A method for synthesizing ferrocene-dihydroisoquinoline and ferrocene-dihydroisoquinoline planar chiral compounds

Abstract

This invention discloses a method for synthesizing ferrocene-isoquinoline and ferrocene-dihydroisoquinoline planar chiral compounds, belonging to the field of asymmetric catalysis technology. Using chiral phosphoric acid (CPA) as a catalyst, 1,4-dihydropyridine compound (HEH) as a hydrogen source, and racemic ferrocene-isoquinoline derivative (+ / -)-1 and ditert-butyl dicarbonate as substrates, two types of planar chiral ferrocene compounds are synthesized through asymmetric transfer hydrogenation resolution. The enantiomeric excess of the ferrocene-isoquinoline planar chiral compounds can reach 95%, while the enantiomeric excess of the ferrocene-dihydroisoquinoline carboxylic acid tert-butyl ester planar chiral compounds can reach 89%, with a resolution coefficient (S value) reaching 50. This invention achieves the hydrogenation kinetic resolution of ferrocene-isoquinoline compounds, is simple to operate, uses commercially available catalysts, operates under mild reaction conditions, and exhibits good resolution effects, showing excellent application prospects.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalysis technology, specifically relating to a method for synthesizing planar chiral compounds of ferrocene-isoquinoline and planar chiral compounds of ferrocene-dihydroisoquinoline carboxylic acid tert-butyl ester through asymmetric transfer hydrogenation kinetic resolution of ferrocene-isoquinoline compounds catalyzed by chiral phosphoric acid. Background Technology

[0002] Planar chiral ferrocene compounds have attracted widespread attention in materials science, medicinal chemistry, and asymmetric catalysis due to their unique structures. In particular, they have been widely used as advantageous frameworks for chiral ligands and catalysts in asymmetric reactions (References: a) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 36, 659. b) Fu, G. Acc. Chem. Res. 2006, 39, 853. c) Liu, C.-X.; Zhao, F.; Gu, Q.; You, S.-L. ACS Cent. Sci. 2023, 9, 2036. d) Fouda, MF; Abd-Elzaher, MM; Abdelsamaia, RA; Labib, AA Appl. Organomet. Chem. 2007, 21, 613.). Therefore, developing efficient methods for synthesizing planar chiral ferrocene compounds is of great significance. Traditional synthetic methods require saturated chiral auxiliaries and complex reaction steps (References: Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, IJAm. Chem. Soc. 1970, 92, 5389.). In recent years, transition metal-catalyzed carbon-hydrogen bond activation for the construction of chiral compounds has become a powerful tool (References: Newton, CG; Wang, S.-G.; Oliveira, CC; Cramer, N. Chem. Rev. 2017, 117, 8908.). The construction of planar chiral ferrocene compounds using this strategy has also made some progress (References: a) López, LA; López, E. Dalton Trans. 2015, 44, 10128. b) Liu, C.-X.; Gu, Q.; You, S.-L. Trends Chem. 2020, 2, 737 c) Zhang, Z.-Z.; Huang, D.-Y.; Shi, B.-F. Org. Biomol. Chem. 2022, 20, 4061.).Considering that kinetic resolution has been developed into an efficient method for synthesizing chiral compounds, it can conveniently construct centrally chiral, axially chiral, and planar chiral compounds (References: a) Rueping, M.; Antonchick, AP; Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 3683. b) Gao, D.-W.; Gu, Q.; You, S.-L. ACS Catal. 2014, 4, 2741. c) Wang, J.; Chen, M.-W.; Ji, Y.; Hu, S.-B.; Zhou, Y.-G. J. A. M. Chem. Soc. 2016, 138, 10413. d) Zhao, Y.; Ding, Y.-X.; Wu, Bo.; Zhou, Y.-G. J. O. R. G. Chem. 2021, 86, 10788.). However, to date, no research has been reported on the efficient synthesis of two types of planar chiral compounds through a kinetic resolution strategy of racemic ferrocene compounds via asymmetric transfer hydrogenation catalyzed by chiral phosphoric acid. Summary of the Invention

[0003] The purpose of this invention is to provide a method for synthesizing planar chiral compounds of ferrocene-1,4-dihydro ...

[0004] To achieve the above objectives, the technical solution of the present invention is as follows:

[0005] This invention provides a method for synthesizing planar chiral compounds of ferrocene α-isoquinoline and ferrocene α-dihydroisoquinoline via asymmetric transfer hydrogenation kinetics. The method uses chiral phosphoric acid (CPA) as a catalyst, 1,4-dihydropyridine compound (HEH) as a hydrogen source, and racemic ferrocene α-isoquinoline derivative (+ / -)-1 and ditert-butyl dicarbonate as substrates. Planar chiral ferrocene α-isoquinoline derivative 1 and ferrocene α-dihydroisoquinoline derivative 2 are synthesized via asymmetric transfer hydrogenation resolution.

[0006] The reaction formula is as follows:

[0007]

[0008] In the formula:

[0009] R1 is hydrogen, C1-C 20 Alkyl groups (preferably C1-C7 alkyl groups, such as methyl or ethyl), C2-C 20alkenyl, C2~C 20 The alkynyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted naphthyl group, wherein the substituents on the substituted phenyl group or the substituted naphthyl group are one or more of CF3, Me, Et, F, Cl, Br, and the number of substituents is 1 to 5; R2 is hydrogen, C1-C 20 The alkyl group (preferably C1 to C7 alkyl group, such as methyl or ethyl), unsubstituted or substituted phenyl group, unsubstituted or substituted naphthyl group, wherein the substituents on the substituted phenyl group or the substituted naphthyl group are one or more of Me, MeO, F, Cl, Br, and the number of substituents is 1 to 5.

[0010] The chiral phosphoric acid CPA is a chiral phosphoric acid with a spirocyclic diol skeleton, an octahydrobinaphthol skeleton, or a binaphthol skeleton, wherein R3 is 2-naphthyl, benzene, 9-anthrayl, 10-phenyl-9-anthrayl, 9-phenanthyl, or a benzene ring containing a substituent, and the substituent is Ph. t One or more of Bu, Me, MeO, CF3, F, Cl, with 1 to 5 substituents;

[0011] The hydrogen source, 1,4-dihydropyridine compound HEH, has R4 and R5 independently represented as OMe, Me, OEt, Et, and O, respectively. i Pr、O t Bu, OBn, or OAllyl.

[0012] Based on the above technical solution, further, the planar chiral ferrocene dihydroisoquinoline derivative 1 or ferrocene dihydroisoquinoline derivative 2 is selected from one of the following: 1a, 2a, 1b, 2b, 1c, 2c, 1d, 2d, 1e, 2e, 1f, 2f, 1g, 2g, 1h, 2h.

[0013]

[0014] Based on the above technical solution, further, the reaction temperature is 30-60℃, preferably 40-60℃, for example 40, 50, 60℃; the reaction time is 10-50 hours, preferably 11-47 hours.

[0015] Based on the above technical solution, the method further includes the following steps:

[0016] Under nitrogen protection, an organic solvent was added to racemic ferrocene-isoquinoline derivative (+ / -)-1, 1,4-dihydropyridine compound HEH, ditert-butyl dicarbonate, and chiral phosphoric acid CPA. After stirring at 30-60°C for 10-50 h, 1,8-diazabicyclo[5.4.0]undec-7-ene was added under nitrogen protection at room temperature and stirred for 20-60 min. Column chromatography was then used to obtain planar chiral ferrocene-isoquinoline derivative 1 and ferrocene-dihydroisoquinoline derivative 2.

[0017] Based on the above technical solution, further, the molar ratio of the 1,4-dihydropyridine compound HEH to the racemic ferrocene isoquinoline derivative (+ / -)-1 is 0.5:1 to 1:1, preferably 0.7:1 to 1:1.

[0018] Based on the above technical solution, further, the molar ratio of the chiral phosphate CPA to the racemic ferrocene isoquinoline derivative (+ / -)-1 is 0.01:1 to 0.10:1, preferably 0.025:1 to 0.05:1.

[0019] Based on the above technical solution, further, the molar ratio of the ditert-butyl dicarbonate to the racemic ferrocene isoquinoline derivative (+ / -)-1 is 1:1 to 1.5:1.

[0020] Based on the above technical solution, further, the molar ratio of 1,8-diazabicyclo[5.4.0]undec-7-ene to racemic ferrocene isoquinoline derivative (+ / -)-1 is 0.1:1 to 0.5:1.

[0021] Based on the above technical solution, the reaction solvent is one or more of ethyl acetate, tetrahydrofuran (THF), dichloromethane, benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene (PhCl), trifluorotoluene (PhCF3), and mesitylene, preferably ethyl acetate, toluene, m-xylene, or mesitylene.

[0022] Based on the above technical solution, further, the amount of solvent used is 2 to 5 mL of solvent per 0.2 mmol of racemic ferrocene isoquinoline derivative (+ / -)-1, preferably 2.5 mL of solvent.

[0023] Based on the above technical solution, furthermore, the racemic ferrocene-isoquinoline derivative (+ / -)-1 includes racemic ferrocene-isoquinoline (+ / -), the chiral phosphoric acid CPA catalyst, organic solvent, and di-tert-butyl dicarbonate are all commercially available and have not undergone special treatment; the 1,4-dihydropyridine compound HEH is synthesized from the corresponding diketone, ammonium acetate, and formaldehyde aqueous solution (or paraformaldehyde); the skeleton of the chiral phosphoric acid CPA is binaphthol, wherein R 3 The compound is 10-phenyl-9-anthrayl; in the 1,4-dihydropyridine compound HEH, R4 is tert-butoxy and R5 is methyl; the solvent is mesitylene, the reaction temperature is 50℃, and the resolution coefficient of the reaction is greater than 50.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The raw materials of this invention are simple, readily available, and inexpensive.

[0026] 2. The present invention has high reactivity, good enantioselectivity, and high resolution coefficient.

[0027] 3. The method of the present invention can obtain planar chiral compounds of ferrocene-isoquinoline and planar chiral compounds of ferrocene-dihydroisoquinoline carboxylic acid tert-butyl ester with various structures.

[0028] 4. The catalyst used in the method of the present invention is commercially available and easy to operate.

[0029] 5. The method of the present invention has mild reaction conditions and is environmentally friendly. Detailed Implementation

[0030] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below.

[0031] The synthesis of the ferrocene-isoquinoline compounds in the examples was based on the following references: a) Wang, Q.; Nie, Y.-H.; Liu, C.-X.; Zhang, W.-W.; Wu, Z.-J.; Gu, Q.; Zheng, C.; You, S.-L. ACS Catal. 2022, 12, 3083. b) Jia, Z.-S.; Yue, Q.; Li, Y.; Xu, X.-T.; Zhang, K.; Shi, B.-F. Beilstein J. Org. Chem. 2021, 17, 2488. c) Johnson, KF; Schmidt, AC; Stanley, L.M. Org. Lett. 2015, 17, 4654. d) Butler, DCD; Richards, C. J. Organometallics 2002,21,5433.e)Lavrard,H.;Popowycz,F.Eur.J.Org.Chem.2017,3,600.f)Liu,L.-T.;Zhang,A.-A .; Zhao, R.-J.; Li, F.; Meng, T.-J.; Ishida, N.; Murakami, M.; Zhao, W.-X.Org.Lett.2014,16,5336.)

[0032] The chiral phosphate in the examples was purchased from Bidex Pharmaceuticals.

[0033] Example 1: Optimization of conditions

[0034] Under nitrogen protection, 4.0 mL of solvent was added to a Schlenk tube containing the racemic substrate ferrocene-isoquinoline (0.2 mmol), chiral phosphoric acid CPA (0.01 mmol), 1,4-dihydropyridine compound HEH (0.2 mmol), and di-tert-butyl dicarbonate (0.2 mmol). After stirring at 50 °C for 11 hours, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 eq.) was added under nitrogen protection at room temperature, and the mixture was stirred for 30 minutes. The mixture was then filtered, the solvent was removed under reduced pressure, and the conversion of the racemic ferrocene-isoquinoline was determined by NMR. The reaction formula and specific structure are as follows:

[0035]

[0036] The conversion of the racemic ferrocene-isoquinoline was determined by NMR. The enantiomeric excess (ee) of the recovered feed and product was determined by chiral liquid chromatography (HPLC). The resolution coefficient (S) was calculated using the formulas S = ln[(1-C)(1-ee1)] / ln[(1-C)(1+ee1)], C = ee1 / (ee1+ee2) (where C is the theoretical conversion calculated based on the enantiomeric excess (ee) of the recovered feed and product). The solvents used, 1,4-dihydropyridine compounds, chiral phosphoric acid, and experimental results are detailed in Table 1.

[0037] Table 1. Screening of solvents, 1,4-dihydropyridine compounds, and chiral phosphoric acid

[0038]

[0039]

[0040] a The reaction temperature is 60℃. b HEH-1: 0.70 eq., c 1,3,5-Trimethylbenzene: 5.0 mL.

[0041] Example 2: Transfer hydrogenation resolution of various ferrocene-isoquinoline compounds

[0042] Under nitrogen protection, 10 mL of solvent 1,3,5-trimethylbenzene was added to a Schlenk tube containing a racemic substrate ferrocene-isoquinoline compound (0.4 mmol), chiral phosphoric acid CPA-5 (0.01 mmol), a 1,4-dihydropyridine compound HEH-1 (0.28 mmol), and di-tert-butyl dicarbonate (0.4 mmol). After the reaction was completed at 50 °C with stirring, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 eq.) was added under nitrogen protection at room temperature, and the mixture was stirred for 30 minutes. The resulting product was purified by column chromatography to obtain the corresponding planar chiral recovered feedstock and the target product. The reaction formula and specific structure are as follows:

[0043]

[0044] The yield was the separation yield, the enantiomeric excess of the recovered raw materials and products was determined by chiral liquid chromatography, and the separation coefficient was calculated by the formula in Example 1.

[0045] The following are the results of resolving racemic substrates of different structures, specifically ferrocene-isoquinoline, using asymmetric transfer hydrogenation kinetics to obtain planar chiral ferrocene-isoquinoline and planar chiral ferrocene-dihydroisoquinoline compounds:

[0046]

[0047] Thanks for watching the snowstorm:

[0048] (S)-Ferroceno[c]isoquinoline(1a):51.5mg,45% yield,94%,[α] 20 D Z+1763(c0.03,CHCl3).HPLC:Chiralcel OD-H column,254nm,30°C,n-Hexane / i-PrOH:90 / 10,flow:0.8mL / min,retention time 11.3min(major)and 19.9min.

[0049] (R)-t-Butyl Ferroceno[c]isoquinoline-4(5H)-carboxylate(2a):74.5mg,48% yield,88%,[α] 20 D Z+347(c 0.88,CHCl3).HPLC:Chiralcel OD-H column,254nm,30°C,n-Hexane / i-PrOH190 / 10,flow:1.0mL / min,retention time 4.8min and 9.1(major)min.

[0050] (S)-6-Methylferroceno[c]isoquinoline(1b):36.9mg,30% yield,95% e,[α] 20 D K+1533(c 0.02,CHCl3).HPLC:Chiralpak AD-H column,254nm,30°C,n-Hexane / i-PrOH:90 / 10,flow:1.0mL / min,retention time 7.9min and 9.1(major)min.

[0051] (R)-t-Butyl 6-Methylferroceno[c]isoquinoline-4(5H)-carboxylate(2b):98.8mg,61% yield,77% e,[α] 20 D=+465(c 0.79,CHCl3).HPLC:Chiralcel OD-H column,254 nm,30℃,n-Hexane / i-PrOH=95 / 5,flow=1.0 mL / min,retention time 4.8 min and5.6(major)min.

[0052] (S)-6-Chloroferroceno[c]isoquinoline(1c):60.1 mg,47%yield,88%ee,[α] 20 D =+1092(c 0.01,CHCl3).HPLC:Chiralpak AD-H column,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=0.8 mL / min,retention time 8.7 min and 9.9(major)min.

[0053] (R)-t-Butyl 6-Chloroferroceno[c]isoquinoline-4(5H)-carboxylate(2c):83.2 mg,49%yield,85%ee,[α] 20 D =+430(c 0.83,CHCl3).HPLC:Chiralcel OD-Hcolumn,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=0.8 mL / min,retention time 5.7min and 7.2(major)min.

[0054] (S)-7-Chloroferroceno[c]isoquinoline(1d):56.3 mg,44%yield,86%ee,[α] 20 D =+1830(c 0.03,CHCl3).HPLC:Chiralcel OD-H column,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=0.7 mL / min,retention time 12.1 min and 19.6(major)min.

[0055] (R)-t-Butyl 7-Chloroferroceno[c]isoquinoline-4(5H)-carboxylate(2d):83.0 mg,49%yield,84%ee,[α] 20 D =+415(c 0.80,CHCl3).HPLC:Chiralpak AD-Hcolumn,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=0.7 mL / min,retention time 6.7min and 8.9(major)min.

[0056] (S)-7-Fluoroferroceno[c]isoquinoline(1e):49.3 mg,40%yield,94%ee,[α] 20 D =+1784(c 0.03,CHCl3).HPLC:Chiralpak AD-H column,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 9.6(major)min and 10.8 min.

[0057] (R)-t-Butyl 7-Fluoroferroceno[c]isoquinoline-4(5H)-carboxylate(2e):84.4 mg,52%yield,75%ee,[α] 20 D =+341(c 0.78,CHCl3).HPLC:Chiralcel AD-Hcolumn,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 5.0min and 6.1(major)min.

[0058] (S)-8-Fluoroferroceno[c]isoquinoline(1f):54.3 mg,45%yield,86%ee,[α] 20 D=+1644(c 0.02,CHCl3).HPLC:Chiralpak AD-H column,254 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0mL / min,the retention time 8.1(major)min and 9.7min.

[0059] (R)-t-Butyl 8-Fluoroferroceno[c]isoquinoline-4(5H)-carboxylate(2f):77.4mg,48%yield,89%ee,[α] 20 D =+130(c 0.77,CHCl3).HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 4.5 min and5.5(major)min.

[0060] (S)-7-Methoxylferroceno[c]isoquinoline(1g):51.0mg,40%yield,95%ee,[α] 20 D =+1073(c 0.01,CHCl3).The HPLC:Chiralcel OJ-H column,254nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 10.1 min and 16.6(major)min.

[0061] (R)-t-Butyl 7-Methoxylferroceno[c]isoquinoline-4(5H)-carboxylate(2g):82.1mg,49%yield,74%ee,[α] 20 D =+324(c 0.72,CHCl3).HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 6.0 min and9.4(major)min.

[0062] (S)-7-Methyl-1'-ethylferroceno[c]isoquinoline(1h):45.9mg,35%yield,95%ee,[α] 20 D =+936 (c 0.02, CHCl3). HPLC: Chiralcel OD-H column, 254nm, 30°C, n-Hexane / i-PrOH=97 / 3, flow=1.0 mL / min, retention time 13.2 min and 17.9(major)min.

[0063] (R)-t-Butyl 7-Methyl-1'-ethylferroceno[c]isoquinoline-4(5H)-carboxylate(2h):92.0mg,53%yield,79%ee,[α] 20 D =+318 (c 0.86, CHCl3). HPLC: Chiralpak AD-H column, 254nm, 30°C, n-Hexane / i-Pr-OH=97 / 3, flow=0.8mL / min, retention time 6.3min and7.8(major)min.

[0064] Example 3: Synthesis of planar chiral ferrocene framework bipyridine ligand 3

[0065]

[0066] A solution of n-butyllithium (2.5 M, 0.14 mL, 0.34 mmol) was added to a solution of 2-bromopyridine (66 mg, 0.42 mmol) in tetrahydrofuran (3.0 mL) at -78 °C. The solution was stirred for 1 hour. Then, the prepared 2-lithiumpyridine solution was added dropwise to a solution of (S)-1a (75 mg, 0.26 mmol) in diethyl ether (3.0 mL) under argon atmosphere at -78 °C. The mixture was heated to 0 °C and stirred for 48 hours. The reaction mixture was purified by silica gel column chromatography to obtain the target product 3.

[0067] The characterization data of the compounds in the examples are as follows:

[0068] (S)-5-(Pyridin-2-yl)ferroceno[c]isoquinoline(3):68mg,71%yield,darkred solid,mp 102-103℃,new compound,Rf =0.15(hexanes / ethyl acetate 3 / 1),99%ee,[α] 20 D = +916(c 0.006, CHCl3). 1 H NMR (400MHz, CDCl3) δ8.78(d,J=4.6Hz,1H),8.21(d,J=8.2Hz,1H),8.05(d,J=7.8Hz,1H),7.94-7.86(m,2H),7.6 9(t,J=7.5Hz,1H),7.49-7.39(m,2H),5.34-5.28(m,1H),5.25-5.22(m,1H),4.32(t,J=2.3Hz,1H),3.86(s,5H). 13 CNMR (100MHz, CDCl3) δ161.0,158.6,148.5,139.7,137.1,131.0,130.0,125.8,1 24.7,124.4,123.2,123.0,102.5,76.2,69.6,69.0,65.5,59.0.HPLC:Chiralpak OD-H column, 254nm, 30℃, n-Hexane / i-PrOH=90 / 10, flow=1.0mL / min, retention time 15.0minand18.3(major)min.The HRMS Calculated for C 22 H 17 FeN2[M+H] + 365.0736, found: 365.0744.

[0069] Example 4: Asymmetric boric acid addition reaction of imine

[0070]

[0071] Under nitrogen protection, Pd(OCOCF3)2 (3.3 mg, 0.01 mmol), chiral NN ligand 3 (4.4 mg, 0.012 mmol), and degassed anhydrous acetone (2.0 mL) were added to a Schlenk tube. The mixture was stirred at room temperature for 1 hour and then dried under vacuum. Then, compound 4 (51.9 mg, 0.20 mmol), 2-naphthoboric acid (69.0 mg, 0.40 mmol), and 1,1,1,3,3,3-hexafluoro-2-propanol (3.0 mL) were added. The mixture was stirred at 30 °C under nitrogen protection for 20 hours, and the solvent was removed under reduced pressure. The solution was purified by column chromatography to give compound 5, 73.0 mg, in 94% yield (90% ee).

[0072] The characterization data of the products in the examples are as follows:

[0073] 1 H NMR (400MHz, CDCl3) δ7.36-7.16(m,10H),6.48(d,J=15.8Hz,1H),6.33(dd,J=15.7,8.5 Hz,1H),4.27(dd,J=10.8,8.6Hz,1H),3.95(d,J=10.9Hz,1H),3.70(s,3H),3.51(s,3H). 13 C NMR (100MHz, CDCl3) δ168.3,167.9,140.3,137.0,132.0,129.3,128.9,128.6,128.0,127.7,127.3,126.5,57.8,52.7,52.6,49.3. HPLC: Chiralpak IAcolumn, 245nm, 30℃, n-Hexane / i-PrOH=90 / 10, flow=1.0mL / min, retention time 10.2min and 21.8min (major).

[0074] Example 5: Palladium-catalyzed enantioselective CH functionalization of indole

[0075]

[0076] Under nitrogen protection, Pd(CH3CN)2Cl2 (3.9 mg, 0.015 mmol), chiral NN ligand 3 (5.5 mg, 0.015 mmol), NaBArF (32.0 mg, 0.036 mmol), and 300 mg of [unclear - possibly a specific substance or concentration] were added. Molecular sieves were added to a Schlenk tube, followed by the addition of 3.0 mL of 1,2-dichloroethane. The mixture was stirred at 30°C for 2 hours under nitrogen protection, then cooled to -5°C. Indole 6 (65.4 mg, 0.45 mmol) was added, and the mixture was stirred for 10 minutes. Benzyl 2-diazo-2-phenylacetate 7 (75.7 mg, 0.30 mmol) was added, and the mixture was stirred at -5°C for 20 hours. The mixture was then rapidly filtered through diatomaceous earth, washed with ethyl acetate / dichloromethane, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by column chromatography to give chiral product 8, 99.8 mg, yield 90%, 78% ee.

[0077] The characterization data of the products in the examples are as follows:

[0078] 1H NMR (400MHz, CDCl3) δ7.44 (d, J = 8.0Hz, 1H), 7.30-7.19 (m, 11H), 7.14 (t, J = 7.6Hz, 1H), 6. 99(t,J=7.5Hz,1H),5.36(s,1H),5.17(dd,J=34.7,12.4Hz,2H),3.66(s,3H),2.30(s,3H). 13 C NMR (100MHz, CDCl3) δ173.1,138.9,136.7,136.0,134.9,128.4,128.3,128.3,128.3,128.1 ,127.0,126.8,120.8,119.5,119.3,108.7,107.8,66.7,48.4,29.6,10.8.HPLC:Chiralpak AS-H column, 254nm, 30℃, n-Hexane / i-PrOH=90 / 10, flow=1.0mL / min, retention time 10.3min and 11.7min (major).

[0079] This invention utilizes asymmetric transfer hydrogenation of racemic ferrocene isoquinoline compounds to synthesize two types of planar chiral ferrocene compounds: planar chiral ferrocene isoquinoline compounds (enantiomeric excess up to 95%) and planar chiral ferrocene dihydroisoquinoline carboxylic acid tert-butyl ester compounds (enantiomeric excess up to 89%), with a resolution coefficient (S value) reaching up to 50. This invention achieves catalytic kinetic resolution, is simple to operate, uses commercially available catalysts, operates under mild reaction conditions, and exhibits good resolution efficiency. The recovered planar chiral ferrocene isoquinoline from the kineticly resolved feedstock can be derivatized to synthesize bipyridine ligands with a planar chiral ferrocene framework, showing excellent application prospects in catalytic asymmetric reactions.

Claims

1. A method for synthesizing ferrocene-isoquinoline and ferrocene-dihydroisoquinoline planar chiral compounds, characterized in that, Using chiral phosphoric acid CPA as a catalyst, 1,4-dihydropyridine compound HEH as a hydrogen source, and racemic ferrocene bisisoquinoline derivative (+ / -)-1 and ditert-butyl dicarbonate as substrates, planar chiral ferrocene bisisoquinoline derivative 1 and ferrocene bisdihydroisoquinoline derivative 2 were synthesized. The reaction formula is as follows: In the formula: R1 is hydrogen, C1-C 20 Alkyl groups, C2-C 20 alkenyl, C2~C 20 The alkynyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted naphthyl group, wherein the substituents on the substituted phenyl group or the substituted naphthyl group are one or more of CF3, Me, Et, F, Cl, Br, and the number of substituents is 1 to 5; R2 is hydrogen, C1-C 20 The alkyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted naphthyl group, wherein the substituents on the substituted phenyl group or the substituted naphthyl group are one or more of Me, MeO, F, Cl, Br, and the number of substituents is 1 to 5. In the chiral phosphoric acid CPA, R3 is 2-naphthyl, benzene, 9-anthrayl, 10-phenyl-9-anthrayl, 9-phenanthyl, or a benzene ring containing a substituent, wherein the substituent is Ph. t One or more of Bu, Me, MeO, CF3, F, Cl, with 1 to 5 substituents; In the 1,4-dihydropyridine compound HEH, R4 and R5 are independently OMe, Me, OEt, Et, and O, respectively. i Pr、O t Bu, OBn, or OAllyl.

2. The method as described in claim 1, characterized in that, The planar chiral ferrocene dihydroisoquinoline derivative 1 or ferrocene dihydroisoquinoline derivative 2 is selected from one of the following: 1a, 2a, 1b, 2b, 1c, 2c, 1d, 2d, 1e, 2e, 1f, 2f, 1g, 2g, 1h, 2h.

3. The method as described in claim 1, characterized in that, The reaction temperature is 30–60℃; the reaction time is 10–50 hours.

4. The method according to any one of claims 1-3, characterized in that, The method includes the following steps: Under nitrogen protection, an organic solvent was added to racemic ferrocene-isoquinoline derivative (+ / -)-1, 1,4-dihydropyridine compound HEH, ditert-butyl dicarbonate, and chiral phosphoric acid CPA. After stirring at 30-60°C for 10-50 h, 1,8-diazabicyclo[5.4.0]undec-7-ene was added under nitrogen protection at room temperature and stirred for 20-60 min. Column chromatography was then used to obtain planar chiral ferrocene-isoquinoline derivative 1 and ferrocene-dihydroisoquinoline derivative 2.

5. The method as described in claim 4, characterized in that, The molar ratio of the 1,4-dihydropyridine compound HEH to the racemic ferrocene isoquinoline derivative (+ / -)-1 is 0.5:1 to 1:1; the molar ratio of the chiral phosphate CPA to the racemic ferrocene isoquinoline derivative (+ / -)-1 is 0.01:1 to 0.10:

1.

6. The method as described in claim 4, characterized in that, The molar ratio of ditert-butyl dicarbonate to racemic ferrocene isoquinoline derivative (+ / -)-1 is 1:1 to 1.5:

1.

7. The method as described in claim 4, characterized in that, The molar ratio of 1,8-diazabicyclo[5.4.0]undec-7-ene to racemic ferroceneisoquinoline derivative (+ / -)-1 is 0.1:1 to 0.5:

1.

8. The method as described in claim 4, characterized in that, The reaction solvent is one or more of ethyl acetate, tetrahydrofuran, dichloromethane, benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, trifluorotoluene, and mesitylene.

9. The method as described in claim 4, characterized in that, The amount of solvent used is 2 to 5 mL per 0.2 mmol of racemic ferrocene isoquinoline derivative (+ / -)-1.

10. The method as described in claim 4, characterized in that, The racemic ferrocene-isoquinoline derivative (+ / -)-1 comprises racemic ferrocene-isoquinoline (+ / -), and the chiral phosphoric acid CPA contains R 3 The compound is 10-phenyl-9-anthrayl; in the 1,4-dihydropyridine compound HEH, R4 is tert-butoxy and R5 is methyl; the solvent is mesitylene, the reaction temperature is 50℃, and the resolution coefficient of the reaction is greater than 50.

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