A method for efficiently synthesizing chiral sulfonamides

Abstract

The application provides a method for efficiently synthesizing chiral sulfenamide, and the specific synthesis method is as follows: aryl / alkenyl borate is used as raw material, and nickel-catalyzed asymmetric addition reaction is used to convert sulfenamide into chiral sulfenamide. The key of the application is that a chiral anion ligand is combined with divalent nickel to generate a high-activity catalytic species which is stable in structure and excellent in catalytic performance, and a series of chiral sulfenamide compounds are constructed. The application has good substrate compatibility, aryl / heteroaryl and alkenyl borate can all react, and the enantioselectivity control is excellent. In the amplification experiment with a scale of 5mmol, the catalyst consumption can be reduced to 0.5%, and the application has potential industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalysis technology, and specifically relates to a method for the efficient synthesis of chiral sulfinamides. Background Technology

[0002] Sulfur-containing compounds have significant applications in biomedicine, materials science, catalysis, and food flavoring (Chem. Rev. 2015, 115, 3036). For example, the proton pump inhibitor Esomeprazole and the ADHD drug Armodafinil are commercially available chiral sulfoxide small molecule drugs. Atuveciclib, containing a chiral sulfoxide imine structure, is a highly selective PTEFb / CDK9 inhibitor, and aminoacyl-tRNA synthetase inhibitors also contain chiral sulfinamide fragments (J. Am.Chem. Soc. 2020, 142, 10899). Furthermore, chiral sulfoxides, chiral sulfoxide imines, and chiral sulfinamides often act as ligands in transition metal-catalyzed asymmetric reactions, and they themselves can also serve as small organic molecule catalysts (Chem. Rev. 2017, 117, 4147).

[0003] The exploration of sulfur sources and catalytic systems is a major research direction for the efficient construction of sulfur-centered chiral compounds. In 2017, Willis developed a stable sulfinylimide reagent with good reactivity. This reagent reacts with organometallic reagents and, after oxidation, is further captured by amines to generate the corresponding sulfoxide imide amide. However, the highly nucleophilic organometallic reagents limit the substrate range of the reaction and also bring inconvenience to experimental operations (Angew. Chem. Int. Ed. 2017, 56, 14937). Subsequently, the research group used a racemic nickel catalyst to achieve a catalytic version of the above reaction (J. Am. Chem. Soc. 2021, 143, 15576). Transition metal-catalyzed asymmetric transformations have advantages such as mild reaction conditions, high functional group compatibility, and effective control of enantioselectivity. Based on this type of sulfinylimide reagent, this invention develops a class of high-performance chiral transition metal catalysts, achieving the efficient synthesis of chiral sulfinamides under mild conditions. Although the research groups of Zhang Junliang (J. Am. Chem. Soc. 2024, 146, 17580) and Shi Zhuangzhi (J. Am. Chem. Soc. 2024, 146, 17587) also achieved the asymmetric transformation of sulfinamides not long ago, the broader substrate range, excellent chiral control and lower catalyst dosage of this invention make it of great significance for the catalytic synthesis of structurally complex chiral sulfinamides. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention discloses a highly efficient method for synthesizing chiral sulfinamides. Specifically, the synthesis method involves using aryl / alkenylboronic esters as raw materials and converting sulfinylimide into chiral sulfinamides via a nickel-catalyzed asymmetric addition reaction. The key to this invention lies in combining a chiral anionic ligand with divalent nickel to generate a structurally stable and highly active catalytic species with excellent catalytic performance, thus constructing a series of chiral sulfinamide compounds. This invention exhibits good substrate compatibility, with both aryl / heteroaryl and alkenylboronic esters capable of reacting, and excellent enantioselectivity control. In a scale-up experiment at 5 mmol (5 mmol refers to sulfinylimide II), the catalyst dosage can be reduced to 0.5% (molar percentage, based on 5 mmol sulfinylimide II), demonstrating potential for industrial application.

[0005] This invention utilizes a chiral anionic ligand to form a highly active catalyst in situ with readily available and inexpensive divalent nickel. Using easily prepared borate ester I as a nucleophile, the asymmetric addition reaction of the S=N bond in sulfinimide II is catalyzed under nitrogen atmosphere and in the presence of an organic solvent and a base, to synthesize the corresponding chiral sulfinamide compounds. Notably, a reaction scale of 5 mmol can be achieved with only 0.5% catalyst. This reaction exhibits mild conditions, high substrate universality, and high enantioselectivity for constructing structurally complex sulfur-containing chiral compounds.

[0006] The present invention adopts the following technical solution:

[0007] A method for efficiently synthesizing chiral sulfinamides includes the following steps: forming a highly active catalyst in situ with divalent nickel via a chiral anionic ligand; using borate ester I as a nucleophile; and catalyzing the asymmetric addition reaction of the S=N bond in sulfinimide II under room temperature and inert gas conditions, in the presence of an organic solvent and an inorganic strong base, to synthesize a chiral sulfinamide compound.

[0008] Furthermore, the inert gas is argon or nitrogen.

[0009] Further, the borate ester I is neopentyl glycol borate; preferably, the borate ester I is 4-tolueneboronic acid neopentyl glycol ester, 4-trifluoromethylphenylboronic acid neopentyl glycol ester, 4-cyanobenzonic acid neopentyl glycol ester, 4-vinylphenylboronic acid neopentyl glycol ester, 3-thiopheneboronic acid neopentyl glycol ester, 6-(4-morpholino)-3-pyridineboronic acid neopentyl glycol ester, quinoline-4-boronic acid neopentyl glycol ester, N-methylindole-5-boronic acid neopentyl glycol ester. One or more of the following: pentylene glycol ester, neopentylene glycol ester of 2-methylbenzothiazol-5-boronic acid, neopentylene glycol ester of pyrene-2-ylboronic acid, neopentylene glycol ester of 4-(1,2,2-tristyryl)phenylboronic acid, neopentylene glycol ester of 1-phenylvinylboronic acid, neopentylene glycol ester of 4-(9-carbazolyl)phenylboronic acid, neopentylene glycol ester of cyclohexene-1-boronic acid, neopentylene glycol ester of cyclopentene-1-boronic acid, and neopentylene glycol ester of E-phenylvinylboronic acid.

[0010] Furthermore, the sulfinimide II is Tr=CPh3. The molar ratio of borate ester I to sulfinimide II is 1.0~1.5:1.0, for example, the molar ratio of borate ester I to sulfinimide II is 1.0:1.0, 1.1:1.0, 1.2:1.0, 1.3:1.0, 1.4:1.0 or 1.5:1.0.

[0011] Further, the divalent nickel catalyst is one of nickel chloride, nickel bromide, nickel bromide of ethylene glycol dimethyl ether, and nickel diacetylacetone, preferably nickel bromide of ethylene glycol dimethyl ether. The molar ratio of the divalent nickel catalyst to sulfinimide II is 0.005~0.1:1~5, for example, the molar ratio of the divalent nickel catalyst to sulfinimide II is 0.005:1~5, 0.006:1~5, 0.007:1~5, 0.008:1~5, 0.009:1~5, 0.01:1~5, 0.03:1~5, 0.05:1~5, 0.09:1~5, or 0.01:1~5.

[0012] Furthermore, the molar ratio of the chiral anionic ligand to the divalent nickel catalyst is 0.5~1.5:1~1.2; for example, the molar ratio of the chiral anionic ligand to the divalent nickel catalyst is 0.5:1~1.2, 0.6:1~1.2, 0.7:1~1.2, 0.8:1~1.2, 0.9:1~1.2, 1.0:1~1.2, 1.1:1~1.2, 1.2:1~1.2, 1.3:1~1.2 or 1.50.5:1~1.2.

[0013] Furthermore, the inorganic strong base is t One of BuONa or MeONa. The molar ratio of the inorganic strong base to sulfinimide II is 0.5 to 1.5:1 (e.g., 0.6:1, 0.8:1, 1:1 or 1.5:1).

[0014] Further, the organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether and ethyl acetate, preferably tert-butyl methyl ether, and the ratio of the organic solvent to sulfinimide II is 0.5~1.5 mL : 0.1 mmol.

[0015] Furthermore, the reaction route of the method is as follows:

[0016] ;

[0017] R is phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-vinylphenyl, 3-thienyl, 3-pyridyl, 4-quinolinyl, a four-membered fused aromatic ring, or a substituted olefin such as cyclohexenyl, cyclopentenyl, or trans-2-styryl; Bneop is neopentane glycol borate, and Tr is triphenylmethyl. The above reaction route uses anionic chiral ligands to generate a highly active catalyst in situ with divalent nickel. In the presence of sodium tert-butoxide, the catalyst catalyzes the asymmetric addition reaction of borate esters to sulfinimides to obtain the corresponding chiral sulfinamides.

[0018] Furthermore, the borate ester I is neopentyl glycol borate, and the amount added is 1.2 equivalents;

[0019] The amount of sulfinimide II added is 1.0 equivalent;

[0020] The nickel catalyst is one of nickel chloride, nickel bromide, nickel bromide of ethylene glycol dimethyl ether, and nickel diacetylacetone, preferably nickel bromide of ethylene glycol dimethyl ether, for example, the amount added is 0.1 or 0.005 equivalents;

[0021] The anionic ligand is one of L1-L6, preferably L4, for example, the amount added is 0.12 or 0.006 equivalents;

[0022] ;

[0023] The inorganic strong base is t BuONa, for example, the amount added is 1.1 equivalents;

[0024] The solvent can be tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, ethyl acetate, etc., preferably tert-butyl methyl ether, for example, the amount added is 0.1M;

[0025] Furthermore, the reaction route of the present invention is as follows:

[0026] ;

[0027] R can be a benzene ring, a substituted benzene ring, a heteroaromatic ring, a fused aromatic ring, a monosubstituted olefin, or a polysubstituted olefin. The above reaction route uses an anionic chiral ligand to generate a highly active catalyst in situ with divalent nickel. In the presence of sodium tert-butoxide, this catalyst catalyzes the asymmetric addition reaction of borate esters to sulfinimides, yielding the corresponding chiral sulfinamide.

[0028] Specifically, the synthesis method of the chiral sulfinamide of the present invention is described in detail below:

[0029] Under nitrogen protection at room temperature, NiBr2DME, ligand, and ligand were added sequentially to a 4 mL reaction flask containing a magnetic magnet using a glove box. t BuONa and anhydrous tert-butyl methyl ether. After stirring for 10 minutes, borate ester I was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box. The mixture was stirred at room temperature until TLC showed that the starting material had been consumed. The reaction system was then directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent to obtain the corresponding chiral sulfinamide.

[0030] Furthermore, the structural formula of the sulfur-containing chiral compound III prepared by the method of the present invention includes the following:

[0031] .

[0032] The present invention has the following positive effects:

[0033] The innovation of this invention lies in the use of chiral anionic ligands coordinated with divalent nickel, which generates structurally stable and highly active catalytic species with excellent catalytic performance. Only 0.5% (molar percentage, based on sulfinimide II) of catalyst is needed to achieve satisfactory yields and enantioselectivity for 5 mmol-scale experiments. The use of non-toxic and odorless sulfinimide as the sulfur source simplifies raw material preparation and avoids the use of malodorous thiols. Boronate esters are widely available, structurally diverse, and easily synthesized. This invention offers mild reaction conditions, simple operation, high functional group compatibility, and excellent enantioselectivity control, providing a reliable method for the synthesis of chiral sulfinamides with potential process applications. Attached Figure Description

[0034] Figure 1 Example 1: Chiral sulfinamide NMR spectrum (H NMR) of the product. Detailed Implementation

[0035] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of the invention described below can be combined with each other as long as they do not conflict with each other. To achieve the above objectives, the invention adopts the following technical solution:

[0036] Example 1:

[0037]

[0038] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.1 mmol sodium tert-butoxide were added sequentially to a 50 mL reaction flask containing a magnetic magnet. t BuONa) and 1 mL anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 19 mL TBME, 2.4 mmol neopentyl glycol 4-tolueneborate, and 2.1 mmol [the rest of the mixture] were added to the above reaction solution. t BuONa, continue stirring for 5 minutes. Finally, add 2 mmol of sulfinimide II to the reaction solution, tighten the cap, and quickly remove the reaction flask from the glove box. Stir at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixture (v:v=3:1) as the developing solvent to obtain the corresponding chiral sulfinamide. The product yield was 80%, the ee value was 92%, and it was a white solid.

[0039] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0040] 1 HNMR (500MHz, CDCl3) δ7.55(d,J=8.3Hz,2H),7.40-7.35(m,6H),7.33(t,J=7.4Hz,6H),7.31-7.25(m,5H),5.17(s,1H),2.39(s,3H). 13 CNMR (126MHz, CDCl3) δ144.63,144.13,141.13,129.62,129.50,127.97,127.40,125.53,73.40,21.28.

[0041] HRMS(ESI)[M+Na] + :calcd.420.1393,found.420.1397.

[0042] [α] D 20 =-13.2 (c=1.73, acetone).

[0043] Figure 1 The image shows the 1H NMR spectrum of the chiral sulfinamide product from Example 1.

[0044] Example 2:

[0045]

[0046] Under nitrogen protection at room temperature, using a glove box, 0.025 mmol NiBr2DME, 0.03 mmol ligand L4, and 0.1 mmol sodium tert-butoxide were added sequentially to a 100 mL reaction flask containing a magnetic magnet. t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 49 mL of TBME, 6 mmol of neopentyl glycol 4-trifluoromethylphenylboronic acid ester and 5.4 mmol of [unspecified ingredient] were added to the above reaction solution. t BuONa, continue stirring for 5 minutes. Finally, add 5 mmol of sulfinimide II to the reaction solution, tighten the cap, and quickly remove the reaction flask from the glove box. Stir at room temperature for 24 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixture (v:v=3:1) as the developing solvent to obtain the corresponding chiral sulfinamide. The product yield was 78%, the ee value was 93%, and it was a white solid.

[0047] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0048] 1 HNMR(500MHz, CDCl3)δ7.70(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),7.34-7.17(m,15H),5.26(s,1H). 13 CNMR(126MHz, CDCl3)δ151.15,144.24,132.79(q,J=32.7Hz),129.46,128.08,127.61,126.26,125.92(q,J=3.7Hz),123.55(q,J=272.6Hz),73.75. 19 FNMR (471MHz, CDCl3) δ -62.71.

[0049] HRMS(ESI)[M+Na] + :calcd.474.1110,found.474.1104.

[0050] [α]D20 = -19.9 (c = 1.95, acetone).

[0051] Example 3:

[0052]

[0053] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 4-cyanobenzeneboronic acid was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 82%, the ee value was 95%, and it was a white solid.

[0054] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0055] 1 HNMR (400MHz, CDCl3) δ7.87-7.71(m,4H),7.39-7.29(m,15H),5.34(s,1H). 13 CNMR(101MHz,Chloroform-d)δ152.26,144.08,132.61,129.43,128.14,127.71,126.57,117.84,114.61,73.87.

[0056] HRMS(ESI)[M+Na] + :calcd.431.1189,found.431.1190.

[0057] [α] D 20 =5.6 (c=1.25, acetone).

[0058] Example 4:

[0059]

[0060] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 4-vinylphenylboronic acid was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 71%, the ee value was 94%, and it was a white solid.

[0061] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0062] 1 HNMR(500MHz, CDCl3)δ7.62(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),7.41-7.36(m,6H),7.35-7.26( m,9H),6.73(dd,J=17.6,10.9Hz,1H),5.83(d,J=17.6Hz,1H),5.35(d,J=10.9Hz,1H),5.21(s,1H). 13 CNMR (126MHz, CDCl3) δ146.24,144.55,140.09,135.71,129.50,128.00,127.46,126.68,125.87,116.10,73.49.

[0063] HRMS(ESI)[M+Na] + :calcd.432.1393,found.432.1394.

[0064] [α] D 20 =8.2 (c=1.28, acetone).

[0065] Example 5:

[0066]

[0067] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 3-thiophene borate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 95%, the ee value was 93%, and it was a white solid.

[0068] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0069] 1 HNMR(400MHz, CDCl3)δ7.70(dd,J=3.2,1.3Hz,1H),7.41-7.26(m,16H)7.10(dd,J=5.1,1.3Hz,1H),5.38(s,1H). 13 CNMR (101MHz, CDCl3) δ147.30,144.52,129.35,128.02,127.70,127.46,126.90,124.88,73.25.

[0070] HRMS(ESI)[M+Na] + :calcd.412.0800,found.412.0812.

[0071] [α] D 20 =16.0 (c=1.19, acetone).

[0072] Example 6:

[0073]

[0074] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 6-(4-morpholino)-3-pyridineboronic acid was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 92%, the ee value was 92%, and it was a white solid.

[0075] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0076] 1 HNMR(400MHz, CDCl3)δ8.41(d,J=2.5Hz,1H),7.76(dd,J=9.0,2.5Hz,1H),7.39-7.28(m,15 H),6.66(d,J=9.0Hz,1H),5.20(s,1H),3.81(t,J=4.9Hz,4H),3.60(td,J=4.4,1.4Hz,4H). 13 CNMR(101MHz, CDCl3)δ160.17,146.48,144.58,135.42,131.18,129.43,128.04,127.48,106.17,73.38,66.57,45.17.

[0077] HRMS(ESI)[M+H] + :calcd.470.1897,found.470.1892.

[0078] [α] D 20 =25.0 (c=0.43, acetone).

[0079] Example 7:

[0080]

[0081] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl quinoline-4-borate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and incubated at 60°C. o The mixture was stirred at C for 24 hours. The reaction system was then directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 40%, with an ee value of 98%, and the product was a white solid.

[0082] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0083] 1 HNMR(500MHz, CDCl3)δ9.11(d,J=4.4Hz,1H),8.24-8.20(m,1H),8.18(d,J=4.4Hz,1H), 7.83-7.76(m,2H),7.52(ddd,J=8.3,6.9,1.3Hz,1H),7.35-7.32(m,15H),5.35(s,1H). 13 CNMR(126MHz, CDCl3)δ152.89,150.31,148.49,143.71,130.13,130.08,129.69,128.01,127.82,127.44,123.70,123.37,116.51,73.94.

[0084] HRMS(ESI)[M+Na] + :calcd.457.1345,found.457.1348.

[0085] [α] D 20 =-78.7 (c=2.2, acetone).

[0086] Example 8:

[0087]

[0088] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol N-methylindole-5-boronate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 95%, the ee value was 93%, and it was a white solid.

[0089] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0090] 1 HNMR(500MHz, CDCl3)δ7.88(d,J=1.7Hz,1H),7.36-7.30(m,7H),7.29-7.22(m,7H),7.2 2-7.19(m,3H),7.03(d,J=3.2Hz,1H),6.46(d,J=2.4Hz,1H),5.09(s,1H),3.72(s,3H). 13 CNMR (126MHz, CDCl3) δ144.85,137.70,137.56,130.39,129.51,128.28,127.92,127.28,118.62,118.31,109.67,102.02,73.27,33.03.

[0091] HRMS(ESI)[M+Na] + :calcd.459.1502,found.459.1498.

[0092] [α] D 20 =6.8 (c=1.31, acetone).

[0093] Example 9:

[0094] ,

[0095] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 2-methylbenzothiazole-5-boronate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 93%, the ee value was 93%, and it was a white solid.

[0096] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0097] 1 HNMR(500MHz, CDCl3)δ8.27(d,J=1.8Hz,1H),7.90(d,J=8.4Hz,1H),7.67(dd,J= 8.4,1.7Hz,1H),7.43-7.37(m,6H),7.37-7.28(m,9H),5.36(s,1H),2.86(s,3H). 13 CNMR(126MHz, CDCl3)δ168.99,153.35,145.57,144.50,138.42,129.50,128.03,127.49,121.88,121.56,119.80,73.65,20.30.

[0098] HRMS(ESI)[M+Na] + :calcd.477.1066,found.477.1075.

[0099] [α] D 20 =8.7 (c=0.55, acetone).

[0100] Example 10:

[0101] ,

[0102] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol pyrene-2-ylboronic acid was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 89%, the ee value was 97%, and it was a white solid.

[0103] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0104] 1 HNMR(400MHz, CDCl3)δ8.78(d,J=8.1Hz,1H),8.26(d,J=8.2Hz,1H),8.24-8.18(m,2H),8. 10(d,J=8.9Hz,1H),8.08-7.98(m,4H),7.47-7.37(m,6H),7.38-7.25(m,9H),5.35(s,1H). 13 CNMR(126MHz, CDCl3)δ144.23,139.47,133.22,131.04,130.40,129.70,128.90,128.53,127.89, 127.55,127.23,127.15,126.42,126.19,126.15,124.99,124.61,124.21,122.21,121.02,73.60.

[0105] HRMS(ESI)[M+Na] + :calcd.530.1549,found.530.1553.

[0106] [α] D 20 =-273.1 (c=0.95, acetone).

[0107] Example 11:

[0108] ,

[0109] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 4-(1,2,2-tristyryl)phenylboronic acid was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 82%, the ee value was 97%, and it was a white solid.

[0110] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0111] 1 HNMR (500MHz, CDCl3) δ7.46-7.37(m,2H),7.36-7.27(m,15H),7.15-7.09(m,11H),7.03-7.00(m,6H),5.17(d,J=6.1Hz,1H). 13 CNMR (126MHz, CDCl3) δ146.65,144.82,144.53,143.18,143.11,143.07,142.40,139.63,131.87, 131.25,131.19,129.53,127.98,127.85,127.82,127.68,127.44,126.80,126.70,125.01,73.42.

[0112] HRMS(ESI)[M+Na] + :calcd.660.2332,found.660.2329.

[0113] [α] D 20 =-5.3 (c=1.70, acetone).

[0114] Example 12:

[0115] ,

[0116] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 1-phenylvinylborate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 85%, the ee value was 96%, and it was a white solid.

[0117] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0118] 1 HNMR (500MHz, CDCl3) δ7.39-7.36(m,3H),7.34-7.31(m,2H),7.25-7.21(m,9H),7.14-7.11(m,6H),6.19(s,1H),5.91(s,1H),4.77(s,1H). 13 CNMR (126MHz, CDCl3) δ155.87,144.21,134.91,129.49,128.74,128.69,127.77,127.39,127.34,117.96,72.92.

[0119] HRMS(ESI)[M+Na] + :calcd.432.1393,found.432.1399.

[0120] [α] D 20 =-13.5 (c=0.35, acetone).

[0121] Example 13:

[0122] ,

[0123] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol 4-(9-carbazolyl)phenylboronic acid was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 93%, the ee value was 92%, and it was a white solid.

[0124] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0125] 1 HNMR(500MHz, CDCl3)δ8.12(d,J=7.8Hz,2H),7.89(d,J=8.6Hz,2H),7.68(d,J=8. 5Hz,2H),7.46-7.39(m,10H),7.39-7.33(m,6H),7.33-7.27(m,5H),5.41(s,1H). 13 CNMR(126MHz, CDCl3)δ145.62,144.46,140.32,140.18,129.50,128.07,127.54,127.44,127.15,126.10,123.62,120.42,120.38,109.57,73.64.

[0126] HRMS(ESI)[M+Na] + :calcd.571.1815,found.571.1816.

[0127] [α] D 20 =6.3 (c=2.20, acetone).

[0128] Example 14:

[0129] ,

[0130] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl cyclohexene-1-boronate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and incubated at 60°C. o The mixture was stirred at C for 24 hours. The reaction system was then directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 58%, the ee value was 92%, and the product was a white solid.

[0131] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0132] 1 HNMR(500MHz, CDCl3)δ7.47-7.17(m,15H),6.41(s,1H),4.81(s,1H),2.44-2.27(m,1H),2 .17(tt,J=6.9,5.3,2.6Hz,2H),2.12-2.04(m,1H),1.82-1.73(m,1H),1.70-1.54(m,3H). 13 CNMR (126MHz, CDCl3) δ144.76,143.47,130.88,129.42,127.88,127.25,72.79,25.45,22.93,22.46,21.89.

[0133] HRMS(ESI)[M+H] + :calcd.388.1730,found.388.1740.

[0134] [α] D 20 =-31.2 (c=1.1, acetone).

[0135] Example 15:

[0136] ,

[0137] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl cyclopentene-1-borate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 89%, the ee value was 95%, and it was a white solid.

[0138] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0139] 1 HNMR(500MHz, CDCl3)δ7.55-7.12(m,15H),6.30(s,1H),4.98(s,1H),2.58(dtt ,J=27.4,6.5,2.2Hz,2H),2.46(ddt,J=8.5,3.5,1.9Hz,2H),2.12-2.00(m,2H). 13 CNMR (126MHz, CDCl3) δ149.05,144.74,136.44,129.26,127.92,127.29,72.80,32.40,30.20,23.74.

[0140] HRMS(ESI)[M+Na] + :calcd.396.1393,found.396.1391.

[0141] [α] D 20 =-6.7 (c=1.00, acetone).

[0142] Example 16:

[0143] ,

[0144] Under nitrogen protection at room temperature, using a glove box, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, and 0.11 mmol sodium tert-butoxide were added sequentially to a 4 mL reaction flask containing a magnetic magnet. tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of neopentyl glycol E-phenylvinyl borate was added to the above reaction solution, and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfinimide II was added to the reaction solution, the cap was tightened, and the reaction flask was quickly removed from the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin-layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfinamide. The product yield was 90%, the ee value was 86%, and it was a white solid.

[0145] The product was analyzed by nuclear magnetic resonance, and its molecular weight and specific rotation were determined by high-resolution mass spectrometry (HRMS). The results are as follows:

[0146] 1HNMR(500MHz, CDCl3)δ7.50-7.26(m,20H),7.23(d,J=15.3Hz,1H),6.70(d,J=15.2Hz,1H),5.09(s,1H).13CN MR(126MHz, CDCl3)δ144.67,136.45,133.81,132.54,129.56,129.18,128.81,128.06,127.78,127.41,72.93.

[0147] HRMS(ESI)[M+Na]+:calcd.432.1393,found.432.1398.

[0148] [α]D20=68.5 (c=1.79, acetone).

[0149] This invention provides a highly efficient catalytic system for constructing chiral sulfinamides. Experimental results show that this invention not only efficiently constructs a series of structurally diverse chiral sulfinamide compounds under mild conditions, but also that the highly active catalytic system allows the reaction to proceed smoothly with relatively low catalyst loading.

Claims

1. A method for efficient synthesis of chiral sulfonamides, characterized by, The method comprises the following steps: The asymmetric addition reaction of S=N bond in sulfilimine II is catalyzed by in-situ formation of high-activity catalytic species of chiral anion ligand and divalent nickel catalyst, with borate I as nucleophile, under the conditions of room temperature and inert gas, in the presence of organic solvent and strong inorganic base, to synthesize chiral sulfilimine compound; the anion ligand is L4, and the structural formula of L4 is as follows: ； The borate I is one or more of 4-tolyl boronic acid neopentyl glycol ester, 4-trifluoromethyl phenyl boronic acid neopentyl glycol ester, 4-cyanophenyl boronic acid neopentyl glycol ester, 4-vinylphenyl boronic acid neopentyl glycol ester, 3-thiophene boronic acid neopentyl glycol ester, 6-(4-morpholinyl)-3-pyridine boronic acid neopentyl glycol ester, quinoline-4-boronic acid neopentyl glycol ester, N-methyl indole-5-boronic acid neopentyl glycol ester, 2-methylbenzothiazole-5-boronic acid neopentyl glycol ester, pyrene-2-yl boronic acid neopentyl glycol ester, 4-(1,2,2-triphenylstyryl) phenyl boronic acid neopentyl glycol ester, 1-phenylvinyl boronic acid neopentyl glycol ester, 4-(9-carbazolyl) phenyl boronic acid neopentyl glycol ester, cyclohexene-1-boronic acid neopentyl glycol ester, cyclopentene-1-boronic acid neopentyl glycol ester and E-phenylvinyl boronic acid neopentyl glycol ester; the molar ratio of divalent nickel catalyst to sulfilimine II is 0.005-0.1:1-5; the molar ratio of chiral anion ligand to divalent nickel catalyst is 0.5-1.5:1-1.2; The sulfilimine II is , Tr = CPh3; the molar ratio of boronate I to sulfilimine II is 1.0 to 1.5: 1.

0.

2. The method of claim 1, wherein, The divalent nickel catalyst is one of nickel chloride, nickel bromide, ethylene glycol dimethyl ether nickel bromide and diacetyl nickel.

3. The method of claim 1, wherein, The inorganic strong base is t one of BuONa or MeONa, and the molar ratio of the inorganic strong base to the sulfmimide II is 0.5 to 1.5:

1.

4. The method of claim 1, wherein, The organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether and ethyl acetate, and the ratio of the organic solvent to sulfilimine II is 0.5-1.5 mL:0.1 mmol.

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