A method for copper-catalyzed carbon-phosphorus bond construction

Abstract

A method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds, wherein in an organic solvent, N-hydroxyphthalimide carboxylic acid ester compounds and disubstituted phosphine hydrogen-borane complexes are reacted with a copper catalyst, 1,1'-binaphthyl-2,2'-bis-diphenylphosphine ligands, a base, a solvent and visible light to generate carbon-phosphorus bond-containing compounds. The method provided by the invention is simple to operate, and raw materials are readily available. In the reaction, a series of N-hydroxyphthalimide carboxylic acid ester compounds are synthesized by a simple synthesis method using cheap and readily available carboxylic acids as starting materials, and a simple and easily synthesized disubstituted phosphine hydrogen-borane complex is used as a raw material. Under the action of a BINAP ligand, visible light-promoted copper catalysis is used to achieve intermolecular C(sp 3 )-P(III) bond, the substrate has good universality, the reaction operation is simple and efficient; the obtained product can be used as a pharmaceutical intermediate or a phosphine ligand.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for constructing a carbon-phosphorus bond catalyzed by copper. Background Art

[0002] Phosphine-containing compounds are among the most widely used ligands, catalysts, and reagents and are also widely used in materials science, pharmaceuticals, and agrochemicals.

[0003] In recent years, there have been some good progress in the functionalization of olefins to form CP(III) bonds, however, it remains relatively unexplored via simpler radical-electrophile cross-coupling reactions. Recent examples of organohalide reactions by Yorimitsu and Oshima and Studer and Smith have shown the great potential of this approach. Since diphosphines have little application in photoredox reactions, phosphine-borane complexes are air-stable compounds that can be easily separated by column chromatography and directly used as phosphine ligand precursors for cross-coupling reactions.

[0004] Copper salts are commonly used materials for photoredox catalysts due to their abundance, low cost, and strong photoinduced reduction or oxidation ability. Visible light-promoted copper catalysis strategies have recently been developed as practical synthetic methods for the formation of CC, CN, CO, and CS bonds. 3 The construction of the )-P(III) bond remains a challenge. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention aims to provide a method for copper-catalyzed construction of carbon-phosphorus bonds using inexpensive copper catalysts, ligands and bases, which has the characteristics of simple reaction, wide substrate range, and economic and green.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A method for copper-catalyzed construction of a carbon-phosphorus bond-containing compound, comprising: using an N-hydroxyphthalimide carboxylic acid ester compound shown in formula 1) and a disubstituted phosphine hydrogen-borane complex shown in formula 2) in an organic solvent under the action of a copper catalyst, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ligand (BINAP), a base, a solvent and visible light to generate a carbon-phosphorus bond-containing compound shown in formula 3);

[0008]

[0009] wherein R1 is selected from one of an electron-rich or electron-withdrawing aromatic substituent, a substrate containing a cycloalkane, a heterocycle, an ester group, a halogen or a carbonyl group, an α-aminoamide and adamantane;

[0010] R2 and R3 are selected from phenyl, 4-chlorophenyl, 4-methylphenyl and thiophene.

[0011] Furthermore, the preparation process of the disubstituted phosphine hydrogen-borane complex is as follows:

[0012] Step 1: Under nitrogen conditions, dissolve the disubstituted phosphine oxide in anhydrous tetrahydrofuran, add phenylsilane dropwise to the disubstituted phosphine oxide at room temperature, and stir for 48-72 hours until the solid is completely converted into a clear liquid;

[0013] Step 2: Under nitrogen conditions, the clear liquid obtained in the first step is dissolved in anhydrous tetrahydrofuran to obtain a disubstituted phosphine hydrogen solution; at 0°C, a tetrahydrofuran solution of borane dimethyl sulfide is added dropwise to the disubstituted phosphine hydrogen solution and stirred for 5 hours; after the reaction is completed, the solvent is removed, and the obtained solid is dissolved in dichloromethane and purified on silica gel by rapid column chromatography to obtain the product.

[0014] Furthermore, the copper catalyst is copper tetraacetonitrile hexafluorophosphate (Cu(CH3CN)4PF6); and the base is diisopropylethylamine.

[0015] Furthermore, the molar ratio of the N-hydroxyphthalimide carboxylic acid ester compound, the disubstituted phosphine-borane complex, the copper catalyst, the ligand and the base is 2:1:0.1:0.1:1.5.

[0016] Furthermore, the organic solvent is tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or ethyl acetate; more preferably tetrahydrofuran.

[0017] Furthermore, the specific conditions of the synthesis method are as follows: placing the copper catalyst, ligand and solvent in a sealed tube under nitrogen and stirring at room temperature for 30 minutes, then adding N-hydroxyphthalimide carboxylic acid ester compounds, disubstituted phosphine hydrogen-borane complexes and bases in a glove box, reacting at room temperature under blue light for 24 hours, and then separating and purifying to obtain the product.

[0018] Furthermore, the separation method is a thin layer chromatography or column chromatography purification method, and the developing solvent used is a mixed solvent of ethyl acetate-petroleum ether.

[0019] The beneficial effects of the present invention are as follows: the reaction uses cheap and readily available carboxylic acids as starting materials to synthesize a series of N-hydroxyphthalimide carboxylic acid ester compounds through a simple synthesis method, and a simple and easily synthesized disubstituted phosphine-borane complex as a raw material, and under the action of BINAP ligands, visible light-promoted copper catalysis realizes the intermolecular C(sp 3 )-P(III) bond, the substrate has good universality, the reaction operation is simple and efficient; the obtained product can be used as a pharmaceutical intermediate or phosphine ligand. DETAILED DESCRIPTION

[0020] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] In addition, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0022] Unless otherwise specified, the raw materials used in the present invention can be purchased from the market.

[0023] The synthesis method of the N-hydroxyphthalimide carboxylate compounds used in the following examples refers to the document Org.Lett.2020,22,24,9562-9567. In this case, the N-hydroxyphthalimide carboxylate compounds of the following specific structural formula were synthesized.

[0024]

[0025] The disubstituted phosphine-borane complex used in the following examples can be prepared by the following synthesis method.

[0026] Step 1: Under nitrogen, dissolve the disubstituted phosphine oxide (5 mmol) in anhydrous tetrahydrofuran (1 mL) or without solvent in a 10 mL Schlenk tube. Add phenylsilane (5 mmol) dropwise to the phosphine oxide at room temperature and stir the reaction mixture for 48-72 hours until the solid is completely converted into a clear liquid. Then, it can be used directly in the next step without post-treatment.

[0027]

[0028] Wherein R2 and R3 are optionally selected from phenyl, 4-chlorophenyl, 4-methylphenyl, thiophene or methyl.

[0029] Step 2: Under nitrogen, disubstituted phosphine (5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) in a 100 mL Schlenk bottle. Borane dimethyl sulfide (5.5 mmol, 2.0 M tetrahydrofuran solution) was added dropwise to the phosphine solution at 0°C, and the reaction mixture was stirred for 5 h to obtain a clear solution. After the reaction was completed, the solvent and excess borane dimethyl sulfide were directly removed on a vacuum pump. The obtained solid was dissolved in DCM and purified on silica gel by flash column chromatography.

[0030]

[0031] The following are the synthesized disubstituted phosphine-borane complexes:

[0032]

[0033] Embodiment 1:

[0034]

[0035] Starting from 1a and 2a, 3a was obtained as a white solid in 80% yield.

[0036] 1 H NMR (400MHz, CDCl3) δ7.69-7.59(m,4H),7.53-7.37(m,6H),7.33-7.24(m,2H),7.24-7.17(m, 1H),7.16-7.09(m,2H),2.71(t,J=7.4Hz,2H),2.28-2.12(m,2H),1.97-1.79(m,2H),0.89(br s,3H).

[0037] 13 C NMR (101MHz, CDCl3) δ140.68, 132.02 (d, J = 9.1Hz), 131.05 (d, J = 2.4Hz), 129.34 (d, J = 55.0Hz), 128.77, 128.67, 128.39 (d, J = 4.8Hz), 126.05, 36.73 (d, J = 14.1Hz), 24.76 (d, J = 37.1Hz), 24.40.

[0038] Taking Example 1 as an example, the synthesis path and synthesis mechanism of the present invention are explained as follows:

[0039]

[0040] First, the ligand and Cu I The in-situ generated complex A reacts with 2a in the presence of a base to generate an intermediate B. B generates an excited intermediate C under the action of visible light, and then reacts with the redox active ester 1a through a single electron transfer process to generate an alkyl radical and a divalent copper species D. The alkyl radical then undergoes oxidative addition with D to generate an intermediate E, which is then eliminated through reduction to obtain the target compound, completing the catalytic cycle. Another possible pathway is that the alkyl radical grabs the H proton of 2a to generate a phosphorus radical intermediate, which then undergoes radical-radical coupling to finally obtain the target compound.

[0041] Embodiment 2:

[0042] Starting from 1b and 2a, 3b was obtained as a yellow solid in 76% yield.

[0043] 1 H NMR (400MHz, CDCl3) δ7.70-7.62(m,4H),7.52-7.38(m,6H),7.18-7.11(m,2H ),6.97(t,J=7.5Hz,1H),6.91-6.80(m,1H),3.66(d,J=11.9Hz,2H),0.89(br s,3H).

[0044] 13 C NMR (101MHz, CDCl3) δ162.00 (d, J = 5.0Hz), 159.55 (d, J = 5.2Hz), 132.59 (d, J = 9.1H z),132.23(d,J=3.8Hz),131.40(d,J=2.4Hz),128.92(d,J=3.1Hz),128.84(d,J=3 .0Hz),128.67(d,J=9.9Hz),128.19,123.73(t,J=3.1Hz),119.51(d,J=4.2Hz),11 9.36(d,J=4.2Hz), 115.26(d,J=2.5Hz), 115.04(d,J=2.4Hz), 26.35(d,J=2.3Hz).

[0045] Embodiment 3:

[0046] Starting from 1c and 2a, 3c was obtained as a yellow solid in 68% yield.

[0047] 1 H NMR (400MHz, CDCl3) δ7.66-7.57(m,4H),7.52-7.40(m,6H),7.29(d,J=8.0Hz, 1H),7.05-6.95(m,2H),6.91(d,J=7.8Hz,1H),3.53(d,J=11.9Hz,2H),0.88(br s,3H).

[0048] 13C NMR (101MHz, CDCl3) δ134.17 (d, J = 4.2Hz), 133.12 (d, J = 4.6Hz), 132.60 (d, J = 9.0Hz), 131.54 (d, J = 2.4Hz), 130.07 (d, J = 3.1Hz), 129.53(d,J=2.7Hz), 128.95(d,J=4.5Hz), 128.81(d,J=9.9Hz), 128.21(d,J=54.2Hz), 121.91(d,J=3.2Hz), 33.76(d,J=31.8Hz).

[0049] Embodiment 4:

[0050] Starting from 1d and 2a, 3d was obtained as a white solid in 73% yield.

[0051] 1 H NMR (400MHz, CDCl3) δ7.65-7.60(m,4H),7.52-7.37(m,6H),7.05(t,J=7.9Hz,1H),6.72(dt,J=8.2, 2.2Hz,1H),6.60-6.52(m,1H),6.47(q,J=2.1Hz,1H),3.60(s,3H),3.58(d,J=11.8Hz,2H),0.88(br s,3H).

[0052] 13 C NMR (101MHz, CDCl3) δ159.13 (d, J = 2.7Hz), 133.29 (d, J = 4.5Hz), 132.73, 131.32 (d, J = 2.5Hz), 129.01 (d, J = 2.6Hz), 128.70 (d, J=9.8Hz), 128.68 (d, J=54.0Hz), 122.70 (d, J=4.7Hz), 115.15 (d, J=4.4Hz), 113.30 (d, J=3.1Hz), 55.04, 34.18 (d, J=32.1Hz).

[0053] Embodiment 5:

[0054] Starting from 1e and 2a, 3e was obtained as a white solid in 73% yield.

[0055] 1H NMR (400MHz, CDCl3) δ7.66-7.61(m,4H),7.50-7.37(m,6H),6.96(d,J=7.7Hz, 2H),6.84(dd,J=8.1,2.2Hz,2H),3.57(d,J=11.9Hz,2H),2.26(s,3H),0.89(br s,3H).

[0056] 13 C NMR (101MHz, CDCl3) δ136.57 (d, J = 3.1Hz), 132.66 (d, J = 8.8Hz), 131.24 (d, J = 2.5Hz), 130.12 (d, J = 4.6Hz), 128 .89(d,J=49.5Hz), 128.79(d,J=2.7Hz), 128.65(d,J=9.1Hz), 128.59, 33.63(d,J=32.5Hz), 21.08(d,J=1.4Hz).

[0057] Embodiment 6:

[0058] Starting from 1f and 2a, 3f was obtained as a yellow solid in 68% yield.

[0059] 1 H NMR (400MHz, CDCl3) δ7.67-7.56(m,4H),7.52-7.38(m,6H),6.92-6.88(m,2H),6.82(t,J=8.6Hz,2H),3.56(d,J=11.8Hz,2H),0.88(br s,3H).

[0060] 13 C NMR (101MHz, CDCl3) δ163.17 (d, J = 3.4Hz), 160.73 (d, J = 3.3Hz), 132.59 (d, J = 8.8Hz), 131.77 (d, J = 4.6Hz), 131.69 (d, J = 4.6Hz), 131.41 (d, J = 2.6Hz), 128.75(d,J=9.9Hz),128.47(d,J=54.5Hz),127.50(d,J=4.1Hz),127.47(d ,J=3.9Hz), 115.07(d,J=2.7Hz), 114.86(d,J=2.6Hz), 33.25(d,J=32.6Hz).

[0061] Embodiment 7:

[0062] Starting from 1g and 2a, 3g of a white solid was obtained in 75% yield.

[0063] 1 H NMR (400MHz, CDCl3) δ7.66-7.57(m,4H),7.51-7.36(m,6H),6.92-6.80(m,2H),6.68(d,J=8.3Hz,2H),3.72(s,3H),3.54(d,J=11.6Hz,2H),0.88(br s,3H).

[0064] 13 C NMR (101MHz, CDCl3) δ158.60 (d, J = 3.1Hz), 132.66 (d, J = 8.8Hz), 131.26 (d, J = 6.5Hz), 131.24, 128.82 (d, J=53.5Hz),128.66(d,J=9.7Hz),123.58(d,J=4.5Hz),113.50(d,J=2.6Hz),55.14,33.17(d,J=32.8Hz).

[0065] Embodiment 8:

[0066] Starting from 1h and 2a, 3h was obtained as a white solid in 63% yield.

[0067] 1 H NMR (400MHz, CDCl3) δ7.62-7.57(m,4H),7.51-7.37(m,6H),6.75(s,2H),3.68(d,J=11.7Hz,2H),2.24(s,3H),1.86(s,6H),0.90(br s,3H).

[0068] 13 C NMR (101MHz, CDCl3) δ137.69 (d, J = 4.2Hz), 136.30 (d, J = 3.4Hz), 132.83 (d, J = 8.8Hz), 131.23 (d, J = 2.4Hz), 129.26 (d, J = 53.1Hz ), 129.10 (d, J = 2.8Hz), 128.59 (d, J = 9.6Hz), 126.84 (d, J = 5.8Hz), 28.65 (d, J = 30.7Hz), 20.87 (d, J = 1.2Hz), 20.70 (d, J = 1.3Hz).

[0069] Embodiment 9:

[0070] Starting from 1i and 2a, 3i was obtained as a white solid in 61% yield.

[0071] 1 H NMR(400MHz,CDCl3)δ7.75-7.68(m,4H),7.52 -7.42(m,6H),7.30-7.23(m,2H),7.22-7.11(m,3H),2.93-2.71(m,2H),2.64-2.41(m,2H),0.89(s,3H).

[0072] 13 C NMR (101MHz, CDCl3) δ 141.24 (d, J = 14.9Hz), 132.14 (d, J = 9.1Hz), 131.27 (d, J = 2.4Hz), 129. 48,128.90(d,J=9.8Hz),128.62,128.05,126.39,29.14(d,J=1.2Hz),27.82(d,J=35.4Hz).

[0073] Embodiment 10:

[0074] Starting from 1j and 2a, 3j was obtained as a yellow solid in 66% yield.

[0075] 1 H NMR (400MHz, CDCl3) δ7.72-7.65(m,4H),7.51-7.41(m,6H),7.33-7.27(m,2H),7.15-7.05(m,2H),2.85-2.75(m,2H),2.54-2.44(m,2H),0.88(br s,3H).

[0076] 13 C NMR(101MHz, CDCl3)δ143.44(d,J=14.6Hz),132.12(d,J=9.2Hz),131.38(d,J=2.5Hz),131.10,130.17,129 .53, 128.95 (d, J = 55.0Hz), 128.94 (d, J = 9.9Hz), 126.83, 122.59, 28.86 (d, J = 1.6Hz), 27.63 (d, J = 35.5Hz).

[0077] Embodiment 11:

[0078] Starting from 1k and 2a, 3k was obtained as a white solid in 54% yield.

[0079] 1 H NMR (400MHz, CDCl3) δ7.72-7.67(m,4H),7.49-7.42(m,6H),7.11-7.02(m,2H),6. 84-6.75(m,2H),3.76(s,3H),2.82-2.69(m,2H),2.53-2.42(m,2H),0.88(s,3H).

[0080] 13 C NMR (101MHz, CDCl3) δ158.14, 133.29 (d, J = 15.0Hz), 132.13 (d, J = 9.1Hz), 131.22 (d, J = 2.6Hz), 129.55, 129.00, 128.86 (d, J = 9.7Hz), 114.00, 55.28, 28.27 (d, J = 1.4Hz), 28.04 (d, J = 35.0Hz).

[0081] Embodiment 12:

[0082] Starting from 11 and 2a, 31 was obtained as a white solid in 50% yield.

[0083] 1 H NMR (400MHz, CDCl3) δ7.63-7.58(m,4H),7.49-7.37(m,6H),7.06-6.99(m,2H),6.87-6.76(m,2 H),3.78(d,J=0.9Hz,3H),2.63(t,J=7.3Hz,2H),2.21-2.14(m,2H),1.89-1.80(m,2H),0.88(br s,3H).

[0084] 13 C NMR (101MHz, CDCl3) δ157.97, 132.80, 132.11 (d, J = 9.1Hz), 131.11 (d, J = 2.4Hz), 129.47 (d, J = 54.9 Hz), 129.40, 128.79 (d, J = 9.9 Hz), 113.84, 55.26, 35.88 (d, J = 14.1 Hz), 24.74 (d, J = 37.3 Hz), 24.66.

[0085] Embodiment 13:

[0086] Starting from 1m and 2a, 3m was obtained as a white solid in 65% yield.

[0087] 1H NMR (400MHz, CDCl3) δ7.68-7.53(m,6H),7.48-7.41(m,2H),7.40-7.28(m,4H),7. 13-7.00(m,2H),7.02-6.90(m,2H),4.02(d,J=11.3Hz,2H),3.76(s,3H),0.89(br s,3H).

[0088] 13 C NMR (101MHz, CDCl3) δ157.39, 133.50 (d, J = 3.4Hz), 132.79 (d, J = 8.8Hz), 131. 29(d,J=2.6Hz),129.90,129.26(d,J=5.4Hz),129.09(d,J=2.1Hz),128.76(d, J=54.5Hz),128.59(d,J=9.9Hz),127.58(d,J=3.4Hz),127.15(d,J=5.6Hz),1 22.56 (d, J = 3.1Hz), 118.48, 103.15 (d, J = 1.6Hz), 55.22, 31.08 (d, J = 31.6Hz).

[0089] Embodiment 14:

[0090] Starting from 1n and 2a, 3n was obtained as a white solid in 46% yield.

[0091] 1 H NMR (400MHz, CDCl3) δ7.64 -7.60(m,4H),7.50-7.38(m,6H),6.84(s,1H),6.63-6.48(m,2H),4.49(t,J=8.7Hz,2H),3.53(d,J=11.6Hz,2H),3.07(t,J=8.7Hz,2H),0.89(br s,3H).

[0092] 13C NMR (101MHz, CDCl3) δ159.16 (d, J = 3.0Hz), 132.68 (d, J = 8.7Hz), 131.23 (d, J = 2.4Hz), 129.76 (d, J = 4.8Hz), 128.87 (d, J = 53.5Hz), 128.6 3(d,J=9.8Hz), 126.96(d,J=4.3Hz), 126.87(d,J=2.6Hz), 123.24(d,J=4.0Hz), 108.66(d,J=2.5Hz), 71.23, 33.46(d,J=32.8Hz), 29.59.

[0093] Embodiment 15:

[0094] Starting from 1o and 2a, 3o was obtained as a white solid in 73% yield.

[0095] 1 H NMR (400MHz, CDCl3) δ7.68-7.63(m,4H),7.49-7.40(m,6H),2.24-2.13(m,2H),1.64-1.55(m,1H),1.43-1.34(m,2H),0.88(d,J=6.6Hz,6H),0.89(br s,3H).

[0096] 13 C NMR (101MHz, CDCl3) δ132.12 (d, J = 8.8Hz), 131.08 (d, J = 2.5Hz), 129.64 (d, J = 5 4.9Hz), 128.78 (d, J = 9.9Hz), 31.52, 29.25 (d, J = 13.7Hz), 23.70, 23.33, 22.02.

[0097] Embodiment 16:

[0098] Starting from 1p and 2a, 3p was obtained as a white solid in 58% yield.

[0099] 1 H NMR (400MHz, CDCl3) δ7.71-7.61(m,4H),7.51-7.40(m,6H),2.35-2.09(m,2H),1.86-1.69(m,3H),1.58-1.46(m,6H),1.10-1.02(m,2H),0.88(br s,3H).

[0100] 13C NMR (101MHz, CDCl3) δ132.12 (d, J = 9.0Hz), 131.07 (d, J = 2.6Hz), 129.68 (d, J = 54.8Hz) ,128.78(d,J=9.9Hz),41.30(d,J=13.7Hz),32.26,28.98,25.12,24.86(d,J=37.0Hz).

[0101] Embodiment 17:

[0102] Starting from 1q and 2a, 3q was obtained as a white solid in 61% yield.

[0103] 1 H NMR (400MHz, CDCl3) δ7.74-7.60(m,4H),7.54-7.32(m,6H),2.27-2.13(m,2H),1.74-1.57(m,4H),1.43-1.35(m,2H),1.30-1.06(m,5H),0.90

[0104] -0.80(m,J=11.7,3.0Hz,2H),0.89(br s,3H).

[0105] 13 C NMR (101MHz, CDCl3) δ132.11 (d, J = 8.8Hz), 131.06 (d, J = 2.5Hz), 129.69 (d, J = 54.6Hz), 12 8.77(d,J=9.9Hz),38.81(d,J=13.3Hz),32.75,30.09,26.46,26.17,23.14(d,J=37.2Hz).

[0106] Embodiment 18:

[0107] Starting from 1r and 2a, 3r was obtained as a white solid in 62% yield.

[0108] 1 H NMR (400MHz, CDCl3) δ7.64-7.55(m,4H),7.50-7.33(m,6H),7.14-7.08(m,1H),7.08-7 .01(m,2H),6.98(dq,J=7.0,1.4Hz,2H),1.78-1.67(m,2H),1.25-1.19(m,2H),0.88(br s,3H).

[0109] 13C NMR (101MHz, CDCl3) δ 132.12 (d, J = 9.1Hz), 131.06 (d, J = 2.4Hz), 129.69 (d, J = 54.9Hz), 128.77 (d, J = 9.6Hz), 31.92 ,31.15(d,J=13.9Hz),29.65,29.63,29.60,29.56,29.40,29.35,29.02,25.61(d,J=37.0Hz),22.95,22.69,14.14.

[0110] Embodiment 19:

[0111] Starting from 1s and 2a, 3s was obtained as a white solid in 69% yield.

[0112] 1 H NMR (400MHz, CDCl3) δ7.70-7.64(m,4H),7.51-7.38(m,6H),3.64(s,3H),2.40(t,J=6.9Hz,2H),2.33-2.20(m,2H),1.90-1.77(m,2H),0.87(br s,3H).

[0113] 13 C NMR (101MHz, CDCl3) δ173.08, 132.12 (d, J = 9.1Hz), 131.23 (d, J = 2.5Hz), 129.14 (d, J = 55.5Hz ), 128.85 (d, J = 9.9Hz), 51.63, 34.57 (d, J = 14.4Hz), 25.03 (d, J = 37.5Hz), 18.65 (d, J = 1.3Hz).

[0114] Embodiment 20:

[0115] Starting from 1t and 2a, 3t was obtained as a white solid in 46% yield.

[0116] 1 H NMR (400MHz, CDCl3) δ7.71-7.63(m,4H),7.52-7.40(m,6H),2.64(td,J=9.2,8.1,6.4Hz,2H),2.52-2.42(m,2H),2.10(s,3H),0.86(br s,3H).

[0117] 13C NMR (101MHz, CDCl3) δ206.24 (d, J = 13.6Hz), 132.08 (d, J = 9.2Hz), 131.42 (d, J = 2.5Hz), 128 .94(d,J=10.1Hz),128.76(d,J=55.5Hz),36.84(d,J=2.3Hz),29.76,19.16(d,J=40.1Hz).

[0118] Embodiment 21:

[0119] Starting from 1u and 2a, 3u was obtained as a yellow solid in 67% yield.

[0120] 1 H NMR (400MHz, CDCl3) δ7.72-7.60(m,4H),7.50-7.40(m,6H),3.33(t,J=6.7Hz,2H),2.20(d dd,J=15.1,9.5,6.2Hz,2H),1.87-1.78(m,2H),1.52(dq,J=8.0,4.5,3.8Hz,4H),0.86(br s,3H).

[0121] 13 C NMR (101MHz, CDCl3) δ132.09 (d, J = 9.1Hz), 131.21 (d, J = 2.4Hz), 129.40 (d, J = 54.9Hz) ,128.85(d,J=9.9Hz),33.47,32.10,29.60(d,J=14.1Hz),25.54(d,J=37.1Hz),22.27.

[0122] Embodiment 22:

[0123] Starting from 1v and 2a, 3v was obtained as a white solid in 67% yield.

[0124] 1 H NMR(400MHz, CDCl3)δ7.46(dd,J=13.2,7.5Hz,4H),7.37–7.26(m,6H),6.24(s,1H),4.40( t,J=7.1Hz,1H),3.71(s,3H),2.15–2.05(m,1H),1.83–1.69(m,1H),1.44(s,9H),0.89(br s,3H).

[0125] 13C NMR (101MHz, CDCl3) δ171.40 (d, J = 4.8Hz), 156.87, 138.54 (d, J = 21.0Hz), 132.74 (d, J = 16.2Hz) ,128.40(d,J=5.8Hz),128.25,79.69,52.46,50.92(d,J=11.4Hz),32.57(d,J=22.9Hz),28.34.

[0126] Embodiment 23:

[0127] Starting from 1w and 2a, 3w was obtained as a white solid in 60% yield.

[0128] 1 H NMR (400MHz, CDCl3) δ7.92-7.87(m,2H),7.57-7.32(m,3H),7.35(t,J=8.7Hz,3H),7.27-7.21(m,2H),7. 18-7.12(m,3H),7.11-7.02(m,2H),3.82(dq,J=14.6,7.1Hz,1H),1.58(dd,J=16.3,7.3Hz,3H),0.88(br s,3H).

[0129] 13 C NMR (101MHz, CDCl3) δ137.82 (d, J = 1.5Hz), 133.08 (d, J = 8.2Hz), 132.83 (d, J = 8. 4Hz),132.14(d,J=9.1Hz),131.40(d,J=2.5Hz),130.90(d,J=2.4Hz),129.32(d ,J=4.3Hz),128.85(d,J=9.5Hz),128.66(d,J=5.4Hz),128.16(d,J=9.9Hz),127 .88(d,J=2.3Hz), 127.13(d,J=2.8Hz), 37.41(d,J=30.9Hz), 16.35(d,J=3.4Hz).

[0130] Embodiment 24:

[0131] Starting from 1x and 2a, 3x was obtained as a white solid in 50% yield.

[0132] 1H NMR (400MHz, CDCl3) δ7.92-7.84(m,2H),7.56-7.45(m,3H),7.35-7.26(m,3H),7.22-7.17(m,2H),7.17 -7.12(m,3H),7.11-7.04(m,2H),3.55-3.47(m,1H),2.21-1.77(m,2H),0.80(t,J=7.3Hz,3H),0.88(br s,3H).

[0133] 13 C NMR (101MHz, CDCl3) δ135.49 (d, J=2.02Hz), 133.03 (d, J=8.3Hz), 132.64 (d, J= 8.3Hz),131.35(d,J=2.5Hz),130.70(d,J=2.6Hz),129.96(d,J=4.8Hz),128.84 (d,J=9.5Hz),128.77(d,J=54.5Hz),128.43,128.09(d,J=9.7Hz),127.93(d,J =2.3Hz), 127.10 (d, J = 2.7Hz), 45.38, 23.44 (d, J = 4.4Hz), 12.90 (d, J = 13.0Hz).

[0134] Embodiment 25:

[0135] Starting from 1y and 2a, 3y was obtained as a white solid in 66% yield.

[0136] 1 H NMR (400MHz, CDCl3) δ7.92-7.87(m,2H),7.58-7.48(m,3H),7.37-7.25(m,3H),7.23-7.18(m,2H),7.02-6.84(m,4H),3.79(dq ,J=14.7,7.2Hz,1H),2.46-2.31(m,2H),1.86-1.73(m,1H),1.58(dd,J=16.5,7.3Hz,3H),0.86(dd,J=6.5,5.2Hz,6H),0.88(br s,3H).

[0137] 13C NMR (101MHz, CDCl3) δ140.59 (d, J = 3.0Hz), 134.90 (d, J = 1.8Hz), 133.15, 132.85 (d, J = 8.4Hz), 132 .14(d,J=9.1Hz),131.34(d,J=2.3Hz),130.75(d,J=2.4Hz),129.33,128.99(d,J=4.3Hz),128.87( d,J=10.1Hz),128.81(d,J=10.1Hz),128.59(d,J=2.3Hz),128.03(d,J=9.8Hz),127.73(d,J=3.2H z), 44.94, 37.16 (d, J = 30.9Hz), 30.16 (d, J = 1.4Hz), 22.27 (d, J = 9.9Hz), 16.27 (d, J = 3.8Hz), 1.04.

[0138] Embodiment 26:

[0139] Starting from 1z and 2a, 3z was obtained as a white solid in 69% yield.

[0140] 1 H NMR(400MHz, CDCl3)δ7.90(q,J=6.3,3.6Hz,2H),7.64(dd,J=8.4,3.4Hz,3H),7.54-7.49(m,2H),7.44(q,J=8.4,7.7Hz,6 H),7.34(s,3H),7.30-7.19(m,3H),3.91(ddt,J=14.4,10.8,6.9Hz,1H),1.58(ddd,J=16.2,7.3,3.8Hz,3H),0.86(s,3H).

[0141] 13 C NMR (101MHz, CDCl3) δ196.26, 138.21, 137.30, 137.16 (d, J = 2.1Hz), 133.14, 133.0 8(d,J=2.0Hz),132.99(d,J=1.0Hz),132.77(d,J=8.2Hz),132.42,131.58,131.36 ,131.07(d,J=6.0Hz),129.99,128.94(d,J=10.1Hz),128.41,128.28,128.26(d,J =53.5Hz), 128.08, 127.43 (d, J = 52.1Hz), 37.30 (d, J = 30.7Hz), 16.19 (d, J = 3.1Hz).

[0142] Embodiment 27:

[0143] Starting from 1za and 2a, 3za was obtained as a white solid in 70% yield.

[0144] 1 H NMR (400MHz, CDCl3) δ8.01-7.97(m,2H),7.85-7.82(m,1H),7.76-7.67(m,3H),7.61-7.51(m,3H),7.51-7.44(m,2H),7.35-7. 30(m,1H),7.25-7.20(m,1H),7.18-7.06(m,3H),6.97-6.92(m,2H),4.81-4.69(m,1H),1.70(dd,J=16.4,7.1Hz,3H),0.89(br s,3H).

[0145] 13 C NMR (101MHz, CDCl3) δ134.47(d,J=1.5Hz), 133.43(d,J=1.4Hz), 133.33(d,J=8.3Hz), 132.43(d,J= 8.4Hz), 132.20 (d, J = 9.1Hz), 131.68 (d, J = 4.6Hz), 131.51 (d, J = 2.4Hz), 130.54 (d, J = 2.5Hz), 128. 91(d,J=9.5Hz),128.80,128.49(d,J=23.8Hz),128.08,127.82(d,J=9.8Hz),127.71(d,J=2.7Hz), 127.16(d,J=5.3Hz), 125.36(d,J=64.1Hz), 125.27(d,J=2.6Hz), 122.25, 17.47(d,J=4.0Hz), 1.03.

[0146] Embodiment 28:

[0147] Starting from 1zb and 2a, 3zb was obtained as a white solid in 43% yield.

[0148] 1 H NMR (400MHz, CDCl3) δ7.73(tt,J=8.0,1.7Hz,4H),7.50-7.37(m,6H),2.71(tq,J=14.0,7.0Hz,1H),1.15(dd,J=16.2,6.9Hz,6H),0.87(br s,3H).

[0149] 13 C NMR (101MHz, CDCl3) δ 132.56 (d, J = 8.5Hz), 131.04 (d, J = 2.6Hz), 128.74 (d, J = 53.4Hz), 128.69 (d, J = 9.6Hz), 23.66 (d, J = 36.8Hz), 16.86 (d, J = 2.2Hz).

[0150] Embodiment 29:

[0151] Starting from 1zc and 2a, 3zc was obtained as a white solid in 50% yield.

[0152] 1 H NMR (400MHz, CDCl3) δ7.67-7.55(m,4H),7.49-7.33(m,6H),7.32-7.19(m,3H),7.12-7.01(m,2H),2.84(d dd,J=13.3,7.9,4.8Hz,1H),2.63-2.39(m,2H),1.95-1.68(m,2H),1.18(dd,J=16.7,7.0Hz,3H),0.88(br s,3H).

[0153] 13 C NMR (101MHz, CDCl3) δ140.86, 132.57 (d, J = 12.1Hz), 132.48 (d, J = 12.1Hz), 131.09 (d, J = 2.4Hz), 130.97 (d, J = 2.4Hz), 128.95 (d, J = 53.5Hz), 128.73 (d ,J=5.0Hz),128.66,128.62,128.45,128.28(d,J=53.5Hz),126.14,33.27( d,J=12.2Hz), 31.86(d,J=3.1Hz), 26.80(d,J=36.5Hz), 13.21(d,J=2.3Hz).

[0154] Embodiment 30:

[0155] Starting from 1zd and 2a, 3zd was obtained as a white solid in 57% yield.

[0156] 1H NMR (400MHz, CDCl3) δ7.74-7.68(m,4H),7.51-7.34(m,6H),2.89-2.77(m,1H),1.84-1.69(m,6H),1.66-1.57(m,2H),0.87(br s,3H).

[0157] 13 C NMR (101MHz, CDCl3) δ132.41(d,J=8.5Hz), 130.91(d,J=2.3Hz), 130.11(d,J=53.9Hz ), 128.63 (d, J = 9.6Hz), 33.20 (d, J = 38.1Hz), 28.17 (d, J = 3.7Hz), 26.64 (d, J = 8.7Hz).

[0158] Embodiment 31:

[0159] Starting from 1ze and 2a, 3ze was obtained as a white solid in 57% yield.

[0160] 1 H NMR(400MHz, CDCl3)δ7.73(t,J=8.7Hz,4H),7.47-7.40(m,6H),2.39(q,J=12 .5Hz,1H),1.78-1.57(m,4H),1.54-1.40(m,2H),1.32-1.18(m,4H),0.87(br s,3H).

[0161] 13 C NMR (101MHz, CDCl3) δ132.63 (d, J = 8.4Hz), 130.99 (d, J = 2.5Hz), 128.68 (d, J = 9.7Hz), 128 .43(d,J=53.5Hz),33.67(d,J=36.2Hz),26.69(d,J=12.3Hz),26.49,25.79(d,J=1.5Hz).

[0162] Embodiment 32:

[0163] Starting from 1zf and 2a, 3zf was obtained as a white solid in 60% yield.

[0164] 1H NMR (400MHz, CDCl3) δ7.71(d,J=9.0Hz,2H),7.44(dt,J=25.2,7.8Hz,6H),7.33(d,J=7.7Hz,2H),7.04(s,2H),6.78(t,J=7.7Hz,1H),6.30(d ,J=7.8Hz,1H),3.98(s,1H),2.61(s,1H),2.52(s,1H),2.26-2.38(m,1H),1.99-2.13(m,1H),1.68-1.79(m,1H),1.50-1.56(m,1H),0.79(br s,3H).

[0165] 13 C NMR (101MHz, CDCl3) δ139.30 (d, J = 4.2Hz), 134.19 (d, J = 8.6Hz), 132.65 (d, J = 8.3Hz), 132.19 ( d,J=5.4Hz),131.42(d,J=2.6Hz),130.90(d,J=2.6Hz),129.65(d,J=54.2Hz),129.32(d,J=8.1 Hz), 129.31, 128.74 (d, J = 9.6Hz), 128.35 (d, J = 9.7Hz), 127.64 (d, J = 51.4Hz), 126.83 (d, J = 2. 7Hz), 125.00 (d, J = 2.3Hz), 37.46 (d, J = 29.6Hz), 28.92, 24.99 (d, J = 3.1Hz), 0.60 (d, J = 4.3Hz).

[0166] Embodiment 33:

[0167] Starting from 1zg and 2a, 3zg was obtained as a white solid in 64% yield.

[0168] 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 35.1Hz, 2H), 7.71-7.47 (m, 5H), 7.47-7.28 (m, 3H), 5.02 (d,J=53.9Hz,1H),3.76-3.35(m,2H),2.34-1.80(m,4H),1.14(d,J=63.8Hz,9H),0.86(br s,3H).

[0169] 13C NMR (101MHz, CDCl3) δ133.52 (d, J = 8.0Hz), 132.98 (d, J = 8.6Hz), 131.58, 129 .43(d,J=272.4Hz),128.90(d,J=9.2Hz),47.22,29.67,28.55,28.12,24.53.

[0170] Embodiment 34:

[0171] Starting from 1zh and 2a, 3zh was obtained as a white solid in 53% yield.

[0172] 1 H NMR (400MHz, CDCl3) δ7.77-7.70(m,4H),7.54-7.39(m,6H),4.15(d,J=22.7Hz,2H),2.82-2.41(m,3H),1.82-1.53(m,5H),1.42(s,9H),0.87(br s,3H).

[0173] 13 C NMR (101MHz, CDCl3) δ154.48, 132.67 (d, J = 8.5Hz), 131.36 (d, J = 2.5Hz), 128.88 (d,J=9.7Hz),127.46(d,J=53.8Hz),79.74,32.47(d,J=37.4Hz),28.38,25.84.

[0174] Embodiment 35:

[0175] Starting from 1zi and 2a, 3zi was obtained as a white solid in 46% yield.

[0176] 1 H NMR (400MHz, CDCl3) δ7.90-7.83(m,4H),7.51-7.40(m,6H),2.00-1.91(m,9H),1.72-1.61(m,6H),0.87(br s,3H).

[0177] 13 C NMR (101MHz, CDCl3) δ134.29 (d, J = 7.7Hz), 130.86 (d, J = 2.5Hz), 128.32 (d, J = 9.5Hz), 12 6.98(d,J=51.2Hz), 37.15, 36.28(d,J=1.5Hz), 34.30(d,J=31.0Hz), 28.05(d,J=9.1Hz).

[0178] Embodiment 36:

[0179] Starting from 1zj and 2a, 3zj was obtained as a white solid in 62% yield.

[0180] 1 H NMR (400MHz, CDCl3) δ7.63-7.55(m,4H),7.50-7.33(m,6H),7.14-7.08(m,1H),7.08-7 .02(m,2H),6.98(dq,J=7.0,1.4Hz,2H),1.77-1.68(m,2H),1.25-1.19(m,2H),0.88(br s,3H).

[0181] 13 C NMR (101MHz, CDCl3) δ139.51 (d, J = 1.2Hz), 133.63 (d, J = 8.5Hz), 132.00 (d, J = 2.3Hz), 131.10 (d, J = 2.5Hz), 128.24 (d, J=9.9Hz), 128.21(d,J=57.4Hz), 127.70(d,J=1.5Hz), 127.17(d,J=1.7Hz), 20.97(d,J=49.9Hz), 12.22(d,J=1.6Hz).

[0182] Embodiment 37:

[0183] Starting from 2b and 2b, 3zk was obtained as a white solid in 57% yield.

[0184] 1 H NMR (400MHz, CDCl3) δ7.58-7.44(m,4H),7.36-7.17(m,7H),7.13(d,J=7.4Hz,2H),2.70 (t,J=7.3Hz,2H),2.38(s,6H),2.21-2.14(m,2H),1.88(dt,J=12.8,7.8Hz,2H),0.91(br s,3H).

[0185] 13C NMR (101MHz, CDCl3) δ 141.45 (d, J = 2.5Hz), 140.91, 132.06 (d, J = 9.3Hz), 129.56 (d, J = 10.1Hz), 128. 52,128.43,126.21(d,J=56.9Hz),126.10,36.87(d,J=14.0Hz),25.11(d,J=37.7Hz),24.54,21.47.

[0186] Embodiment 38:

[0187] Starting from 2c and 2c, 3zl was obtained as a white solid in 70% yield.

[0188] 1 H NMR (400MHz, CDCl3) δ7.55-7.46(m,4H),7.45-7.35(m,4H),7.31-7.25(m,2H),7.24-7.17(m,1H ),7.15-7.06(m,2H),2.70(t,J=7.3Hz,2H),2.24-2.09(m,2H),1.91-1.79(m,2H),0.89(s,3H).

[0189] 13 C NMR (101MHz, CDCl3) δ140.46, 138.04 (d, J = 2.8Hz), 133.38 (d, J = 9.7Hz), 129.28 (d, J = 10. 3Hz), 128.53, 128.49, 127.58 (d, J = 55.0Hz), 126.29, 36.65 (d, J = 14.3Hz), 24.80, 24.41.

[0190] Embodiment 39:

[0191] Starting from 2d and 2d, 3zm was obtained as a white solid in 60% yield.

[0192] 1 H NMR (400MHz, CDCl3) δ7.70-7.67(m,2H),7.61-7.58(m,2H),7.30-7.23(m,2H),7.23-7. 17(m,1H),2.71(t,J=7.5Hz,2H),2.29-2.20(m,2H),1.97-1.85(m,2H),0.89(brs,3H).

[0193] 13C NMR (101MHz, CDCl3) δ140.67, 136.58 (d, J = 10.6Hz), 133.47 (d, J = 2.8Hz), 130.00 (d, J = 57.6H z), 128.46, 128.43 (d, J = 11.6Hz), 126.17, 36.63 (d, J = 14.9Hz), 29.35 (d, J = 40.4Hz), 24.66.

[0194] Embodiment 40:

[0195] Starting from 2e and 2e, 3zn was obtained as a white solid in 65% yield.

[0196] 1 H NMR (400MHz, CDCl3) δ7.70-7.64(m,2H),7.53-7.41(m,3H),7.30-7.22(m,2H),7.22-7.15(m,1H) ,7.10(d,J=7.4Hz,2H),2.65(t,J=6.6Hz,2H),1.90-1.68(m,4H),1.52(d,J=10.1Hz,3H),0.88(br s,3H).

[0197] 13 C NMR (101MHz, CDCl3) δ140.80, 131.42 (d, J = 9.1Hz), 131.26 (d, J = 2.5Hz), 129.60 (d, J = 53.4Hz), 128.86, 12 8.76, 128.44 (d, J = 1.9Hz), 126.12, 36.78 (d, J = 13.5Hz), 26.74 (d, J = 36.4Hz), 24.56, 10.87 (d, J = 38.8Hz).

[0198] The above-prepared C(sp 3 )-P(III) bonds can be used as pharmaceutical intermediates or phosphine ligands. After removing the borane protection, they also have excellent catalytic properties. Take compound 3v as an example.

[0199] 3v can be deprotected from borane to obtain compound 4 (Tetrahedron: Asym. 1997, 8, 715-738). Compound 4 has been confirmed to have excellent catalytic ability in asymmetric 3+2 cycloaddition reactions (J. Am. Chem. Soc. 2007, 129, 10988-10989).

[0200]

[0201] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds, characterized in that: In an organic solvent, an N-hydroxyphthalimide carboxylic acid ester compound represented by formula 1) and a disubstituted phosphine hydrogen-borane complex represented by formula 2) are used in the presence of a copper tetraacetonitrile hexafluorophosphate catalyst, a 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ligand, a base, and blue light to generate a carbon-phosphorus bond-containing compound represented by formula 3); wherein R1 is selected from one of an electron-rich or electron-withdrawing aromatic substituent, a substrate containing a cycloalkane, a heterocycle, an ester group, a halogen or a carbonyl group, an α-aminoamide and adamantane; R2 and R3 are selected from phenyl, 4-chlorophenyl, 4-methylphenyl, and thiophene; The N-hydroxyphthalimide carboxylate compound is selected from one of the following structural formulas:

2. The method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds according to claim 1, characterized in that: The preparation process of the disubstituted phosphine hydrogen-borane complex is as follows: Step 1: Under nitrogen conditions, dissolve the disubstituted phosphine oxide in anhydrous tetrahydrofuran, add phenylsilane dropwise to the disubstituted phosphine oxide at room temperature, and stir for 48-72 hours until the solid is completely converted into a clear liquid; Step 2: Under nitrogen conditions, the clear liquid obtained in the first step is dissolved in anhydrous tetrahydrofuran to obtain a disubstituted phosphine hydrogen solution; at 0°C, a tetrahydrofuran solution of borane dimethyl sulfide is added dropwise to the disubstituted phosphine hydrogen solution and stirred for 5 hours; after the reaction is completed, the solvent is removed, and the obtained solid is dissolved in dichloromethane and purified on silica gel by rapid column chromatography to obtain the product.

3. The method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds according to claim 1, characterized in that: The copper catalyst is tetraacetonitrile copper hexafluorophosphate; and the base is diisopropylethylamine.

4. The method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds according to claim 1, characterized in that: The molar ratio of the N-hydroxyphthalimide carboxylic acid ester compound, the disubstituted phosphine-borane complex, the copper catalyst, the ligand and the base is 2:1:0.1:0.1:1.

5.

5. The method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds according to claim 1, characterized in that: The organic solvent is tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or ethyl acetate.

6. The method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds according to claim 1, characterized in that: The specific conditions of the synthesis method are as follows: a copper catalyst, a ligand and an organic solvent are placed in a sealed tube under nitrogen and stirred at room temperature for 30 minutes, and then an N-hydroxyphthalimide carboxylic acid ester compound, a disubstituted phosphine hydrogen-borane complex and a base are added in a glove box, reacted at room temperature under blue light for 24 hours, and then separated and purified to obtain the product.

7. The method for copper-catalyzed construction of carbon-phosphorus bond-containing compounds according to claim 6, characterized in that: The separation method is a thin layer chromatography or column chromatography purification method, and the developing agent used is a mixed solvent of ethyl acetate-petroleum ether.

Images