CN111646932A - Preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine - Google Patents
Preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine Download PDFInfo
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- CN111646932A CN111646932A CN202010520988.XA CN202010520988A CN111646932A CN 111646932 A CN111646932 A CN 111646932A CN 202010520988 A CN202010520988 A CN 202010520988A CN 111646932 A CN111646932 A CN 111646932A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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Abstract
The invention relates to a preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine, which comprises the following steps: dissolving an additive in a solvent, and reacting with 4-tert-butyl pyridine and a tin reagent under a strong alkali condition to obtain 4-tert-butyl-2-tributylstannyl pyridine; then carrying out coupling reaction with 4-tert-butyl-2, 6-dichloropyridine under the action of a catalyst to obtain 4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine; the invention starts from 4-tert-butylpyridine as a raw material, obtains 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine through two-step reaction, has simple product separation and purification, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine, belonging to the field of organic synthesis.
Background
4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine (I) is used as a ligand, is widely applied to synthesis of a series of transition metal complexes, and is widely applied in the fields of catalytic chemistry, supermolecular chemistry, material chemistry, electrochemistry, research and development of antitumor drugs and the like. For example, the document J.Am.chem.Soc.2003,125,16202-16203 reports that silver ion complexes of I are useful for catalyzing aziridination; J.Am.chem.Soc.2002,124, 11215-11222 reports that the cobalt ion complex of I is used as a high-efficiency electron transfer material in a dye-sensitized solar cell; polyhedron,2018,140,99-108 reported that iron and cobalt complexes of I are useful as galvanic materials for redox flow batteries; WO2019241873A1 reports that the copper ion complex of I can induce the death of immunogen cells and can be used for treating tumors. Therefore, the market prospect of I is very wide.
The existing synthesis process of 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine (I) is as follows:
the document chem. eur.j.2018,24,14830-14835 reports that 4-tert-butylpyridine (II) is reacted with a magnesium catalyst (Mgcat) to give 4,4',4 "-tri-tert-butyl-2, 2 ': 6 ', 2" -terpyridine (I) by air oxidation. In the reaction, a magnesium catalyst is not easy to obtain and needs to be prepared in a glove box, and a ligand also needs to be synthesized through multi-step reactions. The reaction yielded a mixture of I and another product, 4 '-di-tert-butyl-2, 2' -bipyridine (III), with a yield of I of only 21%, which was not separable from III.
Wherein the reagents and conditions used are: 1) mg cat, THF,70 ℃,2 h; 2) oxidation in air.
Patent US2018282278a1 reports that 4-tert-butylpyridine (II) can be reacted with dispersed sodium metal in THF to give I. In this reaction, the yield of 4,4 '-di-tert-butyl-2, 2' -bipyridine (III) was 78%, which was the main product, and the yield of I was only 9%. And dispersed metal sodium is needed in the reaction, so the reaction operation is not easy and the danger is high. Therefore, the process is not suitable for large-scale preparation of I.
Wherein, the reagents and conditions used are: na, THF, paraffinfin oil,25 ℃.
The compound I has wide application in the fields of transition metal catalysis, supermolecular chemistry, photoelectric materials, redox flow batteries, antitumor drugs and the like, and has wide market prospect. Therefore, the development of a synthetic method which is simple and convenient to operate, short in route, high in yield and suitable for large-scale production has important significance.
Disclosure of Invention
The invention aims to provide a method for quickly and efficiently preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine, which solves the problems of low synthesis yield, difficult product separation and purification, high-risk reagent use and the like of the existing method.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine comprises the following synthetic process route:
further, the preparation method comprises the following specific steps:
(1) dissolving an additive in a solvent, and reacting with 4-tert-butyl pyridine (II) and a tin reagent under a strong alkali condition to obtain 4-tert-butyl-2-tributylstannyl pyridine (IV);
(2) 4-tert-butyl-2-tributylstannyl pyridine (IV) and 4-tert-butyl-2, 6-dichloropyridine (V) are subjected to coupling reaction under the action of a catalyst to obtain 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine (I).
Further, in the step (1), the molar ratio of the 4-tert-butylpyridine (II) to the strong base is 1: 1-8; the strong base is n-butyllithium or sec-butyllithium.
Further, the molar ratio of the tin reagent to the 4-tert-butylpyridine (II) in the step (1) is 0.1-6: 1; the tin reagent is tributyltin chloride.
Further, the reaction temperature in the step (1) is-78-60 ℃.
Further, the solvent in the step (1) is any one of pentane, hexane, heptane and octane.
Further, the molar ratio of the additive to the 4-tert-butylpyridine (II) in the step (1) is 0.1-6: 1; the additive is N, N-dimethylethanolamine.
Further, in the step (2), the molar ratio of the 4-tert-butyl-2-tributylstannyl pyridine (IV) to the 4-tert-butyl-2, 6-dichloropyridine (V) is 0.1-6: 1.
further, the molar ratio of the catalyst to the 4-tert-butyl-2-tributylstannyl pyridine (IV) in the step (2) is 0.001-0.5: 1.
further, the catalyst in the step (2) is Pd (dppf) Cl2、Pd(dppf)Cl2·CH2Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dba)2Any one of them.
Further, the reaction temperature of the step (2) is 80-120 ℃.
Compared with the prior art, the invention has the following beneficial effects because the technology is adopted:
the invention provides a method for efficiently and rapidly preparing 4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine; 4,4', 4' '-tri-tert-butyl-2, 2': 6 ', 2' '-terpyridine is obtained from 4-tert-butylpyridine through two-step reaction, the total yield can reach 48.4%, and the product is simple to separate and purify and is suitable for large-scale preparation of 4,4',4 '' -tri-tert-butyl-2, 2 ': 6', 2 '' -terpyridine.
Drawings
FIG. 1 is a NMR spectrum of 4-tert-butyl-2-tributylstannylpyridine obtained in example 1;
FIG. 2 shows the NMR spectra of 4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine prepared in example 3.
Detailed Description
The present invention will be further illustrated with reference to the following specific embodiments.
Example 1
Synthesis of compound IV:
n, N-dimethylethanolamine (131.5 g, 1.48 mol, 2.0 equiv.) was added to 2.5L of N-hexane under nitrogen protection and the temperature was reduced to-20 ℃. N-butyllithium (2.5M in hexanes, 1.18L, 2.96 mol, 4.0 equiv.) was added and reacted at-30 ℃ for 30 minutes, followed by dropwise addition of 4-tert-butylpyridine (100.0 g, 0.74 mol, 1.0 equiv.) and reaction at-20 ℃ for 1 hour after completion of the dropwise addition. And (3) cooling the reaction liquid to-70 ℃, dropwise adding tributyltin chloride (481.7 g, 1.48 mol and 2.0 equiv.), reacting at-70 ℃ for 2 hours after dropwise adding, naturally heating to room temperature, and detecting by TLC to complete the reaction. Adding 1.0L of ice water into the reaction solution, extracting with ethyl acetate (500 mL), washing with water, performing column chromatography, and rapidly leaching with petroleum ether to obtain 210.97g of colorless liquid, wherein the yield is as follows: 67.2% and 85% purity.
1H NMR(400 MHz, CDCl3) （ppm）： 8.63 (dd, J = 5.40, 0.76 Hz, 1H), 7.39(dd, J = 2.20, 0.76 Hz, 1H), 7.11 (m, 1H), 1.61-1.57(m, 6H), 1.52-1.47(m,6H), 1.42-1.38(m, 6H), 1.23(s, 9H), 0.84-0.79(t, 12H)。
LC-MS (ESI+): m/z 424.85 (M+H)。
Example 2
Synthesis of compound IV:
n, N-dimethylethanolamine (44.57 g, 0.50 mol, 2.0 equiv.) was added to 1.0L of N-heptane under nitrogen, and the temperature was reduced to-20 ℃. Sec-butyllithium (1.3M in hexanes, 0.77L, 1.0 mol, 4.0 equiv.) was added and reacted at-30 ℃ for 30 minutes, followed by dropwise addition of 4-tert-butylpyridine (33.80 g, 0.25 mol, 1.0 equiv.) and reaction at-20 ℃ for 1 hour after completion of the dropwise addition. And (3) cooling the reaction liquid to-70 ℃, dropwise adding tributyltin chloride (97.65 g, 0.30 mol and 1.2 equiv.), reacting at-70 ℃ for 2 hours after dropwise adding, naturally heating to room temperature, and detecting by TLC to complete the reaction. Adding 500 mL of ice water into the reaction solution, extracting with ethyl acetate (500 mL), washing with water, performing column chromatography, and rapidly leaching with petroleum ether to obtain 40.83g of colorless liquid, wherein the yield is as follows: 38.5 percent.
Example 3
Synthesis of Compound I:
4-tert-butyl-2-tributylstannylpyridine (IV, 50.00 g, 0.118mol, 2.0 equiv., the organic), 4-tert-butyl-2, 6-dichloropyridine (V, 13.24 g, 0.065 mol, 1.1 equiv.), Pd (dppf) Cl and prepared in example 1 were sequentially added under nitrogen protection2(2.16 g, 3.0 mmol, 5 mol%) was added to 100 mL of toluene, and the mixture was heated to 100 ℃ for 16 hours to complete the TLC reaction. Concentrating the reaction solution under reduced pressure, preparing sand, and performing column chromatography (DCM leaching) to obtain 17.06 g of a white solid, wherein the yield is as follows: 72.0 percent and the purity is 97 percent.
1H NMR（400 M Hz，CDCl3）（ppm）：8.74（d，J = 1.96 Hz, 2H），8.63（d，J = 5.2Hz, 2H），8.48（s，2H），7.34（dd，J = 5.2, 2.0 Hz, 2H），1.47（s，9H），1.44（s，18 H）。
LC-MS (ESI+): m/z 423.95 (M+Na)。
Example 4
Synthesis of Compound I:
4-tert-butyl-2-tributylstannylpyridine (IV, 22.40 g, 0.053mol, 2.2 equiv., the ecological) prepared in example 2, 4-tert-butyl-2, 6-dichloropyridine (V, 5.00 g, 0.024 mol, 1.0 equiv.), Pd (PPh) were sequentially added under nitrogen atmosphere3)4(0.55 g, 0.48 mmol, 2 mol%) was added to 50 mL of 1, 4-dioxane and the reaction was refluxed at 100 ℃ for 48 h. The reaction solution is concentrated, sand is prepared, and column chromatography (DCM leaching) is carried out to obtain 3.40 g of white solid, the yield is 35.3 percent, and the purity is 97 percent.
The above-mentioned embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention should be defined by the claims, and equivalents including technical features of the claims, i.e., equivalent modifications within the scope of the present invention.
Claims (10)
1. A preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2', 6 ', 2' ' -terpyridine is characterized in that the synthesis process route of the preparation method is as follows:
2. the preparation method of 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 1, characterized in that the preparation method comprises the following steps:
(1) dissolving an additive in a solvent, and reacting with 4-tert-butyl pyridine (II) and a tin reagent under a strong alkali condition to obtain 4-tert-butyl-2-tributylstannyl pyridine (IV);
(2) 4-tert-butyl-2-tributylstannyl pyridine (IV) and 4-tert-butyl-2, 6-dichloropyridine (V) are subjected to coupling reaction under the action of a catalyst to obtain 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine (I).
3. The method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 1, wherein the method comprises the following steps: the molar ratio of the 4-tert-butylpyridine (II) to the strong base in the step (1) is 1: 1-8; the strong base is n-butyllithium or sec-butyllithium.
4. The method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: the molar ratio of the tin reagent to the 4-tert-butylpyridine (II) in the step (1) is 0.1-6: 1; the tin reagent is tributyltin chloride.
5. The method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: the reaction temperature in the step (1) is-78-60 ℃; the reaction temperature in the step (2) is 80-120 ℃.
6. The method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: the solvent in the step (1) is any one of pentane, hexane, heptane and octane.
7. The method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: the mol ratio of the additive to the 4-tert-butylpyridine (II) in the step (1) is 0.1-6: 1; the additive is N, N-dimethylethanolamine.
8. The method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: in the step (2), the molar ratio of 4-tert-butyl-2-tributylstannyl pyridine (IV) to 4-tert-butyl-2, 6-dichloropyridine (V) is 0.1-6: 1.
9. the method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: the molar ratio of the catalyst to the 4-tert-butyl-2-tributylstannyl pyridine (IV) in the step (2) is 0.001-0.5: 1.
10. the method for preparing 4,4', 4' ' -tri-tert-butyl-2, 2 ': 6 ', 2' ' -terpyridine according to claim 2, wherein: the catalyst in the step (2) is Pd (dppf) Cl2、Pd(dppf)Cl2· CH2Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(dba)2Any one of them.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443758A (en) * | 2002-12-25 | 2003-09-24 | 中国科学院等离子体物理研究所 | Coupled tert-butyl pyridine, its synthesis method and application |
| CN104798156A (en) * | 2012-11-16 | 2015-07-22 | 富士胶片株式会社 | Photoelectric conversion element, dye-sensitized solar cell, metal complex dye, dye solution, dye-adsorbed electrode, and method for manufacturing dye-sensitized solar cell |
| CN108349892A (en) * | 2015-10-08 | 2018-07-31 | 株式会社神钢环境舒立净 | The synthetic method of Bipyridine compound and the manufacturing method of pyridine compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443758A (en) * | 2002-12-25 | 2003-09-24 | 中国科学院等离子体物理研究所 | Coupled tert-butyl pyridine, its synthesis method and application |
| CN104798156A (en) * | 2012-11-16 | 2015-07-22 | 富士胶片株式会社 | Photoelectric conversion element, dye-sensitized solar cell, metal complex dye, dye solution, dye-adsorbed electrode, and method for manufacturing dye-sensitized solar cell |
| CN108349892A (en) * | 2015-10-08 | 2018-07-31 | 株式会社神钢环境舒立净 | The synthetic method of Bipyridine compound and the manufacturing method of pyridine compounds |
Non-Patent Citations (3)
| Title |
|---|
| DAVID MARTINEAU，ET AL.: "Pyrrolidine-Containing Polypyridines: New Ligands for Improved Visible Light Absorption by Ruthenium Complexes", 《J.ORG.CHEM.》 * |
| MANUEL VAN GEMMEREN，ET AL.: "Switchable Site-Selective Catalytic Carboxylation of Allylic Alcohols with CO2", 《ANGEW. CHEM. INT. ED.》 * |
| SÜLEYMAN KOUML;YTEPE，ET AL.: "Synthesis of polyimide from 5,5"-bis(bromomethyl)-2,2":6",2""-terpyridine and investigation of the polymer sorption behavior towards some metal ions", 《JOURNAL OF HAZARDOUS MATERIALS》 * |
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