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Synthesis of spiro-ring bis-boron catalyst and application thereof in hydrogenation reaction

A catalyst and spiro ring technology, which is applied in the synthesis of spiro diene compounds, can solve the problems of limited chiral boron catalysts, and achieve the effects of solving heavy metal residues, high reactivity, and mild reaction conditions

Active Publication Date: 2019-04-05
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this field is still in its infancy, and the reported chiral boron catalysts are still very limited, and the asymmetric hydrogenation reactions of many heterocyclic compounds have not been well solved. Therefore, the development of new and efficient chiral catalysts is the research field of this field. an important content

Method used

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  • Synthesis of spiro-ring bis-boron catalyst and application thereof in hydrogenation reaction
  • Synthesis of spiro-ring bis-boron catalyst and application thereof in hydrogenation reaction
  • Synthesis of spiro-ring bis-boron catalyst and application thereof in hydrogenation reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Synthesis of Chiral Spirodiene 3a

[0025]

[0026] The first step: resolution of spiro[4.4]-1,6-nonanedione

[0027] (R)-Phenylethylaminooxalazide (4.15 g, 2 eq) was added to a dry 250 mL round bottom flask, followed by 1.52 g of racemic spiro[4.4]-1,6-nonanedione and a small pellet of iodine Simple substance, add 120mL of anhydrous dichloromethane under the protection of argon, install a water separator and reflux condenser, and heat to reflux overnight. After the reaction, the system was cooled to room temperature, and the insoluble solid was removed by diatomaceous earth filtration, and the dichloromethane was removed by rotary evaporation under reduced pressure to obtain a yellow solid crude product, which was recrystallized and purified from anhydrous ethanol to obtain 3.5 g of a white powdery solid dihydrazone compound intermediate , yield 66%.

[0028] 2.0 g of the spirodione dihydrazone compound intermediate was added to a 500 mL eggplant-shaped...

Embodiment 2

[0034] Example 2: Synthesis and identification of spirocyclic bis-boron catalyst 4a

[0035]

[0036] In the glove box, 3a (13.6mg, 0.05mmol), HB(C 6 f 5 ) 2 (34.6mg, 0.1mmol) and toluene (1.0mL), react at 25°C for 15 minutes. Isoquinoline (25.8mg, 0.2mmol) and toluene (0.5mL) were added again, and the reaction was continued at 25°C for 30 minutes. After the reaction was over, the toluene was distilled off under reduced pressure to obtain a white powdery solid, which was added with the internal standard CH 2 Br 2 ,pass 1 H NMR judged that the NMR yield was 95%. The crude product was recrystallized from dichloromethane and n-hexane to obtain product 4a·2L. 1 H NMR (400MHz, CD 2 Cl 2 )δ8.74(s, 2H), 8.04(d, J=6.8Hz, 2H), 7.83(t, J=7.5Hz, 2H), 7.74(d, J=8.1Hz, 2H), 7.62(t, J=7.4Hz, 2H), 7.59-7.30(m, 8H), 7.16(t, J=7.1Hz, 2H), 6.87(br, 2H), 6.69(br, 2H), 2.92(t, J=9.6 Hz, 2H), 2.32-2.18(m, 2H), 2.14(d, J=9.0Hz, 2H), 1.80-1.54(m, 4H), 0.86(dd, J=19.2, 11.5Hz, 2H); 13 ...

Embodiment 3

[0037] Example 3: Synthesis of (R)-2-Methyl-1,2,3,4-tetrahydroquinoline (P1)

[0038]

[0039] Spirochiral diene 3a (3.4mg, 0.0125mmol, 5mol%) and HB(C 6 f 5 ) 2 (8.65 mg, 0.025 mmol, 10 mol%) was added to a 10 mL small test tube, 2 mL of trifluorotoluene was added to dissolve, and the reaction was carried out at 25°C for 15 minutes. The system was cooled to room temperature, then 2-methylquinoline S1 (35.8mg, 0.25mmol) and 3mL benzotrifluoride were added, and then the test tube was transferred to the autoclave, after replacing the hydrogen three times, and finally filled with hydrogen to 50bar,- Reaction at 20°C for 24h. After the reaction, hydrogen was released, the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography to obtain the hydrogenated product P1, a colorless oily liquid, with a yield of 97% and an enantioselectivity of 90% ee. 1 H NMR (400MHz, CDCl 3 )δ7.00-6.95 (m, 2H), 6.68-6.59 (m, 1H),...

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Abstract

The invention relates to a synthesis of spiro-ring diene compound with C2 symmetry, and a a series of chirality spiro-ring bis-boron catalysts prepared by virtue of the reaction of the spiro-ring diene compound and boron hydrides. The spiro-ring bis-boron catalysts have high activity and enantioselectivity in the asymmetric hydrogenation reaction of quinoline compounds, and belong to the technicalfield of application. By adopting the synthesis of spiro-ring bis-boron catalyst and the application thereof in hydrogenation reaction, the problems of the traditional quinoline asymmetric hydrogenation reaction method that precious metal catalysts are used and the functional groups are poor in tolerance can be mainly solved, the nonmetal catalytic quinoline asymmetric hydrogenation reaction canbe realized, the reaction substrate range is wide, and the functional group tolerance is high. The synthesis of spiro-ring bis-boron catalyst and the application thereof in hydrogenation reaction areused in the medicine research and chemical production.

Description

technical field [0001] The present invention relates to a novel class of C 2 Synthesis of symmetrical spiro diene compounds, and then in situ preparation of spiro bis-boron catalysts by hydroboration reaction, this type of spiro bis-boron catalysts showed high activity and enantiotropic Selectivity belongs to the field of organic chemical synthesis methodology research and application technology. Background technique [0002] In 2006, Professor D.W.Stephan of the University of Toronto discovered that B(C 6 f 5 ) 3 Can not form classic Lewis acid-base adducts with bulky bases (tri-tert-butylphosphine), but exist in the form of acid-base pairs, which can activate hydrogen at room temperature and can Reduction of some unsaturated compounds. Based on this, some chiral boron catalysts have been synthesized and applied in the asymmetric hydrogenation of various substrates (as shown in the following formula). However, this field is still in its infancy, and the reported chira...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02B01J31/14C07D215/06
CPCB01J31/146B01J2231/646C07B2200/07C07D215/06C07F5/027
Inventor 王晓晨李祥田俊杰
Owner NANKAI UNIV
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