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Efficient synthesis of β-position chiral bicyclic or polycyclic imidazole derivatives

A technology of polycyclic imidazoles and derivatives, applied in the field of asymmetric catalysis applications, can solve the problems of strict operation, expensive system, harsh conditions and the like

Active Publication Date: 2021-05-28
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In summary, although bicyclic or polycyclic imidazole derivatives with chirality at the β position are ubiquitous in the field of asymmetric catalysis of biologically active molecules and chiral small molecules, the existing synthetic methods are cumbersome or require strict operations. , or the system is expensive, the production cost is high, the conditions are harsh, and the common drawback is that chiral target products need to be resolved to obtain chiral target products, which makes large-scale production face many difficulties

Method used

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  • Efficient synthesis of β-position chiral bicyclic or polycyclic imidazole derivatives
  • Efficient synthesis of β-position chiral bicyclic or polycyclic imidazole derivatives
  • Efficient synthesis of β-position chiral bicyclic or polycyclic imidazole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Synthesis of (R)-3-Propyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0030]

[0031] In a nitrogen atmosphere, add ligand L1 (9.6mg, 5mol%), Ni(cod) 2 (2.8mg, 5mol%), E-1a or Z-1a (40.0mg, 0.2mmol), toluene (2.0mL), then added trimethylaluminum (1M, 40μL, 20mol%), stirred at 100°C for 1 hours, cooled to room temperature, added ethyl acetate to dilute, added 2 mL of 5% ethylenediaminetetraacetic acid disodium salt solution for washing, separated liquids, dried the organic phase with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain the target product 2a , white solid, yield (88%, E-1a as raw material; 92%, Z-1a as raw material). 1 H NMR (400MHz, CDCl 3 )δ7.75-7.69(m,1H),7.32-7.27(m,1H),7.24-7.17(m,2H),4.17-4.08(m,1H),4.05-3.96(m,1H),3.32- 3.22(m,1H),2.91-2.81(m,1H),2.38-2.29(m,1H),2.05-1.96(m,1H),1.68-1.48(m,3H),1.01-0.97(t,J =7.0Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ164.0, 148.7, 132.3, 121.9, 121.7, 119.8, 10...

Embodiment 2

[0032] Example 2: Synthesis of (R)-3-Hexyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0033]

[0034] In a nitrogen atmosphere, add ligand L1 (9.6mg, 5mol%), Ni(cod) 2(2.8mg, 5mol%), 1b (48.4mg, 0.2mmol), toluene (2.0mL), then added trimethylaluminum (1M, 40μL, 20mol%), stirred at 100°C for 1 hour, cooled to room temperature, Add ethyl acetate to dilute, add 2 mL of 5% ethylenediaminetetraacetic acid disodium saline solution to wash, separate liquids, dry the organic phase with anhydrous sodium sulfate, concentrate and separate by column chromatography to obtain the target product 2b, a white solid, yield (87%). 1 H NMR (400MHz, CDCl 3 )δ7.75-7.69(m,1H),7.32-7.27(m,1H),7.24-7.17(m,2H),4.16-4.10(m,1H),4.03-3.97(m,1H),3.29- 3.22(m,1H),2.90-2.82(m,1H),2.38-2.29(m,1H),2.09-1.99(m,1H),1.67-1.45(m,3H),1.40-1.24(m,6H ),0.88(t,J=6.8Hz,3H). 13 CNMR (100MHz, CDCl 3 )δ164.0, 148.8, 132.3, 121.8, 121.7, 119.8, 109.5, 42.1, 36.3, 33.4, 33.3, 31.8, 29.4, 27.4, 22.8, 14.2. HRM...

Embodiment 3

[0035] Example 3: Synthesis of (R)-3-Phenethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0036]

[0037] In a nitrogen atmosphere, add ligand L1 (9.6mg, 5mol%), IPr·HCl (4.3mg, 5mol%), Ni(cod) 2 (5.6mg, 10mol%), 1c (52.4mg, 0.2mmol), toluene (2.0mL), then added trimethylaluminum (1M, 40μL, 20mol%), stirred at 100°C for 5 hours, cooled to room temperature, Add ethyl acetate to dilute, add 2 mL of 5% ethylenediaminetetraacetic acid disodium saline solution to wash, separate liquids, dry the organic phase with anhydrous sodium sulfate, concentrate and separate by column chromatography to obtain the target product 2c, a white solid, yield ( 92%). 1 H NMR (400MHz, CDCl 3 )δ7.73(d,J=7.2Hz,1H),7.32-7.25(m,5H),7.23-7.15(m,3H),4.18-4.08(m,1H),4.03-3.95(m,1H) ,3.31-3.23(m,1H),2.97-2.78(m,3H),2.43-2.32(m,2H),1.99-1.90(m,1H). 13 C NMR (100MHz, CDCl 3 )δ163.6, 148.8, 141.5, 132.3, 128.6, 128.5, 126.1, 121.9, 121.8, 119.9, 109.6, 42.0, 35.6, 35.0, 33.6, 33.4. 18 h 19 N 2 (...

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Abstract

The invention relates to a class of imidazole derivatives substituted with homoallyl groups through intramolecular carbon-hydrogen bond cyclization to efficiently prepare bicyclic or polycyclic imidazole derivatives with β-position chirality in one step, and belongs to the technical field of asymmetric catalysis applications. The key to solving the problem of the present invention is: 1. Find a chiral ligand that is highly efficient and specific to reactivity, site selectivity and corresponding selectivity, so that the reaction can be efficiently obtained in one step with specific high yield and high corresponding Selective β-position chiral imidazole derivatives; 2. Utilize the characteristics of the ligands to design a bimetallic catalytic system, which greatly improves the reactivity and makes it easier to prepare efficiently.

Description

technical field [0001] The invention relates to a method for synthesizing β-position chiral bicyclic or polycyclic imidazole derivatives starting from homoallyl substituted imidazole or benzimidazole derivatives, which belongs to the technical field of asymmetric catalysis application. Background technique [0002] β-chiral bicyclic or polycyclic imidazole skeletons are ubiquitous in the field of asymmetric catalysis of bioactive molecules and chiral small molecules, so they have high application value in bioactivity research and reaction catalysis research. Through this method, not only a series of β-position chiral bicyclic imidazole structures can be conveniently synthesized; a series of β-position chiral tricyclic benzimidazole structures substituted by halogen, alkyl, alkoxy, ester group, etc.; β-position chiral tricyclic pyridoimidazole structure, theophylline skeleton structure, and β-position chiral tetracyclic naphthalene cycloimidazole structure; it is also possibl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D471/14
CPCC07D471/14C07D487/04
Inventor 叶萌春王银霞
Owner NANKAI UNIV