Organophosphine compounds based on cyclophane skeleton and uses thereof

Abstract

The invention discloses an organic phosphine compound based on a cyclophane skeleton and a metal complex based on such a compound as a ligand. The organic phosphine compound based on a cyclophane skeleton is a compound having a general formula A or an enantiomer or a racemate of the compound. These organic phosphorus compounds can be used as ligands or organic catalysts in organic reactions or asymmetric reactions, especially in catalytic or asymmetric catalytic addition reactions, hydrogenation reactions, coupling reactions, cyclization reactions and other reactions, and have economical practicality and industrial application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and relates to an organic phosphine compound based on a cyclophane skeleton and its use. The organic phosphorus compound can be used for metal-catalyzed coupling reaction or asymmetric reaction, or directly catalyze organic reaction. Background Art

[0002] Catalytic reactions, especially asymmetric catalysis, are one of the most active research areas in synthetic chemistry today. This technology can obtain organic molecules, especially optically active molecules, in the most direct and effective way, and has the advantages of being economical and easy to industrialize. The discovery and development of new and efficient (chiral) ligands and their catalysts are the key to achieving efficient and highly selective catalytic reactions, as well as a source of innovation for developing new reactions and promoting the development of medicinal chemistry. The design and synthesis of (chiral) ligands has made rapid progress, as shown in the following structural formulas. Because the applicability of ligands is limited and highly dependent on the reaction substrate, no ligand is universal. Seeking ligands and their catalysts with new frameworks is a challenging task.

[0003] The design of ligands and catalysts that improve catalytic activity and stereoselectivity mainly considers electrical and structural factors (such as dihedral angles, steric hindrance and skeleton rigidity, flexibility, etc.), especially the skeleton and dihedral angles have a great influence on the catalytic reaction yield or selectivity (enantioselectivity, regioselectivity, ring closure stereoselectivity, etc.) (EP1002801; US6333291; CN 1331871C). The generation of ligands and catalysts with skeletons having different dihedral angles indicates that they can have different unique catalytic effects or uses.

[0004]

[0005]

[0006] The present invention intends to design and prepare the corresponding organic phosphine compounds of cyclophane diaryl skeletons by using the enantiomers or racemates of dihalogenated cyclophane synthesized by using cheap and readily available cyclophane as the starting material, including ligands and catalysts such as bisphosphine, bisphosphinate phenol ester, bisamine phosphine, bisbenzylphosphine and bisthiophosphine. Such skeletons are stable and both rigid and flexible, with cheap and abundant raw materials, short synthesis routes, low preparation costs, strong practicality, and easy modification to expand the ligand / catalyst library, which will greatly enrich the derivatives of phosphine ligands and catalysts. Summary of the invention

[0007] The purpose of the present invention is to provide an organic phosphine compound based on a cyclophane skeleton and its use, and to disclose an intermediate and a target ligand and a catalytic preparation method.

[0008] An organic phosphine compound based on a cyclophane skeleton is a compound having the following general formula A or its enantiomer and racemate:

[0009]

[0010] Where R 1-4 Indicates 4 substituents R 1 -R 4 , are independently selected from hydrogen, halogen, nitro, cyano, ester, C1-C 10 Alkyl or perfluoroalkyl, C3-C 10 The cycloalkyl group of C1-C6, alkoxy or perfluoroalkoxy group of C1-C6, aryloxy or substituted aryloxy group, heteroaryloxy or substituted heteroaryloxy group, arylmethyleneoxy or substituted arylmethyleneoxy group, heteroarylmethyleneoxy or substituted heteroarylmethyleneoxy group, silyl group, substituted silyl group, aryl or substituted aryl group, condensed aryl group or substituted condensed aryl group, heteroaryl or substituted heteroaryl group, and any possible combination of the above substituents; wherein the substituted aryloxy group, substituted aryl group, substituted silyl group, substituted condensed aryl group or substituted heteroaryl group has one or more substituents, and the substituents are independently selected from halogen, N-dimethylamino, C1-C4 alkyl or perfluoroalkyl group, C3-C6 cycloalkyl group, C1-C4 alkoxy or perfluoroalkoxy group, methylenedioxy group, aryl, aryloxy group, heteroaryl group; the heteroaryl group is C5-C 14 The heteroaryl group; the substituent R 1 -R 4 Any two adjacent ones can be connected with the benzene ring to form a ring system;

[0011] wherein X is selected from O, CH2, NR, S and a bond between carbon and phosphorus; R is selected from hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, C1-C 10 an alkyl, aryl or perfluoroalkyl substituted sulfonyl group;

[0012] Where R 5 Represents C1-C 10 Alkyl or perfluoroalkyl and substituted alkyl or substituted perfluoroalkyl C3-C 10 cycloalkyl and substituted cycloalkyl, arylmethylene or substituted arylmethylene, aryl or substituted aryl, condensed aryl or substituted condensed aryl, heteroaryl or substituted heteroaryl, C1-C 10 Alkoxy or perfluoroalkoxy, C1-C 10substituted cycloalkyloxy or substituted cycloalkyloxy, aryloxy or substituted aryloxy, fused aryloxy or substituted fused aryloxy, heteroaryloxy or substituted heteroaryloxy, arylmethyleneoxy or substituted arylmethyleneoxy, heteroarylmethyleneoxy or substituted heteroarylmethyleneoxy, substituted propoxy, wherein the substituted aryloxy, substituted propoxy, substituted aryl, substituted fused aryloxy or substituted heteroaryl has one or more substituents independently selected from halogen, N-dimethylamino, C1-C4 alkyl or perfluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or perfluoroalkoxy, methylenedioxy, aryl, aryloxy, heteroaryl; 2 R 5 Can form C3-C 20 Cyclic system or substituted benzoaliphatic cyclic system, OR 6 O ring system, R 6 represents a biaryl, a binaphthyl, a substituted biaryl or a substituted binaphthyl, wherein the substituent may be selected from halogen, nitro, cyano, ester, C1-C 10 Alkyl or perfluoroalkyl, C3-C 10 cycloalkyl, C1-C6 alkoxy or perfluoroalkoxy, aryl.

[0013] The enantiomeric compound of the general formula A may have an optical purity of 85% ee or more.

[0014] In the above technical solution, further, X is selected from the bond between carbon and phosphorus, R 1-4 are all selected from hydrogen, R 5The preparation method of the present invention can be selected from phenyl, pentafluorophenyl, cyclohexyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl or 3,5-bis(trifluoromethyl)-phenyl; the preparation method can be to use the enantiomer or racemate of 4,12-dibromo[2.2]paracyclophane as the starting material, and react with various types of organic boron reagents to obtain a diphenol intermediate of the cyclophane skeleton, triflate reaction, and couple with a phosphorus reagent and reduce to obtain an organic phosphine compound based on the cyclophane skeleton (X is zero, carbon and phosphorus are directly connected), that is, a diphosphine derived from a cyclophane diaryl skeleton; the typical synthesis route can be as follows; wherein the diphenol intermediate of the cyclophane skeleton can also be prepared according to the literature Org. Lett., 2019, 21, 3682, or prepared according to the method disclosed in Chinese Patent 201810727287.6. The diphenol intermediate of the cyclophane skeleton can also be directly prepared according to the known classical coupling method, such as coupling with diarylphosphine under nickel catalysis to prepare the target product. The relevant preparation method can be similar to the process of preparing various phosphine ligands from binaphthol. It should be pointed out that the bisphosphine organic phosphine compounds (X is selected from the bond between carbon and phosphorus) derived from the cyclophane diaryl skeleton conforming to the general formula A can be prepared according to the above method.

[0015]

[0016] Furthermore, the X is selected from oxygen, R 1-4 are all selected from hydrogen, R 5 The preparation method is that the aforementioned diphenol intermediate of the cyclophane skeleton reacts with diarylphosphonium chloride under the action of a base to obtain an organic phosphine compound based on the cyclophane skeleton (X is selected from oxygen), that is, a bisphosphite phenol ester derived from the cyclophane diaryl skeleton. The typical reaction route can be shown as follows:

[0017]

[0018] It should be noted that the organic phosphine compound based on the cyclophane skeleton (X is selected from sulfur) can also be prepared by referring to the above method.

[0019] Further, X is selected from CH2, R 1-4 are all selected from hydrogen, R5 Selected from phenyl, 4-methylphenyl, cyclohexyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 3,5-bis(trifluoromethyl)-phenyl, 3,5-di-tert-butyl-phenyl or 4-dimethylamino-phenyl. The preparation method is a coupling reaction of dibromocyclophane with an organic boron reagent, followed by a bromination reaction, and then a reaction with diarylphosphine under the action of a base to obtain an organic phosphine compound based on a cyclophane skeleton (X is selected from CH2), that is, a dibenzylphosphine derived from a cyclophane diaryl skeleton. A typical reaction route can be shown as follows:

[0020]

[0021] Further, X is selected from NH, R 1-4 are all selected from hydrogen, R 5 The preparation method is selected from phenyl, 4-methylphenyl, cyclohexyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 3,5-bis(trifluoromethyl)-phenyl, 3,5-di-tert-butyl-phenyl or 4-dimethylamino-phenyl. The preparation method is a coupling reaction of the aforementioned dibromocyclophane with an organic boron reagent, and then reacting with diarylphosphine under the action of a base to obtain an organic phosphine compound based on a cyclophane skeleton (X is selected from NH), that is, a diaminophosphine derived from a cyclophane diaryl skeleton. The typical reaction route can be shown as follows:

[0022]

[0023] The present invention also provides a metal complex comprising a metal and the organic phosphine compound based on the cyclophane skeleton, wherein the metal is gold, silver, copper, rhodium, ruthenium, iridium, nickel, molybdenum, iron, platinum, palladium or cobalt. The preparation method of the metal complex can refer to the classical synthesis method of various corresponding phosphine ligand metal complexes derived from binaphthol BINOL. The metal complex can be used for catalytic hydrogenation reaction or the following reactions: Heck reaction, Suzuki-Miyaura reaction, Kumada reaction, Murahashi reaction, amination reaction, N-aryl amination reaction, or Negishi reaction.

[0024] A metal complex conforming to the formula [RuX2(diamine)A] or [Ru(neutral ligand)A]X; wherein X is halogen, ClO4, SbF6, PF6, CF3SO3, BF4 or CH3CO2, the diamine is optically active 1,2-diarylethylenediamine, 1,2-cyclohexanediamine or 1,1-di(4-methoxyphenyl)-2-isopropyl-1,2-ethylenediamine, the neutral ligand is p-cymene or 1,5-cyclooctadiene, and the compound of formula A is the above-mentioned organic phosphine compound based on the cyclophane skeleton. The preparation method of this type of metal complex can refer to the classical synthesis method of phosphine ligand metal complex derived from binaphthol. The metal complex can be used for catalytic asymmetric hydrogenation reaction, and the substrate is preferably selected from imines, ketones, olefinically unsaturated compounds, enamines, enamides and vinyl esters.

[0025] The organophosphine compound based on the cyclophane skeleton can be used as a ligand or chiral ligand in metal-catalyzed addition reaction, hydrogenation reaction, hydroformylation reaction, hydroboration reaction, hydrogenation vinylation reaction, olefin metathesis reaction, hydrogenation carboxylation reaction, isomerization reaction, cyclopropanation reaction, Michael addition reaction, epoxidation reaction, kinetic resolution, Diels-Alder reaction, hydrosilylation reaction, asymmetric allylation reaction, cyclization reaction, coupling reaction and asymmetric reaction thereof; or the organophosphorus compound based on the cyclophane skeleton can be used as an organic catalyst to catalyze cyclization reaction.

[0026] The beneficial effects of the present invention are:

[0027] The present invention develops a new type of organophosphine compound based on a cyclophane skeleton, which is used as a ligand or chiral ligand in metal-catalyzed organic reactions or directly catalyzed organic reactions, and can be used as a chiral phosphine ligand or catalyst to be widely used in various asymmetric catalytic reactions, and has economical practicality and industrial application prospects. DETAILED DESCRIPTION

[0028] The following examples will help to understand the present invention, but are not intended to limit the present invention.

[0029] General reaction conditions: When using air-sensitive reagents, all reactions are controlled in a nitrogen-filled glove box or performed using standard Schlenk techniques. The reaction solvents are dried using a general standard process. Solvents are generally dried under a nitrogen atmosphere. The preparation methods of various cyclophane-based organic phosphine compounds can refer to the classical synthesis processes of various phosphine ligands derived from binaphthol. For organic synthesis technicians, the relevant synthesis methods can be analogized and referenced.

[0030] Example 1 Synthesis of diphenols based on cyclophane skeleton

[0031]

[0032] Add (R)-[2.2]-cyclophane dibromide (3mmol, 1.10g), m-hydroxyphenylboronic acid (15mmol, 1.83g), sodium carbonate (24mmol, 2.54g), tetrakis(triphenylphosphine)palladium (0.3mmol. 364.7mg) to a flask, replace with nitrogen, add dimethyl sulfoxide (30mL) and water (3mL), and react at 90°C for 30 hours. After the reaction is completed, quench the reaction with an appropriate amount of 1M hydrochloric acid, extract the product in the aqueous phase with ethyl acetate three times, combine the organic phases, wash with saturated NaCl solution, then dry with anhydrous NaSO4, concentrate, and then dry-sample with 200 mesh silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:20) to obtain a white solid diphenol (R)-B1 based on a cyclophane skeleton with a yield of 82%. 1 H NMR (400MHz, CDCl3): δ = 7.23-6.23 (m, 14H), 4.84 (s, 2H), 3.53-3.46 (m, 2H), 3.04-2.69 (m, 4H), 2.77-2.70 (m, 2H). Using (S)-[2.2]-p-cyclophane dibromide and (±)-[2.2]-p-cyclophane dibromide as raw materials, the corresponding (S)-B1 (yield 82%) and (±)-B1 (yield 80%) were prepared according to the above process.

[0033]

[0034] In the above preparation process, o-hydroxyphenylboronic acid was used instead of m-hydroxyphenylboronic acid to obtain (R)-B2 with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ7.63 (dd, J=7.6, 1.4Hz, 2H), 7.33–7.25 (m, 2H), 7.03 (m, 2H), 6.95 (d, J=8.1Hz, 2H), 6.83 (d, J=7.4Hz, 2H), 6.72 (m, 4H), 5.21(s,2H),3.22(m,2H),3.17–3.07(m,2H),2.90(m,2H),2.65(m,2H). 13 C NMR (101MHz,CDCl3)δ152.64,141.20,138.11,136.14,133.41,132.96,131.36,129.27, 128.40,126.95,120.45,115.49,34.53,34.32. Similarly, the corresponding (S)-B2 and (±)-B2 were prepared by a similar method.

[0035] Example 2 Synthesis of bistrifluoromethanesulfonate based on cyclophane skeleton

[0036]

[0037] Add (R)-B1 (2.9mmol) to the flask, replace with nitrogen, add trifluoromethanesulfonic anhydride (1.1mL), pyridine (0.6mL) and ultra-dry dichloromethane (30mL) under ice-water bath, warm to room temperature and react for 3 hours. After the reaction is completed, quench the reaction with an appropriate amount of 1M hydrochloric acid, stand and separate, extract the organic phase in the aqueous phase with dichloromethane three times, collect the organic phases, combine, and then dry with anhydrous sodium sulfate, concentrate, and then use 100 mesh silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to obtain a yellow liquid product based on the cyclophane skeleton bistrifluoromethanesulfonate (R)-C1, with a yield of 99%. 1 H NMR(400MHz, CDCl3)δ7.57 (1H),7.51–7.42(m,2H),7.30-7.34(3H),7.23(2H),6.76(d,J=7.7Hz,2H),6.70 (dd,J=7.7,1.5Hz,2H),6.60(d,J=1.6Hz,2H),3.62–3.36(m,2H),3.22–3.08 (m,2H),3.00(m,2H),2.75(m,2H). 13 C NMR (101 MHz, CDCl3) δ 149.64, 143.47, 139.90, 138.28, 137.12, 135.99, 133.23, 130.30, 129.84, 129.01, 121.73, 119.41, 34.44, 34.00. According to the above process, (S)-B1 and (±)-B1 were used instead, and the corresponding (S)-C1 and (±)-C1 were prepared quantitatively.

[0038]

[0039] According to a similar preparation process, the bistrifluoromethanesulfonate (R)-C2 based on the cyclophane skeleton was prepared with a yield of 98%. 1 H NMR (400MHz, CDCl3): δ=7.65-6.54 (m, 14H), 3.12-2.85 (m, 6H), 2.60-2.52 (m, 2H); 13C NMR (101 MHz, CDCl3) δ = 147.23, 139.15, 138.55, 135.38, 134.92, 134.08, 131.39, 130.56, 130.13, 128.97, 128.19, 122.20, 77.34, 77.03, 76.71, 34.50, 33.93 ppm. Similarly, (S)-C2 and (±)-C2 were prepared in almost quantitative amounts.

[0040] Example 3 Synthesis of bisphosphines based on cyclophane skeleton

[0041]

[0042] Add bistrifluoromethanesulfonate (R)-C1 (2.87 mmol) based on cyclophane skeleton, HOPPh2 (11 mmol), palladium acetate (0.28 mmol), 1,4-bis(diphenylphosphinobutane) DPPB (0.28 mmol) to the flask, replace with nitrogen, add diisopropylethylamine (2.4 mL), ultra-dry dimethyl sulfoxide (30 mL), and react at 120°C for 22 hours. After the reaction is completed, quench the reaction with an appropriate amount of 1M hydrochloric acid, stand and separate the liquids, extract the product in the aqueous phase with ethyl acetate three times, collect the organic phases, combine, and then dry with anhydrous NaSO4, concentrate to dryness, and then use 100 mesh silica gel column chromatography (eluent: ethyl acetate) to obtain (R)-D1-1 with a yield of 87%. (R)-D1-1 (0.42 mmol) was added to a single-mouth round-bottom flask, nitrogen was replaced, triethylamine (0.5 mL), trichlorosilane (0.5 mL), and toluene (10 mL) were added, and the reaction was carried out at 100°C for 16 hours. After the reaction was stopped, the reaction was quenched with an appropriate amount of NaOH solution, and the liquid was separated by standing. The product in the aqueous phase was extracted three times with ethyl acetate, and the organic phase was collected and combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then chromatographed on a 200-mesh silica gel column (eluent: ethyl acetate: petroleum ether = 1:50) to obtain (R)-E1-1 with a yield of 90%. Using a similar method, (S)-E1-1 and (±)-E1-1 as well as (R)-E2-1, (S)-E2-1, and (±)-E2-1 were prepared.

[0043] Through the above similar process, a series of organic phosphine compounds were prepared. The structures and analytical characterization results of each compound are as follows:

[0044] (R)-D2-1

[0045] 1H NMR(400MHz,CDCl3)δ7.67-7.65(m,2H),7.54(t,J=6.4Hz,2H),7.41–7.31(m,12H),7.29 (m,3H),7.26–7.20(m,5H),7.20–7.12(m,4H),6.37(s,2H),6.26(d,J=7.6Hz,2H),6.12(d,J= 7.7Hz,2H),2.90–2.65(m,4H),2.55–2.38(m,4H). 31 P NMR(162MHz,CDCl3)δ26.78(s).

[0046] (R)-D1-1

[0047] 1 H NMR(400MHz,CDCl3)δ7.77–7.63(m,11H),7.61–7.48(m,5H),7.48–7.37(m,9H),7.24(d, J=7.6Hz,2H),6.98(s,1H),6.64(d,J=7.7Hz,2H),6.57(dd,J=7.7,1.4Hz,2H),6.34(s,2H),3.30 –3.10(m,2H),3.02–2.91(m,2H),2.88–2.71(m,2H),2.42–2.33(m,2H). 31 P NMR(162MHz, CDCl3)δ29.74(s).

[0048] (R)-E2-1

[0049] 1 H NMR(400MHz,CDCl3)δ7.82–7.69(m,2H),7.46–7.38(m,2H),7.33–7.22(m,8H),7.21– 7.06(m,10H),7.02–6.87(m,6H),6.56–6.48(m,4H),6.45(s,2H),3.01–2.81(m,2H),2.79–2.64 (m,2H),2.59–2.35(m,4H). 31 P NMR(162MHz,CDCl3)δ-13.24(s).

[0050] (R)-E2-2

[0051] 1H NMR(400MHz,CDCl3)δ7.75(dd,J=6.8,4.2Hz,2H),7.39(td,J=7.5,1.3Hz,2H),7.26(s, 1H),7.23(dd,J=7.5,0.9Hz,1H),7.09–7.01(m,8H),7.00–6.95(m,2H),6.93(d,J=7.5Hz,4H), 6.82(t,J=7.6Hz,4H),6.56–6.49(m,4H),6.46(d,J=1.2Hz,2H),2.98–2.86(m,2H),2.76–2.65 (m,2H),2.50–2.39(m,4H),2.33(s,6H),2.23(s,6H). 31 P NMR(162MHz,CDCl3)δ-15.33(s).

[0052] (R)-E2-3

[0053] 1 H NMR(400MHz,CDCl3)δ7.71(dd,J=7.0,4.2Hz,2H),7.39(t,J=7.1Hz,2H),7.30–7.21(m, 2H),6.99(dd,J=7.2,3.1Hz,2H),6.90(s,2H),6.76(d,J=8.8Hz,6H),6.58(d,J=7.7Hz,4H),6.53 (d,J=7.5Hz,2H),6.47(d,J=9.9Hz,4H),2.92(m,2H),2.78–2.63(m,2H),2.58–2.38(m,4H), 2.22(s,12H),2.12(s,12H). 31 P NMR(162MHz,CDCl3)δ-12.80(t).

[0054] (R)-E2-4

[0055] 1H NMR(400MHz,CDCl3)δ7.78–7.68(m,2H),7.38(t,J=7.3Hz,2H),7.25–7.19(m,2H),7.07 (t,J=7.6Hz,4H),6.97–6.90(m,2H),6.86(t,J=7.5Hz,4H),6.80(d,J=8.1Hz,4H),6.66(d,J= 8.1Hz,4H),6.51(q,J=7.7Hz,4H),6.43(s,2H),3.79(s,6H),3.70(s,6H),2.98–2.84(m,2H),2.79 –2.64(m,2H),2.53–2.38(m,4H). 31 P NMR(162MHz,CDCl3)δ-16.23(s).

[0056] (R)-E1-1

[0057] 1 H NMR(400MHz,CDCl3)δ7.49–7.21(m,26H),6.98(d,J=6.8Hz,2H),6.58(d,J=7.7Hz,2H), 6.52(dd,J=7.7,1.2Hz,2H),6.29(d,J=1.3Hz,2H),3.28–3.15(m,2H),3.01–2.85(m,2H),2.81 –2.68(m,2H),2.38–2.21(m,2H). 31 P NMR(162MHz,CDCl3)δ-5.12(s).

[0058] (R)-E1-2

[0059] 1 H NMR(400MHz,CDCl3)δ7.33(d,J=7.5Hz,2H),7.30–7.19(m,12H),7.11-7.16(m,8H),6.95 (d,J=6.9Hz,2H),6.59(d,J=7.7Hz,2H),6.52(d,J=7.6Hz,2H),6.31(s,2H),3.31–3.15(m,2H), 3.00–2.87(m,2H),2.83–2.70(m,2H),2.30(m,14H). 31 P NMR(162MHz,CDCl3)δ-6.80(t).

[0060] (R)-E1-3

[0061] 1 H NMR (400MHz, CDCl3) δ7.30 (dd, J=9.3, 7.5Hz, 4H), 7.20 (dd, J=7.6, 1.6Hz, 2H), 6.98-7.10 (m,10H),6.91–6.82(m,4H),6.59(d,J=7.7Hz,2H),6.52(dd,J=7.7,1.5Hz,2H),6.15(d,J=1.6 Hz,2H),3.33–3.18(m,2H),3.02–2.88(m,2H),2.82–2.70(m,2H),2.42–2.33(m,2H),2.21(s,12H),2.15(s,12H). 31 P NMR (162MHz, CDCl3) δ-4.82 (dt, J = 15.6, 7.8Hz).

[0062] (R)-E1-4

[0063] 1 H NMR (400MHz, CDCl3) δ7.35–7.19(m,14H),6.96(d,J=6.9Hz,2H),6.85-6.90(m,8H),6.59 (d,J=7.7Hz,2H),6.53(d,J=7.4Hz,2H),6.32(s,2H),3.76(s,6H),3.73(s,6H),3.30–3.17(m, 2H),3.00–2.87(m,2H),2.84–2.71(m,2H),2.41–2.27(m,2H). 31 P NMR(162MHz, CDCl3)δ -8.28(t).

[0064] Example 4 Bisphosphonite phenol ester based on cyclophane skeleton

[0065]

[0066] Add (R)-B1 (2mmol) to the flask, replace with nitrogen, inject ultra-dry tetrahydrofuran (30mL), slowly inject n-butyl lithium in n-hexane solution (4mmol butyl lithium) under ice water bath, stir for 30 minutes, inject diphenylphosphine chloride (4mmol). After 12 hours of reaction, quench the reaction with 1mol / L hydrochloric acid, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate, and then chromatograph on silica gel column in nitrogen atmosphere to obtain bisphosphite phenol ester (R)-F1 based on cyclophane skeleton, with a yield of 65%, confirmed by high-resolution mass spectrometry. Using a similar method, the corresponding (S)-F1 (yield 62%) and (±)-F1 (yield 63%) were prepared.

[0067] Example 5 Bisbenzylphosphine derived from cyclophane diaryl skeleton

[0068]

[0069] Add (R)-[2.2]-cyclophane dibromide (3mmol, 1.10g) to a flask, replace with nitrogen, then add m-hydroxymethyl phenylboronic acid (9mmol), sodium carbonate (10mmol, 2mol / L aqueous solution), tetrakis(triphenylphosphine) palladium (0.3mmol, 364.7mg), add toluene (15mL) and ethanol (15mL), and react at 80°C for 5 hours. After the reaction is completed, cool to room temperature, quench the reaction with 1mol / L hydrochloric acid, extract with ethyl acetate, then dry with anhydrous NaSO4, concentrate, and then chromatograph on a silica gel column in a nitrogen atmosphere to obtain dibenzyl bromide (R)-BC based on a cyclophane skeleton with a yield of 75%, confirmed by high-resolution mass spectrometry. Maintaining nitrogen atmosphere, add diphenylphosphine (4mmol) into the flask, inject ultra-dry tetrahydrofuran (30mL), slowly inject n-butyl lithium in n-hexane solution (4mmol butyl lithium) under ice-water bath, stir for 30 minutes, and add (R)-BC (2mmol). After reacting for 12 hours, quench the reaction with 1mol / L hydrochloric acid, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate, and then chromatograph on silica gel column in nitrogen atmosphere (eluent: ethyl acetate / petroleum ether) to obtain bisbenzylphosphine (R)-G1 based on cyclophane skeleton, with a yield of 75%, confirmed by high-resolution mass spectrometry. Using a similar method, the corresponding (S)-G1 (total yield 42%) and (±)-G1 (total yield 45%) were prepared.

[0070] Example 6 Bisamine phosphine derived from cyclophane diaryl skeleton

[0071]

[0072] Add (R)-[2.2]-cyclophane dibromide (3mmol, 1.10g) to the flask, replace with nitrogen, then add m-aminophenylboronic acid monohydrate (9mmol), sodium carbonate (10mmol, 2mol / L aqueous solution), tetrakis(triphenylphosphine)palladium (0.3mmol, 364.7mg), add 1,2-dimethoxyethane (15mL), and react at 80°C for 24 hours. After the reaction is completed, cool to room temperature, quench the reaction with 1mol / L hydrochloric acid, extract with ethyl acetate, then dry with anhydrous NaSO4, concentrate, and then chromatograph on a silica gel column in a nitrogen atmosphere to obtain a diamine (R)-BD based on a cyclophane skeleton with a yield of 78%, confirmed by high-resolution mass spectrometry. Maintaining nitrogen atmosphere, add diphenylphosphine chloride (4mmol) into the flask, inject ultra-dry tetrahydrofuran (30mL), add (R)-BD (1mmol), slowly inject triethylamine (8mmol) under ice-water bath, stir for 30 minutes, react at room temperature for 12 hours, quench the reaction with 1mol / L hydrochloric acid, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate, and then chromatograph on silica gel column under nitrogen atmosphere (eluent: ethyl acetate / petroleum ether) to obtain the diamine (R)-H1 based on cyclophane skeleton with a yield of 55%, confirmed by high-resolution mass spectrometry. Using a similar method, the corresponding (S)-H1 (total yield 40%) and (±)-H1 (total yield 45%) were prepared.

[0073] Example 7

[0074] A general synthesis process of a metal complex comprising a metal and a compound of general formula A or its enantiomer and racemate, the synthesis of PdCl2[(R)-E1-1]: under a nitrogen atmosphere, add a bisphosphine ligand (R)-E1-1 (0.178 mmol) and 2 ml of benzene to a reaction bottle, stir and dissolve thoroughly, and then add 4 ml of benzene solution containing 46 mg of diacetonitrile palladium chloride (0.178 mmol, PdCl2(MeCN)2). Reflux and stir for 2 hours, remove the solvent by rotary evaporation, and vacuum dry to obtain a PdCl2[(R)-E1-1] complex with a yield of 100%. Using a similar method, the corresponding PdCl2[(±)-E1-1] complex, PdCl2[(R)-E2-1] complex, and PdCl2[(±)-E2-1] complex with quantitative yields were prepared.

[0075] Example 8

[0076] A general synthesis process of a complex conforming to the formula [RuX2(diamine)A]: In a glove box under a nitrogen atmosphere, weigh the bisphosphine ligand (R)-E1-1 (0.160 mmol) and [Ru(C6H6)Cl2]2 (0.08 mmol, 40 mg) and add them to a Schlenk reaction tube. Then, inject 3 ml of dry, degassed N,N-dimethylformamide under a nitrogen atmosphere, heat to 100 degrees with stirring for 2 hours, then cool to room temperature, add (R,R)-1,2-diphenylethylenediamine ((R,R)-DPEN, 0.160 mmol), and continue stirring at room temperature for 12 hours. The solvent was removed by vacuum and dried to obtain a quantitative solid product RuCl2-[(R)-E1-1][(R,R)-DPEN]. A similar method was used to prepare RuCl2-[(S)-E1-1][(R,R)-DPEN], RuCl2-[(R)-E2-1][(R,R)-DPEN] and RuCl2-[(S)-E2-1][(R,R)-DPEN] with corresponding quantitative yields. The experimental process of testing asymmetric hydrogenation was as follows: 10 ml of isopropanol was used as solvent, 1 mmol of acetophenone, 1 mmol of potassium tert-butoxide and RuCl2-[(R)-E1-1][(R,R)-DPEN] were added in sequence, and the hydrogenation reaction was carried out at 35 degrees and 30 atmospheres for 12 hours, and the product was completely converted into the reduced product 2-methylbenzyl alcohol. The ee value of the product was as high as 95% after sampling for chiral GC test.

[0077] Example 9

[0078]

[0079] Under nitrogen protection, palladium acetate (5% eq, 0.005 mmol), bisphosphine ligand (±)-E1-1 (5% eq, 0.005 mmol), and 1 mL of toluene were added to the reaction tube, and the reaction was carried out at room temperature for 1 hour to prepare the complex in situ. Then, N-acetyl o-tert-butylaniline substrate S1 (1 eq, 0.1 mmol), phenyl allyl acetate S2 (2 eq, 0.2 mmol), and potassium tert-butoxide (0.24 mmol) were added in sequence, and the reaction was carried out at room temperature for 24 hours until the reaction was complete. The reaction mixture was directly column chromatographed (ethyl acetate and petroleum ether as mixed eluents) to obtain N-acetyl-N-phenyl allyl o-tert-butylaniline P1 with a yield of 90%. 1H NMR (400 MHz, CDCl3) δ7.58 (dd, J=8.1,1.4 Hz,1H),7.38–7.33 (m,2H),7.31 (dd, J=10.1,4.6 Hz,3H),7.26–7.21 (m,1H),7.17–7.12 (m,1H),6.92 (dd, J=7.8,1.5 Hz,1H),6.48–6.29 (m,2H),5.12 (dd, J=14.2,4.5 Hz,1H),3.46 (dd, J=14.0,7.9 Hz,1H),1.81 (s,3H),1.41 (s,9H). Using a similar reaction process, only (±)-E1-1 was replaced by (±)-E2-1, and the yield of P1 was 88%.

[0080] Example 10

[0081]

[0082] Under nitrogen protection, palladium acetate (5% eq, 0.005 mmol), phosphine ligand (R)-E1-1 (5% eq, 0.005 mmol), and 1 mL of toluene were added to the reaction tube, and the reaction was carried out at room temperature for 1 h to prepare the complex in situ. Then, N-Ts-o-tert-butylaniline substrate S3 (1 eq, 0.1 mmol), phenyl allyl acetate S2 (2 eq, 0.2 mmol), and potassium tert-butoxide (0.24 mmol) were added in sequence, and the reaction was carried out at room temperature for 24 hours until the reaction was complete. The reaction mixture was directly column chromatographed (ethyl acetate and petroleum ether as mixed eluents) to obtain N-Ts-N-phenyl allyl o-tert-butylaniline P2 with a yield of 98% and 30% ee; 1 H NMR (400MHz,CDCl3)δ7.65(d, J=8.2Hz,2H),7.57(dd,J=8.2,1.4Hz,1H),7.31–7.26(m,4H),7.25–7.15(m, 4H),7.05–6.93(m,1H),6.49(dd,J=7.9,1.3Hz,1H),6.33(d,J=15.8Hz,1H),6.17–6.02(m,1H),4.36–4.26(m,1H),4.25–4.16(m,1H),2.44(s,3H),1.55(s, 9H). Using a similar reaction process, only (R)-E1-1 was replaced by (R)-E2-1, the yield of P2 was 95%, 70% ee.

[0083] Embodiment 11

[0084]

[0085] Under nitrogen protection, PdCl2 (10%, 0.01mmol), phosphine ligand L (10%, 0.01mmol), 1mL ethanol were added to the reaction tube, stirred at room temperature for 1h for complexation, and then alkynylaniline substrate S4 (1eq, 0.1mmol) was added, and the reaction was carried out at 80℃ for 4h. The solvent was dried and the product was directly purified by silica gel column chromatography to obtain axial chiral product P3, 85% yield, 60% ee; the chiral chromatography conditions were chrialpak IA column, i-PrOH / Hexane= 0.5 / 99.5, flow rate=0.5mL, 254nm. t1(major)=13.2min; t2(minor)=15.2min.

[0086] Example 12

[0087]

[0088] Under nitrogen protection, add diphosphine ligand (R)-E2-1 (0.01mmol), [Pd(C3H5)Cl]2 (0.005mmol) and dichloromethane solution (1mL) into a Schlenk tube, stir at room temperature for 2h, and then add 1,3-diphenyl-2-allyl acetate S5 (0.1mmol); then use a syringe to add a pre-prepared mixture of toluene (1mL), diethyl malonate (0.3mmol) and ZnEt2 (300uL, 1M in hexane) mixed for 0.5h, and then react at room temperature for 4 hours, quench with saturated NH4Cl solution, stand and separate, extract the aqueous phase with ethyl acetate three times, collect the organic phases, combine, wash with saturated brine, and dry over anhydrous NaSO4. Then, the product was concentrated by rotary evaporator and purified by 200 mesh silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1: 10) to obtain the reaction product P4, 96% yield, 70% ee; Chrialpak IA column, i-PrOH / Hexane = 15 / 85, flow rate = 1mL, 254nm. t1 (minor) = 6.8min; t2 (major) = 8.4min. According to the similar reaction process, (R)-F1, (R)-G1 and (R)-H1 were used to replace (R)-E2-1, and the yields of the target products were 85%, 95% and 90%, respectively, and the ee values ​​were 55%, 65% and 75%, respectively.

[0089] Example 13

[0090]

[0091] Under nitrogen atmosphere, phosphine ligand (±)-E1-1 (0.25 mmol) was added to the reaction bottle, and 5 ml of ethanol was added. The mixture was refluxed and stirred to dissolve. The solution was slowly added to 3 ml of ethanol solution in which HAuCl4·4H2O (206 mg, 0.5 mmol) was dissolved. The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was dissolved in 5 ml of dichloromethane. Then 50 ml of petroleum ether was added to precipitate the precipitate. The mixture was filtered, and the filter cake was vacuum dried to obtain a monovalent gold salt complex [(±)-E1-1][AuCl]2 with a yield of 61%. Then, under a nitrogen atmosphere, 0.2 mmol of diketone substrate S6, 0.3 mmol of styrene, 0.015 mmol [(±)-E1-1][AuCl]2, 0.03 mmol of silver trifluoromethanesulfonate and 2 ml of solvent nitromethane were added sequentially into the reaction flask, and the reaction was refluxed for 16 hours. The product was directly purified by column chromatography to obtain the target product P5 with a yield of 92%.

[0092] Embodiment 14

[0093]

[0094] Under nitrogen atmosphere, (±)-E2-1 (0.025 mmol), 0.5 mmol of ethyl propylene carboxylate (In-2) ​​and 0.5 mmol of olefin In-1 were added to the reaction flask, and 3 ml of toluene was injected. The reaction was stirred for 24 hours. The reaction solution was directly subjected to silica gel column chromatography to obtain the [3+2] cyclization product In-3 with a yield of 68%.

[0095] Embodiment 15

[0096]

[0097] Under nitrogen atmosphere, 0.06 mmol of copper trifluoromethanesulfonate and 0.03 mmol of (±)- E2-1 were added to the reaction flask, and 1 ml of 1,2-dichloroethane was injected. The mixture was stirred at room temperature for 30 minutes to obtain a complex of copper trifluoromethanesulfonate and (±)-E2-1 (2:1 composition); then 0.5 mmol of 2-(1-phenylvinyl)benzoic acid S7 and 1 mmol of morpholine benzoate S8 were added, and the mixture was refluxed for 3 hours. After cooling, the mixture was directly purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the target product P6 of the cyclization reaction with a yield of 90%.

[0098] Example 16

[0099]

[0100] 0.03 mmol of [Rh(COD)2BF4] and 0.03 mmol of (±)-E2-1 were stirred in 10 ml of dichloromethane for 30 minutes to obtain a complex, and then 10 ml of dichloromethane containing 5 mmol of A-1 was injected, and the reduction reaction was carried out at room temperature under a hydrogen pressure of 5 standard atmospheres. The reaction was completed after 24 hours, and 100% of the product A-2 could be obtained after purification.

[0101] Embodiment 17

[0102]

[0103] General procedure: Rhodium-phosphine complex was prepared in situ in a glove box by mixing 0.008 mmol (3.7 mg) of [Rh(COD)2PF6] and phosphine ligand (0.8 ml of 10 mg / ml toluene solution of phosphine ligand, 0.012 mmol) in 19.2 ml of dichloromethane. The mixture was stirred for 30 minutes to obtain the complex, and then 2.5 ml of this solution was transferred to a reaction tube containing 0.1 mmol of enamide substrate A-3. The hydrogenation reaction was carried out at room temperature under 25 psi hydrogen pressure for 24 hours, and the reaction was completely completed to produce quantitative product A-4. The enantiomeric excess was tested by chiral GC, and the results were as follows: 81% ee was achieved using phosphine ligand (R)-F1; 75% ee was achieved using phosphine ligand (R)-G1; 91% ee was achieved using phosphine ligand (R)-H1; and 100% yield was achieved using (±)-F1.

[0104] Embodiment 18

[0105] Hydroformylation reaction test process: 1-hexene was used as the substrate for bulk reaction, Rh(acac)(CO)2 concentration was 1mM, phosphine ligand (±)-G1 concentration was 0.41M, 90psig (6.2bar, 1:1 H2 / CO), reaction temperature was 90 degrees, the reaction was continued for 12 hours, and the corresponding hydroformylation product was obtained with a yield of 91%.

Claims

1. An organic phosphine compound based on a cyclophane skeleton, characterized in that: It is a compound having the following general formula A or its enantiomer and racemate: ； X is absent, in which case carbon and phosphorus are directly connected, R 1-4 All are hydrogen, R 5 is selected from phenyl, pentafluorophenyl, cyclohexyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl or 3,5-bis(trifluoromethyl)-phenyl; X is oxygen or sulfur, R 1-4 All are hydrogen, R 5 is selected from phenyl, phenoxy, cyclohexyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 3,5-bis(trifluoromethyl)-phenyl, 3,5-di-tert-butyl-phenyl or 4-dimethylamino-phenyl; X is CH2, R 1-4 All are hydrogen, R 5 is selected from phenyl, 4-methylphenyl, cyclohexyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 3,5-bis(trifluoromethyl)-phenyl, 3,5-di-tert-butyl-phenyl or 4-dimethylamino-phenyl; X is NH, R 1-4 All are hydrogen, R 5 is selected from phenyl, 4-methylphenyl, cyclohexyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxy-phenyl, 3,4,5-trimethyl-phenyl, 3,4,5-trimethoxy-phenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 3,5-bis(trifluoromethyl)-phenyl, 3,5-di-tert-butyl-phenyl or 4-dimethylamino-phenyl.

2. A metal complex, characterized in that The invention comprises a metal and the cyclophane skeleton-based organic phosphine compound as claimed in claim 1, wherein the metal is gold, copper, rhodium, ruthenium or palladium.

3. The metal complex according to claim 2, characterized in that It is used in catalytic hydrogenation reactions or the following reactions: Heck reaction, Suzuki-Miyaura reaction, Kumada reaction, Murahashi reaction, amination reaction, N-aryl amination reaction, or Negishi reaction.

4. A metal complex conforming to the formula [RuX2(diamine)A] or [Ru(neutral ligand)A]X, characterized in that: Wherein X is halogen, ClO4, SbF6, PF6, CF3SO3, BF4 or CH3CO2, the diamine is optically active 1,2-diarylethylenediamine, 1,2-cyclohexanediamine or 1,1-di(4-methoxyphenyl)-2-isopropyl-1,2-ethylenediamine, the neutral ligand is p-cymene or 1,5-cyclooctadiene, the compound A is the organic phosphine compound based on the cyclophane skeleton as claimed in claim 1, and the metal is gold, copper, rhodium, ruthenium or palladium.

5. A metal complex according to claim 4 that conforms to the formula [RuX2(diamine)A] or [Ru(neutral ligand)A]X, characterized in that: The invention is applied to catalyze asymmetric hydrogenation reaction, and the substrate is selected from imine, ketone, olefinically unsaturated compound, enamine, enamide and vinyl ester.

6. An application of the cyclophane skeleton-based organic phosphine compound as claimed in claim 1, characterized in that: It can be used as a ligand or chiral ligand in metal-catalyzed addition reactions, hydrogenation reactions, hydroformylation reactions, cyclization reactions, coupling reactions and asymmetric reactions; or as an organic catalyst to catalyze cyclization reactions.

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