N-heterocyclic carbene catalytic functionalized imine as novel 1, 4-dipole synthon and synthesis application thereof

A nitrogen-heterocyclic carbene and synthon technology, applied in the field of preparation of chiral nitrogen-heterocyclic compounds by 4+2 cyclization reaction, achieves the effects of reduced synthesis cost, good substrate universality, and mild conditions

Active Publication Date: 2021-05-11
NANJING UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are few reports on the reaction of imines with similar electronic properties to aldehydes, and the asymmetric catalytic activation of imines is a great challenge.

Method used

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  • N-heterocyclic carbene catalytic functionalized imine as novel 1, 4-dipole synthon and synthesis application thereof
  • N-heterocyclic carbene catalytic functionalized imine as novel 1, 4-dipole synthon and synthesis application thereof
  • N-heterocyclic carbene catalytic functionalized imine as novel 1, 4-dipole synthon and synthesis application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The following preparation method was adopted to prepare (S)-IV01:

[0057] Add aldimine I (0.12mmol), NHC B (4.8mg, 20mol%), K 3 PO 4 (31.8mg, 0.15mmol), DQ (44.8mg, 0.11mmol), MS (100 mg), then 1 mL of dichloromethane was added to the mixture as a solvent, and finally 1.0 times the amount of trifluoroacetophenone was added to the system. The reaction system was stirred at room temperature for 48 hours. After the completion of the reaction was monitored by TLC, the reaction mixture was separated and purified using a silica gel column. The eluent was ethyl acetate / petroleum ether / dichloromethane=1:8:1, and the product was a white solid. (S)-2,4-diphenyl-4-(trifluoromethyl)-4H-benzo[4,5]imidazo[1,2-c][1,3,5]oxadiazine: 85% yield, 93:7er.HPLC condition: Chiralpak IA (Hex / iPrOH=85 / 15, 1.0mL / min, t R (major)=17.7min,t R (minor) = 16.3min.

[0058] 1 H NMR (400MHz, CDCl 3 )δ8.24(d, J=7.2Hz, 2H), 7.77(d, J=7.6Hz, 1H), 7.73(d, J=7.6Hz, 2H), 7.63-7.59(m, 2H), 7.55- 7...

Embodiment 2

[0108] The following preparation method was adopted to prepare (R)-IV01:

[0109]Add aldimine I (0.12mmol), NHC C (4.8mg, 10mol%), Urea V (9.8mg, 20mol%), K 3 PO 4 (31.8mg, 0.15mmol), DQ (44.8mg, 0.11mmol), MS (100mg), then dichloromethane / n-hexane=(v / v=1:1, 0.1M) was added to the mixture as a solvent, and finally 1.0 times the amount of trifluoroacetophenone was added to the system. The reaction system was stirred at 0°C for 48 hours. After the completion of the reaction was monitored by TLC, the reaction mixture was separated and purified using a silica gel column. The eluent was petroleum ether / dichloromethane=1:6, and the product was a white solid.

[0110] (R)-2,4-diphenyl-4-(trifluoromethyl)-4H-benzo[4,5]imidazo[1,2-c][1,3,5]oxadiazine: 91% yield, 94:6er.HPLC condition: Chiralpak IA (Hex / iPrOH=85 / 15, 1.0mL / min, t R (major)=16.6min,t R (minor) = 17.9min.[α] D 25 (c 1.0, CHCl 3 ) = -53.3.

[0111] 1 H NMR (400MHz, CDCl 3 )δ8.24(d, J=7.2Hz, 2H), 7.77(d, J=7.6H...

Embodiment 3

[0163] Adopt the following preparation method to prepare VII01:

[0164] Add aldimine I (0.12mmol), NHC C (4.8mg, 10mol%), Urea V (9.8mg, 20mol%), K 3 PO 4 (31.8mg, 0.15mmol), DQ (44.8mg, 0.11mmol), MS (100mg) and N-Bn isatin 0.1mmol, then dichloromethane / n-hexane=(v / v=1:1, 0.1M) was added to the mixture as a solvent, and the reaction system was stirred at 0°C for 48 hours, After the completion of the reaction was monitored by TLC, the reaction mixture was separated and purified using a silica gel column, the eluent was ethyl acetate / petroleum ether / dichloromethane=1:4:1, and the product was a white solid.

[0165] (R)-1'-Benzyl-2-phenylspiro[benzo[4,5]imidazo[1,2-c][1,3,5]oxadiazine-4,3'-indole] -2'-Kone:96%yield,99:1er.[α] D 25 (c 1.0, CHCl 3 )=-64.8, HPLC condition: Chiralpak IA (Hex / iPrOH=70 / 30, 1.0mL / min, t R (major)=42.0min,t R (minor)=20.5min).

[0166] 1 H NMR (400MHz, CDCl 3)δ8.23(d,J=8.0Hz,2H),7.77(d,J=8.0Hz,1H),7.60-7.45(m,5H),7.32-7.18(m,7H),6.97(d,J ...

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Abstract

The invention relates to an N-heterocyclic carbene catalytic functionalized imine as a novel 1, 4-dipole synthon and application thereof, and belongs to the field of chemical synthesis. Under the mild reaction condition, a chiral N-heterocyclic carbene catalyst is used for catalyzing and activating aldimine, a novel aza 1, 4-dipole synthon is obtained under the oxidation condition, and the novel organic synthon can be further subjected to 4 + 2 cyclization reaction with trifluoroacetophenone, isatin and an isatin-derived imine substrate to generate a heterocyclic compound with a novel structure and a chiral quaternary carbon center. According to the method disclosed by the invention, the N-heterocyclic carbene catalyst with the same chiral configuration and an achiral thiourea catalyst are used for co-catalysis, so that three-dimensional diverse synthesis of the trifluoroacetophenone compound can be realized. The method is mild in condition and efficient in reaction and has good substrate universality, and the reported aldimine-derived 1, 4-aza dipole synthon provides an important method for synthesizing various functional nitrogen heterocyclic compounds and has the potential of being applied to industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a nitrogen heterocyclic carbene catalytic functionalized aldimine as a novel 1,4-dipolar synthon and its application to a 4+2 ring closure reaction to prepare a chiral nitrogen heterocyclic compound . Background technique [0002] Asymmetric catalysis is the most important method for the preparation of chiral compounds. As an important class of organic small molecule catalysts, nitrogen heterocyclic carbene has played an important role in the field of catalytic synthesis of chiral molecules in recent years and has achieved rapid development. However, most of the reported reaction types are based on the catalytic activation of aldehydes and their ester derivatives by nitrogen heterocyclic carbene. However, the catalytic reaction of imines with similar electronic properties to aldehydes is rarely reported, and the asymmetric catalytic activation of imines is a great challenge. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07D498/20C07D487/20
CPCC07D498/04C07D498/20C07D487/20
Inventor 付振乾王冠杰
Owner NANJING UNIV OF TECH
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