CN105017188B - 一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法 - Google Patents

一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法 Download PDF

Info

Publication number
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
Authority
CN
China
Prior art keywords
cdcl
nmr
alpha
petroleum ether
synthesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201510316094.8A
Other languages
English (en)
Other versions
CN105017188A (zh
Inventor
李毅
欧阳嘉宁
袁耀锋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fuzhou University
Original Assignee
Fuzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fuzhou University filed Critical Fuzhou University
Priority to CN201510316094.8A priority Critical patent/CN105017188B/zh
Publication of CN105017188A publication Critical patent/CN105017188A/zh
Application granted granted Critical
Publication of CN105017188B publication Critical patent/CN105017188B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Abstract

本发明提供了由2‑烯丙氧基苯胺类化合物一种合成3‑卤甲基‑2,3‑二氢苯并呋喃类化合物的方法。与现有方法相比，该方法可适底物范围广，催化剂方便易得，反应条件温和，操作简便，而且反应效率高。

Description

一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法
技术领域
本发明属于合成化学领域，具体涉及一种由金属催化的2-烯丙氧基苯胺类化合物的自由基环化卤化反应，该反应可以实现以2-烯丙氧基苯胺类化合物为原料一步高效地合成3-卤甲基-2,3-二氢苯并呋喃类化合物。
背景技术
3-卤甲基-2,3-二氢苯并呋喃类化合物是一类重要的芳香化合物，广泛存在于具有生物活性的天然产物，是常见的合成药物结构单元。3-卤甲基-2,3-二氢苯并呋喃类化合物本身具有重要的生理活性，同时它又可以作为有机合成中的中间体，在合成中具有潜在的应用价值。a)G.D.McCallion,Curr.Org.Chem.1999,3,67-76.上个世纪八十年代以来，关于3-卤甲基-2,3-二氢苯并呋喃类化合物的合成与研究获得了化学界的广泛关注。目前文献中对3-卤甲基-2,3-二氢苯并呋喃类化合物的合成报道寥寥可数，一类是使用2-烯丙氧基氯苯为原料，在金属钴络合物或光作用下发生自由基环化氯化反应。b)V.F.Patel andG.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.另一类是邻烯丙氧基芳基重氮盐在化学计量的氯化铜作用下生成3-卤甲基-2,3-二氢苯并呋喃类化合物。e)A.L.J.Beckwith and G.F.Meijs,J.C.S.Chem.Comm.1981,136-137；f)G.F.Meijsand A.L.J.Beckwith,J.Am.Chem.Soc.1986,108,5890-5893)这两类方法的缺点是原料难制备或不稳定，反应产率低，副产物多，且需要化学计量的氯化铜试剂或特殊的仪器设备。因而发展一种原料廉价易得、操作方便，条件温和，底物适用范围广而且效率高的合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法是重点和难点。本发明人发展的以2-烯丙氧基苯胺类化合物为原料，在催化量的还原性金属盐作用下合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法弥补了文献报道的不足，为一种简便实用的合成方法。
发明内容
本发明的目的是提供一种有效的合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法。
本发明的方法是一种有效的由2-烯丙氧基苯胺类化合物为起始原料合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法。
本发明的方法是一种有效的以还原性金属盐作为催化剂，由2-烯丙氧基苯胺类化合物合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法。
本发明的方法所合成的3-卤甲基-2,3-二氢苯并呋喃类化合物分子通式是：
发明内容
本发明目的是要提供一种高效地合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法。
该方法是2-烯丙氧基苯胺类化合物为原料，在卤代氢和亚硝酸酯的存在下，以还原性金属盐作为催化剂，反应3-48小时制得3-卤甲基-2,3-二氢苯并呋喃类化合物。
本发明的方法所使用的起始原料2-烯丙氧基苯胺类化合物的分子通式是：所合成的3-卤甲基-2,3-二氢苯并呋喃类化合物的分子通式是：
式中：R1、R2或R3任意选自H、C1-C16的烷基、C3-C16的环烷基；C4-C10的含N、O或S的杂环基或者杂芳基、芳基、R取代的芳基；所述的芳基是苯基或萘基；R为C1-C4的烷基、C1-C4的全氟烷基、卤素或C1-C4的烷氧基；n为1-6中任意数字；X为氯、溴或碘。
本发明的3-卤甲基-2,3-二氢苯并呋喃类化合物均是以2-烯丙氧基苯胺类化合物为原料，在亚硝酸酯、卤代氢和有机溶剂的存在下，以还原性金属盐催化反应制得，可用下式表示：
所述的2-烯丙氧基苯胺类化合物的结构式为：其中n可为1-6中任意数字；R1、R2或R3任意选自H、C1-C16的烷基、C3-C16的环烷基；C4-C10的含N、O或S的杂环基或杂芳基、芳基、R取代的芳基；所述的芳基是苯基或萘基；R为C1-C4的烷基、C1-C4的全氟烷基、卤素或C1-C4的烷氧基。
所述的卤代氢为：氯化氢(溶液或气体)、溴化氢(溶液或气体)或碘化氢(溶液或气体)；
所述的亚硝酸酯类化合物结构式为：R4任意选自H、C1-C16的烷基、C3-C16的环烷基；C4-C10的含N、O或S的杂环基或杂芳基、芳基、R取代的芳基；所述的芳基是苯基或萘基；R为C1-C4的烷基、C1-C4的全氟烷基、卤素或C1-C4的烷氧基。
所述的还原性金属盐为：一价铜盐、二价铜盐、二价锡盐、二价铁盐、三价铁盐或二价钴盐；
所述的2-烯丙氧基苯胺类化合物、卤代氢、亚硝酸酯、还原性金属盐的摩尔比为1：1-5：1-5:0.01-0.5。尤其推荐反应摩尔比为1：2.5：1.1：0.1。
反应温度推荐为-20℃至120℃，进一步推荐反应温度为：0℃至50℃。
本发明中所提到的烷基、烃氧基、酰基等，除非另外说明，均推荐碳数为1～18的基团，进一步推荐碳数为1～10的，尤其推荐碳数为1～5的。本发明中所提到的环烷基，除非另外说明，均指碳数为3～18的基团，进一步推荐碳数为3～10的，尤其推荐碳数为3～7的。本发明中所提到的芳基，除非另外说明，均指苯基、C5～C10的含N、O或S的杂环基，推荐为苯基。本发明中提到的杂芳基，推荐C5～C10的含N、O和S的杂环基。
本发明方法中，所述有机溶剂可以是极性或非极性溶剂。如丙酮、乙腈、苯、四氯化碳、石油醚、四氢呋喃、二甲基亚砜、二甲基甲酰胺、***、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷或二氧六环等。
采用本发明方法所得产物可以经过重结晶，薄层层析，柱层析或减压蒸馏等方法加以分离。如用重结晶的方法，推荐溶剂为非极性溶剂或者极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为石油醚、二氯甲烷―正己烷、异丙醇―石油醚、乙酸乙酯―石油醚、乙酸乙酯―正己烷或异丙醇―乙酸乙酯―石油醚等混合溶剂。用薄层层析和柱层析方法，所用的展开剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为异丙醇―石油醚、乙酸乙酯―石油醚、乙酸乙酯―正己烷或异丙醇―乙酸乙酯―石油醚等混合溶剂，其体积比可以分别是：极性溶剂：非极性溶剂＝1：0.1－500。例如：乙酸乙酯：石油醚＝1：0.1－50，异丙醇：石油醚＝1：0.1－500。
本发明提供了一些新的3-卤甲基-2,3-二氢苯并呋喃类化合物其中例如R1为甲基、苯基、氨基、烷氧基；R2为甲基、苯基；R3为苯基、对甲基苯基、苄基、烷基；n为1、2、3；X为氯、溴、碘。该类化合物可以经常规的金属偶联反应将X取代基进一步转换为烷基、芳基或杂芳基，从而具有广泛的应用。
本发明提供了一种高效的由2-烯丙氧基苯胺类化合物、亚硝酸酯和氢卤酸作用，现场生成的重氮盐，再以还原性金属作为催化剂，高效率一步合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法。与现有方法相比，该方法可适用于多种不同类型的2-烯丙氧基苯胺类化合物，反应条件温和，原料廉价易得，操作简便，从而有利于药物的生产和处理。且反应的产率也较好。
具体实施方式
通过下述实施例将有助于理解本发明，但并不限制本发明的内容。
在氩气保护下，冰浴条件下，向一干燥反应管中依次加入2-烯丙氧基苯胺类化合物(0.5mmol)，丙酮3.0mL，浓盐酸(0.12mL)，搅拌5分钟后，向体系中加叔丁基亚硝酸酯(0.08mL)，反应体系冰浴下搅拌15min后加入铜盐(0.05mmol)，补加丙酮2.0mL,撤去冰浴，将体系升至室温，反应约9h结束，停止搅拌，减压除去溶剂，柱层析，淋洗剂：乙酸乙酯和石油醚，收集组分，得相应产物A。
A1:
石油醚淋洗；无色液体,产率:92％；1H NMR(CDCl3,400MHz)δ7.21(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:
石油醚淋洗；无色液体,产率:87％；1H NMR(CDCl3,400MHz)δ6.98(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)δ-116.19(td,J＝9.2,5.5Hz)；13C NMR(CDCl3,101MHz):δ158.5,156.2,128.3,115.6(d,J＝24.2Hz),111.8(d,J＝24.9Hz),110.1(d,J＝8.4Hz),75.4,46.1,45.0；HRMS(电子轰击)理论计算值C9H8ClFO(M+):186.0248,Found:186.0250；IR(薄膜):νmax(cm-1)＝3056,2957,1370,1245,1080,960,735,596.
A3:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C9H8Cl2O(M+):201.9952,Found:201.9951；IR(薄膜):νmax(cm-1)＝3030,2937,1449,1365,1123,798,741,591.
A4:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C10H11ClO(M+):182.0498,Found:182.0497；IR(薄膜):νmax(cm-1)＝3063,2885,1359,1324,1156,823,745,661.
A5:
石油醚淋洗；无色液体,产率:87％；1H NMR(CDCl3,400MHz)δ7.14(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)δ-112.19(td,J＝9.2,5.5Hz)；13CNMR(CDCl3,101MHz):δ165.1(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(电子轰击)理论计算值C9H8ClFO(M+):186.0248,Found:186.0250；IR(薄膜):νmax(cm-1)＝3046,2990,1379,1245,1075,1078,755,587.
A6:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C10H11ClO2(M+):198.0448,Found:198.0451；IR(薄膜):νmax(cm-1)＝3098,2872,1411,1246,1130,840,765,601.
A7:
乙酸乙酯/石油醚＝1/50,v/v；无色液体,产率:88％；1H NMR(CDCl3,400MHz)δ7.94-7.92(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(电子轰击)理论计算值C11H11ClO3(M+):226.0397,Found:226.0398；IR(薄膜):νmax(cm-1)＝3012,2981,1721,1467,1216,1065,862,823.
A8:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C9H9ClS(M+):184.0031,Found:184.0034；IR(薄膜):νmax(cm-1)＝3046,2877,1756,1436,1264,1165,862,793.
A9:
石油醚淋洗；无色液体,产率: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)；13CNMR(CDCl3,101MHz)δ154.9,129.4,128.5,121.9,120.5,117.3,62.6,48.0,36.2,24.5；HRMS(电子轰击)理论计算值C10H11ClO(M+):182.0498,Found:182.0499；IR(薄膜):νmax(cm-1)＝3070,2952,1309,1226,1174,1084,1019,790,752.
A10:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C11H13ClO(M+):196.0655,Found:196.0657；IR(薄膜):νmax(cm-1)＝3100,2990,1295,1231,1154,830790,580.
A11:
石油醚淋洗；无色液体,产率:88％；d.r 1.3:1；Diastereomer A:1H NMR(CDCl3,400MHz)δ7.29(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(电子轰击)理论计算值C10H11ClO(M+):182.0498,Found:182.0498；DiastereomerB:1H NMR(CDCl3,400MHz)δ7.25(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(电子轰击)理论计算值C10H11ClO(M+):182.0498,Found:182.0499；IR(薄膜):νmax(cm-1)＝3049,2967,2893,1232,1159,1017,971,832,751.
A12:
石油醚淋洗；无色液体,产率: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)δ159.3,129.4,126.7,124.8,120.4,110.0,83.5,51.7,46.5,21.8；HRMS(电子轰击)理论计算值C10H11ClO(M+):182.0498,Found:182.0499；IR(薄膜):νmax(cm-1)＝3060,2897,1288,1245,1090,840765,660.
A13:
石油醚淋洗；无色液体,产率:7％；1H NMR(CDCl3,400MHz)δ7.37(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(电子轰击)理论计算值C11H13ClO(M+):196.0655,Found:196.0657；IR(薄膜):νmax(cm-1)＝3032,2895,1323,1240,1187,833764,598.
A14:
石油醚淋洗；无色液体,产率:70％；1H NMR(CDCl3,400MHz)δ7.47(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]:
石油醚淋洗；无色液体,产率: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:
乙酸乙酯/石油醚＝1/20,v/v；无色液体,产率:90％；1H NMR(CDCl3,400MHz)δ7.72-7.70(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)δ144.4,142.1,133.7,131.3,129.7,129.2,127.2,124.9,123.9,115.2,53.6,46.3,42.8,21.5；HRMS(电子轰击)理论计算值C16H16ClNO2S(M+):321.0590,Found:321.0592；IR(薄膜):νmax(cm-1)＝3087,2857,1347,1272,1165,840754,556.
A17:
乙酸乙酯/石油醚＝1/100,v/v；无色液体,产率:68％；1H NMR(CDCl3,400MHz)δ7.29-7.27(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(电子轰击)理论计算值C13H15ClO2(M+):238.0761,Found:238.0764；IR(薄膜):νmax(cm-1)＝3054,2831,1645,1367,1221,990,890,624.
A18:
乙酸乙酯/石油醚＝1/100,v/v；无色液体,产率:68％；1H NMR(CDCl3,400MHz)δ7.38(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)δ151.9,133.5,129.5,128.7,124.3,117.7,107.7,56.9,51.4,46.8,43.6；HRMS(电子轰击)理论计算值C12H14NCl(M+):207.0815,Found:207.0819；IR(薄膜):νmax(cm-1)＝3075,2821,1675,1461,1150,870,672,560.
A19:
乙酸乙酯/石油醚＝1/100,v/v；无色液体,产率:88％,d.r 4.5:1；1H NMR(CDCl3,400MHz)δ7.43-7.37(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(电子轰击)理论计算值C12H14NCl(M+):244.0655,Found:244.0657；IR(薄膜):νmax(cm-1)＝3085,2844,1265,1223,1055,833,721,590.
A20:
石油醚淋洗；无色液体,产率: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:
石油醚淋洗；无色液体,产率:90％；1H NMR(CDCl3,400MHz)δ7.24(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:
乙酸乙酯/石油醚＝1/20,v/v；无色液体,产率:92％；1H NMR(400MHz,CDCl3)δ7.73-7.70(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(电子轰击)理论计算值C16H16ClNO2S(M+):365.0085,Found:365.0086；IR(薄膜):νmax(cm-1)＝3065,2826,1265,1190,965,876,660,585.
A23:
石油醚淋洗；无色液体,产率:80％；1H NMR(CDCl3,400MHz)δ7.52(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(电子轰击)理论计算值C10H11BrO(M+):225.9993,Found:225.9997；IR(薄膜):νmax(cm-1)＝3095,2880,1192,1094,945,893,780,548.
A24:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C11H13BrO(M+):240.0150,Found:240.0152；IR(薄膜):νmax(cm-1)＝3078,2977,1435,1250,1194,860735,520.
A25:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C10H11BrO(M+):225.9993,Found:225.9995；IR(薄膜):νmax(cm-1)＝3066,2880,1278,1234,1090,830756,680.
A26:
石油醚淋洗；无色液体,产率:21％；1H NMR(CDCl3,400MHz)δ7.37(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(电子轰击)理论计算值C11H13BrO(M+):240.0150,Found:240.0152；IR(薄膜):νmax(cm-1)＝3070,2915,1216,1186,1080,833,697,680.
A27:
石油醚淋洗；无色液体,产率:71％；1H NMR(CDCl3,400MHz)δ7.52(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(电子轰击)理论计算值C12H13BrO(M+):252.0150,Found:252.0152；IR(薄膜):νmax(cm-1)＝3051,2968,1445,1241,1135,865,740,636.
A28:
石油醚淋洗；无色液体,产率: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(电子轰击)理论计算值C9H9BrS(M+):227.9608,Found:227.9610；IR(薄膜):νmax(cm-1)＝3069,2947,1415,1235,1075,837,755,535.
A29:
乙酸乙酯/石油醚＝1/100,v/v；无色液体,产率:91％；d.r 3.5:1；DiastereomerA:1H NMR(CDCl3,400MHz)δ7.41(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(电子轰击)理论计算值C15H13BrO(M+):288.0150,Found:288.0150；Diastereomer B:1H NMR(CDCl3,400MHz)δ7.71(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)；13CNMR(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(电子轰击)理论计算值C15H13BrO(M+):288.0150,Found:288.0150；IR(薄膜):νmax(cm-1)＝3073,2941,1275,1121,1051,825,747,650.

Claims (1)

1.一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法，其特征是：在氩气保护下，冰浴条件下，向一干燥反应管中依次加入2-烯丙氧基苯胺类化合物0.5mmol、丙酮3.0mL、浓盐酸0.12mL，搅拌5分钟后，向体系中加叔丁基亚硝酸酯0.08mL，反应体系冰浴下搅拌15分钟后加入铜盐0.05mmol，补加丙酮2.0mL，撤去冰浴，将体系升至室温，反应约9小时结束，停止搅拌，减压除去溶剂，柱层析，用淋洗剂乙酸乙酯和石油醚淋洗，收集组分制得3-卤甲基-2,3-二氢苯并呋喃类化合物；
上述的2-烯丙氧基苯胺类化合物、浓盐酸、叔丁基亚硝酸酯、铜盐的摩尔比为1:1-5:1-5:0.01-0.5；
所述的2-烯丙氧基苯胺类化合物结构式为：
所述的叔丁基亚硝酸酯结构式为：R4为叔丁基；
所述铜盐为：一价铜盐；
其中n可为1-6中任意数字；
R1、R2或R3任意选自H、C1-C16的烷基、C3-C16的环烷基；
所述合成3-卤甲基-2,3-二氢苯并呋喃类化合物结构式为其中所述的X为：氯。
CN201510316094.8A 2015-06-11 2015-06-11 一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法 Expired - Fee Related CN105017188B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510316094.8A CN105017188B (zh) 2015-06-11 2015-06-11 一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510316094.8A CN105017188B (zh) 2015-06-11 2015-06-11 一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法

Publications (2)

Publication Number Publication Date
CN105017188A CN105017188A (zh) 2015-11-04
CN105017188B true CN105017188B (zh) 2019-03-05

Family

ID=54407538

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510316094.8A Expired - Fee Related CN105017188B (zh) 2015-06-11 2015-06-11 一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法

Country Status (1)

Country Link
CN (1) CN105017188B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6998937B2 (ja) * 2016-08-12 2022-01-18 バイエル・クロップサイエンス・アクチェンゲゼルシャフト ２－（２－ジアゾニウム－６－置換フェニル）エタノール塩を環化させることによる４－置換２，３－ジヒドロ－１－ベンゾフラン誘導体の製造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
CN105017188A (zh) 2015-11-04

Similar Documents

Publication Publication Date Title
JP7038843B2 (ja) Ｒｅｔｒｏｖｉｒｉｄａｅウイルス感染の処置において有用な治療用化合物を調製するための方法および中間体
KR20070037335A (ko) 5-메틸-2-푸르푸랄의 제조방법
CN105017188B (zh) 一种合成3-卤甲基-2,3-二氢苯并呋喃类化合物的方法
KR100483775B1 (ko) 아스코르브산의제조방법
CN113072436A (zh) 一种苄基芳基醚的制备方法
Czifrák et al. Anomeric α-azido acid (2-azido-2-deoxy-hept-2-ulopyranosonic acid) derivatives en route to peptides incorporating sugar amino acids
JP2021533188A (ja) マンノース誘導体の製造方法
CN105732648B (zh) 一种吡咯并呋喃的含氮杂环化合物及合成方法
CN110483406A (zh) 一种合成含n-二氟甲基类化合物的方法
CN109867632A (zh) 一种1,2,3-***衍生物及其合成和应用
CN113072470B (zh) 一种n-乙腈基双苯磺酰亚胺衍生物及其制备方法与应用
CN109574913A (zh) 一种用硝酸盐水合物制备偕二硝基化合物的方法
CN104987317B (zh) 一种合成3-卤甲基苯并呋喃类化合物的方法
CN105037304B (zh) 一种合成3-卤亚甲基-2,3-二氢苯并呋喃类化合物的方法
CN113039175B (zh) 芳基磺酰基丙烯腈的制备方法
CN110746336B (zh) 一种n-甲基-2-氰基-3-芳基吡咯化合物的绿色制备方法
CN109438349A (zh) 6-(α-氰基亚胺)基菲啶类化合物及其合成方法
CN110294688A (zh) 一种γ-位氯取代的叠氮化合物的制备方法
Kumari et al. A Highly Efficient Approach for the Synthesis of Novel Trifluoroacetylated Enaminones using DBU as a Base
KR100965619B1 (ko) 치환된 방향족 붕소산 화합물의 제조방법
JPH0217163A (ja) ジアミノマレオニトリル及びジアミノアクリロニトリル誘導体の製造方法
Voronkov et al. Acyl iodides in organic synthesis: XIII. Reaction of acyl iodides with nitrogen-containing heteroaromatic compounds
JP3883772B2 (ja) フルオロアルキルケトン類の製造法
JP4019125B2 (ja) 高度にフッ素化されたカルボン酸およびその製造方法と中間体
CN117946104A (zh) 一种水相中碘介导的吲哚并[2,3-b]喹啉类化合物的制备方法

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20190305

Termination date: 20200611