one or more embodiments, the volume molar ratio of the solvent to the compound of Formula 3 is 10-30:1, such as 15:1, 20:1, or 25:1.

[0024] In one or more embodiments, the electrolysis current is 6-30 mA.

[0025] In one or more embodiments, the current is 8-20 mA and the voltage of the electrolysis is 2.5-4.5 V.

[0026] In one or more embodiments, the voltage is 2.5-3.5V, such as 3V.

[0027] In one or more embodiments, the reaction temperature is 25-80°C, such as 30°C, 40°C, 50°C, 60°C, 70°C.

[0028] In one or more embodiments, the temperature is 50-80°C.

[0029] In one or more embodiments, the reaction is carried out for 1-20 hours, such as 5, 10, 15 hours.

[0030] In one or more embodiments, the reaction is carried out for 10 hours.

[0031] In one or more embodiments, R 1 、R 2 、R 3 Each is independently in the ortho, meta or para position.

[0032] In one or more embodiments, the C 1-8 The alkyl group is a primary alkyl group, a secondary alkyl group or a tertiary alkyl group.

[0033] In one or more embodiments, the halogen is fluorine, chlorine, bromine, or iodine.

[0034] In one or more embodiments, after the reaction is completed, the solvent is removed by distillation under reduced pressure, the obtained product is mixed with silica gel, and eluted with a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a purified product.

[0035] In one or more embodiments, in order to solve the above technical problems, the present invention provides a method for preparing alkenylsulfenyl imine, comprising: performing constant current electrolysis at a certain temperature on a compound of formula 3 and a compound of formula 2 in the presence of a fluorine source, a base, an electrolyte, and a solvent to obtain a compound of formula 1.

[0036]

[0037] Where electrode is the electrode, F source is the fluorine source, base is the base, solvent is the solvent, electrolyte is the electrolyte, current is the voltage, and temperature is the temperature.

[0038] In some embodiments of the present invention, R 1 、R 2 、R 3 Including but not limited to C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkynyl, halogen, -C(O)H, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, -OC(O)C 1-8 Alkyl, -OC(O)OC 1-8 Alkyl, -C(O)NH2, -C(O)NHC 1-8 Alkyl, -C(O)N(C 1-8 Alkyl)2 and cyano, the substitution position can be ortho, meta or para.

[0039] In one or more embodiments, during the electrolysis process, the electrode materials are arbitrarily selected from two of platinum sheets, carbon sheets, nickel sheets, graphite felt and stainless steel as the anode and cathode.

[0040] In one or more embodiments, the fluorine source is selected from potassium fluoride, cesium fluoride, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, tetrabutylammonium fluoride, and the molar amount is 1-5 times that of compound 3.

[0041] In one or more embodiments, the electrolyte is selected from tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, and tetrabutylammonium fluoride, and the molar amount of the electrolyte is 0.5-3 times that of compound 3.

[0042] In one or more embodiments, the base is selected from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), and the molar amount of the base is 1-5 times that of compound 3.

[0043] In one or more embodiments, the solvent is selected from one or two of acetonitrile, 1,2-dichloroethane, acetone, butanone, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and the volume molar ratio of the solvent to compound 3 is 10-30:1.

[0044] In one or more embodiments, the current of the constant current electrolysis is controlled between 6-30 mA, thereby controlling the voltage of the entire system between 2.5-4.5 V.

[0045] In one or more embodiments, the reaction temperature is controlled between 25-80°C, preferably between 50-80°C.

[0046] In one or more embodiments, post-treatment is as follows: after the reaction is completed, the solvent is removed by distillation under reduced pressure, the sample is mixed with silica gel, and eluted with a system of petroleum ether: ethyl acetate = 10:1 in polarity to obtain the target product.

[0047] One or more embodiments of the present application have at least one of the following beneficial effects:

[0048] a) Introducing green and environmentally friendly electrochemical methods into the synthesis process has the advantages of being safer and more controllable than previous methods;

[0049] b) Changing the two-step reaction of the prior art into a one-step reaction shortens the reaction steps;

[0050] c) It avoids the use of expensive metal photocatalysts and reduces reaction costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 is the H NMR spectrum of the compound of formula 1a of Example 10;

[0052] Figure 2 is the C NMR spectrum of the compound of formula 1a of Example 10;

[0053] Figure 3 is the H NMR spectrum of the compound of formula 1b of Example 11;

[0054] Figure 4 is the C NMR spectrum of the compound of formula 1b of Example 11;

[0055] Figure 5 is the H NMR spectrum of the compound of formula 1c of Example 12;

[0056] Figure 6 is the C NMR spectrum of the compound of formula 1c of Example 12;

[0057] Figure 7 is the H NMR spectrum of the compound of formula 1d of Example 13;

[0058] Figure 8 is the C NMR spectrum of the compound of formula 1d of Example 13;

[0059] Figure 9 is the H NMR spectrum of the compound of formula 1e of Example 14;

[0060] Figure 10 is the C NMR spectrum of the compound of formula 1e of Example 14;

[0061] Figure 11 is the H NMR spectrum of the compound of formula 1f in Example 15;

[0062] Figure 12 is the C NMR spectrum of the compound of formula 1f of Example 15;

[0063] Figure 13 is the NMR fluorine spectrum of the compound of formula 1f in Example 15;

[0064] Figure 14 is the H NMR spectrum of the compound of formula 1g in Example 16;

[0065] Figure 15 This is the C NMR spectrum of the compound of formula 1g in Example 16.

[0066] Figure 16 is the H NMR spectrum of the compound of formula 1h in Example 17;

[0067] Figure 17 This is the C NMR spectrum of the compound of formula 1h in Example 17. DETAILED DESCRIPTION

[0068] The following examples provide further non-limiting details of the technical solution of the present invention. They should not be considered as limiting the scope of the present invention, but are merely exemplary and typical representations of the present invention.

[0069] The solvents, reagents and raw materials used in the present invention are all commercially available chemically pure or analytically pure products.

[0070] Example 1

[0071]

[0072] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0073] Compound 3 (78.0 mg, 0.3 mmol), compound 2 (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using a 10:1 ratio of petroleum ether to ethyl acetate as the eluent. The target molecule 1a was obtained as a pale yellow solid (76.9 mg, 71% yield).

[0074] Proton spectrum, carbon spectrum and mass spectrometry characterization of compound 1a:

[0075] 1 H NMR (400MHz, CDCl3) 68.23 (d, J=6.8Hz, 2H), 7.95 (d, J=8.4Hz, 2H), 7.76 (d, J=15.2 Hz, 1H), 7.53-7.50 (m, 3H), 7.44-7.36 (m, 7H), 7.08 (d, J=15.6Hz, 1H), 2.43 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.8, 144.6, 143.1, 135.9, 132.4, 132.1, 131.3, 130.3, 129.5, 129.1, 128.7, 128.0, 127.5, 125.8, 21.6. HRMS calculated value C 22 H 20 NO2S[M+H] + 362.1209, the measured value is 362.1215.

[0076] Example 2

[0077]

[0078] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:3:3:3.

[0079] Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (152.3 mg, 0.9 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper equipped with two electrodes: a graphite felt anode and a platinum sheet cathode. The system was reacted at 60°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using an eluent of petroleum ether:ethyl acetate = 10:1. The target molecule 1a was obtained as a pale yellow solid (61.7 mg, 57% yield). Compound 1a was characterized by H, C, and MS as in Example 1.

[0080] Example 3

[0081]

[0082] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:5:3.

[0083] Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (228.3 mg, 1.5 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper equipped with two electrodes: a graphite felt anode and a platinum sheet cathode. The system was reacted at 60°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using an eluent of petroleum ether:ethyl acetate = 10:1. The target molecule 1a was obtained as a light yellow solid (41.1 mg, 38% yield). Compound 1a was characterized by H, C, and MS as in Example 1.

[0084] Example 4

[0085]

[0086] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0087] Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), pyridine hydrofluoride (148.5 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper equipped with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using an eluent of petroleum ether:ethyl acetate = 10:1. The target molecule 1a was obtained as a pale yellow solid (68.2 mg, yield 63%). Compound 1a was characterized by H-, C-, and MS spectra as in Example 1.

[0088] Example 5

[0089]

[0090] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0091] Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBN (111.8 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper equipped with two electrodes: a graphite felt anode and a platinum sheet cathode. The system was reacted at 60°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using an eluent of petroleum ether:ethyl acetate = 10:1 to obtain the target molecule 1a as a pale yellow solid (66.0 mg, yield 61%). Compound 1a was characterized by H-, C-, and MS spectra as in Example 1.

[0092] Example 6

[0093]

[0094] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0095] Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetone were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using an eluent of petroleum ether:ethyl acetate = 10:1. The target molecule 1a was obtained as a pale yellow solid (66.9 mg, yield 62%). Compound 1a was characterized by H-, C-, and MS spectra as in Example 1.

[0096] Example 6

[0097]

[0098] The molar ratio of the feed materials was: compound 3a: compound 2a: fluorine source: base: electrolyte = 1:2:5:3:3. Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C under a constant current of 8 mA for 10 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, the sample was mixed with silica gel, and separated on a column using a 10:1 ratio of petroleum ether:ethyl acetate eluent to obtain the target molecule 1a as a pale yellow solid (73.4 mg, 68% yield). The hydrogen spectrum, carbon spectrum and mass spectrum characterization of compound 1a are the same as those in Example 1.

[0099] Example 7

[0100]

[0101] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0102] After adding compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol) and acetonitrile in a reaction bottle in turn, cover the rubber plug, plug in 2 electrodes, respectively, graphite felt anode, platinum sheet cathode. The system is reacted at 60 °C for 10 hours under a constant current of 16 mA. After the reaction is completed, the solvent is removed by distillation under reduced pressure, the sample is mixed on silica gel, separated by column, and the eluent is composed of petroleum ether: ethyl acetate = 10:1 to obtain the target molecule 1a, yellowish solid 63.7 mg, yield 59%. The hydrogen spectrum, carbon spectrum and mass spectrum of compound 1a are characterized as in Example 1.

[0103] Example 8

[0104]

[0105] The molar ratio of the feeding substances is: compound 3a: compound 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0106] After adding compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol) and acetonitrile in a reaction bottle in turn, cover the rubber plug, plug in 2 electrodes, respectively, graphite felt anode, platinum sheet cathode. The system is reacted at 60 °C for 10 hours under a constant current of 16 mA. After the reaction is completed, the solvent is removed by distillation under reduced pressure, the sample is mixed on silica gel, separated by column, and the eluent is composed of petroleum ether: ethyl acetate = 10:1 to obtain the target molecule 1a, yellowish solid 63.7 mg, yield 59%. The hydrogen spectrum, carbon spectrum and mass spectrum of compound 1a are characterized as in Example 1.

[0107] Example 9

[0108]

[0109] The molar ratio of the feeding substances is: compound 3a: compound 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0110] Compound 3a (78.0 mg, 0.3 mmol), compound 2a (62.4 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper equipped with two electrodes: a graphite felt anode and a platinum sheet cathode. The system was reacted at 80°C for 10 hours under a constant current of 12 mA. After the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using an eluent of petroleum ether:ethyl acetate = 10:1. The target molecule 1a was obtained as a light yellow solid (39.8 mg, 37% yield). Compound 1a was characterized by H, C, and MS as in Example 1.

[0111] Example 10

[0112] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2a: fluorine source: base: electrolyte = 1:2:5:3:3.

[0113] Compound 3 (1.58.0 g, 6 mmol), compound 2 (1.25 mg, 12 mmol), triethylamine hydrofluoride (5.08 mg, 30 mmol), DBU (2.74 mg, 18 mmol), tetrabutylammonium fluoride (4.70 mg, 18 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was then capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The system was reacted at 60°C for 20 hours under a constant current of 30 mA. After completion of the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and column chromatography was performed using an eluent of petroleum ether:ethyl acetate = 10:1 to obtain the target molecule 1a as a pale yellow solid (1.49 g, yield 69%). Compound 1a was characterized by H-, C-, and MS spectra as in Example 1.

[0114] Example 11

[0115]

[0116] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2b: fluorine source: base: electrolyte = 1:2:5:3:3.

[0117] Compound 3a (78.0 mg, 0.3 mmol), compound 2b (91.2 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After completion of the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and column chromatography was performed using an eluent of petroleum ether:ethyl acetate = 10:1 to obtain the target molecule 1b as a white solid (93.9 mg, 75% yield).

[0118] Proton spectrum, carbon spectrum and mass spectrometry characterization of compound 1b:

[0119] 1 H NMR (400MHz, CDCl3) δ8.23 (dd, J=8.0, 1.6Hz, 2H), 7.94 (d, J=8.4Hz, 2H), 7.76 (d, J=15.2Hz, 1H), 7.51-7.47 (m, 2H), 7.46-7.44 (m, 2H), 7.42 (t, J=4.0Hz, 2H), 7.40 (d, J=1.6Hz, 1H), 7.36 (d, J=8.0Hz, 2H), 7.04 (d, J=15.6Hz, 1H), 2.43 (s, 3H), 1.31 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 173.8, 155.1, 144.5, 143.1, 136.2, 136.v, 132.1, 130.3, 129.6, 129.5, 128.6, 128.0, 127.5, 126.1, 124.7, 35.v, 31.1, 21.6. HRMS calculated value C 26 H 26 NO2S[M+H] + 418.1835, the measured value is 418.1829.

[0120] Example 12

[0121]

[0122] The molar ratio of the feed materials is: compound of formula 3a: compound of formula 2c: fluorine source: base: electrolyte = 1:2:5:3:3.

[0123] After adding compound 3a (78.0 mg, 0.3 mmol), compound 2c (108 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol) and acetonitrile in a reaction bottle in turn, cover the rubber plug, plug in 2 electrodes, graphite felt anode and platinum plate cathode respectively. The system was reacted at a constant current of 12 mA at 60 °C for 10 hours. After the reaction was completed, the solvent was removed by reduced pressure distillation, and the sample was mixed on silica gel and separated by column chromatography using a eluent composed of petroleum ether: ethyl acetate = 10:1 to obtain the target molecule 1c, white solid 110.1 mg, yield 84%.

[0124] 1 H NMR (600 MHz, CDC13) δ 8.16 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.51-7.48 (m, 1H), 7.4 (s, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.39-7.36 (m, 1H), 7.2-7.28 (m, 3H), 7.25-7.24 (m, 2H), 7.17 (t, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.0-7.0 (dd, J = 7.8, 1.2 Hz, 2H), 2.4 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.0, 155.9, 143.8, 139.1, 136.2, 136.1, 135.2, 131.9, 130.5, 129.8, 129.5, 129.4, 128.8, 128.6, 128.3, 128.1, 127.9, 127.8, 127.7, 21.5. HRMS calcd for C 28 H 24 NO2S[M+H] + 438.1522, found 438.1514.

[0125] Example 13

[0126]

[0127] The amount-of-substance ratio of the feed substances was: compound of formula 3b: compound of formula 2b: fluorine source: base: electrolyte = 1:2:5:3:3.

[0128] After adding compound 3b (83.7 mg, 0.3 mmol), compound 2c (108 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol) and acetonitrile in a reaction bottle in turn, cover the rubber plug, plug in 2 electrodes, respectively, graphite felt anode, platinum plate cathode. The system was reacted at a constant current of 12 mA at 60 °C for 10 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure, the sample was mixed on silica gel, and column separation was performed using eluent composed of petroleum ether: ethyl acetate = 10:1 to obtain the target molecule 1d, white solid 74.7 mg, yield 57%.

[0129] 1 H NMR (600 MHz, CDC13) δ 8.22-8.20 (m, 2H), 7.98 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 15.6 Hz, 1H), 7.53-7.51 (m, 3H), 7.49-7.46 (m, 2H), 7.45-7.41 (m, 4H), 7.01 (d, J = 15.0 Hz, 1H), 1.32 (s, 9H). 13 C NMR (150 MHz, CDC13) δ 173.7, 155.4, 144.0, 140.0, 138.0, 135.6, 132.2, 129.8, 129.4, 129.3, 128.8, 128.7, 128.0, 126.1, 123.8, 35.0, 31.0. HRMS calcd for C 25 H 25 ClNO2S [M+H] + 438.1289, found 438.1282.

[0130] Example 14

[0131]

[0132] The amount-of-substance ratio of the feed substances was: compound of formula 3c: compound of formula 2b: fluorine source: base: electrolyte = 1:2:5:3:3.

[0133] Compound 3c (90.3 mg, 0.3 mmol), compound 2c (108 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After completion of the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using a 10:1 ratio of petroleum ether to ethyl acetate as the eluent. The target molecule 1e was obtained as a white solid (96.4 mg, 70% yield).

[0134] 1 H NMR (600MHz, CDCl3) δ8.27 (dd, J=7.8, 1.2Hz, 2H), 8.01-8.00 (m, 2H), 7.80 (d, J=15.0Hz, 1H), 7.60-7.59 (m, 2H), 7. 53 (t, J=7.2Hz, 1H), 7.49 (d, J=8.4Hz, 2H), 7.46-7.43 (m, 4H), 7.08 (d, J=15.0Hz, 1H), 1.36 (s, 9Hz), 1.34 (s, 9Hz). 13 C NMR (150 MHz, CDCl3) δ 173.7, 157.2, 155.0, 142.9, 136.0, 135.9, 131.9, 129.6, 129.4, 128.5, 127.9, 127.2, 126.6, 125.9, 124.7, 35.1, 34.9, 31.0, 31.0. HRMS calculated for C 29 H 34 NO2S[M+H] + 460.2305, the measured value is 460.2301.

[0135] Example 15

[0136]

[0137] The molar ratio of the feed materials is: compound of formula 3d: compound of formula 2b: fluorine source: base: electrolyte = 1:2:5:3:3.

[0138] Compound 3d (83.1 mg, 0.3 mmol), compound 2c (108 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After completion of the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using a 10:1 ratio of petroleum ether to ethyl acetate as an eluent. The target molecule 1f was obtained as a white solid (87.5 mg, 67% yield).

[0139] 1 H NMR (600MHz, CDCl3) δ8.23 (dd, J=9.0, 5.4Hz, 2H), 7.93 (d, J=8.4Hz, 2H), 7.74 (d, J=15.6Hz, 1H), 7.46 (d, J=8.4Hz, 2H) , 7.41 (d, J = 8.4Hz, 2H), 7.36 (d, J = 7.8Hz, 2H), 7.07 (t, J = 9.0Hz, 2H), 7.04 (d, J = 15.6Hz, 1H), 2.43 (s, 3H), 1.31 (s, 9H). 13 C NMR (150MHz, CDCl3) δ172.7, 166.2 (d, J C-F =250Hz), 155.2, 144.5, 143.2, 136.1, 132.3 (d, J C-F =3.0Hz), 132.0(d, J C-F =9.0Hz), 130.3, 129.6, 128.6, 127.4, 126.1, 124.5, 115.0 (d, J C-F =21.0Hz), 35.0, 31.1, 21.6. 19 F NMR (565 MHz, CDCl3) δ -107.83. HRMS calculated value C 26 H 27 FNO2S[M+H] + 436.1741, the measured value is 436.1730.

[0140] Example 16

[0141]

[0142] The molar ratio of the feed materials is: compound of formula 3e: compound of formula 2b: fluorine source: base: electrolyte = 1:2:5:3:3.

[0143] After adding compound 3e (86.1 mg, 0.3 mmol), compound 2c (108 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol) and acetonitrile in a reaction bottle in turn, cover the rubber plug, plug in 2 electrodes, graphite felt anode and platinum plate cathode respectively. The system was reacted at a constant current of 12 mA at 60 °C for 10 hours. After the reaction was completed, the solvent was removed by reduced pressure distillation, and the sample was mixed on silica gel and separated by column chromatography using a eluent composed of petroleum ether: ethyl acetate = 10:1 to obtain the target molecule 1g, white solid 104.2 mg, yield 78%.

[0144] 1 H NMR (600 MHz, CDC13) δ 7.94 (d, J = 8.4 Hz, 2H), 7.86 (s, 2H), 7.75 (d, J = 15.0 Hz, 1H), 7.50-7.45 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 7.10 (dd, J = 15.6, 2.4 Hz, 1H), 2.42 (s, 3H), 2.37 (s, 6H), 1.32 (s, 9H). 13 C NMR (150 MHz, CDC13) δ 174.1, 155.0, 144.3, 142.9, 137.5, 136.2, 135.8, 133.7, 130.2, 129.6, 128.5, 127.3, 127.2, 126.0, 124.7, 34.9, 31.0, 21.5, 21.2. HRMS calcd for C 28 H 32 NO2S[M+H] + 446.2148, found 446.2143.

[0145] Example 17

[0146]

[0147] The amount-of-substance ratio of the substances charged was: compound of formula 3f: compound of formula 2b: fluorine source: base: electrolyte = 1:2:5:3:3.

[0148] Compound 3f (126.6 mg, 0.3 mmol), compound 2c (108 mg, 0.6 mmol), triethylamine hydrofluoride (253.8 mg, 1.5 mmol), DBU (137.0 mg, 0.9 mmol), tetrabutylammonium fluoride (234.9 mg, 0.9 mmol), and acetonitrile were added to the reaction flask in sequence. The flask was capped with a rubber stopper fitted with two electrodes: a graphite felt anode and a platinum sheet cathode. The reaction was carried out at 60°C for 10 hours under a constant current of 12 mA. After completion of the reaction, the solvent was removed by vacuum distillation, the sample was mixed with silica gel, and separated on a column using a 10:1 ratio of petroleum ether to ethyl acetate as an eluent. The target molecule (1 g) was obtained as a white solid (113.4 mg) in a 65% yield.

[0149] 1 H NMR (600MHz, CDCl3) δ8.30 (d, J=8.4Hz, 2H), 7.92 (d, J=7.8Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.74 (d, J=15.6Hz, 1H), 7.46 (d, J=8.4Hz, 2H), 7.41 (d, J =8.4Hz, 2H), 7.37 (d, J = 7.8Hz, 2H), 7.03 (d, J = 15.6Hz, 1H), 3.10-3.07 (m , 4H), 2.43 (s, 3H), 1.57-1.50 (m, 4H), 1.30 (s, 9H), 0.86 (t, J=7.8Hz, 6H). 13 C NMR (150 MHz, CDCl3) δ 172.3, 155.4, 144.8, 143.5, 143.1, 139.4, 135.7, 130.4, 130.0, 129.4, 128.7, 127.4, 126.7, 126.1, 124.1, 50.0, 35.0, 31.1, 21.9, 21.6, 11.2. HRMS calculated for C 32 H 41 N2O4S2[M+H] + : 581.2502, the measured value is 581.2502.

[0150] The embodiments described above are only preferred solutions of the present application and do not limit the present application in any form. Other variations and modifications are possible without exceeding the technical solutions described in the claims.

Claims

1. A method for preparing alkenylsulfenyl imine, comprising reacting a compound of formula 3 with a compound of formula 2 in the presence of a fluorine source, a base, an electrolyte, and a solvent by constant current electrolysis to obtain an alkenylsulfenyl imine compound of formula 1 R 1 、R 2 、R 3 Each independently selected from C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkynyl, halogen, -C(O)H, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, -OC(O)C 1-8 Alkyl, -OC(O)OC 1-8 Alkyl, -C(O)NH2, -C(O)NHC 1-8 Alkyl, -C(O)N(C 1-8 alkyl)2 and cyano; The electrolysis current is 6-30 mA; The fluorine source is triethylamine hydrogen fluoride or pyridine hydrogen fluoride; The electrolyte is tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate or tetrabutylammonium fluoride; The base is triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD).

2. The preparation method according to claim 1, wherein the compound of Formula 3, the compound of Formula 2, a fluorine source, a base, and an electrolyte are dissolved in the solvent, and an electric current is passed through the solvent to react to obtain the alkenylsulfenyl imide compound of Formula 1.

3. The preparation method according to claim 1, wherein the positive and negative electrodes used in the electrolysis are respectively selected from graphite felt, platinum sheet, nickel sheet, stainless steel and carbon sheet.

4. The preparation method according to claim 1, wherein the graphite felt is the anode and the platinum sheet is the cathode.

5. The preparation method according to claim 1, wherein the molar ratio of the fluorine source to the compound of Formula 3 is 1-5:

1.

6. The preparation method according to claim 1, wherein the molar ratio of the electrolyte to the compound of Formula 3 is 0.5-3:

1.

7. The preparation method according to claim 1, wherein the molar ratio of the base to the compound of formula 3 is 1-5:

1.

8. The preparation method according to claim 1, wherein the solvent is selected from acetonitrile, 1,2-dichloroethane, acetone, butanone, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

9. The preparation method according to claim 1, wherein the volume molar ratio of the solvent to the compound of Formula 3 is 10-30:

1.

10. The preparation method according to claim 1, wherein the current of the electrolysis is 8-20 mA. The preparation method according to claim 1 , wherein the voltage of the electrolysis is 2.5-4.5V.

12. The preparation method according to claim 11, wherein the voltage of the electrolysis is 2.5-3.5V.

13. The preparation method according to claim 1, wherein the reaction temperature is 25-80°C. The preparation method according to claim 13 , wherein the reaction temperature is 50-80° C. The preparation method according to claim 1 , wherein the reaction is carried out for 1-20 hours. The preparation method according to claim 15 , wherein the reaction is carried out for 10 hours.

17. The preparation method according to claim 1, wherein R 1 、R 2 、R 3 Each is independently in the ortho, meta or para position.

18. The preparation method according to claim 1, wherein the C 1-8 The alkyl group is a primary alkyl group, a secondary alkyl group or a tertiary alkyl group. The preparation method according to claim 1 , wherein the halogen is fluorine, chlorine, bromine or iodine.

20. The preparation method according to claim 1, wherein after the reaction is completed, the solvent is removed by distillation under reduced pressure, the obtained product is mixed with silica gel, and eluted with a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a purified product.

Images