Method for synthesizing metallocene borate

Abstract

The invention relates to a method for synthesizing metallocene borate. Specifically, metallocene and commercially available pinacol borane are taken as initial raw materials, and C-H boronation reaction of metallocene is realized under the condition of promotion of an iridium catalyst / nitrogen ligand. The method has the following advantages that the non-oriented metallocene is directly used as a C-H donor, an additional oxidant and a wide substrate range are not needed, and the yield is good.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing metallocene borate. Specifically, a metallocene and commercially available pinacol borane are used as starting materials, and a CH borylation reaction of the metallocene is achieved under the conditions of iridium catalyst / nitrogen ligand promotion. The present invention has the following advantages: a non-directed metallocene is directly used as a CH donor, no additional oxidant is required, a wide substrate range is provided, and a good yield is achieved. Background Art

[0002] Metallocene skeletons are a class of ligands or catalysts with good activity in catalytic reactions. Metallocenes are often introduced into drugs or materials, and boric acid esters are a good reagent for building CC or C-heteroatom bonds. Therefore, it is very meaningful to introduce boron groups on metallocenes. It is reported that the introduction of boron groups on metallocenes generally requires air-sensitive lithium reagents or trihalogenated boron reagents, and the operation is generally cumbersome or produces a large amount of waste, or requires the installation of directing groups on the ferrocene substituent in advance;

[0003] The invention uses commercially available pinacol borane as a raw material, tetramethyl-o-phenanthroline as a ligand and di(1,5-cyclooctadiene)di-M-methoxydiiridium (I) as a catalyst precursor to realize a metallocene CH borate esterification reaction. The reaction has the advantages of a wide range of substrates, a good yield, and no need for a directing group. At present, the reaction system using pinacol diborate as a boron source and cyclooctane as a solvent, and transition metal iridium and 4,4'-di-tert-butyl-2,2'-bipyridine as a catalyst system can only catalyze ferrocene, electron-deficient ferrocene and electron-deficient metallocene (reference: Datta, A. A. and Plenio, H. Ir-catalyzed C–H activation in the synthesis of borylated ferrocenes and halfsandwich compounds. Chem. Commun. 2004, 1508.).

[0004] Compared with the previous metal-catalyzed synthesis method, the present invention can synthesize various metallocene compounds, including electron-rich metallocenes, through an efficient and simple synthesis method. Summary of the invention

[0005] The present invention aims to develop an iridium catalyst to efficiently synthesize metallocene borate using commercially available pinacol borane as a starting material.

[0006] The present invention is achieved through the following technical solutions:

[0007] Metallocene 1 and commercially available pinacol borane 2 can be used to synthesize metallocene borate ester 3 with high selectivity under the action of iridium catalyst and ligand. The reaction formula is shown below:

[0008]

[0009] The specific steps are as follows:

[0010] Under nitrogen atmosphere, metallocene 1, pinacol borane 2, iridium catalyst precursor and ligand were added to a pressure tube, followed by solvent, plugged, and placed in a 100°C oil bath. The target product 3 was generated after 18 hours of reaction. After the reaction, the solvent was dried by spin drying. The mobile phase for column chromatography was petroleum ether / ethyl acetate (volume ratio).

[0011] The present invention uses metallocene and commercially available pinacol borane as starting materials, and realizes the CH borylation reaction of the metallocene under the conditions of iridium catalyst / nitrogen ligand promotion. The molar ratio of the metallocene 1 and the pinacol borane 2 is 1:1.0-1:10, and the preferred ratio is 1:3-1:8.

[0012] The solvent range is one or more of nitromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, water, ethanol, methanol, N,N-dimethylacetamide, N,N-dimethylformamide, trifluoroethanol, hexafluoroisopropanol, and methylcyclohexane, preferably one or two of methanol and methylcyclohexane;

[0013] The concentration of metallocene 1 in the solvent is 0.10-0.40 mol / L, preferably 0.13-0.20 mol / L.

[0014] The iridium catalyst precursor is one or both of (1,5-cyclooctadiene) iridium chloride (I) dimer and bis(1,5-cyclooctadiene) di-M-methoxy diiridium (I), preferably bis(1,5-cyclooctadiene) di-M-methoxy diiridium (I);

[0015] The amount of the iridium catalyst precursor used is 0.01-0.05 molar equivalent of the amount of metallocene 1 used, preferably 0.02-0.04 molar equivalent.

[0016] The ligand is one or more of the following 4,4'-di-tert-butyl-2,2'-bipyridine L5, 1,10-phenanthroline L1,2-methyl-1,10-phenanthroline L3, 2-bromo-1,10-phenanthroline L4, 3,4,7,8-tetramethyl-1,10-phenanthroline L2, L6, L7, preferably 3,4,7,8-tetramethyl-1,10-phenanthroline L2;

[0017]

[0018] The amount of the ligand used is 0.01-0.08 molar equivalent of the amount of metallocene 1 used, preferably 0.05-0.07 molar equivalent.

[0019] The present invention has the following advantages:

[0020] The present invention has the following advantages: the non-directing metallocene directly serves as a CH donor, no additional oxidant is required, the substrate range is wide, and the yield is good. DETAILED DESCRIPTION

[0021] The present invention will be described below with reference to specific embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0022] Example 1

[0023] Table 1

[0024]

[0025] Example

[0026] Under nitrogen atmosphere, 0.2 mmol of metallocene 1 (the corresponding substituents in the compound are: R 1 =Hydrogen, bromine or chlorine; R 2 = hydrogen, methyl, methylthio, trimethylsilyl, pyrrolyl, piperidinyl or morpholinyl, R 3 = methyl, n-propyl or trimethylsilyl; R 4 = bromine or methylthio; M = Fe or Ru, as shown in the corresponding products in Table 1, respectively, corresponding to the substituents at the corresponding positions in the products), 1.0mmol pinacol borane 2, 0.006mmol of iridium catalyst precursor (as shown in the reaction formula in Table 1) and 0.012mmol ligand L2 (as shown in the reaction formula in Table 1), then add one milliliter of methylcyclohexane, plug the mouth of the pressure tube with a stopper, and place the pressure tube in an oil bath at 100°C. After 18h, the target product metallocene borate ester 3 (as shown in Table 1 above) is reacted. After the reaction is completed, the solvent is spin-dried and separated by column chromatography (mobile phase: petroleum ether / ethyl acetate = 30:1, volume ratio) to obtain the target product metallocene borate ester 3. The compound is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and boron spectrum) and high-resolution mass spectrometry.

[0027] The detection data of the target product metallocene borate ester 3 are as follows:

[0028]

[0029] 110.0-111.7℃,81.8mg,95%. 1 H NMR (400 MHz, C 6 D 6)δ8.35(s,1H),7.76(d,J=8.7Hz,1H),7.26(d,J=8.7Hz,1H),4.24(d,J=2.4Hz,2H),3.71(t,J=2.5Hz,1H),1.56(s,15H),1.20(s,12H). 13 C NMR(100MHz,CDCl 3 )δ139.3,126.6,125.6,90.1,87.2,83.5,78.4,66.5,66.4,25.1,24.8,10.1. 11 B NMR(128MHz,CDCl 3 )δ30.8.HRMS calculated forC 25 H 34 BFeO 2 [M+H] + 433.1996,found 433.1994.

[0030]

[0031] CDCl 3 )δ7.93(s,1H),7.52(s,1H),4.64–4.50(m,1H),4.48–4.30(m,1H),4.01–3.84(m,1H),1.65(s,15H),1.36(s,12H). 13 C NMR(100MHz,CDCl 3 )δ138.8,127.8,121.6,91.2,88.3,83.8,78.6,77.5,67.7,67.5,25.1,24.7,10.0. 11 B NMR(128MHz,CDCl 3 )δ30.0.HRMS calculated for C 25 H 33 BBrFeO 2 [M+H] + 511.1101,found 511.1098.

[0032]

[0033] 149.3-150.7℃,90.2mg,97%yield. 1 H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.30(s,1H),4.68–4.52(m,1H),4.45–4.30(m,1H),3.98–3.85(m,1H),1.62(s,15H),1.35(s,12H). 13 C NMR(100MHz,CDCl 3 )δ138.0,132.1,124.2,89.6,88.6,83.8,78.6,77.5,67.5,65.8,25.1,24.7,9.9. 11 B NMR(128MHz,CDCl 3 )δ31.3.HRMS calculated for C 25 H 33 BClFeO 2 [M+H] + 467.1606,found 467.1607.

[0034]

[0035] NMR(700MHz,C 6 D 6 )δ8.20(s,1H),8.03(s,1H),4.40(s,1H),3.99(s,1H),1.72(s,3H),1.55(s,15H),1.16(s,12H). 13 C NMR(175MHz,C 6 D 6 )δ139.5,128.5,122.2,92.0,89.7,89.1,83.6,78.0,67.9,67.9,25.1,24.8,13.4,9.7. 11 B NMR(128MHz,C 6 D 6 )δ33.7.HRMScalculated for C 26 H 35 BBrFeO 2 [M+H] + 525.1257,found 525.1254.

[0036]

[0037] 87.9-89.2℃,81.1mg,91%yield. 1 H NMR(400MHz,CDCl 3)δ7.73(s,1H),7.09(d,J=8.3Hz,1H),7.00(d,J=9.0Hz,1H),4.60–4.30(m,2H),1.80(s,3H),1.38(s,27H). 13 C NMR(100MHz,CDCl 3 )δ140.1,126.7,126.3,92.0,90.4,88.4,83.3,77.9,65.9,25.0,24.6,13.3,9.5. 11 B NMR(128MHz,CDCl 3 )δ30.6.HRMS calculated for C 26 H 36 BFeO 2 [M+H] + 447.2152,found 447.2149.

[0038]

[0039] 80.1mg,84%yield. 1 H NMR(700MHz,CDCl 3 )δ7.94(s,1H),7.43–7.31(m,1H),7.30–7.16(m,1H),4.44(s,2H),2.22(s,3H),1.62(s,15H),1.40(s,12H). 13 C NMR(175MHz,CDCl 3 )δ138.6,127.3,125.0,91.1,88.0,83.6,78.9,77.3,69.0,25.1,24.8,20.7,9.6. 11 B NMR(128MHz,C 6 D 6 )δ30.6.HRMS calculated for C 26 H 36 BFeO 2 S[M+H] + 479.1873,found479.1869.

[0040]

[0041] gum,87.1mg,86%yield. 1 H NMR(700MHz,CDCl 3)δ7.89(s,1H),7.28–7.23(m,1H),7.21–7.13(m,1H),4.43(s,1H),4.39(s,1H),1.48(s,15H),1.36(s,12H),0.21(s,9H). 13 CNMR(175MHz,CDCl 3 )δ140.0,127.2,126.2,93.4,90.3,83.5,81.9,77.7,70.4,70.1,25.1,24.8,10.4,0.2. 11 B NMR(128MHz,CDCl 3 )δ31.2.HRMS calculated for C 28 H 42 BFeO 2 Si[M+H] + 505.2391,found 505.2390.

[0042] Purple solid,mp 178.8-180.2℃,87.8mg,88%yield. 1 H NMR(700MHz,C 6 D 6 )δ8.40(s,1H),7.80(d,J=8.5Hz,1H),7.32(d,J=8.5Hz,1H),3.84(s,1H),3.80(s,1H),2.86–2.79(m,4H),1.64(s,15H),1.56(s,4H),1.22(s,6H),1.21(s,6H). 13 C NMR(175MHz,C 6 D 6 )δ141.9,127.4,126.4,117.1,87.9,84.6,83.4,76.8,53.1,52.1,49.2,25.8,25.4,25.1,10.7. 11 BNMR(128MHz,C 6 D 6 )δ33.2.HRMS calculated for C 29 H 41 BFeNO 2 [M+H] + 502.2574,found502.2578.

[0043] 1-(Piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)

[0044] indenyl-pentamethylcyclopentadienyliron(3i):Purple solid,mp 149.8-150.6℃,81.5mg,79%yield. 1 H NMR(700MHz,C 6 D 6 )δ8.35(s,1H),7.77(d,J=8.6Hz,1H),7.27(d,J=8.6Hz,1H),3.99(s,1H),3.97(s,1H),2.65–2.61(m,4H),1.64(s,15H),1.47–1.41(m,4H),1.32–1.27(m,2H),1.21(s,6H),1.20(s,6H). 13 C NMR(175MHz,C 6 D 6 )δ141.1,126.8,126.7,118.9,87.9,84.6,83.3,77.0,54.6,53.9,51.1,26.0,25.1,24.9,24.7,10.1. 11 B NMR(128MHz,C 6 D 6 )δ32.1.HRMS calculated for C 30 H 43 BFeNO 2 [M+H] + 516.2731,found 516.2726.

[0045]

[0046] Purple solid,mp 171.7-172.8℃,68.7mg,66%yield. 1 H NMR(400MHz,C 6 D 6 )δ8.35(s,1H),7.80(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H),3.90(s,2H),3.63–3.52(m,4H),2.57–2.46(m,4H),1.61(s,15H),1.21(s,12H). 13C NMR(100MHz,C 6 D 6 )δ141.5,127.4,127.2,118.5,88.4,85.1,83.9,77.6,67.3,54.7,54.1,50.9,25.7,25.5,10.7. 11 B NMR(128MHz,C 6 D 6 )δ30.7.HRMS calculated for C 29 H 41 BFeNO 3 [M+H] + 518.2523,found518.2525.

[0047]

[0048] CDCl 3 )δ7.92(s,1H),7.51(s,1H),4.71–4.48(m,1H),4.45–4.25(m,1H),4.00–3.74(m,1H),2.31–1.98(m,2H),1.67(s,6H),1.62(s,6H),1.36(s,12H),1.25–1.09(m,3H),0.84(s,4H). 13 C NMR(100MHz,CDCl 3 )δ138.8,127.8,121.7,91.2,88.3,83.8,82.9,79.9,78.8,78.5,78.36,77.3,67.6,67.4,28.0,25.1,24.7,24.1,14.3,10.2,10.0. 11 B NMR(128MHz,CDCl 3 )δ31.2.HRMS calculated for C 27 H 37 BBrFeO 2 [M+H] + 539.1414,found539.1404.

[0049]

[0050] CDCl 3)δ7.92(s,1H),7.51(s,1H),4.55(d,J=2.4Hz,1H),4.39(d,J=2.5Hz,1H),3.91(t,J=2.8Hz,1H),2.24–2.08(m,2H),1.67(s,3H),1.63(s,3H),1.62(s,3H),1.61(s,3H),1.36(s,6H),1.35(s,6H),1.27–1.21(m,6H),1.17–1.10(m,2H),0.92–0.80(m,3H). 13 CNMR(100MHz,CDCl 3 )δ138.8,127.8,121.7,91.2,88.3,83.7,83.2,78.9,78.8,78.4,78.3,77.3,67.6,67.4,31.8,31.0,29.6,25.9,25.1,24.7,22.8,14.2,10.1,10.0,9.97,9.9. 11 BNMR(128MHz,CDCl 3 )δ31.4.HRMS calculated for C 30 H 43 BBrFeO 2 [M+H] + 581.1883,found581.1886.

[0051]

[0052] NMR(400MHz,CDCl 3 )δ7.96(s,1H),7.54(s,1H),4.78–4.66(m,1H),4.66–4.58(m,1H),4.07–3.97(m,1H),1.81(s,3H),1.56(s,3H),1.53(s,6H),1.36(s,12H),0.38(s,9H). 13 C NMR(100MHz,CDCl 3 )δ138.9,128.4,121.6,91.5,88.3,84.33,84.30,83.8,83.3,

[0053]

[0054] yellow solid,mp 115.8-116.4℃,48.4mg,78%yield. 1 H NMR(400MHz,CDCl3 )δ4.46–4.41(m,2H),4.41–4.36(m,2H),4.15(s,5H),1.35(s,12H). 13 C NMR (100 MHz, CDCl 3 )δ83.3,73.8,72.1,68.6,25.0. 11 B NMR (128MHz, CDCl 3 )δ32.9. This compound can be further used to obtain different types of drugs, which have good effects on breast cancer, ovarian cancer, colorectal cancer and other cancers (reference: B.Sun, et al.Chem.Asian J.2022,17,e202200818); this compound can also be further used to obtain a ligand, which has a good reaction effect in palladium-catalyzed allylic alkylation reaction (reference: You, S.-L. et al.CCS Chem.2020,2,642).

[0055]

[0056] CDCl 3 )δ5.15–5.10(m,2H),4.87–4.81(m,2H),1.30(s,12H). 13 C NMR (100 MHz, CDCl 3 )δ91.7,85.2,84.2,24.7. 11 B NMR (128MHz, CDCl 3 )δ30.2.

[0057]

[0058] Commun.2004,1508)yellow solid,mp 60.1-60.6℃,54.6mg,54%yield. 1 H NMR (400 MHz, CDCl 3 )δ4.63(t,J=1.2Hz,1H),4.59(dd,J=2.4,1.2Hz,1H),4.39(dd,J=2.4,1.3Hz,1H),4.37(dt,J=2.5,1.2Hz ,1H),4.34(dt,J=2.4,1.2Hz,1H),4.19(td,J=2.6,1.4Hz,1H),4.13(td,J=2.6,1.4Hz,1H),1.34(s,12H). 13 C NMR (100 MHz, CDCl 3)δ83.8,80.8,78.8,77.9,75.6,73.79,73.0,70.5,69.4,25.1,25.0. 11 B NMR (128MHz, CDCl 3 )δ32.2.

[0059] Examples 1-8

[0060] Table 2 Investigation of ligands

[0061]

[0062]

[0063] The ligand L may be one or two or more of L1-L8.

Claims

1. A method for synthesizing metallocene borate, characterized in that: The metallocene 1 shown in the following formula and pinacol borane 2 are used as raw materials to generate metallocene borate ester 3 as follows: Where R 1 It is one or more of hydrogen, bromine, chlorine, fluorine, and iodine substituents. When it is one or more of bromine, chlorine, fluorine, and iodine, the number is 1 or 2; R 2 is hydrogen, bromine, methyl, ethyl, n-propyl, isopropyl, methylthio, ethylthio, trimethylsilyl, triethylsilyl, triisopropylsilyl, pyrrolyl, piperidinyl, morpholinyl, aziridine One or more of (azetidinyl); M is one or more of iron, ruthenium, manganese, molybdenum and cobalt; R 3 It is one or more of methyl, ethyl, n-propyl, n-butyl, n-hexyl, trimethylsilyl, triethylsilyl, triisopropylsilyl. R 4 is one or more of hydrogen, chlorine, bromine, iodine, methylthio, ethylthio, and n-propylthio, wherein two R 4 Same or different.

2. The method for synthesizing metallocene borate according to claim 1, characterized in that: The specific steps are as follows: Under an inert atmosphere (such as nitrogen), metallocene 1, pinacol borane 2, iridium catalyst precursor and ligand are added to a reaction vessel, followed by solvent, and the reaction vessel is sealed and reacted at 70-100°C for 6-24h to generate the target product, metallocene borate ester 3.

3. The method according to claim 2, characterized in that: The molar ratio of the metallocene 1 to the pinacol borane 2 is 1:1.0-1:10, preferably 1:3-1:

8.

4. The method according to claim 2, characterized in that: The solvent range is one or more of nitromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, water, ethanol, methanol, N,N-dimethylacetamide, N,N-dimethylformamide, trifluoroethanol, hexafluoroisopropanol, and methylcyclohexane, preferably one or two of methanol and methylcyclohexane; The concentration of metallocene 1 in the solvent is 0.10-0.40 mol / L, preferably 0.13-0.20 mol / L.

5. The method according to claim 2, characterized in that: The iridium catalyst precursor is one or both of (1,5-cyclooctadiene) iridium chloride (I) dimer and bis(1,5-cyclooctadiene) di-M-methoxy diiridium (I), preferably bis(1,5-cyclooctadiene) di-M-methoxy diiridium (I); The amount of the iridium catalyst precursor used is 0.01-0.05 molar equivalent of the amount of metallocene 1 used, preferably 0.02-0.04 molar equivalent.

6. The method according to claim 2, characterized in that: The ligand is one or more of the following 4,4'-di-tert-butyl-2,2'-bipyridine L5, 1,10-phenanthroline L1, 2-methyl-1,10-phenanthroline L3, 2-bromo-1,10-phenanthroline L4, 3,4,7,8-tetramethyl-1,10-phenanthroline L2, L6, L7, preferably 3,4,7,8-tetramethyl-1,10-phenanthroline L2; The amount of the ligand used is 0.01-0.08 molar equivalent of the amount of metallocene 1 used, preferably 0.05-0.07 molar equivalent.

7. The method according to claim 2, characterized in that: After the reaction was completed, the solvent was dried and the product metallocene borate ester 3 was obtained by column chromatography (mobile phase: petroleum ether / ethyl acetate).

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