CN117186117A - Method for synthesizing optically active condensed ring piperidine compounds through asymmetric aza D-A reaction - Google Patents
Method for synthesizing optically active condensed ring piperidine compounds through asymmetric aza D-A reaction Download PDFInfo
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 36
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 28
- 150000002576 ketones Chemical class 0.000 claims abstract description 27
- 239000002808 molecular sieve Substances 0.000 claims abstract description 25
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006208 aza-Diels-Alder reaction Methods 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- KTQYWNARBMKMCX-UHFFFAOYSA-N tetraphenylene Chemical compound C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C2=C1 KTQYWNARBMKMCX-UHFFFAOYSA-N 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 78
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 26
- 239000003054 catalyst Substances 0.000 abstract description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 abstract 2
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 abstract 1
- 229910000085 borane Inorganic materials 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 238000003756 stirring Methods 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- 239000002904 solvent Substances 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- -1 aza dienes Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004768 lowest unoccupied molecular orbital Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- WGDRAVMHLDKGGA-UHFFFAOYSA-N prop-2-en-1-imine Chemical compound [CH2]C=C[NH] WGDRAVMHLDKGGA-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了不对称氮杂D‑A反应合成光学活性稠环哌啶类化合物的方法，属于有机化学领域。以β‑三氟甲基α,β‑不饱和酮1和环状N‑磺酰基酮亚胺2为原料，在手性联二萘酚类配体或四苯并环辛四烯类配体、硼烷四氢呋喃和分子筛存在下，有机溶剂中不对称氮杂Diels‑Alder反应，得到光学活性稠环哌啶类化合物3。本方法反应原料易得，催化剂结构简单，催化效率高，反应条件温和，后处理简单。The invention discloses a method for synthesizing optically active fused ring piperidine compounds through asymmetric aza D-A reaction, and belongs to the field of organic chemistry. Using β-trifluoromethyl α,β-unsaturated ketone 1 and cyclic N-sulfonylketimine 2 as raw materials, chiral binaphthyl ligands or tetrabenzocyclooctatetraene ligands In the presence of borane, tetrahydrofuran and molecular sieves, the asymmetric aza Diels-Alder reaction in organic solvents yields optically active fused ring piperidine compounds 3. The reaction raw materials of this method are easy to obtain, the catalyst structure is simple, the catalytic efficiency is high, the reaction conditions are mild, and the post-processing is simple.
Description
技术领域Technical Field
本发明属于有机化学中的不对称合成技术领域，具体涉及不对称氮杂Diels-Alder反应合成光学活性稠环哌啶类化合物的方法。The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and specifically relates to a method for synthesizing optically active condensed ring piperidine compounds by asymmetric nitrogen-doped Diels-Alder reaction.
背景技术Background Art
光学纯哌啶衍生物是构建天然产物与药物的重要中间体，立体选择性氮杂Diels-Alder反应是有机合成中构建手性哌啶衍生物最为高效的方法之一。Optically pure piperidine derivatives are important intermediates for the construction of natural products and drugs. The stereoselective aza-Diels-Alder reaction is one of the most efficient methods for constructing chiral piperidine derivatives in organic synthesis.
由富电子亲双烯体与缺电子氮杂二烯参与不对称反电子需求氮杂Diels-Alder反应为四氢喹啉和二氢吡啶衍生物合成提供了一条有效途径。发展对映选择性反电子需求氮杂Diels-Alder反应，常采用策略是通过Lewis酸催化或者有机催化，来降低双烯体LUMO轨道能量。The asymmetric reverse electron demanding aza Diels-Alder reaction involving electron-rich dienophiles and electron-deficient aza dienes provides an effective route for the synthesis of tetrahydroquinoline and dihydropyridine derivatives. To develop enantioselective reverse electron demanding aza Diels-Alder reactions, a common strategy is to reduce the LUMO orbital energy of the diene through Lewis acid catalysis or organic catalysis.
2008年，陈应春教授课题组首次报道了以廉价易得手性α,α-二芳基脯氨醇三甲基硅醚为催化剂，实现了N-磺酰基-1-氮杂-1,3-丁二烯与醛反电子需求不对称氮杂Diels-Alder反应，得到多种具有三个连续手性中心光学活性哌啶类化合物(Angew.Chem.Int.Ed.2008,47,9971-9974)。随后，该课题组又利用这种策略实现了多种含氮杂环不对称合成(Angew.Chem.,Int.Ed.2009,48,5474-5477；Chem.Commun.2010,46,2665-2667)。2013年和2014年，该课题组报道了有机胺催化糖精衍生1-氮杂丁二烯与环状2,5-二烯酮或者α,β-不饱和醛之间不对称氮杂Diels-Alder反应，以高对映选择性得到稠环哌啶类化合物(Angew.Chem.,Int.Ed.2013,52,14173-14176；Org.Lett.2014,16,3986-3989.)。目前为止光学活性含三氟甲基的稠环的哌啶衍生物的合成方法还没有被报道。In 2008, Professor Chen Yingchun's research group first reported the use of cheap and readily available chiral α,α-diarylprolinol trimethylsilyl ether as a catalyst to achieve the asymmetric aza-Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadiene with aldehydes to obtain a variety of optically active piperidine compounds with three consecutive chiral centers (Angew. Chem. Int. Ed. 2008, 47, 9971-9974). Subsequently, the research group used this strategy to achieve asymmetric synthesis of a variety of nitrogen-containing heterocycles (Angew. Chem., Int. Ed. 2009, 48, 5474-5477; Chem. Commun. 2010, 46, 2665-2667). In 2013 and 2014, the research group reported the asymmetric aza-Diels-Alder reaction between saccharin-derived 1-azabutadiene and cyclic 2,5-dienones or α,β-unsaturated aldehydes catalyzed by organic amines to obtain fused-ring piperidines with high enantioselectivity (Angew. Chem., Int. Ed. 2013, 52, 14173-14176; Org. Lett. 2014, 16, 3986-3989.). So far, the synthesis of optically active trifluoromethyl-containing fused-ring piperidine derivatives has not been reported.
由于稠环哌啶类化合物在药物化学中的潜在应用价值，因此开发可靠的合成策略以获得结构更加复杂、功能更多样的稠环的哌啶类化合物，特别是光学活性的稠环的哌啶衍生物的合成，将对药物开发具有重大的实用价值。Due to the potential application value of fused-ring piperidine compounds in medicinal chemistry, developing reliable synthetic strategies to obtain fused-ring piperidine compounds with more complex structures and more diverse functions, especially the synthesis of optically active fused-ring piperidine derivatives, will have great practical value for drug development.
发明内容Summary of the invention
为了克服上述技术缺陷，本发明提供了不对称氮杂Diels-Alder反应合成光学活性稠环哌啶类化合物的方法。采用β-三氟甲基α,β-不饱和酮与环状N-磺酰基酮亚胺作为原料，在手性联萘酚类化合物或四苯并环辛四烯类化合物作为配体，硼烷四氢呋喃和分子筛存在下，经过不对称氮杂Diels-Alder反应，以高收率、高非对映选择性、高对映选择性一步合成光学活性含三氟甲基稠环的哌啶衍生物。In order to overcome the above technical defects, the present invention provides a method for synthesizing optically active fused ring piperidine compounds by asymmetric aza-Diels-Alder reaction. β-trifluoromethyl α,β-unsaturated ketone and cyclic N-sulfonyl ketimine are used as raw materials, chiral binaphthol compounds or tetrabenzocyclooctatetraene compounds are used as ligands, borane tetrahydrofuran and molecular sieves are present, and an asymmetric aza-Diels-Alder reaction is performed to synthesize optically active trifluoromethyl fused ring piperidine derivatives in one step with high yield, high diastereoselectivity and high enantioselectivity.
本发明所述不对称氮杂Diels-Alder反应合成光学活性稠环哌啶类化合物的方法，包括如下步骤：以β-三氟甲基α,β-不饱和酮1和环状N-磺酰基酮亚胺2为原料，在手性联萘酚类化合物作为配体，硼烷-四氢呋喃和分子筛存在下，有机溶剂中反应得到含三氟甲基稠环的哌啶类化合物3。The method for synthesizing optically active fused ring piperidine compounds by asymmetric aza-Diels-Alder reaction of the present invention comprises the following steps: using β-trifluoromethyl α,β-unsaturated ketone 1 and cyclic N-sulfonyl ketimine 2 as raw materials, reacting in an organic solvent in the presence of a chiral binaphthol compound as a ligand, borane-tetrahydrofuran and a molecular sieve to obtain a piperidine compound 3 containing a trifluoromethyl fused ring.
反应方程式如下：The reaction equation is as follows:
其中：RF选自三氟甲基或者五氟乙基；R1选自苯基、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基或硝基；R2选自苯基、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基或硝基；R3选自苯基、C1-C4烷基取代苯基、C1-C4烷氧基取代苯基、卤素取代苯基、三氟甲基取代苯基、萘基、呋喃基、噻吩基或叔丁基。Wherein: RF is selected from trifluoromethyl or pentafluoroethyl; R1 is selected from phenyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl or nitro; R2 is selected from phenyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl or nitro; R3 is selected from phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, naphthyl, furanyl, thienyl or tert-butyl.
进一步地，在上述技术方案中，所述手性联二萘酚类化合物为Further, in the above technical solution, the chiral binaphthol compound is
R＝H、Cl、Br、I、Me、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4、 R＝H, Cl, Br, I, Me, Ph, 3,5-Me 2 C 6 H 4 , 3,5-(MeO) 2 C 6 H 4 ,
3,5-(CF3)2C6H4；优选条件下，手性联二萘酚类配体为如下三种：3,5-(CF 3 ) 2 C 6 H 4 ; Under preferred conditions, the chiral binaphthol ligands are the following three:
进一步地，在上述技术方案中，所述手性四苯并环辛四烯酚类化合物为R＝H、F、Cl、Br、I、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4、3,5-(CF3)2C6H4；优选条件下，手性四苯并环辛四烯酚类配体为如下两种：Furthermore, in the above technical solution, the chiral tetrabenzocyclooctatetraenol compound is R＝H, F, Cl, Br, I, Ph, 3,5-Me 2 C 6 H 4 , 3,5-(MeO) 2 C 6 H 4 , 3,5-(CF 3 ) 2 C 6 H 4 ; under preferred conditions, the chiral tetrabenzocyclooctatetraenol ligands are the following two:
进一步地，在上述技术方案中，所述环状N-磺酰基酮亚胺2、β-三氟甲基α,β-不饱和酮1、手性配体与硼烷-四氢呋喃摩尔比为1:1-2:0.0012-0.24:0.001-0.20。Furthermore, in the above technical solution, the molar ratio of the cyclic N-sulfonyl ketimine 2, β-trifluoromethyl α, β-unsaturated ketone 1, chiral ligand and borane-tetrahydrofuran is 1:1-2:0.0012-0.24:0.001-0.20.
进一步地，在上述技术方案中，在上述技术方案中，所述有机溶剂选自甲苯、三氟甲苯、邻二甲苯、间二甲苯、氯苯、1,2-二氯乙烷或甲基叔丁基醚。优选反应溶剂为氯苯。Furthermore, in the above technical solution, in the above technical solution, the organic solvent is selected from toluene, trifluorotoluene, o-xylene, m-xylene, chlorobenzene, 1,2-dichloroethane or methyl tert-butyl ether. Preferably, the reaction solvent is chlorobenzene.
进一步地，在上述技术方案中，反应温度为25-80℃，优选60℃。Furthermore, in the above technical solution, the reaction temperature is 25-80°C, preferably 60°C.
进一步地，在上述技术方案中，所述分子筛选自或分子筛。Further, in the above technical solution, the molecular screening or Molecular sieve.
进一步地，在上述技术方案中，整个反应过程在氮气或氩气下进行，优选氮气。Furthermore, in the above technical solution, the entire reaction process is carried out under nitrogen or argon, preferably nitrogen.
发明有益效果：Beneficial effects of the invention:
本发明反应原料易得，反应条件温和，后处理简单，无需金属催化剂参与，手性联二萘酚类配体可回收再利用，产物收率、对映选择性良好至优秀。The reaction raw materials of the invention are easily available, the reaction conditions are mild, the post-treatment is simple, no metal catalyst is required, the chiral binaphthol ligand can be recycled and reused, and the product yield and enantioselectivity are good to excellent.
具体实施方式DETAILED DESCRIPTION
实施例1条件优化实验Example 1 Condition Optimization Experiment
aβ-三氟甲基α,β-不饱和酮1a(0.12mmol)、环状N-磺酰基酮亚胺2a(0.1mmol)、BH3·THF(0.01mmol,10mol％)、手性配体(0.012mmol,12mol％)、分子筛(100mg)、1.0mL无水溶剂在N2气氛下,dr通过氢核磁共振谱分析,dr>20:1；b分离产率；cee通过HPLC手性柱分析；d40℃；eBH3·THF(0.005mmol,5mol％),L4(0.006mmol,6mol％)；fBH3·THF(0.0025mmol,2.5mol％),L4(0.003mmol,3mol％)；gβ-三氟甲基α,β-不饱和酮1a(0.24mmol)、环状N-磺酰基酮亚胺2a(0.2mmol)、BH3·THF(0.001mmol,1mol％),L4(0.0012mmol,1.2mol％)； a β-trifluoromethyl α,β-unsaturated ketone 1a (0.12 mmol), cyclic N-sulfonyl ketimine 2a (0.1 mmol), BH 3 ·THF (0.01 mmol, 10 mol%), chiral ligand (0.012 mmol, 12 mol%), molecular sieves (100 mg), 1.0 mL of anhydrous solvent under N 2 atmosphere, dr was analyzed by hydrogen nuclear magnetic resonance spectrum, dr>20:1; b separation yield; c ee was analyzed by HPLC chiral column; d 40°C; e BH 3 ·THF (0.005 mmol, 5 mol%), L4 (0.006 mmol, 6 mol%); f BH 3 ·THF (0.0025 mmol, 2.5 mol%), L4 (0.003 mmol, 3 mol%); g β-trifluoromethyl α, β-unsaturated ketone 1a (0.24 mmol), cyclic N-sulfonyl ketimine 2a (0.2 mmol), BH 3 ·THF (0.001 mmol, 1 mol%), L4 (0.0012 mmol, 1.2 mol%);
在反应条件筛选过程中，考察了不同手性配体对反应的影响(标号1-9)，确定了L4为最佳配体。接着考察了不同溶剂对反应影响(标号10-18)，最终选用氯苯作溶剂。同时考察了温度和催化剂用量对反应的影响(标号19-22)，最终选择反应温度为60℃，催化剂用量为2.5mol％。反应条件典型操作如下(以标号21为例)：During the reaction condition screening process, the effects of different chiral ligands on the reaction were investigated (labels 1-9), and L4 was determined to be the best ligand. Then the effects of different solvents on the reaction were investigated (labels 10-18), and chlorobenzene was finally selected as the solvent. At the same time, the effects of temperature and catalyst dosage on the reaction were investigated (labels 19-22), and the reaction temperature was finally selected to be 60°C and the catalyst dosage was 2.5 mol%. The typical operation of the reaction conditions is as follows (taking label 21 as an example):
在氮气保护下，向Schlenk管(无水无氧处理，下同)中加入100mg分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到46.2mg白色固体3aa，收率95％。mp 204-205℃；HPLC(Daicel Chiralpak IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.8min,tR(minor)＝11.5min,99.9:0.1e.r.,>99％ee；[α]D 33＝+31.1(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ11.68(s,1H),7.90(d,J＝7.8Hz,1H),7.79-7.62(m,3H),7.26-7.27(m,1H),7.17-7.13(m,4H),7.09-7.07(m,2H),6.77(d,J＝7.8Hz,1H),6.54(t,J＝7.8Hz,1H),5.91(s,1H),4.74(q,J＝7.2Hz,1H),4.55(d,J＝6.0Hz,1H),4.33-4.23(m,1H)；13C{1H}NMR(150MHz,CDCl3)δ201.6,162.6,138.6,136.8,133.7,131.9,131.3,130.5,129.5,129.3,128.9,128.7,128.0,124.1(q,J＝282.0Hz),121.7,121.3,119.5,118.8,118.6,100.3,52.4(d,J＝33.0Hz),39.3,39.2；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd forC25H18F3NO4SNa 508.0801；Found 508.0798.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 46.2 mg of white solid 3aa, with a yield of 95%. mp 204-205°C; HPLC (Daicel Chiralpak IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=8.8 min, t R (minor)=11.5 min, 99.9:0.1 er,>99% ee; [α] D 33 =+31.1 (c 1.0, CHCl 3 ); 1 H NMR (600 MHz, CDCl 3 )δ11.68(s,1H),7.90(d,J＝7.8Hz,1H),7.79-7.62(m,3H),7.26-7.27(m,1H),7.17-7.13(m,4H),7.09-7.07(m,2H),6.77(d,J＝7.8Hz,1H),6.54(t,J =7.8Hz, 1H), 5.91 (s, 1H), 4.74 (q, J = 7.2Hz, 1H), 4.55 (d, J = 6.0Hz, 1H), 4.33-4.23 (m, 1H); 13 C{ 1 H} NMR (150MHz, CDCl 3 )δ201.6,162.6,138.6,136.8,133.7,131.9,131.3,130.5,129.5,129.3,128.9,128.7,128.0,124.1(q,J=282.0Hz),121.7,121.3,119.5,118.8, 118.6, 100.3, 52.4 (d, J = 33.0Hz), 39.3, 39.2; 19 F{ 1 H} NMR (376MHz, CDCl 3 ) δ-72.0; HRMS (ESI) m/z: [M+Na] + Calcd forC 25 H 18 F 3 NO 4 SNa 508.0801; Found 508.0798 .
实施例2Example 2
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1b(27.6mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到47.5mg白色固体3ba，收率95％。mp 253-255℃；HPLC(Daicel Chiralpak IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝9.3min,tR(minor)＝11.2min,99.9:0.1e.r.,>99％ee；[α]D 33＝+41.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ12.19(s,1H),7.82(d,J＝8.0Hz,1H),7.71-7.53(m,3H),7.10-7.05(m,5H),6.89(d,J＝8.8Hz,1H),6.14(d,J＝2.0Hz,1H),6.00(d,J＝2.0,9.2Hz,1H),5.83(d,J＝1.6Hz,1H),4.66(q,J＝7.6Hz,1H),4.33(d,J＝6.0Hz,1H),4.23-4.22(m,1H),3.66(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ201.4,160.6,138.8,137.9,133.7,132.0,131.3,130.5,129.4,129.3,128.73,128.68,128.0,127.8,124.1(q,J＝282.0Hz),121.7,121.3,119.2,118.2,100.1,52.6(q,J＝32.0Hz),39.53,39.49,20.4；19F{1H}NMR(376MHz,CDCl3)δ-71.9；HRMS(ESI)m/z:[M+Na]+Calcd for C26H20F3NO4SNa 522.0957；Found 522.0952.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1b (27.6 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 47.5 mg of white solid 3ba, with a yield of 95%. mp 253-255°C; HPLC (Daicel Chiralpak IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=9.3 min, t R (minor)=11.2 min, 99.9:0.1 er,>99% ee; [α] D 33 =+41.6 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ12.19(s,1H),7.82(d,J＝8.0Hz,1H),7.71-7.53(m,3H),7.10-7.05(m,5H),6.89(d,J＝8.8Hz,1H),6.14(d,J＝2.0Hz,1H),6.00(d,J＝2.0,9.2Hz,1H), 5.83 (d, J＝1.6Hz, 1H), 4.66 (q, J＝7.6Hz, 1H), 4.33 (d, J＝6.0Hz, 1H), 4.23-4.22 (m, 1H), 3.66 (s, 3H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ201.4,160.6,138.8,137.9,133.7,132.0,131.3,130.5,129.4,129.3,128.73,128.68,128.0,127.8,124.1(q,J＝282.0Hz),121.7,121.3,119.2,118.2,100.1,52.6(q,J＝32.0Hz),39.53,39.49,20.4； 19 F{ 1 H}NMR(376MHz,CDCl 3 )δ-71.9；HRMS(ESI)m/z:[M+Na] + Calcd for C 26 H 20 F 3 NO 4 SNa 522.0957；Found 522.0952.
实施例3Example 3
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(6.4mg,0.12mmol)、BH3·THF(10.0μL,0.01mmol)、β-三氟甲基α,β-不饱和酮1c(29.5mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/3)分离纯化得到42.7mg白色固体3ca，收率83％。mp 242-243℃；HPLC(Daicel Chiralpak IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝11.1min,tR(minor)＝16.1min,99.9:0.1e.r.,>99％ee；[α]D 32＝+56.3(c 0.25,CHCl3)；1H NMR(400MHz,CDCl3)δ12.26(s,1H),7.91-7.61(m,4H),7.18-7.09(m,5H),6.96(d,J＝9.2Hz,1H),6.21(d,J＝2.4Hz,1H),6.07(dd,J＝2.8,9.2Hz,1H),5.91(d,J＝2.8Hz,1H),4.74(q,J＝7.6Hz,1H),4.40(d,J＝6.4Hz,1H),4.30(dd,J＝2.4,6.0Hz,1H),3.73(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ199.2,166.3,165.8,138.9,133.7,131.9,131.2,131.1,130.5,129.3,128.8,128.7,128.0,124.1(q,J＝282.0Hz),121.7,121.3,113.8,108.0,100.7,100.6,55.7,52.5(q,J＝32.0Hz),39.3,39.1；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd forC26H20F3NO5SNa 538.0906；Found 538.0906.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (6.4 mg, 0.12 mmol), BH 3 ·THF (10.0 μL, 0.01 mmol), β-trifluoromethyl α, β-unsaturated ketone 1c (29.5 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/3) to obtain 42.7 mg of white solid 3ca, with a yield of 83%. mp 242-243°C; HPLC (Daicel Chiralpak IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=11.1 min, t R (minor)=16.1 min, 99.9:0.1 er,>99% ee; [α] D 32 =+56.3 (c 0.25, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ12.26(s,1H),7.91-7.61(m,4H),7.18-7.09(m,5H),6.96(d,J＝9.2Hz,1H),6.21(d,J＝2.4Hz,1H),6.07(dd,J＝2.8,9.2Hz,1H),5.91(d,J＝2.8Hz,1H), 4.74 (q, J＝7.6Hz, 1H), 4.40 (d, J＝6.4Hz, 1H), 4.30 (dd, J＝2.4, 6.0Hz, 1H), 3.73 (s, 3H); 13 C{ 1 H} NMR (100MHz, CDCl 3 ) δ199.2,166.3,165.8,138.9,133.7,131.9,131.2,131.1,130.5,129.3,128.8,128.7,128.0,124.1 (q, J ＝ 282.0Hz ) , 121.7,121.3,113.8,108.0 , Found 538.0906.
实施例4Example 4
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1d(28.1mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到46.7mg白色固体3da，收率93％。mp 242-243℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝7.6min,tR(minor)＝10.3min,99.9:0.1e.r.,>99％ee；[α]D 31＝+37.0(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ12.02(s,1H),7.90(d,J＝7.6Hz,1H),7.79-7.62(m,3H),7.15-7.03(m,6H),6.44(dd,J＝2.0,10.0Hz,1H),6.26-6.21(m,1H),5.88(d,J＝2.4Hz,1H),4.74(q,J＝7.2Hz,1H),4.42(d,J＝6.0Hz,1H),4.34-4.33(m,1H)；13C{1H}NMR(100MHz,CDCl3)δ200.5,167.5(d,J＝257.0Hz),165.1(d,J＝15.0Hz),138.5,133.8,132.1,132.0(d,J＝4.0Hz),131.2,130.6,129.2,129.0,128.6,128.2,124.0(q,J＝282.0Hz),121.7,121.3,116.8,107.2(d,J＝23.0Hz),105.0(d,J＝23.0Hz),99.9,52.3(q,J＝32.0Hz),39.5,39.4；19F{1H}NMR(376MHz,CDCl3)δ-72.0,-98.0；HRMS(ESI)m/z:[M+Na]+Calcd for C25H17F4NO4SNa 526.0707；Found526.0707.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1d (28.1 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 46.7 mg of white solid 3da, with a yield of 93%. mp 242-243°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=7.6 min, t R (minor)=10.3 min, 99.9:0.1 er,>99% ee; [α] D 31 =+37.0 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ12.02(s,1H),7.90(d,J＝7.6Hz,1H),7.79-7.62(m,3H),7.15-7.03(m,6H),6.44(dd,J＝2.0,10.0Hz,1H),6.26-6.21(m,1H),5.88(d,J＝2.4Hz,1H),4 .74(q,J＝7.2Hz,1H),4.42(d,J＝6.0Hz,1H),4.34-4.33(m,1H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ200.5,167.5(d,J＝257.0Hz),165.1(d,J＝15.0Hz),138.5,133.8,132.1,132.0(d,J＝4.0Hz),131.2,130.6,129.2,129.0,128.6,128.2,124.0(q,J =282.0Hz), 121.7, 121.3, 116.8, 107.2 (d, J = 23.0Hz), 105.0 (d, J = 23.0Hz), 99.9, 52.3 (q, J = 32.0Hz), 39.5, 39.4; 19 F{ 1 H} NMR (376MHz, CDCl 3 )δ-72.0,-98.0; HRMS(ESI)m/z:[M+Na] + Calcd for C 25 H 17 F 4 NO 4 SNa 526.0707; Found526.0707.
实施例5Example 5
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1e(30.1mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到51.7mg白色固体3ea，收率91％。mp 232-233℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝7.3min,tR(minor)＝8.9min,99.9:0.1e.r.,>99％ee；[α]D 33＝+68.9(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.58(s,1H),7.92-7.65(m,4H),7.20-7.09(m,6H),6.88(d,J＝2.4Hz,1H),6.72(d,J＝8.8Hz,1H),5.87(d,J＝2.8Hz,1H),4.74(q,J＝7.2Hz,1H),4.40-4.35(m,2H)；13C{1H}NMR(100MHz,CDCl3)δ201.1,160.9,138.3,136.6,133.8,132.2,131.2,130.7,129.1,129.0,128.9,128.5,128.4,124.0(q,J＝282.0Hz),123.4,121.8,121.4,120.1,120.0,99.4,52.3(q,J＝32.0Hz),39.7,39.6；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd forC25H17ClF3NO4S Na 542.0411；Found 542.0411.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1e (30.1 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 51.7 mg of white solid 3ea, with a yield of 91%. mp 232-233°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=7.3 min, t R (minor)=8.9 min, 99.9:0.1 er,>99% ee; [α] D 33 =+68.9 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.58(s,1H),7.92-7.65(m,4H),7.20-7.09(m,6H),6.88(d,J＝2.4Hz,1H),6.72(d,J＝8.8Hz,1H),5.87(d,J＝2.8Hz,1H),4.74(q,J＝7.2Hz,1H),4.40- 4.35(m,2H); 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ201.1,160.9,138.3,136.6,133.8,132.2,131.2,130.7,129.1,129.0,128.9,128.5,128.4,124.0(q,J＝282.0Hz),123.4,121.8,121.4,120.1, 120.0, 99.4, 52.3 (q, J=32.0Hz), 39.7, 39.6; 19 F{ 1 H} NMR (376MHz, CDCl 3 ) δ-72.0; HRMS (ESI) m/z: [M+Na] + Calcd forC 25 H 17 ClF 3 NO 4 S Na 542.0411; Found 542.0411 .
实施例6Example 6
在氮气保护下，向Schlenk管中加入100mg分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1f(35.4mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到56.4mg白色固体3fa，收率99％。mp 235-237℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.0min,tR(minor)＝10.3min,99.9:0.1e.r.,>99％ee；[α]D 33＝+41.3(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.76(s,1H),7.90(d,J＝8.0Hz,1H),7.79-7.62(m,3H),7.18-7.15(m,5H),6.97(d,J＝1.2Hz,1H),6.88(d,J＝8.4Hz,1H),6.67-6.65(m,1H),5.88(d,J＝1.6Hz,1H),4.72(q,J＝7.2Hz,1H),4.43(d,J＝2.4Hz,1H),4.33-4.32(m,1H)；13C{1H}NMR(100MHz,CDCl3)δ201.3,162.8,138.4,133.8,132.0,131.3,131.2,130.6,130.4,129.2,129.1,128.6,128.3,124.0(q,J＝281.0Hz),122.3,121.74,121.72,121.4,118.5,99.9,52.3(q,J＝32.0Hz),39.5,39.4；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd for C25H17BrF3NO4SNa585.9906；Found 585.9904.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1f (35.4 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketone imine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 56.4 mg of white solid 3fa, with a yield of 99%. mp 235-237°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=8.0 min, t R (minor)=10.3 min, 99.9:0.1 er,>99% ee; [α] D 33 =+41.3 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.76(s,1H),7.90(d,J＝8.0Hz,1H),7.79-7.62(m,3H),7.18-7.15(m,5H),6.97(d,J＝1.2Hz,1H),6.88(d,J＝8.4Hz,1H),6.67-6.65(m,1H),5.88(d ,J＝1.6Hz,1H),4.72(q,J＝7.2Hz,1H),4.43(d,J＝2.4Hz,1H),4.33-4.32(m,1H); 13 C{ 1 H}NMR (100MHz, CDCl 3 ) δ201.3,162.8,138.4,133.8,132.0,131.3,131.2,130.6,130.4,129.2,129.1,128.6,128.3,124.0 (q, J ＝ 281.0Hz ) , 122.3,121.74,121.72,121 . Found 585.9904.
实施例7Example 7
在氮气保护下，向Schlenk管中加入100mg分子筛、配体L4(6.4mg,0.012mmol)、BH3·THF(10.0μL,0.01mmol)、β-五氟乙基α,β-不饱和酮1g(31.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到34.2mg白色固体3ga，收率64％。mp 214-216℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝80:20,flow rate 1.0mL/min,λ＝254nm)tR(major)＝7.7min,tR(minor)＝9.5min,99.9:0.1e.r.,>99％ee；[α]D 31＝+14.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.64(s,1H),7.89(d,J＝7.6Hz,1H),7.80-7.61(m,3H),7.31-7.27(m,1H),7.16-7.07(m,6H),6.79(d,J＝8.4Hz,1H),6.60-6.56(m,1H),5.95(d,J＝2.0Hz,1H),4.83(dd,J＝8.8,18.4Hz,1H),4.59(d,J＝6.0Hz,1H),4.35-4.33(m,1H)；13C{1H}NMR(100MHz,CDCl3)δ201.1,162.8,138.6,136.8,133.7,132.1,131.2,130.5,129.5,129.0,128.9,128.6,128.0,121.7,121.3,119.4,118.9,118.8,100.7,51.6(t,J＝23.0Hz),38.99,38.95；19F{1H}NMR(376MHz,CDCl3)δ-80.3,-110.1(d,J＝278.2Hz),-121.7(d,J＝278.2Hz)；HRMS(ESI)m/z:[M+Na]+Calcd for C26H18F5NO4SNa 558.0769；Found 558.0760.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (6.4 mg, 0.012 mmol), BH 3 ·THF (10.0 μL, 0.01 mmol), β-pentafluoroethyl α, β-unsaturated ketone 1 g (31.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 34.2 mg of white solid 3ga, with a yield of 64%. mp 214-216°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=80:20, flow rate 1.0 mL/min, λ=254 nm) t R (major)=7.7 min, t R (minor)=9.5 min, 99.9:0.1 er,>99% ee; [α] D 31 =+14.6 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.64(s,1H),7.89(d,J＝7.6Hz,1H),7.80-7.61(m,3H),7.31-7.27(m,1H),7.16-7.07(m,6H),6.79(d,J＝8.4Hz,1H),6.60-6.56(m,1H),5.95(d,J＝ 2.0Hz, 1H), 4.83 (dd, J＝8.8, 18.4Hz, 1H), 4.59 (d, J＝6.0Hz, 1H), 4.35-4.33 (m, 1H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ201.1,162.8,138.6,136.8,133.7,132.1,131.2,130.5,129.5,129.0,128.9,128.6,128.0,121.7,121.3,119.4,118.9,118.8,100.7,51.6(t , J＝23.0Hz), 38.99, 38.95; 19 F{ 1 H} NMR (376MHz, CDCl 3 ) δ -80.3, -110.1 (d, J＝278.2Hz), -121.7 (d, J＝278.2Hz); HRMS (ESI) m/z: [M+Na] + Calcd for C 26 H 18 F 5 NO 4 SNa 558.0769; Found 558.0760.
实施例8Example 8
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(6.4mg,0.012mmol)、BH3·THF(10.0μL,0.01mmol)、β-五氟乙基α,β-不饱和酮1h(33.6mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到27.5mg白色固体3ha，收率50％。mp 196-198℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝80:20,flow rate1.0mL/min,λ＝254nm)tR(major)＝8.5min,tR(minor)＝9.3min,99.9:0.1e.r.,>99％ee；[α]D 33＝+21.9(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.48(s,1H),7.89(d,J＝8.0Hz,1H),7.79-7.61(m,3H),7.17-7.09(m,6H),6.76(s,1H),6.69(d,J＝8.4Hz,1H),5.95(d,J＝2.0Hz,1H),4.85(dd,J＝8.0,18.4Hz,1H),4.55(d,J＝5.6Hz,1H),4.34-4.33(m,1H),2.08(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ200.7,160.8,138.7,138.0,133.7,132.1,131.2,130.5,129.5,128.8,128.6,128.0,127.9,121.7,121.3,119.0,118.5,100.6,51.9(t,J＝23.0Hz),39.4,39.0(d,J＝5.0Hz),20.5；19F{1H}NMR(376MHz,CDCl3)δ-80.3,-110.0(d,J＝274.5Hz),-121.7(d,J＝274.5Hz)；HRMS(ESI)m/z:[M+Na]+Calcd for C27H20F5NO4SNa 572.0925；Found 572.0920.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (6.4 mg, 0.012 mmol), BH 3 ·THF (10.0 μL, 0.01 mmol), β-pentafluoroethyl α, β-unsaturated ketone 1h (33.6 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketone imine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 27.5 mg of white solid 3ha, with a yield of 50%. mp 196-198°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=80:20, flow rate 1.0 mL/min, λ=254 nm) t R (major)=8.5 min, t R (minor)=9.3 min, 99.9:0.1 er,>99% ee; [α] D 33 =+21.9 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.48(s,1H),7.89(d,J＝8.0Hz,1H),7.79-7.61(m,3H),7.17-7.09(m,6H),6.76(s,1H),6.69(d,J＝8.4Hz,1H),5.95(d,J＝2.0Hz,1H),4.85(dd,J＝8.0 ,18.4Hz,1H),4.55(d,J＝5.6Hz,1H),4.34-4.33(m,1H),2.08(s,3H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ200.7,160.8,138.7,138.0,133.7,132.1,131.2,130.5,129.5,128.8,128.6,128.0,127.9,121.7,121.3,119.0,118.5,100.6,51.9(t,J＝23. 0Hz), 39.4, 39.0 (d, J = 5.0Hz), 20.5; 19 F{ 1 H} NMR (376MHz, CDCl 3 ) δ-80.3, -110.0 (d, J = 274.5Hz), -121.7 (d, J = 274.5Hz); HRMS (ESI) m/z: [M+Na] + Calcd for C 27 H 20 F 5 NO 4 SNa 572.0925; Found 572.0920.
实施例9Example 9
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(6.4mg,0.012mmol)、BH3·THF(10.0μL,0.01mmol)、β-五氟乙基α,β-不饱和酮1i(41.4mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到40.0mg白色固体3ia，收率65％。mp 199-201℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝80:20,flow rate 1.0mL/min,λ＝254nm)tR(major)＝7.0min,tR(minor)＝8.6min,99.6:0.4e.r.,>99％ee；[α]D 33＝+59.0(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.74(s,1H),7.89(d,J＝7.6Hz,1H),7.80-7.62(m,3H),7.20-7.13(m,5H),6.98(d,J＝2.0Hz,1H),6.87(d,J＝8.8Hz,1H),6.70(dd,J＝2.0,8.8Hz,1H),5.92(d,J＝2.4Hz,1H),4.81(dd,J＝8.4,18.4Hz,1H),4.47(d,J＝6.4Hz,1H),4.33(dd,J＝2.8,6.0Hz,1H)；13C{1H}NMR(100MHz,CDCl3)δ200.6,162.9,138.4,133.8,132.2,131.4,131.1,130.6,129.8,129.4,129.0,128.5,128.2,122.4,121.9,121.7,121.3,118.3,100.3,51.5(t,J＝23.0Hz),39.2,39.0(d,J＝4.0Hz)；19F{1H}NMR(376MHz,CDCl3)δ-80.3,-110.1(d,J＝274.5Hz),-121.7(d,J＝278.2Hz)；HRMS(ESI)m/z:[M+Na]+Calcd for C26H17BrF5NO4SNa 635.9874；Found635.9878.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (6.4 mg, 0.012 mmol), BH 3 ·THF (10.0 μL, 0.01 mmol), β-pentafluoroethyl α, β-unsaturated ketone 1i (41.4 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 40.0 mg of white solid 3ia, with a yield of 65%. mp 199-201°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=80:20, flow rate 1.0 mL/min, λ=254 nm) t R (major)=7.0 min, t R (minor)=8.6 min, 99.6:0.4 er,>99% ee; [α] D 33 =+59.0 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.74(s,1H),7.89(d,J＝7.6Hz,1H),7.80-7.62(m,3H),7.20-7.13(m,5H),6.98(d,J＝2.0Hz,1H),6.87(d,J＝8.8Hz,1H),6.70(dd,J＝2.0,8.8Hz,1H),5 .92 (d, J＝2.4Hz, 1H), 4.81 (dd, J＝8.4, 18.4Hz, 1H), 4.47 (d, J＝6.4Hz, 1H), 4.33 (dd, J＝2.8, 6.0Hz, 1H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ200.6,162.9,138.4,133.8,132.2,131.4,131.1,130.6,129.8,129.4,129.0,128.5,128.2,122.4,121.9,121.7,121.3,118.3,100.3,51.5(t , J=23.0Hz), 39.2, 39.0 (d, J=4.0Hz); 19 F{ 1 H} NMR (376MHz, CDCl 3 ) δ-80.3, -110.1 (d, J=274.5Hz), -121.7 (d, J=278.2Hz); HRMS (ESI) m/z: [M+Na] + Calcd for C 26 H 17 BrF 5 NO 4 SNa 635.9874; Found 635.9878.
实施例10Example 10
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(6.4mg,0.012mmol)、BH3·THF(10.0μL,0.01mmol)、β-五氟乙基α,β-不饱和酮1j(37.3mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2a(26.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到38.3mg白色固体3ja，收率66％。mp 196-197℃；HPLC(Daicel Chiralcel IG,正己烷/异丙醇＝60:40,flow rate 1.0mL/min,λ＝254nm)tR(minor)＝6.0min,tR(major)＝11.5min,0.5:99.5e.r.,99％ee；[α]D 33＝+63.2(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ12.19(s,1H),8.12(dd,J＝2.4,9.2Hz,1H),7.93-7.91(m,2H),7.82-7.65(m,3H),7.15-7.02(m,1H),6.87(d,J＝9.2Hz,1H),5.90(d,J＝2.4Hz,1H),4.86(dd,J＝8.0,18.0Hz,1H),4.55(d,J＝6.0Hz,1H),4.45-4.44(m,1H)；13C{1H}NMR(100MHz,CDCl3)δ201.1,166.9,139.2,138.1,133.9,132.6,131.1,130.8,129.3,129.2,128.3,125.8,121.8,121.4,119.7,118.3,99.2,51.5(t,J＝22.0Hz),39.7,39.3(d,J＝5.0Hz)；19F{1H}NMR(376MHz,CDCl3)δ-80.3,-110.2(d,J＝278.2Hz),-121.5(d,J＝274.5Hz)；HRMS(ESI)m/z:[M-H]-Calcd for C26 H16F5N2O6S579.0655；Found 579.0646.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (6.4 mg, 0.012 mmol), BH 3 ·THF (10.0 μL, 0.01 mmol), β-pentafluoroethyl α, β-unsaturated ketone 1j (37.3 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2a (26.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 38.3 mg of white solid 3ja, with a yield of 66%. mp 196-197°C; HPLC (Daicel Chiralcel IG, n-hexane/isopropanol=60:40, flow rate 1.0 mL/min, λ=254 nm) t R (minor)=6.0 min, t R (major)=11.5 min, 0.5:99.5 er, 99% ee; [α] D 33 =+63.2 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ12.19(s,1H),8.12(dd,J＝2.4,9.2Hz,1H),7.93-7.91(m,2H),7.82-7.65(m,3H),7.15-7.02(m,1H),6.87(d,J＝9.2Hz,1H),5.90(d,J＝2.4Hz,1H),4. 86 (dd, J＝8.0, 18.0Hz, 1H), 4.55 (d, J＝6.0Hz, 1H), 4.45-4.44 (m, 1H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ201.1,166.9,139.2,138.1,133.9,132.6,131.1,130.8,129.3,129.2,128.3,125.8,121.8,121.4,119.7,118.3,99.2,51.5(t,J=22.0Hz),39. 7,39.3(d,J＝5.0Hz); 19 F{ 1 H}NMR(376MHz, CDCl 3 )δ-80.3,-110.2(d,J＝278.2Hz),-121.5(d,J＝274.5Hz); HRMS(ESI)m/z:[MH] - Calcd for C 26 H 16 F 5 N 2 O 6 S579.0655; Found 579.0646.
实施例11Embodiment 11
根据实施例1反应条件，采用β-三氟甲基α,β-不饱和酮1a与不同环状N-磺酰基酮亚胺2，反应结果如下：According to the reaction conditions of Example 1, β-trifluoromethyl α,β-unsaturated ketone 1a and different cyclic N-sulfonyl ketimine 2 were used, and the reaction results were as follows:
bBH3·THF(5mol％),L4(6mol％)在60℃反应72h.cBH3·THF(10mol％),L4(12mol％)在60℃反应72h. b BH 3 ·THF (5 mol%), L4 (6 mol%) were reacted at 60°C for 72 h. c BH 3 ·THF (10 mol%), L4 (12 mol%) were reacted at 60°C for 72 h.
实施例12Example 12
在氮气保护下，向Schlenk管中加入100mg分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2b(28.3mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到49.7mg白色固体3ab，收率99％。mp 234-236℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝8.8min,tR(minor)＝12.1min,99.8:0.2e.r.,>99％ee；[α]D 32＝+26.5(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.67(s,1H),7.88(d,J＝7.6Hz,1H),7.78-7.60(m,3H),7.30-7.25(m,1H),7.12-7.03(m,3H),6.93(d,J＝8.0Hz,2H),6.77(d,J＝8.4Hz,1H),6.55(t,J＝7.6Hz,1H),5.90(d,J＝2.0Hz,1H),4.73(q,J＝7.2Hz,1H),4.53(d,J＝6.0Hz,1H),4.29-4.28(m,1H),2.16(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ201.7,162.6,137.7,136.6,135.5,133.7,131.7,131.2,130.5,129.6,129.5,129.3,128.5,124.1(q,J＝282.0Hz),121.7,121.3,119.5,118.8,118.5,100.7,52.3(q,J＝31.0Hz),39.4,38.9,21.0；19F{1H}NMR(376MHz,CDCl3)δ-71.9；HRMS(ESI)m/z:[M+Na]+Calcd for C26H20F3NO4SNa 522.0957；Found 522.0956.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2b (28.3 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 49.7 mg of white solid 3ab, with a yield of 99%. mp 234-236°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0mL/min, λ=254nm) t R (major)=8.8min, t R (minor)=12.1min, 99.8:0.2er, >99%ee; [α] D 32 =+26.5 (c 1.0, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ11.67(s,1H),7.88(d,J＝7.6Hz,1H),7.78-7.60(m,3H),7.30-7.25(m,1H),7.12-7.03(m,3H),6.93(d,J＝8.0Hz,2H),6.77(d,J＝8.4Hz,1H),6.55(t ,J＝7.6Hz,1H),5.90(d,J＝2.0Hz,1H),4.73(q,J＝7.2Hz,1H),4.53(d,J＝6.0Hz,1H),4.29-4.28(m,1H),2.16(s,3H); 13 C{ 1 H} NMR (100MHz, CDCl 3 ) δ201.7,162.6,137.7,136.6,135.5,133.7,131.7,131.2,130.5,129.6,129.5,129.3,128.5,124.1 (q , J ＝ 282.0Hz ) , 121.7,121.3,119.5,118.8 , Found 522.0956.
实施例13Example 13
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2e(30.0mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到44.4mg白色固体3ae，收率87％。mp 188-190℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝10.6min,tR(minor)＝14.4min,99.5:0.5e.r.,99％ee；[α]D 33＝+26.0(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.71(s,1H),7.90(d,J＝7.6Hz,1H),7.79-7.61(m,3H),7.31-7.27(m,1H),7.13-7.06(m,3H),6.79(d,J＝8.0Hz,1H),6.67-6.57(m,3H),5.88(s,1H),4.74(q,J＝7.2Hz,1H),4.52(d,J＝6.4Hz,1H),4.29-4.28(m,1H),3.66(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ201.9,162.6,159.3,136.7,133.7,131.7,131.2,130.6,130.5,129.71,129.67,129.3,124.1(q,J＝282.0Hz),121.7,121.3,119.5,118.9,118.6,114.3,100.8,55.4,52.3(q,J＝32.0Hz),39.4,38.6；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd for C26H20F3NO5SNa 538.0906；Found 538.0907.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air three times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2e (30.0 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 44.4 mg of white solid 3ae, with a yield of 87%. mp 188-190°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=10.6 min, t R (minor)=14.4 min, 99.5:0.5 er, 99% ee; [α] D 33 =+26.0 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.71(s,1H),7.90(d,J＝7.6Hz,1H),7.79-7.61(m,3H),7.31-7.27(m,1H),7.13-7.06(m,3H),6.79(d,J＝8.0Hz,1H),6.67-6.57(m,3H),5.88(s,1 H), 4.74 (q, J = 7.2Hz, 1H), 4.52 (d, J = 6.4Hz, 1H), 4.29-4.28 (m, 1H), 3.66 (s, 3H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ201.9,162.6,159.3,136.7,133.7,131.7,131.2,130.6,130.5,129.71,129.67,129.3,124.1(q,J＝282.0Hz),121.7,121.3,119.5,118.9,118.6 ,114.3,100.8,55.4,52.3(q,J=32.0Hz),39.4,38.6; 19 F{ 1 H}NMR (376MHz, CDCl 3 )δ-72.0; HRMS (ESI) m/z: [M+Na] + Calcd for C 26 H 20 F 3 NO 5 SNa 538.0906; Found 538.0907.
实施例14Embodiment 14
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2f(28.7mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到49.8mg白色固体3af，收率99％。mp 240-241℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate 1.0mL/min,λ＝254nm)tR(major)＝7.8min,tR(minor)＝10.2min,99.8:0.2e.r.,>99％ee；[α]D 33＝+20.0(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.65(s,1H),7.89(d,J＝7.6Hz,1H),7.79-7.62(m,3H),7.31(t,J＝7.6Hz,1H),7.16-7.11(m,3H),6.85-6.79(m,3H),6.60(t,J＝7.6Hz,1H),5.84(d,J＝1.6Hz,1H),4.74(q,J＝7.2Hz,1H),4.53(d,J＝6.4Hz,1H),4.32-4.31(m,1H)；13C{1H}NMR(100MHz,CDCl3)δ201.4,162.7,162.3(d,J＝246.0Hz),137.0,134.5(d,J＝3.0Hz),133.7,131.9,131.2,130.6,130.3(d,J＝8.0Hz),129.4,129.2,124.0(q,J＝282.0Hz),121.7,121.3,119.3,119.0,118.8,115.8(d,J＝21.0Hz),100.0,52.2(q,J＝32.0Hz),39.2,38.5；19F{1H}NMR(376MHz,CDCl3)δ-72.0,-114.0；HRMS(ESI)m/z:[M+Na]+Calcd for C25H17F4NO4SNa526.0707；Found 526.0705.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2f (28.7 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 49.8 mg of white solid 3af, with a yield of 99%. mp 240-241°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0mL/min, λ=254nm) t R (major)=7.8min, t R (minor)=10.2min, 99.8:0.2er, >99%ee; [α] D 33 =+20.0 (c 1.0, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ11.65(s,1H),7.89(d,J＝7.6Hz,1H),7.79-7.62(m,3H),7.31(t,J＝7.6Hz,1H),7.16-7.11(m,3H),6.85-6.79(m,3H),6.60(t,J＝7.6Hz,1H),5.84(d ,J＝1.6Hz,1H),4.74(q,J＝7.2Hz,1H),4.53(d,J＝6.4Hz,1H),4.32-4.31(m,1H); 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ201.4,162.7,162.3(d,J＝246.0Hz),137.0,134.5(d,J＝3.0Hz),133.7,131.9,131.2,130.6,130.3(d,J＝8.0Hz),129.4,129.2,124.0(q,J＝282.0Hz ), 121.7, 121.3, 119.3, 119.0, 118.8, 115.8 (d, J = 21.0Hz), 100.0, 52.2 (q, J = 32.0Hz), 39.2, 38.5; 19 F{ 1 H} NMR (376MHz, CDCl 3 )δ-72.0,-114.0; HRMS(ESI)m/z:[M+Na] + Calcd for C 25 H 17 F 4 NO 4 SNa526.0707; Found 526.0705.
实施例15Embodiment 15
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(3.2mg,0.006mmol)、BH3·THF(5.0μL,0.005mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2h(34.8mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到51.3mg白色固体3ah，收率91％。mp 244-245℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate1.0mL/min,λ＝254nm)tR(major)＝7.7min,tR(minor)＝10.2min,99.9:0.1e.r.,>99％ee；[α]D 33＝+18.0(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.61(s,1H),7.89(d,J＝7.6Hz,1H),7.79-7.70(m,2H),7.64(t,J＝7.2Hz,1H),7.35(t,J＝7.6Hz,1H),7.27(d,J＝8.4Hz,2H),7.14(d,J＝8.0Hz,1H),7.06(d,J＝8.4Hz,2H),6.82(d,J＝8.4Hz,1H),6.62(t,J＝7.6Hz,1H),5.84(d,J＝2.0Hz,1H),4.75(q,J＝7.6Hz,1H),4.52(d,J＝6.0Hz,1H),4.29-4.28(m,1H)；13C{1H}NMR(100MHz,CDCl3)δ201.1,162.7,137.7,137.1,133.8,132.0,131.3,130.7,130.4,129.3,129.1,124.0(q,J＝282.0Hz),122.0,121.7,121.4,119.2,119.1,118.9,99.6,52.2(q,J＝32.0Hz),39.1,38.63,38.61；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd for C25H17Br F3NO4SNa 585.9906；Found 585.9903.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (3.2 mg, 0.006 mmol), BH 3 ·THF (5.0 μL, 0.005 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2h (34.8 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 51.3 mg of white solid 3ah, with a yield of 91%. mp 244-245°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=7.7 min, t R (minor)=10.2 min, 99.9:0.1 er,>99% ee; [α] D 33 =+18.0 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.61(s,1H),7.89(d,J＝7.6Hz,1H),7.79-7.70(m,2H),7.64(t,J＝7.2Hz,1H),7.35(t,J＝7.6Hz,1H),7.27(d,J＝8.4Hz,2H),7.14(d,J＝8.0Hz,1H),7. 06(d,J＝8.4Hz,2H),6.82(d,J＝8.4Hz,1H),6.62(t,J＝7.6Hz,1H),5.84(d,J＝2.0Hz,1H),4.75(q,J＝7.6Hz,1H),4.52(d,J＝6.0Hz,1H),4.29-4.28(m,1H) ; 13 C{ 1 H}NMR (100MHz, CDCl 3 ) δ201.1,162.7,137.7,137.1,133.8,132.0,131.3,130.7,130.4,129.3,129.1,124.0(q,J＝282.0Hz),122.0,121.7,121.4,119 .2,119.1,118.9,99.6,52.2(q,J=32.0Hz),39.1,38.63,38.61; 19 F{ 1 H}NMR (376MHz, CDCl 3 )δ-72.0; HRMS (ESI) m/z: [M+Na] + Calcd for C 25 H 17 Br F 3 NO 4 SNa 585.9906; Found 585.9903.
实施例16Example 16
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2i(33.7mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到50.9mg白色固体3ai，收率92％。mp 234-236℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30,flow rate1.0mL/min,λ＝254nm)tR(major)＝6.1min,tR(minor)＝7.8min,99.8:0.2e.r.,>99％ee；[α]D 33＝+9.1(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.56(s,1H),7.91(d,J＝7.6Hz,1H),7.80-7.64(m,3H),7.41-7.28(m,5H),7.09-7.07(m,1H),6.81-6.78(m,1H),6.59-6.54(m,1H),5.87(d,J＝2.8Hz,1H),4.78(q,J＝7.2Hz,1H),4.54(d,J＝6.0Hz,1H),4.39(dd,J＝2.8,6.4Hz,1H)；13C{1H}NMR(150MHz,CDCl3)δ200.9,162.7,142.8,137.2,133.8,132.2,131.3,130.8,130.4(q,J＝33.0Hz),129.2,129.09,129.06,125.8(q,J＝3.0Hz),124.0(q,J＝282.0Hz),123.8(q,J＝270.0Hz),121.8,121.4,119.2,119.0,118.9,98.9,52.3(q,J＝33.0Hz),39.2,39.0；19F{1H}NMR(376MHz,CDCl3)δ-62.9,-71.9；HRMS(ESI)m/z:[M+Na]+Calcd for C26H17F6NO4SNa 576.0675；Found 576.0673.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2i (33.7 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 50.9 mg of white solid 3ai, with a yield of 92%. mp 234-236°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=6.1 min, t R (minor)=7.8 min, 99.8:0.2 er,>99% ee; [α] D 33 =+9.1 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.56(s,1H),7.91(d,J＝7.6Hz,1H),7.80-7.64(m,3H),7.41-7.28(m,5H),7.09-7.07(m,1H),6.81-6.78(m,1H),6.59-6.54(m,1H),5.87(d,J＝2 .8Hz, 1H), 4.78 (q, J＝7.2Hz, 1H), 4.54 (d, J＝6.0Hz, 1H), 4.39 (dd, J＝2.8, 6.4Hz, 1H); 13 C{ 1 H} NMR (150MHz, CDCl 3 )δ200.9,162.7,142.8,137.2,133.8,132.2,131.3,130.8,130.4(q,J＝33.0Hz),129.2,129.09,129.06,125.8(q,J＝3.0Hz),124.0(q,J＝282.0Hz),1 23.8 (q, J=270.0Hz), 121.8, 121.4, 119.2, 119.0, 118.9, 98.9, 52.3 (q, J= 33.0Hz), 39.2, 39.0; 19 F{ 1 H} NMR (376MHz, CDCl 3 )δ-62.9,-71.9; HRMS(ESI)m/z:[M+Na] + Calcd for C 26 H 17 F 6 NO 4 SNa 576.0675; Found 576.0673.
实施例17Embodiment 17
在氮气保护下，向Schlenk管中加入100mg分子筛、配体L4(3.2mg,0.006mmol)、BH3·THF(5.0μL,0.005mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2k(31.9mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到48.1mg白色固体3ak，收率90％。mp 241-242℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30，flow rate 1.0mL/min,λ＝254nm)tR(major)＝11.7min,tR(minor)＝13.8min,99.9:0.1e.r.,>99％ee；[α]D 32＝-102.9(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.58(s,1H),8.13(d,J＝8.4Hz,1H),7.94-7.51(m,8H),7.11-7.05(m,3H),6.64(d,J＝8.4Hz,1H),6.42(d,J＝8.0Hz,1H),6.04(d,J＝1.6Hz,1H),5.98(t,J＝8.0Hz,1H),5.20(d,J＝3.2Hz,1H),4.84-4.78(m,2H)；13C{1H}NMR(100MHz,CDCl3)δ201.7,162.0,136.5,133.99,133.95,133.8,132.3,131.5,131.2,130.6,129.7,129.3,128.6,128.5,127.7,126.4,126.1,125.3,124.3(q,J＝282.0Hz),121.8,121.4,119.5,118.1,100.2,52.3(q,J＝32.0Hz),37.1,34.2；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M+Na]+Calcd forC29H20F3NO4SNa 558.0957；Found 558.0956.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (3.2 mg, 0.006 mmol), BH 3 ·THF (5.0 μL, 0.005 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2k (31.9 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 48.1 mg of white solid 3ak, with a yield of 90%. mp 241-242°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0 mL/min, λ=254 nm) t R (major)=11.7 min, t R (minor)=13.8 min, 99.9:0.1 er,>99% ee; [α] D 32 =-102.9 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ11.58(s,1H),8.13(d,J＝8.4Hz,1H),7.94-7.51(m,8H),7.11-7.05(m,3H),6.64(d,J＝8.4Hz,1H),6.42(d,J＝8.0Hz,1H),6.04(d,J＝1.6Hz,1H),5.98( t, J＝8.0Hz, 1H), 5.20 (d, J＝3.2Hz, 1H), 4.84-4.78 (m, 2H); 13 C{ 1 H} NMR (100MHz, CDCl 3 )δ201.7,162.0,136.5,133.99,133.95,133.8,132.3,131.5,131.2,130.6,129.7,129.3,128.6,128.5,127.7,126.4,126.1,125.3,124.3(q,J＝282.0Hz),121.8,121.4,119.5,118.1,100.2,52.3(q,J＝32.0Hz),37.1,34.2； 19 F{ 1 H}NMR(376MHz,CDCl 3 )δ-72.0；HRMS(ESI)m/z:[M+Na] + Calcd forC 29 H 20 F 3 NO 4 SNa 558.0957; Found 558.0956.
实施例18Embodiment 18
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(6.4mg,0.012mmol)、BH3·THF(10.0μL,0.01mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2n(25.0mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/15-1/1/8)分离纯化得到36.3mg白色固体3an，收率78％。mp 227-230℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30，flow rate 1.0mL/min,λ＝254nm)tR(major)＝5.9min,tR(minor)＝7.3min,99.9:0.1e.r.,>99％ee；[α]D 30＝+75.7(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.84(s,1H),7.84-7.80(m,3H),7.70(t,J＝7.6Hz,1H),7.60-7.52(m,2H),7.01-6.98(m,2H),5.86(d,J＝2.0Hz,1H),4.58(q J＝7.2Hz,1H),4.52(d,J＝4.4Hz,1H),2.78(s,1H),1.00(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ202.2,163.9,137.5,133.6,131.1,130.8,130.1,129.6,128.8,124.0(q,J＝282.0Hz),121.7,121.2,119.7,118.9,100.9,53.4(q,J＝32.0Hz),44.3,34.1,33.1,28.8；19F{1H}NMR(376MHz,CDCl3)δ-71.5；HRMS(ESI)m/z:[M+Na]+Calcdfor C23H22F3N O4SNa 488.1114；Found 488.1112.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (6.4 mg, 0.012 mmol), BH 3 ·THF (10.0 μL, 0.01 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2n (25.0 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/15-1/1/8) to obtain 36.3 mg of white solid 3an, with a yield of 78%. mp 227-230°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0mL/min, λ=254nm) t R (major)=5.9min, t R (minor)=7.3min, 99.9:0.1er, >99%ee; [α] D 30 =+75.7 (c 1.0, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ) δ11.84(s,1H),7.84-7.80(m,3H),7.70(t,J＝7.6Hz,1H),7.60-7.52(m,2H),7.01-6.98(m,2H),5.86(d,J＝2.0Hz,1H),4.58(q J=7.2Hz, 1H), 4.52 (d, J= 4.4Hz, 1H), 2.78 (s, 1H), 1.00 (s, 9H); 13 C{ 1 H} NMR (100MHz, CDCl 3 ) δ 202.2, 163.9, 137.5, 133.6, 131.1, 130.8, 130.1, 129.6, 1 28.8, 124.0 (q, J = 282.0Hz), 121.7, 121.2, 119.7, 118.9, 100.9, 53.4 (q, J = 32.0Hz), 44.3, 34.1, 33.1, 28.8; 19 F{ 1 H} NMR (376MHz, CDCl 3 )δ-71.5; HRMS (ESI) m/z: [M+Na] + Calcdfor C 23 H 22 F 3 NO 4 SNa 488.1114; Found 488.1112.
实施例19Embodiment 19
在氮气保护下，向Schlenk管中加入100mg 分子筛、配体L4(1.6mg,0.003mmol)、BH3·THF(2.5μL,0.0025mmol)、β-三氟甲基α,β-不饱和酮1a(25.9mg,0.12mmol)，抽换气3次，再加入干燥氯苯(1.0mL)，100℃搅拌2h，然后冷却至室温，再在氮气保护下加入环状N-磺酰基酮亚胺2p(28.3mg,0.1mmol)，60℃搅拌72h。TLC显示2a消失，减压除去溶剂后快速硅胶柱层析(乙酸乙酯/二氯甲烷/石油醚＝1/1/10-1/1/5)分离纯化得到49.8mg白色固体3ap，收率99％。mp 248-249℃；HPLC(Daicel Chiralcel IC,正己烷/异丙醇＝70:30，flow rate 1.0mL/min,λ＝254nm)tR(major)＝11.1min,tR(minor)＝15.2min,99.9:0.1e.r.,>99％ee；[α]D 313＝+2.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.69(s,1H),7.76(d,J＝8.0Hz,1H),7.56(s,1H),7.42(d,J＝8.0Hz,1H),7.28-7.24(m,1H),7.17-7.07(m,6H),6.76(d J＝8.4Hz,1H),6.54(t,J＝7.6Hz,1H),5.87(d,J＝1.6Hz,1H),4.72(q,J＝7.2Hz,1H),4.53(d,J＝6.0Hz,1H),4.31-4.30(m,1H),2.51(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ201.6,162.6,144.8,138.7,136.7,132.0,131.6,129.51,129.48,128.8,128.6,128.0,124.1(q,J＝281.0Hz),121.4,119.9,119.5,118.8,118.5,99.8,52.3(q,J＝32.0Hz),39.2,22.1；19F{1H}NMR(376MHz,CDCl3)δ-72.0；HRMS(ESI)m/z:[M-H]-Calcd forC26H19F3NO4S 498.0992；Found 498.0993.Under nitrogen protection, 100 mg of Molecular sieves, ligand L4 (1.6 mg, 0.003 mmol), BH 3 ·THF (2.5 μL, 0.0025 mmol), β-trifluoromethyl α, β-unsaturated ketone 1a (25.9 mg, 0.12 mmol), evacuate the air 3 times, add dry chlorobenzene (1.0 mL), stir at 100°C for 2 h, then cool to room temperature, add cyclic N-sulfonyl ketimine 2p (28.3 mg, 0.1 mmol) under nitrogen protection, and stir at 60°C for 72 h. TLC showed that 2a disappeared, and the solvent was removed under reduced pressure and then separated and purified by rapid silica gel column chromatography (ethyl acetate/dichloromethane/petroleum ether=1/1/10-1/1/5) to obtain 49.8 mg of white solid 3ap, with a yield of 99%. mp 248-249°C; HPLC (Daicel Chiralcel IC, n-hexane/isopropanol=70:30, flow rate 1.0mL/min, λ=254nm) t R (major)=11.1min, t R (minor)=15.2min, 99.9:0.1er, >99%ee; [α] D 313 =+2.6 (c 1.0, CHCl 3 ) ; 1 H NMR (400MHz, CDCl 3 ) δ 11.69 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.28-7.24 (m, 1H), 7.17-7.07 (m, 6H), 6.76 (d J＝8.4Hz,1H),6.54(t,J＝7.6Hz,1H),5.87(d,J＝1.6Hz,1H),4.72(q,J＝7.2Hz,1H),4.53(d,J＝6.0Hz,1H),4.31-4.30(m,1H),2.51(s,3H); 13 C{ 1 H}NMR(1 00MHz,CDCl 3 )δ201.6,162.6,144.8,138.7,136.7,132.0,131.6,129.51,129.48,128.8,128.6,128.0,124.1(q,J=281.0Hz),121.4,119.9,119.5,118.8,118. 5, 99.8, 52.3 (q, J = 32.0Hz), 39.2, 22.1; 19 F{ 1 H} NMR (376MHz, CDCl 3 ) δ-72.0; HRMS (ESI) m/z: [MH] - Calcd forC 26 H 19 F 3 NO 4 S 498.0992; Found 498.0993.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.
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