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Preparation method of α,α-disubstituted isochromans

A technology of isochromans and compounds, which is applied in the field of preparation of α,α-disubstituted isochromans, can solve sensitivity and other problems, and achieve the effects of simple operation, short reaction steps and mild reaction conditions

Active Publication Date: 2021-02-12
XI'AN PETROLEUM UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, the DDQ oxidizer used is sensitive to water and releases highly toxic substances, and the substrate used involves toxic cyanide

Method used

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  • Preparation method of α,α-disubstituted isochromans
  • Preparation method of α,α-disubstituted isochromans
  • Preparation method of α,α-disubstituted isochromans

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Taking the preparation of the following formula compound 1-nitromethyl-1-phenylisochroman as an example, the raw materials used and the preparation method thereof are as follows:

[0037]

[0038] Mix 161mg (0.6mmol) of 1-phenylisochroman and 238mg (0.72mmol) of triphenylmethyltetrafluoroborate in dichloroethane at 20°C, stir the reaction for 1 hour, and add 160uL (3.0mmol ) nitromethane, reacted at 80°C for 24 hours, after the reaction was completed, 2 mL of distilled water was added to the system, extracted three times with 10 mL of dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, suction filtered, concentrated, the crude product Separation by column chromatography (dichloromethane and n-hexane) afforded 1-nitromethyl-1-phenylisochroman as a white solid with a yield of 95%.

[0039] The NMR characterization data are: 1 H NMR (600MHz, CDCl 3 )δ7.40–7.39(m,2H),7.36–7.26(m,7H),5.06(d,J=12.1Hz,1H),4.88(d,J=12.1Hz,1H),4.05(ddd,J ...

Embodiment 2

[0041] Taking the preparation of the following formula compound 1-nitromethyl-1-p-tert-butylphenylisochroman as an example, the raw materials used and the preparation method thereof are as follows:

[0042]

[0043] In Example 2, the 1-phenylisochroman used in Example 1 was replaced with equimolar 1-tert-butylphenylisochroman, and the other steps were the same as in Example 1 to prepare a white solid, which The yield was 92%.

[0044] The NMR characterization data are: 1H NMR (600MHz, CDCl 3 )δ8.20(d, J=8.8Hz, 2H), 7.65(d, J=8.8Hz, 2H), 7.36–7.26(m, 4H), 5.10(d, J=12.1Hz, 1H), 4.84( d,J=12.1Hz,1H),4.03(ddd,J=11.6,6.0,1.8Hz,1H),3.69(td,J=11.4,3.7Hz,1H),3.06–3.01(m,1H),2.64 –2.60(m,1H),1.37(s,9H); 13 C NMR (151MHz, CDCl 3 )δ145.5, 139.8, 139.0, 132.4, 128.5, 128.4, 126.9, 125.7, 123.7, 122.8, 82.0, 79.2, 61.1, 35.2, 31.1. HRMS (ESI) m / z: C 20 h 23 NNaO 3 [M+Na] + The theoretical value is 348.1576, and the measured value is 348.1558.

Embodiment 3

[0046] Taking the preparation of the following formula compound 1-nitromethyl-1-p-chlorophenylisochroman as an example, the raw materials used and the preparation method thereof are as follows:

[0047]

[0048] In Example 3, the 1-phenylisochroman used in Example 1 was replaced with equimolar 1-chlorophenylisochroman, and the other steps were the same as in Example 1 to prepare a white solid with a yield of 92%.

[0049] The NMR characterization data are: 1 H NMR (600MHz, CDCl 3 )δ7.36–7.29(m,4H),7.26–7.22(m,4H),5.07(d,J=12.1Hz,1H),4.93(d,J=12.1Hz,1H),4.05–3.98(m ,1H),3.71–3.67(m,1H),3.06–3.01(m,1H),2.64–2.60(m,1H); 13 C NMR (151MHz, CDCl 3 )δ139.8, 138.6, 133.8, 132.4, 128.4, 128.0, 127.7, 126.9, 125.7, 122.8, 81.7, 78.4, 59.6, 26.9. HRMS (ESI) m / z: C 16 h 14 ClNNaO 3 [M+Na] + The theoretical value is 326.0560, and the measured value is 326.0579.

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Abstract

The preparation method of α,α-disubstituted isochroman compounds, adopts easily synthesized α-monosubstituted isochroman compounds with various structures as raw materials, and directly synthesizes them with nitromethane in one step to obtain α,α-disubstituted isochromans Chromatic compounds. The method used in the invention has short reaction steps, mild reaction conditions, high efficiency and simple operation. In the preparation method, the α-position carbon C-H bond of the α-monosubstituted isochroman compound is directly formed into a C-C bond, which avoids the use of intermediates with lengthy synthesis steps. It is consistent with the current pursuit of the idea of ​​atom economy and sustainable green synthetic chemistry. The preparation of α, α-disubstituted isochroman compounds can undergo a series of chemical transformations to generate various substituted isochroman derivatives, which have great application potential in the preparation of drugs and active natural products.

Description

technical field [0001] The invention relates to a preparation method of α,α-disubstituted isochroman compounds. Background technique [0002] α,α-Disubstituted isochromans are common structural units of many natural products and synthetic drugs with various biological activities. Current syntheses mainly rely on the construction of cyclization reactions involving O-heterocyclic prefunctionalized alcohol groups. For example, in formula 1, terminal alkyne-substituted methoxy functionalized isochromans are obtained with terminal alkyne-functionalized α,α-disubstituted isochromans (Angew.Chem.Int.Ed.2015,54,14154– 14158). [0003] [0004] The intermediate alcohol-functionalized isochromans used above are usually prepared through the route shown in formula 2 (J. Am. Chem. Soc. 2008, 130, 7198-7199). However, its synthesis steps are tedious, and the reaction conditions are harsh due to the use of air-sensitive organolithium reagents. [0005] [0006] For the bimolecula...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/76
CPCC07D311/76
Inventor 吴亚林智伟陈刚李浩
Owner XI'AN PETROLEUM UNIVERSITY
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