Method for synthesizing disulfide derivative based on sulfonyl hydrazide under catalysis of NHC-BH3

Abstract

The invention discloses a method for synthesizing disulfide derivatives based on sulfonyl hydrazide under catalysis of NHC-BH3, which is characterized in that an odorless raw material sulfonyl hydrazide is used for synthesizing symmetric and asymmetric disulfide compounds, and two disulfide bonds can be constructed for cascade reaction; the invention discloses a method for synthesizing disulfide based on sulfonyl hydrazide under the catalysis of NHC-BH3. The method has the advantages of stable and simple raw materials, few additives, easiness in purification, low cost, higher yield, simplicity and convenience in operation, no metal catalyst and the like, and has potential industrial application prospects.

Description

[Technical field]

[0001] The invention belongs to the field of catalytic organic synthesis, and specifically relates to a method for synthesizing disulfide derivatives based on sulfonylhydrazine under NHC-BH3 catalysis. [Background technology]

[0002] N-heterocyclic carbene borane (NHC-BH3) is a stable compound that is easy to prepare and handle and is widely used in synthetic chemistry. 36 Currently, it is used to form CB (Org. Lett. 2022, 24(11), 2232-2237) and SB (J. Am. Chem. Soc. 2013, 135(28), 10484-10491) bonds. In addition, NHC-BH3 has been used for 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 thioethers to thiols (Org. Lett. 2022, 24(46), 8559-8563). In addition, this reagent can be used to activate CX (X = F, Cl, I) to form C-H42 or C (sp 3 )-C(sp 3 )(J.Am.Chem.Soc.2023,145(2),991-999) bond. Nevertheless, there is no report on its application in the construction of disulfides and metal sulfides.

[0003] Sulfur is an important component of life, and sulfide has been widely used in medicine (Science 1997, 277 (5332), 1681-1684). For example, monosulfide compounds are used to treat 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) and other diseases. In addition to existing in drug structures (Chem. Rev. 2012, 112 (4), 2179-2207), disulfide can also serve as a structural bridge for peptides and proteins, thereby playing a variety of key roles in oxidative folding, stability and biological functions (Chem. Rev. 2011, 111 (9), 5768-5783). In addition, these structural bridges can be used for antibody drug coupling (ACS Catal. 2024, 14 (9), 6451-6461). For small molecule symmetrical disulfide derivatives (I), they can be used as sulfidation reagents to construct monosulfide compounds. For example, Zhang et al. used disulfide derivatives (I) to construct N-sulfenyl-sulfonyl imide under electrocatalysis (New J. Chem., 2024, 48, 2576-2583). Such compounds contain important drug skeletons (Chem. Soc. Rev., 2014, 43, 2426-2438). Regarding asymmetrical disulfide derivatives (for example: II and III), they are also good sulfidation reagents. Wang et al. applied asymmetrical disulfide derivatives to the synthesis of vortioxetine (ACS Catal. 2020, 10, 4, 2707-2712). Therefore, the effective synthesis of disulfides is very important.

[0004] At present, the synthesis of disulfides can be divided into four types. The first type is to use sulfides with the same price as the sulfur source, including thiols and sulfur transfer reagents, such as using N-dithiophthalate (Org. Lett. 2024, 26 (17), 3634-3639) and s- (alkyl / phenyl) benzene sulfonate reagents (Angew. Chem., Int. Ed. 2023, 62 (25), e202302199). However, thiols have high volatility and unpleasant odors, and sulfur transfer reagents are unstable and species synthesis is limited. Sulfur salts such as Li2S (The Journal of Organic Chemistry 2022, 87 (21), 14241-14249.) can also be used to obtain disulfides under Pd catalysis. ; However, the use of the noble metal Pd has limitations on the applicability of the substrate. The second reliable method is to use zero-valent monomeric sulfur (Adv. Synth. Catal. 2014, 356 (4), 749-752) as a sulfur source. However, the use of monomeric sulfur results in the resulting product being a mixture of monosulfide and disulfide. The third example is the use of 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), sulfonyl chloride (Adv. Synth. Catal. 2016, 358, 3477) and sulfonyl hydrazide (J. Org. Chem. 2023, 88 (19), 14078-14087). However, it is challenging to reduce hexavalent sulfur compounds to sulfide compounds, and it is usually necessary to use a reducing agent at high temperature (200 ° C) (Chem. Pharm. Bull. 1987, 35 (5), 1770-1776.), or through the combined action of various transition metals, resulting in a narrow substrate range and may cause metal poisoning. And there is currently no method for synthesizing disulfide and its derivatives using NHC-BH3 reduction of sulfonyl hydrazide. [Summary of the invention]

[0005] The invention discloses a method for synthesizing disulfide based on sulfonylhydrazine under NHC-BH3 catalysis, which is characterized in that symmetric and asymmetric disulfide compounds are synthesized using sulfonylhydrazine, an odorless raw material, and two disulfide bonds can also be constructed for tandem reaction; the invention discloses a method for synthesizing disulfide based on sulfonylhydrazine under NHC-BH3 catalysis. The method has the advantages of stable and simple raw materials, few additives, easy purification, low cost, high yield, simple operation and no metal catalyst, and has potential industrial application prospects.

[0006] A method for synthesizing disulfide based on sulfonylhydrazine under NHC-BH3 catalysis, wherein the structural formulas of disulfide derivatives I, II, and III are 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-methyl, and R' is selected from 4-methoxy; R in the compound III is selected from 4-methyl;

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

[0010] In the above synthesis method, the structural formulas of sulfonylhydrazide compounds IV and V and NHC-BH3 catalyst VI are as follows:

[0011]

[0012] wherein said IV compound comprises 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 the Drawings

[0013] Figure 1 The invention provides a route map for preparing symmetrical and asymmetrical disulfides using sulfonylhydrazide compounds as raw materials. [Specific implementation method]

[0014] The present invention provides a method for synthesizing disulfide based on sulfonylhydrazine under NHC-BH3 catalysis, see the attached Figure 1: Using sulfonylhydrazide compounds IV and V as raw materials, toluene as solvent (0.5 mL), 5 mol% NHC-BH3 as catalyst (VI), the reaction conditions are 140°C, and the reaction is carried out under nitrogen environment for 12 hours. After the reaction is completed, column chromatography is used to separate the target product.

[0015] The present invention will be further described below in conjunction with specific preparation examples:

[0016] Preparation Example 1

[0017] Add 0.2mmol of sulfonamide compound IV into a 10mL reaction tube, use toluene as solvent (0.5mL), use 5mol% NHC-BH3 as catalyst (VI), and react for 12h at 140℃ under nitrogen. After the reaction, 1,2-diphenyl disulfide (R=phenyl) was obtained by column chromatography to obtain a white solid with a yield of 82%. Mp: 62-63℃. 1 HNMR(400MHz,Chloroform-d)δ7.50(d,J=8.2Hz,4H),7.33–7.26(m,4H),7.22(dd,J=8.1,6.6Hz,2H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ137.1,129.1,127.5,127.2.HRMS(ESI-TOF)m / z:[MH] - calcd.for C 12 H9S2 - 217.0151; found 217.0155.

[0018] Preparation Example 2

[0019] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 0.01 mol of NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction was completed, 1,2-di-p-toluene disulfide (R=4-tolyl) was separated by column chromatography to obtain a white solid with a yield of 89%.

[0020] Preparation Example 3

[0021] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-dimethyl disulfide (R = 3-tolyl) was separated by column chromatography to obtain a yellow oil with a yield of 66%.

[0022] Preparation Example 4

[0023] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction was completed, 1,2-bis(4-(tert-butyl)phenyl)disulfane (R=4-tert-butylphenyl) was separated by column chromatography to obtain a white solid with a yield of 79%.

[0024] Preparation Example 5

[0025] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-bis(4-fluorophenyl) disulfide (R = 4-fluorophenyl) was separated by column chromatography to obtain green oil with a yield of 61%.

[0026] Preparation Example 6

[0027] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-bis(4-chlorophenyl) disulfide (R = 4-chlorophenyl) was separated by column chromatography to obtain a white solid with a yield of 82%.

[0028] Preparation Example 7

[0029] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-bis(4-bromophenyl)disulfane (R=4-bromophenyl) was separated by column chromatography to obtain a white solid with a yield of 92%.

[0030] Preparation Example 8

[0031] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-bis(3-bromophenyl)disulfane (R=3-bromophenyl) was separated by column chromatography to obtain brown oil with a yield of 88%.

[0032] Preparation Example 9

[0033] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-bis(2-bromophenyl)disulfane (R=2-bromophenyl) was separated by column chromatography to obtain green oil with a yield of 59%.

[0034] Preparation Example 10

[0035] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-diphenyl disulfide (R = 4-iodophenyl) was separated by column chromatography to obtain a white solid with a yield of 51%.

[0036] Preparation Example 11

[0037] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-bis(4-methoxyphenyl)disulfane (R=4-methoxy) was separated by column chromatography to obtain a white solid with a yield of 84%.

[0038] Preparation Example 12

[0039] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction was completed, 1,2-bis(4-(trifluoromethoxy)phenyl)disulfane (R=4-trifluoromethoxyphenyl) was separated by column chromatography to obtain a white solid with a yield of 50%.

[0040] Preparation Example 13

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

[0042] Preparation Example 14

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

[0044] Preparation Example 15

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

[0046] Preparation Example 16

[0047] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 4,4'-dithiodibenzoyl dibenzonitrile (R = 4-carbonitrile phenyl) was separated by column chromatography to obtain a yellow solid with a yield of 40%.

[0048] Preparation Example 17

[0049] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140° C. and 12 h under nitrogen environment. After the reaction was completed, 1,2-di(naphthalene-2-yl) disulfide (R=2-naphthyl) was separated by column chromatography to obtain a white solid with a yield of 48%.

[0050] Preparation Example 18

[0051] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% of NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140° C. and 12 h under nitrogen. After the reaction, 5,5'-disulfadialkylbis(N,N-dimethylnaphthalene-1-amine) (R=5-(N,N-dimethylamino)-1-naphthyl) was obtained by column chromatography to obtain green oil with a yield of 45%.

[0052] Preparation Example 19

[0053] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 5 mol% NHC-BH3 was used as catalyst (VI), and the reaction conditions were 140°C and 12 hours under nitrogen environment. After the reaction, 1,2-dibenzyl disulfane (R = benzyl) was separated by column chromatography to obtain a colorless solid with a yield of 63%.

[0054] (The general formula of the product corresponding to Preparation Example 1-19 is disulfide derivative I.)

[0055] Preparation Example 20

[0056] In a 10 mL reaction tube, 0.1 mmol of p-methylsulfonamide and 0.1 mmol of p-methoxysulfonamide were added, toluene was used as solvent (0.5 mL), 0.01 mmol of NHC-BH3 was used as catalyst (VI), the reaction conditions were 140° C., and the reaction was carried out under nitrogen atmosphere for 12 hours. After the reaction was completed, 1-(4-methoxyphenyl)-2-(p-tolyl) disulfane was separated by column chromatography to obtain a white solid with a yield of 50%. 1 H NMR (400MHz, Chloroform-d) δ7.44-7.35 (m, 4H), 7.11 (d, J=7.8Hz, 2H), 6.82 (dd, J=8.6, 1.3Hz, 2H), 3.79 (s, 3H), 2.33 (s, 3H). 13 C{ 1H}NMR (101MHz, CDCl3) δ159.9, 137.8, 134.2, 132.1, 129.9, 129.3, 128.4, 114.8, 55.5, 21.2.HRMS (ESI-TOF) m / z: [M+H] + calcd.for C 14 H 15 OS2 + 263.0559; found 263.0556.HRMS(ESI-TOF)m / z:[M+H] + calcd.forC 14 H 15 OS2 + 263.0559; found 263.0556.

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

[0058] Preparation Example 21

[0059] In a 10 mL reaction tube, 0.1 mmol of sulfonamide compound V and 0.2 mmol of p-methylsulfonyl hydrazide were added, toluene was used as solvent (0.5 mL), 0.02 mmol of NHC-BH3 was used as catalyst (VI), the reaction conditions were 140° C., and the reaction was carried out under nitrogen atmosphere for 12 hours. After the reaction was completed, 2,2′-(oxybis(4,1-phenylene))bis(1-(p-tolyl)disulfane) was obtained by column chromatography separation, and butter was obtained with a yield of 18%. 1 H NMR (400MHz, Chloroform-d) δ7.41 (dd, J=21.0, 6.6Hz, 8H), 7.12 (d, J=7.8Hz, 4H), 6.91 (d, J=7.7Hz, 4H), 2.33 (s, 6H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ156.8, 137.9, 133.8, 131.9, 130.9, 130.0, 129.0, 119.6, 21.2.HRMS (ESI-TOF) m / z: [MH] - calcd.for C 26 H 21 OS4 - 477.0481; found 477.0484.

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

[0061] Preparation Example 22

[0062] In a 10 mL reaction tube, 0.2 mmol of sulfonamide compound IV was added, toluene was used as solvent (0.5 mL), 0.01 mol of NHC-BH3 was used as catalyst (VI), and the reaction conditions were 120° C. and 12 h under nitrogen environment. After the reaction was completed, 1,2-di-p-toluene disulfide (R=4-tolyl) was separated by column chromatography to obtain a white solid with a yield of 70%.

Claims

1. A method for synthesizing disulfide derivatives based on sulfonylhydrazine under NHC-BH3 catalysis, characterized in that: The steps include: In an organic solvent, using sulfonylhydrazide compound IV as a raw material, using sulfonylhydrazide compound IV and sulfonylhydrazide compound IV' as raw materials, or using sulfonylhydrazide compound IV and sulfonamide compound V as raw materials, using NHC-BH3(VI) as a catalyst, reacting at 120-140°C in a nitrogen environment for 12h to obtain disulfide derivative I, disulfide derivative II or disulfide derivative III: The chemical formula of the sulfonylhydrazine compound IV is: R-SO2NHNH2; The chemical formula of sulfonylhydrazide compound IV' is: R'-SO2, NHNH2; The chemical formula of sulfonamide compound V is: The chemical formula of NHC-BH3 compound VI is: In the disulfide derivative I, 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-(N,N-dimethylamino)-1-naphthyl, benzyl; in the disulfide derivative II, R is selected from 4-methyl, and R' is selected from 4-methoxy; in the disulfide derivative III, R is selected from 4-methyl.

2. The method for synthesizing disulfide derivatives based on sulfonylhydrazine under NHC-BH3 catalysis as claimed in claim 1, characterized in that: When generating disulfide derivative I, sulfonylhydrazide compound IV is used as raw material; when generating disulfide derivative II, sulfonylhydrazide compound IV and sulfonylhydrazide compound IV' are used as raw materials, and the molar ratio of sulfonylhydrazide compound IV to sulfonylhydrazide compound IV' is 1:1; when generating disulfide derivative III, sulfonylhydrazide compound IV and sulfonamide compound V are used as raw materials, and the molar ratio of sulfonylhydrazide compound IV to sulfonamide compound V is 2:

1.

3. The method for synthesizing disulfide derivatives based on sulfonylhydrazine under NHC-BH3 catalysis as claimed in claim 1, characterized in that: The molar ratio of raw material to NHC-BH3 is 20:

1.

4. The method for synthesizing disulfide derivatives based on sulfonylhydrazine under NHC-BH3 catalysis as claimed in claim 1, characterized in that: The organic solvent is toluene.

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