CN105017188B - A method of synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class compound - Google Patents

A method of synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class compound Download PDF

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CN105017188B
CN105017188B CN201510316094.8A CN201510316094A CN105017188B CN 105017188 B CN105017188 B CN 105017188B CN 201510316094 A CN201510316094 A CN 201510316094A CN 105017188 B CN105017188 B CN 105017188B
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petroleum ether
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CN105017188A (en
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李毅
欧阳嘉宁
袁耀锋
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Fuzhou University
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    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals 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
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 by a kind of method for synthesizing 3- halogen methyl -2,3- Dihydrobenzofuranes class compound of 2- allyloxy amino benzenes compounds.Compared with the conventional method, this method can fit that substrate spectrum is wide, and convenient catalyst is easy to get, and reaction condition is mild, easy to operate, and reaction efficiency is high.

Description

A method of synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class compound
Technical field
The invention belongs to synthesis chemical fields, and in particular to a kind of 2- allyloxy amino benzenes compounds by metal catalytic The cyclization halogenation of freedom, which may be implemented efficiently to close by one step of raw material of 2- allyloxy amino benzenes compounds At 3- halogen methyl -2,3- Dihydrobenzofuranes class compound.
Background technique
3- halogen methyl -2,3- Dihydrobenzofuranes class compound is a kind of important aromatic compound, is widely present in tool There is the natural products of bioactivity, is common synthetic drug structural unit.3- halogen methyl -2,3- Dihydrobenzofuranes class chemical combination Object itself has important physiological activity, while it can be used as the intermediate in organic synthesis again, has in synthesis potential Application value.A) G.D.McCallion, Curr.Org.Chem.1999,3 since 67-76. eighties of last century the eighties, have been closed The extensive concern of region of chemistry is obtained in the synthesis and research of 3- halogen methyl -2,3- Dihydrobenzofuranes class compound.Text at present Very few to the synthesis report of 3- halogen methyl -2,3- Dihydrobenzofuranes class compound in offering, one kind is using 2- allyl oxygen Base chlorobenzene is raw material, issues and is born from by cyclization chlorination reaction in metal cobalt complex or light action.b)V.F.Patel and G.Pattenden J.Chem.Soc.Perkin Trans.1 1990,2703-2708；c)V.Dichiarante, M.Fagnoni, M.Mella, and A.Albini, Chem.Eur.J.2006,12,3905-3915；d)Y.Suzuki, Y.Okita, T.Morita and Y.Yoshimi, Tetrahedron Lett.2014,55,3355-3357. another kind of is adjacent Allyloxy aryl diazonium salts generate 3- halogen methyl -2,3- Dihydrobenzofuranes class chemical combination under the copper chloride effect of stoichiometry Object.e)A.L.J.Beckwith and G.F.Meijs,J.C.S.Chem.Comm.1981,136-137；f)G.F.Meijs And A.L.J.Beckwith, J.Am.Chem.Soc.1986,108,5890-5893) these two kinds of methods the shortcomings that be raw material hardly possible Preparation or it is unstable, reaction yield is low, and by-product is more, and need stoichiometry chlorination copper reagent or special instrument and equipment. Thus develop a kind of raw material cheap and easy to get, easy to operate, mild condition, wide application range of substrates and high-efficient synthesis 3- halogen The method of methyl -2,3- Dihydrobenzofuranes class compound is key points and difficulties.The present inventor development with 2- allyloxy benzene Aminated compounds is raw material, and 3- halogen methyl -2,3- Dihydrobenzofuranes class is synthesized under the reducing metal salt action of catalytic amount The method of compound compensates for deficiency reported in the literature, for a kind of simple and practical synthetic method.
Summary of the invention
The object of the present invention is to provide a kind of sides of effective synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class compound Method.
It is effectively that starting material synthesizes 3- halogen first by 2- allyloxy amino benzenes compounds that method of the invention, which is a kind of, The method of base -2,3- Dihydrobenzofuranes class compound.
Method of the invention is one kind effectively using reducing metal salt as catalyst, by 2- allyloxy phenyl amines The method for closing object synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class compound.
3- halogen methyl -2,3- Dihydrobenzofuranes class compound molecule general formula synthesized by method of the invention is:
Summary of the invention
The invention aims to provide a kind of side for being efficiently synthesized 3- halogen methyl -2,3- Dihydrobenzofuranes class compound Method.
This method is that 2- allyloxy amino benzenes compounds are raw material, in the presence of halocarbon and nitrous acid ester, with also Originality metal salt reacts 3-48 hours and 3- halogen methyl -2,3- Dihydrobenzofuranes class compound is made as catalyst.
The general molecular formula of starting material 2- allyloxy amino benzenes compounds used in method of the invention is:The general molecular formula of synthesized 3- halogen methyl -2,3- Dihydrobenzofuranes class compound is:
In formula: R1、R2Or R3Arbitrarily it is selected from H, C1-C16Alkyl, C3-C16Naphthenic base；C4-C10Containing the miscellaneous of N, O or S The aryl that ring group or heteroaryl, aryl, R replace；The aryl is phenyl or naphthyl；R is C1-C4Alkyl, C1-C4's Perfluoroalkyl, halogen or C1-C4Alkoxy；N is Any Digit in 1-6；X is chlorine, bromine or iodine.
3- halogen methyl -2,3- Dihydrobenzofuranes class compound of the invention is with 2- allyloxy amino benzenes compounds It is made, can be used down with the catalysis reaction of reducing metal salt in the presence of nitrous acid ester, halocarbon and organic solvent for raw material Formula indicates:
The structural formula of the 2- allyloxy amino benzenes compounds are as follows:Wherein n can be Any Digit in 1-6；R1、R2Or R3Arbitrarily it is selected from H, C1-C16Alkyl, C3-C16Naphthenic base；C4-C10Containing the miscellaneous of N, O or S The aryl that ring group or heteroaryl, aryl, R replace；The aryl is phenyl or naphthyl；R is C1-C4Alkyl, C1-C4It is complete Fluoroalkyl, halogen or C1-C4Alkoxy.
The halocarbon are as follows: hydrogen chloride (solution or gas), hydrogen bromide (solution or gas) or hydrogen iodide (solution or gas Body)；
The nitrite compounds structural formula are as follows:R4Arbitrarily it is selected from H, C1-C16Alkyl, C3-C16 Naphthenic base；C4-C10Heterocycle containing N, O or S or the aryl that replaces of heteroaryl, aryl, R；The aryl be phenyl or Naphthalene；R is C1-C4Alkyl, C1-C4Perfluoroalkyl, halogen or C1-C4Alkoxy.
The reducing metal salt are as follows: cuprous salt, cupric salt, stannous salt, divalent iron salt, trivalent iron salt or two Valence cobalt salt；
The 2- allyloxy amino benzenes compounds, halocarbon, nitrous acid ester, reducing metal salt molar ratio be 1: 1-5:1-5:0.01-0.5.Especially recommendation response molar ratio is 1:2.5:1.1:0.1.
Reaction temperature is recommended as -20 DEG C to 120 DEG C, it is further recommended that reaction temperature are as follows: 0 DEG C to 50 DEG C.
Alkyl mentioned in the present invention, oxyl, acyl group etc., unless otherwise stated, recommendation carbon number be 1~18 base Group, it is further recommended that carbon number is 1~10, it is particularly recommended that carbon number is 1~5.Naphthenic base mentioned in the present invention, unless separately External declaration refers both to the group that carbon number is 3~18, it is further recommended that carbon number is 3~10, it is particularly recommended that carbon number is 3~7.This The aryl being previously mentioned in invention refers both to phenyl, C unless otherwise stated5~C10The heterocycle containing N, O or S, be recommended as phenyl. Heteroaryl mentioned in the present invention recommends C5~C10The heterocycle containing N, O and S.
In the method for the present invention, the organic solvent can be polarity or nonpolar solvent.Such as acetone, acetonitrile, benzene, four chlorinations Carbon, petroleum ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, ether, methylene chloride, chloroform, toluene, diformazan Benzene, hexamethylene, n-hexane, normal heptane or dioxane etc..
It can be by recrystallization, thin-layer chromatography, the methods of column chromatography or vacuum distillation using the method for the present invention products therefrom It is separated.Such as with the method for recrystallization, recommending solvent is the mixing of nonpolar solvent or polar solvent and nonpolar solvent Solvent.Recommending solvent can be petroleum ether, methylene chloride-n-hexane, isopropanol-petroleum ether, ethyl acetate-petroleum ether, acetic acid The mixed solvents such as ethyl ester-n-hexane or isopropanol-ethyl acetate-petroleum ether.It is used with thin-layer chromatography and column chromatography method Solvent be polar solvent and nonpolar solvent mixed solvent.Recommending solvent can be isopropanol-petroleum ether, acetic acid second The mixed solvents such as ester-petroleum ether, ethyl acetate-n-hexane or isopropanol-ethyl acetate-petroleum ether, volume ratio can be with It is respectively: polar solvent: nonpolar solvent=1:0.1-500.Such as: ethyl acetate: petroleum ether=1:0.1-50, isopropyl Alcohol: petroleum ether=1:0.1-500.
The present invention provides some new 3- halogen methyl -2,3- Dihydrobenzofuranes class compounds Wherein such as R1For methyl, phenyl, amino, alkoxy；R2For methyl, phenyl；R3For phenyl, p-methylphenyl, benzyl, alkyl； N is 1,2,3；X is chlorine, bromine, iodine.X substituent group can be further converted by such compound through conventional metal coupling reaction Alkyl, aryl or heteroaryl, to have a wide range of applications.
It is efficiently acted on by 2- allyloxy amino benzenes compounds, nitrous acid ester and halogen acids the present invention provides a kind of, The diazonium salt locally produced, then using reducing metal as catalyst, high efficiency one-step synthesis 3- halogen methyl -2,3- dihydrobenzo The method of furfuran compound.Compared with the conventional method, this method is applicable to a variety of different types of 2- allyloxy aniline Class compound, reaction condition is mild, and raw material is cheap and easy to get, easy to operate, to be conducive to the production and processing of drug.And it reacts Yield it is also preferable.
Specific embodiment
It will be helpful to understand the present invention by following embodiments, but be not intended to limit the contents of the present invention.
Under protection of argon gas, under condition of ice bath, 2- allyloxy phenyl amines chemical combination is sequentially added into a dry reaction pipe Object (0.5mmol), acetone 3.0mL, concentrated hydrochloric acid (0.12mL), stirring after five minutes, alpha..alpha.-dimethylethyl nitrite ester are added into system (0.08mL) is added mantoquita (0.05mmol) after stirring 15min under reaction system ice bath, adds acetone 2.0mL, remove ice bath, System is warmed to room temperature, reaction about 9h terminates, and stops stirring, and solvent, column chromatography, eluent: ethyl acetate and stone is removed under reduced pressure Oily ether collects component, obtains corresponding product A.
A1:
Petroleum ether elution；Colourless liquid, yield: 92%；1H NMR(CDCl3, 400MHz) and δ 7.21 (d, J=8.0,1H), 7.17 (t, J=7.8,1H), 6.87 (t, J=8.0,1H), 6.81 (d, J=8.0Hz, 1H), 4.62 (t, J=9.2,1H), 4.46 (dd, J=9.4,5.0Hz, 1H), 3.89-3.76 (m, 2H), 3.58-3.63 (m, 1H)
A2:
Petroleum ether elution；Colourless liquid, yield: 87%；1H NMR(CDCl3, 400MHz) δ 6.98 (dd, J=8.0, 2.8Hz, 1H), 6.86-6.91 (m, 1H), 6.73-6.76 (m, 1H), 4.69 (t, J=9.2Hz, 1H), 4.52 (dd, J=9.2, 4.8Hz,1H),3.72-3.85(m,2H),3.59-3.63(m,1H)；19F NMR(CDCl3, 376MHz) and δ -116.19 (td, J= 9.2,5.5Hz)；13C NMR(CDCl3, 101MHz): δ 158.5,156.2,128.3,115.6 (d, J=24.2Hz), 111.8 (d, J=24.9Hz), 110.1 (d, J=8.4Hz), 75.4,46.1,45.0；HRMS (electron bombardment) calculated value C9H8ClFO(M+):186.0248,Found:186.0250；IR (film): νmax(cm-1)=3056,2957,1370,1245, 1080,960,735,596.
A3:
Petroleum ether elution；Colourless liquid, yield: 91%；1H NMR(CDCl3,300MHz)δ7.23(s,1H),7.16(dd, J=8.8,2.2Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 4.70 (t, J=9.0Hz, 1H), 4.53 (dd, J=9.6, 5.2Hz,1H),3.72-3.85(m,2H),3.67-3.62(m,1H)；13C NMR(CDCl3,101MHz):δ158.9,129.3, 128.8,125.2,124.8,110.9,75.3,46.1,44.7；HRMS (electron bombardment) calculated value C9H8Cl2O(M+): 201.9952,Found:201.9951；IR (film): νmax(cm-1)=3030,2937,1449,1365,1123,798,741, 591.
A4:
Petroleum ether elution；Colourless liquid, yield: 84%；1H NMR(CDCl3,400MHz)δ7.02(s,1H),6.96(d,J =8.0Hz, 1H), 6.70 (d, J=8.0Hz, 1H), 4.61 (t, J=9.0Hz, 1H), 4.45 (dd, J=9.2,4.8Hz, 1H), 3.70-3.77(m,2H),3.50-3.56(m,1H),2.28(s,3H)；13C NMR(CDCl3,101MHz):δ158.1,130.0, 129.8,126.9,125.2,109.5,74.9,46.6,45.0,20.8；HRMS (electron bombardment) calculated value C10H11ClO (M+):182.0498,Found:182.0497；IR (film): νmax(cm-1)=3063,2885,1359,1324,1156,823, 745,661.
A5:
Petroleum ether elution；Colourless liquid, yield: 87%；1H NMR(CDCl3, 400MHz) δ 7.14 (dd, J=8.0, 5.6Hz, 1H), 6.61-6.51 (m, 2H), 4.68 (t, J=9.0Hz, 1H), 4.52 (dd, J=9.6,4.8Hz, 1H), 3.78- 3.68(m,2H),3.52-3.57(m,1H)；19F NMR(CDCl3, 376MHz) and δ -112.19 (td, J=9.2,5.5Hz)；13C NMR(CDCl3, 101MHz): δ 165.1 (d, J=243.0Hz), 161.6 (d, J=13.2Hz), 125.1 (d, J=10.8Hz), 122.7 (d, J=2.6Hz), 107.4 (d, J=23.0Hz), 98.5 (d, J=26.5Hz), 76.1,46.5 (d, J=1.5Hz), 44.1；HRMS (electron bombardment) calculated value C9H8ClFO(M+):186.0248,Found:186.0250；IR (film): νmax (cm-1)=3046,2990,1379,1245,1075,1078,755,587.
A6:
Petroleum ether elution；Colourless liquid, yield: 87%；1H NMR(CDCl3,400MHz)δ6.84(s,1H),6.75(d,J =1.6Hz, 2H), 4.66 (t, J=9.2Hz, 1H), 4.49 (dd, J=9.4,4.8Hz, 1H), 3.84-3.73 (m, 5H), 3.63-3.56(m,1H)；13C NMR(CDCl3,101MHz)δ154.3,154.1,127.8,114.3,110.9,109.9, 75.1,56.0,46.4,45.3；HRMS (electron bombardment) calculated value C10H11ClO2(M+):198.0448,Found: 198.0451；IR (film): νmax(cm-1)=3098,2872,1411,1246,1130,840,765,601.
A7:
Ethyl acetate/petroleum ether=1/50, v/v；Colourless liquid, yield: 88%；1H NMR(CDCl3,400MHz)δ 7.94-7.92 (m, 2H), 6.82 (d, J=9.2Hz, 1H), 4.74 (t, J=9.2Hz, 1H), 4.58 (dd, J=9.2,4.0Hz, 1H),3.89-3.77(m,5H),3.57-3.62(m,1H)；13C NMR(CDCl3,101MHz)δ166.62,164.3,132.2, 127.6,126.6,123.0,109.7,75.8,51.9,46.2,44.1；HRMS (electron bombardment) calculated value C11H11ClO3 (M+):226.0397,Found:226.0398；IR (film): νmax(cm-1)=3012,2981,1721,1467,1216, 1065,862,823.
A8:
Petroleum ether elution；Colourless liquid, yield: 61%；1H NMR(CDCl3,400MHz)δ7.25-7.18(m,3H), 7.08 (t, J=7.2Hz, 1H), 3.74-3.82 (m, 1H), 3.74-3.68 (m, 2H), 3.61-3.70 (m, 1H), 3.41-3.50 (m,1H)；13C NMR(CDCl3,101MHz)δ141.7,139.2,128.7,124.8,124.4,122.7,50.5,45.4, 36.4；HRMS (electron bombardment) calculated value C9H9ClS(M+):184.0031,Found:184.0034；IR (film): νmax (cm-1)=3046,2877,1756,1436,1264,1165,862,793.
A9:
Petroleum ether elution；Colourless liquid, yield: 72%；1H NMR(CDCl3,400MHz)δ7.18-3.21(m,2H), 6.93 (t, J=7.4Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 4.25-4.30 (m, 1H), 4.23-4.11 (m, 1H), 3.92 (dd, J=11.2,4.0Hz, 1H), 3.65 (t, J=11.0Hz, 1H), 3.16-3.22 (m, 1H), 2.13-2.74 (m, 2H)；13C NMR(CDCl3,101MHz)δ154.9,129.4,128.5,121.9,120.5,117.3,62.6,48.0,36.2,24.5； HRMS (electron bombardment) calculated value C10H11ClO(M+):182.0498,Found:182.0499；IR (film): νmax(cm-1)=3070,2952,1309,1226,1174,1084,1019,790,752.
A10:
Petroleum ether elution；Colourless liquid, yield: 69%；1H NMR(CDCl3,400MHz)δ7.45-7.51(m,1H), 7.19 (td, J=7.4,2.0Hz, 1H), 7.01-7.05 (m, 1H), 6.94 (dd, J=7.5,2.0Hz, 1H), 4.04-3.85 (m, 3H), 3.68 (dd, J=12.4,7.0Hz, 1H), 3.07-3.12 (m, 1H), 1.98 (dt, J=12.9,7.0Hz, 1H), 1.63-1.82(m,2H),1.51-1.58(m,1H).13C NMR(CDCl3,101MHz)δ158.5,133.3,130.6,128.1, 121.1,114.2,70.7,50.2,45.4,29.4,27.9；HRMS (electron bombardment) calculated value C11H13ClO(M+): 196.0655,Found:196.0657；IR (film): νmax(cm-1)=3100,2990,1295,1231,1154,830790, 580.
A11:
Petroleum ether elution；Colourless liquid, yield: 88%；d.r 1.3:1；Diastereomer A:1H NMR(CDCl3, 400MHz) δ 7.29 (d, J=7.6,1H), 7.18 (t J=7.4,1H), 6.88 (t, J=7.4Hz, 1H), 6.81 (d, J= 8.0Hz, 1H), 4.63-4.55 (m, 2H), 4.19 (t, J=6.6Hz, 1H), 3.67 (q, J=6.6Hz, 1H), 1.55 (d J= 6.8,3H).13C NMR(CDCl3,101MHz)δ160.7,129.3,126.3,125.6,109.9,74.2,59.7,50.4, 22.3；HRMS (electron bombardment) calculated value C10H11ClO(M+):182.0498,Found:182.0498；Diastereomer B:1H NMR(CDCl3, 400MHz) and δ 7.25 (d, J=7.2Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 6.88 (t, J= 7.4Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 4.66-4.55 (m, 2H), 4.32-4.26 (m, 1H), 3.89-3.84 (m, 1H), 1.36 (d, J=6.8Hz, 3H)13C NMR(CDCl3,101MHz)δ160.5,129.4,126.8,125.0,120.5, 109.9,72.6,58.9,49.7,19.8；HRMS (electron bombardment) calculated value C10H11ClO(M+):182.0498,Found: 182.0499；IR (film): νmax(cm-1)=3049,2967,2893,1232,1159,1017,971,832,751.
A12:
Petroleum ether elution；Colourless liquid, yield: 88%, d.r 10:1；1H NMR(CDCl3,400MHz)δ7.25-7.21 (m, 2H), 6.91 (t, J=7.4Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 4.82-4.76 (m, 1H), 3.85-3.81 (m, 1H), 3.63-3.58 (m, 1H), 3.43-3.38 (m, 1H), 1.52 (d, J=6.3Hz, 3H)；13C NMR(CDCl3,101MHz)δ 159.3,129.4,126.7,124.8,120.4,110.0,83.5,51.7,46.5,21.8；The theoretical meter of HRMS (electron bombardment) Calculation value C10H11ClO(M+):182.0498,Found:182.0499；IR (film): νmax(cm-1)=3060,2897,1288, 1245,1090,840765,660.
A13:
Petroleum ether elution；Colourless liquid, yield: 7%；1H NMR(CDCl3, 400MHz) and δ 7.37 (d, J=7.6Hz, 1H), 7.22 (t, J=7.8Hz, 1H), 6.89 (t, J=7.4Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 4.75-4.75 (m, 1H), 4.60 (t, J=9.4Hz, 1H), 3.77 (dd, J=9.2,3.6Hz, 1H), 1.60 (s, 3H), 1.50 (s, 3H)13C NMR (CDCl3,101MHz)δ161.1,129.4,126.3,126.2,120.2,109.9,74.2,72.1,54.9,30.2,27.8； HRMS (electron bombardment) calculated value C11H13ClO(M+):196.0655,Found:196.0657；IR (film): νmax(cm-1)=3032,2895,1323,1240,1187,833764,598.
A14:
Petroleum ether elution；Colourless liquid, yield: 70%；1H NMR(CDCl3, 400MHz) δ 7.47 (d, J=7.4Hz, 1H), 7.22 (t, J=7.8Hz, 1H), 6.94 (t, J=7.4Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 4.71 (s, 1H), 3.74-3.67 (m, 1H), 3.20 (t, J=7.8Hz, 1H)), 2.29-2.14 (m, 2H), 1.79-1.89 (m, 2H), 1.64- 1.75(m,2H).
A15[3]:
Petroleum ether elution；Colourless liquid, yield: 85%；1H NMR(CDCl3,400MHz)δ7.24-7.20(m,1H), 7.17-7.15 (m, 1H), 6.96-6.92 (m, 1H), 6.86 (d, J=8.0,1H), 4.64 (d, J=8.0Hz, 1H), 4.21- 4.19(m,1H),3.67-3.60(m,2H),1.53(s,3H).
A16:
Ethyl acetate/petroleum ether=1/20, v/v；Colourless liquid, yield: 90%；1H NMR(CDCl3,400MHz)δ 7.72-7.70 (m, 3H), 7.29-7.25 (m, 3H), 7.15 (d, J=7.5Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 4.06- 3.94(m,2H),3.54-3.46(m,2H),3.10-3.05(m,1H),2.39(s,3H)；13C NMR(CDCl3,101MHz)δ 144.4,142.1,133.7,131.3,129.7,129.2,127.2,124.9,123.9,115.2,53.6,46.3,42.8, 21.5；HRMS (electron bombardment) calculated value C16H16ClNO2S(M+):321.0590,Found:321.0592；IR (film): νmax(cm-1)=3087,2857,1347,1272,1165,840754,556.
A17:
Ethyl acetate/petroleum ether=1/100, v/v；Colourless liquid, yield: 68%；1H NMR(CDCl3,400MHz)δ 7.29-7.27 (m, 1H), 7.21 (d, J=7.8Hz, 1H), 6.91 (d, J=7.4Hz, 1H), 6.84 (d, J=7.6Hz, 1H), 6.00-5.93 (m, 1H), 5.38-5.25 (m, 2H), 4.70 (dd, J=9.6,4.8Hz, 1H), 4.61 (t, J=9.2Hz, 1H), 4.27 (q, J=5.4Hz, 1H), 4.11 (dt, J=5.6,1.4Hz, 2H), 4.04-3.99 (m, 1H), 3.76 (dd, J=10.6, 5.0Hz, 1H), 3.69 (dd, J=10.6,5.0Hz, 1H)；13C NMR(CDCl3,101MHz)δ160.5,134.0,129.2, 126.2,125.0,120.5,117.7,109.9,73.3,72.4,71.5,61.9,45.6；HRMS (electron bombardment) theoretical calculation Value C13H15ClO2(M+):238.0761,Found:238.0764；IR (film): νmax(cm-1)=3054,2831,1645, 1367,1221,990,890,624.
A18:
Ethyl acetate/petroleum ether=1/100, v/v；Colourless liquid, yield: 68%；1H NMR(CDCl3,400MHz)δ 7.38 (d, J=7.6Hz, 1H), 7.18 (t, J=7.8Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.97 (t, J=7.8Hz, 1H), 5.79-5.89 (m, 2H), 5.23-5.14 (m, 4H), 3.74 (d, J=6.0Hz, 4H)；13C NMR(CDCl3,101MHz)δ 151.9,133.5,129.5,128.7,124.3,117.7,107.7,56.9,51.4,46.8,43.6；HRMS (electron bombardment) Calculated value C12H14NCl(M+):207.0815,Found:207.0819；IR (film): νmax(cm-1)=3075,2821, 1675,1461,1150,870,672,560.
A19:
Ethyl acetate/petroleum ether=1/100, v/v；Colourless liquid, yield: 88%, d.r 4.5:1；1H NMR(CDCl3, 400MHz) δ 7.43-7.37 (m, 5H), 7.13 (t, J=7.8Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 6.60 (t, J= 7.4Hz, 1H), 6.10 (d, J=7.6Hz, 1H), 4.89 (d, J=10.0Hz, 1H), 4.83-4.75 (m, 2H), 4.20-4.44 (m,1H)；13C NMR(CDCl3,101MHz)δ160.7,139.4,129.3,128.9,128.7,128.1,125.9,125.8, 120.0,109.9,75.4,65.6,50.7；HRMS (electron bombardment) calculated value C12H14NCl(M+):244.0655, Found:244.0657；IR (film): νmax(cm-1)=3085,2844,1265,1223,1055,833,721,590.
A20:
Petroleum ether elution；Colourless liquid, yield: 92%；1H NMR(CDCl3,400MHz)δ7.29-7.21(m,2H), 6.92 (t, J=7.4Hz, 1H), 6.85 (d, J=8.0Hz, 1H), 4.69 (t, J=9.0Hz, 1H), 4.50 (dd, J=9.4, 5.2Hz, 1H), 3.94-3.87 (m, 1H), 3.67 (dd, J=10.0,4.4Hz, 1H), 3.45 (t, J=9.8Hz, 1H)
A21:
Petroleum ether elution；Colourless liquid, yield: 90%；1H NMR(CDCl3, 400MHz) δ 7.24 (t, J=7.8Hz, 1H), 7.16 (d, J=7.2,1H), 6.94 (t, J=7.2Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 4.63 (d, J= 8.8Hz, 1H), 4.21 (d, J=8.8Hz, 1H), 3.57-3.52 (m, 2H), 1.56 (s, 3H)
A22:
Ethyl acetate/petroleum ether=1/20, v/v；Colourless liquid, yield: 92%；1H NMR(400MHz,CDCl3)δ 7.73-7.70 (m, 3H), 7.29-7.26 (m, 3H), 7.2 (d, J=7.4Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 4.08- 4.02 (m, 1H), 3.96-3.92m, 1H), 3.58-3.51 (m, 1H), 3.40 (dd, J=10.0,4.4Hz, 1H), 2.89 (t, J =10.0Hz, 1H), 2.39 (s, 3H)；13C NMR(CDCl3,101MHz)δ144.4,142.0,133.7,131.9,129.7, 129.2,127.3,124.8,123.9,115.3,54.7,42.7,34.7,21.5；HRMS (electron bombardment) calculated value C16H16ClNO2S(M+):365.0085,Found:365.0086；IR (film): νmax(cm-1)=3065,2826,1265, 1190,965,876,660,585.
A23:
Petroleum ether elution；Colourless liquid, yield: 80%；1H NMR(CDCl3, 400MHz) δ 7.52 (d, J=7.4Hz, 1H), 7.22 (t, J=7.8Hz, 1H), 6.94 (t, J=7.6Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 4.67-4.64 (m, 1H),3.84-3.78(m,1H),3.42-3.38(m,1H),2.33–2.25(m,2H),1.92-1.77(m,3H),1.72-1.65 (m,1H)；13C NMR(CDCl3,101MHz)δ154.7,129.5,128.6,122.5,120.5,117.3,62.5,37.1, 36.0,25.4；HRMS (electron bombardment) calculated value C10H11BrO(M+):225.9993,Found:225.9997；IR is (thin Film): νmax(cm-1)=3095,2880,1192,1094,945,893,780,548.
A24:
Petroleum ether elution；Colourless liquid, yield: 77%；1H NMR(CDCl3,400MHz)δ7.45-7.32(m,1H), 7.14-7.17 (m, 1H), 7.03 (td, J=7.4,2.0Hz, 1H), 6.91 (dd, J=7.4,2.0Hz, 1H), 4.10 (dt, J= 11.4,7.0Hz, 1H), 3.86-3.93 (m, 1H), 3.55 (dd, J=12.4,6.9Hz, 1H), 3.15-3.21 (m, 1H), 2.09 (dq, J=12.9,6.9Hz, 1H), 1.85 (dt, J=13.1,7.0Hz, 1H), 1.80-1.68 (m, 1H), 1.68-1.57 (m, 1H).13C NMR(CDCl3,101MHz)δ158.4,134.7,128.8,127.8,120.5,113.8,70.7,41.1,35.1, 31.7,27.9；HRMS (electron bombardment) calculated value C11H13BrO(M+):240.0150,Found:240.0152；IR is (thin Film): νmax(cm-1)=3078,2977,1435,1250,1194,860735,520.
A25:
Petroleum ether elution；Colourless liquid, yield: 91%, d.r 10:1；1H NMR(CDCl3,400MHz)δ7.25-7.21 (m, 2H), 6.91 (t, J=7.4,1H), 6.84 (d, J=8.0Hz, 1H), 4.79-4.73 (m, 1H), 3.72-3.66 (m, 1H), 3.49-3.42 (m, 2H), 1.51 (d, J=6.4, Hz, 3H)13C NMR(CDCl3,101MHz)δ159.2,129.4,127.3, 124.8,120.4,110.1,84.4,51.4,35.0,21.8；HRMS (electron bombardment) calculated value C10H11BrO(M+): 225.9993,Found:225.9995；IR (film): νmax(cm-1)=3066,2880,1278,1234,1090,830756, 680.
A26:
Petroleum ether elution；Colourless liquid, yield: 21%；1H NMR(CDCl3, 400MHz) δ 7.37 (d, J=7.2Hz, 1H), 7.23 (t, J=7.8Hz, 1H), 6.89 (t, J=7.6Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 4.79-4.76 (m, 1H), 4.62 (t, J=9.4Hz, 1H), 3.91 (d, J=9.2, Hz, 1H), 1.91 (s, 3H), 1.67 (s, 3H)；13C NMR (CDCl3,101MHz)δ161.2,129.4,126.2,126.0,120.1,110.0,75.3,69.0,55.9,32.2,29.1； HRMS (electron bombardment) calculated value C11H13BrO(M+):240.0150,Found:240.0152；IR (film): νmax(cm-1)=3070,2915,1216,1186,1080,833,697,680.
A27:
Petroleum ether elution；Colourless liquid, yield: 71%；1H NMR(CDCl3, 400MHz) δ 7.52 (d, J=7.4Hz, 1H), 7.22 (t, J=7.8Hz, 1H), 6.94 (t, J=7.6Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 4.67-4.64 (m, 1H),3.84-3.78(m,1H),3.42-3.38(m,1H),2.33-2.25(m,2H),1.92-1.77(m,3H),1.72-1.65 (m,1H)；13C NMR(CDCl3,101MHz)δ159.4,131.6,128.8,125.4,120.7,110.2,83.7,55.4, 50.5,34.9,26.8,21.5；HRMS (electron bombardment) calculated value C12H13BrO(M+):252.0150,Found: 252.0152；IR (film): νmax(cm-1)=3051,2968,1445,1241,1135,865,740,636.
A28:
Petroleum ether elution；Colourless liquid, yield: 35%；1H NMR(CDCl3,400MHz)δ7.27-7.18(m,3H), 7.13-7.04(m,1H),3.80-3.86(m,1H),3.70-3.54(m,3H),3.41-3.35(m,1H)；13C NMR(CDCl3, 101MHz)δ141.7,139.7,128.7,124.8,124.5,122.8,50.4,37.5,34.2；HRMS (electron bombardment) is theoretical Calculated value C9H9BrS(M+):227.9608,Found:227.9610；IR (film): νmax(cm-1)=3069,2947,1415, 1235,1075,837,755,535.
A29:
Ethyl acetate/petroleum ether=1/100, v/v；Colourless liquid, yield: 91%；d.r 3.5:1；Diastereomer A:1H NMR(CDCl3, 400MHz) and δ 7.41 (s, 5H), 7.12 (t, J=7.8Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 6.58 (t, J=7.6Hz, 1H), 6.08 (d, J=7.6Hz, 1H), 4.98 (d, J=10.4Hz, 1H), 4.85-4.74 (m, 2H), 4.40-4.34(m,1H)；13C NMR(CDCl3,101MHz)δ160.8,140.1,129.3,128.9,128.8,128.3, 126.1,125.8,120.1,110.0,57.7,50.3；HRMS (electron bombardment) calculated value C15H13BrO(M+): 288.0150,Found:288.0150；Diastereomer B:1H NMR(CDCl3, 400MHz) δ 7.71 (d, J=7.6Hz, 1H), 7.43-7.32 (m, 5H), 7.23 (t, J=7.8Hz, 1H), 6.95 (t, J=7.4Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 5.02 (d, J=9.6Hz, 1H), 4.41-4.36 (m, 1H), 4.32-4.27 (m, 1H), 4.18-1.14 (m, 1H)；13C NMR(CDCl3,101MHz)160.5,140.0,129.4,128.9,128.7,127.9,127.5,126.7,109.9,74.5, 56.7,50.0；HRMS (electron bombardment) calculated value C15H13BrO(M+):288.0150,Found:288.0150；IR is (thin Film): νmax(cm-1)=3073,2941,1275,1121,1051,825,747,650.

Claims (1)

1. a kind of method of synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class compound, it is characterized in that: under protection of argon gas, Under condition of ice bath, 2- allyloxy amino benzenes compounds 0.5mmol, acetone 3.0mL, dense is sequentially added into a dry reaction pipe Hydrochloric acid 0.12mL, stirring after five minutes, alpha..alpha.-dimethylethyl nitrite ester 0.08mL are added into system, stirs 15 points under reaction system ice bath Mantoquita 0.05mmol is added after clock, adds acetone 2.0mL, removes ice bath, system is warmed to room temperature, reaction terminates for about 9 hours, stops It only stirs, solvent is removed under reduced pressure, column chromatography is eluted with eluent ethyl acetate and petroleum ether, collects component and 3- halogen methyl-is made 2,3- Dihydrobenzofuranes class compound；
Above-mentioned 2- allyloxy amino benzenes compounds, concentrated hydrochloric acid, alpha..alpha.-dimethylethyl nitrite ester, mantoquita molar ratio be 1:1-5:1- 5:0.01-0.5；
The 2- allyloxy amino benzenes compounds structural formula are as follows:
The alpha..alpha.-dimethylethyl nitrite ester structure formula are as follows:R4For tert-butyl；
The mantoquita are as follows: cuprous salt；
Wherein n can be Any Digit in 1-6；
R1、R2Or R3Arbitrarily it is selected from H, C1-C16Alkyl, C3-C16Naphthenic base；
The synthesis 3- halogen methyl -2,3- Dihydrobenzofuranes class structural formula of compound isThe wherein X Are as follows: chlorine.
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Title
Cyclizing radical carboiodination, carbotelluration,and Carboaminoxylation of Aryl Amines;Marcel Hartmann 和 Armido Studer;《Angew.Chem.int.Ed.》;20141231;第2014卷(第53期);8180-8183
Iododediazoniation of arenediazonium salts accompanied by aryl radical ring closure;Athelstan L. 等人;《J.Org.Chem.》;19871231;第1987卷(第52期);1922-1930
Twofold Carbon-Carbon Bond Formation by Intra- and Intermolecular Radical Reactions of Aryl Diazomium salts;Hannelore Jasch 等人;《Chemistry - A European Journal》;20130513;第2013卷(第19期);8411-8416

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