CN115651016A - Chiral diphosphine ligand with alkyl skeleton and preparation method thereof - Google Patents

Chiral diphosphine ligand with alkyl skeleton and preparation method thereof Download PDF

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CN115651016A
CN115651016A CN202211366731.9A CN202211366731A CN115651016A CN 115651016 A CN115651016 A CN 115651016A CN 202211366731 A CN202211366731 A CN 202211366731A CN 115651016 A CN115651016 A CN 115651016A
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郭昌
张家殷
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University of Science and Technology of China USTC
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Abstract

The invention relates to the technical field of asymmetric organic synthesis, and discloses a chiral diphosphine ligand with an alkyl skeleton and a preparation method thereof. The chiral diphosphine ligand is mainly characterized by having a chiral alkyl chain skeleton. The chiral diphosphine ligand can be synthesized by using optically active diol with alkyl chain skeleton as chiral starting material. The chiral diphosphine ligand greatly expands the original ligand, greatly enriches the application range of the ligand in asymmetric organic synthesis, can be widely applied to a plurality of asymmetric organic catalytic reactions, and has the advantages of mild reaction conditions, good yield, high enantioselectivity and wide application prospect.

Description

Chiral diphosphine ligand with alkyl skeleton and preparation method thereof
Technical Field
The invention relates to the technical field of asymmetric organic synthesis, in particular to a chiral diphosphine ligand with an alkyl skeleton and a preparation method thereof.
Background
To date, asymmetric organocatalysis remains a very important area in chemical synthesis and research hotspot [ a) Kolb, h.c.; vannieuwenze, m.s.; sharpless, K.B.Catalytic asymmetry Chem.Rev.1994,94,2483-2547; b) Karjalainen, o.k.; koskinen, A.M.P.Diastereoscopic Synthesis of viral Amino alcohols. Org.biomol.chem.2012,10,4311-4326]. The catalyst system using metal and chiral ligand has the characteristics of good controllability, high reaction activity, high catalytic efficiency and the like. The design and development of novel chiral ligands and catalytic systems are particularly important for asymmetric synthesis catalysis. The chiral diphosphine ligand of the alkyl skeleton and metal Lewis acid can activate allyl derivatives to form chiral active intermediates, so that chiral control is realized, and chiral catalytic reaction [ Liu, X.T.; zhang, y.q.; han, x.y.; sun, s.p.; zhang, q.w.; ni-catalyzed asymmetry of secondary phosphorus oxides. J.Am.chem.Soc.2019, 141,16584-16589. However, at present, the developed systems and varieties of chiral diphosphine ligands with alkyl skeletons are very few, and the similar alkyl chiral diphosphine ligands reported include the following:
Figure BDA0003919809770000011
the ligand which has been reported at present has very limited types, less selectivity and less diversity, and has larger limitation in application. Therefore, in the research of asymmetric catalytic synthesis, the design and synthesis of chiral diphosphine ligand have important significance, and the asymmetric induction and control of reaction are directly influenced. Therefore, there is a need to develop a simple, readily available preparation method for such ligands that can prepare a wide variety of alkylphosphine ligands.
Disclosure of Invention
The invention provides a chiral diphosphine ligand of an alkyl skeleton and a preparation method thereof, the chiral diphosphine ligand of the alkyl skeleton makes up the vacancy of the existing ligand, and can show good activity and excellent enantioselectivity in the reaction of catalytic construction of allylation.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
the invention provides a chiral diphosphine ligand of an alkyl skeleton, which is a photochemically active compound with a structural formula (1):
Figure BDA0003919809770000021
wherein, represents a chiral carbon atom, and Ar represents an aryl group;
the aryl group is selected from substituted phenyl, substituted or unsubstituted naphthyl, phenanthryl and heterocyclic aryl;
R 1 and R 2 Each independently selected from halogen, hydrogen, alkyl, aryl;
n＝0～6。
in a preferred embodiment of the invention, the chiral bisphosphine ligand has the same levorotatory or dextrorotatory form of formula (1).
The invention also provides a preparation method of the chiral diphosphine ligand, which comprises the following steps:
(1) Carrying out a first reaction on the compound B to obtain a compound C; the reaction route is as follows:
Figure BDA0003919809770000022
(2) Carrying out a second reaction on the compound D to obtain a compound E; the reaction route is as follows:
Figure BDA0003919809770000023
(3) Carrying out a third reaction on the compound C and the compound E to obtain a compound F; the reaction route is as follows:
Figure BDA0003919809770000031
(4) Carrying out a fourth reaction on the compound F to obtain a compound A, namely a chiral diphosphine ligand; the reaction route is as follows:
Figure BDA0003919809770000032
in a preferred embodiment of the present invention, in step (1), the step of the first reaction comprises: dissolving optically active diol in pyridine under argon atmosphere, cooling a reaction system to 0 ℃, slowly dropwise adding p-toluenesulfonyl chloride dissolved in pyridine into the reaction solution, reacting at room temperature for 24-48 hours after dropwise adding, adding water and dichloromethane after reaction, obtaining an organic phase after layering, washing with dilute hydrochloric acid, washing with saturated sodium bicarbonate solution, drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a white solid, dissolving the solid in methanol again, and recrystallizing to obtain a compound C; wherein the molar equivalent ratio of the optically active diol to the p-toluenesulfonyl chloride is 1:2-10.
In a preferred embodiment of the present invention, in step (2), the preparation method of compound D comprises: under the protection of argon, mixing aryl bromide and magnesium chips in an organic solvent according to an equivalent ratio of 1:1-5, then adding a catalytic amount of 1,2-dibromoethane or elementary iodine as an initiator, heating and refluxing for 8-12 hours, cooling to room temperature, and then placing a reaction system at 0 ℃; and then adding diethyl phosphite into the Grignard reagent under the protection of argon, wherein the molar ratio of aryl bromide to diethyl phosphite is 3-4:1, and reacting for 10-12 hours at room temperature after the addition is finished. After the reaction is finished, slowly adding saturated ammonium chloride into the reaction system to quench the reaction, adding ethyl acetate for extraction, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound D.
In a preferred embodiment of the present invention, in the step (2), the step of the second reaction comprises: dissolving a compound D in an organic solvent under the protection of argon, slowly adding a reducing agent, reacting for 5-24 hours after the addition is finished, dropwise adding a 2M sodium hydroxide aqueous solution to quench the reaction after the reaction is finished, adding ethyl acetate to extract, washing an organic phase for multiple times by using the 2M sodium hydroxide aqueous solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to dryness to obtain a crude product, directly dissolving the intermediate in a dry organic solvent without further purification, adding a borane complex, reacting for 2-24 hours at room temperature, adding water and ethyl acetate to the reaction system to extract, drying an organic phase, decompressing and concentrating to dryness, and purifying by column chromatography to obtain a compound E; the molar ratio of the compound D to the reducing agent is 1-5:1, and the molar ratio of the compound D to the borane complex is 1-5:1; the reducing agent is sodium borohydride, silane, lithium aluminum hydride, diisobutyl aluminum hydride and the like, and the borane complex is sodium borohydride, borane dimethyl sulfide complex and borane tetrahydrofuran complex.
In a preferred embodiment of the invention, in the step (3), under the protection of argon, the compound E is dissolved in an organic solvent, the temperature is reduced to-78 to-20 ℃, alkali is slowly added, and the reaction system is stirred for 10 to 60 minutes at the temperature; dissolving the compound C obtained in the step 1 in an organic solvent, slowly dropwise adding the organic solvent into the reaction system, reacting at the temperature for 20-40 minutes, then moving to room temperature for reacting for 6-96 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain a compound F; the molar equivalent ratio of the compound E to the alkali is 1:1-3, and the molar equivalent ratio of the compound E to the compound C is 2-5:1; the base is alkyl or aryl lithium or lithium diisopropylamide.
In a preferred embodiment of the present invention, in step (4), compound F and a base are dissolved in an organic solvent under the protection of argon gas
Reacting at 30-100 ℃ for 12-36 hours, cooling the reaction system to room temperature after the reaction is finished, concentrating the organic solvent under reduced pressure to dryness, and performing column chromatography to obtain a chiral diphosphine ligand compound A; the base is morpholine, ethylenediamine, triethylenediamine, diisopropylamine, triethylamine or quinuclidine.
In a preferred embodiment of the present invention, the organic solvent is one of benzene, toluene, xylene, carbon tetrachloride, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, or dimethylsulfoxide.
The preparation process of the chiral diphosphine ligand with the alkyl skeleton can be represented by the following reaction general formula:
Figure BDA0003919809770000041
the invention provides a chiral diphosphine ligand of an alkyl skeleton and a synthesis method thereof, which take diol with optical activity as a starting material to synthesize the diphosphine ligand efficiently through two to three steps of reactions, greatly expand the types of ligands of alkyl skeleton families and have wider application. In the reaction of catalyzing propargyl carbonate and phosphine reagent, the catalyst shows higher catalytic activity and high-efficiency stereoselectivity, and has good catalytic reaction effect. In addition, the ligand has more applications in a plurality of catalytic reactions, and has very wide application prospects.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Detailed Description
The following describes the embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The present invention will be described in detail below by way of examples.
Example 1: preparation of ((2R, 4R) -pentane-2,4-diyl) bis (di (naphthalen-2-yl) phosphine)
Figure BDA0003919809770000051
Step 1: dissolving 30 mmol of (R, R) -2,4-pentanediol in 50 ml of pyridine under the atmosphere of argon, cooling a reaction system to 0 ℃, slowly dripping p-toluenesulfonyl chloride (120 mmol) dissolved in the pyridine into the reaction liquid, reacting at room temperature for 24 hours after dripping is finished, adding water and dichloromethane after the reaction is finished, obtaining an organic phase after layering, washing by using dilute hydrochloric acid, washing by using a saturated sodium bicarbonate solution, drying by using anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a white solid, re-dissolving the solid into methanol, re-crystallizing to obtain a compound 1b, wherein the yield of the product is 65%;
step 2: under the protection of argon, 60 mmol of 2-bromonaphthalene and magnesium chips are mixed in anhydrous ether according to the equivalent ratio of 1.5, then 0.5 ml of 1,2-dibromoethane is added, the mixture is heated and refluxed for 8 to 12 hours, the reaction system is cooled to 0 ℃, 20 mmol of diethyl phosphite is added into the reaction system, and the mixture is reacted at room temperature for 10 to 12 hours after the addition is finished. After the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction, adding ethyl acetate to extract, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 1e, wherein the yield of the product is 70%;
and step 3: dissolving 10 mmol of compound 1e in n-hexane under the protection of argon, slowly adding 15 mmol of diisobutylaluminum hydride, reacting for 6 hours, after the reaction is finished, slowly adding 2M sodium hydroxide aqueous solution to quench the reaction, adding ethyl acetate for extraction, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and obtaining a crude product without further purification. Dissolving the obtained crude product in anhydrous ether, adding 15 mmol of borane tetrahydrofuran complex, reacting at room temperature for 2 hours, adding water and ethyl acetate for extraction after the reaction is finished, drying, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 1f with a product yield of 45%;
and 4, step 4: under the protection of argon, 3 mmol of compound 1e are dissolved in 10 ml of diethyl ether and cooled to-78 ℃, at which temperature 5 mmol of methyllithium are slowly added and stirred at this temperature for 10 minutes; dissolving the compound 1b (1 mmol) obtained in the step 1 in 2 ml of N, N-dimethylformamide, slowly adding the mixture into the reaction system, reacting at room temperature for 6 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain 1g of a compound, wherein the yield of the product is 81%;
and 5: under the protection of argon, 0.8 mmol of compound 1g is dissolved in 2 ml of ethylenediamine, the reaction is carried out for 6 hours at 40 ℃, the organic solvent is decompressed and concentrated to be dry after being cooled to room temperature, and the chiral diphosphine ligand compound 1a is obtained through column chromatography, wherein the yield of the product is 92%.
Figure BDA0003919809770000061
1 H NMR(500MHz,CDCl 3 )δ8.04–7.93(m,4H),7.84–7.65(m,10H),7.62–7.53 (m,2H),7.51–7.32(m,12H),2.91–2.64(m,2H),1.69–1.52(m,2H),1.19–1.08(m,6H). 13 C NMR(125MHz,CDCl 3 )δ134.62,134.60(d,J＝15.1Hz),134.44(d,J＝6.5Hz), 134.27,134.22(d,J＝14.1Hz),133.48,133.24(d,J＝9.2Hz),129.76(d,J＝14.0Hz), 129.63(d,J＝13.5Hz),128.14,127.93,127.90,127.88,127.86,127.80,127.77,126.71, 126.35,37.00(t,J＝18.6Hz),27.35(t,J＝11.2Hz),16.13(d,J＝16.1Hz). 31 P NMR(202 MHz,CDCl 3 )δ0.68.APCI-MS:calculated[C 45 H 38 P 2 +H] + :641.2522,found:641.2528. [α] 20 D ＝-124.3(c＝0.73,CH 2 Cl 2 ).
Example 2: preparation of ((2S, 4S) -pentane-2,4-diyl) bis (3,5-di-tert-butylphenyl) phosphine)
Step 1: the same as in embodiment 1.
Step 2: under the protection of argon, 80 mmol of 3,5-di-tert-butyl bromobenzene and magnesium chips are mixed in anhydrous ether according to the equivalent ratio of 1.5, then 0.5 ml of 1,2-dibromoethane is added, the mixture is heated and refluxed for 15 hours, the reaction system is cooled to 0 ℃, 30 mmol of diethyl phosphite is added into the reaction system, and the reaction system reacts for 12 hours at room temperature after the addition is finished. After the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction, adding ethyl acetate to extract, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 2e, wherein the yield of the product is 78%;
and step 3: under the protection of argon, 20 mmol of the compound 1e is dissolved in n-hexane, 30 mmol of diisobutyl aluminum hydride is slowly added to react for 8 hours, after the reaction is finished, 2M sodium hydroxide aqueous solution is slowly added to quench the reaction, ethyl acetate is added to extract, an organic phase is dried by anhydrous sodium sulfate, and the mixture is filtered, decompressed and concentrated to be dry to obtain a crude product without further purification. Dissolving the obtained crude product in anhydrous ether, adding 50 mmol of borane tetrahydrofuran complex, reacting at room temperature for 5 hours, adding water and ethyl acetate for extraction after the reaction is finished, drying, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 2f with a product yield of 63%;
and 4, step 4: under the protection of argon, compound 10 mmol of 2e is dissolved in 30 ml of diethyl ether and cooled to-78 ℃, at which temperature 15 mmol of methyllithium are slowly added and stirred at this temperature for 15 minutes; dissolving the compound 1b (3 mmol) obtained in the step 1 in 5 ml of N, N-dimethylformamide, slowly adding the mixture into the reaction system, reacting at room temperature for 8 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain 2g of a compound, wherein the yield of the product is 76%;
and 5: under the protection of argon, 2g of 2 mmol of compound is dissolved in 3 ml of ethylenediamine, the reaction is carried out for 8 hours at 40 ℃, the organic solvent is decompressed and concentrated to be dry after being cooled to room temperature, the chiral diphosphine ligand compound 2a is obtained through column chromatography, and the product yield is 96%.
Figure BDA0003919809770000071
1 H NMR(500MHz,CDCl 3 )δ7.40–7.34(m,6H),7.32–7.29(m,2H),7.27–7.23(m, 4H),2.61–2.44(m,2H),1.47–1.39(m,2H),1.31–1.19(m,72H),1.02(dd,J＝15.4,6.7Hz, 6H). 31 P NMR(202MHz,CDCl 3 )δ3.19. 13 C NMR(125MHz,CDCl 3 )δ150.26(d,J＝7.3 Hz),150.11(d,J＝6.6Hz),136.67,134.68,128.35(d,J＝20.4Hz),127.65(d,J＝19.1Hz), 123.22,122.53,36.43(t,J＝17.4Hz),34.97,31.62,31.57,27.62(t,J＝10.7Hz),15.81(d,J＝ 17.3Hz).ESI-MS:calculated[C 61 H 91 P 2 +H] + :889.6904,found:889.6899.[α] 20 D ＝-0.5(c ＝1.01,CH 2 Cl 2 ).
Example 3: preparation of ((2S, 4S) -pentane-2,4-diyl) bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine)
Step 1: the same as in embodiment 1.
Step 2: under the protection of argon, 80 mmol of 4-bromo-2,6-di-tert-butyl anisole and magnesium turnings are mixed in anhydrous ether according to an equivalent ratio of 1.5, then 0.5 ml of 1,2-dibromoethane is added, the heating reflux is carried out for 18 hours, the reaction system is cooled to 0 ℃, 30 mmol of diethyl phosphite is added to the reaction system, and the reaction is carried out at room temperature for 16 hours after the addition is completed. After the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction, adding ethyl acetate to extract, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 3e, wherein the yield of the product is 73%;
and step 3: under the protection of argon, 20 mmol of the compound 3e is dissolved in n-hexane, 25 mmol of diisobutylaluminum hydride is slowly added to react for 6 hours, after the reaction is completed, 2M sodium hydroxide aqueous solution is slowly added to quench the reaction, ethyl acetate is added to extract, an organic phase is dried by anhydrous sodium sulfate, and the mixture is filtered, decompressed and concentrated to dryness to obtain a crude product without further purification. Dissolving the obtained crude product in anhydrous ether, adding 30 mmol of borane tetrahydrofuran complex, reacting at room temperature for 2 hours, adding water and ethyl acetate for extraction after the reaction is finished, drying, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 2f with a product yield of 56%;
and 4, step 4: dissolving 10 mmol of the compound 3e in 20 ml of diethyl ether under argon protection, cooling to-78 ℃, slowly adding 15 mmol of methyllithium at the temperature, and stirring for 10 minutes at the temperature; dissolving the compound 1b (3 mmol) obtained in the step 1 in 2 ml of N, N-dimethylformamide, slowly adding the mixture into the reaction system, reacting at room temperature for 16 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain 3g of a compound, wherein the yield of the product is 86%;
and 5: under the protection of argon, 3g of 3 mmol of compound is dissolved in 2 ml of ethylenediamine, the mixture reacts for 6 hours at 40 ℃, the organic solvent is decompressed and concentrated to be dry after being cooled to room temperature, and the chiral diphosphine ligand compound 3a is obtained through column chromatography, wherein the yield of the product is 93%.
Figure BDA0003919809770000091
1 H NMR(500MHz,CDCl 3 )δ7.32(s,2H),7.30(s,2H),7.18(s,2H),7.16(s,2H),3.59 (s,6H),3.57(s,6H),2.40–2.21(m,2H),1.37–1.29(m,38H),1.28(s,36H),0.94–0.83(m, 6H). 31 P NMR(202MHz,CDCl 3 )δ0.33. 13 C NMR(125MHz,CDCl 3 )δ160.57,160.04, 143.40(d,J＝7.4Hz),143.10(d,J＝7.0Hz),132.49(d,J＝21.3Hz),131.94(d,J＝20.0Hz), 64.34,64.27,35.93,35.91,32.25,32.20,32.09(dd,J＝5.4,2.1Hz),28.11(t,J＝10.2Hz), 15.88(d,J＝17.4Hz).ESI-MS:calculated[C 65 H 102 O 4 P 2 +H] + :1009.7326,found: 1009.7336.[α] 20 D ＝-51.1(c＝0.60,CH 2 Cl 2 ).
Example 4: preparation of ((2S, 4S) -pentane-2,4-diyl) bis (3,5-diethylphenyl) phosphine)
Step 1: the same as in embodiment 1.
Step 2: 80 mmol of 3,5-diethylbromobenzene and magnesium turnings are mixed in anhydrous ether at an equivalent ratio of 1.9 under the protection of argon, 0.5 ml of 1,2-dibromoethane is added, the mixture is heated and refluxed for 18 hours, the reaction system is cooled to 0 ℃, 25 mmol of diethyl phosphite is added to the reaction system, and the reaction is carried out at room temperature for 15 hours after the addition is completed. After the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction, adding ethyl acetate to extract, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 4e, wherein the yield of the product is 75%;
and step 3: under the protection of argon, 20 mmol of the compound 4e is dissolved in n-hexane, 30 mmol of diisobutyl aluminum hydride is slowly added to react for 3 hours, after the reaction is finished, 2M sodium hydroxide aqueous solution is slowly added to quench the reaction, ethyl acetate is added to extract, an organic phase is dried by anhydrous sodium sulfate, and the mixture is filtered, decompressed and concentrated to be dry to obtain a crude product without further purification. Dissolving the obtained crude product in anhydrous ether, adding 30 mmol of borane tetrahydrofuran complex, reacting at room temperature for 2 hours, adding water and ethyl acetate for extraction after the reaction is finished, drying, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 4f with a product yield of 50%;
and 4, step 4: dissolving 10 mmol of the compound 4e in 30 ml of diethyl ether under the protection of argon, cooling to-78 ℃, slowly adding 15 mmol of methyllithium at the temperature, and stirring for 10 minutes at the temperature; dissolving the compound 1b (3.5 mmol) obtained in the step 1 in 2 ml of N, N-dimethylformamide, slowly adding the mixture into the reaction system, reacting at room temperature for 20 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain 4g of a compound, wherein the yield of the product is 89%;
and 5: under the protection of argon, dissolving 4g of 2 mmol of compound into 2 ml of ethylenediamine, reacting at 60 ℃ for 6 hours, cooling to room temperature, concentrating the organic solvent under reduced pressure to dryness, and performing column chromatography to obtain chiral diphosphine ligand compound 4a, wherein the yield of the product is 92%.
Figure BDA0003919809770000101
1 H NMR(600MHz,CDCl 3 )δ7.14–7.05(m,8H),6.97–6.91(m,4H),2.79–2.44(m, 16H)1.41–1.34(m,24H),1.28–1.21(m,2H),1.19–1.13(m,2H),0.99(dd,J＝15.2,6.4 Hz,6H). 31 P NMR(243MHz,CDCl 3 )δ1.10. 13 C NMR(150MHz,CDCl 3 )δ144.60(d,J ＝11.9Hz),143.97(d,J＝7.1Hz),130.75(d,J＝19.0Hz),130.59,130.47(d,J＝18.8Hz), 130.46,128.19(d,J＝36.2Hz),127.86(d,J＝8.5Hz),36.38(t,J＝17.0Hz),28.91,27.30(t, J＝10.1Hz),15.74,15.64(d,J＝7.3Hz).
Example 5: preparation of ((2S, 4S) -pentane-2,4-diyl) bis ([ 1,1' -biphenyl ] -3-yl) phosphine)
Step 1: same as in embodiment 1.
Step 2: under the protection of argon, 80 mmol of 3-bromobiphenyl and magnesium chips are mixed in anhydrous ether according to an equivalent ratio of 1.5, then 0.5 ml of 1,2-dibromoethane is added, the mixture is heated and refluxed for 18 hours, the reaction system is cooled to 0 ℃, 25 mmol of diethyl phosphite is added to the reaction system, and after the addition is completed, the reaction is carried out at room temperature for 15 hours. After the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction, adding ethyl acetate to extract, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 5e, wherein the yield of the product is 70%;
and step 3: under the protection of argon, 20 mmol of the compound 5e is dissolved in n-hexane, 30 mmol of diisobutyl aluminum hydride is slowly added to react for 5 hours, after the reaction is finished, 2M sodium hydroxide aqueous solution is slowly added to quench the reaction, ethyl acetate is added to extract, an organic phase is dried by anhydrous sodium sulfate, and the mixture is filtered, decompressed and concentrated to be dry to obtain a crude product without further purification. Dissolving the obtained crude product in anhydrous ether, adding 30 mmol of borane tetrahydrofuran complex, reacting at room temperature for 2 hours, adding water and ethyl acetate for extraction after the reaction is finished, drying, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 5f with a product yield of 56%;
and 4, step 4: dissolving 10 mmol of compound 5e in 30 ml of diethyl ether under argon protection, cooling to-78 ℃, slowly adding 15 mmol of methyllithium at the temperature, and stirring for 10 minutes at the temperature; dissolving the compound 1b (3.5 mmol) obtained in the step 1 in 2 ml of N, N-dimethylformamide, slowly adding the mixture into the reaction system, reacting at room temperature for 20 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain 5g of a compound, wherein the yield of the product is 89%;
and 5: under the protection of argon, dissolving 5g of 2 mmol of compound into 2 ml of ethylenediamine, reacting at 60 ℃ for 6 hours, cooling to room temperature, concentrating the organic solvent under reduced pressure to dryness, and performing column chromatography to obtain chiral diphosphine ligand compound 5a, wherein the yield of the product is 92%.
Figure BDA0003919809770000111
1 H NMR(600MHz,CDCl 3 )δ7.72–7.66(m,4H),7.55–7.51(m,2H),7.52–7.45(m, 10H),7.44–7.35(m,14H),7.35–7.28(m,6H),2.66–2.57(m,2H),1.58–1.48(m,2H), 1.07(dd,J＝15.2,6.8Hz,6H). 31 P NMR(243MHz,CDCl 3 )δ0.87.
Example 6: preparation of ((2S, 4S) -pentane-2,4-diyl) bis (4-methoxy-3,5-dimethylphenyl) phosphine)
Step 1: the same as in embodiment 1.
And 2, step: under the protection of argon, 80 mmol of 4-bromo-2,6-dimethyl anisole and magnesium chips are mixed in anhydrous ether according to an equivalent ratio of 1.5, then 0.5 ml of 1,2-dibromoethane is added, the mixture is heated and refluxed for 20 hours, the reaction system is cooled to 0 ℃, 25 mmol of diethyl phosphite is added into the reaction system, and after the addition is completed, the mixture is reacted at room temperature for 15 hours. After the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction, adding ethyl acetate to extract, washing an organic phase with the saturated ammonium chloride, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 6e, wherein the yield of the product is 75%;
and step 3: under the protection of argon, 20 mmol of the compound 6e is dissolved in n-hexane, 30 mmol of diisobutyl aluminum hydride is slowly added to react for 6 hours, after the reaction is finished, 2M sodium hydroxide aqueous solution is slowly added to quench the reaction, ethyl acetate is added to extract, an organic phase is dried by anhydrous sodium sulfate, and the mixture is filtered, decompressed and concentrated to be dry to obtain a crude product without further purification. Dissolving the obtained crude product in anhydrous ether, adding 30 mmol of borane tetrahydrofuran complex, reacting at room temperature for 3 hours, adding water and ethyl acetate for extraction after the reaction is finished, drying, concentrating under reduced pressure to dryness, and purifying by column chromatography to obtain a compound 6f with a product yield of 58%;
and 4, step 4: under the protection of argon, compound 10 mmol of 6e is dissolved in 30 ml of diethyl ether and cooled to-78 ℃, at which temperature 15 mmol of methyllithium are slowly added and stirred for 20 minutes at this temperature; dissolving the compound 1b (3.5 mmol) obtained in the step 1 in 2 ml of N, N-dimethylformamide, slowly adding the mixture into the reaction system, reacting at room temperature for 20 hours, adding diluted hydrochloric acid after the reaction is finished to quench the reaction, adding water and ethyl acetate for extraction, drying an organic phase by using anhydrous magnesium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then carrying out column chromatography to obtain 6g of a compound, wherein the yield of the product is 87%;
and 5: under the protection of argon, 6g of 2 mmol of compound is dissolved in 2 ml of ethylenediamine, the mixture reacts for 6 hours at 60 ℃, the organic solvent is decompressed and concentrated to be dry after being cooled to room temperature, and the chiral diphosphine ligand compound 6a is obtained through column chromatography, wherein the yield of the product is 92%.
Figure BDA0003919809770000121
1 H NMR(600MHz,CDCl3)δ7.13–7.06(m,8H),3.70(s,6H),3.68(s,6H),2.48–2.37(m, 2H),2.23(s,12H),2.22(s,12H),1.37–1.29(m,2H),0.96(dd,J＝15.8,6.7Hz,6H). 31 P NMR(243MHz,CDCl3)δ-3.38. 13 C NMR(150MHz,CDCl3)δ157.81(d,J＝8.0Hz), 134.31(d,J＝20.3Hz),134.17(d,J＝20.3Hz),130.90(d,J＝7.7Hz),130.85(d,J＝7.9Hz), 59.76,59.72,36.39(t,J＝21.4Hz),27.57(dd,J＝11.6,8.1Hz),16.31,16.28,15.77(d,J＝ 17.5Hz).
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.

Claims (10)

1. A chiral bisphosphine ligand of alkyl skeleton, characterized in that it is a photochemically active compound of the formula (1):
Figure FDA0003919809760000011
wherein, represents a chiral carbon atom, and Ar represents an aryl group;
the aryl group is selected from substituted phenyl, substituted or unsubstituted naphthyl, phenanthryl and heterocyclic aryl;
R 1 and R 2 Each independently selected from halogen, hydrogen, alkyl, aryl;
n＝0～6。
2. the chiral bisphosphine ligand according to claim 1, characterized in that it has the same structural formula (1) as the levorotatory or dextrorotatory isomer.
3. A process for the preparation of a chiral bisphosphine ligand according to claim 1 or 2, comprising:
(1) Carrying out a first reaction on the compound B to obtain a compound C; reaction scheme is as follows:
Figure FDA0003919809760000012
(2) Carrying out a second reaction on the compound D to obtain a compound E; reaction scheme is as follows:
Figure FDA0003919809760000013
(3) Carrying out a third reaction on the compound C and the compound E to obtain a compound F; reaction scheme is as follows:
Figure FDA0003919809760000014
(4) Carrying out a fourth reaction on the compound F to obtain a compound A, namely a chiral diphosphine ligand; reaction scheme is as follows:
Figure FDA0003919809760000021
4. the process for preparing a chiral bisphosphine ligand according to claim 3, characterized in that, in step (1), the step of the first reaction comprises: cooling the glycol dissolved in the pyridine to 0 ℃, adding the p-toluenesulfonyl chloride dissolved in the pyridine, reacting at room temperature for 24-48 hours, layering, washing, drying and concentrating to obtain an intermediate, dissolving the intermediate in methanol, and recrystallizing to obtain the compound C.
5. The process for preparing chiral bisphosphine ligands according to claim 4, wherein the molar equivalent ratio of the diol to the tosyl chloride is 1:2-10.
6. A process for the preparation of chiral bisphosphine ligand according to claim 3, characterized in that in step (2), the process for the preparation of compound D comprises: mixing aryl bromide and magnesium chips in a molar equivalent ratio of 1:1-5 in an organic solvent, adding an initiator, heating and refluxing for 8-12 hours, then placing a reaction system at 0 ℃, adding diethyl phosphite, wherein the molar ratio of the aryl bromide to the diethyl phosphite is 3-4:1, reacting at room temperature for 10-12 hours, then adding saturated ammonium chloride for quenching reaction, extracting, washing, drying, filtering, concentrating, and purifying by column chromatography to obtain a compound D;
preferably, the initiator is 1,2-dibromoethane or elemental iodine.
7. The process for preparing a chiral bisphosphine ligand according to claim 3, wherein in step (2), the step of the second reaction comprises: mixing the compound D, an organic solvent and a reducing agent for reaction for 5-24 hours, adding an aqueous solution of sodium hydroxide for quenching reaction, extracting, washing, drying and concentrating to obtain an intermediate, reacting the intermediate, the organic solvent and a borane complex at room temperature for 2-24 hours, extracting, drying, concentrating and purifying by column chromatography to obtain a compound E;
preferably, the molar ratio of compound D to reducing agent is 1-5:1;
preferably, the molar ratio of compound D to borane complex is from 1 to 5:1;
preferably, the reducing agent is one of sodium borohydride, silane, lithium aluminum hydride or diisobutyl aluminum hydride;
preferably, the borane complex is one of sodium borohydride, borane dimethylsulfide complex, or borane tetrahydrofuran complex.
8. The preparation method of chiral diphosphine ligand according to claim 3, wherein in step (3), compound E is dissolved in organic solvent, cooled to-78-20 ℃, added with alkali and stirred for 10-60 min, added with compound C, reacted at the temperature for 20-40 min, then reacted at room temperature for 6-96 h, added with dilute hydrochloric acid to quench the reaction, extracted, dried, filtered, concentrated, and subjected to column chromatography to obtain compound F;
preferably, the molar equivalent ratio of compound E to base is 1:1-3;
preferably, the molar equivalent ratio of compound E to compound C is 2 to 5:1;
preferably, the base is one of an alkyl, aryl lithium or lithium diisopropylamide.
9. The method for preparing chiral diphosphine ligand according to claim 3, wherein in step (4), compound F and base are dissolved in organic solvent, and reacted at 30-100 ℃ for 12-36 hours, concentrated, and subjected to column chromatography to obtain chiral diphosphine ligand compound A;
preferably, the base is one of morpholine, ethylenediamine, triethylenediamine, diisopropylamine, triethylamine or quinuclidine.
10. The process for the preparation of a chiral bisphosphine ligand according to any one of claims 4-9, wherein the organic solvent is one of benzene, toluene, xylene, carbon tetrachloride, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, or dimethylsulfoxide.
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