Synthesis method and application of chiral quinoline-imidazoline ligand

Abstract

The invention relates to a chiral quinoline-imidazoline ligand as well as a synthesis method and application thereof. The synthesis method mainly comprises the following steps: condensing quinoline-8-formic acid and beta-amino alcohol to obtain amide, and then reacting the amide with primary amine under the action of thionyl chloride or / and phosphorus pentachloride to obtain the quinoline-imidazoline ligand. The chiral quinoline-imidazoline ligand can be used for asymmetric bifunctionalization reaction of transition metal catalyzed olefin tethered amine acyl chloride and olefin of halide to synthesize chiral lactam compounds with high yield and high enantioselectivity. The method is green and environment-friendly, the chiral ligand with asymmetric catalytic regulation potential is synthesized from cheap and easily available raw materials by a simple and efficient route, the synthesis reaction speed is high, the yield is high, and the product is stable to water and oxygen and easy to store; and the ligand has important practical application value and potential in the field of asymmetric catalysis.

Description

technical field

[0001] The present invention relates to a synthesis method and application of a quinoline-imidazoline ligand, especially a chiral 8-(4,5-dihydro-1H-imidazolyl) quinoline ligand and its preparation method and The application of the invention in the asymmetric difunctionalization reaction of olefin-tethered amide chloride and halide belongs to the technical field of organic synthesis. Background technique

[0002] Asymmetric catalysis is a very important branch in the field of organic chemistry. Due to its central role in the development of chiral drugs, pesticides and other functional materials, asymmetric catalytic synthesis has developed rapidly in the past few decades, and it is still one of the hotspots that chemists are most concerned about. Metal asymmetric catalytic reactions involve a wider range of asymmetric catalytic reactions that can be carried out, and the structures of chiral compounds that can be synthesized are also diverse and complex. Sinc...

Examples

Embodiment 1

[0085] Embodiment 1: Synthesis of (S)-N-(1-hydroxyl-3,3-dimethyl-but-2-yl)quinoline-8-carboxamide:

[0086]

[0087] Quinoline-8-carboxylic acid (173.1mg, 1mmol) was added to a dry reaction flask of 100mL, replaced by a nitrogen atmosphere, dichloromethane (20mL), N-methylmorpholine (0.30mL, 2.7mmol) were added, and Place the reaction bottle in an ice-water bath, add isobutyl chloroformate (0.15mL, 1.15mmol), stir in an ice-water bath for 1 hour, then add (S)-2-amino-3,3-dimethyl-1-butanol Alcohol (175.8mg, 1.5mmol), returned to room temperature, stirred for 24 hours, and the reaction was complete as monitored by TLC. Add water (20mL) to the reaction solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×3), combine the organic phases, then wash with saturated sodium chloride solution, separate the layers, and dry the organic phase with anhydrous sodium sulfate , concentrated under reduced pressure, column chromatography (petroleum et...

Embodiment 2

[0089] Example 2: Synthesis of (S)-8-(4-tert-butyl-1-p-tolyl-4,5-dihydro-1H-imidazol2-yl)quinoline:

[0090]

[0091] In a 50mL reaction tube, (S)-N-(1-hydroxy-3,3-dimethyl-but-2-yl)quinoline-8-carboxamide (S)-1a-b (1.5mmol) Dissolve in thionyl chloride (1.5mL), reflux at 90°C for 12 hours, until the TLC reaction is complete, desolvate under reduced pressure, the solid does not need further post-treatment, directly add to a 50mL reaction tube, add ether (10mL) to dissolve, add Triethylamine (15mmol) was added to p-methylaniline (1.65mmol), and stirred at room temperature for 12 hours until the TLC reaction was complete. Add 10% sodium hydroxide solution to the reaction solution to quench, extract with dichloromethane (30mL×3), combine the organic phases, then wash with saturated sodium chloride solution, separate the layers, dry the organic phase with anhydrous sodium sulfate, reduce Concentrate under reduced pressure, and column chromatography (dichloromethane / methanol=10...

Embodiment 3

[0092] Example 3: Synthesis of (S)-8-(4-tert-butyl-1-phenyl-4,5-dihydro-1H-imidazol2-yl)quinoline:

[0093]

[0094] The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2mmol, light yellow solid, 43.8mg, yield 66%, 1 H NMR (400MHz, CDCl 3 ): δ8.74(dd, J=4.0, 1.6Hz, 1H), 8.07(dd, J=8.4, 1.6Hz, 1H), 7.95(d, J=7.2Hz, 1H), 7.87(d, J= 8.4,1H),7.56(t,J=7.6Hz,1H),7.29(dd,J=8.0,4.0Hz,1H),6.92(t,J=8.0Hz,2H),6.77(d,J=7.2 Hz, 1H), 6.67(d, J=8.0Hz, 1H), 4.31-4.19(m, 2H), 3.96(dd, J=8.4, 7.6Hz, 1H), 1.11(s, 9H); 13 C NMR (100MHz, CDCl 3 ):δ161.2,150.8,145.9,141.0,136.0,131.3,130.4,128.5,128.2,126.3,123.1,121.5,120.5,72.3,53.2,34.6,26.1; HRMS(ESI):[M+H] + Calcd for C 22 h 24 N 3 + :330.1965; found: 330.1967.

technical field

[0001] The present invention relates to a synthesis method and application of a quinoline-imidazoline ligand, especially a chiral 8-(4,5-dihydro-1H-imidazolyl) quinoline ligand and its preparation method and The application of the invention in the asymmetric difunctionalization reaction of olefin-tethered amide chloride and halide belongs to the technical field of organic synthesis. Background technique

[0002] Asymmetric catalysis is a very important branch in the field of organic chemistry. Due to its central role in the development of chiral drugs, pesticides and other functional materials, asymmetric catalytic synthesis has developed rapidly in the past few decades, and it is still one of the hotspots that chemists are most concerned about. Metal asymmetric catalytic reactions involve a wider range of asymmetric catalytic reactions that can be carried out, and the structures of chiral compounds that can be synthesized are also diverse and complex. Sinc...

Examples

Embodiment 1

[0085] Embodiment 1: Synthesis of (S)-N-(1-hydroxyl-3,3-dimethyl-but-2-yl)quinoline-8-carboxamide:

[0086]

[0087] Quinoline-8-carboxylic acid (173.1mg, 1mmol) was added to a dry reaction flask of 100mL, replaced by a nitrogen atmosphere, dichloromethane (20mL), N-methylmorpholine (0.30mL, 2.7mmol) were added, and Place the reaction bottle in an ice-water bath, add isobutyl chloroformate (0.15mL, 1.15mmol), stir in an ice-water bath for 1 hour, then add (S)-2-amino-3,3-dimethyl-1-butanol Alcohol (175.8mg, 1.5mmol), returned to room temperature, stirred for 24 hours, and the reaction was complete as monitored by TLC. Add water (20mL) to the reaction solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×3), combine the organic phases, then wash with saturated sodium chloride solution, separate the layers, and dry the organic phase with anhydrous sodium sulfate , concentrated under reduced pressure, column chromatography (petroleum et...

Embodiment 2

[0089] Example 2: Synthesis of (S)-8-(4-tert-butyl-1-p-tolyl-4,5-dihydro-1H-imidazol2-yl)quinoline:

[0090]

[0091] In a 50mL reaction tube, (S)-N-(1-hydroxy-3,3-dimethyl-but-2-yl)quinoline-8-carboxamide (S)-1a-b (1.5mmol) Dissolve in thionyl chloride (1.5mL), reflux at 90°C for 12 hours, until the TLC reaction is complete, desolvate under reduced pressure, the solid does not need further post-treatment, directly add to a 50mL reaction tube, add ether (10mL) to dissolve, add Triethylamine (15mmol) was added to p-methylaniline (1.65mmol), and stirred at room temperature for 12 hours until the TLC reaction was complete. Add 10% sodium hydroxide solution to the reaction solution to quench, extract with dichloromethane (30mL×3), combine the organic phases, then wash with saturated sodium chloride solution, separate the layers, dry the organic phase with anhydrous sodium sulfate, reduce Concentrate under reduced pressure, and column chromatography (dichloromethane / methanol=10...

Embodiment 3

[0092] Example 3: Synthesis of (S)-8-(4-tert-butyl-1-phenyl-4,5-dihydro-1H-imidazol2-yl)quinoline:

[0093]

[0094] The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2mmol, light yellow solid, 43.8mg, yield 66%, 1 H NMR (400MHz, CDCl 3 ): δ8.74(dd, J=4.0, 1.6Hz, 1H), 8.07(dd, J=8.4, 1.6Hz, 1H), 7.95(d, J=7.2Hz, 1H), 7.87(d, J= 8.4,1H),7.56(t,J=7.6Hz,1H),7.29(dd,J=8.0,4.0Hz,1H),6.92(t,J=8.0Hz,2H),6.77(d,J=7.2 Hz, 1H), 6.67(d, J=8.0Hz, 1H), 4.31-4.19(m, 2H), 3.96(dd, J=8.4, 7.6Hz, 1H), 1.11(s, 9H); 13 C NMR (100MHz, CDCl 3 ):δ161.2,150.8,145.9,141.0,136.0,131.3,130.4,128.5,128.2,126.3,123.1,121.5,120.5,72.3,53.2,34.6,26.1; HRMS(ESI):[M+H] + Calcd for C 22 h 24 N 3 + :330.1965; found: 330.1967.

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