Method for efficiently synthesizing chiral sulfinamide

Abstract

The invention provides a method for efficiently synthesizing chiral sulfinamide, which specifically comprises the following steps: by taking aryl / alkenyl boric acid ester as a raw material, converting sulfinyl imide into chiral sulfinamide through asymmetric addition reaction catalyzed by nickel. The key point of the invention is that a chiral anion ligand is combined with bivalent nickel to generate a high-activity catalytic species with a stable structure and excellent catalytic performance, and a series of chiral sulfinamide compounds are constructed; the method has good substrate compatibility, aryl / heteroaryl and alkenyl borate can react, and enantioselectivity control is excellent; in a 5mmol scale amplification experiment, the dosage of the catalyst can be reduced to 0.5%, and the catalyst has a potential industrial application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of asymmetric catalysis, and particularly relates to a method for efficiently synthesizing chiral sulfenamide. Background Art

[0002] Sulfur-containing compounds have important application value in the fields of biomedicine, materials science, catalytic synthesis and food flavors (Chem. Rev. 2015, 115, 3036). For example, the proton pump inhibitor Esomeprazole and the drug Armodafinil for treating ADHD are both commercially available chiral sulfoxide small molecule drugs. Atuveciclib containing a chiral sulfoximine structure is a highly selective PTEFb / CDK9 inhibitor, and aminoacyl-tRNA synthetase inhibitors also contain chiral sulfenamide fragments (J. Am. Chem. Soc. 2020, 142, 10899). In addition, chiral sulfoxides, chiral sulfoximines, chiral sulfenamides, etc. are often used as ligands to participate in transition metal-catalyzed asymmetric reactions, and they themselves can also be used as organic small molecule catalysts (Chem. Rev. 2017, 117, 4147).

[0003] The exploration of sulfur sources and catalytic systems is the main research direction for the efficient construction of sulfur-centered chiral compounds. In 2017, Willis developed a stable sulfenyl imine reagent with good reactivity. It can react with organometallic reagents and then be further captured by amines to generate the corresponding sulfenyl imine amides after oxidation. However, the highly nucleophilic organometallic reagents limit the substrate range of the reaction and also bring inconvenience to the experimental operation (Angew. Chem. Int. Ed. 2017, 56, 14937). Subsequently, the research group used a racemic nickel catalyst to realize the catalytic version of the above reaction (J. Am. Chem. Soc. 2021, 143, 15576). Transition metal-catalyzed asymmetric transformation has the advantages of mild reaction conditions, high functional group compatibility, and effective control of the enantioselectivity of the reaction. Based on this type of sulfenyl imine reagent, the present invention has developed a class of chiral transition metal catalysts with excellent performance, and achieved efficient synthesis of chiral sulfenyl amides 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 sulfenyl imines not long ago, the wider substrate range, excellent chiral control and lower catalyst dosage of the present invention make it of great significance for the catalytic synthesis of complex chiral sulfenamides. Summary of the invention

[0004] In order to solve the above technical problems, the present invention discloses a method for efficiently synthesizing chiral sulfenamides. The specific synthesis method is: using aryl / alkenyl borate as a raw material, sulfenyl imine is converted into chiral sulfenamide through a nickel-catalyzed asymmetric addition reaction. The key of the present invention is to combine the chiral anion ligand with divalent nickel to generate a highly active catalytic species with stable structure and excellent catalytic performance, and construct a series of chiral sulfenyl amide compounds; the present invention has good substrate compatibility, aryl / heteroaryl and alkenyl borate can react, and the enantioselectivity is excellent; in the 5mmol (5mmol refers to sulfenyl imine II) scale scale scale experiment, the catalyst dosage can be reduced to 0.5% (molar percentage, based on 5mmol sulfenyl imine II), which has potential industrial application prospects.

[0005] The present invention forms a highly active catalyst in situ by using a chiral anionic ligand and cheap and readily available divalent nickel, and uses an easily prepared boric acid ester I as a nucleophilic reagent to catalyze the asymmetric addition reaction of the S=N bond in sulfinyl imine II at room temperature and nitrogen in the presence of an organic solvent and a base to synthesize the corresponding chiral sulfinamide compound. It is worth mentioning that a 5 mmol scale reaction can be achieved with a 0.5% catalyst dosage. The reaction conditions are mild, the substrate is highly universal, and a complex sulfur-containing chiral center compound can be constructed with high enantioselectivity.

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

[0007] A method for efficiently synthesizing chiral sulfenamides comprises the following steps: forming a high-activity catalyst in situ by a chiral anion ligand and divalent nickel, taking borate ester I as a nucleophilic reagent, catalyzing an asymmetric addition reaction of the S=N bond in sulfenyl imine II at room temperature and inert gas conditions in the presence of an organic solvent and an inorganic strong base, and synthesizing a chiral sulfenamide compound.

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

[0009] Further, the boric acid ester I is neopentyl glycol borate; preferably, the boric acid ester I is 4-toluene boronic acid neopentyl glycol ester, 4-trifluoromethylbenzene boronic acid neopentyl glycol ester, 4-cyanobenzene boronic acid neopentyl glycol ester, 4-vinylbenzene boronic acid neopentyl glycol ester, 3-thiophene boronic acid neopentyl glycol ester, 6-(4-morpholinyl)-3-pyridine boronic acid neopentyl glycol ester, quinoline-4-boric acid neopentyl glycol ester, N-methylindole-5-boric acid neopentyl glycol ester, One or more of pentyl glycol ester, 2-methylbenzothiazole-5-boric acid neopentyl glycol ester, pyrene-2-ylboric acid neopentyl glycol ester, 4-(1,2,2-triphenylphenyl)phenylboric acid neopentyl glycol ester, 1-phenylvinylboric acid neopentyl glycol ester, 4-(9-carbazolyl)phenylboric acid neopentyl glycol ester, cyclohexene-1-boric acid neopentyl glycol ester, cyclopentene-1-boric acid neopentyl glycol ester and E-phenylvinylboric acid neopentyl glycol ester.

[0010] Further, the sulfenyl imine II is , Tr = CPh3. The molar ratio of boric acid ester I to sulfinyl imine II is 1.0 to 1.5:1.0, for example, the molar ratio of boric acid ester I to sulfinyl imine 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, ethylene glycol dimethyl ether nickel bromide and diacetylacetonate nickel, preferably ethylene glycol dimethyl ether nickel bromide. The molar ratio of the divalent nickel catalyst to the sulfinyl imine II is 0.005-0.1:1-5, for example, the molar ratio of the divalent nickel catalyst to the sulfinyl imine 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 A kind of BuONa or MeONa. The molar ratio of the inorganic strong base to the sulfenyl imine 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 the sulfenyl imine II is 0.5~1.5mL:0.1mmol.

[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-quinolyl, a four-membered fused aromatic ring, a substituted olefin such as cyclohexenyl, cyclopentenyl or trans-2-phenylvinyl; Bneop is boronic acid neopentane glycol ester, and Tr is trityl; the above reaction route uses an anionic chiral ligand and divalent nickel to in situ generate a highly active catalyst, and in the presence of an additive sodium tert-butoxide, catalyzes the asymmetric addition reaction of boric ester to sulfinyl imine to obtain the corresponding chiral sulfinamide.

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

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

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

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

[0022] ;

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

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

[0025] Further, the reaction scheme of the present invention is as follows:

[0026] ;

[0027] Wherein R is a benzene ring, a substituted benzene ring, a heteroaromatic ring, a condensed aromatic ring, a monosubstituted olefin or a polysubstituted olefin. The above reaction route uses an anionic chiral ligand and divalent nickel to generate a highly active catalyst in situ, and in the presence of an additive sodium tert-butoxide, catalyzes the asymmetric addition reaction of boric acid ester to sulfinyl imine to obtain the corresponding chiral sulfinamide.

[0028] Specifically, the synthesis method of the chiral sulfenamide of the present invention, the specific preparation process is described as follows:

[0029] At room temperature and under nitrogen protection, NiBr2DME, ligand, 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, sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box, and stirred at room temperature until TLC showed that the raw materials had been consumed. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent to obtain the corresponding chiral sulfenamide.

[0030] Furthermore, the structural formula of the sulfur-containing chiral center 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 the present invention lies in the use of chiral anionic ligands coordinated with divalent nickel to generate highly active catalytic species with stable structure and excellent catalytic performance. Only 0.5% (molar percentage, based on sulfinyl imine II) of catalyst dosage can achieve a 5 mmol scale scale-up experiment with satisfactory yield and enantioselectivity; non-toxic and odorless sulfinyl imine is used as the sulfur source, the raw material preparation is simple and the use of malodorous thiols can be avoided; boric acid esters are widely available, with diverse structures and easy to synthesize. The present invention has mild reaction conditions, simple operation, high functional group compatibility, and excellent enantioselectivity control, providing a reliable scheme for the synthesis of chiral sulfinamides, and has potential process application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Example 1 Chiral sulfenamide product H-NMR spectrum. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other. In order to achieve the above-mentioned purpose, the present invention adopts the following technical solution:

[0036] Embodiment 1:

[0037]

[0038] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.1 mmol sodium tert-butoxide ( t After stirring for 10 minutes, 19 mL of TBME, 2.4 mmol of 4-tolueneboronic acid neopentyl glycol ester and 2.1 mmol of t BuONa, and continue stirring for 5 minutes. Finally, 2 mmol of sulfenyl imine II was added to the reaction solution, and the reaction bottle was quickly moved out of the glove box after tightening the lid, and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 80% and an ee value of 92%, as 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 This is the H NMR spectrum of the chiral sulfenamide product of Example 1.

[0044] Embodiment 2:

[0045]

[0046] At room temperature and under nitrogen protection, 0.025 mmol NiBr2DME, 0.03 mmol ligand L4, 0.1 mmol sodium tert-butoxide ( t After stirring for 10 minutes, 49 mL of TBME, 6 mmol of 4-trifluoromethylphenylboronic acid neopentyl glycol ester and 5.4 mmol of t BuONa, and continue stirring for 5 minutes. Finally, 5 mmol of sulfenyl imine II was added to the reaction solution, and the reaction bottle was quickly moved out of the glove box after tightening the lid, and stirred at room temperature for 24 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 78% and an ee value of 93%, as 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] Embodiment 3:

[0052]

[0053] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 4-cyanophenylboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 82% and an ee value of 95%, as 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] Embodiment 4:

[0059]

[0060] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 4-vinylbenzeneboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 71% and an ee value of 94%, as 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] Embodiment 5:

[0066]

[0067] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( t BuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 3-thiopheneboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 95% and an ee value of 93%, as 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] Embodiment 6:

[0073]

[0074] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 6-(4-morpholinyl)-3-pyridineboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 92% and an ee value of 92%, as 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] Embodiment 7:

[0080]

[0081] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of quinoline-4-boronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened, and the reaction bottle was quickly moved out of the glove box and heated at 60 o C for 24 hours. The reaction system was directly separated by preparative thin layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) as the developing solvent to obtain the corresponding chiral sulfenamide with a product yield of 40% and an ee value of 98% as 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] Embodiment 8:

[0087]

[0088] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of N-methylindole-5-boric acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 95% and an ee value of 93%, as 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] Embodiment 9:

[0094] ,

[0095] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 2-methylbenzothiazole-5-boronic acid neopentyl glycol ester was added to the above reaction solution and continued to stir for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 93% and an ee value of 93%, as 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] Embodiment 10:

[0101] ,

[0102] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of pyrene-2-ylboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 89% and an ee value of 97%, as 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] Embodiment 11:

[0108] ,

[0109] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 4-(1,2,2-triphenylethylene)phenylboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 82% and an ee value of 97%, as 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] Embodiment 12:

[0115] ,

[0116] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 1-phenylvinylboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 85% and an ee value of 96%, as 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] Embodiment 13:

[0122] ,

[0123] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of 4-(9-carbazolyl)phenylboronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 93% and an ee value of 92%, as 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] Embodiment 14:

[0129] ,

[0130] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of cyclohexene-1-boronic acid neopentyl glycol ester was added to the above reaction solution and continued to stir for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened, and the reaction bottle was quickly moved out of the glove box and heated at 60 o C for 24 hours. The reaction system was directly separated by preparative thin layer chromatography using a petroleum ether / acetone mixed solvent (v:v=3:1) as the developing solvent to obtain the corresponding chiral sulfenamide with a product yield of 58% and an ee value of 92% as 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] Embodiment 15:

[0136] ,

[0137] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of cyclopentene-1-boronic acid neopentyl glycol ester was added to the above reaction solution and stirring was continued for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1), and the corresponding chiral sulfenamide was obtained, with a product yield of 89% and an ee value of 95%, as 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] Embodiment 16:

[0143] ,

[0144] At room temperature and under nitrogen protection, 0.01 mmol NiBr2DME, 0.012 mmol ligand L4, 0.11 mmol sodium tert-butoxide ( tBuONa) and 1 mL of anhydrous tert-butyl methyl ether (TBME). After stirring for 10 minutes, 0.12 mmol of E-phenyl vinyl boric acid neopentyl glycol ester was added to the above reaction solution and continued to stir for 5 minutes. Finally, 0.1 mmol of sulfenyl imine II was added to the reaction solution, the lid was tightened and the reaction bottle was quickly moved out of the glove box and stirred at room temperature for 10 hours. The reaction system was directly separated by preparative thin layer chromatography, and the developing solvent was a petroleum ether / acetone mixed solvent (v:v=3:1) to obtain the corresponding chiral sulfenamide, with a product yield of 90% and an ee value of 86%, as 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] The present invention provides an efficient catalytic system for constructing chiral sulfenamides. It can be seen from the experimental results that the present invention can not only efficiently construct a series of chiral sulfenamide compounds with diverse structures under mild conditions, but also the highly active catalytic system enables the reaction to proceed smoothly at a lower catalyst loading.

Claims

1. A method for efficiently synthesizing chiral sulfenamides, characterized in that: The following steps are involved: A chiral sulfenamide compound is synthesized by in situ formation of highly active catalytic species by chiral anionic ligands and divalent nickel catalysts, and using borate ester I as a nucleophile, at room temperature and inert gas conditions, in the presence of an organic solvent and an inorganic strong base, catalyzing the asymmetric addition reaction of the S=N bond in sulfenyl imine II.

2. The method according to claim 1, characterized in that The boric acid ester I is neopentyl glycol borate; preferably, the boric acid ester I is 4-toluene boronic acid neopentyl glycol ester, 4-trifluoromethylbenzene boronic acid neopentyl glycol ester, 4-cyanobenzene boronic acid neopentyl glycol ester, 4-vinylbenzene boronic acid neopentyl glycol ester, 3-thiophene boronic acid neopentyl glycol ester, 6-(4-morpholinyl)-3-pyridine boronic acid neopentyl glycol ester, quinoline-4-boric acid neopentyl glycol ester, N-methylindole-5-boric acid neopentyl glycol ester, One or more of alcohol esters, 2-methylbenzothiazole-5-boric acid neopentyl glycol ester, pyrene-2-ylboric acid neopentyl glycol ester, 4-(1,2,2-triphenylphenyl)phenylboric acid neopentyl glycol ester, 1-phenylvinylboric acid neopentyl glycol ester, 4-(9-carbazolyl)phenylboric acid neopentyl glycol ester, cyclohexene-1-boric acid neopentyl glycol ester, cyclopentene-1-boric acid neopentyl glycol ester and E-phenylvinylboric acid neopentyl glycol ester.

3. The method according to claim 1, characterized in that The sulfenyl imine II is , Tr=CPh3; the molar ratio of borate ester I to sulfinyl imine II is 1.0~1.5:1.

0.

4. The method according to claim 1, characterized in that: The divalent nickel catalyst is one of nickel chloride, nickel bromide, ethylene glycol dimethyl ether nickel bromide and diacetylacetonate nickel, preferably ethylene glycol dimethyl ether nickel bromide; the molar ratio of the divalent nickel catalyst to the sulfenyl imine II is 0.005-0.1:1-5.

5. The method according to claim 1, characterized in that The anionic ligand is one of L1-L6, preferably L4, and the molar ratio of the chiral anionic ligand to the divalent nickel catalyst is 0.5-1.5:1-1.2; 。 6. The method according to claim 1, characterized in that The inorganic strong base is t One of BuONa or MeONa, the molar ratio of the inorganic strong base to the sulfenyl imine II is 0.5~1.5:

1.

7. The method according to claim 1, characterized in that 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 the sulfenyl imine II is 0.5-1.5 mL:0.1 mmol.

8. The method according to claim 1, characterized in that The reaction route of the method is as follows: ； R is phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-vinylphenyl, 3-thienyl, 3-pyridyl, 4-quinolyl, a four-membered fused aromatic ring, a substituted olefin such as cyclohexenyl, cyclopentenyl or trans-2-phenylvinyl; Bneop is a neopentyl glycol borate ester group, and Tr is a trityl group; the above reaction route uses an anionic chiral ligand and divalent nickel to in situ generate a highly active catalyst, and in the presence of an additive sodium tert-butoxide, catalyzes the asymmetric addition reaction of boric acid ester to sulfinyl imine to obtain the corresponding chiral sulfinamide.

9. The chiral sulfenamide prepared by the method according to any one of claims 1 to 7, characterized in that: The chiral sulfenamide is a sulfur-containing chiral center compound III, and the chiral sulfenamide structural formula includes one or more of the following structural formulas: 。

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