A method for synthesizing 2,3-dihydrobenzofuran compounds

A technology for dihydrobenzene and compounds, which is applied in steroids, chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, etc., can solve the problem of poor universality of epoxy substrates, poor reaction selectivity, and raw material synthesis. difficult problem

Inactive Publication Date: 2019-12-10
WUHAN UNIV
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Problems solved by technology

At present, there are many reports on the synthesis methods of 2,3-dihydrobenzofuran compounds [a) Bertolini, F.; Pineschi, M.Org.Prep.Proced.Int.2009,41,385.b) Sheppard, T.D.J.Chem .Res.2011,35,377.], but starting from simple raw materials, there are few reports on the efficient preparation of 2,3-dihydrobenzofuran compounds
There are two main synthesis methods known at present: the first is to alkylate the phenol at the ortho position, and then add the phenolic hydroxyl group to the double bond to obtain 2,3-dihydrobenzofuran compounds [a) Ohkawa, S.; Fukatsu, K.; Miki, S.; Hashimoto, T.; Sakamoto, J.; Doi, T.; ; Addla, D.; Sridhar, B. Synthesis 2010, 3745.c) Schlgter, J.; Blazejak, M.; Hintermann, L. ChemCatChem2013, 5, 3309.], but the method requires a strong base in the first step, The latter step requires the use of a strong acid; the second is to use 2-(trimethylsilyl)aryl trifluoromethanesulfonate as an aryne precursor for a [3+2] cycloaddition reaction with an epoxy compound Synthesis of 2,3-dihydrobenzofuran compounds [Beltrán-Rodil, S.; D.; Guitián, E.Synlett.2007,1308.], but this method has disadvantages such as difficult synthesis of raw materials, poor reaction selectivity, and poor universality of epoxy substrates

Method used

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  • A method for synthesizing 2,3-dihydrobenzofuran compounds
  • A method for synthesizing 2,3-dihydrobenzofuran compounds
  • A method for synthesizing 2,3-dihydrobenzofuran compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0051] Example 1: Preparation of 7-methyl-2-(phenoxymethyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

[0052]

[0053] Under the protection of an inert gas, add Pd(OAc) to a dry 4.0mL reaction bottle equipped with a magnetic stir bar 2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO 2 K (3.5 mg, 10 mol%), methyl 3-methyl-4-iodobenzoate (0.2 mmol, 1.0 equiv.), phenyl glycidyl ether (0.6 mmol, 3.0 equiv.) and dry N-methylpyrrolidone (1.0 mL). The vial was capped and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80°C and stirred for 24 hours. After the reaction vessel was cooled to room temperature, it was quenched with water (10 mL), extracted with methyl tert-butyl ether (3×10 mL), Na 2 SO 4 Dry, filter and concentrate in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=10:1 (v / v), to obtain 7-methyl-2-(phenoxymethyl)-2,3-dihydrobenzofuran - 49 mg of methyl 5-carboxylate (white so...

Embodiment 2

[0054] Example 2: Preparation and gram-level preparation of (R)-7-methyl-2-(benzyloxymethyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

[0055]

[0056] Under the protection of an inert gas, add Pd(OAc) to a dry 4.0mL reaction bottle equipped with a magnetic stir bar 2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO 2 K (3.5mg, 10mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), (R)-benzyl glycidyl ether (0.6mmol, 3.0equiv.) and dry N - Methylpyrrolidone (1.0 mL). The vial was capped and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80°C and stirred for 24 hours. After the reaction vessel was cooled to room temperature, it was quenched with water (10 mL), extracted with methyl tert-butyl ether (3×10 mL), Na 2 SO 4 Dry, filter and concentrate in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=10:1 (v / v), to obtain 7-methyl-2-(benzyloxymethyl)-2,3-dihydrobenzofuran - 58 m...

Embodiment 3

[0058] Example 3: Preparation of 7-methyl-2-(butyryloxymethyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

[0059]

[0060] Under the protection of an inert gas, add Pd(OAc) to a dry 4.0mL reaction bottle equipped with a magnetic stir bar 2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO 2 K (3.5 mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2 mmol, 1.0 equiv.), glycidyl n-butyrate (0.6 mmol, 3.0 equiv.) and dry N-methyl Pyrrolidone (1.0 mL). The vial was capped and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80°C and stirred for 24 hours. After the reaction vessel was cooled to room temperature, it was quenched with water (10 mL), extracted with methyl tert-butyl ether (3×10 mL), Na 2 SO 4 Dry, filter and concentrate in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=10:1 (v / v), to obtain 7-methyl-2-(butyryloxymethyl)-2,3-dihydrobenzo 53 mg of methyl furan-5-carboxylate (lig...

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Abstract

The invention provides a method for synthesizing a 2,3-dihydrobenzofurans compound. The method comprises the following steps: dissolving aromatic iodide, an epoxy compound, a palladium catalyst, a phosphine ligand and a norborene derivative in an organic solvent together; then carrying out stirring reaction at the temperature of 30-120 DEG C; and carrying out separation and purification after reaction to obtain the 2,3-dihydrobenzofurans compound. By the method, the 2,3-dihydrobenzofurans compound can be synthesized efficiently, economically and environmentally friendly. The method is gentle in condition, good in substrate universality and high in yield, and the prepared 2,3-dihydrobenzofurans compound is widely applied to the fields of medicinal chemistry and organic chemistry.

Description

technical field [0001] The invention relates to a method for synthesizing 2,3-dihydrobenzofuran compounds, belonging to the field of organic synthesis. Background technique [0002] 2,3-Dihydrobenzofuran is an important structural unit widely present in many biologically active natural products and pharmaceutical molecular structures[a) Nichols,D.E.; Hoffman,A.J.; Oberlender,R.A.; Riggs,R.M.J. Med.Chem.1986,29,302.b) Saito, M.; Ueo, M.; Kametaka, S.; Saigo, O.; Uchida, S.; Mori, A.; Ishii, K. Biol. Pharm. Bull. 2008, 31, 1959.c) Huang, Z.; Cui, Q.; Xiong, L.; Wang, Z.; Wang, K.; Zhao, Q.; Bi, F.; Wang, Q.J. Agric. FoodChem. 2009, 57, 2447.d) Lee, I.-S.; Kim, H.-J.; Youn, U.-J.; .-C.; Kim, J.-P.; Ha, D.T.; Ngoc, T.M.; Min, B.-S.; Lee, S.-M.; K.; Bae, K.-H. Helv. Chim. Acta. 2010, 93, 272. e). Radadiya, A; Shah, A. Eur. J. Med. Chem. 2015, 97, 356.]. At present, there are many reports on the synthesis methods of 2,3-dihydrobenzofuran compounds [a) Bertolini, F.; Pineschi, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/80C07D307/79C07D307/81C07D405/06C07D405/12C07J17/00C07F7/18
CPCC07D307/79C07D307/80C07D307/81C07D405/06C07D405/12C07F7/1892C07J17/00Y02P20/55
Inventor 周强辉吴承贵程鸿刚
Owner WUHAN UNIV
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