A method for the synthesis of disulfide derivatives based on sulfoximines catalyzed by n-hc-bh3

Abstract

The application discloses a method for synthesizing a disulfide derivative based on a sulfonyl hydride under NHC-BH3 catalysis, and uses the odorless sulfonyl hydride to synthesize symmetrical and asymmetrical disulfide compounds, and can also construct two disulfide bonds for a cascade reaction; the application discloses a method for synthesizing a disulfide based on a sulfonyl hydride under NHC-BH3 catalysis. The method has the advantages of stable and simple raw materials, less additives, easy purification, low cost, high yield, simple operation and no metal catalyst, and has potential industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of catalytic organic synthesis, and in particular relates to a method for synthesizing disulfide derivatives based on sulfilimine catalyzed by NHC-BH3.

BACKGROUND

[0002] N-heterocyclic carbene borane (NHC-BH3) is a stable compound, easy to prepare and handle, and is widely used in synthetic chemistry.36Currently, it is used to form C-B (Org. Lett. 2022, 24(11), 2232-2237) and S-B (J. Am. Chem. Soc. 2013, 135(28), 10484-10491) bonds. In addition, NHC-BH3 has been used in reduction reactions, including the reduction of ketones to alcohols (Org. Lett. 2012, 14(17), 4540-4543), the elimination of cyano groups (Angew. Chem., Int. Ed. 2024, 63(25), e202405779) and the reduction of sulfides to thiols (Org. Lett. 2022, 24(46), 8559-8563). In addition, this reagent can be used to activate C-X (X = F, Cl, I) to form C-H42or C(sp 3 )-C(sp 3 )(J. Am. Chem. Soc. 2023, 145(2), 991-999) bonds. Despite this, there is currently no report on its application in the construction of disulfides and metal sulfides.

[0003] Sulfur is an important component of life, and thioethers have been widely used in medicine (Science 1997, 277(5332), 1681-1684). For example, monosulfide compounds are used to treat diseases such as cancer (J. Med. Chem. 2014, 57(6), 2275-2291), Alzheimer's disease (Bioorg. Chem. 2016, 64, 13-20.) and diabetes (Eur. J. Med. Chem. 2014, 74, 179-186). In addition to existing in drug structures (Chem. Rev. 2012, 112(4), 2179-2207), disulfides can also serve as structural bridges for peptides and proteins, thereby playing a variety of key roles in oxidative folding, stability and biological function (Chem. Rev. 2011, 111(9), 5768-5783). In addition, these structural bridges can be used for antibody drug conjugation (ACS Catal. 2024, 14(9), 6451-6461). For small molecule symmetric disulfide derivatives (I), they can be used as sulfuration reagents to construct monosulfide compounds. Zhang et al. used disulfide derivatives (I) to construct N-sulfenyl-sulfonimidamides under electrocatalysis (New J. Chem. 2024, 48, 2576-2583), and such compounds contain important drug scaffolds (Chem. Soc. Rev. 2014, 43, 2426-2438). Asymmetric disulfide derivatives (e.g., II and III) are also good sulfuration reagents. Wang et al. applied asymmetric disulfide derivatives to the synthesis of vortioxetine (ACS Catal. 2020, 10, 4, 2707-2712). Therefore, the efficient synthesis of disulfides is very important.

[0004] Currently, the synthesis of disulfides can be divided into four types. The first type is to use thioethers with the same valence as the sulfur source, including thiols and sulfur transfer reagents, such as using N-dithio-o-phenyl (Org. Lett. 2024, 26(17), 3634-3639) and s-(alkyl / phenyl) benzenesulfonate reagents (Angew. Chem., Int. Ed. 2023, 62(25), e202302199). However, thiols have high volatility and unpleasant odor, and sulfur transfer reagents are unstable and limited in species synthesis. Sulfur salts such as Li2S (The Journal of Organic Chemistry 2022, 87(21), 14241-14249.) can also obtain disulfides under Pd catalysis. However, the use of noble metal Pd has limited applicability to substrates. The second reliable method is to use zero-valent monomer sulfur (Adv. Synth. Catal. 2014, 356(4), 749-752) as a sulfur source. However, the use of monomer sulfur results in a mixture of mono- and disulfides. The third type is an example of using tetravalent sulfides as reactants, including sulfinic acid (ACS Catalysis 2023, 13(20), 13474-13483.); Na2S2O3 (Green Chem. 2021, 23(16), 6059-6064). However, tetravalent sulfur such as sulfinic acid is easily oxidized. The fourth mode uses hexavalent sulfur as a sulfur source. These high-valent sulfides include sulfonic acid (Synthesis 1982, 1982(02), 152-155), sulfuryl chloride (Adv. Synth. Catal. 2016, 358, 3477), and sulfonhydrazide (J. Org. Chem. 2023, 88(19), 14078-14087). However, it is challenging to reduce hexavalent sulfur compounds to sulfide compounds, which usually requires the use of reducing agents at high temperatures (200°C) (Chem. Pharm. Bull. 1987, 35(5), 1770-1776.), or through the combined action of various transition metals, resulting in a narrow range of substrates and possible metal poisoning. And there is no method for synthesizing disulfides and their derivatives by reducing sulfonamides using NHC-BH3. SUMMARY

[0005] The application discloses a method for synthesizing disulfides based on sulfonamides under the catalysis of NHC-BH3, which is characterized by using odorless raw materials sulfonamides to synthesize symmetric and asymmetric disulfide compounds, and can also construct two disulfide bonds for tandem reactions. The application discloses a method for synthesizing disulfides based on sulfonamides under the catalysis of NHC-BH3. The method has the advantages of stable and simple raw materials, less additives, easy purification, low cost, high yield, simple operation and no metal catalyst, and has potential industrial application prospects.

[0006] A method for synthesizing disulfides based on sulfhydryl in the presence of NHC-BH3, wherein the structural formula of disulfide derivatives I, II, III is as follows:

[0007]

[0008] wherein R in the compound I is selected from 4-methylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-iodophenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-biphenyl, 2,3-dihydrobenzofuran, 4-trifluoromethylphenyl, 4-cyanophenyl, 2-naphthyl, 5-(N,N-dimethylamino)-1-naphthyl, benzyl; R' in the compound II is selected from 4-methoxy; R in the compound III is selected from 4-methyl;

[0009] wherein the synthesis method of the compound I, II, III is characterized in that, sulfhydryl hydrazide compounds IV and V are used as raw materials, toluene is used as solvent (0.5 mL), 5 mol% of NHC-BH3 is used as catalyst (VI), the reaction condition is 140°C, and the reaction is carried out under nitrogen environment for 12 h, to obtain symmetrical and asymmetrical disulfides I, II and III;

[0010] In the above synthesis method, the structural formula of the sulfhydryl hydrazide compounds IV and V and the NHC-BH3 catalyst VI is as follows:

[0011]

[0012] wherein the compound IV includes R is selected from 4-methylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-iodophenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-biphenyl, 2,3-dihydrobenzofuran, 4-trifluoromethylphenyl, 4-cyanophenyl, 2-naphthyl, 5-(dimethylamino)-1-naphthyl, benzyl; BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 is a route map provided by the present application for preparing symmetrical and asymmetrical disulfides by using sulfhydryl hydrazide compounds as raw materials. DETAILED DESCRIPTION

[0014] A method for synthesizing disulfides based on sulfhydryl in the presence of NHC-BH3 provided by the present application, please refer to the attached Figure 1: with sulfonamide compounds IV and V as raw materials, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), the reaction condition is 140°C, under the nitrogen environment for 12 h, after the reaction is completed, the target product is obtained by using column chromatography separation means.

[0015] The application is further described below in combination with specific preparation examples:

[0016] Preparation Example 1

[0017] In a 10 mL reaction tube, sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), the reaction condition is 140°C, under the nitrogen environment for 12 h. After the reaction is completed, 1,2-diphenyl disulfide (R=phenyl) is obtained by column chromatography separation, and white solid is obtained, with a yield of 82%. Mp: 62-63°C. 1 HNMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 8.2 Hz, 4H), 7.33-7.26 (m, 4H), 7.22 (dd, J = 8.1, 6.6 Hz, 2H). 13 C{ 1 H}NMR (101 MHz, CDCl3) δ 137.1, 129.1, 127.5, 127.2. HRMS (ESI-TOF) m / z: [M-H] - calcd. for C 12 H9S2 - 217.0151; found 217.0155.

[0018] Preparation Example 2

[0019] In a 10 mL reaction tube, sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), the reaction condition is 140°C, under the nitrogen environment for 12 h. After the reaction is completed, 1,2-diphenyl disulfide (R=phenyl) is obtained by column chromatography separation, and white solid is obtained, with a yield of 82%. Mp: 62-63°C.

[0020] Preparation Example 3

[0021] In a 10 mL reaction tube was added sulfonamide IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen atmosphere for 12 h. After the reaction was completed, column chromatography was used to isolate 1,2-bis(3- chlorophenyl)disulfane (R = 3-chlorophenyl) to obtain a yellow solid with a yield of 82%.

[0022] Preparation Example 4

[0023] In a 10 mL reaction tube was added sulfonamide IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen atmosphere for 12 h. After the reaction was completed, column chromatography was used to isolate 1,2-bis(3- chlorophenyl)disulfane (R = 3-chlorophenyl) to obtain a yellow solid with a yield of 82%.

[0024] Preparation Example 5

[0025] In a 10 mL reaction tube was added sulfonamide IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen atmosphere for 12 h. After the reaction was completed, column chromatography was used to isolate 1,2-bis(3- chlorophenyl)disulfane (R = 3-chlorophenyl) to obtain a yellow solid with a yield of 82%.

[0026] Preparation Example 6

[0027] In a 10 mL reaction tube was added sulfonamide IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen atmosphere for 12 h. After the reaction was completed, column chromatography was used to isolate 1,2-bis(3- chlorophenyl)disulfane (R = 3-chlorophenyl) to obtain a yellow solid with a yield of 82%.

[0028] Preparation Example 7

[0029] In a 10 mL reaction tube was added sulfonamide IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen atmosphere for 12 h. After the reaction was completed, column chromatography was used to isolate 1,2-bis(3- chlorophenyl)disulfane (R = 3-chlorophenyl) to obtain a yellow solid with a yield of 82%.

[0030] Preparation Example 8

[0031] In a 10 mL reaction tube was added sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen for 12 h. After the reaction was completed, column chromatography was used to separate 1,2-bis(3-bromophenyl)disulfane (R = 3-bromophenyl) to obtain brown oil, yield 88%.

[0032] Preparation Example 9

[0033] In a 10 mL reaction tube was added sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen for 12 h. After the reaction was completed, column chromatography was used to separate 1,2-bis(3-bromophenyl)disulfane (R = 3-bromophenyl) to obtain brown oil, yield 88%.

[0034] Preparation Example 10

[0035] In a 10 mL reaction tube was added sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen for 12 h. After the reaction was completed, column chromatography was used to separate 1,2-bis(3-bromophenyl)disulfane (R = 3-bromophenyl) to obtain brown oil, yield 88%.

[0036] Preparation Example 11

[0037] In a 10 mL reaction tube was added sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen for 12 h. After the reaction was completed, column chromatography was used to separate 1,2-bis(3-bromophenyl)disulfane (R = 3-bromophenyl) to obtain brown oil, yield 88%.

[0038] Preparation Example 12

[0039] In a 10 mL reaction tube was added sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3as catalyst (VI), reaction conditions at 140 °C, under nitrogen for 12 h. After the reaction was completed, column chromatography was used to separate 1,2-bis(3-bromophenyl)disulfane (R = 3-bromophenyl) to obtain brown oil, yield 88%.

[0040] Preparation Example 13

[0041] In a 10 mL reaction tube, sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions 140 °C, under nitrogen for 12 h. After the reaction, column chromatography was separated to obtain 1,2-bis([1,1'-biphenyl]-4-yl)disulfide (R = biphenyl), white solid, yield 62%.

[0042] Preparation Example 14

[0043] In a 10 mL reaction tube, sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions 140 °C, under nitrogen for 12 h. After the reaction, column chromatography was separated to obtain 1,2-bis(2,3-dihydrobenzofuran-5-yl)disulfide (R = 2,3-dihydrobenzofuran-5-yl), colorless solid, yield 68%.

[0044] Preparation Example 15

[0045] In a 10 mL reaction tube, sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions 140 °C, under nitrogen for 12 h. After the reaction, column chromatography was separated to obtain 1,2-bis(4-(trifluoromethyl)phenyl)disulfane (R = 4-trifluoromethylphenyl), white solid, yield 69%.

[0046] Preparation Example 16

[0047] In a 10 mL reaction tube, sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), using 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions 140 °C, under nitrogen for 12 h. After the reaction, column chromatography was separated to obtain 4,4'-dithiobiscinnamonic acid (R = 4-cyanophenyl), yellow solid, yield 40%.

[0048] Preparation Example 17

[0049] In a 10 mL reaction tube, add sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), use 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions are 140 °C, under nitrogen for 12 h. After the reaction is completed, column chromatography is separated to obtain 1,2-di(naphthalen-2-yl)disulfane (R = 2-naphthyl) to obtain white solid, yield 48%.

[0050] Preparation Example 18

[0051] In a 10 mL reaction tube, add sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), use 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions are 140 °C, under nitrogen for 12 h. After the reaction is completed, column chromatography is separated to obtain 5,5'-dithiobis(N,N-dimethylnaphthalen-1-amine) (R = 5-(N,N-dimethylamino)-1-naphthyl) to obtain green oil, yield 45%.

[0052] Preparation Example 19

[0053] In a 10 mL reaction tube, add sulfonamide compound IV 0.2 mmol, toluene as solvent (0.5 mL), use 5 mol% of NHC-BH3 as catalyst (VI), reaction conditions are 140 °C, under nitrogen for 12 h. After the reaction is completed, column chromatography is separated to obtain 1,2-dibenzyl disulfane (R = benzyl) to obtain colorless solid, yield 63%.

[0054] (Preparation example 1-19 corresponds to the product general formula is a disulfide derivative I.)

[0055] Preparation Example 20

[0056] In a 10 mL reaction tube, add p-methyl sulfonamide 0.1 mmol and p-methoxy sulfonamide 0.1 mmol, toluene as solvent (0.5 mL), use 0.01 mmol of NHC-BH3 as catalyst (VI), reaction conditions are 140 °C, under nitrogen for 12 h. After the reaction is completed, column chromatography is separated to obtain 1-(4-methoxyphenyl)-2-(p-tolyl) disulfane to obtain white solid, yield 50%. 1 H NMR (400 MHz, Chloroform-d) δ 7.44-7.35 (m, 4H), 7.11 (d, J = 7.8 Hz, 2H), 6.82 (dd, J = 8.6, 1.3 Hz, 2H), 3.79 (s, 3H), 2.33 (s, 3H). 13 C{ 1H NMR (400 MHz, Chloroform-d) δ 7.41 (dd, J = 21.0, 6.6 Hz, 8H), 7.12 (d, J = 7.8 Hz, 4H), 6.91 (d, J = 7.7 Hz, 4H), 2.33 (s, 6H). + calcd. for C 14 H 15 OS2 + 263.0559; found 263.0556. HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 14 H 15 OS2 + 263.0559; found 263.0556.

[0057] (Preparation Example 20 corresponds to the product of general formula is a disulfide derivative II.)

[0058] Preparation Example 21

[0059] In a 10 mL reaction tube, sulfonamide compound V 0.1 mmol and p-toluenesulfonyl hydrazine 0.2 mmol were added, toluene was used as solvent (0.5 mL), 0.02 mmol of NHC-BH3 was used as catalyst (VI), the reaction condition was 140°C, and the reaction was carried out under nitrogen for 12 h. After the reaction was completed, 2,2'-(oxybis(4,1-phenylene))bis(1-(p-tolyl)disulfane) was separated by column chromatography to obtain yellow butter, with a yield of 18%. 1 H NMR (400 MHz, Chloroform-d) δ 7.41 (dd, J = 21.0, 6.6 Hz, 8H), 7.12 (d, J = 7.8 Hz, 4H), 6.91 (d, J = 7.7 Hz, 4H), 2.33 (s, 6H). 13 C{ 1 H NMR (400 MHz, Chloroform-d) δ 7.41 (dd, J = 21.0, 6.6 Hz, 8H), 7.12 (d, J = 7.8 Hz, 4H), 6.91 (d, J = 7.7 Hz, 4H), 2.33 (s, 6H). - calcd. for C 26 H 21 OS4 - 477.0481; found 477.0484.

[0060] (Preparation Example 21 corresponds to the product of general formula is a disulfide derivative III.)

[0061] Preparation Example 22

[0062] To a 10 mL reaction tube was added sulfonamide compound IV (0.2 mmol), toluene as solvent (0.5 mL), and 0.01 mol of NHC-BH3as catalyst (VI). The reaction was carried out at 120 °C under nitrogen for 12 h. After the reaction was completed, 1,2-di-p-tolyl disulfide (R = 4-tolyl) was isolated by column chromatography as a white solid in 70% yield.

Claims

1. A method for the synthesis of disulfide derivatives based on sulfoximes catalyzed by NHC-BH3, characterized by, The method comprises the following steps: The sulfonamide compound V has the following formula: The sulfonamide compound V has the following formula: The sulfonamide compound V has the following formula: The sulfonamide compound V has the following formula: The sulfonamide compound V has the following formula: The sulfonamide compound V has the following formula: The sulfonamide compound V has the following formula:

2. The process for the synthesis of disulfide derivatives catalyzed by NHC-BH3 based on sulfilimine according to claim 1, characterized in that, The sulfonamide compound V has the following formula:

3. 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