CN110183498B - Chiral ferrocene phosphine nitrogen tridentate ligand and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a chiral ferrocene phosphine nitrogen tridentate ligand and a preparation method and application thereof, wherein the structural general formula of the chiral ferrocene phosphine nitrogen tridentate ligand is shown as a formula (I) or a formula (II):
in formula (I) or formula (II): r1、R2Each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, aryl or heterocyclic aryl; r3Is aryl, heterocyclic aryl or C1-C6 alkyl, R4Is hydrogen, C1-C6 alkyl, aryl or heterocyclic aryl; in the structural general formulas in the formula (I) and the formula (II), imidazole groups or substituted benzimidazole groups are contained respectively; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl. The chiral ferrocene phosphine nitrogen tridentate ligand has the advantages of simple and convenient synthesis and stable existence in the air, can be coordinated with cheap metal to prepare a cheap metal catalyst, and has good application in asymmetric hydrogenation of ketone.
Description
Technical Field
The invention relates to a chiral ferrocene phosphine nitrogen tridentate ligand and a preparation method and application thereof.
Background
The chiral secondary alcohol is an important intermediate for synthesizing chiral drugs, fine chemicals, agricultural chemicals, other special materials and the like. Many drugs containing chiral secondary alcohols have been approved clinically for the market as first line therapeutics for patients. For example: treatment of Crizotinib (Crizotinib) for ROS1 positive non-small cell lung cancer patients; duloxetine (Duloxetine) for use in the treatment of depression and anxiety; and so on (J.mol.Catal.,2013,27(2): 99; J.mol.Catal.,2013,27: 507). Asymmetric catalytic hydrogenation is one of the simplest, efficient, and green methods for obtaining chiral alcohols and other chiral compounds. Among them, chiral catalysts generated by complexing chiral ligands with metals are the core hot spot of asymmetric catalytic hydrogenation research, and designing and synthesizing novel and efficient chiral ligands or chiral catalysts is the direction of research efforts of scientists (ChemCatChem,2018,25: 2612; Science,2013,34: 1229; angew.chem.int.ed.,2002,41: 1998). However, the metal centers of the high-efficiency chiral catalytic systems reported at present mainly focus on noble metals such as ruthenium, rhodium, iridium, palladium and the like, the metals are expensive and scarce in reserves, and the environment-friendly type is inferior to the cheap metals of the former transition series, and the development of the former transition series cheap metal systems has important practical significance from the aspects of sustainable development and green chemistry.
The transition metal manganese is reported to be abundant in earth crust, easy to develop and exploit, and low in price, and is increasingly valued by scientists. At present, the manganese-catalyzed asymmetric hydrogenation reaction has achieved some satisfactory results, but compared with a noble metal catalyst, the manganese-catalyzed asymmetric hydrogenation reaction still has the defects of low catalytic activity, low stereoselectivity, limited substrate application range and the like (Acc.chem.Res.,2015,48: 1979; Acc.chem.Res.,2018,51: 1558; Synthesis,2017,49: 3377). Therefore, designing and synthesizing a novel chiral ligand, and complexing with cheap metal to efficiently regulate and control the chemical, regional and stereoselectivity of the latent chiral compound have important practical significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a chiral ferrocenyl phosphine nitrogen tridentate ligand, a preparation method and application thereof.
The chiral ferrocene phosphine nitrogen tridentate ligand is characterized in that the structural general formula is shown as a formula (I) or a formula (II):
in formula (I) or formula (II): r1、R2Each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, aryl or heterocyclic aryl; r3Is aryl, heterocyclic aryl or C1-C6 alkyl, R4Is hydrogen, C1-C6 alkyl, aryl or heterocyclic aryl;
in the structural general formulas in the formula (I) and the formula (II), imidazole groups or substituted benzimidazole groups are contained respectively; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl.
The specific molecular structural formula of the compound with the structural general formula of the formula (I) is shown in any one of the formulas (I-1) to (I-7):
the compound of the general structural formula of the formula (II) has a specific molecular structural formula shown as the formula (II-1):
the preparation method of the chiral ferrocene phosphine nitrogen tridentate ligand is characterized by comprising the following steps of: under the protection of nitrogen, dissolving chiral phosphine ferrocene-alpha-ethylamine shown as a formula (III) or a formula (IV) and an imidazole carbonyl compound shown as a formula (V) in an alcohol solvent, reacting for 1-24 hours at 20-80 ℃, tracking by TLC (thin layer chromatography) until the reaction is complete, and adding sodium borohydride at-20-60 ℃ to continue reacting for 1-12 hours; after the reaction is finished, decompressing and concentrating the reaction liquid to recover the solvent, and separating the concentrated residue by column chromatography to obtain the chiral ferrocene nitrogen phosphine tridentate ligand shown in the formula (I) or the formula (II);
in the formula (III) or the formula (IV), R1、R2Each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, aryl or heterocyclic aryl;
in the formula (V), R3Is aryl, heterocyclic aryl or C1-C6 alkyl, R4Is hydrogen, C1-C6 alkyl, aryl or heterocyclic aryl;
in the general structural formula of the formula (V), an imidazole group or a substituted benzimidazole group is contained; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl.
Further, the mass ratio of the chiral phosphine ferrocene-alpha-ethylamine shown in the formula (III) or the formula (IV), the imidazole carbonyl compound shown in the formula (V) and the sodium borohydride is 1: 1.0-1.5: 2.0-5.0; the alcohol solvent is methanol, ethanol or isopropanol.
The preparation method of the chiral ferrocene phosphine nitrogen tridentate ligand has the following reaction general formula:
the application of the chiral ferrocene phosphine nitrogen tridentate ligand in preparing the cheap metal catalyst is characterized in that the chiral ferrocene phosphine nitrogen tridentate ligand and the cheap metal complex are mixed and reacted to prepare the cheap metal catalyst.
Further, the cheap metal complex is Mn (CO)5Br。
Further, the ratio of the amount of the chiral ferrocenyl phosphine nitrogen tridentate ligand to the amount of the cheap metal complex substance is 1: 1.0-2.0, and 1:1.1 is preferred.
The application of the cheap metal catalyst in the asymmetric hydrogenation reaction of ketone has the following general formula:
compared with the prior art, the invention has the following beneficial effects:
1) the chiral ferrocene phosphine nitrogen tridentate ligand provided by the invention is simple and convenient to synthesize, is stable in air, and is suitable for large-scale preparation. Has good activity and enantioselectivity to carbon-oxygen double bonds, and has important research value and application prospect.
2) The chiral ferrocene phosphine nitrogen tridentate ligand provided by the invention is mixed with a cheap metal complex for reaction, so that a cheap metal catalyst can be prepared. The cheap metal catalyst has good application in asymmetric hydrogenation reaction of ketone, including asymmetric hydrogenation reaction, asymmetric hydrogen transfer reaction, asymmetric hydrosilation reaction and asymmetric hydroboration reaction.
3) The aryl alkyl ketone can be hydrogenated and reduced by a hydrogen donor under the alkaline condition under the catalysis of the cheap metal catalyst. The ligand and the metal are the core of catalytic reaction, and the reaction can be greatly influenced by fine adjustment of the ligand environment, so that the adjustability of the ligand determines the substrate application range of the catalyst to a great extent, and different substrates may need ligands with different steric hindrance and electric property to catalyze and realize high reactivity and high selectivity. The ligand of the invention is very easy to regulate and control in steric hindrance and electrical property, thus having wide substrate application range.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1: preparation of chiral ligand I-1
A100 mL three-necked flask was charged with the compound represented by the formula (III-1) (4.13g,10.0mmol) and the compound represented by the formula (V-1) (2.05g,11.0mmol), and then 50mL of methanol was added under nitrogen protection, followed by reaction at 80 ℃ for 5 hours, followed by cooling to 60 ℃ and then adding sodium borohydride (1.5g,40mmol) directly and reacting for 4 hours. After the reaction is finished, the reaction liquid is decompressed and concentrated to recover methanol, and the concentrated residue is separated by column chromatography to obtain orange yellow solid chiral ligand I-1(4.1g, yield is 71%), mp 82-83 ℃ and alpha]D 20＝125.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand I-1:1H NMR(600MHz,CDCl3)δ7.57-7.55(m,2H),7.41-7.37(m,3H),7.25-7.23(m,2H),7.19-7.17(m,2H),7.16-7.15(m,2H),6.88-6.86(m,3H),6.66(s,1H),5.29(s,1H),4.77(d,J＝16.2Hz,1H),4.58(d,J＝16.2Hz,1H),4.48(s,1H),4.31(s,1H),4.09-4.08(m,1H),3.94(s,5H),3.86(s,1H),3.67-3.66(m,1H),3.58-3.56(m,1H),3.49-3.47(m,1H),3.11-3.09(m,1H),1.50-1.49(m,3H).13C NMR(150MHz,CDCl3)δ146.4,136.8,135.2(d,J＝21.3Hz),135.1(d,J＝17.7Hz),132.4,132.3,129.1,128.6,128.1,128.0,127.9,127.7,127.5,126.8,125.2,124.9,120.3,117.4,112.3,71.1,69.5,69.2,68.9,53.3,52.1,48.8,43.1,29.6,28.4,19.9.31P NMR(162MHz,CDCl3)δ-23.25.HRMS(ESI)calcd for C35H34FeN3P[M+H]+:584.1913,found:584.1821。
example 2: preparation of chiral ligand I-2
To a compound represented by the formula (III-1) (4.13g,10.0mmol) and a compound represented by the formula (V-2) (2.36g,10.0mmol) in a 100mL three-necked flask, 50mL of ethanol was added under nitrogen protection, the mixture was reacted at 50 ℃ for 12 hours, and then, after cooling to 0 ℃, sodium borohydride (1.1g,30mmol) was added and reacted for 8 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to recover ethanol, and the concentrated residue is separated by column chromatography to obtain orange-yellow solid chiral ligand I-2(4.7g, yield is 75%). mp 84-85 deg.C, [ alpha ]]D 20＝120.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand I-2:1H NMR(600MHz,CDCl3)δ7.71(d,J＝7.8Hz,1H),7.55-7.53(m,2H),7.21-7.36(m,3H),7.21-7.14(m,8H),7.09-7.07(m,3H),7.02-6.99(m,1H),6.85-6.83(m,2H),5.03(d,J＝16.8Hz,1H),4.87(d,J＝16.8Hz,1H),4.48(s,1H),4.31(s,1H),4.17-4.15(m,1H),3.95(s,5H),3.86(s,1H),3.74(d,J＝13.8Hz,1H),3.65(d,J＝13.8Hz,1H),1.52(d,J＝6.6Hz,3H).13C NMR(150MHz,CDCl3)δ153.1,142.4,140.5(d,J＝10.5Hz),137.6(d,J＝9.0Hz),136.6,135.7,135.3,135.1,132.5,132.4,129.2,128.7,128.2,128.12,128.07,127.8,127.5,126.3,122.4,121.8,119.5,109.6,97.8(d,J＝25.5Hz),75.0(d,J＝9.0Hz),71.3(d,J＝4.5Hz),69.7,69.3,69.0(d,J＝4.5Hz),51.4(d,J＝9.0Hz),46.4,44.0,20.0.31PNMR(162MHz,CDCl3)δ-24.25.HRMS(ESI)calcd for C39H36FeN3P[M+H]+:634.2069,found:634.1996。
example 3: preparation of chiral ligand I-4
To a 100mL three-necked flask containing a compound represented by the formula (III-1) (4.13g,10.0mmol) and a compound represented by the formula (V-3) (4.59g,15.0mmol), 50mL of isopropanol was added under nitrogen protection, the mixture was reacted at 80 ℃ for 24 hours, and then cooled to-20 ℃ and sodium borohydride (1.9g,50 mm) was addedol) for 10 h. After the reaction is finished, the reaction solution is decompressed and concentrated to recover isopropanol, and the concentrated residue is separated by column chromatography to obtain orange-yellow solid chiral ligand I-4(4.4g, yield 57%). mp 83-84 deg.C, [ alpha ]]D 20＝125.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand I-4:1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.0Hz,1H),7.57-7.53(m,3H),7.41-7.37(m,3H),7.35(d,J＝7.6Hz,2H),7.28(d,J＝7.6Hz,1H),7.24-7.20(m,2H),7.18-7.09(m,4H),6.87(d,J＝8.0Hz,1H),4.46(s,1H),4.28(s,1H),4.21(s,1H),4.04(s,5H),3.80(s,1H),3.43-3.34(m,2H),1.94-1.89(m,1H),1.79-1.77(m,1H),1.49(d,J＝6.4Hz,3H),1.10(d,J＝6.8Hz,6H),0.95(d,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ153.7,147.5,147.4,142.4,137.5,137.1,135.1,134.9,132.4,132.2,130.1,129.0,128.2,128.2,128.1,128.0,124.3,122.4,121.8,119.5,110.1,75.0,74.9,71.0,70.2,69.6,68.8,68.5,60.4,51.5,51.5,43.5,28.1,28.1,25.1,23.6,23.5,21.2,21.0,14.2.31P NMR(162MHz,CDCl3)δ-24.92.HRMS(ESI)calcd forC44H46FeN3P[M+H]+:704.2852,found:704.2851。
example 4: preparation of chiral ligand I-5
To a compound represented by the formula (III-1) (4.13g,10.0mmol) and a compound represented by the formula (V-4) (2.75g,11.0mmol) in a 100mL three-necked flask, 50mL of methanol was added under nitrogen protection, and after reaction at 20 ℃ for 24 hours, sodium borohydride (0.76g,20mmol) was directly added and reacted for 8 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to recover methanol, and the concentrated residue is separated by column chromatography to obtain orange-yellow solid chiral ligand I-5(4.2g, yield 72%). mp 88-89 deg.C, [ alpha ]]D 20＝120.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand I-5:1H NMR(400MHz,CDCl3)δ7.62-7.57(m,2H),7.47(s,1H),7.42-7.41(s,3H),7.28-7.24(t,J＝7.2Hz,2H),7.19-7.16(m,2H),7.12-7.11(m,1H),6.97(s,1H),4.56(s,1H),4.37-4.36(m,1H),4.23-4.16(m,1H),4.01(s,5H),3.92(s,1H),3.80-3.68(m,2H),3.29(s,3H),2.41-2.39(d,J＝4.8Hz,6H),1.60-1.58(d,J＝6.4Hz,3H).13C NMR(100MHz,CDCl3)δ151.9,140.6,140.16,140.1,137.4,137.3,134.9,134.8,134.4,132.3,132.1,130.8,130.0,128.9,128.0,127.9,127.8,127.7,119.2,109.0,97.8,97.6,77.2,76.8,76.5,71.0,69.4,69.1,68.9,60.2,51.2,43.6,29.1,20.3,20.0,19.9.31P NMR(162MHz,CDCl3)δ-24.75.HRMS(ESI)calcd for C35H36FeN3P[M+H]+:586.2069；Found:586.1976.
example 5: preparation of chiral ligand I-6
To a 100mL three-necked flask containing the compound represented by the formula (III-2) (4.67g,10mmol) and the compound represented by the formula (V-2) (2.59g,11.0mmol), 50mL of methanol was added under nitrogen protection, and after reaction at 50 ℃ for 12 hours, sodium borohydride (1.1g,30mmol) was added directly and reacted for 6 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to recover methanol, and the concentrated residue is separated by column chromatography to obtain orange-yellow solid chiral ligand I-6(4.1g, yield 57%). mp 79-80 deg.C, [ alpha ]]D 20＝125.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand I-6:1H NMR(400MHz,CDCl3)7.71-7.69(d,J＝7.6Hz,1H),7.24-7.23(m,7H),7.09-7.07(m,1H),6.99(s,1H),6.87-6.85(m,2H),6.80-6.78(d,J＝7.2Hz,2H),6.59(s,1H),5.05-4.90(m,2H),4.46(s,1H),4.28(s,1H),4.20-4.11(m,1H),3.97(s,5H),3.84(s,1H),3.72-3.61(m,2H),2.60-2.54(m,1H),2.31(s,6H),2.02(s,6H),1.50-1.48(d,J＝6.4Hz,3H).13CNMR(100MHz,CDCl3)δ153.0,142.3,139.7,139.6,137.3,137.2,137.1,137.1,137.0,136.9,136.4,135.5,132.7,132.5,130.5,130.0,129.9,129.6,128.5,127.2,126.1,122.0,121.4,119.3,109.3,97.5,97.3,75.3,71.2,69.4,68.7,51.4,51.3,46.2,46.0,43.8,29.5,21.1,20.9,19.7,11.1.31P NMR(162MHz,CDCl3)δ-24.11.HRMS(ESI)calcd for C43H44FeN3P[M+H]+:690.2695,found:690.2213。
example 6: preparation of chiral ligand I-7
To a compound represented by the formula (III-3) (3.45g,10mmol) and a compound represented by the formula (V-2) (2.59g,11.0mmol) in a 100mL three-necked flask, 50mL of methanol was added under nitrogen protection, and after 12 hours at 50 ℃, sodium borohydride (1.1g,30mmol) was directly added and reacted for 4 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to recover methanol, and the concentrated residue is separated by column chromatography to obtain orange-yellow solid chiral ligand I-7(3.5g, yield is 62%). mp 84-85 deg.C, [ alpha ]]D 20＝121.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand I-7:1H NMR(400MHz,CDCl3):δ7.74-7.72(m,1H),7.22-7.20(m,2H),7.05-7.04(m,2H),5.48(d,J＝8.0Hz,2H),4.39(s,1H),4.28(s,1H),4.23(s,1H),4.14-4.13(m,7H),4.01-3.99(m,1H),3.91(s,2H),1.54(d,J＝6.4Hz,3H),1.41-1.30(m,9H),1.25(s,2H),1.03-0.98(dd,J＝13.2,6.8Hz,3H),0.77-0.72(dd,J＝14.0,6.8Hz,3H).13C NMR(100MHz,CDCl3)δ153.2,142.3,136.2,135.6,128.6,127.4,126.2,122.3,121.6,119.4,109.4,97.4,70.6,69.9,69.3,68.3,67.3,50.9(d,J＝9.0Hz),46.8,43.6,29.5,25.9(d,J＝13.0Hz),24.9(d,J＝10.0Hz),,24.8,22.7,22.5,21.0,20.8,20.1,19.9,19.2.31PNMR(162MHz,CDCl3)δ-9.15.HRMS(ESI)calcd for C33H40FeN3P[M+H]+:566.2382,found:566.2388。
example 7: preparation of chiral ligand II-1
To a 100mL three-necked flask containing the compound represented by the formula (IV-1) (4.13g,10.0mmol) and the compound represented by the formula (V-5) (1.76g,11.0mmol), 50mL of methanol was added under nitrogen, and the mixture was reacted at 50 ℃ to obtain a mixtureAfter 24 hours, sodium borohydride (1.1g,30mmol) was added directly and reacted for 4 h. After the reaction is finished, the reaction solution is decompressed and concentrated to recover methanol, and the concentrated residue is separated by column chromatography to obtain orange-yellow solid chiral ligand II-1(4.17g, yield 75%). mp 90-92 deg.C, [ alpha ]]D 20＝125.0(c＝0.5,CHCl3)。
Characterization data for chiral ligand II-1:1H NMR(400MHz,Chloroform-d):δ7.76(s,1H),7.64(s,2H),7.46(s,3H),7.28(m,5H),7.19(t,J＝6.8Hz,2H),7.11(m,1H),4.61(s,1H),4.42(s,1H),4.31-4.28(m,1H),4.07(s,5H),3.97(s,1H),3.86(d,J＝14.0Hz,1H),3.78(d,J＝14.0Hz,1H)3.38(s,3H),1.66(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ152.6,141.9,139.9,139.8,137.2,137.1,135.7,134.9,134.7,132.2,132.0,128.8,127.8,127.5,121.8,121.3,119.0,108.6,97.5,97.3,74.6,74.6,71.0,69.9,69.3,69.0,68.8,51.0,43.4,29.0,19.8.31P NMR(162MHz,CDCl3)δ-24.91.HRMS(ESI)calcd for C33H32FeN3P[M+H]+:558.1756,found:558.1668。
example 8: preparation of (R) -phenethyl alcohol 2A
(1) Chiral ligand I-1(5.8mg,0.011mmol), Mn (CO)5Br (3.0mg,0.01mmol) was added into a reaction flask, DMF (2mL) was added under argon atmosphere, and after stirring at reflux overnight, the reaction solution was concentrated under high vacuum to remove excess solvent, and a cheap metal catalyst was prepared for use.
(2) Adding the compound (240mg,2mmol) shown in the formula (1A), lithium hydroxide (1.0mg,0.04mmol), isopropanol (2mL) and the cheap metal catalyst prepared in the step (1) into a 5mL hydrogenation bottle in sequence, putting the hydrogenation bottle into a hydrogenation reaction kettle, replacing hydrogen for three times, and filling H with the pressure of 3Mpa2And reacting at room temperature for 10 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite, and the filtrate is detected: the conversion of the compound of formula (1A) was 99% by GC and the enantiomer of the compound of formula (2A) was determined as the reaction product by HPLCThe ee value of the selectivity was 54.5%. Determining the enantiomeric excess by using an HPLC Chiralpak OJ-H chiral chromatographic column, wherein the ratio of n-hexane to isopropanol is 90:10 (v/v); the flow rate is 0.8 mL/min; UV detection is at 220 nm; t is tR(S)＝10.45min(minor),tR(R)＝11.77min(major)。
Example 9: preparation of (R) -phenethyl alcohol 2A
(1) Chiral ligand I-2(6.3mg,0.011mmol), Mn (CO)5Br (3.0mg,0.01mmol) was added into a reaction flask, DMF (2mL) was added under argon atmosphere, and after stirring at reflux overnight, the reaction solution was concentrated under high vacuum to remove excess solvent, and a cheap metal catalyst was prepared for use.
(2) Adding the compound (1.2g,10mmol) shown in the formula (1A), lithium hydroxide (5mg,0.2mmol), isopropanol (10mL) and the cheap metal catalyst prepared in the step (1) into a 25mL hydrogenation bottle in sequence, putting the hydrogenation bottle into a hydrogenation reaction kettle, replacing hydrogen for three times, and filling H with the pressure of 3Mpa2And reacting at room temperature for 10 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite, and the filtrate is detected: the conversion of the compound represented by the formula (1A) was 99% by GC and the ee value of the enantioselectivity of the reaction product, the compound represented by the formula (2A), was 73.3% by HPLC.
Example 10: preparation of (R) -phenethyl alcohol 2A
(1) Chiral ligand I-5(5.8mg,0.011mmol), Mn (CO)5Br (3.0mg,0.01mmol) was added into a reaction flask, DMF (2mL) was added under argon atmosphere, and after stirring at reflux overnight, the reaction solution was concentrated under high vacuum to remove excess solvent, and a cheap metal catalyst was prepared for use.
(2) Taking the compound (1.20g,10mmol) shown in the formula (1A), lithium hydroxide (5mg,0.2mmol), isopropanol (10mL), and the cheap metal catalyst prepared in the step (1) and adding the components in turnAdding into a 25mL hydrogenation bottle, placing the hydrogenation bottle into a hydrogenation reaction kettle, replacing hydrogen for three times, and filling H with pressure of 3Mpa2And reacting at room temperature for 10 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite, and the filtrate is detected: the conversion of the compound represented by the formula (1A) was 99% by GC and the ee value of the enantioselectivity of the reaction product, the compound represented by the formula (2A), was 65.2% by HPLC.
Example 11: preparation of (R) -phenethyl alcohol 2A
(1) Chiral ligand I-6(6.9mg,0.011mmol), Mn (CO)5Br (3.0mg,0.01mmol) was added into a reaction flask, DMF (2mL) was added under argon atmosphere, and after stirring at reflux overnight, the reaction solution was concentrated under high vacuum to remove excess solvent, and a cheap metal catalyst was prepared for use.
(2) Taking the compound (1.20g,10mmol) shown in the formula (1A), lithium hydroxide (5mg,0.2mmol), isopropanol (10mL), adding the cheap metal catalyst prepared in the step (1) into a hydrogenation bottle of 25mL, putting the hydrogenation bottle into a hydrogenation reaction kettle, replacing hydrogen for three times, and filling H with the pressure of 3Mpa2And reacting at room temperature for 10 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite, and the filtrate is detected: the conversion of the compound represented by the formula (1A) was 99% by GC, and the ee value of the enantioselectivity of the reaction product, the compound represented by the formula (2A), was 58.2% by HPLC.
Example 12: preparation of (S) -phenethyl alcohol 2A
(1) Chiral ligand II-1(5.7mg,0.011mmol), Mn (CO)5Br (3.0mg,0.01mmol) was added into a reaction flask, DMF (2mL) was added under argon atmosphere, and after stirring at reflux overnight, the reaction solution was concentrated under high vacuum to remove excess solvent, and a cheap metal catalyst was prepared for use.
(2) Is represented by formula (1A)The compound (1.20g,10mmol), lithium hydroxide (0.5mg,0.02mmol), ethanol (2mL), the cheap metal catalyst prepared in step (1) were sequentially added into a 5mL hydrogenation bottle, the hydrogenation bottle was placed into a hydrogenation reaction kettle, hydrogen was substituted three times, and then H with 30atm pressure was charged2And reacting at room temperature for 10 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite, and the filtrate is detected: the conversion of the compound represented by the formula (1A) was 99% by GC, and the enantioselectivity ee value (-71.2%) of the reaction product, the compound represented by the formula (2A'), was determined by HPLC.
Examples 13 to 23: preparation of chiral secondary alcohol (R) -2B-2L
(1) Chiral ligand I-2(6.3mg,0.011mmol), Mn (CO)5Br (3.0mg,0.01mmol) was added into a reaction flask, DMF (2mL) was added under argon atmosphere, and after stirring at reflux overnight, the reaction solution was concentrated under high vacuum to remove excess solvent, and a cheap metal catalyst was prepared for use.
(2) Taking 1B-1L (10mmol) of arylethanone compound, 5mg of lithium hydroxide (0.2 mmol) and 10mL of isopropanol (1), sequentially adding the cheap metal catalyst prepared in the step (1) into a 25mL hydrogenation bottle, putting the hydrogenation bottle into a hydrogenation reaction kettle, replacing hydrogen for three times, and filling H with 3Mpa pressure2And reacting at room temperature for 10 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite, and the filtrate is detected: the conversion of 1B-1L was determined by GC and the enantioselectivity ee of the reaction product 2B-2L was determined by HPLC. The specific results are as follows:
the statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (8)
1. A chiral ferrocene phosphine nitrogen tridentate ligand is characterized in that the structural general formula is shown as a formula (I) or a formula (II):
in formula (I) or formula (II): r1、R2Each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl or aryl, the aryl is benzene; r3Is aryl or alkyl of C1-C6, R4Hydrogen, C1-C6 alkyl or aryl, wherein the aryl is benzene;
in the structural general formulas in the formula (I) and the formula (II), imidazole groups or substituted benzimidazole groups are contained respectively; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl;
wherein the molecular structural formula of the chiral ferrocenyl phosphine nitrogen tridentate ligand excludes a structure shown as a formula (I-4):
2. a chiral ferrocene phosphine nitrogen tridentate ligand is characterized in that a compound with a general structural formula shown in a formula (I) is shown in the following structural formula:
3. the chiral ferrocenyl phosphine nitrogen tridentate ligand as set forth in claim 1, which is characterized in that the compound of the general structural formula (II) has the specific molecular structural formula shown in formula (II-1):
4. a method for preparing the chiral ferrocenyl phosphine nitrogen tridentate ligand as defined in claim 1, which is characterized by comprising the following steps: under the protection of nitrogen, dissolving chiral phosphine ferrocene-alpha-ethylamine shown as a formula (III) or a formula (IV) and an imidazole carbonyl compound shown as a formula (V) in an alcohol solvent, reacting for 1-24 hours at 20-80 ℃, tracking by TLC (thin layer chromatography) until the reaction is complete, and adding sodium borohydride at-20-60 ℃ to continue reacting for 1-12 hours; after the reaction is finished, decompressing and concentrating the reaction liquid to recover the solvent, and separating the concentrated residue by column chromatography to obtain the chiral ferrocene nitrogen phosphine tridentate ligand shown in the formula (I) or the formula (II);
in the formula (III) or the formula (IV), R1、R2Each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl or aryl, the aryl is benzene;
in the formula (V), R3Is aryl or alkyl of C1-C6, R4Hydrogen, C1-C6 alkyl or aryl, wherein the aryl is benzene;
in the general structural formula of the formula (V), an imidazole group or a substituted benzimidazole group is contained; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl.
5. The method for preparing the chiral ferrocene phosphine nitrogen tridentate ligand according to claim 4, wherein the amount ratio of the chiral phosphine ferrocene-alpha-ethylamine shown in the formula (III) or the formula (IV), the imidazole carbonyl compound shown in the formula (V) and the sodium borohydride is 1: 1.0-1.5: 2.0-5.0; the alcohol solvent is methanol, ethanol or isopropanol.
6. The application of the chiral ferrocenyl phosphine nitrogen tridentate ligand of any one of claims 1 to 3 in preparation of a cheap metal catalyst, which is characterized in that the chiral ferrocenyl phosphine nitrogen tridentate ligand is mixed with a cheap metal complex for reaction to prepare the cheap metal catalyst; the cheap metal complex is Mn (CO)5Br。
7. The use according to claim 6, wherein the ratio of the amount of the chiral ferrocenylphosphinothricin nitrogen tridentate ligand to the amount of the cheap metal complex substance is 1: 1.0-2.0.
8. Use according to claim 7, characterized in that the ratio of the amount of substance of the chiral ferrocenylphosphine nitrogen tridentate ligand to the cheap metal complex is 1: 1.1.
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| CN107522751A (en) * | 2016-06-21 | 2017-12-29 | 中国科学院大连化学物理研究所 | A kind of high steric-hindrance amino chiral ferrocene P, N, N part and preparation method and application |
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