CN110627785A - Preparation method of 1, 5-tetrahydronaphthyridine derivative - Google Patents
Preparation method of 1, 5-tetrahydronaphthyridine derivative Download PDFInfo
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Abstract
The invention discloses a preparation method of a 1, 5-tetrahydronaphthyridine derivative, which realizes the synthesis of the 1, 5-tetrahydronaphthyridine derivative with diversified structures by catalyzing carbon-hydrogen bond activation/functionalization of pyridine by rare earth. In particular to a method for preparing 1, 5-tetrahydronaphthyridine derivatives by taking various 3-alkene butylaminopyridines as raw materials under the protection of nitrogen under a rare earth catalytic system. The method has the advantages of wide raw material source or easy preparation, simple and convenient operation, controllable selectivity, high yield, mild conditions and wide universality.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 1, 5-tetrahydronaphthyridine derivative for realizing structural diversification by pyridine carbon-hydrogen bond activation and intramolecular cyclization reaction.
Background
The 1, 5-tetrahydronaphthyridine derivatives are important organic compounds, which are important components of natural products and medicines. Therefore, the development of new and diversified and efficient methods for synthesizing 1, 5-tetrahydronaphthyridine derivatives has been an important issue in organic synthetic chemistry.
In the existing technology for preparing 1, 5-tetrahydronaphthyridine derivatives, the synthesis of the 1, 5-tetrahydronaphthyridine derivatives is always realized by adopting a catalytic hydrogenation or hydrogen transfer reduction method. The literature (org. Lett.2016,18,2730-2733) reports a process for preparing 1, 5-tetrahydronaphthyridine derivatives using ruthenium as a catalyst, hydrogen as a reducing agent and isopropanol or n-butanol as a solvent. This type of reaction presents a narrow substrate range and is difficult to derivatize with functional groups. And moreover, hydrogen which is flammable and has potential safety hazards is used as a hydrogen source, so that the operation is inconvenient and has certain limitations. The literature (Organometallics 2016,35,943-949) reports a process for the synthesis of 1, 5-tetrahydronaphthyridine derivatives by means of a hydrogen transfer reaction reduction strategy, which, although not requiring the direct use of hydrogen as the hydrogen source, utilizes an alcohol via a hydrogen transfer process. In the actual process, hydrogen is released to achieve the aim of transfer hydrogenation, so that the method has certain limitation, certain potential safety hazard and generally moderate yield.
Disclosure of Invention
In order to solve the problems and the defects in the prior art, the invention aims to provide the preparation method of the 1, 5-tetrahydronaphthyridine derivative, which avoids using hydrogen, improves the safety of the preparation process, and has wide raw material source and simple and convenient operation.
In order to achieve the purpose, the technical scheme of the invention comprises the following steps:
under the existence of inert atmosphere and rare earth catalyst, taking an alkene butylamino pyridine compound shown in a formula (I) as a raw material, and preparing a 1, 5-tetrahydronaphthyridine derivative shown in a formula (II) through carbon-hydrogen bond activation and intramolecular insertion cyclization reaction; the reaction formula is as follows:
in the above formula, R1Is hydrogen, methyl or halogen; r2Is hydrogen or methyl; r3Is methyl, phenyl or benzyl;
R4is hydrogen;
the rare earth catalyst is selected from Ln [ N (SiMe)3)2]3Ln ═ Sc, Y, La-Lu and rare earth alkyl complexes;
the solvent is toluene or n-hexane or tetrahydrofuran.
The additive is dibenzylamine, and the yield of the reaction can be greatly improved by using catalytic amount of dibenzylamine.
It is further provided that the inert atmosphere is nitrogen.
It is further provided that the molar ratio of the enamino pyridine compound/rare earth catalyst is 1.0/0.1.
The reaction temperature is further set to be 80-100 ℃, and the reaction time is 24-48 h.
Through intensive research, the inventor discovers that the synthesis of the 1, 5-tetrahydronaphthyridine derivative with diversified structures is realized by catalyzing carbon-hydrogen bond activation/intramolecular insertion cyclization reaction of pyridine under a rare earth catalytic system, and the method has the advantages of high atom economy, relatively mild reaction conditions and safe and simple operation. Compared with the prior method, the method has the advantages that the reaction conditions and the substrate universality are obviously improved, and no chemical reagents such as hydrogen and the like with potential safety hazards are adopted, which is difficult to realize by other methods. The invention has the following advantages and innovations:
(1) the reaction universality is good, the yield is high, most of the reaction yield is over 80 percent, and the atom economy is high;
(2) the method is an important supplement of carbon-hydrogen bond activation/functionalization of pyridine catalyzed by rare earth, and provides an important idea for constructing a nitrogen-containing heterocyclic compound;
(3) the reaction condition is mild, a large amount of complex additives are not needed, and compared with a plurality of transition metal catalyzed pyridine carbon-hydrogen bond activation reactions, the reaction only needs to add dibenzylamine with a catalytic amount and a simple structure, so that the cost is reduced, and the dibenzylamine is easy to recover.
(4) The method does not need hydrogen which is inflammable and inconvenient to store and transport as a chemical raw material;
(5) the rare earth silicon amino complex catalyst is simple, moderate in price and commercially available;
compared with the prior art, the invention has the following beneficial effects:
the 1, 5-tetrahydronaphthyridine derivative prepared by the method has high quality and high yield; the reaction universality is good, the reaction atom economy is high, and the post-treatment is convenient; the method realizes the activation of carbon-hydrogen bond of pyridine catalyzed by rare earth metal complex to construct the pyridine-fused ring compound for the first time, and provides important reference for the construction of 1, 5-tetrahydronaphthyridine derivatives and other heterocyclic compounds.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples.
Example 1
Preparation of 4-methyl-1-phenyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula as follows:
under the protection of nitrogen, adding raw material N-alkenyl butyl-N-phenylpyridine-3-amine (0.5mmol) and catalyst Y [ N (SiMe)3)2]3(10 mol%), dibenzylamine (10 mol%), toluene (3mL) and reacted at 100 ℃ for 24h, and the isolated yield of the product is 93%.
1H NMR(CDCl3,500MHz,ppm):δ7.96(dd,J＝1.3,4.6Hz,1H),7.37(t,J＝8.2Hz,2H),7.21(d,J＝8.3Hz,2H),7.14(t,J＝7.4Hz,1H),6.97(dd,J＝1.2,8.3Hz,1H),6.83(dd,J＝4.6,8.3Hz,1H),3.69-3.56(m,2H),3.17-3.09(m,1H),2.24-2.17(m,1H),1.90-1.83(m,1H),1.43(d,J＝7.0Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ148.8,147.2,140.6,138.5,129.9,125.2,124.8,121.6,121.5,47.9,33.9,29.7,20.9。
Example 2
Preparation of 4, 6-dimethyl-1-phenyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula:
under the protection of nitrogen, raw material N-alkenyl butyl-N-phenyl-6-methylpyridine-3-amine (0.5mmol) and catalyst Y [ N (SiMe) are added3)2]3(10 mol%), toluene (3mL), dibenzylamine (10 mol%), reacted at 100 ℃ for 24h, and the isolated yield was 91%.
1H NMR(CDCl3,500MHz,ppm):δ7.35(t,J＝8.2Hz,2H),7.18(d,J＝7.5Hz,2H),7.10(t,J＝7.4Hz,1H),6.98(d,J＝8.4Hz,1H),6.72(d,J＝8.4Hz,1H),3.66-3.56(m,2H),3.16-3.10(m,1H),2.45(s,3H),2.22-2.16(m,1H),1.87-1.82(m,1H),1.41(d,J＝7.1Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ148.5,147.8,147.2,137.7,129.7,124.4,124.1,123.3,121.1,47.4,33.8,29.6,23.4,21.4。
Example 3
Preparation of 6-chloro-4-methyl-1-phenyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula as follows:
under the protection of nitrogen, raw material N-alkene butyl-6-chlorine-N-methylpyridine-3-amine (0.5mmol), dibenzylamine (10 mol%) and catalyst Y [ N (SiMe) are added3)2]3(10 mol%) and toluene (3mL) were reacted at 100 ℃ for 24h, and the product was isolated in 86% yield.
1H NMR(CDCl3,500MHz,ppm):δ7.38(t,J＝7.6Hz,2H),7.20-7.15(m,3H),6.92(d,J＝8.6Hz,1H),6.82(d,J＝8.6Hz,1H),3.66-3.56(m,2H),3.13-3.06(m,1H),2.21-2.15(m,1H),1.88-1.82(m,1H),1.41(d,J＝7.1Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ148.9,147.0,139.6,138.7,129.9,125.2,125.1,124.6,121.6,47.8,33.8,29.4,21.0。
Example 4
The preparation of 1-benzyl-4-methyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine has the following structural formula:
under the protection of nitrogen, raw material N-alkene butyl-N-benzyl pyridine-3-amine (0.5mmol), dibenzylamine (10 mol%) and catalyst Y [ N (SiMe) are added3)2]3(10 mol%) and toluene (3mL) at 100 deg.C for 24h, the product was isolated in 93% yield.
1H NMR(CDCl3,500MHz,ppm):δ7.85(d,J＝4.5Hz,1H),7.33(t,J＝7.4Hz,2H),7.26-7.22(m,3H),6.87(dd,J＝4.6,8.2Hz,1H),6.71(d,J＝7.8Hz,1H),4.47(d,J＝4.7Hz,2H),3.48-3.43(m,1H),3.38-3.33(m,1H),3.14-3.07(m,1H),2.19-2.13(m,1H),1.88-1.82(m,1H),1.40(d,J＝7.0Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ147.4,141.3,138.0,136.3,128.9,127.2,126.6,122.1,117.1,54.7,46.6,34.1,29.2,20.7。
Example 5
Preparation of 1-phenethyl-4-methyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula is as follows:
under the protection of nitrogen, raw material N-allyl-N-phenethyl pyridine-3-amine (0.5mmol), dibenzylamine (10 mol%) and catalyst Y [ N (SiMe)3)2]3(10 mol%) and toluene (3mL) at 100 deg.C for 24h, with an isolated yield of 94%.
1H NMR(CDCl3,500MHz,ppm):δ7.84(dd,J＝1.3,4.6Hz,1H),7.31(t,J＝6.9Hz,2H),7.25-7.20(m,3H),6.97(dd,J＝4.6,8.3Hz,1H),6.85(dd,J＝1.1,8.3Hz,1H),3.56-3.43(m,2H),3.26-3.20(m,1H),3.15-3.09(m,1H),3.04-2.96(m,1H),2.85(t,J＝7.6Hz,2H),2.04-1.97(m,1H),1.74-1.67(m,1H),1.32(d,J＝7.1Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ147.7,140.6,139.6,135.9,128.9,128.7,126.5,122.1,116.3,52.8,46.1,34.0,32.3,28.9,20.8。
Example 6
4-methyl-1-benzyl-1, 2,3, 4-tetrahydro-1, 5-benzonaphthyridine, the structural formula of which is as follows:
under the protection of nitrogen, adding raw material N-alkenyl butyl-N-benzyl quinoline-3-amine (0.5mmol), dibenzyl amine (10 mol%) and catalyst Y [ N (SiMe)3)2]3(10 mol%) and toluene (3mL) at 100 deg.C for 24h, the product isolated in 91% yield.
1H NMR(CDCl3,500MHz,ppm):δ7.88(d,J＝4.8Hz,1H),7.23(d,J＝8.0Hz,1H),7.17(d,J＝8.3Hz,2H),7.10(d,J＝8.4Hz,2H),6.93(dd,J＝5.1,7.8Hz,1H),4.09(t,J＝9.0Hz,1H),3.57(t,J＝8.7Hz,1H),3.52-3.46(m,1H),2.33(s,3H),1.46(d,J＝6.8Hz,3H),.13C NMR(CDCl3,125MHz,ppm):δ157.7,141.2,141.1,138.6,131.5,130.0,121.7,117.7,113.2,58.5,36.2,20.8,18.1。
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (5)
1. A preparation method of a 1, 5-tetrahydronaphthyridine derivative is characterized by comprising the following steps:
under the existence of inert atmosphere and rare earth catalyst, taking an alkene butylamino pyridine compound shown in a formula (I) as a raw material, and preparing a 1, 5-tetrahydronaphthyridine derivative shown in a formula (II) through carbon-hydrogen bond activation and intramolecular insertion cyclization reaction; the reaction formula is as follows:
in the above formula, R1Is hydrogen, methyl or halogen; r2Is hydrogen or methyl; r3Is methyl, phenyl or benzyl;
R4is hydrogen;
the rare earth catalyst is selected from Ln [ N (SiMe)3)2]3Ln ═ Sc, Y, La-Lu and rare earth alkyl complexes;
the solvent is toluene or n-hexane or tetrahydrofuran;
the additive is dibenzylamine.
2. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the inert atmosphere is nitrogen.
3. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the mol ratio of the alkene butylaminopyridine compound to the rare earth catalyst is 1.0/0.1.
4. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the reaction temperature is 80-100 ℃, and the reaction time is 24-48 h.
5. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the amount of dibenzylamine added was the same as the amount of the catalyst.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1678581A (en) * | 2002-07-03 | 2005-10-05 | 拜耳医药保健股份公司 | Indolin phenylsulfonamide derivatives |
| CN104870441A (en) * | 2012-10-19 | 2015-08-26 | 阿斯特克斯治疗有限公司 | Bicyclic heterocycle compounds and their uses in therapy |
| WO2019020792A1 (en) * | 2017-07-27 | 2019-01-31 | Esteve Pharmaceuticals, S.A. | New propanamine derivatives for treating pain and pain related conditions |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1678581A (en) * | 2002-07-03 | 2005-10-05 | 拜耳医药保健股份公司 | Indolin phenylsulfonamide derivatives |
| CN104870441A (en) * | 2012-10-19 | 2015-08-26 | 阿斯特克斯治疗有限公司 | Bicyclic heterocycle compounds and their uses in therapy |
| WO2019020792A1 (en) * | 2017-07-27 | 2019-01-31 | Esteve Pharmaceuticals, S.A. | New propanamine derivatives for treating pain and pain related conditions |
Non-Patent Citations (3)
| Title |
|---|
| GUOYONG SONG等: "Enantioselective C−H Bond Addition of Pyridines to Alkenes Catalyzed by Chiral Half-Sandwich Rare-Earth Complexes", 《J. AM. CHEM. SOC.》 * |
| MATTHIAS WESTERHAUSEN等: "Bis(trimethylsilyl)amides and -methanides of yttrium - molecular structures of tris(diethylether-O)lithium-(m-chloro)-tris[bis(trimethylsilyl)methyl]yttriate, solvent-free yttrium tris[bis(trimethylsilyl)amide] as well as the bis(benzonitrile) complex", 《ZEITSCHRIFT FUER ANORGANISCHE UND ALLGEMEINE CHEMIE》 * |
| SAMUELE BORDI等: "Hydropyridylation of Olefins by Intramolecular Minisci Reaction", 《ORG. LETT.》 * |
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