Chiral diphenyl ether-dinitrogen oxygen ligand BPE-2NO, preparation method thereof and application of chiral diphenyl ether-dinitrogen oxygen ligand BPE-2NO in asymmetric catalytic reaction

Abstract

The invention discloses a chiral diphenyl ether-dinitrogen oxygen ligand BPE-2NO and a preparation method of the chiral diphenyl ether-dinitrogen oxygen ligand BPE-2NO. The preparation method comprises the following steps: carrying out condensation reaction on corresponding prolinamide or hydroxyprolinamide 1 and diphenyl ether-dicarboxaldehyde 2 to generate an intermediate 3, and carrying out nitrogen oxidation reaction on nitrogen atoms in the intermediate 3 under the action of an oxidizing agent m-chloroperoxybenzoic acid to generate the final product chiral diphenyl ether-dinitrogen oxygen ligand BPE-2NO. The ligand comprises a diphenyl ether group and a nitrogen-oxygen group, wherein diphenyl ether can be used as a bridge to link two dinitrogen-oxygen groups derived from pyrrolo-imidazolone; according to the chiral ligand metal palladium compound disclosed by the invention, oxygen atoms of nitrogen-oxygen groups belong to electron-rich coordination sites and can form coordination with Lewis acid soft metal palladium, so that the chiral ligand metal palladium compound is generated and is applied as a chiral ligand in an asymmetric catalysis indole Friedel-Crafts alkylation reaction, and the synthesis method of the chiral ligand metal palladium compound is very economical, simple and convenient. And the compound also has good air stability and wide applicability, and has good compatibility with various substituent groups.

Description

Technical Field

[0001] The invention relates to the technical field of chiral chemistry and asymmetric catalytic synthesis, in particular to a chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO and a preparation method thereof and application thereof in asymmetric catalytic indole-involved Friedel-Crafts alkylation reaction. Background Art

[0002] Chiral pharmaceuticals are at the forefront of the pharmaceutical industry, and the Nobel Prizes in Chemistry in 2001 and 2021 were awarded to the main contributors to chiral catalysis. There are currently about 2,000 drugs in use in the world, of which chiral drugs account for more than 50%. Among the 250 drugs commonly used in clinical practice, there are as many as 200 chiral drugs.

[0003] The key preparation technology of chiral drugs was selected as one of the "Top Ten Chemical Technology Inventions that Changed the World" proposed by IUPAC. Asymmetric catalysis technology is the most efficient and green way to obtain chiral molecules. One of its core scientific issues is the creation of dominant chiral ligands and catalysts. The design and synthesis of original dominant chiral ligands play a key role in the development of asymmetric catalytic reactions. It is the most attractive and challenging goal in asymmetric catalysis and can provide core technology for the efficient and green synthesis of chiral drugs and candidate drugs. In addition, economically feasible synthetic routes are also crucial for dominant chiral ligands, so that they can be widely used. In particular, N-oxides of amines are highly polar substances, which can be easily prepared by N-oxidation of pyridine compounds or tertiary amines. The oxygen atoms generated in N-oxides belong to electron-rich coordination sites. Therefore, the unique properties of the electron pairs of N-oxides provide opportunities to form complexes with a variety of metals. Some research focuses on the development of new chiral amine N-oxide ligands for metal-catalyzed reactions.

[0004] In tertiary amine-derived N-oxides, if the parent tertiary amine contains three different groups, the nitrogen center on the corresponding N-oxyl group will produce a stable chiral center. In this context, we therefore designed and developed a new type of chiral diphenyl ether-diazotoxy ligand BPE-2NO and tested their application in the asymmetric Friedel-Crafts alkylation reaction of indole. Based on the design and synthesis of the new type of chiral diphenyl ether-diazotoxy ligand, our design ideas refer to the "eagle" bionic model diagram: the dizotoxy group is likened to the two "eagle" claws, the two phenyl groups are likened to the "eagle" wings, and the diphenyl ether group is likened to the "eagle" body (such as Figure 1 and Figure 2 shown). Summary of the invention

[0005] The purpose of the present invention is to provide a chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO and its preparation method and application. The ligand comprises a diphenyl ether group and a nitroxide group. The diphenyl ether can be used as a "bridge" to link two pyrroloimidazole-derived bis-nitrogen oxide groups; the oxygen atom of the nitroxide group belongs to an electron-rich coordination site, which can form a coordination with Lewis acid soft metal palladium to generate a chiral ligand metal palladium complex, which is used as a chiral ligand in an asymmetric catalytic reaction. Therefore, the chiral ligand BPE-2NO provided by the present invention has important application value in the field of asymmetric catalytic synthesis, and its synthesis method is very economical and simple. It also has good air stability, wide applicability, and good compatibility with various substituents.

[0006] The present invention is achieved as follows: a chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO, characterized in that the compound has a structure as shown in the general formula (I);

[0007]

[0008] In the formula, R is hydroxyl or hydrogen; Ar is fluorine, chlorine, bromine, ethyl, tert-butyl, isopropyl, methyl or a benzene ring substituted with hydrogen.

[0009] Among them, the chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO is specifically one of the following structural formulas:

[0010]

[0011] The preparation method of chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO is characterized in that: the corresponding proline amide or hydroxyproline amide 1 and diphenyl ether-diformaldehyde 2 are first subjected to a condensation reaction to generate an intermediate 3, and then the nitrogen atom in the intermediate 3 is subjected to a nitrogen oxidation reaction under the action of an oxidant, meta-chloroperbenzoic acid, to generate the final product chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO.

[0012] The synthetic route is as follows:

[0013]

[0014] The present invention also finds the application of chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO as a ligand in the Friedel-Crafts alkylation reaction involving asymmetric catalysis of indole.

[0015] Our design ideas are:

[0016]

[0017] The mechanism of the Friedel-Crafts alkylation reaction of indole catalyzed by the chiral ligand BPE-2NO is as follows:

[0018]

[0019] By adopting the above technical scheme, the corresponding proline amide or hydroxyproline amide 1 and diphenyl ether-diformaldehyde 2 first undergo condensation reaction to generate intermediate 3, and then the nitrogen atom in intermediate 3 undergoes nitrogen oxidation reaction under the action of oxidant meta-chloroperbenzoic acid to generate the final product chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO. This type of ligand contains a diphenyl ether group and a nitroxide group, and diphenyl ether can be used as a "bridge" to link two pyrroloimidazole-derived bis-nitrogen oxide groups; the oxygen atom of the nitroxide group belongs to an electron-rich coordination site, which can form a coordination with Lewis acid soft metal palladium to generate a chiral ligand metal palladium complex, which is used as a chiral ligand in asymmetric catalytic reactions. Therefore, the chiral ligand BPE-2NO provided by the present invention has important application value in the field of asymmetric catalytic synthesis, and its synthesis method is very economical and simple. It also has good air stability, wide applicability, and good compatibility with various substituents. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 and Figure 2 The design idea and creative diagram of a chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO synthesized by the present invention;

[0021] Figure 2 The "eagle" bionic model diagram referred to in the present invention: the dinitrogen oxide group is likened to the two "eagle" claws, the two phenyl groups are likened to the "eagle" wings, and the diphenyl ether group is likened to the "eagle" body;

[0022] Figure 3 and Figure 4 The spectrum data of the chiral ligand BPE-1-2NO of the embodiment of the present invention;

[0023] Figure 5 The racemic and chiral liquid phase spectrum data of compound 6a of the embodiment of the present invention; DETAILED DESCRIPTION

[0024] (I) Preparation of chiral diphenyl ether-bis(nitrogen oxide) ligand BPE-2NO

[0025]

[0026] Chiral diphenyl ether-dinitrogen oxide ligand BPE-1-2NO: The raw material proline amide 1a (2.5 eq) and diphenyl ether-diformaldehyde (1 eq, 0.78 mmol) 2 were dissolved in an appropriate amount of anhydrous ethanol, refluxed for 12 h, and the reaction solution was treated and purified by column chromatography to obtain a white solid intermediate 3. The intermediate 3 (100 mg, 1 eq) of the second step reaction and m-chloroperbenzoic acid (3.0 eq) were dissolved in an appropriate amount of dichloromethane, reacted at room temperature for 20 min, and the reaction solution was treated and purified by column chromatography to obtain a light yellow solid BPE-1-2NO; the total yield was 47%, >20:1dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.29(m,2H),2.44-2.65(m,6H),4.05-4.15(m,4H),4.64-4.67(m,2H ),6.51(d,J=8.0Hz,2H),7.19-7.32(m,10H),7.46(s,2H),7.53-7.56(m,4H),7.63-7.65(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.6,24.3,71.8,76.8,83.0,118.5,122.7,123.1,124.0, 126.8,128.5,129.0,131.8,135.5,157.3,167.8; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 34 N4NaO5[M+Na] + :625.2420;Found:625.2414.

[0027] The preparation method of the chiral diphenyl ether-bis-nitrogen oxide ligands BPE-2-2NO to BPE-15-2NO prepared in the examples is the same as that of the chiral ligand BPE-1-2NO, and the feed ratio is the same as that of the ligand BPE-1-2NO, and the ligands BPE-2-2NO to BPE-15-2NO can be obtained. The reaction yields are shown in Table 1, but it should be emphasized that the examples are intended to illustrate rather than limit the scope of the present invention. The compounds of the present invention are not limited to the contents shown in Table 1.

[0028] Table 1 shows the chemical structure of the chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO.

[0029]

[0030] This example prepares the chiral ligand BPE-2-2NO: light yellow solid, total yield 43%, 19:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows:1 H NMR (CD3OD, 400MHz) δ: 2.63-2.69 (m, 2H), 2.81-2.87 (m, 2H), 4.14 (d, J = 12.8Hz, 2H), 4.34-4.39 (m, 2H), 4.69 (s, 2H), 4.89-4. 92(m,2H),6.55(d,J=8.0Hz,2H),7.20-7.26(m,4H),7.30-7.35(m,6H),7.42(s,2H),7.52(d,J=8.0Hz,4H),7.63-7.65(m,2H); 13 C NMR(CD3OD,100MHz)δ:35.4,70.3,76.4,76.6,83.4,118.6,121.7,123.2,124.1, 126.9,129.0,129.1,132.1,135.3,157.3,167.3; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 34 N4NaO7[M+Na] + :657.2313;Found:657.2305.

[0031] This example prepares the chiral ligand BPE-3-2NO: light yellow solid, total yield 44%, 18:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.24 (s, 6H), 2.63-2.69 (m, 2H), 2.80-2.86 (m, 2H), 4.14 (d, J = 12.4Hz, 2H), 4.34-4.38 (m, 2H), 4.67-4.70 (m, 2H) ,4.89-4.91(m,2H),6.53(d,J=8.0Hz,2H),7.04(d,J=7.6Hz,2H),7.18-7.25(m,4H),7.30-7.37(m,6H),7.45(s,2H),7.63-7.66(m,2H); 13 C NMR(CD3OD,100MHz)δ:20.1,35.4,70.3,76.4,76.7,83.4,118.5,120.3,121.8,123.5,124 .1,127.6,128.8,129.1,132.0,135.3,139.3,157.4,167.2; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 38 N4NaO7[M+Na] +:685.2623;Found:685.2607.

[0032] This example prepares the chiral ligand BPE-4-2NO: light yellow solid, total yield 37%, 12:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.30(m,2H),2.45-2.65(m,6H),4.01-4.16(m,4H),4.65-4.68(m,2H),6.66( d,J=8.0Hz,2H),7.21-7.29(m,4H),7.36-7.38(m,4H),7.56(s,2H),7.60-7.65(m,4H),7.82-7.83(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.6,24.4,71.9,76.8,82.6,118.7,121.4,122.2,122.3,123.1,124.2,125 .2,128.5,129.0,129.5,130.5,132.1,137.0,157.4,163.5,167.7; HRMS(ESI-TOF)m / z:Calcd.forC 36 H 32 Br2N4NaO5[M+Na] + :781.0632;Found:781.0632.

[0033] This example prepares the chiral ligand BPE-5-2NO: light yellow solid, total yield 40%, 16:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.30(m,2H),2.44-2.50(m,2H),2.53-2.65(m,4H),4.05-4.18(m,4H),4.64-4.67(m,2 H),6.51(d,J=8.0Hz,2H),7.02-7.07(m,4H),7.24-7.34(m,4H),7.42(s,2H),7.53-7.57(m,4H),7.64-7.66(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.6,24.3,71.8,76.7,83.2,115.7(d,J CF =22.4Hz),118.4,122.5,124.1,125.5(d,J CF=8.2Hz),128.6,131.5,131.6,131.9,157.2,160.8(d,J CF =245.3Hz),167.8; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 32 F2N4NaO5[M+Na] + :661.2221;Found:661.2210.

[0034] This example prepares the chiral ligand BPE-6-2NO: light yellow solid, total yield 39%, 18:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.64-2.70 (m, 2H), 2.82-2.88 (m, 2H), 4.16 (d, J = 12.4Hz, 2H), 4.33-4.38 (m, 2H), 4.68-4.71 (m, 2H), 4.8 9-4.93(m,2H),6.61(d,J=8.0Hz,2H),7.26-7.33(m,6H),7.35-7.40(m,2H),7.43(s,2H),7.51-7.55(m,4H),7.61-7.64(m,2H); 13 C NMR(CD3OD,100MHz)δ:35.4,62.1,70.2,76.5,83.2,116.1,118.6,121.5,124.2,124.5, 128.4,128.9,129.0,132.1,132.2,134.1,157.2,167.2; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 32 Cl2N4NaO7[M+Na] + :725.1531;Found:725.1526.

[0035] This example prepares the chiral ligand BPE-7-2NO: light yellow solid, total yield 41%, 17:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR (CD3OD, 400MHz) δ: 2.64-2.70 (m, 2H), 2.81-2.87 (m, 2H), 4.16 (d, J = 12.4Hz, 2H), 4.35-4.39 (m, 2H), 4.70 (s, 2H), 4.89-4.9 2(m,2H),6.54(d,J=8.4Hz,2H),7.04-7.08(m,4H),7.25-7.28(m,2H),7.33-7.38(m,4H),7.52-7.55(m,4H),7.65-7.67(m,2H); 13 C NMR(CD3OD,100MHz)δ:35.3,62.1,70.3,76.5,83.5,115.7(d,J CF =23.4Hz),118.5,121.6,124.2,125.6(d,J CF =8.3Hz),129.1,131.4(d,J CF =3.1Hz),132.2,157.2,161.7(d,J CF =245.2Hz),167.3; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 32 F2N4NaO7[M+Na] + :693.2121;Found:693.2113.

[0036] This example prepares the chiral ligand BPE-8-2NO: light yellow solid, total yield 41%, 18:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.14-1.18(m,6H),2.55-2.68(m,6H),2.80-2.86(m ,2H),4.15(d,J=12.4Hz,2H),4.33-4.37(m,2H),4.67-4.69(m,2H),4.88- 4.90(m,2H),6.53(d,J=8.0Hz,2H),7.15(d,J=8.4Hz,4H),7.22-7.26(m,2 H),7.29-7.34(m,2H),7.36(s,2H),7.39-7.42(m,4H),7.63-7.66(m,2H); 13C NMR(CD3OD,100MHz)δ:14.6,27.9,35.4,70.3,76.4,76.6,83.6,118.6,121.8,123.3,1 24.1,128.3,129.0,132.0,132.9,143.5,157.3,167.3; HRMS(ESI-TOF)m / z:Calcd.for C 40 H 42 N4NaO7[M+Na] + :713.2935;Found:713.2928.

[0037] This example prepares the chiral ligand BPE-9-2NO: light yellow solid, total yield 42%, 18:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.17-1.19(m,12H),2.62-2.68(m,2H),2.80-2.88( m,4H),4.17(d,J=12.4Hz,2H),4.32-4.36(m,2H),4.66-4.69(m,2H),4.88 -4.90(m,2H),6.53(d,J=8.0Hz,2H),7.18(d,J=8.4Hz,4H),7.22-7.26(m, 2H),7.28-7.32(m,2H),7.36(s,2H),7.40-7.43(m,4H),7.64-7.66(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.9,33.6,35.4,70.3,76.4,76.5,83.5,118.6,121.9,123.3,1 24.1,126.9,129.0,132.0,132.9,148.0,157.2,167.3; HRMS(ESI-TOF)m / z:Calcd.for C 42 H 46 N4NaO7[M+Na] + :741.3245;Found:741.3236.

[0038] This example prepares the chiral ligand BPE-11-2NO: light yellow solid, total yield 37%, 20:1dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1H NMR (CD3OD, 400MHz) δ: 2.27 (s, 6H), 2.66-2.72 (m, 2H), 2.78-2.84 (m, 2H), 4.04 (d, J = 13.6Hz, 2H), 4.43-4.47 (m, 2H), 4.75 (s, 2H) ),5.00-5.04(m,2H),6.07(d,J=8.0Hz,2H),7.08-7.10(m,4H),7.17(d,J=7.6Hz,4H),7.24(d,J=4.8Hz,6H),7.81-7.84(m,2H); 13 C NMR(CD3OD,100MHz)δ:17.6,35.4,70.2,76.8,77.1,84.4,118.4,121.6,123.8,126.5,126 .6,128.7,130.6,131.5,132.1,133.1,136.1,157.1,167.3; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 38 N4NaO7[M+Na] + :685.2622;Found:685.2613.

[0039] This example prepares the chiral ligand BPE-12-2NO: light yellow solid, total yield 39%, 15:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.30(m,2H),2.44-2.66(m,6H),4.03-4.17(m,4H),4.66-4.69(m,2H),6.65(d,J =8.4Hz,2H),7.20-7.24(m,2H),7.25-7.31(m,4H),7.34-7.38(m,2H),7.57-7.63(m,6H),7.71-7.72(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.6,24.4,71.9,76.8,82.6,118.6,120.9,122.4,124.2,126 .5,128.5,130.3,132.1,134.5,136.9,157.4,167.7; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 32 Cl2N4NaO5[M+Na] + :693.1642;Found:693.1634.

[0040] This example prepares the chiral ligand BPE-13-2NO: light yellow solid, total yield 42%, 15:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.17-1.19(m,12H),2.22-2.26(m,2H),2.43-2.63(m,6H),2.81-2.88(m,2H),4.09-4. 14(m,4H),4.64-4.67(m,2H),6.49(d,J=5.2Hz,2H),7.16-7.26(m,8H),7.39-7.44(m,6H),7.63-7.65(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.6,22.9,24.3,33.6,71.7,76.7,83.2,118.5,122.8,123.3,1 24.0,126.9,128.5,131.7,133.1,148.0,157.2,167.8; HRMS(ESI-TOF)m / z:Calcd.for C 42 H 46 N4NaO5[M+Na] + :709.3358;Found:709.3347.

[0041] This example prepares the chiral ligand BPE-14-2NO: light yellow solid, total yield 40%, 16:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.22-2.29(m,2H),2.44-2.65(m,6H),4.07-4.13(m,4H),4.64-4.68(m,2H),6.59(d,J =8.0Hz,2H),7.23-7.27(m,2H),7.31-7.35(m,2H),7.42-7.45(m,4H),7.47-7.50(m,6H),7.60-7.63(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.6,24.3,71.8,76.7,82.7,118.5,119.8,122.4,124.2, 124.6,128.5,131.9,132.0,134.7,157.2,167.7; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 33 Br2N4O5[M+H] +:759.0782;Found:759.0775.

[0042] This example prepares the chiral ligand BPE-15-2NO: light yellow solid, total yield 42%, 20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR (CD3OD, 400MHz) δ: 1.26 (s, 18H), 2.63-2.69 (m, 2H), 2.80-2.86 (m, 2H), 4.18 (d, J = 12.8Hz, 2H), 4.32-4.36 (m, 2H), 4.68 (s, 2H),4.89-4.91(m,2H),6.53(d,J=8.0Hz,2H),7.24-7.29(m,4H),7.33-7.37(m,6H),7.42(d,J=8.8Hz,4H),7.64-7.66(m,2H); 13 C NMR(CD3OD,100MHz)δ:30.3,34.1,35.4,70.3,76.4,76.5,83.5,118.6,121.9,122.9,1 24.1,125.9,128.9,132.0,132.6,150.2,157.2,167.3; HRMS(ESI-TOF)m / z:Calcd.for C 44 H 50 N4NaO7[M+Na] + :769.3534;Found:769.3523.

[0043] (II) Application of Chiral Diphenyl Ether-Dinitrogen Oxide Ligand BPE-2NO in Asymmetric Catalytic Friedel-Crafts Alkylation of Indole

[0044] The chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO of formula (1) of the present invention comprises a diphenyl ether group and a nitroxide group, wherein the diphenyl ether group can be used as a "bridge" to link two bis-nitrogen oxide groups derived from pyrroloimidazoles; the oxygen atom of the nitroxide group belongs to an electron-rich coordination site, and can form a coordination with Lewis acid soft metal palladium to generate a chiral ligand metal palladium complex, which is used as a dominant chiral ligand in the Friedel-Crafts alkylation reaction involving asymmetric catalysis of indole. However, it should be emphasized that the chiral ligand BPE-2NO of the present invention is not limited to being used as a chiral ligand in the asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0045] Example 1: Application of chiral ligand BPE-2NO with various substituents in asymmetric catalytic reactions

[0046] In order to demonstrate the application value of the developed chiral ligand BPE-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of indole 4a and enone lactam 5a as the template reaction, and selected compounds BPE-1-2NO~BPE-15-2NO as chiral ligands to in situ generate chiral complexes with Lewis acid Pd(OAc)2 to verify the asymmetric catalytic effect of the chiral ligand BPE-2NO (Table 2).

[0047] Table 2 shows the application of chiral ligand BPE-2NO with various substituents in asymmetric catalytic reactions

[0048]

[0049] Experimental conclusion: The asymmetric catalytic Friedel-Crafts alkylation template reaction of indole 4a and enone lactam 5a was selected as the evaluation index. The experimental results show that the chiral ligands BPE-1-2NO~BPE-15-2NO with various substituents shown in formula (1) all show asymmetric catalytic effects in the Friedel-Crafts alkylation reaction of indole 4a and enone lactam 5a, and can be developed into a new advantageous chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO, which is worthy of further in-depth study.

[0050] Example 2: Application of chiral ligand BPE-1-2NO in asymmetric catalytic reactions

[0051] In order to demonstrate the application value of the developed chiral ligand BPE-1-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of indoles 4 with various substituents and enone lactams 5 with various substituents as the template reaction to verify the catalytic effect of the chiral ligand BPE-1-2NO (Table 3).

[0052] Table 3 shows the application of chiral ligand BPE-1-2NO in asymmetric catalytic reactions

[0053]

[0054] Experimental conclusion: The asymmetric catalytic Friedel-Crafts alkylation template reaction of various substituted indoles 4 and various substituted enone lactams 5 was selected as the evaluation index. The experimental results show that the chiral ligand BPE-1-2NO represented by formula (1) generates a chiral complex in situ with Lewis acid Pd(CH2CO2)2, and shows asymmetric catalytic effect in the Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted enone lactams 5. It can be developed into a new dominant chiral ligand and is worthy of further in-depth study.

Claims

1. A chiral diphenyl ether-bis(nitrogen oxide) ligand BPE-2NO, characterized in that: The compound has a structure as shown in general formula (I); In the formula, R is hydroxyl or hydrogen; Ar is fluorine, chlorine, bromine, ethyl, tert-butyl, isopropyl, methyl or a benzene ring substituted with hydrogen. Among them, the chiral diphenyl ether-dinitrogen oxide ligand BPE-2NO is specifically one of the following structural formulas:

2. A method for preparing the chiral diphenyl ether-bis(nitrogen oxide) ligand BPE-2NO as claimed in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with diphenyl ether-diformaldehyde 2 to generate an intermediate 3, and then the nitrogen atom in the intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperbenzoic acid to generate the final product, a chiral diphenyl ether-bis-nitrogen oxide ligand BPE-2NO. The synthetic route is as follows:

3. A use of the chiral diphenyl ether-diazotoxide ligand BPE-2NO as claimed in claim 1 as a ligand in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole.

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