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

A method of synthesis 2,3- Dihydrobenzofuranes class compounds Download PDF

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CN108329285A
CN108329285A CN201810299042.8A CN201810299042A CN108329285A CN 108329285 A CN108329285 A CN 108329285A CN 201810299042 A CN201810299042 A CN 201810299042A CN 108329285 A CN108329285 A CN 108329285A
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methyl
phosphine
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dihydrobenzofuranes
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周强辉
吴承贵
程鸿刚
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Wuhan University WHU
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    • 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
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • 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
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Abstract

The present invention provides a kind of methods of 2,3 Dihydrobenzofuranes class compounds of synthesis.Aromatic iodide, epoxide, palladium catalyst, Phosphine ligands, norbornene derivative are first dissolved in organic solvent by the present invention together, are then stirred to react at 30 DEG C to 120 DEG C, and separating-purifying is to get to 2,3 Dihydrobenzofuranes class compounds after reaction.This method can efficiently, it is economical, greenly synthesize 2,3 Dihydrobenzofuranes class compounds.This method mild condition, substrate universality is good, and yield is high, and 2,3 prepared Dihydrobenzofuranes class compounds are widely used in pharmaceutical chemistry and organic chemistry filed.

Description

A method of synthesis 2,3- Dihydrobenzofuranes class compounds
Technical field
The present invention relates to a kind of methods of synthesis 2,3- Dihydrobenzofuranes class compounds, belong to organic synthesis field.
Background technology
2,3- Dihydrobenzofuranes are a kind of important structural units, are widely present in many biologically active natural [a) Nichols, D.E. in product and pharmaceutical molecules structure；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).Radadiya,A；Shah,A.Eur.J.Med.Chem.2015,97, 356.].Currently, for 2, there are many report [a) Bertolini, F. for the synthetic method of 3- Dihydrobenzofuranes class compounds； Pineschi,M.Org.Prep.Proced.Int.2009,41,385.b)Sheppard,T.D.J.Chem.Res.2011,35, 377.], but from simple raw material, the method for efficiently preparing 2,3- Dihydrobenzofuranes class compounds is but rarely reported. There are two types of the primary synthetic methods being currently known：The first is first in phenol ortho alkylation, and then phenolic hydroxyl group is to double bond addition, Obtain 2,3- Dihydrobenzofuranes class 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.], but this method back needs to use highly basic, latter step needs to use strong acid；The Two kinds are that [3+2] ring is occurred with epoxide and is added using trifluoromethanesulfonic acid -2- (trimethyl silicon substrate) aryl esters as aryne precursor At reaction synthesis 2,3- Dihydrobenzofuranes classes compound [Beltr á n-Rodil, S.；D.；Guitián, E.Synlett.2007,1308.], but this method is difficult with Material synthesis, reaction selectivity is poor, epoxy substrate universality is poor The shortcomings of.In order to solve problem above, we have developed using fragrant iodo object simple and easy to get, epoxide as raw material, with Palladium compound/phosphorus ligand is catalyst, norbornene derivative is co-catalyst, carries out reaction and prepares 2,3- Dihydrobenzofuranes The new method of class compound.This method raw material is easy to get, is easy to operate, mild condition, wide application range of substrates, contains 2 for synthesis, The important drugs molecule and natural products of 3- Dihydrobenzofuranes structural units provide a kind of very efficient, convergence method.
Invention content
In order to solve the problems in the existing technology, the present invention provides one kind and efficiently synthesizing 2,3- Dihydrobenzofuranes classes The method of compound.
Technical solution provided by the invention is specific as follows：
A kind of method of synthesis 2,3- Dihydrobenzofuranes class compounds, carries out in accordance with the following steps：Under nitrogen protection, By fragrant iodo object A, epoxide B, palladium catalyst, Phosphine ligands and norbornene derivative under conditions of alkali-free, in machine It is stirred to react in solvent, preferred 30-120 DEG C of temperature, separating-purifying is to get to 2,3- Dihydrobenzofuranes classes after reaction Close object.
The reaction equation of the present invention can indicate as follows：
Wherein, formula A compounds represent fragrant iodo object, and formula B compounds represent epoxide, formula C and formula D compound generations Table 2,3- Dihydrobenzofuranes class compounds.
Wherein, n is the number of substituent group, 0≤n≤4.When n >=2, each R1Independently selected from substitution or unsubstituting aromatic yl, One in heterocyclic aryl, alkyl, substitution alkyl, ester group, amide groups, cyano, nitro, sulfonyl, alkoxy, alkylthio group, halogen Kind.R2And R3Independently selected from hydrogen, substitution or unsubstituting aromatic yl, substitution or unsubstituting heterocycle aryl, alkyl, substitution alkyl, ester One kind in base, cyano, nitro, amide groups, sulfonyl, halogen.
Above-mentioned substituted or unsubstituted aryl refers to unsubstituted aryl or can carry the aryl of one or more substituent groups. The substituent group does not limit in any way, common substituent group for example aryl, heterocyclic aryl, alkyl, ester group, cyano, nitro, Amide groups, sulfonyl, alkoxy and halogen etc..On the aromatic radical can carry these substituent groups in it is one or more, work as tool When having multiple substituent groups, this multiple substituent group can be identical or different.
Above-mentioned substituted or unsubstituted heterocyclic aryl can refer to unsubstituted heterocyclic aryl or can be taken with one or more The heterocyclic aryl of Dai Ji, unsubstituted heterocyclic aryl can be furans, pyrroles, pyridine, indoles, naphthalene, anthracene, carbazole, green onion etc., described Substituent group does not limit in any way, common substituent group such as aryl, heterocyclic aryl, alkyl, ester group, cyano, nitro, amide Base, sulfonyl, alkoxy and halogen etc..On the aromatic radical can carry these substituent groups in it is one or more, when with more When a substituent group, this multiple substituent group can be identical or different.
Abovementioned alkyl refers to the alkyl with 1~20 carbon atom.
Above-mentioned substitution alkyl can be expressed asWherein m be 0 and arbitrary positive integer, preferably m be 0 to 20 between it is whole Number, X can be-OR4、-OSi(R4)3、-SR4、-SSiR4、-SeR4、-N(R4)2、-Si(R4)3Equal groups, wherein R4It represents hydrogen, take Generation or unsubstituting aromatic yl, substitution or unsubstituting heterocycle aryl, alkyl, ester group, cyano, nitro, amide groups, sulfonyl, halogen etc., And can be one or more in these substituent groups, when with multiple substituent groups, this multiple substituent group can be identical or not Together.
Above-mentioned alkoxy refers to the alkoxy with 1~10 carbon atom.
Above-mentioned substituent R2And R3, may be the same or different.
Norbornene derivative described in the method for the present invention, structural formula can be expressed as：
Wherein (R5)oSubstituent group on the five-membered ring of the left side, each o independently are 1 to 8 integer；(R6)pFor in double bond Substituent group, each p independently are 0 to 2 integer.R5Configuration can be inner mold (Endo) or external form (Exo).
I), can be identical when substituent group number is multiple on the five-membered ring of the left side, it can not also be identical；Substituent group in double bond , can be identical when number is 2, it can not also be identical.
ii)R5And R6The type of substituent group can be identical, can not also be identical.
Iii) each R5And R6It independently is CO2M (carboxylate of metal ions M), ester group, cyano, nitro, amide groups, sulphur One kind in acyl group, alkoxy, aryl, heterocyclic aryl, alkyl, substitution alkyl, halogen, M are selected from Li+、Na+、K+、Rb+、Cs+、 Mg2+、Ca2+、Sr2+、Ba2+In one kind.The aryl can carry one or more substituent groups, and substituent group is not with any side Formula limits, including common substituent group is such as aryl, alkyl, substitution alkyl, alkoxy, ester group, cyano, nitro, halogen.Institute Stating on aromatic radical can carry one or more in these substituent groups, and when with multiple substituent groups, this multiple substituent group can be with It is identical or different.
Abovementioned alkyl refers to the alkyl with 1~10 carbon atom.
Above-mentioned alkoxy refers to the alkoxy with 1~10 carbon atom.
In the method for the present invention, solvent is Conventional solvents, such as methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- Methyltetrahydrofuran, ether, dimethyl second diether, methyl tertiary butyl ether(MTBE), six alkane of 1,4- epoxies, six alkane of 1,3- epoxies, dichloromethane Alkane, 1,2- dichloroethanes, chloroform, carbon tetrachloride, C4-12Saturated alkane, C3-12Fluoro or chloralkane, benzene, toluene, two Toluene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetone, N-Methyl pyrrolidone, second Nitrile, C3-12Saturated alkyl nitrile etc..
The present invention preferably reacts at 30 DEG C to 120 DEG C.
It is preferable to use palladium catalysts to promote to react for the catalyst of the present invention, adoptable palladium catalyst include zeroth order or The palladium compound of divalent, such as：Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2Deng.Useful commercial reagent is not necessarily to specially treated.
Phosphine ligands, such as triaryl phosphine (such as phenyl, furyl), trialkyl phosphine (such as ring can be used in the ligand of the present invention Hexyl etc.), XPhos (dicyclohexyl (2', 4', 6'- triisopropyl-[1,1'- diphenyl] -2- bases) phosphine), BrettPhos (two Cyclohexyl (2', 4', 6'- triisopropyl -3,6- dimethoxys-[1,1'- diphenyl] -2- bases) phosphine), SPhos (dicyclohexyls (2', 6'- dimethoxy-[1,1'- diphenyl] -2- bases) phosphine), DavePhos (2'- (dicyclohexyl phosphino-)-N, N- dimethyl - [1,1'- diphenyl] -2- amine), RuPhos (dicyclohexyl (2', 6'- diisopropoxy-[1,1'- diphenyl] -2- bases) phosphine), Three (furans -2- bases) phosphines, (3S, 5S, 7S)-adamantane -1- bases ((1R, 5S)-adamantane -2- bases) (butyl) phosphine etc..Quotient can be used Product reagent is not necessarily to specially treated.
The invention further relates to a kind of 5-HT2CReceptor stimulating agent (5-HT2C receptor agonist)WAY-255719 And the like preparation method, carry out in accordance with the following steps：
(1) under nitrogen protection, biphenyl type aryl iodide E and amino substitution epoxide F in catalyst, match Under body, norbornene derivative effect, reaction (catalyst, ligand, norbornene derivative and definition described previously in a solvent It is identical), compound G is prepared, without separation；
(2) the amino protecting group R in G is sloughed10, prepare compound H
Wherein catalyst, ligand, norbornene derivative, the definition of solvent are same as above；Wherein, (R7)x(R8)y For the substituent group on aromatic iodide：i)(R7)xMiddle x be 0 to 5 integer, when having multiple substituent groups, substituent group can it is identical or It is different；(R8)yThe integer that middle y is 0 to 3, when having multiple substituent groups, substituent group can be identical or different；ii)R7And R8Substituent group It can be identical or different；Iii) each R7And R8It independently is aryl, heterocyclic aryl, alkyl, substitution alkyl, ester group, cyano, nitre Base, amide groups, sulfonyl, alkoxy and halogen etc..R9For hydrogen, aryl, heterocyclic aryl, alkyl, substitution alkyl, ester group, amide Base, sulfonyl and alkoxy etc..R9Can also be tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxy-benzyl (PMB), alkane acyl The protecting group or precursor of the amino such as base, sulfonyl, phthalyl and nitrine.R10For tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl Base, to the protecting group or precursor of the amino such as methoxy-benzyl (PMB), alkanoyl, sulfonyl, phthalyl and nitrine.R7 And R8For aryl or heterocyclic aryl when, aryl or heterocyclic aryl can carry one or more substituent groups, and substituent group is not with any Mode limits, including common substituent group is such as aryl, alkyl, substitution alkyl, alkoxy, ester group, cyano, nitro, halogen. It can be carried on the aromatic radical one or more in these substituent groups；When with multiple substituent groups, this multiple substituent group can With identical or different.The integer that z is 1 to 10 indicates the length of carbochain in 1 bit substituent of epoxy.
In step (2), described sloughs R10The condition and method of protecting group are the conventional method of the such reaction in this field And condition, i.e., after step (1), without subsequent processing, utilize (i) catalytic hydrogenation, (ii) trifluoroacetic acid or (iii) H2NNH2·H2O etc. sloughs amino protecting group R10.
Abovementioned alkyl refers to alkyl, such as methyl, ethyl, isopropyl etc. with 1~10 carbon atom.
Above-mentioned alkoxy refers to the alkoxy with 1~10 carbon atom, such as methoxyl group etc..
Above-mentioned halogen refers to fluorine, chlorine, bromine atom.
The molar ratio of two kinds of reactants of the method for the present invention is fragrant iodo object:Epoxide=1:1-10, preferably It is 1:3.
The above-mentioned reaction time, reaction temperature was 30-120 DEG C within 48 hours.Oil bath (such as silicon can be used in heating process Oil, paraffin oil etc.) or other mode of heatings.
The present invention preferably after completion of the reaction post-processes reaction product, including suction filtration, concentration, recrystallization and column layer The purification process such as analysis.
Sand core funnel can be used to filter at reduced pressure for the suction filtration process.
The methods of air-distillation, vacuum distillation can be used in the concentration process, such as is concentrated with rotavapor under vacuum.
The purification process is to obtain pure product by column chromatography.
The method of the invention realizes aromatic iodides and epoxide coupling conversion to obtain 2,3- Dihydrobenzofuranes Class compound, it is efficient, it is at low cost, it can be widely used for preparing the compound for including 2,3- Dihydrobenzofuranes structural units.With The prior art is compared, and the present invention has the following advantages：
1. primary raw material according to the present invention is the aromatic iodide and epoxide being easy to get, this raw material useful commercial Change reagent, is not necessarily to specially treated, and cheap, can largely be prepared with simple method；
2. the catalyst that the reaction involved by the method for the present invention uses is cheap palladium compound and phosphorus ligand, compared to it Catalyst or complex compound that preceding coupling reaction uses etc. are an important improvement；
3. norbornene of catalytic amount that the reaction involved by the method for the present invention uses or derivatives thereof is used as co-catalyst, So that side reaction is less, reaction system is more clean；
4. the method for the present invention need not be promoted with alkali；
5. the optical purity for the chiral epoxy raw material that the method for the present invention is used is fully retained in the product；
6. the reaction condition involved by the method for the present invention has good functional group's tolerance and substrate universality, substituent group Can be alkyl, alkoxy, cyano, ester group, nitro, halogen atom (F, Cl, Br) etc., the alkyl of various straight chains or branch also may be used To complete reaction.
Specific implementation mode
The present invention is further described with reference to embodiment, palladium catalyst is with Pd (OAc) in following embodiment2For, phosphine For ligand is with dicyclohexyl (2', 4', 6'- triisopropyl-[1,1'- diphenyl] -2- bases) phosphine (i.e. XPhos), norbornene Derivative is with NBE-CO2For K, organic solvent by taking N-Methyl pyrrolidone as an example, but do not limit the invention in any way Protection domain.
Embodiment 1：The preparation of 7- methyl -2- (phenoxymethyl) -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), phenyl glycidyl ether (0.6mmol, 3.0equiv.) and dry N- methylpyrroles Alkanone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings 24 later Hour.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=10:1 (v/v), obtains 7- first Base -2- (phenoxymethyl) -2,3- Dihydrobenzofuranes -5- methyl formates 49mg (white solid, yield 82%).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(ESI-TOF)：Calculated value：C18H18NaO4[M+Na+] 321.1097, measured value： 321.1100。
Embodiment 2：(R) preparation of -7- methyl -2- (benzyloxymethyl) -2,3- Dihydrobenzofuranes -5- methyl formates and It is prepared by gram-grade
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), (R)-benzyl glycidyl ether (0.6mmol, 3.0equiv.) and dry N- methyl Pyrrolidones (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred It mixes 24 hours.It after reaction vessel is cooled to room temperature, is quenched with water (10mL), is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=10:1 (v/v), obtains To 7- methyl -2- (benzyloxymethyl) -2,3- Dihydrobenzofuranes -5- methyl formates 58mg (pale yellowish oil liquid, yield 93%, ee>99%).1H NMR(400MHz,CDCl3)：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)：Calculated value：C19H20NaO4[M+Na+] 335.1254, measured value：335.1259.
Under inert gas protection, Pd (OAc) is added into dry and 50mL reaction bulbs equipped with magnetic stir bar2 (112.3mg, 10mol%), XPhos (476.7mg, 20mol%), NBE-CO2K (88.1mg, 10mol%), -4 iodine of 3- methyl Methyl benzoate (5mmol, 1.0equiv.), (R)-benzyl glycidyl ether (15mmol, 3.0equiv.) and dry N- first Base pyrrolidones (10mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred It mixes 24 hours.It after reaction vessel is cooled to room temperature, is quenched with water (100mL), is extracted with methyl tertiary butyl ether(MTBE) (3 × 100mL), Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=10:1 (v/v), obtains To 7- methyl -2- (benzyloxymethyl) -2,3- Dihydrobenzofuranes -5- methyl formate 1.33g, (pale yellowish oil liquid, yield 85%).
Embodiment 3：The preparation of 7- methyl -2- (butyryl acyloxy methyl) -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), n-butyric acie ethylene oxidic ester (0.6mmol, 3.0equiv.) and dry N- methyl pyrroles Pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings later 24 hours.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4 It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=10:1 (v/v), obtains 7- first Base -2- (butyryl acyloxy methyl) -2,3- Dihydrobenzofuranes -5- methyl formates 53mg (pale yellowish oil liquid, yield 91%) 。1H NMR(400MHz,CDCl3)：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)：Calculated value：C16H20NaO5 [M+Na+] 315.1203, measured value：315.1206.
Embodiment 4：The preparation of 7- methyl -2- (methoxy) -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), methyl glycidyl ether (0.6mmol, 3.0equiv.) and dry N- methylpyrroles Alkanone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings 24 later Hour.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=10:1 (v/v), obtains 7- first Base -2- (methoxy) -2,3- Dihydrobenzofuranes -5- methyl formates 34mg (pale yellowish oil liquid, yield 72%).1H NMR(400MHz,CDCl3)：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)：Calculated value：C13H16NaO4[M+Na+] 259.0941, measured value：259.0942.
Embodiment 5：The preparation of 7- methyl -2- methylol -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), glycidol (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=2:1 (v/v) obtains 7- methyl -2- hydroxyls Methyl -2,3- Dihydrobenzofuranes -5- methyl formates 32mg (colourless oil liquid, yield 73%).1H NMR(400MHz, CDCl3)：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)：Calculated value：C12H14NaO4[M+Na+] 245.0784, measured value：245.0792.
Embodiment 6：The preparation of 7- methyl -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v), obtains 7- methyl -2,3- Dihydrobenzofuranes -5- methyl formates 32mg (yellow oily liquid, yield 83%).1HNMR(400MHz,CDCl3)：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 value：C11H12NaO3[M+Na+] 215.0679, measured value：215.0683.
Embodiment 7：The preparation of 2,7- dimethyl -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), propylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v), obtains 2,7- dimethyl- 2,3- Dihydrobenzofuranes -5- methyl formates 40mg (white solid, yield 97%).1HNMR(400MHz,CDCl3)：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)：Calculated value：C12H15O3[M+H+] 207.1016, measured value：207.1018.
Embodiment 8：The preparation of 7- methyl -2- normal-butyl -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), 1,2- oxepanes (0.6mmol, 3.0equiv.) and dry N- crassitudes Ketone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, and it is small to heat the mixture to 80 DEG C of stirrings 24 later When.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, Filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v) obtains 7- methyl -2- Normal-butyl -2,3- Dihydrobenzofuranes -5- methyl formates 35mg (pale yellowish oil 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)：Calculated value：C15H20NaO3[M+Na+] 271.1305, actual measurement Value：271.1312.
Embodiment 9：The preparation of 7- methyl -2- positive decyl -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), 1,2- Epoxydodecanes (0.6mmol, 3.0equiv.) and dry N- methylpyrroles Alkanone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings 24 later Hour.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=50:1 (v/v), obtains 7- first Base -2- positive decyl -2,3- Dihydrobenzofuranes -5- methyl formates 45mg (yellow oily liquid, yield 67%).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)：Calculated value：C21H32NaO3[M+Na+] 355.2244, measured value：355.2245.
Embodiment 10：The preparation of 7- methyl -2- n-hexadecyl -2,3- Dihydrobenzofuranes -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), 1,2- epoxies octadecane (0.6mmol, 3.0equiv.) and dry N- methylpyrroles Alkanone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings 24 later Hour.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=50:1 (v/v), obtains 7- first Base -2- n-hexadecyl -2,3- Dihydrobenzofuranes -5- methyl formates 67mg (white solid, yield 80%).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)：Calculated value：C27H44NaO3[M+Na+] 439.3183, measured value：439.3184.
Embodiment 11：7- methyl -2- ((1,3- dioxoisoindolin -2- bases) methyl) -2,3- Dihydrobenzofuranes -5- The preparation of methyl formate
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), N- (2,3- glycidyl) phthalic amide (0.6mmol, 3.0equiv.) and dry Dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, later adds mixture Heat stirs 24 hours to 80 DEG C.After reaction vessel is cooled to room temperature, be quenched with water (10mL), with methyl tertiary butyl ether(MTBE) (3 × It 10mL) extracts, Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=2:1 (v/v), 7- methyl -2- ((1,3- dioxoisoindolin -2- bases) methyl) -2,3- Dihydrobenzofuranes -5- formic acid first is obtained Ester 42mg (white solid, yield 60%).1H NMR(400MHz,CDCl3)：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)：Calculated value：C20H17NNaO5[M+Na+] 374.0999, measured value： 374.1008。
Embodiment 12：7- methyl -2- (((9H- carbazole -4- bases) oxygroup) methyl) -2,3- Dihydrobenzofuranes -5- formic acid The preparation of methyl esters
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), 4- propylene oxide oxygroup carbazoles (0.6mmol, 3.0equiv.) and dry N- methyl Pyrrolidones (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred It mixes 24 hours.It after reaction vessel is cooled to room temperature, is quenched with water (10mL), is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=5:1 (v/v), obtains 7- methyl -2- (((9H- carbazole -4- bases) oxygroup) methyl) -2,3- Dihydrobenzofuranes -5- methyl formates 69mg (white solid, Yield 89%).1H NMR(400MHz,CDCl3)：δ 8.08 (s, 1H), 7.81 (d, J=8.0Hz, 2H), 7.65 (d, J= 8.0Hz, 1H), 7.36-7.30 (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)：Calculated value：C24H21NNaO4[M+Na+] 410.1357, measured value：410.1365.
Embodiment 13：7- methyl -2- ((((8R, 9S, 13S, 14S) -7,8,9,11,12,13,14,15,16,17- decahydros - 13- methyl-17s-oxo -6H- cyclopentas [a] phenanthrene -3- bases) oxygroup) methyl) -2,3- Dihydrobenzofuranes -5- formic acid first The preparation of ester
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), (8R, 9S, 13S, 14S) -6,7,8,9,11,12,13,14,15,16- decahydro -13- Methyl -3- (((R)-ethylene oxide -2- bases) methoxyl group) -17H- cyclopentas [a] phenanthrene -17- ketone (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, 80 DEG C are heated the mixture to later to stir 24 hours.After reaction vessel is cooled to room temperature, it is quenched with water (10mL), uses methyl- tert Butyl ether (3 × 10mL) extracts, Na2SO4It is dry, filtering, reduced under vacuum.To be purified with column chromatography, eluant, eluent is dichloromethane, Obtain 7- methyl -2- ((((8R, 9S, 13S, 14S) -7,8,9,11,12,13,14,15,16,17- decahydros -13- methyl-17s-oxygen Generation -6H- cyclopentas [a] phenanthrene -3- bases) oxygroup) methyl) -2,3- Dihydrobenzofuranes -5- methyl formate 74mg (colorless oils Shape 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, 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：C30H34NaO5[M+Na+] 497.2298, measured value：497.2307.
Embodiment 14：(2R) -7- methyl -2- ((((4R) -4- ((3S, 8R, 9S, 10S, 13R, 14S, 17R) -10,13- two Ten hexahydro -3- hydroxyl -1H- cyclopentas [a] phenanthrene -17- bases of methyl) valeryl) oxygroup) methyl) -2,3- dihydrobenzo furans It mutters the preparations of -5- methyl formates
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), -4 iodobenzene first of 3- methyl Sour methyl esters (0.2mmol, 1.0equiv.), (4R) -4- ((3S, 8R, 9S, 10S, 13R, 14S, 17R) -3- hydroxyls -10,13- bis- Ten hexahydro -1H- cyclopentas [a] phenanthrene -17- bases of methyl) valeric acid (0.6mmol, 3.0equiv.) and dry N- methylpyrroles Alkanone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings 24 later Hour.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is toluene:Ether=2:1 (v/v) obtains (2R) -7- methyl - 2- ((((4R) -4- (ten hexahydro -3- hydroxyl -1H- cyclopentadiene of (3S, 8R, 9S, 10S, 13R, 14S, 17R) -10,13- dimethyl And [a] phenanthrene -17- bases) valeryl) oxygroup) methyl) -2,3- Dihydrobenzofuranes -5- methyl formates 99mg (colourless oil 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),1.30-1.16(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)： Calculated value：C36H52NaO6[M+Na+] 603.3656, measured value：603.3658.
Embodiment 15：The preparation of 7- methyl -2,3- Dihydrobenzofuranes
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- iodotoluenes (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL). Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours.Reaction vessel It after being cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, it filters, under vacuum Concentration.Purified with column chromatography, eluant, eluent is petroleum ether, obtains 7- methyl -2,3- Dihydrobenzofuranes 23mg (colorless oil liquid Body, yield 85%).1H NMR(400MHz,CDCl3)：δ 7.04 (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).
Embodiment 16：The preparation of 7- isopropyl -2,3- Dihydrobenzofuranes
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- iodine cumenes (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL). Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours.Reaction vessel It after being cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, it filters, under vacuum Concentration.Purified with column chromatography, eluant, eluent is petroleum ether, obtains 7- isopropyl -2,3- Dihydrobenzofuranes 25mg (colorless oil liquid Body, yield 77%).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)：Calculated value：C11H15O[M+H+] 163.1123, measured value：163.1126.
Embodiment 17：The preparation of 7- phenyl -2,3- Dihydrobenzofuranes
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- iodine biphenyl (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL). Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours.Reaction vessel It after being cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, it filters, under vacuum Concentration.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=50:1 (v/v) obtains 7- phenyl -2,3- dihydrobenzos Furans 26mg (colourless oil 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)：Calculated value：C14H12NaO[M+Na+] 219.0780, measured value：219.0770.
Embodiment 18：The preparation of tertiary butyl ((2,3- Dihydrobenzofuranes -7- bases) methoxyl group) dimethylsilane
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), (benzyloxy) (tertiary fourth Base) dimethylsilane (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N- methyl pyrroles Pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, heats the mixture to 80 DEG C of stirrings later 24 hours.It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4 It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether, obtains tertiary butyl ((2,3- dihydrobenzo furans Mutter -7- bases) methoxyl group) dimethylsilane 29mg (colourless oil 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)：It is theoretical Calculated value：C15H24NaO2Si[M+Na+] 287.1438, measured value：287.1440.
Embodiment 19：The preparation of 2- (2,3- Dihydrobenzofuranes -7- bases) acetonitrile
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- (2- iodophenyls) second Nitrile (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v) obtains 2- (2,3- dihydros Benzofuran -7- bases) acetonitrile 26mg (colourless oil liquid, yield 82%).1H NMR(400MHz,CDCl3)：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 value：C10H10NO[M+H+] 160.0762, measured value：160.0761.
Embodiment 20：The preparation of 2- (2,3- Dihydrobenzofuranes -7- bases) methyl acetate
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- iodobenzene methyl acetates (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL). Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours.Reaction vessel It after being cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, it filters, under vacuum Concentration.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v) obtains 2- (2,3- Dihydrobenzofuranes- 7- yls) methyl acetate 25mg (colourless oil 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)：Calculated value：C11H12NaO3[M+Na+] 215.0679, measured value：215.0677.
Embodiment 21：The preparation of the fluoro- 2,3- Dihydrobenzofuranes of 7- methyl -6-
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2Fluoro- 3 iodine of K (3.5mg, 10mol%), 2- methyl-1s- Benzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v) obtains 7- methyl -6- Fluoro- 2,3- Dihydrobenzofuranes 25mg (pale yellowish oil liquid, yield 65%).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)：Calculated value：C9H10FO[M+H+] 153.0710, measured value：153.0720.
Embodiment 22：The preparation of the chloro- 2,3- Dihydrobenzofuranes of 7- methyl -6-
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2Chloro- 3 iodine of K (3.5mg, 10mol%), 2- methyl-1s- Benzene (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=20:1 (v/v) obtains 7- methyl -6- Chloro- 2,3- Dihydrobenzofuranes 22mg (yellow oily liquid, yield 64%).1H NMR(400MHz,CDCl3)：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 value：C9H10ClO[M+H+] 169.0420, measured value：169.0422.
Embodiment 23：The preparation of 7- methyl -2,3- Dihydrobenzofuranes -6- formic acid glycol esters
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- methyl -3- iodobenzene first Sour (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=2:1 (v/v), obtains 7- methyl -2,3- Dihydrobenzofuranes -6- formic acid glycol esters 22mg (pale yellowish oil 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)：It is theoretical Calculated value：C12H14NaO4[M+Na+] 245.0784, measured value：245.0790.
Embodiment 24：The preparation of -5 nitro -2,3- Dihydrobenzofuranes of 7- methyl
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- methyl -4- nitros - 1- iodobenzenes (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=10:1 (v/v) obtains 7- methyl -5- nitre Base -2,3- Dihydrobenzofuranes 22mg (yellow solid, yield 60%).1H NMR(400MHz,CDCl3)：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)：Calculated value： C9H9NNaO3[M+Na+] 202.0475, measured value：202.0477.
Embodiment 25：The preparation of N, 7- dimethyl -2,3- Dihydrobenzofuranes -5- formamides
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), N, 3- dimethyl -4- iodine Benzamide (0.2mmol, 1.0equiv.), ethylene oxide (0.6mmol, 3.0equiv.) and dry N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, is heated the mixture to 80 DEG C later and is stirred 24 hours. It after reaction vessel is cooled to room temperature, is quenched, is extracted with methyl tertiary butyl ether(MTBE) (3 × 10mL), Na with water (10mL)2SO4It is dry, mistake Filter, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=2:1 (v/v) obtains N, 7- dimethyl- 2,3- Dihydrobenzofuranes -5- formamides 29mg (white solid, yield 76%).1H NMR(400MHz,CDCl3)：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)：Calculated value：C11H14NO2[M+H+] 192.1019, measured value： 192.1022。
Embodiment 26：(R) -2- ((7- (2,6- 3,5-dimethylphenyls) -2,3- Dihydrobenzofuranes -2- bases) methyl) iso-indoles The preparation of quinoline -1,3- diketone
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2,6- dimethyl diphenyls (0.2mmol, 1.0equiv.), (R)-N- (2,3- glycidyl) phthalic amide (0.6mmol, 3.0equiv.) and drying N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, later heats mixture It is stirred 24 hours to 80 DEG C.It after reaction vessel is cooled to room temperature, is quenched with water (10mL), with methyl tertiary butyl ether(MTBE) (3 × 10mL) Extraction, Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=5:1(v/ V), (R) -2- ((7- (2,6- 3,5-dimethylphenyl) -2,3- Dihydrobenzofuranes -2- bases) methyl) isoindoline -1,3- bis- is obtained Ketone 41mg (colourless oil liquid, yield 53%).1H NMR(400MHz,CDCl3)：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)：It is theoretical Calculated value：C25H21NNaO3[M+Na+] 406.1414, measured value：406.1415.
Embodiment 27：(R) -2- ((7- (2- fluorophenyls) -2,3- Dihydrobenzofuranes -2- bases) methyl) isoindoline -1, The preparation of 3- diketone
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- fluorine biphenyl (0.2mmol, 1.0equiv.), (R)-N- (2,3- glycidyl) phthalic amide (0.6mmol, 3.0equiv.) and drying N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, later heats mixture It is stirred 24 hours to 80 DEG C.It after reaction vessel is cooled to room temperature, is quenched with water (10mL), with methyl tertiary butyl ether(MTBE) (3 × 10mL) Extraction, Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=5:1(v/ V), (R) -2- ((7- (2- fluorophenyls) -2,3- Dihydrobenzofuranes -2- bases) methyl) isoindoline -1,3- diketone 36mg is obtained (yellow oily liquid, yield 48%).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) .HRMS (ESI-TOF)：Calculated value： C23H16FNNaO3[M+Na+] 396.1006, measured value：396.1007.
Embodiment 28：(R) -2- ((7- (2- methoxyphenyls) -2,3- Dihydrobenzofuranes -2- bases) methyl) iso-indoles The preparation of quinoline -1,3- diketone
Under inert gas protection, Pd (OAc) is added into dry and 4.0mL reaction bulbs equipped with magnetic stir bar2 (2.2mg, 10mol%), XPhos (19.1mg, 20mol%), NBE-CO2K (3.5mg, 10mol%), 2- methoxyl biphenyls (0.2mmol, 1.0equiv.), (R)-N- (2,3- glycidyl) phthalic amide (0.6mmol, 3.0equiv.) and drying N-Methyl pyrrolidone (1.0mL).Reaction bulb is sealed and is stirred at room temperature about 5 minutes, later heats mixture It is stirred 24 hours to 80 DEG C.It after reaction vessel is cooled to room temperature, is quenched with water (10mL), with methyl tertiary butyl ether(MTBE) (3 × 10mL) Extraction, Na2SO4It is dry, filtering, reduced under vacuum.Purified with column chromatography, eluant, eluent is petroleum ether:Ethyl acetate=5:1(v/ V), (R) -2- ((7- (2- methoxyphenyls) -2,3- Dihydrobenzofuranes -2- bases) methyl) isoindoline -1,3- diketone is obtained 48mg (yellow oily liquid, yield 62%).1H NMR(400MHz,CDCl3)：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)：Calculated value： C24H19NNaO4[M+Na+] 408.1206, measured value：408.1213.

Claims (10)

1. a kind of method of synthesis 2,3- Dihydrobenzofuranes class compounds, which is characterized in that include the following steps：It is protected in nitrogen Under shield, fragrant iodo object A, epoxide B, palladium catalyst, Phosphine ligands and norbornene derivative are had in 30-120 DEG C It is stirred to react in solvent, after reaction separating-purifying, obtains 2,3- Dihydrobenzofuranes class compounds C and D；Reaction equation For：
Wherein, n is the number of substituent group, 0≤n≤4；
R1For aryl, heterocyclic aryl, C1-20Alkyl, C1-20Alkoxy, C1-20Alkylthio group, ester group, amide groups, cyano, nitro, sulphonyl Base or halogen；As n >=2, each R1It is identical or different；
R2For hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, cyano, nitro, amide groups, sulfonyl or halogen；
R3For hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, cyano, nitro, amide groups, sulfonyl or halogen.
2. preparation method according to claim 1, it is characterised in that：Aryl iodide A and feeding intake for epoxide B are rubbed You are than being 1:0.01~10.
3. according to the method described in claim 1, it is characterized in that：The norbornene derivative, has the following structure：
Wherein：
R5For the substituent group on five-membered ring, o represents substituent group number, 1≤o≤8；
R6For the substituent group in double bond, p represents substituent group number, 0≤p≤2；
R5、R6Independently selected from the carboxylate of metal ions M, ester group, cyano, nitro, amide groups, sulfonyl, C1-10Alkoxy, Aryl, heterocyclic aryl, C1-10One kind in alkyl, halogen, M Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+In It is a kind of；When o >=2, each R5It is identical or different；When p=2, each R6It is identical or different.
4. according to the method described in claim 1, it is characterized in that：The palladium catalyst is Pd (PPh3)4、Pd(dba)2、Pd2 (dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2Or [Pd (allyl) Cl]2。
5. according to the method described in claim 1, it is characterized in that：The Phosphine ligands are triaryl phosphine, trialkyl phosphine, two rings Hexyl (2', 4', 6'- triisopropyl-[1,1'- diphenyl] -2- bases) phosphine, dicyclohexyl (2', 4', 6'- triisopropyl -3,6- Dimethoxy-[1,1'- diphenyl] -2- bases) phosphine), dicyclohexyl (2', 6'- dimethoxy-[1,1'- diphenyl] -2- bases) Phosphine, 2'- (dicyclohexyl phosphino-)-N, N- dimethyl-[1,1'- diphenyl] -2- amine, dicyclohexyl (2', 6'- diisopropoxy - [1,1'- diphenyl] -2- bases) phosphine, three (furans -2- bases) phosphines, (3S, 5S, 7S)-adamantane -1- base ((1R, 5S)-adamantane - 2- yls) one kind in (butyl) phosphine.
6. according to the method described in claim 5, it is characterized in that：The triaryl phosphine is triphenylphosphine or three furyls Phosphine；The trialkyl phosphine is tricyclohexyl phosphine.
7. according to the method described in claim 1, it is characterized in that：The organic solvent is methanol, ethyl alcohol, isopropanol, uncle Butanol, tetrahydrofuran, 2- methyltetrahydrofurans, ether, dimethyl second diether, methyl tertiary butyl ether(MTBE), six alkane of 1,4- epoxies, 1,3- Six alkane of epoxy, dichloromethane, 1,2- dichloroethanes, chloroform, carbon tetrachloride, C4-12Saturated alkane, C3-12Fluoro or chloro Alkane, benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetone, N- Methyl pyrrolidone, acetonitrile, C3-12One or more of saturated alkyl nitrile.
8. according to the method described in claim 1, it is characterized in that：The palladium catalyst is Pd (OAc)2, the Phosphine ligands For dicyclohexyl (2', 4', 6'- triisopropyl-[1,1'- diphenyl] -2- bases) phosphine, the norbornene derivative is drop ice Piece olefinic carboxylic acid salt, the organic solvent are N-Methyl pyrrolidone.
9. according to the method described in claim 1, it is characterized in that：Under nitrogen protection, biphenyl type aryl iodide E and amino Substituted epoxide F reacts in organic solvent under the action of palladium catalyst, Phosphine ligands and norbornene derivative, obtains To intermediate G the amino protecting group R in intermediate G is sloughed without separation10, 5-HT is made2CReceptor stimulating agent H；Reaction equation For：
Wherein：
X, y represents the number of substituent group, and z represents the number of methylene, 0≤x≤5,0≤y≤3,1≤z≤10；
R7And R8For the substituent group on aromatic iodide, R7And R8Independently selected from aryl, heterocyclic aryl, C1-20Alkyl, ester group, cyanogen One kind in base, nitro, amide groups, sulfonyl, alkoxy, halogen；When x >=2, each R7It is identical or different；When y >=2, each R8Phase It is same or different；
R9For hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxy carbonyl Base, benzyl, to one kind in methoxy-benzyl, alkanoyl, sulfonyl, phthalyl, nitrine；
R10For tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxy-benzyl, alkanoyl, sulfonyl, phthalyl, nitrine In one kind.
10. according to the method described in claim 9, it is characterized in that：X=2, y=1, z=1, R7For Cl, R8For F, R9For hydrogen, 5-HT2CThe structural formula of receptor stimulating agent H is
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110156657A (en) * 2019-04-17 2019-08-23 兰州大学 A kind of synthetic method of 4- amino indole
CN112174995A (en) * 2020-10-27 2021-01-05 武汉大学 Double-silicon compound, preparation method and application thereof
CN114920793A (en) * 2022-06-01 2022-08-19 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

Citations (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
CN102822160A (en) * 2010-03-30 2012-12-12 赛诺菲 Method for preparing 3-keto-benzofurane derivatives

Patent Citations (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
CN102822160A (en) * 2010-03-30 2012-12-12 赛诺菲 Method for preparing 3-keto-benzofurane derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RENHE LI ET AL.: "Direct Annulation between Aryl Iodides and Epoxides through Palladium/Norbornene Cooperative Catalysis", 《ANGEW. CHEM. INT. ED.》 *

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CN110156657A (en) * 2019-04-17 2019-08-23 兰州大学 A kind of synthetic method of 4- amino indole
CN110156657B (en) * 2019-04-17 2022-04-12 兰州大学 Synthesis method of 4-aminoindole
CN112174995A (en) * 2020-10-27 2021-01-05 武汉大学 Double-silicon compound, preparation method and application thereof
CN112174995B (en) * 2020-10-27 2021-12-03 武汉大学 Double-silicon compound, preparation method and application thereof
CN114920793A (en) * 2022-06-01 2022-08-19 贵州大学 Estrone compound containing isopropanolamine substructure, preparation method, composition and application
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

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