CN105037304B - 一种合成3-卤亚甲基-2,3-二氢苯并呋喃类化合物的方法 - Google Patents

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

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CN105037304B
CN105037304B CN201510315875.5A CN201510315875A CN105037304B CN 105037304 B CN105037304 B CN 105037304B CN 201510315875 A CN201510315875 A CN 201510315875A CN 105037304 B CN105037304 B CN 105037304B
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CN105037304A (zh
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李毅
王雪凤
游毅
袁耀锋
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Fuzhou University
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Abstract

本发明提供了2‑炔丙氧基苯胺类化合物高效的一步合成3‑卤亚甲基‑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且方便易得，反应条件温和，操作简便，而且反应效率高，有利于药物的生产和处理。

Description

一种合成3-卤亚甲基-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-炔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-炔丙氧基苯胺类化合物为原料一步高效地合成3-卤亚甲基-2,3-二氢苯并呋喃类化合物。
背景技术
3-卤亚甲基-2,3-二氢苯并呋喃类化合物是一类重要的有机合成中间体，在合成中具有潜在的应用价值。目前已知文献中关于合成对3-卤亚甲基-2,3-二氢苯并呋喃类化合物的报道仅有一例，使用3-氯炔丙氧基-邻-碘苯为起始原料，在-78摄氏度的低温下和金属锂试剂反应环化，以水淬灭反应制得。a)R.Lhermet,M.Ahmad,C.Fressign,B.Silvi,M.Durandetti and J.Maddaluno Chem.Eur.J.2014,20,10249–10254.此类方法的缺点是起始原料难制备，步骤繁琐，反应条件苛刻，操作不便。
因而发展一种原料廉价易得、步骤简单、操作方便、条件温和、底物适用范围广而且效率高的合成3-卤亚甲基-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-炔丙氧基苯胺类化合物为原料，以还原性金属盐作为催化剂，合成3-卤亚甲基-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-卤亚甲基-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-炔丙氧基苯胺类化合物为起始原料合成3-卤亚甲基-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-炔丙氧基苯胺类化合物合成3-卤亚甲基-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-卤亚甲基-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-卤亚甲基-2,3-二氢苯并呋喃类化合物的方法。
该方法是2-炔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-卤亚甲基-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-炔丙氧基苯胺类化合物的分子通式是：所合成的3-卤亚甲基-2,3-二氢苯并呋喃类化合物的分子通式是：
式中：R1、R2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；X为氯、溴或碘。
本发明的3-卤亚甲基-2,3-二氢苯并呋喃类化合物均是以2-炔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，以还原性金属盐作为催化剂制得，可用下式表示：
所述的2-炔丙氧基苯胺类化合物的结构式为:其中R1、R2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：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-炔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25℃。
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、乙醚、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，推荐溶剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为二氯甲烷―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、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＝1:0.1－500，异丙醇:石油醚＝1:0.1－500。
本发明提供了一些新的3-卤亚甲基-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、对甲基苯基、苄基、烷基；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-炔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，再以还原性金属盐作为催化剂，高效率一步合成3-卤亚甲基-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-炔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，从而有利于药物或者药物中间体的生产和处理。且反应的产率较好。
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-炔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后加入醋酸亚铜(0.1mmol)，补加丙酮2.0mL，于冰浴或室温下继续反应1-3h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；无色油状物,顺式:反式＝2:1,总产率:88％；
顺式-A1:1H NMR(400MHz,CDCl3)δ7.32(d,J＝7.6Hz,1H),7.21(t,J＝7.8Hz,1H),6.93-6.84(m,2H),6.37(t,J＝2.8Hz,1H),5.15(d,J＝2.8Hz,2H)；13C NMR(101MHz,CDCl3)δ163.8,139.2,130.7,123.5,121.0,120.6,110.9,105.7,74.3；IR(薄膜):νmax(cm-1)＝3060,1649,1500,1460,1230,1089,805,744；HRMS(EI) calcd for(M+)C9H7ClO:166.0190,Found:166.0188.
反式-A1:1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.0Hz,1H),7.31-7.27(m,1H),6.95(t,J＝7.6Hz,1H),6.87(d,J＝8.0Hz,1H),6.02(s,1H),5.10(d,J＝2.8Hz,2H).
A2:
石油醚淋洗；无色油状物,顺式:反式＝1.8:1,总产率:84％；
顺式-A2:1H NMR(400MHz,CDCl3)δ6.98(dd,J＝7.8,2.8Hz,1H),6.91(td,J＝8.8,2.8Hz,1H),6.79(dd,J＝8.8,4.0Hz,1H),6.36(t,J＝3.2Hz,1H),5.17(d,J＝3.2Hz,2H)；13CNMR(101MHz,CDCl3)δ159.9(d,J＝1.4Hz),158.8,156.4,138.9(d,J＝3.2Hz),124.3(d,J＝9.4Hz),117.4(d,J＝24.9Hz),111.4(d,J＝8.6Hz),107.0(dd,J＝13.2,12.1Hz),74.9；19FNMR(376MHz,None)δ-123.1；IR(薄膜):νmax(cm-1)＝3061,1642,1502,1460,1230,1211,1089,745；HRMS(EI)calcd for(M+)C9H6ClFO:184.0084,Found:184.0087.
反式-A2:1H NMR(400MHz,CDCl3)δ7.74(dd,J＝8.6,2.6Hz,1H),6.96(td,J＝8.8,2.6Hz,1H),6.78(dd,J＝8.8,4.1Hz,1H),6.05(t,J＝2.4Hz,1H),5.12(d,J＝2.8Hz,2H)；13CNMR(101MHz,CDCl3)δ160.5(d,J＝1.3Hz),157.2(d,J＝237.3Hz),136.5(d,J＝3.2Hz),124.9(d,J＝9.9Hz),117.8(d,J＝24.9Hz),112.2(d,J＝26.3Hz),110.6(d,J＝8.5Hz),107.2(d,J＝1.1Hz),74.9；19F NMR(376MHz,None)δ-123.1；IR(薄膜):νmax(cm-1)＝3061,1502,1460,1230,1211,1089,980,745；HRMS(EI)calcd for(M+)C9H6ClFO:184.0091,Found:184.0090.
A3:
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:87％；
顺式-A3:1H NMR(400MHz,CDCl3)δ7.25(d,J＝2.0Hz,1H),7.15(dd,J＝8.8,2.4Hz,1H),6.79(d,J＝8.8Hz,1H),6.37(t,J＝3.6Hz,1H),5.16(d,J＝3.6Hz,2H)；13C NMR(101MHz,CDCl3)δ162.4,138.2,130.5,126.1,125.0,120.5,111.9,107.2,74.9；IR(薄膜):νmax(cm-1)＝3061,1649,1500,1460,1235,1089,744,730；HRMS(EI)calcd for(M+)C9H6Cl2O:199.9800,Found:199.9799.
反式-A3:1H NMR(400MHz,CDCl3)δ8.00(d,J＝2.4Hz,1H),7.20(dd,J＝8.6,2.4Hz,1H),6.79(d,J＝8.6Hz,1H),6.07(t,J＝2.4Hz,1H),5.12(d,J＝2.4Hz,2H)；13C NMR(101MHz,CDCl3)δ163.0,135.9,131.0,125.7,125.6,125.5,111.3,107.5,74.9；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1235,1089,980,744,730；HRMS(EI)calcd for(M+)C9H6Cl2O:199.9800,Found:199.9802.
A4:
石油醚淋洗；无色油状物,顺式:反式＝2.5:1,总产率:79％；
顺式-A4:1H NMR(400MHz,CDCl3)δ7.13(s,1H),7.02(d,J＝8.4Hz,1H),6.77(d,J＝8.4Hz,1H),6.33(t,J＝3.2Hz,1H),5.13(d,J＝3.2Hz,2H),2.30(s,3H). 13C NMR(101MHz,CDCl3)δ162.0,139.4,131.5,130.4,123.3,120.7,110.5,105.3,74.4,20.8；IR(薄膜):νmax(cm-1)＝3060,1649,1500,1450,1375,1230,1089,744；HRMS(EI)calcd for(M+)C10H9ClO:180.0342,Found:180.0344.
反式-A4:1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.06(d,J＝8.2Hz,1H),6.76(d,J＝8.2Hz,1H),6.00(d,J＝1.2Hz,1H),5.08(s,2H),2.33(s,3H).13C NMR(101MHz,CDCl3)δ162.6,137.1,131.9,130.2,126.0,124.0,109.9,105.6,74.4,21.0；IR(薄膜):νmax(cm-1)＝3060,1500,1450,1375,1230,1089,980,744；HRMS(EI)calcd for(M+)C10H9ClO:180.0335,Found:180.0338.
A5:
石油醚淋洗；无色油状物,顺式:反式＝1.6:1,总产率:76％；
顺式-A5:1H NMR(400MHz,CDCl3)δ7.36(dd,J＝7.8,1.2Hz 1H),7.25(dd,J＝7.8,1.2Hz,1H),6.78(t,J＝7.8Hz,1H),6.40(t,J＝3.2Hz,1H),5.22(d,J＝3.2Hz,2H)；13C NMR(101MHz,CDCl3)δ160.7,138.7,133.4,124.9,122.4,119.5,107.5,103.9,74.7；IR(薄膜):νmax(cm-1)＝3061,1649,1500,1460,1230,1089,740,668；HRMS(EI)calcd for(M+)C9H6BrClO:243.9295,Found:243.9296.
反式-A5:1H NMR(400MHz,CDCl3)δ7.98(dd,J＝7.8,1.0Hz,1H),7.41(dd,J＝7.8,1.0Hz,1H),6.84(t,J＝7.8Hz,1H),6.07(t,J＝2.8Hz,1H),5.19(d,J＝2.8Hz,2H)；13C NMR(101MHz,CDCl3)δ161.3,136.5,133.9,125.5,124.7,122.3,107.7,103.4,74.7；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1230,1089,980,740,668；HRMS(EI)calcd for(M+)C9H6BrClO:243.9291,Found:243.9288.
A6:
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:93％；
顺式-A6:H NMR(400MHz,CDCl3)δ7.44(d,J＝2.0Hz,1H),7.32(dd,J＝2.0,8.4Hz,1H),6.78(d,J＝8.4Hz,1H),6.41(t,J＝3.6Hz,1H),5.19(d,J＝3.2Hz,2H)； 13C NMR(101MHz,CDCl3)δ162.8,138.0,133.3,125.6,123.5,113.1,112.5,107.3,74.9；IR(薄膜):νmax(cm-1)＝3061,1649,1500,1460,1230,1089,740,669；HRMS(EI)calcd for(M+)C9H6BrClO:243.9291,Found:243.9293.
反式-A6:1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.33(d,J＝8.8Hz,1H),6.73(d,J＝8.8Hz,1H),6.06(t,J＝2.4Hz,1H),5.11(d,J＝2.4Hz,2H)；13C NMR(101MHz,CDCl3)δ163.5,135.7,133.8,128.4,126.2,112.9,111.9,107.6,74.8；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1250,1089,980,740,668；HRMS(EI)calcd for(M+)C9H6BrClO:243.9291,Found:243.9289.
A7:
乙酸乙酯/石油醚＝1/50,v/v；无色油状物,顺式:反式＝2:1,总产率:88％；
顺式-A7:1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.87(d,J＝8.8Hz,1H),6.89(d,J＝8.8Hz,1H),6.51(t,J＝3.2Hz,1H),5.23(d,J＝3.2Hz,2H),2.56(s,3H)；13C NMR(101MHz,CDCl3)δ196.3,167.3,137.6,132.2,130.9,124.1,121.2,110.6,107.8,75.4,26；IR(薄膜):νmax(cm-1)＝3068,1720,1649,1500,1460,1230,1089,744；HRMS(ESI)calcd for(MH+)C11H10ClO2:209.0364,Found:209.0363.
反式-A7:1H NMR(400MHz,CDCl3)δ8.63(s,1H),7.93(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,1H),6.12(s,1H),5.19(d,J＝2.4Hz,2H),2.58(s,3H)；13C NMR(101MHz,CDCl3)δ196.4,168.0,135.3,132.6,130.9,126.6,124.5,110.3,107.8,75.4,26.5；IR(薄膜):νmax(cm-1)＝3068,1720,1500,1460,1230,1089,980,744；HRMS(ESI)calcd for(MH+)C11H10ClO2:209.0361,Found:209.0359.
A8:
乙酸乙酯/石油醚＝1/100,v/v；无色油状物,顺式:反式＝2:1,总产率:92％；
顺式-A8:1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.95(d,J＝8.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.50(t,J＝4.0Hz,1H),5.23(d,J＝4.0Hz,2H),3.91(s,3H)；13C NMR(101MHz,CDCl3)δ167.2,166.4,137.7,132.9,123.9,123.3,122.5,110.6,107.5,75.4,52.1；IR(薄膜):νmax(cm-1)＝3058,1735,1649,1590,1500,1230,1083,744；HRMS(ESI)calcd for(MH+)C11H10ClO3:225.0313,Found:225.0308.
反式-A8:1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.00(d,J＝8.5Hz,1H),6.88(d,J＝8.5Hz,1H),6.11(d,J＝0.6Hz,1H),5.19(d,J＝1.4Hz,2H),3.91(s,3H)； 13C NMR(101MHz,CDCl3)δ167.9,166.6,135.4,133.7,127.6,124.4,123.2,110.2,107.8,75.3,52.1；IR(薄膜):νmax(cm-1)＝3058,1735,1590,1500,1230,1083,980,744；HRMS(ESI)calcd for(MH+)C11H10ClO3:225.0313,Found:225.0308.
A9:
石油醚淋洗；无色油状物,顺式:反式＝1.5:1,总产率:76％；
顺式-A9:1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.0Hz,1H),7.71(d,J＝8.2Hz,2H),7.29-7.21(m,4H),7.00(t,J＝7.6Hz,1H),6.37(t,J＝3.2Hz,1H),4.58(d,J＝3.2Hz,2H),2.37(s,3H)；13C NMR(101MHz,CDCl3)δ144.5(d,J＝2.8Hz),135.7,133.8,130.4,129.9,127.2,127.1,123.8,120.5,115.2,108.3,53.9,21.6；IR(薄膜):νmax(cm-1)＝3061,1735,1649,1590,1500,1230,1089,744；HRMS(ESI)calcd for(M+Na)C16H14ClNNaO2S+:342.0326,Found:342.0328.
反式-A9:1H NMR(400MHz,CDCl3)δ8.09(d,J＝7.6Hz,1H),7.77(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,2H),7.34(t,J＝7.6Hz,1H),7.26(d,J＝7.6Hz,2H),7.08(t,J＝7.6Hz,1H),6.06(s,1H),4.57(s,2H),2.39(s,3H).
A10:
石油醚淋洗；无色油状物,顺式:反式＝1:1,总产率:76％；
顺式-A10:1H NMR(400MHz,CDCl3)δ8.31(dd,J＝8.0,1.6Hz,1H),7.28-7.23(m,1H),6.96(dt,J＝8.0,1.2Hz,1H),6.89(dd,J＝8.0,1.2Hz,1H),6.07(t,J＝1.2Hz,1H),4.32(t,J＝5.6Hz,2H),2.64(td,J＝5.6,1.2Hz,2H).
反式-A10:1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.0,1.6Hz,1H),7.20-7.14(m,1H),6.91-6.84(m,2H),6.61(t,J＝1.8Hz,1H),4.21(t,J＝1.8Hz,2H),2.82(td,J＝6.0,1.6Hz,2H)；13C NMR(101MHz,CDCl3)δ154.1,131.4,129.6,123.5,121.1,
120.3,117.9,111.9,65.6,26.2；IR(薄膜):νmax(cm-1)＝3061,1649,1500,1460,1238,1090,805,744；HRMS(EI)calcd for(M+)C10H9ClO:180.0342,Found:180.0343.
在氩气保护下，冰浴条件下，向一干燥反应管中依次加入2-炔丙氧基苯胺类化合物(0.5mmol)，丙酮(3.0mL)，溴化氢的水溶液(0.18mL)，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后加入醋酸 亚铜(0.1mmol)，补加丙酮2.0mL，于冰浴或室温下继续反应1-3h结束，停止搅拌，减压除去溶剂，饱和硫代硫酸钠水溶液洗涤，二氯甲烷萃取，无水硫酸钠干燥，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B。
B1：
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:87％；
顺式-B1:1H NMR(400MHz,CDCl3)δ7.31(d,J＝7.6Hz,1H),7.20(t,J＝7.8Hz,1H),6.94-6.86(m,2H),6.37(t,J＝2.8Hz,1H),5.13(d,J＝2.8Hz,2H)；13C NMR(101MHz,CDCl3)δ163.8,139.1,130.5,123.4,121.0,120.3,110.9,95.7,74.3；IR(薄膜):νmax(cm-1)＝3060,1635,1500,1460,1250,1080,889,672；HRMS(EI)calcd for(M+)C9H7BrO:209.9680,Found:209.9679
反式-B1:1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.0Hz,1H),7.31-7.27(m,1H),6.96(t,J＝7.8Hz,1H),6.85(d,J＝8.0Hz,1H),5.96(t,J＝2.6Hz,1H),5.08(d,J＝2.6Hz,2H)；13C NMR(101MHz,CDCl3)δ163.8,139.1,130.7,125.4,123.2,120.6,110.9,95.9,74.3；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1250,1080,980,890,672；HRMS(EI)calcd for(M+)C9H7BrO:209.9680,Found:209.9679.
B2：
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:85％；
顺式-B2:1H NMR(400MHz,CDCl3)δ6.89(dd,J＝7.8,2.8Hz,1H),6.83(td,J＝8.6,2.8Hz,1H),6.76(dd,J＝8.6,4.0Hz,1H),6.31(t,J＝3.4Hz,1H),5.17(d,J＝3.4Hz,2H)；13CNMR(101MHz,CDCl3)δ159.3(d,J＝1.4Hz),158.8,156.4,138.9(d,J＝3.2Hz),124.3(d,J＝9.4Hz),118.9(d,J＝24.9Hz),111.4(d,J＝8.6Hz),98.0(dd,J＝13.2,10.2Hz),74.9；19FNMR(376MHz,None)δ-125.3；IR(薄膜): νmax(cm-1)＝3061,1635,1502,1460,1246,1211,1080,678；HRMS(EI)calcd for(M+)C9H6BrFO:227.9586,Found:227.9588.
反式-B2:1H NMR(400MHz,CDCl3)δ7.71(dd,J＝8.6,2.6Hz,1H),6.93(td,J＝8.8,2.6Hz,1H),6.78(dd,J＝8.8,4.0Hz,1H),6.04(t,J＝2.8Hz,1H),5.11(d,J＝2.8Hz,2H)；13CNMR(101MHz,CDCl3)δ160.5(d,J＝1.3Hz),157.2(d,J＝237.3Hz),136.5(d,J＝3.2Hz),124.9(d,J＝9.9Hz),117.8(d,J＝24.9Hz),112.2(d,J＝26.3Hz),110.6(d,J＝8.4Hz),97.6(d,J＝1.0Hz),74.9；19F NMR(376MHz,None)δ-125.2；IR(薄膜):νmax(cm-1)＝3061,1502,1460,1245,1211,1080,980,678；
HRMS(EI)calcd for(M+)C9H6BrFO:227.9586,Found:227.9584.
B3：
石油醚淋洗；无色油状物,顺式:反式＝1.7:1,总产率:86％；
顺式-B3:1H NMR(400MHz,CDCl3)δ7.23(d,J＝2.0Hz,1H),7.15(dd,J＝8.8,2.4Hz,1H),6.73(d,J＝8.8Hz,1H),6.38(t,J＝3.6Hz,1H),5.15(d,J＝3.6Hz,2H)；13C NMR(101MHz,CDCl3)δ162.4,138.0,130.0,126.4,123.0,120.5,110.9,97.2,74.9；IR(薄膜):νmax(cm-1)＝3061,1640,1500,1460,1235,1080,674,730；HRMS(EI)calcd for(M+)C9H6BrClO:243.9291,Found:243.9290.
反式-B3:1H NMR(400MHz,CDCl3)δ8.00(d,J＝2.4Hz,1H),7.16(dd,J＝8.6,2.4Hz,1H),6.75(d,J＝8.6Hz,1H),6.07(t,J＝2.4Hz,1H),5.11(d,J＝2.4Hz,2H)；13C NMR(101MHz,CDCl3)δ163.0,135.9,131.0,125.7,124.9,124.5,110.3,97.5,74.9；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1250,1080,975,674,730；HRMS(EI)calcd for(M+)C9H6BrClO:243.9291,Found:243.9290.
B4：
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:81％；
顺式-B4:1H NMR(400MHz,CDCl3)δ7.13(s,1H),7.02(d,J＝8.4Hz,1H),6.75 (d,J＝8.4Hz,1H),6.33(t,J＝3.2Hz,1H),5.12(d,J＝3.2Hz,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ162.0,139.4,131.5,128.4,123.3,120.7,110.5,95.5,74.4,20.8；IR(薄膜):νmax(cm-1)＝3060,1649,1500,1450,1375,1250,1080,674；HRMS(EI)calcd for(M+)C10H9BrO:223.9837,Found:223.9834.
反式-B4:1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.05(d,J＝8.2Hz,1H),6.78(d,J＝8.2Hz,1H),5.99(t,J＝1.4Hz,1H),5.09(d,J＝1.6Hz,2H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ162.6,137.1,131.9,128.2,126.0,124.0,109.9,95.6,74.4,21.0；IR(薄膜):νmax(cm-1)＝3060,1500,1450,1375,1250,1080,980,674；HRMS(EI)calcd for(M+)C10H9BrO:223.9835,Found:223.9833.
B5：
石油醚淋洗；无色油状物,顺式:反式＝1.8:1,总产率:74％；
顺式-B5:1H NMR(400MHz,CDCl3)δ7.36(dd,J＝7.8,1.2Hz 1H),7.21(dd,J＝7.8,1.2Hz,1H),6.78(t,J＝7.8Hz,1H),6.42(t,J＝3.2Hz,1H),5.21(d,J＝3.2Hz,2H)；13C NMR(101MHz,CDCl3)δ160.6,137.7,133.5,124.8,121.4,118.5,106.5,94.3,74.5；IR(薄膜):νmax(cm-1)＝3061,1635,1500,1460,1250,1080,672,668；HRMS(EI)calcd for(M+)C9H6Br2O:287.8781,Found:287.8784.
反式-B5:1H NMR(400MHz,CDCl3)δ7.95(dd,J＝7.6,1.2Hz,1H),7.41(dd,J＝7.6,1.2Hz,1H),6.80(t,J＝7.8Hz,1H),6.09(t,J＝2.8Hz,1H),5.17(d,J＝2.8Hz,2H)；13C NMR(101MHz,CDCl3)δ161.2,135.5,132.9,125.6,124.7,121.3,107.7,94.8,74.5；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1250,1080,980,672,668；HRMS(EI)calcd for(M+)C9H6Br2O:287.8785,Found:287.8787.
B6：
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:90％；
顺式-B6:H NMR(400MHz,CDCl3)δ7.44(d,J＝2.2Hz,1H),7.30(dd,J＝2.2,8.2Hz,1H),6.76(d,J＝8.2Hz,1H),6.43(t,J＝3.6Hz,1H),5.17(d,J＝3.2Hz,2H)； 13C NMR(101MHz,CDCl3)δ162.6,137.8,133.3,125.1,123.5,113.1,112.5,97.3,74.9；IR(薄膜):νmax(cm-1)＝3061,1649,1500,1460,1250,1080,670,669；HRMS(EI)calcd for(M+)C9H6Br2O:287.8785,Found:287.8787.
反式-B6:1H NMR(400MHz,CDCl3)δ8.13(s,1H),7.31(d,J＝8.8Hz,1H),6.73(d,J＝8.8Hz,1H),6.04(t,J＝2.4Hz,1H),5.11(d,J＝2.4Hz,2H)；13C NMR(101MHz,CDCl3)δ162.5,135.7,133.8,127.4,126.2,112.9,111.1,97.6,74.8；IR(薄膜):νmax(cm-1)＝3061,1500,1460,1250,1080,980,670,668；HRMS(EI)calcd for(M+)C9H6Br2O:287.8785,Found:287.8787.
B7：
乙酸乙酯/石油醚＝1/50,v/v；无色油状物,顺式:反式＝2:1,总产率:84％；
顺式-B7:1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.85(d,J＝8.8Hz,1H),6.88(d,J＝8.8Hz,1H),6.53(t,J＝3.2Hz,1H),5.21(d,J＝3.2Hz,2H),2.56(s,3H)；13C NMR(101MHz,CDCl3)δ196.3,167.3,137.8,132.2,128.6,124.1,121.2,111.6,97.8,75.4,26.0；IR(薄膜):νmax(cm-1)＝3068,1720,1649,1500,1460,1250,1080,678；HRMS(ESI)calcd for(MH+)C11H10BrO2:252.9859,Found:252.9855.
反式-B7:1H NMR(400MHz,CDCl3)δ8.61(s,1H),7.90(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),6.13(t,J＝2.4Hz,1H),5.19(d,J＝2.4Hz,2H),2.56(s,3H)；13C NMR(101MHz,CDCl3)δ196.4,168.0,135.3,132.6,128.3,126.6,124.5,111.3,97.8,75.4,26.5；IR(薄膜):νmax(cm-1)＝3068,1720,1500,1460,1250,1080,980,678；HRMS(ESI)calcd for(MH+)C11H10BrO2:252.9859,Found:252.9855.
B8：
乙酸乙酯/石油醚＝1/100,v/v；无色油状物,顺式:反式＝2:1,总产率:89％；
顺式-B8:1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.95(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,1H),6.49(t,J＝3.8Hz,1H),5.22(d,J＝3.8Hz,2H),3.91(s,3H)；13C NMR(101MHz,CDCl3)δ167.0,166.6,137.3,132.9,123.9,123.3,120.0,110.6,97.9,75.4,52.1；IR(薄膜):νmax(cm-1)＝3058,1735,1649,1590,1500,1250,1083,677；HRMS(ESI)calcd for(MH+)C11H10BrO3:268.9808,Found:268.9806.
反式-B8:1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.00(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),6.10(t,J＝1.6Hz,1H),5.18(d,J＝1.6Hz,2H),3.91(s,3H)；13C NMR(101MHz,CDCl3)δ167.2,166.6,134.4,130.7,125.6,124.4,120.2,110.0,97.9,75.3,52.1；IR(薄膜):νmax(cm-1)＝3058,1735,1590,1500,1250,1083,980,677；HRMS(ESI)calcd for(MH+)C11H10BrO3:268.9808,Found:268.9810.
在氩气保护下，冰浴条件下，向一干燥反应管中依次加入2-炔丙氧基苯胺类化合物(0.5mmol)，丙酮(3.0mL)，碘化氢的水溶液(0.15mL)，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后加入醋酸亚铜(0.1mmol)，补加丙酮2.0mL，于冰浴或室温下继续反应1-3h结束，停止搅拌，减压除去溶剂，饱和硫代硫酸钠水溶液洗涤，二氯甲烷萃取，无水硫酸钠干燥，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C。
C1:
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:88％；
顺式-C1:1H NMR(400MHz,CDCl3)δ7.14(d,J＝7.6Hz,1H),6.93(t,J＝7.8Hz,1H),6.91-6.74(m,2H),6.37(t,J＝3.2Hz,1H),4.95(d,J＝3.2Hz,2H).
反式-C1:1H NMR(400MHz,CDCl3)δ8.25(d,J＝7.8Hz,1H),7.31-7.27(m,1H),7.25(t,J＝7.6Hz,1H),7.18(d,J＝7.8Hz,1H),6.00(t,J＝3.0Hz,1H),4.90(d,J＝3.0Hz,2H).
C2:
石油醚淋洗；无色油状物,顺式:反式＝2:1,总产率:87％；
顺式-C2:1H NMR(400MHz,CDCl3)δ7.15(d,J＝2.0Hz,1H),7.05(dd,J＝8.8,2.4Hz,1H),6.79(d,J＝8.8Hz,1H),6.35(t,J＝3.6Hz,1H),4.96(d,J＝3.6Hz,2H)；13C NMR(101MHz,CDCl3)δ172.4,158.2,127.5,126.2,123.0,120.5,111.9,67.5,64.4；IR(薄膜):νmax(cm-1)＝3035,1649,1500,1460,1244,1076,720,600；HRMS(EI)calcd for(M+)C9H6ClIO:291.9149,Found:291.9146.
反式-C2:1H NMR(400MHz,CDCl3)δ8.08(d,J＝2.4Hz,1H),7.24(dd,J＝8.6,2.4Hz,1H),6.79(d,J＝8.6Hz,1H),6.01(t,J＝2.0Hz,1H),4.92(d,J＝2.2Hz,2H)；13C NMR(101MHz,CDCl3)δ172.0,157.9,127.0,126.7,123.6,120.5,111.3,74.9,64.1；IR(薄膜):νmax(cm-1)＝3035,1500,1460,1244,1076,966,720,600；HRMS(EI)calcd for(M+)C9H6ClIO:291.9152,Found:291.9154.

Claims (1)

1.一种合成3-卤亚甲基-2,3-二氢苯并呋喃类化合物的方法，其特征是在有机溶剂的存在下和温度为冰浴或室温，以2-炔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-卤亚甲基-2,3-二氢苯并呋喃类化合物；
上述的2-炔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；
所述的2-炔丙氧基苯胺类化合物结构式为:
所述的卤代氢为:溶液或气体状态的氯化氢、溶液或气体状态的溴化氢或溶液或气体状态的碘化氢；
所述的亚硝酸酯为叔丁基亚硝酸酯；
所述的还原性金属盐为醋酸亚铜；
R1或R2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；
所述化合物结构式为的化合物，其中，所述的X为：氯、溴或碘；
有机溶剂是丙酮。
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