CN108329285A - A method of synthesis 2,3- Dihydrobenzofuranes class compounds - Google Patents

Abstract

The invention provides a method for synthesizing 2,3-dihydrobenzofuran compounds. In the present invention, aromatic iodides, epoxy compounds, palladium catalysts, phosphine ligands, and norbornene derivatives are first dissolved in an organic solvent, then stirred and reacted at 30°C to 120°C, and separated and purified after the reaction to obtain 2 ,3‑Dihydrobenzofuran compounds. The method can efficiently, economically and greenly synthesize 2,3-dihydrobenzofuran compounds. The method has mild conditions, good substrate universality and high yield, and the prepared 2,3-dihydrobenzofuran compounds are widely used in the fields of medicinal chemistry and organic chemistry.

Description

A method for synthesizing 2,3-dihydrobenzofuran compounds

technical field

The invention relates to a method for synthesizing 2,3-dihydrobenzofuran compounds, belonging to the field of organic synthesis.

Background technique

2,3-Dihydrobenzofuran is an important structural unit widely present in many biologically active natural products and pharmaceutical molecular structures [a) Nichols, DE; Hoffman, AJ; Oberlender, RA; Riggs, RMJMed .Chem.1986,29,302.b) Saito, M.; Ueo, M.; Kametaka, S.; Saigo, O.; Uchida, S.; , 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,QJAgric.FoodChem.2009,57,2447.d)Lee,I.-S.;Kim,H.-J.;Youn,U.-J.;Chen,Q.- C.; Kim, J.-P.; Ha, DT; Ngoc, TM; Min, B.-S.; Lee, S.-M.; ; 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, M.Org.Prep.Proced.Int.2009,41,385.b) Sheppard, TDJChem. 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 needs to use a strong base in the first step, and the latter One step requires the use of a strong acid; the second is to use trifluoromethanesulfonic acid-2-(trimethylsilyl)aryl ester as an aryne precursor, which is synthesized by [3+2] cycloaddition reaction with epoxy compound 2,3-Dihydrobenzofurans [Beltrán-Rodil, S.; D.; Guitián, E.Synlett.2007,1308.], but this method has disadvantages such as difficult raw material synthesis, poor reaction selectivity, and poor universality of epoxy substrates. In order to solve the above problems, we have developed a reaction to prepare 2,3-bis(2,3-bis) by using simple and easy-to-obtain aromatic iodides and epoxy compounds as raw materials, palladium compound/phosphorus ligand as catalyst, and norbornene derivative as cocatalyst. A new approach to hydrobenzofurans. The method has easy-to-obtain raw materials, simple operation, mild conditions, and a wide range of substrates. It provides a very efficient and convergent method for the synthesis of important drug molecules and natural products containing 2,3-dihydrobenzofuran structural units.

Contents of the invention

In order to solve the problems in the prior art, the present invention provides a method for efficiently synthesizing 2,3-dihydrobenzofuran compounds.

The technical scheme provided by the invention is specifically as follows:

A method for synthesizing 2,3-dihydrobenzofuran compounds, carried out according to the following steps: under nitrogen protection, aromatic iodide A, epoxy compound B, palladium catalyst, phosphine ligand and norbornene derivative Stir the reaction in an organic solvent under the condition of no alkali, the temperature is preferably 30-120° C., and separate and purify after the reaction to obtain 2,3-dihydrobenzofuran compounds.

Reaction formula of the present invention can be expressed as follows:

Wherein, the compound of formula A represents an aromatic iodide, the compound of formula B represents an epoxy compound, and the compounds of formula C and D represent 2,3-dihydrobenzofuran compounds.

Wherein, n is the number of substituents, 0≤n≤4. When n≥2, each ^R1 is independently selected from substituted or unsubstituted aryl, heterocyclic aryl, alkyl, substituted alkyl, ester, amido, cyano, nitro, sulfonyl, alkoxy , one of alkylthio and halogen. R ^and R are ^{independently} selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, alkyl, substituted alkyl, ester, cyano, nitro, amido, sulfonyl, halogen One of.

The above-mentioned substituted or unsubstituted aryl refers to an unsubstituted aryl or an aryl which may have one or more substituents. The substituents are not limited in any way, and common substituents include aryl, heterocyclic aryl, alkyl, ester, cyano, nitro, amido, sulfonyl, alkoxy and halogen. The aromatic group may have one or more of these substituents, and when there are multiple substituents, the multiple substituents may be the same or different.

The above-mentioned substituted or unsubstituted heterocyclic aryl can refer to an unsubstituted heterocyclic aryl or a heterocyclic aryl that can have one or more substituents, and the unsubstituted heterocyclic aryl can be furan, pyrrole, pyridine , indole, naphthalene, anthracene, carbazole, onion, etc., the substituents are not limited in any way, common substituents such as aryl, heteroaryl, alkyl, ester, cyano, nitro, amide group, sulfonyl group, alkoxy group and halogen, etc. The aromatic group may have one or more of these substituents, and when there are multiple substituents, the multiple substituents may be the same or different.

The above-mentioned alkyl refers to an alkyl group having 1 to 20 carbon atoms.

The above-mentioned substituted alkyl groups can be expressed as Where m is 0 and any positive integer, preferably m is an integer between 0 and 20, X can be -OR ⁴ , -OSi(R ⁴ ) ₃ , -SR ⁴ , -SSiR ⁴ , -SeR ⁴ , -N(R ⁴ ) ₂ , -Si(R ⁴ ) ₃ and other groups, wherein R ⁴ represents hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, alkyl, ester, cyano, nitro, amide group, sulfonyl group, halogen, etc., and may be one or more of these substituents. When there are multiple substituents, the multiple substituents may be the same or different.

The aforementioned alkoxy group refers to an alkoxy group having 1 to 10 carbon atoms.

The above substituents R ² and R ³ may be the same or different.

The norbornene derivative described in the method of the present invention, its structural formula can be expressed as:

Where (R ⁵ ) is a substituent on the five-membered ring to the left _{of o} , each o is independently an integer from 1 to 8; (R ⁶ ) _p is a substituent on a double bond, and each p is independently 0 to 2 integer. The configuration of R ⁵ can be endo (Endo) or exo (Exo).

i) When the number of substituents on the left five-membered ring is multiple, they may be the same or different; when the number of substituents on the double bond is 2, they may be the same or different.

ii) The types of R ⁵ and R ⁶ substituents may be the same or different.

iii) Each of ^R5 and ^R6 is independently _CO2M (carboxylate of metal ion M), ester group, cyano group, nitro group, amido group, sulfonyl group, alkoxy group, aryl group, heterocyclic aromatic group One of base, alkyl, substituted alkyl, halogen, M is selected from Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ A sort of. The aryl group may have one or more substituents, and the substituents are not limited in any way, including common substituents such as aryl, alkyl, substituted alkyl, alkoxy, ester, cyano, Nitro, halogen, etc. The aromatic group may have one or more of these substituents, and when there are multiple substituents, the multiple substituents may be the same or different.

The above-mentioned alkyl refers to an alkyl group having 1 to 10 carbon atoms.

The aforementioned alkoxy group refers to an alkoxy group having 1 to 10 carbon atoms.

In the method of the present invention, the solvent is a conventional solvent, such as methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ether, dimethyl diethylene ether, methyl tert-butyl ether, 1, 4-epoxyhexane, 1,3-epoxyhexane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C _4-12 saturated alkanes, C _3-12 fluorine Substituted or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile , C _3-12 saturated alkyl nitrile, etc.

In the present invention, it is preferred to carry out the reaction at 30°C to 120°C.

The catalyst of the present invention preferably uses a palladium catalyst to promote the reaction. The palladium catalyst that can be used includes zero-valent or divalent palladium compounds, such as: Pd(PPh ₃ ) ₄ , Pd(dba) ₂ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , Pd(PhCN) ₂ Cl ₂ , Pd(MeCN) ₂ Cl ₂ , PdCl ₂ , [Pd(allyl)Cl] ₂ , etc. Commercial reagents can be used without special handling.

The ligands of the present invention can be phosphine ligands, such as triarylphosphine (such as phenyl, furyl, etc.), trialkylphosphine (such as cyclohexyl, etc.), XPhos (dicyclohexyl (2', 4', 6' -triisopropyl-[1,1'-diphenyl]-2-yl)phosphine), BrettPhos (dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethyl Oxy-[1,1'-diphenyl]-2-yl)phosphine), SPhos(dicyclohexyl(2',6'-dimethoxy-[1,1'-diphenyl]-2 -yl)phosphine), DavePhos (2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-diphenyl]-2-amine), RuPhos (dicyclohexyl(2 ',6'-diisopropoxy-[1,1'-diphenyl]-2-yl)phosphine), tri(furan-2-yl)phosphine, (3S,5S,7S)-adamantane- 1-yl((1R,5S)-adamantan-2-yl)(butyl)phosphine and the like. Commercial reagents can be used without special handling.

The present invention also relates to a preparation method of a class of 5-HT _2C receptor agonist (5-HT _2C receptor agonist) WAY-255719 and its analogues, which are carried out according to the following steps:

(1) Under the protection of nitrogen, biphenyl aryl iodide E and amino-substituted epoxy compound F react in a solvent under the action of catalyst, ligand, norbornene derivative (catalyst, ligand, norbornene Alkene derivatives are as defined above), and compound G is prepared without separation;

(2) Remove the amino protecting group R ¹⁰ in G to prepare compound H

Wherein the definitions of catalyst, ligand, norbornene derivative and solvent are the same as above; wherein, (R ⁷ ) _x and (R ⁸ ) _y are substituents on the aromatic iodide: i) in (R ⁷ ) _x x is an integer from 0 to 5, and when there are multiple substituents, the substituents can be the same or different; (R ⁸ ) _y in y is an integer from 0 to 3, and when there are multiple substituents, the substituents can be the same or different; ii) ^R7 and ^R8 substituents can be the same or different; iii) each ^R7 and ^R8 are independently aryl, heteroaryl, alkyl, substituted alkyl, ester, cyano, nitro, Amide, sulfonyl, alkoxy and halogen etc. R ⁹ is hydrogen, aryl, heterocyclic aryl, alkyl, substituted alkyl, ester, amido, sulfonyl, alkoxy and the like. ^R9 can also be a protecting group or a precursor of an amino group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl (PMB), alkanoyl, sulfonyl, phthaloyl and azide. R ¹⁰ is a protecting group or precursor of an amino group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl (PMB), alkanoyl, sulfonyl, phthaloyl and azide. When R ⁷ and R ⁸ are aryl or heterocyclic aryl, the aryl or heterocyclic aryl may have one or more substituents, and the substituents are not limited in any way, including common substituents such as aryl, Alkyl, substituted alkyl, alkoxy, ester, cyano, nitro, halogen, etc. The aryl group may have one or more of these substituents; when there are multiple substituents, the multiple substituents may be the same or different. z is an integer from 1 to 10, representing the length of the carbon chain in the epoxy 1-position substituent.

In step (2), the conditions and methods for removing the ^R10 protecting group are conventional methods and conditions for this type of reaction in the art, that is, after step (1) is finished, no follow-up treatment is required, and (i) catalytic hydrogenation , (ii) trifluoroacetic acid or (iii) H ₂ NNH ₂ ·H ₂ O etc. to remove the amino protecting group R ¹⁰ .

The above-mentioned alkyl refers to an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, isopropyl and the like.

The above-mentioned alkoxy group refers to an alkoxy group having 1 to 10 carbon atoms, such as methoxy group and the like.

The aforementioned halogen refers to fluorine, chlorine and bromine atoms.

The molar ratio of the two reactants in the method of the present invention is aromatic iodide: epoxy compound=1:1-10, preferably 1:3.

The above reaction time is within 48 hours, and the reaction temperature is 30-120°C. The heating process may use an oil bath (such as silicone oil, paraffin oil, etc.) or other heating methods.

In the present invention, after the reaction is completed, the reaction product is preferably post-treated, including purification methods such as suction filtration, concentration, recrystallization and column chromatography.

The suction filtration process can use a sand core funnel to filter under reduced pressure.

The concentration process can adopt methods such as atmospheric distillation and vacuum distillation, for example, vacuum concentration with a rotary evaporator.

The purification process is to obtain a pure product by column chromatography.

The method of the present invention realizes the coupling conversion of aromatic iodide and epoxy compound to obtain 2,3-dihydrobenzofuran compounds, has high efficiency and low cost, and can be widely used in the preparation of 2,3-dihydrobenzofuran compounds Compounds with structural units. Compared with the prior art, the present invention has the following advantages:

1. The main raw materials involved in the present invention are easily available aromatic iodides and epoxy compounds. This raw material can be commercialized reagents without special treatment, and is cheap, and can be prepared in large quantities by simple methods;

2. The catalyst used in the reaction involved in the method of the present invention is cheap palladium compound and phosphorus ligand, which is an important improvement compared to the catalyst or complex used in the previous coupling reaction;

3. The catalytic amount of norbornene or its derivatives used in the reaction involved in the method of the present invention is used as a cocatalyst, so that there are fewer side reactions and the reaction system is cleaner;

4. The inventive method does not need to be promoted with alkali;

5. The optical purity of the chiral epoxy raw material used in the inventive method is fully retained in the product;

6. The reaction conditions involved in the method of the present invention have good functional group tolerance and substrate universality, and the substituents can be alkyl, alkoxy, cyano, ester, nitro, halogen atoms (F, Cl, Br) etc., various linear or branched alkyl groups can also complete the reaction.

Detailed ways

The present invention is further described below in conjunction with the examples. In the following examples, the palladium catalyst is Pd(OAc) ₂ is an example, and the phosphine ligand is dicyclohexyl (2', 4', 6'-triisopropyl-[1,1 '-diphenyl]-2-yl)phosphine (i.e. XPhos) as an example, norbornene derivatives as NBE-CO ₂ K as an example, organic solvents as N-methylpyrrolidone, but not limited in any way protection scope of the present invention.

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

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), phenyl glycidyl ether (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidone (1.0mL ). 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated 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 solid, yield 82%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.73(s, 1H), 7.72(s, 1H), 7.31-7.27(m, 2H), 6.97(t, J=7.4Hz, 1H), 6.92(d ,J=8.1Hz,2H),5.25-5.18(m,1H),4.22(dd,J=10.1,5.6Hz,1H),4.13(dd,J=10.1,4.9Hz,1H),3.87(s, 3H), 3.41(dd, J＝15.8, 9.6Hz, 1H), 3.20(dd, J＝15.8, 7.0Hz, 1H), 2.22(s, 3H).HRMS(ESI-TOF): Theoretical calculation value: C ₁₈ H ₁₈ NaO ₄ [M+Na ⁺ ] 321.1097, found: 321.1100.

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

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), (R)-benzyl glycidyl ether (0.6mmol, 3.0equiv.) 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated 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 mg of methyl 5-carboxylate (light yellow oily liquid, yield 93%, ee>99%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.69(s, 2H), 7.37-7.27(m, 5H), 5.08-5.01(m, 1H), 4.66-4.58(m, 2H), 3.86(s, 3H),3.72-3.63(m,2H),3.28(dd,J＝15.7,9.6Hz,1H),3.05(dd,J＝15.7,7.3Hz,1H),2.24(s,3H).HRMS(ESI -TOF): theoretically calculated value: C ₁₉ H ₂₀ NaO ₄ [M+Na ⁺ ] 335.1254, measured value: 335.1259.

Under the protection of inert gas, add Pd(OAc) ₂ (112.3mg, 10mol%), XPhos (476.7mg, 20mol%), NBE-CO ₂ K (88.1mg , 10mol%), methyl 3-methyl-4-iodobenzoate (5mmol, 1.0equiv.), (R)-benzyl glycidyl ether (15mmol, 3.0equiv.) and dry N-methylpyrrolidone (10mL ). 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 (100 _mL ), extracted with methyl tert-butyl ether (3 x 100 mL), dried over _Na2SO4 , filtered and concentrated 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 - 1.33 g of methyl 5-formate, (light yellow oily liquid, yield 85%).

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

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), glycidyl n-butyrate (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated 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 (light yellow oily liquid, yield 91%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.70(s, 2H), 5.09-5.03(m, 1H), 4.35-4.23(m, 2H), 3.86(s, 3H), 3.33(dd, J= 15.8,9.7Hz,1H),3.01(dd,J＝15.8,7.0Hz,1H),2.30(t,J＝8.0Hz,2H),2.21(s,3H),1.63-1.56(m,2H), 0.92(t, J=8.0Hz, 3H).HRMS(ESI-TOF): Theoretical calculated value: C ₁₆ H ₂₀ NaO ₅ [M+Na ⁺ ]315.1203, measured value: 315.1206.

Example 4: Preparation of 7-methyl-2-(methoxymethyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), methyl glycidyl ether (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidone (1.0mL ). 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=10:1 (v/v), to obtain 7-methyl-2-(methoxymethyl)-2,3-dihydrobenzofuran - 34 mg of methyl 5-carboxylate (light yellow oily liquid, yield 72%). ¹ HNMR (400MHz, CDCl ₃ ): δ7.69(s,2H),5.04-4.97(m,1H),3.85(s,3H),3.65-3.56(m,2H),3.43(s,3H), 3.27(dd, J＝15.7, 9.5Hz, 1H), 3.02(dd, J＝15.7, 7.6Hz, 1H), 2.22(s, 3H).HRMS(ESI-TOF): theoretically calculated value: C ₁₃ H ₁₆ NaO ₄ [M+Na ⁺ ]259.0941, measured value: 259.0942.

Example 5: Preparation of methyl 7-methyl-2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), methyl 3-methyl-4-iodobenzoate (0.2 mmol, 1.0 equiv.), glycidol (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=2:1 (v/v), to obtain 7-methyl-2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylic acid 32 mg of methyl ester (colorless oily liquid, yield 73%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.70(s,2H),5.02-4.95(m,1H),3.92-3.88(m,1H),3.86(s,3H),3.78-3.73(m, 1H), 3.27(dd, J＝15.7, 9.5Hz, 1H), 3.06(dd, J＝15.7, 7.6Hz, 1H), 2.22(s, 3H), 2.01(brs, 1H).HRMS(ESI-TOF ): theoretically calculated value: C ₁₂ H ₁₄ NaO ₄ [M+Na ⁺ ] 245.0784, measured value: 245.0792.

Example 6: Preparation of methyl 7-methyl-2,3-dihydrobenzofuran-5-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidone (1.0mL) . 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=20:1 (v/v), to obtain 32 mg of methyl 7-methyl-2,3-dihydrobenzofuran-5-carboxylate (yellow oil liquid, 83% yield). ¹ HNMR (400MHz, CDCl ₃ ): δ7.72(s, 1H), 7.70(s, 1H), 4.64(t, J=8.8Hz, 2H), 3.86(s, 3H), 3.24(t, J= 8.8Hz, 2H), 2.22(s, 3H). HRMS (ESI-TOF): Calculated theoretically: C ₁₁ H ₁₂ NaO ₃ [M+Na ⁺ ] 215.0679, found: 215.0683.

Example 7: Preparation of methyl 2,7-dimethyl-2,3-dihydrobenzofuran-5-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), methyl 3-methyl-4-iodobenzoate (0.2 mmol, 1.0 equiv.), propylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 20:1 (v/v), to obtain 40 mg of methyl 2,7-dimethyl-2,3-dihydrobenzofuran-5-carboxylate (White solid, 97% yield). ¹ HNMR (400MHz, CDCl ₃ ): δ7.68(s, 2H), 5.03-4.94(m, 1H), 3.85(s, 3H), 3.33(dd, J=16.0, 8.0Hz, 1H), 2.82( dd, J=16.0, 8.0Hz, 1H), 2.21(s, 3H), 1.48(d, J=8.0Hz, 3H). HRMS (ESI-TOF): theoretically calculated value: C ₁₂ H ₁₅ O ₃ [M +H ⁺ ] 207.1016, measured value: 207.1018.

Example 8: Preparation of methyl 7-methyl-2-n-butyl-2,3-dihydrobenzofuran-5-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), 1,2-epoxyhexane (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=20:1 (v/v), to obtain 7-methyl-2-n-butyl-2,3-dihydrobenzofuran-5-carboxylic acid 35 mg of methyl ester (light yellow oily liquid, yield 71%). ¹ HNMR (400MHz, CDCl ₃ ): δ7.68(s, 2H), 4.87-4.80(m, 1H), 3.86(s, 3H), 3.29(dd, J=16.0, 8.0Hz, 1H), 3.86( dd,J＝16.0,8.0Hz,1H),2.21(s,3H),1.89-1.80(m,1H),1.71-1.64(m,1H),1.53-1.44(m,4H),0.93(t, J=8.0Hz, 3H). HRMS (ESI-TOF): Theoretical calculated value: C ₁₅ H ₂₀ NaO ₃ [M+Na ⁺ ] 271.1305, measured value: 271.1312.

Example 9: Preparation of methyl 7-methyl-2-n-decyl-2,3-dihydrobenzofuran-5-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), 1,2-epoxydodecane (0.6mmol, 3.0equiv.) 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=50:1 (v/v), to obtain 7-methyl-2-n-decyl-2,3-dihydrobenzofuran-5-carboxylic acid Methyl ester 45 mg (yellow oily liquid, yield 67%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.68(s, 2H), 4.87-4.80(m, 1H), 3.86(s, 3H), 3.29(dd, J=16.0, 8.0Hz, 1H), 2.86 (dd,J=16.0,8.0Hz,1H),2.21(s,3H),1.88-1.79(m,1H),1.71-1.62(m,1H),1.47-1.26(m,16H),0.88(t , J = 8.0 Hz, 3H). HRMS (ESI-TOF): Calculated theoretically: C ₂₁ H ₃₂ NaO ₃ [M+Na ⁺ ] 355.2244, found: 355.2245.

Example 10: Preparation of 7-methyl-2-n-hexadecyl-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), 1,2-epoxyoctadecane (0.6mmol, 3.0equiv.) 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=50:1 (v/v), to obtain 7-methyl-2-n-hexadecyl-2,3-dihydrobenzofuran-5 - Methyl formate 67 mg (white solid, yield 80%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.68(s, 2H), 4.87-4.80(m, 1H), 3.86(s, 3H), 3.29(dd, J=16.0, 8.0Hz, 1H), 2.86 (dd,J=16.0,8.0Hz,1H),2.21(s,3H),1.88-1.79(m,1H),1.71-1.63(m,1H),1.42-1.25(m,28H),0.88(t , J=8.0Hz, 3H). HRMS (ESI-TOF): Theoretical calculated value: C ₂₇ H ₄₄ NaO ₃ [M+Na ⁺ ] 439.3183, found value: 439.3184.

Example 11: Preparation of 7-methyl-2-((1,3-dioxoisoindoline-2-yl)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), N-(2,3-epoxypropyl)phthalamide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=2:1 (v/v), to obtain 7-methyl-2-((1,3-dioxoisoindoline-2-yl )methyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester 42 mg (white solid, yield 60%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.88-7.85(m,2H),7.74-7.72(m,2H),7.70(s,1H),7.68(s,1H),5.20-5.13(m, 1H), 4.01(dd, J=16.0, 8.0Hz, 1H), 3.85(s, 3H), 3.82(dd, J=12.0, 4.0Hz, 1H), 3.38(dd, J=16.0, 8.0Hz, 1H ), 3.04 (dd, J＝6.0, 8.0Hz, 1H), 2.15 (s, 3H). HRMS (ESI-TOF): theoretically calculated value: C ₂₀ H ₁₇ NNaO ₅ [M+Na ⁺ ] 374.0999, measured value : 374.1008.

Example 12: Preparation of 7-methyl-2-(((9H-carbazol-4-yl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 3-methyl-4-iodobenzoic acid methyl ester (0.2mmol, 1.0equiv.), 4-epoxypropaneoxycarbazole (0.6mmol, 3.0equiv.) 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=5:1 (v/v), to obtain 7-methyl-2-(((9H-carbazol-4-yl)oxy)methyl )-2,3-Dihydrobenzofuran-5-carboxylic acid methyl ester 69 mg (white solid, yield 89%). ¹ H NMR (400MHz, CDCl ₃ ): δ8.08(s, 1H), 7.81(d, J=8.0Hz, 2H), 7.65(d, J=8.0Hz, 1H), 7.36-7.30(m, 3H ), 7.05(d, J=8.0Hz, 1H), 7.00-6.96(m, 1H), 6.67(d, J=8.0Hz, 1H), 5.43-5.37(m, 1H), 4.47(dd, J= 12.0,4.0Hz,1H),4.42-4.38(m,1H),3.91(s,3H),3.55(dd,J＝12.0,8.0Hz,1H),3.45(dd,J＝16.0,4.0Hz,1H ), 2.25 (s, 3H). HRMS (ESI-TOF): Calcd: C ₂₄ H ₂₁ NNaO ₄ [M+Na ⁺ ] 410.1357, Found: 410.1365.

Example 13: 7-methyl-2-((((8R,9S,13S,14S)-7,8,9,11,12,13,14,15,16,17-decahydro-13-methanol Preparation of methyl-17-oxo-6H-cyclopentadieno[a]phenanthrene-3-yl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4-iodobenzoate (0.2mmol, 1.0equiv.), (8R,9S,13S,14S)-6,7,8,9,11,12,13, 14,15,16-Decahydro-13-methyl-3-(((R)-oxiran-2-yl)methoxy)-17H-cyclopentadieno[a]phenanthrene-17- Ketone (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purification by column chromatography with dichloromethane as the eluent gave 7-methyl-2-((((8R,9S,13S,14S)-7,8,9,11,12,13,14,15, 16,17-Decahydro-13-methyl-17-oxo-6H-cyclopentadien[a]phenanthrene-3-yl)oxy)methyl)-2,3-dihydrobenzofuran- 74 mg of methyl 5-formate (colorless oily liquid, yield 78%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.72(s, 1H), 7.71(s, 1H), 7.20(d, J=8.0Hz, 1H), 6.74(dd, J=8.5, 2.7Hz, 1H ),6.67(d,J=2.7Hz,1H),5.23-5.17(m,1H),4.19(dd,J=10.1,5.6Hz,1H),4.10(dd,J=10.2,4.9Hz,1H) ,3.87(s,3H),3.40(dd,J=15.8,9.6Hz,1H),3.18(dd,J=15.8,6.9Hz,1H),2.90-2.86(m,2H),2.54-2.47(m ,1H),2.42-2.38(m,1H),2.28-2.22(m,4H),2.19-1.94(m,4H),1.68-1.62(m,1H),1.57-1.40(m,5H),0.91 (s,3H).HRMS(ESI-TOF): Calculated value: C ₃₀ H ₃₄ NaO ₅ [M+Na ⁺ ] 497.2298, found value: 497.2307.

Example 14: (2R)-7-Methyl-2-((((4R)-4-((3S,8R,9S,10S,13R,14S,17R)-10,13-Dimethylhexadecane Preparation of Hydrogen-3-Hydroxy-1H-Cyclopenta[a]phenanthrene-17-yl)pentanoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), (4R)-4-((3S,8R,9S,10S,13R,14S,17R)-3 -Hydroxy-10,13-dimethylhexadecahydro-1H-cyclopentadien[a]phenanthrene-17-yl)pentanoic acid (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was toluene:ether=2:1 (v/v), to obtain (2R)-7-methyl-2-((((4R)-4-((3S,8R,9S ,10S,13R,14S,17R)-10,13-Dimethylhexadecahydro-3-hydroxy-1H-cyclopentadien[a]phenanthrene-17-yl)pentanoyl)oxy)methyl) -99 mg of methyl 2,3-dihydrobenzofuran-5-carboxylate (colorless oily liquid, yield 85%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.70(s, 2H), 5.09-5.02(m, 1H), 4.33(dd, J=11.9, 3.8Hz, 1H), 4.24(dd, J=11.9, 6.0Hz, 1H), 3.86(s, 3H), 3.66-3.58(m, 1H), 3.33(dd, J＝15.8, 9.7Hz, 1H), 3.02(dd, J＝15.8, 7.0Hz, 1H), 2.39-2.31(m,1H),2.25-2.17(m,4H),1.96-1.91(m,1H),1.85-1.67(m,6H),1.55-1.52(m,2H),1.40-1.33(m ,6H),1.30-1.16(m,6H),1.11-0.95(m,6H),0.91(s,3H),0.87(d,J=6.5Hz,3H),0.61(s,3H).HRMS( ESI-TOF): theoretically calculated value: C ₃₆ H ₅₂ NaO ₆ [M+Na ⁺ ] 603.3656, measured value: 603.3658.

Example 15: Preparation of 7-methyl-2,3-dihydrobenzofuran

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), 2-iodotoluene (0.2 mmol, 1.0 equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography with petroleum ether as the eluent to obtain 23 mg of 7-methyl-2,3-dihydrobenzofuran (colorless oily liquid, yield 85%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.04(d, J=8.0Hz, 1H), 6.94(d, J=8.0Hz, 1H), 6.76(t, J=7.4Hz, 1H), 4.56( t,J=8.0Hz, 2H), 3.22(t,J=8.0Hz, 2H), 3.03(s,3H).

Example 16: Preparation of 7-isopropyl-2,3-dihydrobenzofuran

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), 2-iodocumene (0.2 mmol, 1.0 equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography with petroleum ether as the eluent to obtain 25 mg of 7-isopropyl-2,3-dihydrobenzofuran (colorless oily liquid, yield 77%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.06-7.01(m, 2H), 6.84-6.81(m, 1H), 4.57(t, J=8.7Hz, 2H), 3.21(t, J=8.7Hz ,2H),3.15-3.05(m,1H),1.26(s,3H),1.25(s,3H).HRMS(ESI-TOF): Theoretical calculation value: C ₁₁ H ₁₅ O[M+H ⁺ ]163.1123 , measured value: 163.1126.

Example 17: Preparation of 7-phenyl-2,3-dihydrobenzofuran

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), 2-iodobiphenyl (0.2 mmol, 1.0 equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=50:1 (v/v), to obtain 26 mg of 7-phenyl-2,3-dihydrobenzofuran (colorless oily liquid, yield 65 %). ¹ HNMR (400MHz, CDCl ₃ ): δ7.70(d, J=7.4Hz, 2H), 7.43(t, J=7.7Hz, 2H), 7.33-7.26(m, 2H), 7.19(d, J= 7.2Hz, 1H), 6.94(t, J=7.5Hz, 1H), 4.62(t, J=8.8Hz, 2H), 3.28(t, J=8.8Hz, 2H).HRMS(ESI-TOF): theoretical Calculated: _C14H12NaO [M+Na ⁺ ] 219.0780 _, found: 219.0770.

Example 18: Preparation of tert-butyl ((2,3-dihydrobenzofuran-7-yl)methoxy)dimethylsilane

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), (benzyloxy)(tert-butyl)dimethylsilane (0.2mmol, 1.0equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether, to obtain 29 mg of tert-butyl ((2,3-dihydrobenzofuran-7-yl) methoxy) dimethylsilane (colorless oily liquid, yield 55 %). ¹ H NMR (400MHz, CDCl ₃ ): δ7.25(d, J=7.1Hz, 1H), 7.10(d, J=7.3Hz, 1H), 6.86(t, J=7.5Hz, 1H), 4.74( s,2H),4.57(t,J=8.7Hz,2H),3.20(t,J=8.7Hz,2H),0.95(s,9H),0.11(s,6H).HRMS(ESI-TOF): Theoretical calculated value: C ₁₅ H ₂₄ NaO ₂ Si [M+Na ⁺ ] 287.1438, found value: 287.1440.

Example 19: Preparation of 2-(2,3-dihydrobenzofuran-7-yl)acetonitrile

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), 2-(2-iodophenyl)acetonitrile (0.2 mmol, 1.0 equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether: ethyl acetate=20:1 (v/v), to obtain 26 mg of 2-(2,3-dihydrobenzofuran-7-yl) acetonitrile (colorless oily liquid , yield 82%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.18-7.13(m, 2H), 6.86(t, J=7.5Hz, 1H), 4.61(t, J=8.8Hz, 2H), 3.66(s, 2H ), 3.24 (t, J=8.8Hz, 2H). HRMS (ESI-TOF): calculated theoretically: C ₁₀ H ₁₀ NO [M+H ⁺ ] 160.0762, found: 160.0761.

Example 20: Preparation of 2-(2,3-dihydrobenzofuran-7-yl)methyl acetate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), methyl 2-iodophenylacetate (0.2 mmol, 1.0 equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether: ethyl acetate=20:1 (v/v), to obtain 25 mg of methyl 2-(2,3-dihydrobenzofuran-7-yl) (colorless Oily liquid, 65% yield). ¹ H NMR (400MHz, CDCl ₃ ): δ7.12(d, J=6.5Hz, 1H), 7.01(d, J=7.6Hz, 1H), 6.81(t, J=7.5Hz, 1H), 4.57( t, J=8.7Hz, 2H), 3.70(s, 3H), 3.61(s, 2H), 3.22(t, J=8.7Hz, 2H).HRMS(ESI-TOF): theoretically calculated value: C ₁₁ H ₁₂ NaO ₃ [M+Na ⁺ ] 215.0679, found value: 215.0677.

Example 21: Preparation of 7-methyl-6-fluoro-2,3-dihydrobenzofuran

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 2-methyl-1-fluoro-3 iodobenzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidone (1.0mL ). 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=20:1 (v/v), to obtain 25 mg of 7-methyl-6-fluoro-2,3-dihydrobenzofuran (light yellow oily liquid , yield 65%). ¹ H NMR (400MHz, CDCl ₃ ): δ6.94-6.90(m, 1H), 6.54-6.49(m, 1H), 4.61(t, J=8.0Hz, 2H), 3.17(t, J=8.0Hz ,2H), 2.12(s,3H).HRMS (APCI-TOF): Theoretical calculated value: C ₉ H ₁₀ FO [M+H ⁺ ] 153.0710, found value: 153.0720.

Example 22: Preparation of 7-methyl-6-chloro-2,3-dihydrobenzofuran

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 2-methyl-1-chloro-3-iodobenzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidone (1.0mL ). 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=20:1 (v/v), to obtain 22 mg of 7-methyl-6-chloro-2,3-dihydrobenzofuran (yellow oily liquid, Yield 64%). ¹ H NMR (400MHz, CDCl ₃ ): δ6.93(d, J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H), 4.59(t, J=8.0Hz, 2H), 3.21- 3.16 (m, 2H), 2.23 (s, 3H). HRMS (APCI-TOF): calculated theoretically: C ₉ H ₁₀ ClO [M+H ⁺ ] 169.0420, found: 169.0422.

Example 23: Preparation of ethylene glycol 7-methyl-2,3-dihydrobenzofuran-6-carboxylate

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10 mol%), 2-methyl-3-iodobenzoic acid (0.2 mmol, 1.0 equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=2:1 (v/v), to obtain 22 mg of ethylene glycol 7-methyl-2,3-dihydrobenzofuran-6-carboxylate ( Pale yellow oily liquid, yield 50%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.45(d, J=7.8Hz, 1H), 7.05(d, J=7.8Hz, 1H), 4.59(t, J=8.8Hz, 2H), 4.42- 4.40(m, 2H), 3.95-3.92(m, 2H), 3.25(t, J=8.8Hz, 2H), 2.43(s, 3H), 2.18(s, 1H).HRMS(ESI-TOF): theoretical Calculated: _C12H14NaO4 [M+Na ⁺ ] _245.0784 , found: 245.0790 _.

Example 24: Preparation of 7-methyl-5-nitro-2,3-dihydrobenzofuran

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 2-methyl-4-nitro-1-iodobenzene (0.2mmol, 1.0equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=10:1 (v/v), to obtain 22 mg of 7-methyl-5-nitro-2,3-dihydrobenzofuran (yellow solid, Yield 60%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.93(s, 2H), 4.73(t, J=8.8Hz, 2H), 3.29(t, J=8.8Hz, 2H), 2.24(s, 3H). HRMS (ESI-TOF): Theoretical calculated value: C ₉ H ₉ NNaO ₃ [M+Na ⁺ ] 202.0475, found value: 202.0477.

Example 25: Preparation of N,7-dimethyl-2,3-dihydrobenzofuran-5-carboxamide

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), N,3-dimethyl-4-iodobenzamide (0.2mmol, 1.0equiv.), ethylene oxide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=2:1 (v/v), to obtain 29 mg of N,7-dimethyl-2,3-dihydrobenzofuran-5-carboxamide ( White solid, 76% yield). ¹ H NMR (400MHz, CDCl ₃ ): δ7.47(s,1H),7.37(s,1H),6.25(s,1H),4.60(t,J=8.8Hz,2H),3.19(t,J =8.8Hz, 2H), 2.96(d, J=4.8Hz, 3H), 2.19(s, 3H).HRMS(ESI-TOF): theoretically calculated value: C ₁₁ H ₁₄ NO ₂ [M+H ⁺ ]192.1019 , measured value: 192.1022.

Example 26: (R)-2-((7-(2,6-dimethylphenyl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindoline-1, Preparation of 3-diketones

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 2,6-dimethylbiphenyl (0.2mmol, 1.0equiv.), (R)-N-(2,3-epoxypropyl)phthalamide (0.6mmol, 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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=5:1 (v/v), to obtain (R)-2-((7-(2,6-dimethylphenyl)-2, 41 mg of 3-dihydrobenzofuran-2-yl)methyl)isoindoline-1,3-dione (colorless oily liquid, yield 53%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.86-7.82(m,2H),7.74-7.69(m,2H),7.19-7.16(m,1H),7.13-7.11(m,2H),7.04- 7.00(m,2H),6.92(m,1H),5.18-5.10(m,1H),4.11(dd,J＝13.8,7.6Hz,1H),3.83(dd,J＝13.8,5.5Hz,1H) ,3.42(dd,J=15.8,9.5Hz,1H),3.13(dd,J=15.8,6.2Hz,1H),2.34(s,3H),2.20(s,3H).HRMS(ESI-TOF): Theoretical calculated value: C ₂₅ H ₂₁ NNaO ₃ [M+Na ⁺ ] 406.1414, found value: 406.1415.

Example 27: (R)-2-((7-(2-fluorophenyl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindoline-1,3-dione preparation of

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 2-fluorobiphenyl (0.2mmol, 1.0equiv.), (R)-N-(2,3-epoxypropyl) phthalamide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent was petroleum ether:ethyl acetate=5:1 (v/v), to obtain (R)-2-((7-(2-fluorophenyl)-2,3-dihydro Benzofuran-2-yl)methyl)isoindoline-1,3-dione 36 mg (yellow oily liquid, yield 48%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.87-7.82(m,2H),7.74-7.71(m,2H),7.58-7.53(m,1H),7.28-7.18(m,2H),7.21- 7.18(m,1H),7.15-7.05(m,2H),6.84(m,1H),5.18-5.11(m,1H),4.10(dd,J＝13.9,7.5Hz,1H),3.88(dd, J＝13.9, 5.4Hz, 1H), 3.42(dd, J＝15.7, 9.4Hz, 1H), 3.14(dd, J＝15.8, 6.0Hz, 1H).HRMS (ESI-TOF): Theoretical calculation value: C ₂₃ H ₁₆ FNNaO ₃ [M+Na ⁺ ] 396.1006, found: 396.1007.

Example 28: (R)-2-((7-(2-methoxyphenyl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindoline-1,3- Preparation of diketones

Under the protection of inert gas, add Pd(OAc) ₂ (2.2 mg, 10 mol%), XPhos (19.1 mg, 20 mol%), NBE-CO ₂ K (3.5 mg, 10mol%), 2-methoxybiphenyl (0.2mmol, 1.0equiv.), (R)-N-(2,3-epoxypropyl)phthalamide (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 x 10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. Purified by column chromatography, the eluent is petroleum ether:ethyl acetate=5:1 (v/v), to obtain (R)-2-((7-(2-methoxyphenyl)-2,3- Dihydrobenzofuran-2-yl)methyl)isoindoline-1,3-dione 48 mg (yellow oily liquid, yield 62%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.86-7.84(m, 2H), 7.73-7.70(m, 2H), 7.28-7.22(m, 1H), 7.28-7.22(m, 2H), 7.15( d,J=8.0Hz,1H),6.97-6.89(m,3H),5.17-5.17(m,1H),4.09(dd,J=13.8,7.5Hz,1H),3.87(dd,J=13.8, 5.7Hz, 1H), 3.77(s, 3H), 3.39(dd, J＝15.7, 9.4Hz, 1H), 3.12(dd, J＝15.7, 6.2Hz, 1H).HRMS (ESI-TOF): theoretical calculation Value: C ₂₄ H ₁₉ NNaO ₄ [M+Na ⁺ ] 408.1206, Found: 408.1213.

Claims (10)

1. a method for synthesizing 2,3-dihydrobenzofuran compounds, is characterized in that, comprises the following steps: under nitrogen protection, aromatic iodide A, epoxy compound B, palladium catalyst, phosphine ligand and The norbornene derivatives are stirred and reacted in an organic solvent at 30-120°C, separated and purified after the reaction to obtain 2,3-dihydrobenzofuran compounds C and D; the reaction formula is: Wherein, n is the number of substituents, 0≤n≤4; R ¹ is aryl, heteroaryl, C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkylthio, ester, amido, cyano, nitro, sulfonyl or halogen ; When n≥2, each R ¹ is the same or different; ^R is hydrogen, aryl, heteroaryl, C _1-20 alkyl, ester, cyano, nitro, amido, sulfonyl or halogen; R ³ is hydrogen, aryl, heteroaryl, C _1-20 alkyl, ester, cyano, nitro, amido, sulfonyl or halogen. 2. The preparation method according to claim 1, characterized in that: the molar ratio of aryl iodide A and epoxy compound B is 1:0.01-10. 3. The method according to claim 1, characterized in that: the norbornene derivative has the following structure: in: R ⁵ is a substituent on the five-membered ring, o represents the number of substituents, 1≤o≤8; R ⁶ is a substituent on the double bond, p represents the number of substituents, 0≤p≤2; R ⁵ and R ⁶ are independently selected from carboxylates, ester groups, cyano groups, nitro groups, amido groups, sulfonyl groups, C _1-10 alkoxy groups, aryl groups, heterocyclic aryl groups, C ₁ One of _-10 alkyl and halogen, M is one of Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ ; o≥ When 2, each R ⁵ is the same or different; when p=2, each R ⁶ is the same or different. 4. The method according to claim 1, characterized in that: the palladium catalyst is Pd(PPh ₃ ) ₄ , Pd(dba) ₂ , Pd ₂ (dba) ₃ , Pd(OAc) ₂ , Pd(PhCN ) ₂ Cl ₂ , Pd(MeCN) ₂ Cl ₂ , PdCl ₂ or [Pd(allyl)Cl] ₂ . 5. The method according to claim 1, characterized in that: the phosphine ligand is triarylphosphine, trialkylphosphine, dicyclohexyl (2', 4', 6'-triisopropyl-[ 1,1'-diphenyl]-2-yl)phosphine, dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-di phenyl]-2-yl)phosphine), dicyclohexyl (2',6'-dimethoxy-[1,1'-diphenyl]-2-yl)phosphine, 2'-(dicyclohexyl Phosphino)-N,N-dimethyl-[1,1'-diphenyl]-2-amine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-di Phenyl]-2-yl)phosphine, tri(furan-2-yl)phosphine, (3S,5S,7S)-adamantan-1-yl ((1R,5S)-adamantan-2-yl)(butyl base) one of the phosphines. 6. The method according to claim 5, characterized in that: said triarylphosphine is triphenylphosphine or trifurylphosphine; said trialkylphosphine is tricyclohexylphosphine. 7. the method according to claim 1 is characterized in that: described organic solvent is methyl alcohol, ethanol, Virahol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ether, dimethyl glycol ether, Methyl tert-butyl ether, 1,4-epoxyhexane, 1,3-epoxyhexane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C _4-12 Saturated alkanes, C _3-12 fluorinated or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, One or more of acetone, N-methylpyrrolidone, acetonitrile, and C _3-12 saturated alkyl nitriles. 8. The method according to claim 1, characterized in that: the palladium catalyst is Pd(OAc) ₂ , and the phosphine ligand is dicyclohexyl (2',4',6'-triisopropyl base-[1,1'-diphenyl]-2-yl)phosphine, the norbornene derivative is norbornene carboxylate, and the organic solvent is N-methylpyrrolidone. 9. the method according to claim 1 is characterized in that: under nitrogen protection, biphenyl type aryl iodide E and amino-substituted epoxy compound F are in the presence of palladium catalyst, phosphine ligand and norbornene derivative React in an organic solvent under the action to obtain the intermediate G without separation, remove the amino protecting group R ¹⁰ in the intermediate G, and obtain the 5-HT _2C receptor agonist H; the reaction formula is: in: x, y represent the number of substituents, z represents the number of methylene, 0≤x≤5, 0≤y≤3, 1≤z≤10; R ⁷ and R ⁸ are substituents on the aromatic iodide, R ⁷ and R ⁸ are independently selected from aryl, heterocyclic aryl, C _1-20 alkyl, ester, cyano, nitro, amido, One of sulfonyl, alkoxy and halogen; when x≥2, each ^R7 is the same or different; when y≥2, each ^R8 is the same or different; R ⁹ is hydrogen, aryl, heterocyclic aryl, C _1-20 alkyl, ester, amido, sulfonyl, alkoxy, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl One of the group, alkanoyl, sulfonyl, phthaloyl, azide; R ¹⁰ is one of tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, alkanoyl, sulfonyl, phthaloyl, and azide. 10. The method according to claim 9, characterized in that: x=2, y=1, z=1, R ⁷ is Cl, R ⁸ is F, R ⁹ is hydrogen, 5-HT _2C receptor agonist The structural formula of H is