CN112321627A - Axial chiral arylethynyl silane compound and preparation method thereof - Google Patents

Axial chiral arylethynyl silane compound and preparation method thereof Download PDF

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CN112321627A
CN112321627A CN202011271503.4A CN202011271503A CN112321627A CN 112321627 A CN112321627 A CN 112321627A CN 202011271503 A CN202011271503 A CN 202011271503A CN 112321627 A CN112321627 A CN 112321627A
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arylethynyl
arylcyclohex
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崔玉明
徐利文
李钊
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Hangzhou Normal University
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Abstract

The invention relates to the technical field of organic synthesis and discloses an axial chiral arylethynyl silane compound and a preparation method thereof, wherein the structural formula of the axial chiral arylethynyl silane compound is shown as a formula (1), and the preparation method comprises the steps of taking a complex formed by palladium salt and a ligand as a catalyst precursor and taking 2-arylcyclohex-2-ene-1-ketoxime and 2-bromoethyl ketoneTaking alkynyl silane as a reactant, and carrying out asymmetric alkynyl on a carbon-hydrogen bond in the reactant in a reaction medium in the presence of an oxidant to obtain the axial chiral arylethynyl silane compound; the method has good adaptability to aryl and alkynyl silane containing substituent groups with different properties, a series of axial chiral arylethynyl silane compounds can be obtained with moderate to good yield and enantioselectivity, the silicon substituent groups in the compounds are easy to carry out a series of conversions, and the derivatives can be used as chiral ligands and catalysts for asymmetric catalytic reactions.
Figure DDA0002777828350000011

Description

Axial chiral arylethynyl silane compound and preparation method thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an axial chiral arylethynyl silane compound and a preparation method thereof.
Background
The axial chiral compound is widely existed in biological activity and drug molecules, and has wider application as a chiral ligand and a catalyst in asymmetric catalytic reaction. Compared with the more studied biaryl (hetero) ring type axial chiral compounds, the research on synthesis and application of aryl olefin compounds with one chiral axis between an aromatic ring and an olefin is relatively delayed, and the reason is mainly that the compounds have low rotational energy barrier and are easy to racemize and difficult to control the stereoselectivity of the reaction. The preparation of axial chiral aryl olefin compounds was earlier obtained by chemical resolution, and the synthesis of such compounds by asymmetric catalytic reaction was only recently reported, such as palladium-catalyzed coupling reaction (palladium-catalyzed synthesis of 2-arylcyclohexenyl-2-arylketene-synthesized chiral platform molecule of 2-arylcyclohexenyl-2-arylketene-synthesized chiral synthesis platform molecule of 552. Angel. chem. int. Ed.,2016,55, 2186-190) developed by Takayasu (organic enantioselective catalytic synthesis of sulfone-containing axial chiral styrene, J.Am. chem. Soc.2018,140,7056-7060), Shifeng (axial chiral aromatic ethylene-indole skeleton: a new member of the family of atropisomers and its catalytic asymmetric synthesis, Chinese Journal of Chemistry,2020,38,543-, angew. chem. int. ed.,2017,56, 4777-. Although some progress has been made in the catalytic synthesis of axial chiral aryl olefins, there is still much research space worth exploring synthetic chemistry. For example, in order to obtain target axial chiral arylalkene compounds of stable structure, lengthy synthetic routes are usually required to prepare aryl halides and organometallic reagents that are polysubstituted and highly hindered, which to some extent hinders the application of asymmetric cross-coupling methodologies in the field of axial chiral arylalkene synthesis. In addition, these catalytic reactions suffer from problems such as lower atom economy, limited range of substrates for the reaction, low turnover and lower stereoselectivity.
The C-H bond activation strategy is an effective method for directly and quickly constructing C-C bonds and C-heteroatom bonds, greatly improves the economic utilization rate and the synthesis efficiency of atoms, reduces the discharge of wastes, and is a green chemical method. With the continuous and intensive research of chemists in the field in recent years, a plurality of reports have been made on the synthesis of biaryl (hetero) ring type axial chiral compounds by catalyzing asymmetric C-H functionalization, particularly dynamic kinetic resolution reaction, and the functionalization of regioselectivity and stereoselectivity can be realized on aryl substrates with specific structures. In 2018, Xuliwen and the like take oxime ether as a guide group, higher yield and enantioselectivity are obtained in the catalytic synthesis of an axial chiral aryl olefin compound by utilizing palladium-catalyzed asymmetric aryl C-H bond olefination reaction, and the guide group in a product can be removed under an acidic condition (the axial chiral aryl ethylene is synthesized by palladium-catalyzed asymmetric carbon-hydrogen bond olefination, chem. In 2020, the axial chiral aryl olefin is synthesized by using an instantaneous guiding group strategy by using a propylene-catalyzed alkenylation method based on an aminoamide instantaneous guiding group strategy to synthesize axial chiral styrene, Angew.Chem.int.Ed.2020, 59 and 6576-doped 6580. Similarly, based on palladium catalyst, Stylon (axial chiral styrene synthesized by asymmetric carbon-hydrogen bond functionalization under palladium catalysis, Chem,2020,6,1-15), pyridine is also used as a guide group to realize the alkenyl and alkynylation reactions of aryl C-H bonds, but the catalyst system uses unusual ligands and a large amount of high boiling point solvents. To our knowledge, the synthesis of axially chiral arylalkenes by secondary C-H bond functionalization starting from simpler substrates has not been reported.
Disclosure of Invention
Aiming at the defects of complex substrate, scarce raw material sources such as ligand and the like, high melting point of solvent and the like of the method for preparing axial chiral aryl alkene in the prior art, the invention provides the method for preparing the axial chiral arylethynyl silane compound.
In order to achieve the purpose, the invention adopts the technical scheme that:
an axial chiral arylethynyl silane compound having the structural formula (1):
Figure RE-GDA0002849940660000021
wherein R is1、R4、R5、R6Independently is C1～6Alkyl or C6～10Any of aryl groups; r2Selected from hydrogen, C1～6Alkyl or C6～10Any of aryl groups; r3Is selected from C1～6Alkyl, alkoxy, C6～10Aryl or halogen. The compound can be used as a chiral ligand and a catalyst in asymmetric catalytic reaction.
Preferably, R1、R4、R5、R6Independently is any one of methyl, isopropyl, tertiary butyl or phenyl; r2Selected from any one of hydrogen, methyl, phenyl or benzyl; r3Selected from any one of methyl, methoxy, phenyl, fluorine, chlorine or bromine.
The invention also provides a preparation method of the axial chiral arylethynyl silane compound, which comprises the steps of taking a complex formed by palladium salt and a ligand as a catalyst precursor, taking 2-arylcyclohex-2-ene-1-ketoxime and 2-bromoethynyl silane as reactants, and carrying out asymmetric alkynyl on carbon-hydrogen bonds in the reactants in a reaction medium in the presence of an oxidant to obtain the axial chiral arylethynyl silane compound;
the structural general formula of the 2-arylcyclohex-2-en-1-one oxime is shown as (2), and the structural general formula of the 2-bromoethynylsilane is shown as (3):
Figure RE-GDA0002849940660000031
wherein R is1、R2、R3、R4、R5、R6Is as defined above. The specific reaction formula is as follows:
Figure RE-GDA0002849940660000032
the method has good adaptability to aryl and alkynyl silane containing substituent groups with different properties, a series of axial chiral arylethynyl silane compounds can be obtained with moderate to good yield and enantioselectivity, the silicon substituent groups in the compounds are easy to carry out a series of conversions, and the derivatives can be used as chiral ligands and catalysts for asymmetric catalytic reactions.
Specifically, the preparation method of the axial chiral arylethynyl silane compound comprises the following steps: mixing and reacting 2-arylcyclohex-2-ene-1-ketoxime, 2-bromoethynylsilane, palladium salt, a ligand and an oxidant in a reaction medium to obtain the axial chiral arylethynylsilane compound.
The ligand is any one of N-single protection chiral amino acid, including Boc-D-valine (Boc-D-Val-OH), Boc-L-isoleucine (Boc-lle-OH), Boc-L-phenylalanine (Boc-Phe-OH), N-Boc-L-tertiary leucine (Boc-L-TLE-OH), N-acetyl-L-alanine (N-Ac-L-Ala-OH), N-benzyloxycarbonyl-L-valine (N-CBZ-L-Val-OH), N-benzyloxycarbonyl-L-phenylalanine (CBZ-L-Phe-OH), N-acetyl-L-leucine (N-Ac-L-Leu-OH), the structural formulas are respectively shown as follows:
Figure RE-GDA0002849940660000033
the palladium salt is selected from any one or more of palladium acetate, palladium trifluoroacetate, palladium tetranitrile tetrafluoroborate or palladium chloride.
The oxidant is one or more selected from silver acetate, silver trifluoromethanesulfonate, silver oxide and silver carbonate.
The reaction medium comprises any one or more of methanol, tetrahydrofuran, dichloromethane, diethyl ether, ethyl acetate and acetone.
The molar concentration of the 2-arylcyclohex-2-ene-1-ketoxime in the reaction liquid is 0.1-1 mol/L; the dosage of the 2-bromoacetylene silane is 110-300 mol% of the 2-arylcyclohex-2-ene-1-one oxime.
The amount of the palladium salt is 1-10 mol% of the 2-arylcyclohex-2-ene-1-ketoxime; the dosage of the ligand is 2-20 mol% of 2-arylcyclohex-2-ene-1-ketoxime; the dosage of the oxidant is 110-300 mol% of the 2-arylcyclohex-2-ene-1-ketoxime.
The reaction conditions are 40-70 ℃ in an air environment, and the reaction time is 10-48 h.
Compared with the prior art, the invention has the following beneficial effects:
(1) the catalyst palladium salt and the N-single protection chiral amino acid ligand of the preparation method are commercial reagents, and the raw materials of the 2-arylcyclohex-2-ene-1-ketoxime and the alkyne derivatives are low in price and easy to obtain, low in production cost and easy to industrially popularize.
(2) The axial chiral arylethynyl silane compound prepared by the invention has moderate to good yield and enantioselectivity, and the silicon substituent in the compound is easy to carry out a series of conversions, and the derivative can be used as a chiral ligand and a catalyst for asymmetric catalytic reaction.
(3) The preparation method can be carried out at 40-70 ℃, low-boiling-point methanol is used as a solvent, a catalytic system is simple, and the obtained derivative has a good effect when used in the catalytic system.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the reaction product (E) -3-methyl-2- (2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) cyclohex-2-en-1-one-O-methyloxime in example 1.
FIG. 2 is a carbon spectrum of the reaction product (E) -3-methyl-2- (2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) cyclohex-2-en-1-one-O-methyloxime in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. Those skilled in the art should understand that they can make modifications and equivalents without departing from the spirit and scope of the present invention, and all such modifications and equivalents are intended to be included within the scope of the present invention.
Example 1
(E) -3-methyl-2- (2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) cyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000051
To a 25mL reaction tube were added 3-methyl-2-naphthylcyclohex-2-en-1-one-O-methyloxime (0.13g,0.2mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium acetate (0.005g,10 mol%), N-acetyl-L-alanine (0.0053g,20 mol%), silver carbonate (0.165g,0.6mmol), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture was purified by flash column chromatography to give a yellow liquid (82mg,0.184mmol) in 92% yield.
The nuclear magnetic hydrogen spectrum is shown in figure 1,1H NMR(400MHz,CDCl3) δ 7.82-7.77(m,1H),7.68(dd, J ═ 12.8, 4.9Hz,2H),7.56(d, J ═ 8.4Hz,1H),7.43(m,2H),3.52(s,3H),2.88-2.75(m,1H),2.59(m, 1H),2.34(m,2H),1.95(m,2H),1.44(s,3H),1.11(d, J ═ 2.1Hz,18H), the carbon spectrum is as shown in fig. 2,13C NMR(100MHz,CDCl3)δ155.78(s),143.66(s),140.31(s),133.01(s),132.15(s),129.28(s), 128.61(s),128.07(s),126.69(s),126.32(s),126.26(s),126.14(s),120.92(s),107.35(s),92.41 (s),61.53(s),31.92(s),23.01(s),21.44(s),21.22(s),18.85(d,J＝1.6Hz),11.45(s).HRMS (ESI)m/z:[M+Na]+calculated for C29H40NOSi 446.2859:446.2874 HPLC using a Chiralpak AD-H + OX-H column (hexane: 2-propanol ═ 99.2:0.8, 0.3mL/min, 254nm, 99% ee); the major enantiomer tr is 26.590 min and the minor enantiomer tr is 27.771 min. [ alpha ] to]25D＝31(c＝0.01,CHCl3)
Example 2:
(E) -3-methyl-2- (4-methyl-2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) cyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000052
To a 25mL reaction tube was added 3-methyl-2-naphthylmethyl-2-cyclohexen-1-one-O-methyloxime (0.056g,0.2mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium chloride (0.0018g,5 mol%), Boc-D-valine (0.0043g,10 mol%), silver triflate (0.102g,0.4mmol), and methanol (1mL) was added. The reaction tube was moved to a 50 ℃ oil bath for 40 hours. The mixture was purified by flash column chromatography to give a white liquid (36.8mg,0.08mmol) in 40% yield.
1H NMR(400MHz,CDCl3)δ7.95(d,J＝8.0Hz,1H),7.74-7.65(m,1H),7.51-7.37(m, 3H),3.53(s,3H),2.82(m,1H),2.67(s,3H),2.63-2.50(m,1H),2.34(m,2H),1.95(m,2H), 1.45(s,3H),1.12(d,J＝2.5Hz,18H).13C NMR(100MHz,CDCl3)δ155.89(s),143.69(s), 138.62(s),132.85(s),132.40(s),132.24(s),129.72(s),128.75(s),126.92(s),125.99(s), 125.88(s),124.24(s),120.44(s),107.56(s),91.98(s),61.52(s),31.94(s),23.05(s),21.47(s), 21.24(s),19.38(s),18.86(d,J＝1.5Hz),11.46(s).HRMS(ESI)m/z:[M+Na]+calculated for C30H42NOSi 460.3041:460.3030 HPLC using a Chiralpak AD-H + OX-H column (hexane: 2-propanol ═ 99.2:0.8, 0.3mL/min, 254nm, 95% ee); the major enantiomer tr is 28.538min and the minor enantiomer tr is 26.513 min. [ alpha ] to]25D＝10(c＝0.007,CHCl3)
Example 3:
(E) -2' -methoxy-6-methyl-6 ' ((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000061
To a 25mL reaction tube was added 3-methyl-2- (2-methoxyphenyl) cyclohex-2-en-1-one-O-methyloxime (0.049g,0.2 mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.4mmol), palladium tetra-acetonitrile tetrafluoroborate (0.009g,10 mol%), Boc-L-isoleucine (0.0093g,20 mol%), silver carbonate (0.11g,0.4mmol), and tetrahydrofuran (2mL) was added. The reaction tube was moved to a 60 ℃ oil bath for reaction for 36 hours. The mixture was purified by flash column chromatography to give a white liquid (32.4mg, 0.076mmol) in 38% yield.
1H NMR(400MHz,CDCl3)δ7.16(m,2H),6.87(dd,J＝7.9,1.3Hz,1H),3.74(s,3H), 3.66(s,3H),2.68-2.52(m,2H),2.33-2.16(m,2H),1.89-1.77(m,2H),1.56(s,3H),1.08(d,J＝ 2.7Hz,18H).13C NMR(100MHz,CDCl3)δ157.18(s),155.63(s),142.54(s),130.81(s), 127.50(s),126.75(s),125.25(s),125.03(s),111.61(s),106.51(s),91.41(s),61.48(s),56.32 (s),31.71(s),22.87(s),21.43(s),21.02(s),18.80(d,J＝1.3Hz),11.43(s).HRMS(ESI)m/z: [M+Na]+calculated for C26H40NO2Si 426.2807:426.2823 HPLC using a Chiralpak AD-H + OX-H column (hexane: 2-propanol ═ 99.2:0.8, 0.3mL/min, 254nm, 97% ee); the major enantiomer tr is 30.165min and the minor enantiomer tr is 27.576 min. [ alpha ] to]25D＝52(c＝0.01,CHCl3)。
Example 4:
(E) -2- (4-bromo-2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000071
To a 25mL reaction tube was added 3-methyl-2-naphthylbromocyclohex-2-en-1-one-O-methyloxime (0.0684g,0.2mmol), (2-bromoethynyl) triisopropylsilane (0.059g,0.22mmol), palladium trifluoroacetate (0.0033g,5 mol%), Boc-L-phenylalanine (0.0053g,10 mol%), silver carbonate (0.11g,0.4mmol), and dichloromethane (0.5mL) was further added. The reaction tube was moved to a 50 ℃ oil bath for reaction for 32 hours. The mixture was purified by flash column chromatography to give a yellow liquid (38.9mg,0.074 mmol) in 31% yield.
1H NMR(400MHz,CDCl3)δ8.32-8.15(m,1H),7.62(d,J＝8.7Hz,1H),7.44(m,2H), 6.89(s,1H),4.03(s,3H),3.55(s,3H),2.82(m,1H),2.67-2.51(m,1H),2.35(m,2H),1.94(m, 2H),1.47(s,3H),1.13(s,18H).13C NMR(100MHz,CDCl3)δ155.9,153.9,144.0,133.0(d,J ＝3.3Hz),128.5,126.7,126.2,125.7,125.6,122.0,120.4,107.7,106.8,91.9,61.5,55.6,31.9, 27.1,23.1,21.5,21.3,18.9(d,J＝1.6Hz),11.5.HRMS(ESI)m/z:[M+Na]+calculated for C23H29BrNOSi 444.1168:442.1196.HPLC determination of ee with Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.25mL/min, 254nm, 96% ee); the main enantiomer tr is 30.001min and the secondary enantiomer tr is 28.961 min. [ alpha ] to]25D＝9(c＝0.005,CHCl3)。
Example 5:
(E) -3-methyl-2- (4- ((triisopropylsilyl) ethynyl) -1, 2-dihydroacenaphthenyl-5-yl) cyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000072
To a 25mL reaction tube was added 3-methyl-2-naphthylhexanylcyclohex-2-en-1-one-O-methyloxime (0.058g,0.2 mmol), (2-bromoethynyl) triisopropylsilane (0.11g,0.4mmol), palladium acetate (0.0005g,1 mol%), N-acetyl-L-alanine (0.0005g,2 mol%), silver oxide (0.05g,0.4mmol), and diethyl ether (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 27 hours. The mixture was purified by flash column chromatography to give a yellow liquid (32.1mg,0.064mmol) in 32% yield.
1H NMR(400MHz,CDCl3)δ7.30(s,1H),7.29-7.22(m,2H),7.17-7.14(m,1H),3.46(s, 3H),3.29(m,4H),2.79-2.68(m,1H),2.48(m,1H),2.24(m,2H),1.92-1.78(m,2H),1.39(s, 3H),1.03(d,J＝2.7Hz,18H).13C NMR(100MHz,CDCl3)δ155.9,145.8,144.3,143.6,139.0, 136.1,130.5,128.1,128.0,122.8,122.3,121.4,119.8,108.3,91.7,61.5,31.9,30.6,30.0,23.1, 21.5,21.3,18.9,18.9,11.5.HRMS(ESI)m/z:[M+Na]+calculated for C31H42NOSi 472.3040: 472.3030 HPLC using a Chiralpak AD-H + OX-H column (hexane: 2-propanol ═ 99.2:0.8, 0.3mL/min, 254nm, 90% ee); the major enantiomer tr is 30.707min and the minor enantiomer tr is 27.450 min. [ alpha ] to]25D＝11(c＝0.005, CHCl3)
Example 6:
(E) -2',4', 6-trimethyl-6 '((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000081
To a 25mL reaction tube was added 3-methyl-2- (2, 3-dimethylphenyl) cyclohex-2-en-1-one-O-methyloxime (0.049g,0.2 mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium acetate (0.005g,10 mol%), N-Boc-L-tert-leucine (0.0093g,20 mol%), silver carbonate (0.061g,0.22mmol), and methanol (0.2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 23 hours. The mixture was purified by flash column chromatography to give a white liquid (56.0mg, 0.13mmol) in 66% yield.
1H NMR(400MHz,CDCl3)δ7.19(s,1H),6.97(s,1H),3.67(s,3H),2.76-2.65(m,1H), 2.51(m,1H),2.29(s,3H),2.24(t,J＝6.1Hz,2H),2.07(s,3H),1.94-1.75(m,2H),1.51(s,3H), 1.09(d,J＝3.3Hz,18H).13C NMR(100MHz,CDCl3)δ155.5,142.1,138.1,136.6,135.7, 130.8,130.7,129.6,123.4,107.3,90.2,61.6,31.7,22.9,21.2,21.1,21.0,19.8,18.8,18.8,11.5. HRMS(ESI)m/z:[M+Na]+calculated for C27H42NOSi 424.3041:424.3030 HPLC using a Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 98% ee); the main enantiomer tr is 26.812min and the secondary enantiomer tr is 24.293 min. [ alpha ] to]25D＝8(c＝0.02,CHCl3)
Example 7:
(E) -2' -fluoro-6-methyl-6 ' - ((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000082
To a 25mL reaction tube was added 3-methyl-2- (2-fluorophenyl) cyclohex-2-en-1-one-O-methyloxime (0.047g,0.2 mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium acetate (0.005g,10 mol%), N-acetyl-L-leucine (0.0069g,20 mol%), silver carbonate (0.165g,0.6mmol), and ethyl acetate (2mL) was added. The reaction tube was moved to a 70 ℃ oil bath for 18 hours. The mixture was purified by flash column chromatography to give a yellow liquid (41.4mg,0.1mmol) in 50% yield.
1H NMR(400MHz,CDCl3)δ7.30(m,1H),7.18(m,1H),7.05-6.97(m,1H),3.67(s,3H), 2.74-2.63(m,1H),2.60-2.47(m,1H),2.26(m,2H),1.90-1.77(m,2H),1.60(s,3H),1.08(s, 18H).13C NMR(100MHz,CDCl3)δ161.1,158.6,155.2,143.9,129.1,128.9,128.5,128.4, 128.1,127.9,126.0,125.9,124.6,115.6,115.3,105.3(d,J＝4.1Hz),92.8,61.6,31.7,22.8,21.5, 20.9,18.8,18.8,11.4.HRMS(ESI)m/z:[M+Na]+calculated for C25H37FNOSi:414.2634: 414.2623.HPLC determination of ee with Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 80% ee); the main enantiomer tr is 24.959min and the secondary enantiomer tr is 26.866 min. [ alpha ] to]25D＝4(c＝0.01, CHCl3)
Example 8:
(E) -2',4', 6-trimethyl-6 '((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000091
To a 25mL reaction tube was added 3-methyl-2- (2, 3-dimethylphenyl) cyclohex-2-en-1-one-O-methyloxime (0.049g,0.2 mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium tetraacetonitrile tetrafluoroborate (0.0054g,6 mol%), N-benzyloxycarbonyl-L-valine (0.0060g,12 mol%), silver carbonate (0.165g,0.6mmol), and methanol (2mL) was added. The reaction tube was moved to a 50 ℃ oil bath for reaction for 15 hours. The mixture was purified by flash column chromatography to give a yellow liquid (58.5 mg,0.138mmol) in 60% yield.
1H NMR(400MHz,CDCl3)δ7.19(s,1H),6.97(s,1H),3.67(s,3H),2.76-2.65(m,1H), 2.51(m,1H),2.29(s,3H),2.24(t,J＝6.1Hz,2H),2.07(s,3H),1.94-1.75(m,2H),1.51(s,3H), 1.09(d,J＝3.3Hz,18H).13C NMR(100MHz,CDCl3)δ155.5,142.1,138.1,136.6,135.7, 130.8,130.7,129.6,123.4,107.3,90.2,61.6,31.7,22.9,21.2,21.1,21.0,19.8,18.8,18.8,11.5. HRMS(ESI)m/z:[M+Na]+calculated for C27H42NOSi:424.3041:424.3030 HPLC determination of ee values with a Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 90% ee); the main enantiomer tr is 26.812min and the secondary enantiomer tr is 24.293 min. [ alpha ] to]25D＝8(c＝0.02,CHCl3)
Example 9:
(E) -3-methyl-2- (2- ((triethylsilyl) ethynyl) naphthalen-1-yl) cyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000101
To a 25mL reaction tube was added 3-phenyl-2-naphthylcyclohex-2-en-1-one-O-methyloxime (0.053g,0.3mmol), (2-bromoethynyl) triethylsilane (0.13g,0.6mmol), palladium acetate (0.0025g,5 mol%), N-acetyl-L-alanine (0.0027g,10 mol%), silver carbonate (0.165g,0.6mmol), and acetone (2mL) was added. The reaction tube was moved to a 50 ℃ oil bath for 10 hours. The mixture was purified by flash column chromatography to give a white liquid (29.9mg,0.074mmol) in 37% yield.
1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.6Hz,1H),7.69(t,J＝7.6Hz,2H),7.55(d,J＝ 8.5Hz,1H),7.47-7.37(m,2H),3.52(s,3H),2.86-2.74(m,1H),2.68-2.55(m,1H),2.42-2.29(m, 2H),2.00-1.89(m,2H),1.45(s,3H),1.03(t,J＝7.9Hz,9H),0.64(q,J＝7.9Hz,6H).13C NMR (100MHz,CDCl3)δ155.8,143.7,140.7,133.0,132.2,128.9,128.5,128.1,126.7,126.5,126.2, 126.2,120.6,106.6,93.6,61.6,32.0,23.1,21.4,21.3,7.7,4.7.HRMS(ESI)m/z:[M+Na]+ calculated for C26H34NOSi:404.2420:404.2404.HPLC with Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 94% ee); the main enantiomer tr is 25.868min and the secondary enantiomer tr is 25.514 min. [ alpha ] to]25D＝+19.5(c＝0.4,CHCl3).
Example 10:
(E) -2- (4-bromo-2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000102
To a 25mL reaction tube was added 3-methyl-2-naphthylbromocyclohex-2-en-1-one-O-methyloxime (0.0684g,0.2mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium acetate (0.0025g,5 mol%), N-benzyloxycarbonyl-L-phenylalanine (0.006g,10 mol%), silver carbonate (0.083g,0.3mmol), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture was purified by flash column chromatography to give a yellow liquid (57.8mg,0.11mmol) in 52% yield.
1H NMR(400MHz,CDCl3)δ8.32-8.15(m,1H),7.62(d,J＝8.7Hz,1H),7.44(m,2H), 6.89(s,1H),4.03(s,3H),3.55(s,3H),2.82(m,1H),2.67-2.51(m,1H),2.35(m,2H),1.94(m, 2H),1.47(s,3H),1.13(s,18H).13C NMR(100MHz,CDCl3)δ156.0,153.9,144.0,133.0(d,J＝ 3.3Hz),128.5,126.7,126.2,125.7,125.6,122.0,120.4,107.7,106.8,91.9,61.5,55.6,32.0, 27.1,23.1,21.5,21.3,18.9(d,J＝1.6Hz),11.5.HRMS(ESI)m/z:[M+Na]+calculated for C23H29BrNOSi 444.1168:442.1196.HPLC determination of ee with Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.25mL/min, 254nm, 93% ee); the main enantiomer tr is 30.001min and the secondary enantiomer tr is 28.961 min. [ alpha ] to]25D＝9(c＝0.005,CHCl3)
Example 11:
(E) -2- (2- ((tert-butyldimethylsilyl) ethynyl) naphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000111
To a 25mL reaction tube was added 3-methyl-2-naphthylcyclohex-2-en-1-one-O-methyloxime (0.053g,0.2mmol), (2-bromoethynyl) tert-butyldimethylsilane (0.09g,0.4mmol), palladium acetate (0.005g,10 mol%), N-acetyl-L-alanine (0.0053g,20 mol%), silver carbonate (0.165g,0.6mmol), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 24 hours. The mixture was purified by flash column chromatography to give a yellow liquid (45.3mg,0.112mmol) in 56% yield.
1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.4Hz,1H),7.52(t,J＝7.4Hz,2H),7.39(d,J＝ 8.5Hz,1H),7.30-7.20(m,2H),3.36(s,3H),2.69-2.58(m,1H),2.52-2.39(m,1H),2.26-2.14(m, 2H),1.84-1.73(m,2H),1.29(s,3H),0.81(s,9H),-0.00(s,6H).13C NMR(100MHz,CDCl3)δ 155.8(d,J＝40.6Hz),143.7(d,J＝37.6Hz),140.6,132.9(d,J＝33.8Hz),132.2,128.9,128.5, 128.1,126.7,126.5,126.2(d,J＝2.8Hz),120.5,105.8,94.5,61.6,32.0,26.3,23.0,21.4,21.3, 16.8,-4.3.HRMS(ESI)m/z:[M+Na]+calculated for C26H34NOSi:404.2388:404.2404.HPLC with Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 96% ee); the main enantiomer tr is 26.623min and the secondary enantiomer tr is 25.496 min. [ alpha ] to]25D＝+20(c＝0.4,CHCl3).
Example 12:
(E) -2- (2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5, 6-dihydro- [1,1' -biphenyl ] -3(4H) -O-methyloxime
Figure RE-GDA0002849940660000121
To a 25mL reaction tube were added 3-phenyl-2-naphthylcyclohex-2-en-1-one-O-methyloxime (0.065g,0.2mmol), (2-bromoethynyl) triisopropylsilane (0.16g,0.6mmol), palladium acetate (0.005g,10 mol%), N-acetyl-L-alanine (0.0053g,20 mol%), silver carbonate (0.165g,0.6mmol), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture from which methanol was removed was purified by flash column chromatography to give a brown liquid (48.8mg,0.096 mmol) in 48% yield.
1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.8Hz,1H),7.58-7.51(m,1H),7.45(d,J＝8.5 Hz,1H),7.32(d,J＝8.5Hz,1H),7.25(m,2H),6.94(m,2H),6.85-6.75(m,3H),3.48(s,3H), 2.86(m,1H),2.71-2.44(m,3H),2.15-1.90(m,2H),1.07(s,18H).
13C NMR(100MHz,CDCl3)δ155.7,146.2,142.2,139.8,132.7,132.2,130.1,128.9, 127.9,127.4,127.0,126.7,126.7,126.4,126.0,125.9,122.2,108.0,93.1,61.7,32.6,23.2,21.6, 18.9,18.9,11.5.HRMS(ESI)m/z:[M+Na]+calculated for C34H42NOSi:508.3046, found: 508.3030 HPLC using a Chiralpak AD-H + OX-H column (hexane: 2-propanol 99.2:0.8, 0.3mL/min, 254nm, 98% ee); the major enantiomer tr is 26.451min and the minor enantiomer tr is 27.181 min. [ alpha ] to]25D＝-51(c＝0.02,CHCl3)
Example 13:
(E) -3 '-methoxy-6-methyl-2', 6 '-bis ((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000122
(E) -3 '-methoxy-6-methyl-4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime (0.3mmol), palladium acetate (6.7mg,10 mol%), N-acetyl-L-alanine (7.9mg,20 mol%), silver carbonate (250mg,0.9mmol,0.9mmol) were added to the magneton-containing tube. Thereafter, methanol (3.0mL) was added using a syringe. (2-bromoethynyl) triisopropylsilane (240mg,0.9mmol) was then added to the above. The reaction mixture was stirred in an oil bath for 48 hours at 40 ℃. The reaction mixture was cooled to room temperature. The mixture was purified by flash column chromatography to give a white liquid (63mg,0.156mmol) in 52% yield.
1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.6Hz,1H),6.64(d,J＝8.6Hz,1H),3.80(s, 3H),3.58(s,3H),2.52-2.44(m,2H),2.13(t,J＝6.0Hz,2H),1.76-1.71(m,2H),1.47(s,3H), 1.00(d,J＝9.1Hz,36H).13C NMR(101MHz,Chloroform-d)δ160.7,154.9,146.2,141.9, 133.5,129.5,116.4,113.5,108.7,106.0,101.6,97.0,89.8,61.4,55.8,31.6,22.6,21.1,20.7, 18.7,11.3.HRMS(ESI)m/z:[M+Na]+calculated for C37H60NO2Si2606.4167:606.4157. measuring ee value by chiral OD-H + OX-H column (hexane: 2-propanol ═ 99:1, 0.3mL/min, 254nm, 90% ee) HPLC; the major enantiomer tr is 24.549min and the minor enantiomer tr is 25.522 min. [ alpha ] to]25D＝+21.2(c＝0.5,CHCl3).
Example 14:
(E) -3', 6-dimethyl-2', 6 '-bis ((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000131
(E) -3', 6-dimethyl-4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime (0.3mmol), palladium acetate (6.7mg,10 mol%), N-acetyl-L-alanine (7.9mg,20 mol%), silver carbonate (250mg,0.9mmol,0.9mmol) were added to the magneton-containing tube. Thereafter, methanol (3.0mL) was added using a syringe. (2-bromoethynyl) triisopropylsilane (240mg,0.9mmol) was then added to the above. The reaction mixture was stirred in an oil bath for 48 hours at 40 ℃. The reaction mixture was cooled to room temperature. The mixture was purified by flash column chromatography to give a white liquid (45.0mg,0.108mmol) in 36% yield.
1H NMR(400MHz,CDCl3)δ7.35(d,J＝7.8Hz,1H),7.06(d,J＝7.9Hz,1H),3.65(s, 3H),2.57(t,J＝6.7Hz,2H),2.47(s,3H),2.21(t,J＝6.0Hz,2H),1.85-1.79(m,2H),1.53(s, 3H),1.08(d,36H).13C NMR(100MHz,CDCl3)δ155.2,144.4,141.9,141.1,132.0,130.2, 127.6,124.1,121.5,106.4,104.6,96.5,91.0,61.5,31.7,22.8,21.8,21.3,20.8,18.9,18.8,18.8, 11.4,11.4.HRMS(ESI)m/z:[M+Na]+calculated for C23H29BrNOSi 444.1168:442.1196.HPLC determination of ee with Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 98% ee); the main enantiomer tr is 35.237min and the secondary enantiomer tr is 38.653 min. [ alpha ] to]25D＝-2(c＝1.7, CHCl3).
Example 15:
(E) -3 '-fluoro-6-methyl-2', 6 '-bis ((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000141
(E) -3 '-fluoro-6-methyl-4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime (0.3mmol), palladium acetate (6.7mg,10 mol%), N-acetyl-L-alanine (7.9mg,20 mol%), silver carbonate (250mg,0.9mmol,0.9mmol) were added to the magneton-containing tube. Thereafter, methanol (3.0mL) was added using a syringe. (2-bromoethynyl) triisopropylsilane (240mg,0.9mmol) was then added to the above. The reaction mixture was stirred in an oil bath for 48 hours at 40 ℃. The reaction mixture was cooled to room temperature. The mixture was purified by flash column chromatography to give a yellow liquid (90.9mg,0.153mmol) in 51% yield.
1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.6,5.5Hz,1H),6.92(t,J＝8.6Hz,1H),3.66 (s,3H),2.57(t,J＝6.6Hz,2H),2.22(t,J＝5.9Hz,2H),1.85-1.79(m,2H),1.56(s,3H),1.08(d, J＝6.1Hz,36H).13C NMR(100MHz,CDCl3)δ164.4,161.9,154.8,146.9,142.5,133.6,133.6, 129.1,120.2(d,J＝3.5Hz),113.8,113.6,113.3,113.2,105.2,98.7,91.6,61.5,31.7,22.7,21.2, 20.8,18.8,18.8,18.8,18.8,11.4,11.4,1.2.HRMS(ESI)m/z:[M+Na]+calculated for C36H57FNOSi2594.3958:594.3957. measuring ee value by high performance liquid chromatography using Chiralpak INC column (hexane: 2-propanol 98:2, 1.0mL/min, 254nm, 34% ee); the major enantiomer tr-1.922 min. [ alpha ] to]25D＝-4.23 (c＝1.5,CHCl3).
Example 16:
(E) -3- ((E) -2' - (methoxyimino) -4,6' -dimethyl-6- ((triisopropylsilyl) ethynyl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-yl) acrylic acid ethyl ester
Figure RE-GDA0002849940660000142
(E) -4', 6-dimethyl-4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime (0.3mmol), palladium acetate (6.7mg,10 mol%), N-acetyl-L-alanine (7.9mg,20 mol%), silver carbonate (250mg,0.9mmol,0.9mmol) were added to the magneton-containing tube. Thereafter, methanol (2.0mL) was added using a syringe. Ethyl acrylate (98uL,0.9mmol) was then added to the above. The reaction mixture was stirred in an oil bath for 48 hours at 40 ℃. The reaction mixture was cooled to room temperature. The intermediate purified by flash column chromatography (0.2mmol), palladium acetate (5.0mg,10 mol%), N-acetyl-L-alanine (5.3mg,20 mol%), silver carbonate (165mg,0.6mmol) were added to a tube containing magnetons. Thereafter, methanol (2.0mL) was added using a syringe. (2-bromoethynyl) triisopropylsilane (160mg,0.6mmol) was then added to the above. The reaction mixture was stirred in an oil bath at 40 ℃ for 48 hours, and the mixture was purified by flash column chromatography to give a yellow liquid (71.1 mg,0.142mmol) with a yield of 71%.
1H NMR(400MHz,CDCl3)δ7.51(d,J＝16.0Hz,1H),7.31(d,J＝17.6Hz,2H),6.25(d, J＝16.0Hz,1H),4.14(q,J＝7.1Hz,2H),3.55(s,3H),2.75-2.65(m,1H),2.42-2.32(m,1H), 2.27(s,3H),2.23-2.14(m,2H),1.85-1.73(m,2H),1.39(s,3H),1.25-1.17(m,6H),1.00(d,J＝ 2.5Hz,18H).13C NMR(100MHz,CDCl3)δ167.3,155.9,143.9,143.5,139.6,136.3,135.1, 133.5,128.3,126.5,124.6,118.7,106.2,91.8,61.6,60.4,31.8,29.8,22.9,21.4,21.1,21.0,18.8, 18.8,14.4,11.4.HRMS(ESI)m/z:[M+Na]+calculated for C31H46NO3508.3221:508.3241. HPLC using Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 98% ee) to determine the ee value; the main enantiomer tr is 28.850min and the secondary enantiomer tr is 26.132 min. [ alpha ] to]25D＝-16(c＝2.3, CHCl3).
Example 17:
(E) -3', 6-dimethyl-2' - ((triisopropylsilyl) ethynyl) -6'- ((E) -2- (trimethylsilyl) ethenyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000151
(E) -3', 6-dimethyl-4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime (0.3mmol), palladium acetate (6.7mg,10 mol%), N-acetyl-L-alanine (7.9mg,20 mol%), silver carbonate (250mg,0.9mmol,0.9mmol) were added to the magneton-containing tube. Thereafter, methanol (2.0mL) was added using a syringe. Vinyl silane (132uL, 0.9mmol) was then added to the above. The reaction mixture was stirred in an oil bath for 48 hours at 40 ℃. The intermediate purified by flash column chromatography (0.2mmol), palladium acetate (5.0mg,10 mol%), N-acetyl-L-alanine (5.3mg,20 mol%) and silver carbonate (165mg,0.6mmol) were added to a tube containing magnetons. Thereafter, methanol (2.0mL) was added using a syringe. (2-bromoethynyl) triisopropylsilane (160mg,0.6mmol) was then added to the above. The reaction mixture was stirred in an oil bath at 40 ℃ for 48 hours and the mixture was purified by flash column chromatography to give a yellow liquid (52.8mg,0.104mmol) in 52% yield.
1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),6.75(d,J＝ 19.2Hz,1H),6.26(d,J＝19.2Hz,1H),3.64(s,3H),2.81-2.69(m,1H),2.54-2.47(m,1H),2.46 (s,3H),2.28-2.21(m,2H),1.94-1.86(m,1H),1.81-1.74(m,1H),1.44(s,3H),1.09(d,J＝2.6 Hz,18H),0.08(s,9H).13C NMR(100MHz,CDCl3)δ155.6,142.8,142.4,140.3,140.2,134.9, 129.2,128.7,128.0,124.1,123.9,105.3,95.9,61.6,31.9,22.9,21.6,21.4,21.2,18.9,18.8,11.5, -1.0.HRMS(ESI)m/z:[M+Na]+calculated for C31H50NOSi2508.3430:508.3425.HPLC using Chiralpak AD-H + OX-H column (hexane: 2-propanol ═ 99.2:0.8, 0.3mL/min, 254nm, 100% ee); the major enantiomer tr-27.850 min. [ alpha ] to]25D＝-29(c＝0.9,CHCl3).
Example 18:
(E) -2'- ((tert-butyldimethylsilyl) ethynyl) -4', 6-dimethyl-6 '- ((triisopropylsilyl) ethynyl) -4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime
Figure RE-GDA0002849940660000161
(E) -4 '-chloro-6-methyl-4, 5-dihydro- [1,1' -biphenyl ] -2(3H) -O-methyloxime (0.3mmol), palladium acetate (6.7mg,10 mol%), N-acetyl-L-alanine (7.9mg,20 mol%), silver carbonate (250mg,0.9mmol,0.9mmol) were added to the magneton-containing tube. Thereafter, methanol (2.0mL) was added using a syringe. Then (2-bromoethynyl) tert-butyldimethylsilane (0.195g,0.9mmol) was added to the above. The reaction mixture was stirred in an oil bath for 48 hours at 40 ℃. The intermediate purified by flash column chromatography (0.2mmol), palladium acetate (5.0mg,10 mol%), N-acetyl-L-alanine (5.3mg,20 mol%), silver carbonate (165mg,0.6mmol) were added to a tube containing magnetons. Thereafter, methanol (2.0mL) was added using a syringe. (2-bromoethynyl) triisopropylsilane (160mg,0.6mmol) was then added to the above. The reaction mixture was stirred in an oil bath at 40 ℃ for 48 hours and the mixture was purified by flash column chromatography to give a yellow liquid (40.9mg, 0.072mmol) in 36% yield.
1H NMR(400MHz,CDCl3)δ7.41(s,2H),3.66(s,3H),2.62-2.49(m,2H),2.23-2.19(m, 2H),1.84-1.77(m,2H),1.54(s,3H),1.25(s,3H),1.06(s,18H),0.93(s,9H),0.11(s,6H).13C NMR(100MHz,CDCl3)δ155.0,142.9,142.7,132.3,132.0,131.7,128.8,125.9,125.5,104.7, 103.4,95.7,93.7,61.6,31.7,29.9,26.2,22.8,21.2,20.8,18.8(d,J＝1.6Hz),16.7,11.4,-4.5. HRMS(ESI)m/z:[M+Na]+calculated for C33H51ClNOSi2568.3182:568.3192. measuring the ee value by HPLC using Chiralpak AD-H + OX-H column (hexane: 2-propanol 99:1, 0.3mL/min, 254nm, 98% ee); the main enantiomer tr is 28.850min and the secondary enantiomer tr is 26.132 min. [ alpha ] to]25D＝-9.17(c＝0.6,CHCl3).
Example 19:
(E) -2- (2-ethynylnaphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000171
(E) -3-methyl-2- (2- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) cyclohex-2-en-1-one-O-methyloxime (700 mg,2.6mmol), diethyl ether (11mL) was added sequentially to a 25mL round bottom flask. After the magnetons were dissolved by stirring, a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.2mL,3.2mmol) was added and stirring was continued for 1 h. The mixture was purified by flash column chromatography to give a pale yellow liquid (458.4mg,1.586mmol) in 61% yield.
1H NMR(400MHz,CDCl3)δ7.71-7.64(m,1H),7.59(d,J＝8.5Hz,2H),7.45(d,J＝8.5 Hz,1H),7.35-7.26(m,2H),3.41(s,3H),2.98(s,1H),2.70-2.55(m,2H),2.26(t,J＝6.1Hz, 2H),1.89-1.77(m,2H),1.34(s,3H).13C NMR(100MHz,CDCl3)δ156.0,143.9,141.0,133.1, 132.1,128.8,128.3,128.1,126.9,126.4,126.4,126.3,119.4,83.7,79.3,61.6,31.9,23.1,21.4, 21.2.HRMS(ESI)m/z:[M+Na]+calculated for C20H20No. 568.3182:568.3192.HPLC with Chiralpak IA + OX-H column (hexane: 2-propanol 99:1, 0.8mL/min, 254nm, 98% ee); the main enantiomer tr is 10.739min and the secondary enantiomer tr is 11.377 min. [ alpha ] to]25D＝61(c＝0.004,CHCl3)
Example 20:
(E) -2- (2- (1-benzyl-1H-1, 2, 3-triazol-4-yl) naphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime
Figure RE-GDA0002849940660000172
(E) -2- (2-ethynylnaphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime (0.2mmol), benzyl azide (0.2mmol), CuI (10 mol%), DMF (2mL) were mixed in a flask and the reaction stirred at 80 ℃ for 12 h. In the optimization procedure, the progress of the reaction was followed using GC (internal standard: benzophenone) and thin layer chromatography. After completion of the reaction, the reaction mixture was cooled to room temperature, and the mixture was purified by flash column chromatography to give a white solid (51.5mg, 0.122mmol) with a yield of 61%.
1H NMR(400MHz,CDCl3)δ8.11(d,J＝8.6Hz,1H),7.74(dd,J＝16.0,8.2Hz,2H),7.55 (d,J＝8.1Hz,1H),7.34-7.25(m,6H),7.14(d,J＝7.5Hz,2H),5.51(d,J＝14.8Hz,1H),5.34 (d,J＝14.8Hz,1H),3.34(s,3H),2.63-2.53(m,1H),2.23-2.09(m,2H),1.78-1.64(m,2H), 1.44-1.34(m,1H),1.09(s,3H).13C NMR(100MHz,CDCl3)δ155.7,147.4,143.9,135.0,133.7, 133.2,132.3,129.2,128.8,128.5,128.1,128.0,127.4,127.2,126.2,126.0,126.0,125.7,121.7, 61.6,54.0,31.6,22.7,21.2,20.7.HRMS(ESI)m/z:[M+Na]+calculated for C27H26N4NaO 445.1983:445.1999.HPLC determination of ee with Chiralpak AD-H + OX-H column (hexane: 2-propanol ═ 99:1, 0.3mL/min, 254nm, 88% ee); the main enantiomer tr is 10.739min and the secondary enantiomer tr is 11.377 min. [ alpha ] to]25D＝+10.6(c＝0.57,CHCl3).
Example 21:
the compound (E) -2- (2- (1-benzyl-1H-1, 2, 3-triazol-4-yl) naphthalen-1-yl) -3-methylcyclohex-2-en-1-one-O-methyloxime obtained in example 21 forms a catalyst with copper which can be used for the catalytic asymmetric synthesis of chiral amines, the route being shown in the following reaction scheme:
Figure RE-GDA0002849940660000181
at room temperature under nitrogen, (CuOTf)2·C6H6(0.02mmol) was added to a solution of chiral ligand L (0.02mmol) in toluene (2 mL). After stirring for 10min, imine (0.2mmol) and phenylacetylene (0.3mmol) were added. The reaction mixture was stirred at room temperature for 72h and the mixture was purified by flash column chromatography to give a yellow liquid in 72% yield and 34% ee.
HPLC using a Chiralpak OX-H + OX-H column (hexane: 2-propanol ═ 98:2, 0.7mL/min, 254nm, 34% ee) to determine the ee value; the main enantiomer tr-11.106 min and the secondary enantiomer tr-12.078min。[α]25 D＝-7.12(c＝2.60, CHCl3).
Comparative example 1:
the preparation method is the same as that of example 21, but the chiral ligand L is not added, and the ee value of the product obtained after the same treatment is 0 through HPLC (high performance liquid chromatography) measurement, and the product is a racemic compound, thereby indicating that the ligand L plays a chiral induction role in a catalytic reaction.

Claims (10)

1. An axial chiral arylethynylsilane compound, characterized in that its structural formula (1) is represented by:
Figure FDA0002777828320000011
wherein R is1、R4、R5、R6Independently is C1～6Alkyl or C6～10Any of aryl groups; r2Selected from hydrogen, C1～6Alkyl or C6～10Any of aryl groups; r3Is selected from C1～6Alkyl, alkoxy, C6～10Aryl or halogen.
2. The axially chiral arylethynyl silane compound of claim 1, wherein R is1、R4、R5、R6Independently is any one of methyl, isopropyl, tertiary butyl or phenyl; r2Selected from any one of hydrogen, methyl, phenyl or benzyl; r3Selected from any one of methyl, methoxy, phenyl, fluorine, chlorine or bromine.
3. The preparation method of the axial chiral arylethynyl silane compound according to claim 1 or 2, wherein a complex formed by palladium salt and a ligand is used as a catalyst precursor, 2-arylcyclohex-2-en-1-one oxime and 2-bromoethynyl silane are used as reactants, and in the presence of an oxidant, asymmetric alkynylation is carried out on carbon-hydrogen bonds in the reactants in a reaction medium to obtain the axial chiral arylethynyl silane compound;
the structural general formula of the 2-arylcyclohex-2-en-1-one oxime is shown as (2), and the structural general formula of the 2-bromoethynylsilane is shown as (3):
Figure FDA0002777828320000012
wherein R is1、R2、R3、R4、R5、R6Is as defined in claim 1.
4. The method for preparing an axial chiral arylethynylsilane compound of claim 3, wherein the ligand is an N-single protected chiral amino acid, including any one of Boc-D-Val-OH, Boc-lle-OH, Boc-Phe-OH, Boc-L-TLE-OH, N-Ac-L-Ala-OH, N-CBZ-L-Val-OH, CBZ-L-Phe-OH, and N-Ac-L-Leu-OH, and the structural formulas are respectively as follows:
Figure FDA0002777828320000021
5. the method for preparing an axially chiral arylethynylsilane compound of claim 3, wherein the palladium salt is selected from any one or more of palladium acetate, palladium trifluoroacetate, palladium tetranitrile tetrafluoroborate and palladium chloride.
6. The method for preparing an axially chiral arylethynylsilane compound of claim 3, wherein the oxidant is selected from one or more of silver acetate, silver trifluoromethanesulfonate, silver oxide and silver carbonate.
7. The method for preparing an axially chiral arylethynylsilane compound of claim 3, wherein the reaction medium comprises a mixture of any one or more of methanol, tetrahydrofuran, dichloromethane, diethyl ether, ethyl acetate, and acetone.
8. The method for preparing the axial chiral arylethynylsilane compound according to claim 3, wherein the molar concentration of the 2-arylcyclohex-2-en-1-one oxime in the reaction solution is 0.1-1 mol/L; the dosage of the 2-bromoacetylene silane is 110-300 mol% of the 2-arylcyclohex-2-ene-1-one oxime.
9. The method for preparing the axial chiral arylethynylsilane compound of claim 3, wherein the amount of the palladium salt is 1-10 mol% of the 2-arylcyclohex-2-en-1-one oxime; the dosage of the ligand is 2-20 mol% of 2-arylcyclohex-2-ene-1-ketoxime; the dosage of the oxidant is 110-300 mol% of the 2-arylcyclohex-2-ene-1-ketoxime.
10. The method for preparing the axial chiral arylethynylsilane compound according to claim 3, wherein the reaction condition is 40-70 ℃ in an air environment, and the reaction time is 10-48 h.
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