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Method for synthesizing polysubstituted amino isoquinoline compound by cyclizing pyridine and alkyne under catalysis of rhodium

An aminoisoquinoline, rhodium-catalyzed pyridine technology, applied in organic chemistry and other directions, can solve the problems of high substrate, poor applicability of reactive substrate functional groups, etc., and achieves the effect of simple process, convenient industrial production, and few by-products

Active Publication Date: 2020-10-23
LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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AI Technical Summary

Problems solved by technology

The traditional synthesis method is mainly prepared by intramolecular cyclization of functionalized substrates, which has relatively high requirements for substrates, poor reactivity and applicability of substrate functional groups

Method used

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  • Method for synthesizing polysubstituted amino isoquinoline compound by cyclizing pyridine and alkyne under catalysis of rhodium
  • Method for synthesizing polysubstituted amino isoquinoline compound by cyclizing pyridine and alkyne under catalysis of rhodium
  • Method for synthesizing polysubstituted amino isoquinoline compound by cyclizing pyridine and alkyne under catalysis of rhodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1: Synthesis of 3,3-dimethyl-2-(5,6,7,8-tetraphenyl-1-isoquinolinyl)isoindole (R = phenyl):

[0020] In a 25 ml Young’s tube, add 3,3-dimethyl-2-pyridylisoindole-1-one (1 mmol), diphenylacetylene (2.4 mmol), Cp*Rh(CH 3 CN) 3 (SbF 6 ) 2 (5 mol%) and silver acetate (2.2 mmol). Finally, add 5 mL of 1,2-dichloroethane solvent to the reaction tube, and react at 100°C for 24 hours; after the reaction, the reaction solution is cooled to room temperature and reduced The organic solvent was removed by pressure to obtain the crude product, which was further separated by silica column chromatography and eluted with petroleum ether / ethyl acetate (volume ratio 10 / 1) to obtain pure product 3,3-dimethyl-2-(5, 6,7,8-Tetraphenyl-1-isoquinolinyl)isoindol-1-one, the yield was 93%. 1 H NMR (400 MHz, CDCl 3 ) δ8.29 (d, J = 5.7 Hz, 1H), 7.57 ((d, J = 7.5 Hz, 1H), 7.39 (td, J = 7.5, 1.1 Hz, 1H), 7.35-7.27 (m, 3H), 7.25-7.22 (m, 1H), 7.22-7.14 (m, 2H), 7.13-7.06 (m, 3H), 6.94 (d, J = 7...

Embodiment 2

[0021] Example 2: Synthesis of 3,3-dimethyl-2-(5,6,7,8-tetra(4-methylphenyl)-1-isoquinolinyl)isoindol-1-one ( R = 4-methylphenyl):

[0022] In a 25 ml Young’s tube, add 3,3-dimethyl-2-pyridylisoindol-1-one (1 mmol), 1,2-bis(4-methylbenzene)acetylene (2.4 mmol), Cp*Rh(CH 3 CN) 3 (SbF 6 ) 2 (5 mol%) and silver acetate (2.2 mmol). Finally, add 5 mL of 1,2-dichloroethane solvent to the reaction tube, and react at 100°C for 24 hours. After the reaction, the reaction solution is cooled to room temperature. The organic solvent was removed by pressure to obtain the crude product, which was further separated by silica column chromatography and eluted with petroleum ether / ethyl acetate (volume ratio 10 / 1) to obtain pure product 3,3-dimethyl-2-(5, 6,7,8-Tetra(4-methylphenyl)-1-isoquinolinyl)isoindol-1-one, the yield is 80%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (d, J = 5.7 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.38 (td, J = 7.5, 1.0 Hz, 1H), 7.30 (d, J = 5.6Hz, 1H), 7.26-7.23 (m, 1H), 7.20 (d...

Embodiment 3

[0023] Example 3: Synthesis of 3,3-Dimethyl-2-(5,6,7,8-tetra(4-methoxyphenyl)-1-isoquinolinyl)isoindol-1-one (R = 4-methoxyphenyl):

[0024] In a 25 ml Young’s tube, add 3,3-dimethyl-2-pyridylisoindol-1-one (1 mmol), 1,2-bis(4-methoxybenzene)acetylene ( 2.4 mmol), Cp*Rh(CH 3 CN) 3 (SbF 6 ) 2 (5 mol%) and silver acetate (2.2 mmol). Finally, add 5 mL of 1,2-dichloroethane solvent to the reaction tube, and react at 100°C for 24 hours. After the reaction, the reaction solution is cooled to room temperature. The organic solvent was removed by pressure to obtain a crude product, which was further separated by silica column chromatography, and eluted with petroleum ether / ethyl acetate (volume ratio 5 / 1) to obtain pure product 3,3-dimethyl-2-(5, 6,7,8-Tetra(4-methoxyphenyl)-1-isoquinolinyl)isoindol-1-one, the yield is 76%. 1 H NMR (400 MHz, CDCl 3 ) δ8.26 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.41 (td, J = 7.5, 1.1 Hz, 1H), 7.33 (d, J = 5.6Hz, 1H), 7.28-7.22 (m, 2H), 7.16 (...

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Abstract

The invention discloses a method for synthesizing a polysubstituted aminoisoquinoline compound by cyclizing pyridine and alkyne under the catalysis of rhodium, which comprises the following steps: byusing a pentamethylcyclopentadienyl rhodium complex as a catalyst and a 2-aminopyridine derivative and an internal alkyne compound as raw materials, reacting in an organic solvent at 30-150 DEG C for1-24 hours, cooling the reaction solution after the reaction is finished, removing the organic solvent under reduced pressure; purifying the crude product through a silicon dioxide column, and elutingwith petroleum ether / ethyl acetate to obtain the pure polysubstituted aminoisoquinoline derivative. According to the method, a guide group (carbonyl) or a steric hindrance group (methyl) is introduced into the reaction to realize C-H bond activation and avoid the coordination effect of pyridine on the metal catalyst, and the regulation and control of the reaction activity and selectivity are efficiently realized through the regulation and control of the group with large steric hindrance. The obtained generation target products are high in selectivity, and the selectivity is 90% or above, byproducts are few, and the product separation cost is reduced, and the method is simple in synthesis process, mild in reaction condition and convenient for industrial production.

Description

Technical field [0001] The invention relates to a method for synthesizing polysubstituted isoquinoline compounds, in particular to a method for synthesizing polysubstituted amino isoquinoline derivatives with pyridine catalyzed by rhodium metal, and belongs to the technical field of organic chemical synthesis. Background technique [0002] Isoquinoline and its derivatives are widely present in drug molecules and natural products. They are an important type of active molecular skeleton with high application value. Traditional synthetic methods are mainly prepared by intramolecular cyclization of functionalized substrates, which require relatively high substrates, and have poor reactivity and applicability of substrate functional groups. Compared with traditional synthesis methods, transition metal-catalyzed C-H activated cyclization reactions have good application advantages. Summary of the invention [0003] The purpose of the present invention is to provide a method for synthesi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D413/04C07D417/14
CPCC07D401/04C07D413/04C07D417/14
Inventor 石利军李福伟高广孙鹏赵泽伦王嘉
Owner LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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