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Method for efficiently synthesizing optically active poly-substituted 2,3-dihydrobenzofuran compound through catalysis of asymmetric organic phosphine

A compound, the technology of dihydrobenzene, applied in the direction of organic chemistry, organic chemistry, etc., can solve the problems rarely reported, such as Yang Qingqing et al., and achieve good industrial application prospects, low cost, and small dosage

Active Publication Date: 2018-12-14
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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Problems solved by technology

[0004] Due to the importance of the 2,3-dihydrobenzofuran structure, researchers have developed a variety of legitimate methods to construct this framework, such as asymmetric hydrogenation, metal-mediated transformation, organocatalytic [3+2] cyclization, Intramolecular cyclization, but these methods also have their own shortcomings, so new types of legal methods need to be developed
[0005] O-quinone methides are a class of versatile structural units that can serve as Michael acceptors in conjugate additions and as oxadienes in cyclization reactions, although there are enantiomers of o-quinone methides However, the [4+1] cycloaddition reaction has been reported rarely. Yang Qingqing et al. reported the asymmetry between the in situ generated o-quinone methide and sulfur ylide [4 +1] Cyclization reaction using chiral urea as catalyst to obtain chiral 2,3-dihydrobenzofuran in good yield and moderate enantioselectivity requires 1.0 equivalent of CsF and 1.0 equivalent of 18-crown-6; Han Zhiyong developed a phase-transfer catalyst-mediated enantioselective [4+1] cycloaddition of o-quinone methides and bromomalonic acid to obtain optically active dioxanes in high yields with moderate to high ee values. Hydrobenzofuran, the reaction requires 1.5 equivalents of Cs 2 CO 3 ; Shi Feng et al. established the asymmetric [4+1] cyclization of o-quinone methides with 3-chlorooxindole, with K 2 HPO 4 (2.5 equivalents) and Na 2 SO 4 (7.0 equivalents), in the presence of square amide (30mol%), dihydrobenzofuran was constructed in high yield and high asymmetric selectivity

Method used

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  • Method for efficiently synthesizing optically active poly-substituted 2,3-dihydrobenzofuran compound through catalysis of asymmetric organic phosphine
  • Method for efficiently synthesizing optically active poly-substituted 2,3-dihydrobenzofuran compound through catalysis of asymmetric organic phosphine
  • Method for efficiently synthesizing optically active poly-substituted 2,3-dihydrobenzofuran compound through catalysis of asymmetric organic phosphine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In a sealed tube under nitrogen atmosphere, a mixture of compound la (0.2 mmol), compound 2a (0.3 mmol), catalyst I (0.02 mmol) in MeCN (2.0 mL) was stirred at 25 °C for 4.5 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the corresponding product 3aa.

[0033]

[0034] Yield 70%, dr>20:1, 73% ee.

[0035] 1 H NMR (500Hz, CDCl 3 ): δ (ppm) 7.10 (d, J = 8.5Hz, 2H), 6.85 (d, J = 9.0Hz, 2H), 6.51 (s, 1H), 6.43 (s, 1H), 6.30 (s, 1H) ,5.89-5.87(m,3H),5.31(d,J=5.0Hz,1H),4.30(d,J=5.0Hz,1H),3.78(s,3H),3.74(s,3H). 13 C NMR (126Hz, CDCl 3 ): δ (ppm) 166.0, 158.7, 154.0, 147.9, 142.3, 139.3, 135.5, 128.8, 125.5, 120.8, 114.1, 105.6, 101.4, 93.0, 89.6, 55.4, 54.4, 52.0. HRMS: Accurate mass calculation [M+ H] + (C 20 h 19 o 6 ) is m / z 355.11761, and the measured value is m / z 355.11679.HPLC conditions: Daicel Chiralpak OD-H column, n-hexane / isopropanol=90 / 10, flow rate=1.0mL / min, λ...

Embodiment 2

[0037] In a sealed tube under nitrogen atmosphere, a mixture of compound la (0.2 mmol), compound 2a (0.3 mmol), catalyst II (0.02 mmol) in MeCN (2.0 mL) was stirred at 25 °C for 4.5 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the corresponding product 3aa.

[0038] Yield 60%, dr>20:1, -63% ee.

[0039]

Embodiment 3

[0041] In a sealed tube under nitrogen atmosphere, a mixture of compound la (0.2 mmol), compound 2a (0.3 mmol), catalyst III (0.02 mmol) in MeCN (2.0 mL) was stirred at 25 °C for 4.5 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the corresponding product 3aa.

[0042] Yield 66%, dr>20:1, 80% ee.

[0043]

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Abstract

The invention belongs to the field of an organic synthesis method and discloses a method for efficiently synthesizing an optically active poly-substituted 2,3-dihydrobenzofuran compound through catalysis of asymmetric organic phosphine. A chiral phosphine compound serves as a catalyst, and a compound of a formula A1 or a compound of a formula A2 or a compound of a formula B perform reaction to obtain a compound of a formula C1 or a compound of a formula C2 separately (the formulas are as shown in the specification), wherein R1 is alkyl, R2 is alkyl or benzyl, R3 is alkyl, R4 is hydrogen, halogen or alkoxy and R5 is hydrogen, halogen or alkoxy. According to the method, the catalytic effect is good; Morita-Baylis-Hillman carbonic ester reacts with an o-quinone methyl compound to obtain a series of 2,3-dihydrobenzofuran with optical activity; and the method is high in yield, high in stereoselectivity, high in catalytic efficiency, simple to operate and low in cost, and has a very good industrialized application prospect.

Description

technical field [0001] The invention belongs to the field of organic synthesis methods, in particular to a method for efficiently synthesizing optically active multi-substituted 2,3-dihydrobenzofuran compounds by catalyzing an asymmetric organophosphine. Background technique [0002] The 2,3-dihydrobenzofuran ring structure is the core skeleton of many important natural products and drugs. For example, the natural product megapodiol is a potential anti-leukemia drug. Tremetone and hydroxytremetone isolated from Eupatorium urticaefolium have insecticidal properties. Hydroxytremetone It also has anti-HIV activity, allergy activity, and plant growth inhibitory activity. [0003] [0004] Due to the importance of the 2,3-dihydrobenzofuran structure, researchers have developed a variety of legitimate methods to construct this framework, such as asymmetric hydrogenation, metal-mediated transformation, organocatalytic [3+2] cyclization, Intramolecular cyclization, but these met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04C07D307/80
CPCC07B2200/07C07D307/80C07D493/04
Inventor 李鹏飞程玉宇方志强
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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