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Method for synthesizing 2,3-dihydrobenzofurans compound

A technology of dihydrobenzene and compounds, applied in the direction of steroids, chemical instruments and methods, compounds of group 4/14 elements of the periodic table, etc., which can solve the problems of poor reaction selectivity, poor universality of epoxy substrates, and raw material synthesis Difficulty and other issues

Inactive Publication Date: 2018-07-27
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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  • Method for synthesizing 2,3-dihydrobenzofurans compound
  • Method for synthesizing 2,3-dihydrobenzofurans compound
  • Method for synthesizing 2,3-dihydrobenzofurans compound

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 Applications(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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