Chiral bis-thiophene-bis-nitrogen oxide ligands, methods for their preparation and use in asymmetric catalysis

Abstract

The application discloses chiral bis-thiophene-bis-nitrogen-oxygen ligands BbTh-2NO and BTh-2NO. The ligands comprise bis-thiophene groups and nitrogen-oxygen groups (sulfur atoms of the bis-thiophene and oxygen atoms of the nitrogen-oxygen groups belong to electron-rich coordination sites), can form six-membered ring coordination with Lewis acid soft metal palladium, thereby generating chiral ligand metal palladium complexes, and are applied as chiral ligands in asymmetric catalytic reactions. Therefore, the application has important application value in the field of asymmetric catalytic synthesis, and a synthesis method thereof is very economical and simple. The application also has good air stability, wide applicability and good compatibility for various substituents.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chiral chemistry and asymmetric catalytic synthesis, in particular to a chiral bis-thiophene-bis-nitrogen oxide ligand (BbTh-2NO and BTh-2NO), a preparation method thereof and an application thereof in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole. BACKGROUND

[0002] Chiral pharmaceuticals are the frontier of the pharmaceutical industry. The Nobel Prize in Chemistry in 2001 and 2021 was awarded to the main contributors of chiral catalysis. At present, the total number of drugs used in the world is about 2000, and more than 50% of them are chiral drugs. Among the 250 commonly used drugs in clinical practice, as many as 200 are chiral drugs.

[0003] The key preparation technology of chiral drugs is selected as one of the "ten chemical technology inventions that have changed the world" proposed by IUPAC. Asymmetric catalysis technology is the most efficient and green way to obtain chiral molecules. One of the core scientific problems is the creation of superior chiral ligands and catalysts. The design and synthesis of original superior chiral ligands play a key role in the development of asymmetric catalytic reactions and are the most attractive and challenging goal in asymmetric catalysis. They can provide core technology for the efficient and green synthesis of chiral drugs and candidate drugs. In addition, an economically viable synthesis route is also crucial for superior chiral ligands, so that they can be widely used. In particular, the N-oxide of amine is a highly polar substance, which can be easily prepared by N-oxidation of pyridine compounds or tertiary amines. The oxygen atom generated in the N-oxide belongs to a rich electron coordination site. Therefore, the unique properties of the electron pair of the N-oxide provide an opportunity to form complexes with a variety of metals. Some studies focus on developing new chiral amine N-oxide ligands for metal-catalyzed reactions.

[0004] In the N-oxide derived from tertiary amines, if the parent tertiary amine contains three different groups, a stable chiral center will be generated at the nitrogen center of the corresponding N-oxyl group. In this context, therefore, we designed and developed a new type of chiral bis-thiophene-bis-nitrogen oxide ligand (BbTh-2NO and BTh-2NO) and tested their application in asymmetric Friedel-Crafts alkylation reaction of indole. Based on the design and synthesis of the new type of chiral bis-thiophene-bis-nitrogen oxide ligand, our design idea refers to the "eagle" biomimetic model figure: the two "eagle" claws are analogous to the two nitrogen oxide groups, the two phenyl groups are analogous to the "eagle" wings, and the bis-thiophene group is analogous to the "eagle" body (as shown in Figure 1 and Figure 2 ). SUMMARY

[0005] The application aims to provide chiral bithiophene-bisnitrogen oxide ligands (BbTh-2NO and BTh-2NO) and a preparation method and application thereof, the ligands comprising a bithiophene group and a nitrogen oxide group (sulfur atoms of the bithiophene and oxygen atoms of the nitrogen oxide group belong to electron-rich coordination sites), can form a six-membered ring coordination with a Lewis acid soft metal palladium, thereby generating a chiral ligand metal palladium complex, and are applied as chiral ligands in asymmetric catalytic reactions. Therefore, the application has important application value in the field of asymmetric catalytic synthesis, and the synthesis method is very economical and simple. The chiral ligands also have good air stability, wide applicability and good compatibility with various substituents.

[0006] The application is achieved as follows: a chiral bithiophene-bisnitrogen oxide ligand (BbTh-2NO and BTh-2NO), characterized in that the chiral bithiophene-bisnitrogen oxide ligand BbTh-2NO has a structure as shown in a general formula (I), and the chiral bithiophene-bisnitrogen oxide ligand BTh-2NO has a structure as shown in a general formula (II).

[0007]

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

[0009] The preparation method of the chiral bithiophene-bisnitrogen oxide ligand BbTh-2NO is characterized in that: a corresponding proline amide or hydroxyproline amide 1 is first subjected to a condensation reaction with a bithiophene-dimethyl form aldehyde 2 to generate an intermediate 3, and then a nitrogen atom in the intermediate 3 is subjected to a nitrogen oxidation reaction under the action of an oxidant m-chloroperoxybenzoic acid to generate the final product chiral bithiophene-bisnitrogen oxide ligand BbTh-2NO.

[0010] The synthesis route is as follows:

[0011]

[0012] The preparation method of the chiral bithiophene-bisnitrogen oxide ligand BTh-2NO is characterized in that: a corresponding proline amide or hydroxyproline amide 1 is first subjected to a condensation reaction with a bithiophene-dimethyl form aldehyde 2 to generate an intermediate 3, and then a nitrogen atom in the intermediate 3 is subjected to a nitrogen oxidation reaction under the action of an oxidant m-chloroperoxybenzoic acid to generate the final product chiral bithiophene-bisnitrogen oxide ligand BbTh-2NO.

[0013] The synthesis route is as follows:

[0014]

[0015] The application also discloses application of the chiral bithiophene-dinitrogen oxide ligand BTh-2NO as a ligand in an asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0016] The application also discloses application of the chiral bithiophene-dinitrogen oxide ligand BTh-2NO as a ligand in an asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0017] Our design idea is:

[0018]

[0019] The mechanism of the chiral bithiophene-dinitrogen oxide ligand BbTh-2NO ligand in the asymmetric catalytic Friedel-Crafts alkylation reaction of indole is as follows:

[0020]

[0021] By adopting the above technical scheme, the corresponding proline amide or hydroxyproline amide 1 is firstly subjected to condensation reaction with bithiophene-dimethyl form 2 to generate intermediate 3, then the nitrogen atom in the intermediate 3 is subjected to nitrogen oxidation reaction under the action of an oxidant m-chloroperoxybenzoic acid to generate the final product chiral bithiophene-dinitrogen oxide ligand BbTh-2NO; the corresponding proline amide or hydroxyproline amide 1 is firstly subjected to condensation reaction with bithiophene-dimethyl form 2 to generate intermediate 3, then the nitrogen atom in the intermediate 3 is subjected to nitrogen oxidation reaction under the action of an oxidant m-chloroperoxybenzoic acid to generate the final product chiral bithiophene-dinitrogen oxide ligand BTh-2NO. The ligand contains a bithiophene group and a nitrogen oxide group (the sulfur atom of the bithiophene and the oxygen atom of the nitrogen oxide group are rich in electron coordination sites), can form a six-membered ring coordination with a Lewis acid soft metal palladium, thereby generating a chiral ligand metal palladium complex, and is applied as a chiral ligand in an asymmetric catalytic reaction. Therefore, the chiral ligand metal palladium complex has important application value in the field of asymmetric catalytic synthesis, and the synthesis method is very economical and simple. The chiral ligand metal palladium complex also has good air stability, wide applicability and good compatibility for various substituents. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 and Figure 2 A design idea and creativity diagram of a chiral bithiophene-dinitrogen oxide ligand (BbTh-2NO and BTh-2NO) synthesized by the application;

[0023] Figure 2 A "hawk" biomimetic model diagram referenced by the application: the two "hawk" claws are analogous to the bithiophene group, the two phenyl groups are analogous to the wings of the "hawk", and the bithiophene group is analogous to the main body of the "hawk";

[0024] Figure 3 and Figure 4 The chiral ligand BbTh-1-2NO spectrum data of the embodiment of the present application;

[0025] Figure 5 and Figure 6 The chiral ligand BTh-4-2NO spectrum data of the embodiment of the present application; DETAILED DESCRIPTION

[0026] (I) Preparation of chiral bithienyl-bisnitrogen oxide ligand BbTh-2NO

[0027]

[0028] Chiral bithienyl-bisnitrogen oxide ligand BbTh-1-2NO: The starting proline amide 1a (2.5 eq) and bithienyl-dimethylaldehyde (1 eq, 0.78 mmol) 2 were dissolved in a proper amount of anhydrous ethanol, and refluxed for 12 h. After the reaction solution was treated, the intermediate 3 was obtained by column chromatography purification as a white solid. The intermediate 3 (100 mg, 1 eq) of the second step reaction was dissolved in a proper amount of dichloromethane, and reacted with meta-chloroperbenzoic acid (3.0 eq) at room temperature for 20 min. After the reaction solution was treated, BbTh-1-2NO was obtained by column chromatography purification as a light yellow solid; melting point: 232.5-233.4 °C, [a] D 20 = +7.4 (c 0.50, CHCl3); total yield 61%, >20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.24-2.26 (m, 2H), 2.39-2.45 (m, 2H), 2.50-2.60 (m, 4H), 3.76-3.80 (m, 2H), 3.94-4.01 (m, 2H), 4.47-4.50 (m, 2H), 7.02 (s, 2H), 7.18-7.22 (m, 2H), 7.30-7.34 (m, 4H), 7.51 (d, J = 8.0 Hz, 4H), 7.64 (s, 2H); 13 CNMR (CD3OD, 100 MHz) δ: 22.5, 24.1, 69.5, 76.3, 85.2, 115.3, 122.9, 124.4, 126.9, 128.9, 135.3, 137.0, 140.8, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 28 N4NaO4S2[M+Na] + : 595.1440; Found: 595.1433.

[0029] The preparation method of chiral bithiophene-dinitrogen oxide ligand BbTh-2-2NO~BbTh-14-2NO is the same as chiral ligand BbTh-1-2NO, the same feeding ratio as ligand BbTh-1-2NO, and ligand BbTh-2-2NO~BbTh-14-2NO can be obtained, the reaction yield is shown in Table 1, but it is emphasized that the examples are intended to illustrate but not limit the scope of the present application. The compounds of the present application are not limited to what is represented in Table 1.

[0030] Table 1 is the chemical structure of chiral bithiophene-dinitrogen oxide ligand BbTh-2NO

[0031]

[0032] The present example prepares chiral ligand Bbth-2-2NO: light yellow solid, melting point: 249.0-250.3℃; total yield 62%, >20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test are as follows: 1 HNMR(CD3OD,400MHz)δ:2.47-2.53(m,2H),2.63-2.70(m,2H),3.61(d,J=12.8Hz,2H),4.12-4.17(m,2H),4.55-4.58(m,2H),4.63-4.67(m,2H),6.91(s,2H),7.06-7.10(m,2H),7.17-7.21(m,4H),7.31-7.34(m,4H),7.53(s,2H); 13 C NMR(CD3OD,100MHz)δ:35.1,69.9,75.2,76.7,86.0,115.3,123.5,124.9,127.0,128.8,135.0,135.4,141.3,166.8;HRMS(ESI-TOF)m / z:Calcd.for C 30 H 28 N4NaO6S2[M+Na] + :627.1336;Found:627.1329.

[0033] The present example prepares chiral ligand Bbth-3-2NO: light yellow solid, melting point: 230.6-231.7℃; total yield 60%, 17:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test are as follows: 1H NMR (CD3OD, 400 MHz) δ: 1.13-1.16 (m, 6H), 2.25-2.28 (m, 2H), 2.40-2.46 (m, 2H), 2.54-2.60 (m, 8H), 3.77-3.81 (m, 2H), 3.94-3.99 (m, 2H), 4.47-4.50 (m, 2H), 6.97 (s, 2H), 7.13-7.20 (m, 4H), 7.40 (d, J = 8.8 Hz, 4H), 7.63 (s, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 14.5, 22.4, 24.1, 27.9, 69.5, 76.2, 85.3, 123.0, 124.3, 127.4, 128.2, 132.9, 137.1, 140.8, 143.4, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 34 H 36 N4NaO4S2[M+Na] + : 651.2065; Found: 651.2059.

[0034] The present example prepared chiral ligand Bbth-4-2NO: yellowish solid, melting point: 226.1-227.6 °C, [a] D 20 = -48.4 (c 0.50, CHCl3); total yield 59%, 16:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.40-2.45 (m, 4H), 2.53-2.57 (m, 2H), 2.69-2.76 (m, 2H), 3.71-3.77 (m, 2H), 4.13-4.20 (m, 2H), 4.57-4.61 (m, 2H), 6.91 (s, 2H), 7.17-7.21 (m, 2H), 7.29-7.34 (m, 4H), 7.48 (d, J = 7.6 Hz, 2H), 7.67 (s, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 23.0, 24.7, 68.8, 77.8, 85.5, 125.6, 127.7, 130.2, 130.6, 131.1, 132.2, 135.2, 141.5, 167.6; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 26 Cl2N4NaO4S2[M+Na] + : 663.0660; Found: 663.0651.

[0035] This example prepared chiral ligand Bbth-5-2NO: light yellow solid, melting point: 223.6-224.4 °C, [a] D 20 = -11.2 (c 0.50, CHCl3); total yield 61%, 19:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.15-2.22 (m, 2H), 2.29-2.36 (m, 2H), 2.39-2.53 (m, 4H), 3.65-3.70 (m, 2H), 3.85-3.93 (m, 2H), 4.38-4.42 (m, 2H), 6.90 (s, 2H), 6.94-6.98 (m, 4H), 7.40-7.43 (m, 4H), 7.56 (s, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 22.6, 24.2, 69.4, 76.5, 85.3, 115.5 (d, J CF = 23.1 Hz), 124.7, 125.5 (d, J CF = 9.3 Hz), 131.3, 131.4, 136.7, 141.0, 161.7 (d, J CF = 245.0 Hz), 167.3; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 26 F2N4NaO4S2[M+Na] + : 631.1254; Found: 631.1247.

[0036] This example prepared chiral ligand Bbth-6-2NO: light yellow solid, melting point: 235.6-236.5 °C, [a] D 20 = -18.8 (c 0.60, CHCl3); total yield 61%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.21-2.26 (m, 8H), 2.37-2.42 (m, 2H), 2.49-2.59 (m, 4H), 3.75-3.79 (m, 2H), 3.92-3.99 (m, 2H), 4.46-4.49 (m, 2H), 6.96 (s, 2H), 7.10 (d, J = 8.4 Hz, 4H), 7.36 (d, J = 8.4 Hz, 4H), 7.63 (s, 2H); 13C NMR (CD3OD, 100 MHz) δ: 19.6, 22.5, 24.1, 69.5, 76.3, 85.3, 115.6, 122.9, 124.4, 129.4, 132.7, 137.0, 137.1, 140.8, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 32 N4NaO4S2[M+Na] + : 623.1753; Found: 623.1745.

[0037] The chiral ligand Bbth-8-2NO was prepared in this example: pale yellow solid, m.p. 234.2-235.5 °C, [a] D 20 = -21.2 (c 0.55, CHCl3); overall yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 1.01-1.04 (m, 12H), 2.12-2.13 (m, 2H), 2.28-2.32 (m, 2H), 2.41-2.43 (m, 4H), 2.67-2.72 (m, 2H), 3.67-3.68 (m, 2H), 3.83-3.85 (m, 2H), 4.35-4.37 (m, 2H), 6.86 (d, J = 5.6 Hz, 2H), 7.05-7.08 (m, 4H), 7.29-7.33 (m, 4H), 7.52 (d, J = 6.0 Hz, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 22.5, 22.9, 24.1, 33.5, 69.6, 76.2, 85.3, 115.6, 122.9, 124.4, 126.8, 133.0, 137.2, 140.8, 147.9, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 36 H 40 N4NaO4S2[M+Na] + : 679.2383; Found: 679.2378.

[0038] The chiral ligand Bbth-8-2NO was prepared in this example: pale yellow solid, m.p. 234.2-235.5 °C, [a] D 20 = -21.2 (c 0.55, CHCl3); overall yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1H NMR (CD3OD, 400 MHz) δ: 2.22-2.35 (m, 4H), 2.41-2.46 (m, 2H), 2.53-2.59 (m, 2H), 3.65-3.71 (m, 2H), 3.92-3.99 (m, 2H), 4.45-4.48 (m, 2H), 6.77 (s, 2H), 7.01-7.06 (m, 2H), 7.08-7.13 (m, 2H), 7.24-7.30 (m, 4H), 7.60 (s, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 22.7, 24.3, 69.2, 76.7, 85.7, 116.3 (d, J CF = 19.3 Hz), 121.7 (d, J CF = 13.1 Hz), 124.6, 125.0, 128.9, 130.6 (d, J CF = 8.2 Hz), 136.0, 141.2, 157.8 (d, J CF = 249.2 Hz), 167.5; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 26 F2N4NaO4S2[M + Na] + : 631.1254; Found: 631.1256.

[0039] The present example prepared chiral ligand Bbth-9-2NO: yellowish solid, melting point: 237.5-238.4 °C, [a] D 20 = +25.1 (c 0.52, CHCl3); overall yield 61%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 1.24 (s, 18H), 2.24-2.27 (m, 2H), 2.40-2.46 (m, 2H), 2.49-2.60 (m, 4H), 3.78-3.82 (m, 2H), 3.94-4.01 (m, 2H), 4.47-4.50 (m, 2H), 6.99 (s, 2H), 7.35 (d, J = 8.8 Hz, 4H), 7.43 (d, J = 8.8 Hz, 4H), 7.64 (s, 2H); 13C NMR (CD3OD, 100 MHz) δ: 22.4, 24.0, 30.2, 34.0, 69.6, 76.1, 85.2, 122.4, 124.3, 125.8, 132.7, 137.2, 140.8, 150.1, 167.1; HRMS (ESI-TOF) m / z: Calcd. for C 38 H 44 N4NaO4S2[M+Na] + : 707.2693; Found: 707.2685.

[0040] The chiral ligand Bbth-10-2NO was prepared in this example: pale yellow solid, m.p. 247.2-248.2 °C, [a] D 20 = -0.3 (c 0.50, CHCl3); overall yield 61%, 20:1 dr; results of NMR and high resolution mass spectrometry tests, etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.14-2.16 (m, 2H), 2.30-2.36 (m, 2H), 2.40-2.50 (m, 4H), 3.66-3.70 (m, 2H), 3.83-3.90 (m, 2H), 4.37-4.40 (m, 2H), 6.82-6.87 (m, 2H), 6.97 (s, 2H), 7.18-7.22 (m, 4H), 7.37 (d, J = 10.4 Hz, 2H), 7.57 (s, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 22.4, 24.1, 69.5, 76.2, 84.7, 109.7 (d, J CF = 26.1 Hz), 113.2 (d, J CF = 21.2 Hz), 117.8, 117.9, 124.4, 130.3 (d, J CF = 9.1 Hz), 136.8, 136.9 (d, J CF = 10.1 Hz), 140.9, 162.8 (d, J CF = 250.1 Hz), 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 26 F2N4NaO4S2[M+Na] + : 631.1256; Found: 631.1256.

[0041] The chiral ligand Bbth-11-2NO was prepared in this example: pale yellow solid, m.p. 246.6-247.2 °C, [a]D 20 = -39.3 (c 0.54, CHCl3); overall yield 61%, >20:1 dr; results of NMR and high resolution mass spectrometry tests etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.31-2.35 (m, 4H), 2.42-2.46 (m, 2H), 2.60-2.67 (m, 2H), 3.59-3.65 (m, 2H), 4.07-4.14 (m, 2H), 4.47-4.51 (m, 2H), 6.83 (s, 2H), 7.09-7.17 (m, 6H), 7.52-7.55 (m, 4H); 13 CNMR (CD3OD, 100 MHz) δ: 23.1, 24.7, 68.7, 78.2, 85.5, 122.1, 125.8, 128.2, 130.8, 131.1, 132.7, 133.4, 134.7, 141.6, 167.5; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 27 Br2N4O4S2[M+H] + : 728.9835; Found: 728.9833.

[0042] The present example prepared chiral ligand Bbth-12-2NO: yellowish solid, melting point: 238.0-239.1 °C, [a] D 20 = -39.3 (c 0.54, CHCl3); overall yield 61%, >20:1 dr; results of NMR and high resolution mass spectrometry tests etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.31-2.35 (m, 4H), 2.42-2.46 (m, 2H), 2.60-2.67 (m, 2H), 3.59-3.65 (m, 2H), 4.07-4.14 (m, 2H), 4.47-4.51 (m, 2H), 6.83 (s, 2H), 7.09-7.17 (m, 6H), 7.52-7.55 (m, 4H); 13 CNMR (CD3OD, 100 MHz) δ: 23.1, 24.7, 68.7, 78.2, 85.5, 122.1, 125.8, 128.2, 130.8, 131.1, 132.7, 133.4, 134.7, 141.6, 167.5; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 32N4NaO6S2[M + Na] + : 655.1655; Found: 655.1653.

[0043] This example prepared chiral ligand Bbth-13-2NO: pale yellow solid, melting point: 235.0-236.5 °C, [a] D 20 = -7.6 (c 0.50, CHCl3); total yield 57%, 16: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.10-2.17 (m, 2H), 2.27-2.33 (m, 2H), 2.36-2.49 (m, 4H), 3.64-3.68 (m, 2H), 3.82-3.89 (m, 2H), 4.37-4.40 (m, 2H), 6.97 (s, 2H), 7.06-7.10 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.33-7.35 (m, 2H), 7.57 (s, 2H), 7.72-7.73 (m, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 22.5, 24.2, 69.5, 76.3, 84.7, 121.1, 122.1, 124.6, 125.5, 129.6, 130.4, 130.5, 136.7, 136.8, 141.0, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 30 H 27 Br2N4O4S2[M + H] + : 728.9835; Found: 728.9834.

[0044] (B) Preparation of chiral bithiophene-bisnitrogen oxide ligand BTh-2NO

[0045]

[0046] Chiral bithiophene-bisnitrogen oxide ligand BTh-1-2NO: The starting proline amide 1a (2.5 eq) and bithiophene-dicarboxaldehyde (1 eq, 0.78 mmol) 2' were dissolved in an appropriate amount of absolute ethanol and refluxed for 12 h. After the reaction solution was treated, the intermediate 3' was obtained as a white solid by column chromatography purification. 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 and reacted at room temperature for 20 min. After the reaction solution was treated, BTh-1-2NO was obtained as a light yellow solid by column chromatography purification, melting point: 247.0-247.9 °C, total yield 37%, >20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.58-2.64 (m, 2H), 2.72-2.79 (m, 2H), 3.66 (d, J = 12.8 Hz, 2H), 4.21-4.26 (m, 2H), 4.68 (s, 2H), 4.73-4.77 (m, 2H), 6.95 (s, 2H), 7.12 (d, J = 2.8 Hz, 2H), 7.18-7.22 (m, 2H), 7.29-7.33 (m, 6H), 7.40 (d, J = 7.6 Hz, 4H); 13 C NMR (CD3OD, 100 MHz) δ: 35.1, 69.9, 74.9, 77.0, 85.8, 123.3, 123.8, 127.0, 128.8, 130.6, 133.7, 135.0, 141.8, 166.9; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 31 N4O6S2[M+H] + : 631.1676; Found: 631.1667.

[0047] The preparation method of chiral bithiophene-bisnitrogen oxide ligands BTh-1-2NO ~ BTh-10-2NO prepared by the examples is the same as that of chiral bithiophene-bisnitrogen oxide ligand BTh-1-2NO, and the same feeding ratio as ligand BTh-1-2NO can obtain ligands BTh-1-2NO ~ BTh-10-2NO, and the reaction yield is shown in Table 2, but it should be emphasized that the examples are intended to illustrate rather than limit the scope of the present application. The compounds of the present application are not limited to what is represented in Table 2.

[0048] Table 2 is the chemical structure of preparing chiral bithiophene-bisnitrogen oxide ligand BTh-2NO

[0049]

[0050] The present example prepared chiral ligand BTh-2-2NO: light yellow solid, total yield 25%, 14:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test, etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.27-2.32 (m, 2H), 2.38-2.47 (m, 2H), 2.49-2.54 (m, 2H), 2.59-2.65 (m, 2H), 3.72-3.77 (m, 2H), 3.92-3.99 (m, 2H), 4.46-4.50 (m, 2H), 7.00 (s, 2H), 7.20-7.24 (m, 4H), 7.30-7.32 (m, 4H), 7.40 (d, J = 8.4 Hz, 2H), 7.70 (s, 2H); 13 CNMR (CD3OD, 100 MHz) δ: 22.5, 24.1, 69.0, 76.4, 84.3, 120.9, 122.8, 123.9, 126.7, 130.1, 132.0, 133.0, 134.4, 136.6, 141.1, 167.3; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 29 Cl2N4O4S2[M+H] + : 667.1002; Found: 667.0993.

[0051] The present example prepared chiral ligand BTh-3-2NO: light yellow solid, melting point: 245.9-246.6℃, total yield 36%, >20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test, etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 1.13 (s, 6H), 1.14 (s, 6H), 2.22-2.25 (m, 2H), 2.38-2.45 (m, 2H), 2.50-2.61 (m, 4H), 2.78-2.85 (m, 2H), 3.76-3.80 (m, 2H), 3.92-3.99 (m, 2H), 4.43-4.46 (m, 2H), 6.87 (d, J = 3.6 Hz, 2H), 6.92 (s, 2H), 7.21-7.23 (m, 6H), 7.46 (d, J = 8.4 Hz, 4H); 13 CNMR (CD3OD, 100 MHz) δ: 22.5, 23.0, 24.1, 33.6, 69.4, 76.2, 84.8, 123.0, 123.8, 127.0, 132.7, 133.0, 140.5, 148.0, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 38 H43 N4O4S2[M+H] + : 683.2720; Found: 683.2721.

[0052] The chiral ligand BTh-4-2NO was prepared in this example: pale yellow solid, melting point: 231.1-232.4 °C, overall yield 34%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.25-2.26 (m, 2H), 2.28 (s, 6H), 2.39-2.45 (m, 2H), 2.49-2.63 (m, 4H), 3.74-3.79 (m, 2H), 3.92-3.99 (m, 2H), 4.45-4.48 (m, 2H), 6.94 (s, 2H), 7.04 (d, J = 7.2 Hz, 2H), 7.15-7.17 (m, 2H), 7.20-7.28 (m, 6H), 7.36 (s, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 20.0, 22.5, 24.1, 69.1, 76.4, 84.8, 120.1, 123.6, 123.8, 127.7, 128.8, 132.6, 132.9, 135.1, 139.2, 140.8, 167.3; HRMS (ESI-TOF) m / z: Calcd. for C 34 H 35 N4O4S2[M+H] + : 627.2091; Found: 627.2085.

[0053] The chiral ligand BTh-5-2NO was prepared in this example: pale yellow solid, melting point: 232.9-233.4 °C, overall yield 31%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 HNMR (CD3OD, 400 MHz) δ: 2.24-2.36 (m, 14H), 2.45-2.55 (m, 4H), 2.76-2.85 (m, 2H), 3.48-3.56 (m, 2H), 3.86-3.92 (m, 2H), 4.52-4.56 (m, 2H), 6.86 (s, 2H), 6.95-7.00 (m, 6H), 7.04 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H); 13C NMR (CD3OD, 100 MHz) δ: 17.6, 17.8, 23.4, 25.2, 66.1, 80.0, 85.4, 121.6, 127.0, 128.2, 128.5, 128.8, 131.1, 134.2, 135.5, 138.5, 143.3, 167.6; HRMS (ESI-TOF) m / z: Calcd. for C 36 H 38 N4NaO4S2[M+Na] + : 677.2217; Found: 677.2213.

[0054] The chiral ligand BTh-6-2NO was prepared in this example: pale yellow solid, melting point: 223.7-224.4 °C, overall yield 30%, 20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.29-2.34 (m, 2H), 2.38-2.45 (m, 2H), 2.50-2.66 (m, 4H), 3.72-3.78 (m, 2H), 3.94-4.01 (m, 2H), 4.47-4.50 (m, 2H), 6.93 (s, 2H), 7.08-7.12 (m, 4H), 7.19 (d, J = 4.0 Hz, 2H), 7.31 (d, J = 3.6 Hz, 2H), 7.49-7.52 (m, 4H); 13 C NMR (CD3OD, 100 MHz) δ: 22.5, 24.2, 68.9, 76.6, 84.9, 115.5 (d, J CF = 23.4 Hz), 123.7, 125.6 (d, J CF = 8.3 Hz), 131.3, 132.1, 133.2, 141.2, 161.2 (d, J CF = 245.1 Hz), 167.3; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 28 F2N4NaO4S2[M+Na] + : 657.1405; Found: 657.1396.

[0055] The chiral ligand BTh-7-2NO was prepared in this example: pale yellow solid, melting point: 224.0-225.4 °C, overall yield 31%, 18:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1H NMR (CD3OD, 400 MHz) δ: 1.12-1.16 (m, 3H), 2.25-2.30 (m, 2H), 2.39-2.45 (m, 2H), 2.51-2.62 (m, 8H), 3.74-3.79 (m, 2H), 3.92-3.99 (m, 2H), 4.44-4.47 (m, 2H), 6.91 (s, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.8 Hz, 4H), 7.25-7.27 (m, 2H), 7.38-7.41 (m, 4H); 13 C NMR (CD3OD, 100 MHz) δ: 14.5, 22.5, 24.1, 27.9, 69.2, 76.4, 84.9, 123.1, 123.8, 128.3, 132.6, 132.8, 133.0, 140.8, 143.5, 167.2; HRMS (ESI-TOF) m / z: Calcd. for C 36 H 38 N4NaO4S2[M+Na] + : 677.2217; Found: 677.2207.

[0056] The present example prepared chiral ligand BTh-8-2NO: yellowish solid, melting point: 237.8-238.4 °C, total yield 30%, 17:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.29 (s, 6H), 2.36-2.43 (m, 4H), 2.47-2.54 (m, 2H), 2.67-2.75 (m, 2H), 3.60-3.67 (m, 2H), 3.91-3.98 (m, 2H), 4.55-4.59 (m, 2H), 6.89 (s, 2H), 7.05 (d, J = 4.0 Hz, 2H), 7.10-7.13 (m, 2H), 7.17-7.20 (m, 6H), 7.24 (d, J = 4.0 Hz, 2H); 13 C NMR (CD3OD, 100 MHz) δ: 17.3, 23.0, 24.9, 67.8, 78.7, 86.1, 122.5, 126.4, 128.6, 130.1, 131.0, 132.8, 134.3, 136.6, 142.3, 167.4; HRMS (ESI-TOF) m / z: Calcd. for C 34 H 34 N4NaO4S2[M+Na] + : 649.1905; Found: 649.1888.

[0057] The present example prepared chiral ligand BTh-9-2NO: light yellow solid, melting point: 235.6-236.4 °C, total yield 30%, 20: 1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test and the like are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.37-2.44 (m, 4H), 2.49-2.56 (m, 2H), 2.71-2.78 (m, 2H), 3.66-3.72 (m, 2H), 4.06-4.13 (m, 2H), 4.57-4.60 (m, 2H), 6.88 (s, 2H), 7.13 (d, J = 3.6 Hz, 2H), 7.22-7.36 (m, 8H), 7.45-7.48 (m, 2H); 13 CNMR (CD3OD, 100 MHz) δ: 23.1, 24.8, 68.2, 78.2, 85.3, 123.0, 127.8, 130.1, 130.2, 130.6, 130.8, 131.2, 132.3, 134.4, 142.4, 167.7; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 28 Cl2N4NaO4S2[M+Na] + : 689.0817; Found: 689.0812.

[0058] The present example prepared chiral ligand BTh-10-2NO: light yellow solid, melting point: 221.1-222.4 °C, total yield 31%, 12: 1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test and the like are as follows: 1 H NMR (CD3OD, 400 MHz) δ: 2.25-2.30 (m, 2H), 2.39-2.45 (m, 2H), 2.49-2.64 (m, 4H), 3.72-3.77 (m, 2H), 3.91-3.98 (m, 2H), 4.46-4.50 (m, 2H), 7.00 (s, 2H), 7.15-7.17 (m, 2H), 7.22-7.26 (m, 2H), 7.30 (d, J = 4.0 Hz, 2H), 7.34-7.37 (m, 2H), 7.43-7.46 (m, 2H), 7.84-7.85 (m, 2H); 13C NMR (CD3OD, 100 MHz) δ: 22.5, 24.2, 69.0, 76.4, 84.3, 121.3, 122.1, 123.9, 125.7, 129.7, 130.4, 132.0, 133.1, 136.7, 141.1, 167.3; HRMS (ESI-TOF) m / z: Calcd. for C 32 H 28 Br2N4NaO4S2[M+Na] + : 776.9811; Found: 776.9812.

[0059] (III) Application of chiral bithiophene-bisoxazoline ligands (BbTh-2NO and BTh-2NO) in asymmetric catalytic Friedel-Crafts alkylation of indole

[0060] The chiral bithiophene-bisoxazoline ligands (BbTh-2NO and BTh-2NO) of formula (1) of the present application contain bithiophene groups and oxazoline groups (the sulfur atoms of bithiophene and the oxygen atoms of oxazoline belong to electron-rich coordination sites), which can form six-membered ring coordination with Lewis acid soft metal palladium, thus generating chiral ligand metal palladium complex, which is applied as a dominant chiral ligand in asymmetric catalytic Friedel-Crafts alkylation of indole. It should be emphasized that the chiral bithiophene-bisoxazoline ligands (BbTh-2NO and BTh-2NO) of the present application are not limited to only being applied as chiral ligands in asymmetric catalytic Friedel-Crafts alkylation of indole.

[0061] Example 1: Application of chiral bithiophene-bisoxazoline ligands BbTh-2NO with various substituents in asymmetric catalytic Friedel-Crafts alkylation of indole 4a and enone lactam 5a

[0062] In order to prove the application value of the developed chiral ligand BbTh-2NO in asymmetric catalytic system, we choose the Friedel-Crafts alkylation reaction of indole 4a and enone lactam 5a as a template reaction, and select compounds BbTh-1-2NO~BbTh-13-2NO as chiral bithiophene-bisoxazoline ligands to generate chiral complex in situ with Lewis acid Pd(CH2CO2)2, and verify the asymmetric catalytic effect of chiral ligand BbTh-2NO (Table 3).

[0063] Table 3 is the application of chiral ligand BbTh-2NO with various substituents in asymmetric catalytic reaction

[0064]

[0065] Experimental conclusion: Friedel-Crafts alkylation template reaction of asymmetric catalysis of indole 4a and enone lactam 5a was selected as evaluation index. The experimental results show that the chiral ligand BbTh-1-2NO represented by formula (1) and Lewis acid Pd(CH2CO2)2 in situ generate chiral complex, which shows asymmetric catalysis effect in Friedel-Crafts alkylation reaction of indole 4a and enone lactam 5a, and can develop into a new advantage chiral and thienyl-bis-nitrogen oxygen ligand BbTh-2NO, which is worth further in-depth study.

[0066] Example 2: Application of chiral ligand BbTh-1-2NO in asymmetric catalysis of Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted enone lactams 5

[0067] In order to prove the application value of the developed chiral ligand BbTh-1-2NO in asymmetric catalysis system, Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted enone lactams 5 is selected as a template reaction to verify the catalytic effect of chiral ligand BbTh-1-2NO (Table 4).

[0068] Table 4 is the application of chiral ligand BbTh-1-2NO in asymmetric catalysis reaction

[0069]

[0070] Experimental conclusion: Friedel-Crafts alkylation template reaction of asymmetric catalysis of various substituted indoles 4 and various substituted enone lactams 5 was selected as evaluation index. The experimental results show that the chiral ligand BbTh-1-2NO represented by formula (1) and Lewis acid Pd(CH2CO2)2 in situ generate chiral complex, which shows asymmetric catalysis effect in Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted enone lactams 5, and can develop into a new advantage chiral ligand, which is worth further in-depth study.

[0071] Example 3: Application of chiral ligand BbTh-1-2NO in asymmetric catalysis of Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted enone lactams 5

[0072] In order to prove the application value of the developed chiral ligand BTh-2NO in asymmetric catalytic system, we select the Friedel-Crafts alkylation reaction of indole 4a and enone lactam 5a as a template reaction, and select compounds BTh-1-2NO~BTh-10-2NO as chiral dithiophene-bisnitrogen oxide ligand and Lewis acid Pd(CH2CO2)2 in situ to generate chiral complex, and verify the asymmetric catalytic effect of chiral ligand BTh-2NO (Table 5).

[0073] Table 5 is the application of chiral ligand BTh-2NO with various substituents in asymmetric catalytic reaction

[0074]

[0075] Experimental conclusion: The Friedel-Crafts alkylation template reaction of asymmetric catalysis of indole 4a and enone lactam 5a is selected as the evaluation index. The experimental results show that the chiral complex of various substituents of chiral ligand BTh-1-2NO~BTh-10-2NO and Lewis acid Pd(CH2CO2)2 in situ generates chiral complex, which shows asymmetric catalytic effect in the Friedel-Crafts alkylation reaction of indole 4a and enone lactam 5a, and can develop into a new advantage chiral dithiophene-bisnitrogen oxide ligand BTh-2NO, which is worth further in-depth study.

Claims

1. A chiral bisthiophene-bis(nitroxide) ligand BbTh-2NO and BTh-2NO, characterized in that: The chiral bisthiophene-bisoxo-ligand BbTh-2NO has the structure shown in general formula (Ⅰ), and the chiral bisthiophene-bisoxo-ligand BTh-2NO has the structure shown in general formula (Ⅱ). （I） （Ⅱ）； In the formula, R is a hydroxyl group or hydrogen; Ar is a benzene ring substituted with fluorine, chlorine, bromine, ethyl, tert-butyl, isopropyl, methoxy, methyl, or hydrogen.

2. A chiral thiophene-bis(nitroxide) ligand BbTh-2NO, characterized in that: Specifically, it is one of the following structural formulas: 。 3. A chiral bithiophene-bis(nitroxide) ligand BTh-2NO is characterized by: Specifically, it is one of the following structural formulas: 。 4. A method for preparing the chiral thiophene-bis(nitroxide) ligand BbTh-2NO as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 and bisthiophene-dicarboxaldehyde 2 first undergo a condensation reaction to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant metachloroperoxybenzoic acid to generate the final product chiral bisthiophene-dinitrogen oxide ligand BbTh-2NO. The synthesis route is as follows: 。 5. A method for preparing the chiral bithiophene-bis(nitroxide) ligand BTh-2NO as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 undergoes a condensation reaction with bithiophene-bis(formaldehyde) 2′ to generate intermediate 3′. Then, the nitrogen atom in intermediate 3′ undergoes a nitrogen oxidation reaction under the action of the oxidant metachloroperoxybenzoic acid to generate the final product chiral bithiophene-bis(nitrogen oxide) ligand BTh-2NO. The synthesis route is as follows: 。 6. The application of the chiral thiophene-bis(nitroxide) ligand BbTh-2NO as described in claim 1 as a ligand in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole, characterized in that: Applications in the following reactions: 。 7. The application of the chiral bithiophene-bis(nitroxide) ligand BTh-2NO as described in claim 1 in the asymmetric catalytic Friedel-Crafts alkylation reaction involving indole, characterized in that: Applications in the following reactions: 。

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