Efficient preparation of o-amidated aryl heterocyclic derivatives by transition metal catalyzed C-H coupling

A technology of transition metal catalysis and heterocycles, applied in chemical recycling, organic chemistry, etc., can solve the problems of unrealistic industrial production, harsh reaction conditions, low atom utilization, etc., and achieve good thermal and chemical stability, Good solubility, the effect of improving the utilization rate of atoms

Inactive Publication Date: 2018-10-12
SICHUAN UNIV
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Problems solved by technology

[0004] The present invention uses N 1 ,N 3 - Disubstituted imidazole-type ionic liquid as solvent, bisoxazolone compound as amide source, and transition metal catalyzed C-H coupling reaction to efficiently prepare ortho-amidated aryl heterocycle derivatives, solving the traditional ortho-amidated aryl heterocycle In the synthesis of quasi-derivatives, there are problems such as lengthy steps, harsh reaction conditions, low atom utilization, use of toxic organic solvents, environmental pollution, high cost, and inability to realize industrial production. This provides a milder and faster method than existing reports. , simple, effective, environmentally friendly and recyclable reaction system preparation method, which reduces the production of finished products, avoids environmental pollution, and the by-product is only carbon dioxide, which greatly improves the utilization rate of atoms

Method used

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  • Efficient preparation of o-amidated aryl heterocyclic derivatives by transition metal catalyzed C-H coupling
  • Efficient preparation of o-amidated aryl heterocyclic derivatives by transition metal catalyzed C-H coupling
  • Efficient preparation of o-amidated aryl heterocyclic derivatives by transition metal catalyzed C-H coupling

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Experimental program
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Effect test

Embodiment 1

[0028] Implementation example 1: N Synthesis of -(2-(2-pyridyl)phenyl)benzamide

[0029] (1) Add 2-phenylpyridine (31.0 mg, 0.20 mmol), 3-phenyl-1,4,2-dioxazol-5-one (39.2 mg, 0.24 mmol) sequentially into a clean reactor, Dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (6.3 mg, 0.01 mmol), silver hexafluoroantimonate (13.7 mg, 0.04 mmol), 1-butyl-3-methyl Imidazolium tetrafluoroborate (0.4 mL), stirred at room temperature for 1 hour.

[0030] (2) After the reaction was completed, ether was added for extraction (1 mL×5), the ether layer was collected, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) After purification, 48.3 mg of the target product was obtained as a white solid with a yield of 88%. Melting point: 107-108 o C; 1 H NMR (400 MHz, DMSO- d 6 ) δ8.81 (d, J = 4.0 Hz, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.05-7.94 (m, 5H), 7.61 (d, J = 8.0 Hz, 3H)...

Embodiment 2

[0031] Implementation example 2: 4-chloro- N Synthesis of -(2-(2-pyridyl)phenyl)benzamide

[0032] (1) Add 2-(4-chlorophenyl)pyridine (37.9 mg, 0.20 mmol), 3-phenyl-1,4,2-dioxazol-5-one (39.2 mg , 0.24 mmol), dichloro(pentamethylcyclopentadienyl) rhodium (III) dimer (6.3 mg, 0.01 mmol), silver hexafluoroantimonate (13.7 mg, 0.04 mmol), 1-butyl -3-Methylimidazolium tetrafluoroborate (0.4 mL), stirred at room temperature for 1 hour.

[0033] (2) After the reaction was completed, ether was added for extraction (1 mL×5), the ether layer was collected, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) After purification, 59.3 mg of the target product was obtained as a white solid with a yield of 96%. Melting point: 153-155 o C; 1 H NMR (400 MHz, DMSO- d 6 ) δ8.82 (d, J = 4.0 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.04-8.02(m, 2H), 7.98-7.95 (m, 3H), 7.68 (d, J =8.0 H...

Embodiment 3

[0034] Implementation example 3: N -(2-(1 H Synthesis of -pyrrolyl)phenyl)benzamide

[0035] (1) Add 1-phenylpyrazole (28.8 mg, 0.20 mmol) and 3-phenyl-1,4,2-dioxazol-5-one (39.2 mg, 0.24 mmol) sequentially into a clean reactor , dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (6.3 mg, 0.01 mmol), silver hexafluoroantimonate (13.7 mg, 0.04 mmol), 1-butyl-3-methano imidazolium tetrafluoroborate (0.4 mL), stirred at room temperature for 3 hours.

[0036] (2) After the reaction was completed, ether was added for extraction (1 mL×5), the ether layer was collected, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) After purification, 47.1 mg of the target product was obtained as a white solid with a yield of 90%. Melting point: 126-128 o C; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.24 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 2.0 ...

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Abstract

The invention relates to a novel green synthesis method for preparing o-amidated aryl heterocyclic derivatives from an N1,N3-disubstituted imidazole ionic liquid as a solvent and dioxazolone compoundsas an amide source by transition metal catalyzed C-H coupling reaction. Compared with the traditional technology, the method is safer, simpler, more efficient and more environmentally friendly; a functional group has good tolerance and high yield; the solvent and a catalyst can be recycled, and the cost is greatly reduced; the by-product is merely carbon dioxide, a large amount of waste is avoided, and the atomic utilization rate is increased; pre-activation of a substrate is not needed, the reaction conditions are mild, and the operation difficulty is reduced. An o-amidated aryl heterocyclicderivative molecular library can be obtained efficiently and quickly, natural compounds can be modified later, and accordingly, new drug candidate molecules are synthesized.

Description

technical field [0001] The present invention relates to a N-based 1 ,N 3 - A new green synthesis method for the efficient preparation of ortho-amidated aryl heterocyclic derivatives by disubstituted imidazole-type ionic liquids as solvents, bisoxazolone compounds as amide sources, and transition metal-catalyzed C-H coupling reactions. Background technique [0002] Ortho-amidated aryl heterocyclic derivatives are a very important class of drugs, natural products, active biomolecules and so on. Its synthesis method research has been highly valued by domestic and foreign academic and industrial circles [see: (a) T. Watanabe, Y. Takahashi, T. Takahashi, H. Nukaya, Y. Terao, T. Hirayama, K. Wakabayashi, Mutation Research , 2002, 519 , 187; (b) W. Kemnitzer, N. Sirisoma, S. Jiang, S. Kasibhatal, C. Crogan-Grundy, B. Tseng, J. Drewe, S. X. Cai, Bioorg. Med. Chem. Lett. 2010, 20 , 1288.]. At present, the method for directly synthesizing o-amidoaryl heterocyclic derivatives...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/40C07D207/09C07D217/14C07D409/04C07D405/04C07D401/14
CPCC07D207/09C07D213/40C07D217/14C07D401/14C07D405/04C07D409/04Y02P20/584
Inventor 吴勇海俐余昕玲马强赖睿智
Owner SICHUAN UNIV
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