Method for synthesizing difluorohydromethylated 2, 3-dihydrobenzopyran-4-one derivative

A technology of dihydrobenzopyran and difluorohydromethyltriphenylphosphine bromide, which is applied in the fields of chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., and can solve the problems of high toxicity and environmental hazards of individual reagents Large, high reaction temperature and other issues, to achieve the effect of a wide range of substrates, safety and environmental friendliness, and mild reaction conditions

Pending Publication Date: 2022-08-05
SHANGRAO NORMAL UNIV
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Problems solved by technology

However, the above-mentioned synthesis methods often have some disadvantages to varying degrees: high reaction temperature, poor chemical regioselectivity, use of expensive metal catalysts, high toxicity of individual reagents, serious environmental pollution, low reaction yield; and most methods The functional groups introduced on the molecular skeleton of 2,3-dihydrochroman-4-one are relatively limited
However, only three substrates have been reported for the synthesis of difluorohydromethylated 2,3-dihydrochromen-4-one derivatives in this method, and the photosensitizer (Ir[ dF(CF 3 )ppy] 2 (dtbpy)PF 6 ) is complex and cumbersome to synthesize (need to operate in a glove box), and is not commercialized. It has strong corrosiveness, pungent smell and toxicity, and difluoroacetic acid, which is harmful to the environment, is used as a difluorohydromethylation reagent, which limits Its application in actual production

Method used

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  • Method for synthesizing difluorohydromethylated 2, 3-dihydrobenzopyran-4-one derivative
  • Method for synthesizing difluorohydromethylated 2, 3-dihydrobenzopyran-4-one derivative
  • Method for synthesizing difluorohydromethylated 2, 3-dihydrobenzopyran-4-one derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] At room temperature, magneton, 2-allyloxybenzaldehyde (0.2mmol, 32.5mg), difluorohydromethyltriphenylphosphine bromide (0.3mmol, 117.6mg) and fac- Ir(ppy) 3 (0.004mmol, 2.62mg) after three vacuum changes of argon, add 2,6-Lutidine (0.3mmol, 32.2mg) and 2mL DMSO, react under 5W blue light irradiation for 24h, after the reaction, add 10mL water, ethyl acetate ( 15mL*3) extraction, the organic phases were combined, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, and separated and purified by column chromatography to obtain this example 3-(2,2-difluoroethyl) -2,3-Dihydrobenzopyran-4-one product 36.1 mg, yield 85%, colorless liquid. 1 H NMR (400MHz, CDCl 3 )δ7.89(dd,J=7.9,1.4Hz,1H),7.52–7.45(m,1H),7.03(t,J=7.5Hz,1H),6.98(d,J=8.4Hz,1H), 6.14(tdd, J=56.7,5.4,3.2Hz,1H),4.72-4.57(m,1H),4.23(t,J=11.7Hz,1H),3.08(td,J=11.8,5.9Hz,1H) ,2.67–2.39(m,1H),2.00–1.78(m,1H). 13 C NMR (101MHz, CDCl 3 )δ192.49,161.56, 136.17,127.38,121.60...

Embodiment 2

[0026]

[0027] At room temperature, in a 25ml reaction tube were sequentially added magneton, 2-allyloxy-3-methylbenzaldehyde (0.2mmol, 35.4mg), difluorohydromethyltriphenylphosphine bromide (0.3mmol, 117.6 mg) and fac-Ir (ppy) 3 (0.004mmol, 2.62mg) after three vacuum changes of argon, add 2,6-Lutidine (0.3mmol, 32.2mg) and 2mL DMSO, react under 5W blue light irradiation for 24h, after the reaction, add 10mL water, ethyl acetate ( 15mL*3) extraction, the organic phases were combined, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, and separated and purified by column chromatography to obtain the present example 8-methyl-3-(2,2- Difluoroethyl)-2,3-dihydrobenzopyran-4-one product 31.4 mg, yield 70%, colorless liquid. 1 H NMR (400MHz, CDCl 3 ) δ7.74(dd,J=7.9,1.2Hz,1H),7.42-7.30(m,1H),6.93(t,J=7.6Hz,1H),6.15(tdd,J=56.7,5.5,3.2Hz ,1H),4.67(dd,J=11.4,5.2Hz,1H),4.23(t,J=11.7Hz,1H),3.06(qd,J=6.7,1.0Hz,1H),2.52(ddddd,J= 23.8, 16.1, 15.0, 5.9...

Embodiment 3

[0029]

[0030] At room temperature, in a 25ml reaction tube were sequentially added magneton, 2-allyloxy-4-methylbenzaldehyde (0.2mmol, 35.4mg), difluorohydromethyltriphenylphosphine bromide (0.3mmol, 117.6 mg) and fac-Ir (ppy) 3 (0.004mmol, 2.62mg) after three vacuum changes of argon, add 2,6-Lutidine (0.3mmol, 32.2mg) and 2mL DMSO, react under 5W blue light irradiation for 24h, after the reaction, add 10mL water, ethyl acetate ( 15mL*3) extraction, the organic phases were combined, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, and separated and purified by column chromatography to obtain the present example 7-methyl-3-(2,2- Difluoroethyl)-2,3-dihydrobenzopyran-4-one product 29.0 mg, yield 64%, colorless liquid. 1 H NMR (400MHz, CDCl 3 ) δ7.77(d,J=8.0Hz,1H),6.85(d,J=8.1Hz,1H),6.78(s,1H),6.14(tdd,J=56.7,5.5,3.2Hz,1H), 4.59(dd,J=11.4,5.2Hz,1H),4.20(t,J=11.6Hz,1H),3.03(td,J=11.9,6.0Hz,1H),2.60 –2.42(m,1H),2.36 (s,3H),1.96–1.78(m,1H)...

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Abstract

According to the method for synthesizing the difluorohydromethylated 2, 3-dihydrobenzopyran-4-one derivative, difluorohydromethyl triphenylphosphonium bromide is adopted as a difluorohydromethylation reagent, tris (2-phenylpyridine) iridium is adopted as a photocatalyst, and the difluorohydromethylated 2, 3-dihydrobenzopyran-4-one derivative is synthesized under the conditions of alkali and illumination. According to the invention, difluoromethyl triphenylphosphonium bromide which is stable and easy to obtain is used as a difluoromethylation reagent, so that the defects of strong corrosivity, irritation and toxicity of difluoroacetic acid are overcome. The stable, easily available and commercialized tris (2-phenylpyridine) iridium is used for replacing (Ir [dF (CF3) ppy] 2 (dtbpy) PF6) as a photocatalyst, so that the tedious synthesis of a complex photocatalyst is avoided. The method has the advantages of simple process flow, easily available raw materials, mild reaction conditions, simple and efficient operation, wide substrate application range, stable and easily controllable process, safety and environmental friendliness, and is suitable for industrial production.

Description

technical field [0001] A method for synthesizing difluorohydromethylated 2,3-dihydrobenzopyran-4-one derivatives of the present invention involves stabilizing and readily available difluorohydromethyltriphenyl bromide under visible light irradiation conditions. Phosphine is a difluorohydromethylation reagent, and commercial tris(2-phenylpyridine) iridium is a photocatalyst, which can efficiently realize the tandem difluorohydromethylation cyclization of alkenals, and construct C-CF in one step 2 The invention discloses a method for synthesizing a difluorohydromethylated 2,3-dihydrobenzopyran-4-one derivative with an H bond and a C-C(O) bond, which specifically belongs to the technical field of organic synthesis. Background technique [0002] 2,3-Dihydrobenzopyran-4-one skeleton structure molecules widely exist in various pharmaceutical intermediates, natural products and biologically active molecules, and are the building blocks for the synthesis of various complex and valua...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/22C07D311/86C07C67/347C07C69/757
CPCC07D311/22C07D311/86C07C67/347C07C2602/28C07C69/757Y02P20/584
Inventor 毛刘量陈理温小洪全丽霞周安西祝显虹
Owner SHANGRAO NORMAL UNIV
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