Process for the preparation of sulfonamides by condensation of sodium sulfinates and aromatic amines catalyzed by chiral pyridine nitrogens

Abstract

The application discloses a method for preparing sulfilimine by condensation of sodium sulfinates and aromatic amines catalyzed by chiral pyridine N-oxides, and belongs to the field of organic chemistry. Sodium sulfinates and aromatic amines or alcohols are used as raw materials, and a reaction is carried out in the presence of a chiral 4-aryl pyridine N-oxide catalyst to obtain chiral sulfilimine and sulfinate, respectively. In the application, the oxygen anion in the chiral 4-aryl pyridine N-oxide catalyst acts as a nucleophilic site to participate in acyl transfer to obtain a chiral mixed anhydride intermediate, which is reacted with different nucleophilic reagents to generate chiral sulfilimine or sulfinate. The method has the advantages of good yield, high enantioselectivity, wide substrate universality and the like, and the product can also be subjected to various derivatization conversions.

Description

TECHNICAL FIELD

[0001] The application relates to a method for preparing a sulfilimine by condensing a sodium sulfinate and an aromatic amine under the catalysis of a chiral pyridine N-oxide, and belongs to the technical field of asymmetric synthesis in organic chemistry. BACKGROUND

[0002] Optically active sulfilimines and sulfinate esters and their derivatives are important bioactive molecules, such as (R)-omeprazole and (R)-sulindac, which are already on the market, and chiral sulfilimines can be oxidized to obtain optically pure sulfimides, sulfimide esters, sulfimide fluorides, sulfimide sulfites and azides.

[0003] In 2022, Tan Choon-Hong et al. reported an asymmetric condensation reaction of potassium sulfinate and alcohol catalyzed by a chiral tetraquaternary ammonium salt, obtaining a series of chiral sulfinate compounds (Nature 2022, 604, 298), but when aniline is used as a substrate, the yield of sulfilimine is low and the product is racemic.

[0004]

[0005] In 2023, Yan Hailong et al. reported a reaction for constructing chiral sulfinate esters by asymmetric deoxygenation of benzenesulfonyl cyanide, and synthesized a series of chiral sulfinate compounds (Nat. Chem. 2023, 15, 185), but when amine is used as a nucleophile, the sulfilimine obtained is racemic.

[0006]

[0007] There are reports on the asymmetric synthesis of sulfilimines, which need to synthesize chiral sulfinate esters first, and then undergo nucleophilic substitution reaction with amine to obtain sulfilimine. Therefore, it is of great significance to develop an effective synthesis method to prepare chiral sulfilimines and sulfinate esters and their derivatives. SUMMARY

[0008] In order to solve the above technical problems, the application discloses a method for synthesizing chiral sulfilimines and sulfinate esters catalyzed by a chiral 4-aryl pyridine N-oxide catalyst. Unlike the previous method for synthesizing sulfilimines, the chiral catalyst of the 4-aryl pyridine N-oxide in the application utilizes the oxygen atom in the pyridine N-oxide as a nucleophilic site to participate in the acyl transfer reaction, and the hydrogen in the catalyst molecule also plays a key role.

[0009] The method for asymmetrically synthesizing sulfilimines and sulfinate esters by acyl transfer disclosed by the application comprises the following steps: using sodium sulfinate 1, chloroformate 2, amine 3 or alcohol 4 as raw materials, and in the presence of a chiral 4-aryl pyridine N-oxide catalyst, an asymmetric acyl transfer sulfilimination reaction is carried out to obtain chiral sulfilimine 5 or sulfinate ester 6, respectively; the reaction equation is as follows:

[0010]

[0011] wherein: R is selected from C1-C8 alkyl, fluorine-containing C1-C8 alkyl, C3-C6 cycloalkyl, substituted phenyl, substituted naphthyl, substituted pyridyl, substituted thienyl, substituted oxazole, styryl, and each of the above is substituted with C1-C8 alkyl, C1-C4 alkoxy, halogen, nitrile, nitro, carboxylate; R' is selected from C1-C8 alkyl; R 1 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkoxycarbonyl, halogen, nitro, alkenyl, alkynyl, phenoxy; R 2 is selected from hydrogen or benzyl; R 3 is selected from C1-C8 alkyl, substituted phenylalkynyl, five- or six-membered sugar.

[0012] Further, in the above technical solution, the 4-arylpyridine nitrogen oxide chiral catalyst is selected from:

[0013]

[0014] Further, in the above technical solution, the 4-arylpyridine nitrogen oxide chiral catalyst preferably has the structure C1.

[0015] Further, in the above technical solution, the reaction is carried out in an organic solvent selected from toluene, diethyl ether, dichloromethane, methyl tert-butyl ether or ethyl acetate; preferably, the organic solvent is ethyl acetate.

[0016] Further, in the above technical solution, a base is added to the reaction, and the base is selected from potassium carbonate, sodium carbonate, dipotassium hydrogen phosphate, lithium carbonate, triethylamine, etc.; preferably, the base is potassium carbonate.

[0017] Further, in the above technical solution, the molar ratio of the chloroformate to the amine or alcohol is 1-2:1; preferably, the molar ratio is 1.2-2:1.

[0018] Further, in the above technical solution, the catalytic reaction temperature is -50°C to -20°C.

[0019] The application also provides a method for synthesizing sulfonimidate, sulfonimidamide, sulfonimidyl fluoride and sulfonimidyl azide, comprising the following steps: obtaining the chiral sulfonamide 5 by using the above synthesis method, then obtaining the chiral sulfonimidyl chloride by oxidizing the chiral sulfonamide 5 with tert-butyl hypochlorite, and then reacting with different nucleophiles to obtain sulfonimidate, sulfonimidamide, sulfonimidyl fluoride and sulfonimidyl azide, and the specific corresponding reaction structures are as follows:

[0020]

[0021] Furthermore, in the above technical solution, the solvent for the catalytic oxidation reaction is tetrahydrofuran.

[0022] Beneficial effects of the invention:

[0023] 1. Using sodium sulfinate, chloroformate, amine, or alcohol as starting materials, a chiral sulfinamide or sulfinate product can be obtained in one step via acyl transfer sulfinylation. Subsequent catalytic oxidation synthesizes several chiral drug analogs, including sulfonylimide esters, sulfonylimides, sulfonylimide fluorides, and sulfonylimide azides. The starting materials are readily available, and the reaction yield and enantioselectivity can reach up to 99% and 99% ee, respectively.

[0024] 2. Unlike previous DMAP catalytic reaction mechanisms, the 4-arylpyridine nitrogen-oxygen chiral catalyst in this invention utilizes the oxygen atom in pyridine nitrogen-oxygen as a nucleophilic site to participate in the dynamic kinetic resolution reaction. The hydrogen in the catalyst molecule also plays a key role. At the same time, the reaction process involves the intermediate of chiral mixed acid anhydride, which is then nucleophilically substituted by a nucleophilic reagent to obtain the product. Detailed Implementation

[0025] Example 1

[0026]

[0027]

[0028]

[0029] a Unless otherwise specified, the reaction conditions were as follows: 1a (0.14 mmol), 2 (0.2 mmol), 3a (0.1 mmol), catalyst (5 mol%), K2CO3 (0.14 mmol) in EtOAc (1 mL) reacted at -20 °C for 24 h. b NMR yield. c The determination was made by chiral HPLC analysis. d Added MS (20mg). e Add H2O (10 mol%).

[0030] 1) Screening of alkalis

[0031]

[0032]

[0033] aReaction conditions: 1a (0.14 mmol), 2 (0.2 mmol), 3a (0.1 mmol), catalyst C1 (5 mol%), K2CO3 (0.14 mmol) in EtOAc (1 mL) at -20 °C for 24 h. b NMR yield. c Determined by chiral HPLC analysis.

[0034] 2) Screening of the ratio of chloroformate and starting arylamine

[0035]

[0036]

[0037] Reaction conditions: 1a (0.14 mmol), 2 (0.2 mmol), 3a (0.1 mmol), catalyst C1 (5 mol%), K2CO3 (0.14 mmol) in EtOAc (1 mL) at -20 °C for 24 h. b NMR yield. c Determined by chiral HPLC analysis.

[0038] 3) Screening of the solvent

[0039]

[0040]

[0041] Reaction conditions: 1a (0.14 mmol), 2 (0.2 mmol), 3a (0.1 mmol), catalyst C1 (5 mol%), K2CO3 (0.14 mmol) in solvent (1 mL) at -20 °C for 24 h. b NMR yield. c Determined by chiral HPLC analysis.

[0042] During the reaction condition screening, first the effect of catalyst on the reaction was investigated (label 1-10). At the same time, the effect of pyridine N-oxide catalysts containing different substituents on the sulfinylation reaction, as well as the base, solvent, and the ratio of chloroformate and amine used in the reaction were compared. Finally, C1 was determined as the best catalyst, the addition amount was 5 mol%, ethyl acetate was the best reaction solvent, and 1.4 equivalents of potassium carbonate was the best reaction condition.

[0043] Procedure for reaction condition investigation (example with entry 18): In a dry 5 mL reaction tube, chiral catalyst CI (2.8 mg, 0.05 mmol, 10 mol%), sodium 4-methylbenzenesulfinate la (24.9 mg, 0.14 mmol), K2CO3(19.3 mg, 0.14 mmol), 2,6-dimethylaniline 3a (12.1 mg, 0.1 mmol), and water (0.18 mg, 0.01 mmol) were added, followed by ethyl acetate (1.0 mL). The reaction was stirred at -20 °C for 10 min, after which chloroformate 2d (35.7 mg, 0.2 mmol) was added and the reaction was stirred. After the reaction was completed, the product was isolated by column chromatography. 23.5 mg of white solid 4a was obtained in 91% yield with 96% ee. HPLC CHIRALCEL IF, n-hexane / 2-propanol = 80 / 20, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 8.100 min (minor), 8.862 min (major).[α] D 25 = -17.9 (c = 0.33, EtOAc). 1 H NMR (600 MHz, CDC13) δ 7.81 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.08-7.11 (m, 2H), 7.03-7.07 (m, 1H), 5.59 (s, 1H), 2.46 (s, 3H), 2.43 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 143.3, 142.0, 137.1, 133.9, 129.9, 129.1, 126.3, 125.4, 21.6, 19.4.

[0044] Example 2

[0045] In a dry 5 mL reaction tube, chiral catalyst CI (2.8 mg, 0.05 mmol, 10 mol%) or C4 (2.8 mg, 0.05 mmol, 10 mol%), sodium sulfinates la-la / (0.14 mmol) and arylamines 3a-3q (0.1 mmol), water (0.18 mg, 0.01 mmol) were added, followed by ethyl acetate (1.0 mL). The reaction was stirred at -20 °C for 10 min, after which chloroformate 2d (35.7 mg, 0.2 mmol) was added and the reaction was stirred. After the reaction was completed, the product was isolated by column chromatography. Specific results are as follows:

[0046]

[0047]

[0048] Reaction conditions: la (0.14 mmol), 2d (0.2 mmol), 3a (0.1 mmol), catalyst C1 (5 mol%), K2CO3 (0.14 mmol) in solvent (1 mL) at -20 °C for 24 h, isolated yield. a Reaction at -50 °C, catalyst C4 (5 mol%). b Catalyst C4 (5 mol%), c Potassium sulfinic acid instead of sodium sulfinic acid, d Isopropyl chloroformate instead of 2,4-dimethyl-3-pentyl chloroformate.

[0049] Representative NMR characterization data are as follows:

[0050] (S)-N-(2,6-Dimethylphenyl)benzenesulfinamide (5b)

[0051] Colorless oil, 11.0 mg, 45% yield. [a] D 25 = -17.9 (c = 0.33, EtOAc). HPLC CHIRALCEL IF, n-hexane / 2-propanol = 80 / 20, flow rate = 1.0 mL / min, λ = 250 nm, retention time: 7.538 min (minor), 8.659 min (major), 94% ee. 1 H NMR (600 MHz, CDC13) δ 7.91-7.96 (m, 2H), 7.55-7.61 (m, 3H), 7.09-7.12 (m, 2H), 7.03-7.07 (m, 1H), 5.58 (s, 1H), 2.44 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 146.3, 137.1, 133.9, 131.6, 129.3, 129.1, 126.4, 125.5, 19.4.

[0052] (S)-4-Cyclohexyl-N-(2,6-dimethylphenyl)benzenesulfinamide (5c) Colorless oil, 27.8 mg, 85% yield. [a] D 25= -8.4 (c = 0.77, EtOAc). HPLC CHIRALCEL IF, n-hexane / 2-propanol = 80 / 20, flow rate = 1.0 mL / min, λ = 250 nm, retention time: 6.367 min (minor), 7.349 min (major), 90% ee. 1 H NMR (600 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.78 (dt, J = 8.4, 2.4 Hz, 2H), 7.48 (dt, J = 8.4, 2.4 Hz, 2H), 7.07-7.11 (m, 2H), 7.01-7.06 (m, 1H), 2.57-2.65 (m, 1H), 2.37 (s, 6H), 1.78-1.84 (m, 4H), 1.68-1.76 (m, 1H), 1.34-1.50 (m, 4H), 1.21-1.30 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO-d6) δ 150.8, 143.3, 137.8, 135.2, 128.4, 127.3, 126.0, 125.6, 43.7, 33.81, 33.79, 26.3, 25.5, 19.0.

[0053] (S)-4-(tert-butyl)-N-(2,6-dimethylphenyl)benzenesulfinamide (5d) White solid, 27.7 mg, 92% yield, Mp. 107.7-109.0 °C. [a] D 25 = -8.4 (c = 0.77, EtOAc). HPLC CHIRALCEL IF, n-hexane / 2-propanol = 80 / 20, flow rate = 1.0 mL / min, λ = 250 nm, retention time: 6.367 min (minor), 7.349 min (major), 90% ee. 1 H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.08-7.13 (m, 2H), 7.03-7.07 (m, 1H), 5.59 (s, 1H), 2.44 (s, 6H), 1.38 (s, 9H). 13 C{ 1H NMR (150 MHz, CDC13) δ 155.2, 143.2, 137.2, 133.9, 129.1, 126.3, 125.3, 35.1, 31.4, 19.4.

[0054] (S)-N-(2,6-Dimethylphenyl)-[1,1'-biphenyl]-4-sulfinamide (5e)

[0055] White solid, 30.2 mg, 94% yield, Mp. 134.1-137.2 °C. [a] D 25 = -26.5 (c = 0.28, EtOAc). HPLC CHIRALCEL IF, n-hexane / 2-propanol = 80 / 20, flow rate = 1.0 mL / min, λ = 250 nm, retention time: 9.621 min (minor), 11.614 min (major), 96% ee. 1 H NMR (400 MHz, CDC13) δ 8.00 (dt, J = 8.4, 2.4 Hz, 2H), 7.79 (dt, J = 8.4, 2.0 Hz, 2H), 7.61-7.67 (m, 2H), 7.46-7.53 (m, 2H), 7.39-7.45 (m, 1H), 7.09-7.16 (m, 2H), 7.04-7.09 (m, 1H), 5.66 (s, 1H), 2.46 (s, 6H), 13 C{ 1 H NMR (100 MHz, CDC13) δ 145.0, 144.6, 139.9, 137.1, 134.0, 129.2, 129.1, 128.3, 128.0, 127.5, 126.4, 126.1, 19.4.

[0056] (S)-N-(2,6-Dimethylphenyl)-4-methoxybenzenesulfinamide (4f)

[0057] White solid, 16.2 mg, 59% yield, Mp. 111.2-113.5 °C. [a] D 25= 26.4 (c = 0.28, EtOAc). HPLC CHIRALCEL IF, n-hexane / 2-propanol = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm, retention time: 7.378 min (minor), 8.440 min (major), 95% ee. 1 H NMR (400 MHz, CDC13) δ 7.81 - 7.87 (m, 2H), 7.02 - 7.12 (m, 5H), 5.53 (s, 1H), 3.89 (s, 3H), 2.43 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 162.3, 137.7, 137.1, 133.9, 129.1, 127.2, 126.3, 114.6, 55.7, 19.4.

[0058] (S)-N-(2,6-dimethylphenyl)methanesulfinamide (5ab)

[0059] White solid, 8.4 mg, 46% yield, Mp. 121.4-124.1 °C. [a] D 25 = 26.4 (c = 0.28, EtOAc). HPLC CHIRALCEL IF, n-hexane / 2-propanol = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm, retention time: 7.378 min (minor), 8.440 min (major), 95% ee. 1 H NMR (400 MHz, CDC13) δ 7.81 - 7.87 (m, 2H), 7.02 - 7.12 (m, 5H), 5.53 (s, 1H), 3.89 (s, 3H), 2.43 (s, 6H). 1 H NMR (400 MHz, CDC13) δ 6.95 - 7.15 (m, 3H), 2.84 (s, 1H), 2.35 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 162.3, 137.7, 137.1, 133.9, 129.1, 127.2, 126.3, 114.6, 55.7, 19.4.

[0060] Example 3

[0061] Asymmetric acyl transfer sulfinylation reaction for synthesis of chiral sulfinates.

[0062]

[0063] Typical procedure: In a dry 5 mL reaction tube, chiral catalyst CI (2.8 mg, 0.05 mmol, 10 mol%), sodium sulfinate la (17.2 mg, 0.10 mmol) and 2,4-dimethyl-3-pentanol 5 (13.7 mg, 0.12 mmol), water (0.18 mg, 0.01 mmol) and potassium carbonate (19.3 mg, 0.14 mmol) were added, followed by ethyl acetate (1.0 mL), the reaction was stirred at -20 °C for 10 min, then chloroformate 2d (25.0 mg, 0.14 mmol) was added and the reaction was stirred. After the reaction was completed, the product was isolated by column chromatography. 22.1 mg of colorless oil 6a was obtained in 87% yield with 98% ee.[α] D 25 = 137.7 (c = 1.0, CH2Cl2). HPLC CHIRALCEL IC, n-hexane / 2-propanol = 95 / 5, flow rate = 1.0 mL / min, λ = 250 nm, retention time: 13.167 min (major), 14.458 min (minor), 98% ee. 1 H NMR (400 MHz, CDC13) δ 7.66 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.83 (t, J = 5.6 Hz, 1H), 2.42 (s, 3H), 1.87 - 2.06 (m, 2H), 0.95 - 1.02 (m, 9H), 0.92 (d, J = 6.8 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDC13) δ 144.3, 142.5, 129.7, 124.8, 92.0, 30.8, 30.2, 21.7, 20.5, 20.0, 18.2, 17.6.

[0064] Example 4

[0065] In a dry 5 mL reaction tube, chiral catalyst CI (2.8 mg, 0.05 mmol, 10 mol%), sodium sulfinate la-la / (0.14 mmol), alcohol 5a-5k (0.12 mmol), water (0.18 mg, 0.01 mmol) and potassium carbonate (19.3 mg, 0.14 mmol) were added, followed by ethyl acetate (1.0 mL), the reaction was stirred at -20 °C for 10 min, then chloroformate 2d (35.7 mg, 0.14 mmol) was added and the reaction was stirred. After the reaction was completed, the product was isolated by column chromatography. The specific results are as follows:

[0066]

[0067] Reaction conditions: 1 (0.14 mmol), 2 (0.14 mmol), 4 (0.1 mmol), catalyst CI (5 mol%), K2CO3(0.14 mmol), ethyl acetate (1 mL), -20 °C for 24 h, isolated yield. a Potassium sulfinates instead of sodium sulfinates, b Isopropyl chloroformate instead of 2,4-dimethyl-3-pentyl chloroformate.

[0068] Representative NMR characterization data are as follows:

[0069] (R)-2,4-Dimethylpentan-3-yl-benzenesulfinate (6b)

[0070] Colorless oil, 13.9 mg, 58% yield. [a] D 23 = 129.4 (c = 0.26, CH2Cl2). HPLC CHIRALCEL IC, n-hexane / 2-propanol = 97 / 3, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 12.127 min (major), 13.262 min (minor), 97% ee. 1 H NMR (600 MHz, CDC13) δ 7.75-7.81 (m, 2H), 7.49-7.56 (m, 3H), 3.85 (t, J = 5.4 Hz, 1H), 1.98-2.07 (m, 1H), 1.90-1.96 (m, 1H), 0.96-1.03 (m, 9H), 0.93 (d, J = 6.6 Hz, 3H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 147.1, 132.0, 129.1, 124.9, 92.2, 30.8, 30.2, 20.5, 20.0, 18.2, 17.6.

[0071] (R)-2,4-Dimethylpentan-3-yl-4-bromobenzenesulfinate (6f)

[0072] Colorless oil, 20.9 mg, 65% yield. [a] D 23= 158.0 (c = 0.30, CH2Cl2). HPLC CHIRALCEL IC, n-hexane / 2-propanol = 90 / 10, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 7.692 min (major), 8.972 min (minor), 95% ee. 1 H NMR (400 MHz, CDC13) δ 8.27 (s, 1H), 7.95 - 8.01 (m, 2H), 7.88 - 7.93 (m, 1H), 7.83 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.54 - 7.64 (m, 2H) 3.90 (t, J = 5.6 Hz, 1H), 1.90 - 2.08 (m, 2H), 0.98 - 1.06 (m, 9H), 0.95 (d, J = 6.8 Hz, 3H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 146.2, 132.4, 126.7, 126.5, 92.6, 30.8, 30.2, 20.5, 20.0, 18.1, 17.6.

[0073] (R)-2,4-Dimethylpentan-3-yl-naphthalene-2-sulfinate (61)

[0074] Colorless oil, 22.3 mg, 77% yield. [a] D 23 = 103.2 (c = 0.38, CH2Cl2). HPLC CHIRALCEL IC, n-hexane / 2-propanol = 95 / 5, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 12.533 min (major), 14.480 min (minor), 97% ee. 1 H NMR (400 MHz, CDC13) δ 8.27 (s, 1H), 7.95 - 8.01 (m, 2H), 7.88 - 7.93 (m, 1H), 7.83 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.54 - 7.64 (m, 2H) 3.90 (t, J = 5.6 Hz, 1H), 1.90 - 2.08 (m, 2H), 0.98 - 1.06 (m, 9H), 0.95 (d, J = 6.8 Hz, 3H). 13 C{ 1H NMR (100 MHz, CDC13) δ 144.3, 135.1, 132.7, 129.4, 129.2, 128.2, 128.1, 127.2, 125.6, 120.8, 92.3, 30.8, 30.2, 20.5, 20.1, 18.2, 17.6.

[0075] (R)-2,4-Dimethylpentan-3-yl-methanesulfinate (6s)

[0076] Colorless oil, 11.0 mg, 62% yield. [a] D 23 = 45.2 (c = 1.10, CH2Cl2). HP LC CHIRALCEL IC, n-hexane / 2-propanol = 90 / 10, flow rate = 1.0 mL / min, λ = 215 nm, retention time: 10.461 min (major), 12.478 min (minor), 99% ee. 1 H NMR (600 MHz, CDC13) δ 3.60 (t, J = 6.0 Hz, 1H), 2.64 (s, 3H), 1.83-1.98 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.92 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13) δ 92.7, 44.4, 30.5, 30.0, 20.3, 20.0, 17.9, 17.3.

[0077] Example 6

[0078]

[0079] In a dry 5 mL reaction tube, chiral catalyst Cl (2.8 mg, 0.05 mmol, 10 mol%), glyburide sulfinate potassium 1z (54.9 mg, 0.14 mmol), K2CO3(19.3 mg, 0.14 mmol), 2,6-dimethylaniline 3a (12.2 mg, 0.1 mmol) and water (0.18 mg, 0.01 mmol) were added, followed by ethyl acetate (1.0 mL), the reaction was placed in -20 °C stirring for 10 minutes, then chloroformate 2d (35.7 mg, 0.2 mmol) was added and the reaction was stirred. The reaction was completed, column chromatography was separated to obtain 34.7 mg of white solid 4z, yield 76%, 94% ee. Mp. 131.1-132.2 °C. D 23 = 13.6 (c = 0.28, CH2Cl2). HPLC CHIRALCEL IE, n-hexane / 2-propanol = 50 / 50, flow rate = 0.8 mL / min, λ = 250 nm, retention time: 35.976 min (minor), 47.563 min (major), 94% ee. 1 H NMR (600 MHz, CDC13) δ 8.17 (d, J = 3.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.85 (t, J = 5.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 9.0, 3.0 Hz, 1H), 7.07-7.11 (m, 2H), 7.03-7.07 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.60 (s, 1H), 3.83 (s, 3H), 3.70-3.80 (m, 2H), 3.02 (t, J = 7.2 Hz, 2H). 2.42 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 164.1, 156.0, 144.5, 143.3, 137.0, 133.9, 132.5, 132.1, 129.8, 129.1, 126.9, 126.4, 125.8, 122.9, 113.0, 56.4, 41.0, 35.7, 19.3.

[0080] Example 7

[0081]

[0082] In a dry 5 mL reaction tube, add sulfilimine 4a (25.9 mg, 0.1 mmol) and tetrahydrofuran (1 mL), stir the reaction at -30 °C for 10 minutes, then add tert-butyl hypochlorite (17.8 mg, 0.13 mmol) and stir for 1 hour. Then add 30% sodium methoxide solution (8.1 mg, 0.15 mmol) and stir for 0.5 hours. Quench the reaction with 5 mL water and isolate by column chromatography to give 18.2 mg of colorless oily liquid 7a in 63% yield with 95% ee. D 23 = 23.5 (c = 0.93, CH2Cl2). HPLC CHIRALCEL IG, n-hexane / 2-propanol = 90 / 10, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 6.622 min (major), 7.162 min (minor). 1 H NMR (400 MHz, CDC13) δ 7.99 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H), 6.91 (t, J = 7.6 Hz, 1H), 3.60 (s, 3H), 2.46 (s, 3H), 2.38 (s, 6H). 13 C{ 1 H} NMR (100 MHz, CDC13) δ 144.1, 138.9, 134.5, 134.0, 129.8, 128.1, 123.6, 56.5, 21.7, 19.7.

[0083] Example 8

[0084]

[0085] In a dry 5 mL reaction tube, add sulfilimine 4a (25.9 mg, 0.1 mmol) and tetrahydrofuran (1 mL), stir the reaction at -30 °C for 10 minutes, then add tert-butyl hypochlorite (17.8 mg, 0.13 mmol) and stir for 1 hour. Then add n-butylamine (16.1 mg, 0.22 mmol) and stir for 4 hours. Quench the reaction with 5 mL water and isolate by column chromatography to give 20.5 mg of colorless oily liquid 7c in 62% yield with 90% ee. D 25= 16.4 (c = 1.05, CH2Cl2). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 6.540 min (minor), 7.243 min (major). 1 H NMR (400 MHz, CDC13) δ 7.91 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.6 Hz, 2H), 6.86 (t, J = 7.6 Hz, 1H), 4.13 (s, 1H), 3.07-2.96 (m, 1H), 2.89-2.78 (m, 1H), 2.43 (s, 3H), 2.37 (s, 6H), 1.41-1.25 (m, 2H), 1.13-1.24 (m, 2H), 0.79 (q, J = 7.2 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDC13) δ 142.7, 140.2, 138.9, 133.8, 129.6, 128.2, 127.4, 123.0, 43.6, 31.9, 21.6, 20.2, 19.9, 13.7.

[0086] Example 9

[0087]

[0088] In a dry 5 mL reaction tube, sulfilimine 4a (25.9 mg, 0.1 mmol) was added and then tetrahydrofuran (1 mL) was added, the reaction was stirred at -30 °C for 10 min, then tert-butyl hypochlorite (17.8 mg, 0.13 mmol) was added and stirred for 1 h. Then KF (12.8 mg, 0.22 mmol) and 18-crown-6 (31.7 mg, 0.12 mmol) were added and stirred for 3 h, the reaction was quenched by adding 5 mL water. Column chromatography separation to obtain 7d 13.3 mg, yield 48%, 93% ee. D 25 = 29.7 (c = 0.59, CH2Cl2). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 6.540 min (minor), 7.243 min (major). 1H NMR (600 MHz, CDC13) δ 8.10 (d, J = 7.2 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 7.2 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H), 2.50 (s, 3H), 2.35 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13) δ 145.6, 136.8 (d, J C-F = 5.4 Hz), 133.4 (d, J C-F = 10.7 Hz), 133.0 (d, J C-F = 18.4 Hz), 130.0, 128.2, 128.0, 124.7, 21.9, 19.3. 19 F NMR (565 MHz, CDC13): δ 92.25.

[0089] The above examples describe the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. Process for the synthesis of chiral sulfonamides and sulfonates by asymmetric acyl transfer sulfonylation, characterized in that, The method comprises the following steps: asymmetric acyl transfer sulfinylation reaction is carried out by taking sodium sulfinic acid 1, chloroformic acid ester 2, amine 3 or alcohol 4 as raw materials in the presence of 4-aryl pyridine nitrogen oxide chiral catalyst, and chiral sulfonamide 5 or sulfinate 6 is obtained respectively; the reaction equation is as follows: The 4-aryl pyridine nitrogen oxide chiral catalyst is selected from the following: ； The reaction is carried out in the presence of a base selected from the group consisting of triethylamine, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate or lithium carbonate; R is selected from the group consisting of C1-C8 alkyl, fluorine containing C1-C8 alkyl, C3-C6 cycloalkyl, substituted phenyl, substituted naphthyl, substituted pyridyl, substituted thienyl, substituted oxazole, styryl, R' is selected from the group consisting of C1-C8 alkyl; R 1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkoxycarbonyl, halogen, nitro, alkenyl, alkynyl, phenoxy; R 2 is selected from the group consisting of hydrogen or benzyl; R 3 is selected from the group consisting of C1-C8 alkyl, substituted phenylalkynyl, five or six membered sugar; the substitutions are selected from the group consisting of C1-C8 alkyl, C1-C4 alkoxy, halogen, nitrile, nitro, carboxylate.

2. The process for the synthesis of chiral sulfmides and sulfmtes according to claim 1, characterized by the fact that: The chiral 4-aryl pyridine nitrogen oxide chiral catalyst is selected from C1.

3. The process for the synthesis of chiral sulfmides and sulfmtes according to claim 1, characterized by the fact that: The reaction is carried out in an organic solvent, and the organic solvent is selected from toluene, diethyl ether, dichloromethane, methyl tert-butyl ether or ethyl acetate.

4. The process for the asymmetric acyl transfer synthesis of sulfmides and sulfmides according to claim 1, characterized in that: The chloroformic acid ester is selected from ethyl chloroformate, isopropyl chloroformate, cyclopentyl chloroformate and 2,4-dimethyl-3-pentyl chloroformate.

5. The method of asymmetric acyl transfer synthesis of sulfenamides and sulfenates according to claim 1, characterized in that: The molar ratio of the chloroformic acid ester to the amine or alcohol is 1-2:

1.

6. The process for the asymmetric acyl transfer synthesis of sulfenamides and sulfenates according to claim 1, characterized in that: The reaction temperature is-50 DEG C to-20 DEG C.

Images