CN108329285B - Method for synthesizing 2, 3-dihydrobenzofuran compound - Google Patents

Method for synthesizing 2, 3-dihydrobenzofuran compound Download PDF

Info

Publication number
CN108329285B
CN108329285B CN201810299042.8A CN201810299042A CN108329285B CN 108329285 B CN108329285 B CN 108329285B CN 201810299042 A CN201810299042 A CN 201810299042A CN 108329285 B CN108329285 B CN 108329285B
Authority
CN
China
Prior art keywords
methyl
equal
phosphine
dihydrobenzofuran
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201810299042.8A
Other languages
Chinese (zh)
Other versions
CN108329285A (en
Inventor
周强辉
吴承贵
程鸿刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan University WHU
Original Assignee
Wuhan University WHU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan University WHU filed Critical Wuhan University WHU
Priority to CN201810299042.8A priority Critical patent/CN108329285B/en
Publication of CN108329285A publication Critical patent/CN108329285A/en
Application granted granted Critical
Publication of CN108329285B publication Critical patent/CN108329285B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides a method for synthesizing 2, 3-dihydrobenzofuran compounds. The method comprises the steps of dissolving aromatic iodide, an epoxy compound, a palladium catalyst, a phosphine ligand and a norbornene derivative in an organic solvent, stirring the mixture at a temperature of between 30 and 120 ℃ for reaction, and separating and purifying the reaction product after the reaction to obtain the 2, 3-dihydrobenzofuran compound. The method can synthesize the 2, 3-dihydrobenzofuran compound efficiently, economically and greenly. The method has the advantages of mild conditions, good substrate universality and high yield, and the prepared 2, 3-dihydrobenzofuran compound is widely applied to the fields of pharmaceutical chemistry and organic chemistry.

Description

Method for synthesizing 2, 3-dihydrobenzofuran compound
Technical Field
The invention relates to a method for synthesizing 2, 3-dihydrobenzofuran compounds, belonging to the field of organic synthesis.
Background
2, 3-dihydrobenzofuran is an important building block, 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.; hosaka, h.; sakamoto, k.; nakahara, t.; 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.; chen, Q. -C.; kim, j. -p.; ha, d.t.; ngoc, t.m.; min, b. -s.; lee, s. -m.; jung, h. -j.; na, M. -K.; bae, k. — h.helv.chim.acta.2010,93,272.e). radaiya, a; shah, a.eur.j.med.chem.2015,97,356.]. Currently, there are many reports on the synthesis of 2, 3-dihydrobenzofuran compounds [ a) bertholini, f.; pinischi, m.org.prep.proced.int.2009,41,385.b) Sheppard, t.d.j.chem.res.2011,35,377.]However, a method for efficiently producing 2, 3-dihydrobenzofuran compounds from simple raw materials has been reported. There are two major synthetic methods known today: the first is that phenol is firstly alkylated at the ortho position, and then the phenolic hydroxyl group is added to double bonds to obtain 2, 3-dihydrobenzofuran compounds [ a) Ohkawa, S.; fukatsu, K.；Miki,S.；Hashimoto,T.；Sakamoto,J.；Doi,T.；Nagai,Y.；Aono,T.J.Med.Chem.1997,40,559.b)Kantevari,S.；Addla,D.；Sridhar,B.Synthesis 2010,3745.c)Schlgter,J.；Blazejak,M.；Hintermann,L.ChemCatChem2013,5,3309.]However, the method needs strong base in the former step and strong acid in the latter step; the second method is to take triflic acid-2- (trimethylsilyl) aryl ester as an aryne precursor to generate [3+2 ] with an epoxy compound]Cycloaddition reaction to synthesize 2, 3-dihydrobenzofuran compounds [ Beltr n-Rodil, S.;D.；Guitián,E.Synlett.2007,1308.]However, this method has disadvantages of difficulty in synthesizing raw materials, poor reaction selectivity, poor universality of epoxy substrates, and the like. In order to solve the above problems, we have developed a novel method for preparing 2, 3-dihydrobenzofuran compounds by reacting aromatic iodo compounds and epoxy compounds, which are easily available, as raw materials, a palladium compound/phosphorus ligand as a catalyst, and a norbornene derivative as a cocatalyst. The method has the advantages of easily available raw materials, simple operation, mild conditions and wide substrate application range, and provides a very efficient and convergent method for synthesizing important drug molecules and natural products containing 2, 3-dihydrobenzofuran structural units.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for efficiently synthesizing 2, 3-dihydrobenzofuran compounds.
the technical scheme provided by the invention is as follows:
A method for synthesizing 2, 3-dihydrobenzofuran compounds comprises the following steps: under the protection of nitrogen, stirring an aromatic iodide A, an epoxy compound B, a palladium catalyst, a phosphine ligand and a norbornene derivative in an organic solvent under the alkali-free condition for reaction, wherein the temperature is preferably 30-120 ℃, and separating and purifying after the reaction is finished to obtain the 2, 3-dihydrobenzofuran compound.
The reaction formula of the present invention can be represented as follows:
Wherein, the compound of formula A represents aromatic iodide, the compound of formula B represents epoxy compound, and the compounds of formula C and formula D represent 2, 3-dihydrobenzofuran compounds.
Wherein n is the number of the substituent groups, and n is more than or equal to 0 and less than or equal to 4. When n is greater than or equal to 2, each R1Independently selected from one of substituted or unsubstituted aryl, heterocyclic aryl, alkyl, substituted alkyl, ester group, amido, cyano, nitro, sulfonyl, alkoxy, alkylthio and halogen. R2And R3Independently selected from one of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, alkyl, substituted alkyl, ester group, cyano, nitro, amido, sulfonyl and halogen.
the above-mentioned substituted or unsubstituted aryl group means an unsubstituted aryl group or an aryl group which may have one or more substituents. The substituents are not limited in any way, and common substituents are, for example, aryl, heteroaryl, alkyl, ester, cyano, nitro, amido, sulfonyl, alkoxy, halogen, and the like. The aromatic group may have one or more of these substituents, and when a plurality of substituents are present, the plurality of substituents may be the same or different.
The above-mentioned substituted or unsubstituted heterocyclic aryl group may refer to an unsubstituted heterocyclic aryl group which may be furan, pyrrole, pyridine, indole, naphthalene, anthracene, carbazole, onion, etc., or a heterocyclic aryl group which may have one or more substituents which are not limited in any way, and common substituents such as aryl group, heterocyclic aryl group, alkyl group, ester group, cyano group, nitro group, amide group, sulfonyl group, alkoxy group, halogen, etc. The aromatic group may have one or more of these substituents, and when a plurality of substituents are present, the plurality of substituents may be the same or different.
The alkyl group is an alkyl group having 1 to 20 carbon atoms.
The substituted alkyl group can be represented bywherein m is 0 and any positive integer, preferably m is an integer between 0 and 20, and X may be-OR4、-OSi(R4)3、-SR4、-SSiR4、-SeR4、-N(R4)2、-Si(R4)3Etc. wherein R is4Represents hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, alkyl, ester, cyano, nitro, amide, sulfonyl, halogen, etc., and may be one or more of these substituents, and when there are a plurality of substituents, the plurality of substituents may be the same or different.
The alkoxy group is an alkoxy group having 1 to 10 carbon atoms.
The above-mentioned substituent R2And R3They may be the same or different.
the norbornene derivative according to the method of the present invention may have a structural formula represented by:
Wherein (R)5)osubstituents on the left five-membered ring, each o is independently an integer from 1 to 8; (R)6)pEach p is independently an integer from 0 to 2, a substituent on the double bond. R5May be of the Endo (Endo) or Exo (Exo) configuration.
i) When the number of the substituents on the left five-membered ring is more than one, the substituents can be the same or different; when the number of the substituents on the double bond is 2, the substituents may be the same or different.
ii)R5and R6The substituents may be the same or different.
iii) each R5And R6Independently of each other is CO2m (carboxylate of metal ion M), ester group, cyano, nitro, amido, sulfonyl, alkoxy, aryl, heterocyclic aryl, alkyl, substituted alkyl and one of halogens, wherein M is selected from Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+One kind of (1). The aryl group may carry one or more substituents, and the substituents are not limited in any way, and include common substituents such as aryl, alkyl, substituted alkyl, alkoxy, ester, cyano, nitro, halogen, and the like. The aromatic group may have one or more of these substituents, and when a plurality of substituents are present, the plurality of substituents may be the same or different.
The alkyl group is an alkyl group having 1 to 10 carbon atoms.
the alkoxy group is an alkoxy group having 1 to 10 carbon atoms.
In the process of the present invention, the solvent is a conventional solvent such as methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethylether, methyl t-butyl ether, 1, 4-epoxyhexa-xane, 1, 3-epoxyhexa-xane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, C4-12Saturated alkane of (C)3-12fluoro or chloro alkane, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C3-12And saturated alkylnitriles of (1).
The reaction is preferably carried out at 30 ℃ to 120 ℃ in the present invention.
The catalyst of the present invention preferably uses a palladium catalyst to promote the reaction, and palladium catalysts which may be used include zero-valent or divalent palladium compounds such as: pd (PPh)3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2And the like. Commercial reagents can be used without special treatment.
The ligands of the present invention may employ phosphine ligands such as triarylphosphines (e.g., phenyl, furyl, etc.), trialkylphosphines (e.g., cyclohexyl, etc.), XPhos (dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -diphenyl ] -2-yl) phosphine), Brettphos (dicyclohexyl (2',4',6 '-triisopropyl-3, 6-dimethoxy- [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 '-diisopropyloxy- [1,1' -diphenyl ] -2-yl) phosphine), tris (furan-2-yl) phosphine, (3S,5S,7S) -adamantan-1-yl ((1R,5S) -adamantan-2-yl) (butyl) phosphine, and the like. Commercial reagents can be used without special treatment.
The invention also relates to a class of 5-HT2CReceptor agonists (5-HT)2CA method for preparing receptor agonist) WAY-255719 and analogues thereof, comprising the following steps:
(1) Under the protection of nitrogen, reacting biphenyl aryl iodide E and amino substituted epoxy compound F in a solvent under the action of a catalyst, a ligand and a norbornene derivative (the catalyst, the ligand and the norbornene derivative are the same as defined in the specification), and preparing a compound G without separation;
(2) Removing the amino protecting group R in G10Preparation of Compound H
Wherein the definitions of the catalyst, the ligand, the norbornene derivative and the solvent are the same as above; wherein (R)7)xAnd (R)8)yIs a substituent on the aromatic iodide: i) (R)7)xWherein x is an integer of 0 to 5, and when a plurality of substituents are present, the substituents may be the same or different; (R)8)yWherein y is an integer of 0 to 3, and when a plurality of substituents are present, the substituents may be the same or different; ii) R7And R8The substituents may be the same or different; iii) each R7And R8Independently aryl, heterocyclic aryl, alkyl, substituted alkyl, ester, cyano, nitro, amido, sulfonyl, alkoxy, halogen, and the like. R9Hydrogen, aryl, heterocyclic aryl, alkyl, substituted alkyl, ester, amide, sulfonyl, alkoxy, and the like. R9it may also be t-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl (PMB), alkanoyl, sulfonyl, phthaloyl, azide, etcA protecting group or precursor of an amino group. R10The protecting group or precursor of amino group is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl (PMB), alkanoyl, sulfonyl, phthaloyl and azide. R7And R8in the case of aryl or heterocyclic aryl, the aryl or heterocyclic aryl may carry one or more substituents, and the substituents are not limited in any way, and include common substituents such as aryl, alkyl, substituted alkyl, alkoxy, ester, cyano, nitro, halogen and the like. The aromatic group may carry one or more of these substituents; when a plurality of substituents are present, the plurality of substituents may be the same or different. z is an integer from 1 to 10 and represents the length of the carbon chain in the substituent at the 1-position of the epoxy.
In the step (2), the removal of R10The conditions and methods for protecting groups are conventional in the art and are conventional in such reactions, i.e., after step (1) is complete, without subsequent treatment, by (i) catalytic hydrogenation, (ii) trifluoroacetic acid or (iii) H2NNH2·H2O, etc. removing amino protecting group R10and (4) finishing.
the alkyl group is an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, isopropyl, etc.
The alkoxy group is an alkoxy group having 1 to 10 carbon atoms, such as methoxy group.
The halogen is fluorine, chlorine or bromine atom.
The molar ratio of the two reactants fed in the method is 1:1-10, preferably 1:3, of the aromatic iodide and the epoxy compound.
The reaction time is within 48 hours, and the reaction temperature is 30-120 ℃. The heating process may use an oil bath (e.g., silicone oil, paraffin oil, etc.) or other heating means.
The invention preferably carries out post-treatment on the reaction product after the reaction is finished, and comprises purification methods such as suction filtration, concentration, recrystallization, column chromatography and the like.
The suction filtration process can be carried out using a sand core funnel under reduced pressure.
The concentration process can adopt methods such as atmospheric distillation, reduced pressure distillation and the like, for example, vacuum concentration by a rotary evaporator.
The purification process is to obtain a pure product by column chromatography.
The method realizes the coupling conversion of the aromatic iodide and the epoxy compound to obtain the 2, 3-dihydrobenzofuran compound, has high efficiency and low cost, and can be widely used for preparing the compound containing the 2, 3-dihydrobenzofuran structural unit. Compared with the prior art, the invention has the following advantages:
1. The main raw materials related by the invention are easily obtained aromatic iodide and epoxy compound, the raw materials can be commercialized reagent, special treatment is not needed, the price is low, and the raw materials can be prepared in large scale by a simple method;
2. The catalyst used in the reaction related to the method of the invention is cheap palladium compound and phosphorus ligand, and is an important improvement compared with the catalyst or complex used in the previous coupling reaction;
3. the catalytic amount of norbornene or norbornene derivatives used in the reaction related to the method of the invention is used as a cocatalyst, so that the side reactions are less, and the reaction system is cleaner;
4. The method of the invention does not need alkali to promote;
5. The optical purity of the chiral epoxy raw material used in the method is completely reserved in the product;
6. The reaction conditions involved in the method of the invention have good functional group tolerance and substrate universality, the substituent can be alkyl, alkoxy, cyano, ester group, nitro, halogen atom (F, Cl, Br) and the like, and various straight chain or branched chain alkyls can also complete the reaction.
Detailed Description
The invention is further described in the following examples in which the palladium catalyst is Pd (OAc)2For example, the phosphine ligand is dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -diphenyl)]-2-yl) phosphine (i.e., XPhos) as an example, norbornene derivative NBE-CO2K is exemplified by N-methylpyrrolidone, but does not limit the scope of the invention in any way.
Example 1: preparation of methyl 7-methyl-2- (phenoxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), phenyl glycidyl ether (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate 10:1(v/v) gave 49mg of methyl 7-methyl-2- (phenoxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate (white solid, 82% yield).1H NMR(400MHz,CDCl3): δ 7.73(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 (TOF-TOF): theoretical calculation value: c18H18NaO4[M+Na+]321.1097, found: 321.1100.
Example 2: preparation and gram-scale preparation of (R) -7-methyl-2- (benzyloxymethyl) -2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester
to a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), (R) -benzylMonoglycidyl ether (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate 10:1(v/v) gave 58mg of methyl 7-methyl-2- (benzyloxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate (pale yellow oily liquid, 93% yield, ee)>99％)。1H NMR(400MHz,CDCl3): δ 7.69(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): theoretical calculation value: c19H20NaO4[M+Na+]335.1254, found: 335.1259.
To a 50mL reaction flask, dried and equipped with a magnetic stir bar, was added Pd (OAc) under inert gas2(112.3mg，10mol％)、XPhos(476.7mg，20mol％)、NBE-CO2K (88.1mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (5mmol, 1.0equiv.), (R) -benzyl glycidyl ether (15mmol, 3.0equiv.), and dry N-methylpyrrolidinone (10 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (100mL), extract with methyl tert-butyl ether (3X 100mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate 10:1(v/v) gave 1.33g of methyl 7-methyl-2- (benzyloxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate (light yellow oily liquid, 85% yield).
example 3: preparation of methyl 7-methyl-2- (butyryloxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate
Under the protection of inert gas, toTo a 4.0mL reaction flask, dried and equipped with a magnetic stirrer, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), glycidyl N-butyrate (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate 10:1(v/v) gave 53mg of methyl 7-methyl-2- (butyryloxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate (pale yellow oily liquid, 91% yield).1H NMR(400MHz,CDCl3): δ 7.70(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 calculation value: c16H20NaO5[M+Na+]315.1203, found: 315.1206.
Example 4: preparation of methyl 7-methyl-2- (methoxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate
to a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2k (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), methyl glycidyl ether (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purifying by column chromatography, eluting withEthyl acetate 10:1(v/v) as petroleum ether to give 34mg (pale yellow oily liquid, yield 72%) of methyl 7-methyl-2- (methoxymethyl) -2, 3-dihydrobenzofuran-5-carboxylate.1H NMR(400MHz,CDCl3): δ 7.69(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): theoretical calculation value: c13H16NaO4[M+Na+]259.0941, found: 259.0942.
Example 5: preparation of methyl 7-methyl-2-hydroxymethyl-2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), glycidol (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate 2:1(v/v) gave 32mg of methyl 7-methyl-2-hydroxymethyl-2, 3-dihydrobenzofuran-5-carboxylate (73% yield as a colorless oily liquid).1H NMR(400MHz,CDCl3): δ 7.70(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): theoretical calculation value: c12H14NaO4[M+Na+]245.0784, found: 245.0792.
example 6: preparation of methyl 7-methyl-2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether and ethyl acetate 20:1(v/v) gave 32mg of methyl 7-methyl-2, 3-dihydrobenzofuran-5-carboxylate (yellow oily liquid, 83% yield).1HNMR(400MHz,CDCl3): δ 7.72(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): theoretical calculation value: c11H12NaO3[M+Na+]215.0679, found: 215.0683.
Example 7: preparation of methyl 2, 7-dimethyl-2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), propylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purifying by column chromatography with eluent of stoneEthyl acetate ═ 20:1(v/v) to give methyl 2, 7-dimethyl-2, 3-dihydrobenzofuran-5-carboxylate 40mg (white solid, yield 97%).1HNMR(400MHz,CDCl3): δ 7.68(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): theoretical calculation value: c12H15O3[M+H+]207.1016, found: 207.1018.
Example 8: preparation of methyl 7-methyl-2-n-butyl-2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), 1, 2-epoxyhexane (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate ═ 20:1(v/v) gave 35mg of methyl 7-methyl-2-n-butyl-2, 3-dihydrobenzofuran-5-carboxylate (pale yellow oily liquid, yield 71%).1HNMR(400MHz,CDCl3): δ 7.68(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 calculation value: c15H20NaO3[M+Na+]271.1305, found: 271.1312.
example 9: preparation of methyl 7-methyl-2-n-decyl-2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), 1, 2-epoxydodecane (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate 50:1(v/v) gave 45mg of methyl 7-methyl-2-n-decyl-2, 3-dihydrobenzofuran-5-carboxylate (yellow oily liquid, 67% yield).1H NMR(400MHz,CDCl3): δ 7.68(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 ═ 8.0Hz,3H), HRMS (ESI-TOF): theoretical calculation value: c21H32NaO3[M+Na+]355.2244, found: 355.2245.
Example 10: preparation of methyl 7-methyl-2-n-hexadecyl-2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2k (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), 1, 2-epoxyoctadecane (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After the reaction vessel was cooled to room temperature, quenched with water (10mL) and quenched with formazanTert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether and ethyl acetate 50:1(v/v) gave 67mg of methyl 7-methyl-2-n-hexadecyl-2, 3-dihydrobenzofuran-5-carboxylate (white solid, 80% yield).1H NMR(400MHz,CDCl3): δ 7.68(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 calculation value: c27H44NaO3[M+Na+]439.3183, found: 439.3184.
Example 11: preparation of methyl 7-methyl-2- ((1, 3-dioxoisoindolin-2-yl) methyl) -2, 3-dihydrobenzofuran-5-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), N- (2, 3-epoxypropyl) phthalimide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate ═ 2:1(v/v) gave 42mg (white solid, 60% yield) of methyl 7-methyl-2- ((1, 3-dioxoisoindolin-2-yl) methyl) -2, 3-dihydrobenzofuran-5-carboxylate.1H NMR(400MHz,CDCl3): δ 7.88-7.85(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): theoretical meterCalculating the value: c20H17NNaO5[M+Na+]374.0999, found: 374.1008.
Example 12: preparation of methyl 7-methyl-2- (((9H-carbazol-4-yl) oxy) methyl) -2, 3-dihydrobenzofuran-5-carboxylate
to a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2k (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), 4-epoxypropyleneoxycarbazole (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether and ethyl acetate 5:1(v/v) as eluent to give 69mg (white solid, yield 89%) of methyl 7-methyl-2- (((9H-carbazol-4-yl) oxy) methyl) -2, 3-dihydrobenzofuran-5-carboxylate.1H NMR(400MHz,CDCl3): δ 8.08(s,1H),7.81(d, J ═ 8.0Hz,2H),7.65(d, J ═ 8.0Hz,1H),7.36 to 7.30(m,3H),7.05(d, J ═ 8.0Hz,1H),7.00 to 6.96(m,1H),6.67(d, J ═ 8.0Hz,1H),5.43 to 5.37(m,1H),4.47(dd, J ═ 12.0,4.0Hz,1H),4.42 to 4.38(m,1H),3.91(s,3H),3.55(dd, J ═ 12.0,8.0Hz,1H),3.45 (ESI, J ═ 16.0,4.0Hz,1H),2.25 (ms, 3H), TOF (TOF): theoretical calculation value: c24H21NNaO4[M+Na+]410.1357, found: 410.1365.
Example 13: preparation of methyl 7-methyl-2- (((((8R, 9S,13S,14S) -7,8,9,11,12,13,14,15,16, 17-decahydro-13-methyl-17-oxo-6H-cyclopenta [ a ] phenanthren-3-yl) oxy) methyl) -2, 3-dihydrobenzofuran-5-carboxylate
to a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2k (3.5mg, 10 mol%), 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-cyclopenta [ a]Phenanthren-17-one (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purifying by column chromatography, eluting with dichloromethane, to obtain 7-methyl-2- (((((8R, 9S,13S,14S) -7,8,9,11,12,13,14,15,16, 17-decahydro-13-methyl-17-oxo-6H-cyclopenta [ a ] methyl ester]Phenanthren-3-yl) oxy) methyl) -2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester 74mg (colorless oily liquid, yield 78%).1H NMR(400MHz,CDCl3): δ 7.72(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, ddh), 3.18 (J ═ 15.8,6.9Hz,1H),2.90-2.86(m,2H),2.54-2.47(m,1H),2.42 (m, 2.42-2H), 2.42 (m ═ 2H), 2.42 (TOF (m,1H), 2.42-2.42 (m,1H), 2.26H, 1H), 2.26-5 (TOF (m,1H), 2.22.22H, 1H): theoretical calculation value: c30H34NaO5[M+Na+]497.2298, found: 497.2307.
Example 14: preparation of methyl (2R) -7-methyl-2- (((((4R) -4- ((3S,8R,9S,10S,13R,14S,17R) -10, 13-dimethylhexadecahydro-3-hydroxy-1H-cyclopenta [ a ] phenanthren-17-yl) pentanoyl) oxy) methyl) -2, 3-dihydrobenzofuran-5-carboxylate
4.0m dried and equipped with magnetic stirrer under inert gasPd (OAc) is added into an L reaction bottle2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), methyl 3-methyl-4 iodobenzoate (0.2mmol, 1.0equiv.), (4R) -4- ((3S,8R,9S,10S,13R,14S,17R) -3-hydroxy-10, 13-dimethylhexadecahydro-1H-cyclopenta [ a ] a]Phenanthren-17-yl) pentanoic acid (0.6mmol, 3.0equiv.) and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purifying by column chromatography, eluting with toluene and ethyl 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-cyclopenta [ a ]]Phenanthren-17-yl) pentanoyl) oxy) methyl) -2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester 99mg (colorless oily liquid, yield 85%).1H NMR(400MHz,CDCl3): δ 7.70(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), 1.30-1.30 (m,6H), 1.95 (m,6H), 3.5H, 1H, 11H, 1H), 1H (m,6H), 1.87 (TOF (H), 3.6H), 5.3.5H, 1H), 1H), 3.95 (m, 3H): theoretical calculation value: c36H52NaO6[M+Na+]603.3656, found: 603.3658.
Example 15: preparation of 7-methyl-2, 3-dihydrobenzofuran
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-iodotoluene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 deg.CAfter a few minutes, the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether gave 23mg (colorless oily liquid, yield 85%) of 7-methyl-2, 3-dihydrobenzofuran.1H NMR(400MHz,CDCl3)：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
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-iodocumene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether gave 7-isopropyl-2, 3-dihydrobenzofuran at 25mg (colorless oily liquid, 77% yield).1H NMR(400MHz,CDCl3): δ 7.06-7.01(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: c11H15O[M+H+]163.1123, found: 163.1126.
Example 17: preparation of 7-phenyl-2, 3-dihydrobenzofuran
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-iodobiphenyl (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether and ethyl acetate 50:1(v/v) as eluent to give 26mg of 7-phenyl-2, 3-dihydrobenzofuran (colorless oily liquid, yield 65%).1HNMR(400MHz,CDCl3): δ 7.70(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 calculation value: c14H12NaO[M+Na+]219.0780, found: 219.0770.
Example 18: preparation of tert-butyl ((2, 3-dihydrobenzofuran-7-yl) methoxy) dimethylsilane
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), (benzyloxy) (tert-butyl) dimethylsilane (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purifying by column chromatography using petroleum ether as eluent to obtain tert-butyl ((2, 3-dihydrobenzofuran-7-yl) methoxy) diMethylsilane 29mg (colorless oily liquid, yield 55%).1H NMR(400MHz,CDCl3): δ 7.25(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 calculation value: c15H24NaO2Si[M+Na+]287.1438, found: 287.1440.
Example 19: preparation of 2- (2, 3-dihydrobenzofuran-7-yl) acetonitrile
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2- (2-iodophenyl) acetonitrile (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidinone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether, ethyl acetate ═ 20:1(v/v) as an eluent, to give 26mg of 2- (2, 3-dihydrobenzofuran-7-yl) acetonitrile (colorless oily liquid, yield 82%).1H NMR(400MHz,CDCl3): δ 7.18-7.13(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): theoretical calculation value: c10H10NO[M+H+]160.0762, found: 160.0761.
Example 20: preparation of methyl 2- (2, 3-dihydrobenzofuran-7-yl) acetate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2k (3.5mg, 10 mol%), methyl 2-iodophenylacetate (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether, ethyl acetate ═ 20:1(v/v) as eluent, to give 25mg of methyl 2- (2, 3-dihydrobenzofuran-7-yl) acetate (colorless oily liquid, yield 65%).1H NMR(400MHz,CDCl3): δ 7.12(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): theoretical calculation value: c11H12NaO3[M+Na+]215.0679, found: 215.0677.
Example 21: preparation of 7-methyl-6-fluoro-2, 3-dihydrobenzofuran
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-methyl-1-fluoro-3 iodobenzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether and ethyl acetate 20:1(v/v) gave 25mg (light yellow oily liquid, 65% yield) of 7-methyl-6-fluoro-2, 3-dihydrobenzofuran.1H NMR(400MHz,CDCl3)：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 calculation value: c9H10FO[M+H+]153.0710, found: 153.0720.
Example 22: preparation of 7-methyl-6-chloro-2, 3-dihydrobenzofuran
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-methyl-1-chloro-3 iodobenzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether and ethyl acetate 20:1(v/v) as eluent to give 22mg of 7-methyl-6-chloro-2, 3-dihydrobenzofuran as a yellow oily liquid in 64% yield.1H NMR(400MHz,CDCl3): δ 6.93(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): theoretical calculation value: c9H10ClO[M+H+]169.0420, found: 169.0422.
example 23: preparation of ethylene 7-methyl-2, 3-dihydrobenzofuran-6-carboxylate
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-methyl-3-iodobenzoic acid (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and driedN-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether, ethyl acetate ═ 2:1(v/v) as eluent, to give 22mg of 7-methyl-2, 3-dihydrobenzofuran-6-carboxylic acid ethylene glycol ester (pale yellow oily liquid, yield 50%).1H NMR(400MHz,CDCl3): δ 7.45(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 calculation value: c12H14NaO4[M+Na+]245.0784, found: 245.0790.
example 24: preparation of 7-methyl-5-nitro-2, 3-dihydrobenzofuran
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-methyl-4-nitro-1-iodobenzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether and ethyl acetate 10:1(v/v) gave 22mg (yellow solid, 60% yield) of 7-methyl-5-nitro-2, 3-dihydrobenzofuran.1H NMR(400MHz,CDCl3): δ 7.93(s,2H),4.73(t, J ═ 8.8Hz,2H),3.29(t, J ═ 8.8Hz,2H),2.24(s,3H), HRMS (ESI-TOF): theoretical calculation value: c9H9NNaO3[M+Na+]202.0475, found: 202.0477.
Example 25: preparation of N, 7-dimethyl-2, 3-dihydrobenzofuran-5-carboxamide
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), N, 3-dimethyl-4-iodobenzamide (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification by column chromatography eluting with petroleum ether ethyl acetate ═ 2:1(v/v) gave 29mg of N, 7-dimethyl-2, 3-dihydrobenzofuran-5-carboxamide (white solid, 76% yield).1H NMR(400MHz,CDCl3): δ 7.47(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): theoretical calculation value: c11H14NO2[M+H+]192.1019, found: 192.1022.
Example 26: preparation of (R) -2- ((7- (2, 6-dimethylphenyl) -2, 3-dihydrobenzofuran-2-yl) methyl) isoindoline-1, 3-dione
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2, 6-dimethylbiphenyl (0.2mmol, 1.0equiv.), (R) -N- (2, 3-epoxypropyl) phthalimide (0.6mmol, 3.0equiv.), and dried N-methylpyrrolidone (1.0 mL). The reaction bottle is sealed by a coverafter stirring for about 5 minutes at room temperature, the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether and ethyl acetate 5:1(v/v) as eluent to give 41mg (R) -2- ((7- (2, 6-dimethylphenyl) -2, 3-dihydrobenzofuran-2-yl) methyl) isoindoline-1, 3-dione (colorless oily liquid, yield 53%).1H NMR(400MHz,CDCl3): δ 7.86-7.82(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 calculation value: c25H21NNaO3[M+Na+]406.1414, found: 406.1415.
Example 27: preparation of (R) -2- ((7- (2-fluorophenyl) -2, 3-dihydrobenzofuran-2-yl) methyl) isoindoline-1, 3-dione
to a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-fluorobiphenyl (0.2mmol, 1.0equiv.), (R) -N- (2, 3-epoxypropyl) phthalic diamide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL.). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4dried, filtered and concentrated under vacuum. Purification was performed by column chromatography eluting with petroleum ether ethyl acetate ═ 5:1(v/v) to give 36mg (R) -2- ((7- (2-fluorophenyl) -2, 3-dihydrobenzofuran-2-yl) methyl) isoindoline-1, 3-dione (yellow oily liquid, 48% yield).1H NMR(400MHz,CDCl3)：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), ms (TOF-ESI): theoretical calculation value: c23H16FNNaO3[M+Na+]396.1006, found: 396.1007.
example 28: preparation of (R) -2- ((7- (2-methoxyphenyl) -2, 3-dihydrobenzofuran-2-yl) methyl) isoindoline-1, 3-dione
To a dry 4.0mL reaction flask equipped with a magnetic stirrer, under inert gas, was added Pd (OAc)2(2.2mg，10mol％)、XPhos(19.1mg，20mol％)、NBE-CO2K (3.5mg, 10 mol%), 2-methoxybiphenyl (0.2mmol, 1.0equiv.), (R) -N- (2, 3-epoxypropyl) phthalimide (0.6mmol, 3.0equiv.), and dry N-methylpyrrolidone (1.0 mL). The reaction flask was capped and sealed and stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 ℃ and stirred for 24 hours. After cooling the reaction vessel to room temperature, quench with water (10mL), extract with methyl tert-butyl ether (3X 10mL), Na2SO4Dried, filtered and concentrated under vacuum. Purification was performed by column chromatography using petroleum ether and ethyl acetate 5:1(v/v) as eluent to give 48mg (R) -2- ((7- (2-methoxyphenyl) -2, 3-dihydrobenzofuran-2-yl) methyl) isoindoline-1, 3-dione (yellow oily liquid, yield 62%).1H NMR(400MHz,CDCl3): δ 7.86-7.84(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 ═ 13.8,5.7, 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: c24H19NNaO4[M+Na+]408.1206, found: 408.1213.

Claims (9)

1. A method for synthesizing 2, 3-dihydrobenzofuran compounds is characterized by comprising the following steps: under the protection of nitrogen, stirring aromatic iodide A, epoxy compound B, palladium catalyst, phosphine ligand and norbornene derivative in an organic solvent at 30-120 ℃ for reaction, and separating and purifying after the reaction is finished to obtain 2, 3-dihydrobenzofuran compounds C and D; the reaction formula is as follows:
wherein n is the number of the substituent groups, and n is more than or equal to 0 and less than or equal to 4;
R1Is aryl, heterocyclic aryl, C1-20Alkyl radical, C1-20Alkoxy radical, C1-20Alkylthio, ester, amide, cyano, nitro, sulfonyl or halogen; when n is not less than 2, each R1The same or different;
R2Is hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester, cyano, nitro, amide, sulfonyl, or halogen;
R3Is hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester, cyano, nitro, amide, sulfonyl, or halogen;
The norbornene derivative has the following structure:
Wherein:
R5is a substituent on a five-membered ring, o represents the number of the substituent, and o is more than or equal to 1 and less than or equal to 8;
R6Is a substituent on a double bond, p represents the number of the substituent, and p is more than or equal to 0 and less than or equal to 2;
R5、R6Independently selected from the group consisting of carboxylate, ester, cyano, nitro, amido, sulfonyl, C of a metal ion M1-10Alkoxy, aryl, heterocyclic aryl, C1-10One of alkyl and halogen, M is Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+One of (1); when o is greater than or equal to 2, each R5The same or different; when p is 2, each R6The same or different;
the R is5、R6At least one carboxylate selected from the group consisting of metal ions M.
2. The method of claim 1, wherein: the feeding molar ratio of the aryl iodide A to the epoxy compound B is 1: 0.01-10.
3. The method of claim 1, wherein: the palladium catalyst is Pd (PPh)3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2Or [ Pd (allyl) Cl]2。
4. The method of claim 1, wherein: 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' -diphenyl ] -2-yl) phosphine), dicyclohexyl (2',6' -dimethoxy- [1,1 '-diphenyl ] -2-yl) phosphine, 2' - (dicyclohexylphosphino) -N, N-dimethyl- [1,1 '-diphenyl ] -2-amine, dicyclohexyl (2',6 '-diisopropoxy- [1,1' -diphenyl ] -2-yl) phosphine, N, One of tris (furan-2-yl) phosphine, (3S,5S,7S) -adamantan-1-yl ((1R,5S) -adamantan-2-yl) (butyl) phosphine.
5. The method of claim 4, wherein: the triaryl phosphine is triphenylphosphine or trifuryl phosphine; the trialkyl phosphine is tricyclohexyl phosphine.
6. The method of claim 1, wherein: the organic solvent is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol etherMethyl tert-butyl ether, 1, 4-epoxyhexaalkane, 1, 3-epoxyhexaalkane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride and C4-12Saturated alkane of (C)3-12Fluoro or chloro alkane, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C3-12One or more saturated alkyl nitriles.
7. The method of claim 1, wherein: the palladium catalyst is Pd (OAc)2The phosphine ligand is dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -diphenyl)]-2-yl) phosphine, said norbornene derivative is norbornene carboxylate, and said organic solvent is N-methylpyrrolidone.
8. the method of claim 1, wherein: under the protection of nitrogen, biphenyl aryl iodide E and amino-substituted epoxy compound F react in an organic solvent under the action of a palladium catalyst, a phosphine ligand and a norbornene derivative to obtain an intermediate G, and an amino protecting group R in the intermediate G is removed without separation10To obtain 5-HT2CA receptor agonist H; the reaction formula is as follows:
Wherein:
x and y represent the number of substituent groups, z represents the number of methylene, x is more than or equal to 0 and less than or equal to 5, y is more than or equal to 0 and less than or equal to 3, and z is more than or equal to 1 and less than or equal to 10;
R7And R8Is a substituent on the aromatic iodide, R7And R8Independently selected from aryl, heterocyclic aryl, C1-20One of alkyl, ester group, cyano, nitro, amido, sulfonyl, alkoxy and halogen; when x is greater than or equal to 2, each R7The same or different; when y is greater than or equal to 2, each R8The same or different;
R9Is hydrogen, aryl, heterocyclic aryl, C1-20One of alkyl, ester group, amido, sulfonyl, alkoxy, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, alkanoyl, sulfonyl, phthaloyl and azide;
R10Is one of tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, alkanoyl, sulfonyl, phthaloyl and azide.
9. The method of claim 8, wherein: x 2, y 1, z 1, R7is Cl, R8Is F, R9Is hydrogen, 5-HT2CThe structural formula of the receptor agonist H is
CN201810299042.8A 2018-04-04 2018-04-04 Method for synthesizing 2, 3-dihydrobenzofuran compound Expired - Fee Related CN108329285B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810299042.8A CN108329285B (en) 2018-04-04 2018-04-04 Method for synthesizing 2, 3-dihydrobenzofuran compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810299042.8A CN108329285B (en) 2018-04-04 2018-04-04 Method for synthesizing 2, 3-dihydrobenzofuran compound

Publications (2)

Publication Number Publication Date
CN108329285A CN108329285A (en) 2018-07-27
CN108329285B true CN108329285B (en) 2019-12-10

Family

ID=62932619

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810299042.8A Expired - Fee Related CN108329285B (en) 2018-04-04 2018-04-04 Method for synthesizing 2, 3-dihydrobenzofuran compound

Country Status (1)

Country Link
CN (1) CN108329285B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110156657B (en) * 2019-04-17 2022-04-12 兰州大学 Synthesis method of 4-aminoindole
CN112174995B (en) * 2020-10-27 2021-12-03 武汉大学 Double-silicon compound, preparation method and application thereof
CN114920793B (en) * 2022-06-01 2023-08-08 贵州大学 Estrone compound containing isopropanolamine substructure, preparation method, composition and application
CN115353484A (en) * 2022-07-05 2022-11-18 西北师范大学 Synthetic method of 4-amino substituted carbazole, dibenzo [ b, d ] furan and fluorene derivatives

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3503997A (en) * 1969-02-07 1970-03-31 Standard Oil Co Alpha-hydroxynitrile production
WO2008024953A2 (en) * 2006-08-25 2008-02-28 Brandeis University Transition metal-catalyzed alkylation of c-h bonds with organoboron reagents
FR2958289B1 (en) * 2010-03-30 2012-06-15 Sanofi Aventis PROCESS FOR THE PREPARATION OF 3-KETO-BENZOFURAN DERIVATIVES

Also Published As

Publication number Publication date
CN108329285A (en) 2018-07-27

Similar Documents

Publication Publication Date Title
CN108329285B (en) Method for synthesizing 2, 3-dihydrobenzofuran compound
TW202026280A (en) Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylate and preparation process thereof
CN108997215B (en) Preparation method of 1,2,3, 4-tetrahydroisoquinoline derivative
KR20150040340A (en) Process and intermediates for preparing integrase inhibitors
JP2014201545A (en) METHOD OF MANUFACTURING 2-HYDROXYMETHYL-2,3-DIHYDRO-THIENO[3,4-b][1,4]DIOXIN-5,7-DICARBOXYLIC ACID DIALKYL ESTER
CN110437068B (en) Preparation method of aromatic methylation
CN111592507A (en) Novel green and simple method for preparing polysubstituted furan
Meshram et al. Bismuthtriflate-catalyzed Reaction of N-Alkylisatins with Allyltrimethylsilane
EP0834497B1 (en) Process for producing 3-isochromanones
CN112920033A (en) Preparation method of o-alkynyl phenylcyclobutanone and preparation method of naphthalenone
CN109535120B (en) Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone
CN111484436A (en) Method for introducing isopentenyl group to C3 position of indole
CN115215814A (en) Synthetic method of isoxazolidine compounds
CN110294708B (en) Preparation method of trifluoroethylselenophenanthridine and 3, 4-dihydroisoquinoline derivatives
CN107935913B (en) Carbazole compound and synthesis method and application thereof
CN106957318B (en) Condensed polycyclic indoline compound, preparation method, pharmaceutical composition and application thereof
CN106831522B (en) Lactam compound and preparation method thereof
CN115260096B (en) Method for synthesizing dihydroisoquinolinones based on carbon monoxide gas or carbon monoxide substitution source
CN110330456B (en) Synthetic method of 2,2, 2-trifluoroethyl substituted phenanthridine compound
CN115160356B (en) Method for effectively preparing vinyl silane derivative through cascade three-component reaction
CN113149923B (en) 3-cyano-N-oxidoisoxazoline compound and synthetic method thereof
KR101529963B1 (en) Method for preparing everolimus and its intermediates
CN109776465B (en) Synthesis method of benzodihydrofuran derivative with C2 quaternary carbon center
CN114437061B (en) Preparation method of diketone compound and preparation method of imidazole derivative
CN109824620B (en) Preparation method of benzoxazepine seven-membered ring

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20191210