CN115368199B - 一种乙烯基环丙烷化合物的制备方法 - Google Patents

一种乙烯基环丙烷化合物的制备方法 Download PDF

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CN115368199B
CN115368199B CN202110540929.3A CN202110540929A CN115368199B CN 115368199 B CN115368199 B CN 115368199B CN 202110540929 A CN202110540929 A CN 202110540929A CN 115368199 B CN115368199 B CN 115368199B
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祝诗发
贺川
王永东
黄志鹏
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Xinyuan Guangzhou Pharmaceutical Research Co ltd
GENIFARM (GUANGZHOU) TECHNOLOGY Inc
South China University of Technology SCUT
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GENIFARM (GUANGZHOU) TECHNOLOGY Inc
South China University of Technology SCUT
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Abstract

本发明提供了一种乙烯基环丙烷化合物的制备方法，包括如下步骤：式A所示化合物与式B所示化合物，在氮杂卡宾铜催化剂、提供氢源的硅试剂、溶剂和有机碱的条件下，反应生成式C所示乙烯基环丙烷化合物。上述合成方法原料简单，催化剂价格低廉，底物适应性强，不需要手型配体参与，因此，有望用于工业生产。

Description

一种乙烯基环丙烷化合物的制备方法
技术领域
本发明涉及有机合成技术领域，更具体地，涉及一种乙烯基环丙烷化合物的制备方法。
背景技术
乙烯基环丙烷是有机合成化学中一类重要的合成砌块。由于同时含有烯烃和具有较强张力的环丙烷官能团，乙烯基环丙烷有着丰富的反应活性，能够发生重排、过渡金属催化环化等多种化学反应。这些反应被广泛用于各种环状分子的合成。同时乙烯基环丙烷结构普遍存在天然产物和活性药物分子中。另外，各种取代的乙烯基环丙烷的简单、高效合成方法的发展，进一步推动了这类化合物在有机合成、医药、农药和化工等领域的应用。
目前乙烯基环丙烷有以下较为成熟的合成方法：(a)乙烯基环庚烯化合物在金催化剂或锌催化剂作用下经Retro-Buchner反应制得(ACS Catal.2017,7,3668-3675、Org.Lett.2018,20,4341-4345)；(b)环丙烯化合物与烯基硼酸化合物在钴催化剂作用下制得(Angew.Chem.Int.Ed.2019,58,11049–11053)。不足之处在于，使用了较为昂贵的金催化剂，或者需要提前制备结构较为复杂的乙烯基环庚烯化合物或环丙烯化合物原料。
发明内容
本发明为克服上述乙烯基环丙烷在合成过程中催化剂昂贵和需要提前制备结构较为复杂的乙烯环庚烯或环丙烯化合物原料的缺陷，提供一种乙烯基环丙烷化合物的制备方法。
为实现上述目的，本发明采用的技术方案是：
一种乙烯基环丙烷化合物的制备方法，包括如下步骤：
式A所示化合物与式B所示化合物，在氮杂卡宾铜催化剂、提供氢源的硅试剂、溶剂和有机碱的条件下，反应生成式C所示乙烯基环丙烷化合物；
其中，R1选自C6-C14芳基、苯并呋喃基、C1-C10烷基或C3-C8环烷基；
R2选自氢原子或C1-C10烷基；
R1和R2还可以通过C2～C10烷基链相连成环；
R3选自甲酸甲酯基、乙酰基、对甲苯磺酰基或三氟甲磺酰基；
R4选自氢原子、苯基、C1-C10烷基或三甲基硅氧基；
R5选自氢原子、C6-C14芳基、C1-C10烷基、C1～C6烷氧基或三甲基硅氧基；
R6和R7可以相同或不同，独立选自氢原子或C1～C6烷基；
R4和R6还可以通过C2～C10烷基链相连成环；所述烷基链上有一个或多个杂原子；
所述R1、R4、R5上的任意一个或多个氢原子可以被取代基取代，各取代基独立选自C1～C6直链或支链烷基、C1～C6直链或支链烷氧基、卤素原子、硝基、三氟甲基、苯基或乙烯基。
本发明的原料来源易得，采用铜催化剂替换了价格昂贵的金催化剂，底物适应性强，所述制备方法可以有望用于大规模工业生产。
优选地，R1选自C6-C10芳基、苯并呋喃基、C1-C8烷基或C3-C6环烷基；R2选自氢或C1-C6烷基；R3选自甲酸甲酯基、乙酰基、对甲苯磺酰基或三氟甲磺酰基；R4选自氢、苯基、C1-C6烷基或三甲基硅氧基；R5选自氢、C6-C10芳基、C1-C6烷基、C1～C6烷氧基或三甲基硅氧基；R6和R7可以相同或不同，独立选自氢或C1～C6烷基。R4和R6还可以通过C2～C10烷基链相连成环；所述烷基链上有一个杂原子。
优选地，R1选自C4烷基、R2选自氢原子、R4选自甲基、R5选自C6芳基、R6和R7选自氢原子。
取代基定义和一般术语
本发明使用的术语“芳基”，表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基的实例可以包括苯基，茚基，萘基、菲和蔥等等。所述的烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
本发明使用的术语“烷基”，表示含有1至10个碳原子，饱和的直链、支链或环状的一价烃基基团。在一实施方案中，烷基基团含有1-10个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子：在一实施方案中，烷基基团含有1-4个碳原子。所述的烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。
术语“卤素”指氟、氯、溴、碘。
优选地，氮杂卡宾铜催化剂选自IPrCuCl、SIPrCuCl、IMesCuCl或SIMesCuCl。
优选地，提供氢源的硅试剂选自苯硅烷、三苯基硅烷、聚甲基氢硅氧烷、四甲基二硅氮烷、三甲氧基硅烷或三乙基硅烷。
优选地，有机碱选自叔丁醇锂、叔丁醇钾或叔丁醇钠。
优选地，反应中式A所示化合物、式B所示化合物、氮杂卡宾铜催化剂、提供氢源的硅试剂和有机碱的摩尔比例为1.0:(1.0～5.0)：(0.0001～0.1)：(1.0～2.0)：(1.0～2.0)。
更优选地，反应中式A所示化合物、式B所示化合物、氮杂卡宾铜催化剂、提供氢源的硅试剂和有机碱的摩尔比例为1.0:(1.2～2.0)：(0.001～0.01)：(1.0～1.5)：(1.0～1.5)。
优选地，所述反应的温度为25～60℃。
优选地，所述溶剂选自乙二醇二甲醚(DME)、四氢呋喃(THF)、甲苯(toluene)、二氯甲烷(DCM)、二氯乙烷(DCE)、乙腈(MeCN)、1,4-二氧六环(1,4-dioxane)中的一种。
更优选地，所述溶剂选自乙二醇二甲醚(DME)、四氢呋喃(THF)、乙腈(MeCN)、1,4-二氧六环(1,4-dioxane)中的一种。
优选地，所述式A所示化合物可以参考已知文献制得(例如Angewandte Chemie-International Edition,2008,vol.47,#20,p.3777–3780；Advanced Synthesis andCatalysis,2011,vol.353,#10,p.1741-1755)。
作为一种实施方式，可以按照以下操作制备：取干燥的烧瓶，加入式A1所示化合物和干燥的四氢呋喃，冷却。加入乙炔基溴化镁，升至室温。反应结束后重新冷却，加入氯化铵溶液淬灭。有机相用乙酸乙酯萃取，硫酸钠干燥，减压除去溶剂。将残余物加入二氯甲烷溶解，冷却，加入吡啶，滴入氯甲酸甲酯。滴加完毕后加入4-二甲氨基吡啶，反应升至室温保温。加入盐酸，有机相用二氯甲烷萃取，硫酸钠干燥，减压除去溶剂后柱层析分离得到式A所示化合物(R3＝CO2Me)。
类似的，当选用对甲苯磺酰氯、乙酸酐或三氟甲磺酸酐等试剂代替氯甲酸甲酯对羟基进行保护时，可以同样得到类似化合物(A-Ts，A-Ac，A-Tf，即R3＝Ts、Ac、Tf)。
更进一步地，作为发明可以制得的乙烯基环丙烷化合物，部分列举如下：
与现有技术相比，本发明的有益效果是：
本发明提供了一种乙烯基环丙烷化合物的制备方法，将式A所示化合物与式B所示化合物，在氮杂卡宾铜催化剂、硅试剂、溶剂和碱的条件下，反应生成式C所示乙烯基环丙烷化合物。上述合成方法原料简单，催化剂价格低廉，底物适应性强，不需要手型配体参与，因此，有望用于大规模工业生产。
具体实施方式
以下结合具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备，可以直接购买或通过已知文献方法合成。
实施例1
本实施例提供一种1-甲基-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
(1)取干燥的烧瓶，加入苯甲醛(5.0g,47mmol,1.0eq)和干燥的四氢呋喃(200ml)，冷却至0℃。加入乙炔基溴化镁(0.5mol/L in THF,142mL,70mmol,1.5eq)，缓慢升至室温。反应结束后重新冷却至0℃，加入氯化铵溶液淬灭。有机相用乙酸乙酯萃取，硫酸钠干燥，减压除去溶剂。将残余物加入二氯甲烷(200ml)溶解，冷却至0℃，加入吡啶(11mL,140mmol,3.0eq)，滴入氯甲酸甲酯(6.6g,70mmol,1.5eq)。滴加完毕后加入4-二甲氨基吡啶(573mg,4.7mmol,0.1eq)，反应升至室温保温1小时。加入2N盐酸，有机相用二氯甲烷萃取，硫酸钠干燥，减压除去溶剂后柱层析分离(石油醚/乙酸乙酯＝20/1)得到式A1所示化合物(8.0g，89％)。1H NMR(500MHz,CDCl3)δ7.64–7.50(m,2H),7.39(dd,J＝6.3,1.5Hz,3H),6.30(d,J＝2.3Hz,1H),3.81(s,3H),2.73(d,J＝2.3Hz,1H).13C NMR(126MHz,CDCl3)δ154.9,135.9,129.4,128.8,127.8,79.7,76.5,69.4,55.2.IR(KBr,cm-1)3290,2958,1750,1442,1260,931,697.HRMS(ESI)calcd for C11H10NaO3 +[M+Na]+:213.0528,found 213.0529.
(2)取一干燥的带搅拌子的希莱克管加入叔丁醇锂(21mg,0.26mmol,1.0eq)、IPrCuCl(1.3mg，0.026％mmol,1％eq)和三苯基硅烷(82mg,0.31mmol,1.2eq)，氮气置换三次后加入乙二醇二甲醚(2ml)，室温搅拌5分钟。加入式A1所示化合物(50mg,0.26mmol,1.0eq)，继续搅拌5分钟。加入4-甲基苯乙烯(46mg,0.39mmol,1.5eq)，升至40℃保温12小时。加入饱和氯化铵溶液，随后用乙酸乙酯萃取(3×10mL)，有机相饱和食盐水洗，硫酸钠干燥，减压除去多余溶剂，柱层析分离(洗脱剂：石油醚)得到式C1所示化合物1-甲基-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(49mg，81％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.25–7.22(m,2H),7.21–7.17(m,4H),7.14(t,J＝8.3Hz,3H),6.55(d,J＝15.7Hz,1H),5.59(dd,J＝15.7,9.5Hz,1H),2.44(td,J＝8.6,6.4Hz,1H),2.37(s,3H),2.03(qd,J＝8.8,5.4Hz,1H),1.41–1.33(m,1H),1.14(dt,J＝6.6,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ137.9,135.7,135.6,130.9,129.5,129.2,128.9,128.5,126.6,125.8,23.6,22.7,21.2,12.7.IR(KBr,cm-1)3023,2921,1515,1447,959,814,692,440.HRMS(ESI)calcd for C18H18Na+[M+Na]+:257.1301,found:257.1302.
实施例2
本实施例提供一种((E)-2-((1R，2R)-2-苯基环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到((E)-2-((1R，2R)-2-苯基环丙基)乙烯基)苯(43mg，75％)。1H NMR(500MHz,CDCl3)δ7.45–7.26(m,4.5H),7.24–7.19(m,3.3H),7.17–7.11(m,3.2H),6.53(d,J＝15.7Hz,1.1H),5.96(dd,J＝15.8Hz,0.1H),5.55(dd,J＝15.7,9.5Hz,1H),2.47(td,J＝8.6,6.4Hz,1H),2.04(qd,J＝8.8,5.5Hz,1.1H),1.86(m,0.1H),1.42–1.36(m,1.2H),1.25(m,0.1H),1.16(q,J＝5.7Hz,1.1H).13C NMR(126MHz,CDCl3)δ138.8,137.9,130.7,129.7,129.3,128.5,128.2,126.7,126.2,125.8,24.0,22.8,12.7.IR(KBr,cm-1)3024,2923,1601,1495,1448,1074,959,769,722,695,440.HRMS(ESI)calcd for C17H16Na+[M+Na]+:243.1144,found:243.1143.
实施例3
本实施例提供一种1-(叔丁基)-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以4-叔丁基苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-(叔丁基)-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(47mg，82％，dr＝12:1)。1H NMR(500MHz,CDCl3)δ7.34–7.26(m,2.3H),7.22(s,1H),7.20–7.15(m,4H),7.14–7.08(m,3H),6.50(d,J＝15.7Hz,1.06H),5.90(dd,J＝15.8,8.7Hz,0.08H),5.56(dd,J＝15.7,9.5Hz,1H),2.39(td,J＝8.6,6.5Hz,1H),2.26(ddd,J＝8.6,7.2,4.0Hz,0.05H),2.22–2.18(m,0.05H),1.98(qd,J＝8.7,5.3Hz,1H),1.89(ddd,J＝7.1,5.9,3.9Hz,0.04H),1.86–1.79(m,0.05H),1.34(dd,J＝8.4,5.1Hz,1.06H),1.30(s,9H),1.09(dt,J＝6.5,5.3Hz,1.04H).13CNMR(126MHz,CDCl3)δ148.9,138.0,135.7,131.1,129.5,128.9,128.5,126.6,125.8,125.1,34.5,31.5,23.6,22.8,12.9.IR(KBr,cm-1)2962,2867,1514,1363,1268,959,843,749,693.HRMS(ESI)calcd for C17H15Na+[M+Na]+:242.1066,found:242.1064.
实施例4
本实施例提供一种1-(甲氧基)-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以4-甲氧基苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-(甲氧基)-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(56mg，87％，dr＝15:1)。1H NMR(500MHz,CDCl3)δ7.24–7.09(m,7H),6.93–6.83(m,2H),6.52(d,J＝15.8Hz,1H),5.52(dd,J＝15.8,9.5Hz,1H),3.81(s,3H),2.40(td,J＝8.6,6.4Hz,1H),1.98(qd,J＝8.8,5.4Hz,1H),1.35(td,J＝8.4,5.1Hz,1H),1.07(dt,J＝6.3,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ158.1,137.9,131.1,130.9,130.4,129.4,128.5,126.6,125.8,113.7,55.4,23.2,22.5,12.8.IR(KBr,cm-1)2955,1515,1441,1292,1188,1015,959,904,829,779,692,544.HRMS(ESI)calcd for C18H18NaO+[M+Na]+:273.1250,found:273.1256.
实施例5
本实施例提供一种1-氟-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以4-氟苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-氟-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(40mg，65％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.25–7.20(m,4H),7.19–7.12(m,3H),7.02–6.95(m,2H),6.52(d,J＝15.7Hz,1H),5.47(dd,J＝15.7,9.4Hz,1H),2.41(dd,J＝8.7,6.6Hz,1H),2.01(dt,J＝8.9,4.4Hz,1H),1.38(td,J＝8.5,5.2Hz,1H),1.08(dt,J＝6.5,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ161.5(d,J＝243.9Hz),137.7,134.5(d,J＝3.1Hz),130.8(d,J＝7.9Hz),130.4,129.8,128.5,126.8,125.8,115.0(d,J＝21.1Hz),23.2,22.5,12.8.19F NMR(471MHz,CDCl3)-117.1.IR(KBr,cm-1)3434,3025,1510,1265,1222,1156,960,843,742,683.HRMS(ESI)calcd for C17H16F+[M+H]+:239.1231,found:239.1233.
实施例6
本实施例提供一种4-((1R，2R)-2-((E)-苯乙烯基)环丙基)-1,1'-联苯，所述制备如下：
以4-乙烯基联苯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到4-((1R，2R)-2-((E)-苯乙烯基)环丙基)-1,1'-联苯(55mg，71％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.62(dd,J＝8.2,1.4Hz,2H),7.58–7.52(m,2H),7.44(dd,J＝8.5,7.0Hz,2H),7.38–7.31(m,3H),7.24–7.19(m,2H),7.19–7.15(m,2H),7.15–7.10(m,1H),6.56(d,J＝15.7Hz,1H),5.61(dd,J＝15.7,9.5Hz,1H),2.49(td,J＝8.6,6.5Hz,1H),2.07(qd,J＝8.8,5.5Hz,1H),1.42(td,J＝8.4,5.2Hz,1H),1.19(dt,J＝6.6,5.5Hz,1H).13C NMR(126MHz,CDCl3)δ141.1,138.9,138.1,137.8,130.6,129.8,129.6,128.8,128.5,127.2,127.1,126.9,126.7,125.8,23.7,23.0,12.9.IR(KBr,cm-1)3022,2925,1599,1495,1444,1074,955,767,723,695,441.HRMS(ESI)calcd for C23H20Na+[M+Na]+:319.1457,found:319.1460.
实施例7
本实施例提供一种1-((1R，2R)-2-((E)-苯乙烯基)环丙基)-4-(三氟甲基)苯的制备方法，所述制备方法如下：
以4-三氟甲基苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-((1R，2R)-2-((E)-苯乙烯基)环丙基)-4-(三氟甲基)苯(41mg,55％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.54(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.24–7.19(m,2H),7.17–7.12(m,3H),6.53(d,J＝15.7Hz,1H),5.48(dd,J＝15.7,9.3Hz,1H),2.47(q,J＝8.1Hz,1H),2.10(qd,J＝8.9,5.6Hz,1H),1.44(td,J＝8.4,5.4Hz,1H),1.18(q,J＝5.8Hz,1H).13CNMR(126MHz,CDCl3)δ143.2,137.5,130.6,129.5,129.4,128.6,127.0,125.8,125.2(q,J＝3.7Hz),23.8,23.2,12.9.19F NMR(471MHz,CDCl3)-62.3.IR(KBr,cm-1)3027,1723,1494,1325,1118,692,440.HRMS(ESI)calcd for C18H15F3Na+[M+Na]+:311.1018,found:311.1015.
实施例8
本实施例提供一种1-甲基-2-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以2-甲基苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-甲基-2-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(48mg,79％，dr＝10:1)。1H NMR(500MHz,CDCl3)δ7.42(d,J＝7.4Hz,0.9H),7.39–7.32(m,5.9H),7.29–7.23(m,0.6H),7.19–7.12(m,2.9H),6.61(d,J＝15.7Hz,0.39H),6.51(d,J＝15.7Hz,1H),6.21(dd,J＝15.7,8.6Hz,0.36H),5.36(dd,J＝15.7,9.8Hz,1H),1.96(td,J＝8.7,5.9Hz,0.39H),1.87(dt,J＝9.8,6.7Hz,1H),1.53(s,1.97H),1.50(s,3H),1.21(d,J＝6.7Hz,1.99H),1.00(t,J＝5.4Hz,0.34H).13C NMR(126MHz,CDCl3)δ147.6,143.6,138.0,137.8,132.78,130.8,130.2,129.7,128.7,128.5,128.5,128.4,128.2,126.9,126.8,126.5,126.3,125.9,125.7,30.5,29.8,29.5,28.8,27.6,22.3,21.3,21.2.IR(KBr,cm-1)3059,3024,2954,1645,1494,1072,959,764,747,696.HRMS(ESI)calcd for C18H18Na+[M+Na]+:257.1301,found:257.1303.
实施例9
本实施例提供一种1-甲基-3-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以3-甲基苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-甲基-3-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(49mg,81％，dr＝13.3:1)。1H NMR(500MHz,CDCl3)δ7.41–7.30(m,0.8H),7.28(m,0.8H),7.25–7.21(m,3H),7.19–7.17(m,3H),7.15–7.10(m,1H),7.07(dd,J＝17.7,7.6Hz,2H),6.56(d,J＝15.7Hz,1.07H),5.96(dd,J＝15.8,8.8Hz,0.07H),5.69–5.53(dd,J＝15.6,8.6Hz,1H),2.50–2.42(m,1.08H),2.37(s,3.16H),2.05(qd,J＝8.9,5.3Hz,1.1H),1.39(tdd,J＝8.4,5.1,1.1Hz,1.06H),1.16(q,J＝5.7Hz,1.06H).13C NMR(126MHz,CDCl3)δ138.7,137.9,137.7,130.8,130.2,129.6,128.5,128.1,126.9,126.6,126.1,125.8,23.9,22.8,21.6,12.7.IR(KBr,cm-1)3025,1596,1480,1265,1078,960,745,697.HRMS(ESI)calcd for C18H18Na+[M+Na]+:257.1301,found:257.1300.
实施例10
本实施例提供一种1-氯-3-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯，所述制备如下：
以3-氯苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-氯-3-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(45mg,68％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.24(d,J＝3.4Hz,1.5H),7.22–7.16(m,4.1H),7.16–7.09(m,4.1H),6.51(d,J＝15.7Hz,1.05H),5.88(dd,J＝15.8,8.6Hz,0.05H),5.48(dd,J＝15.7,9.4Hz,1H),2.46–2.36(m,1.01H),2.03(dd,J＝8.9,5.6Hz,1.09H),1.37(td,J＝8.4,5.3Hz,1.06H),1.11(q,J＝5.8Hz,1.04H).13C NMR(126MHz,CDCl3)δ141.1,137.6,134.1,130.3,129.8,129.5,129.4,128.5,127.4,126.9,126.4,125.8,23.7,22.9,12.7.IR(KBr,cm-1)3023,2929,1644,1596,1446,1215,1072,958,751,695,443.HRMS(ESI)calcd for C17H15ClNa+[M+Na]+:277.0754,found:277.0750.
实施例11
本实施例提供一种1-溴-2-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以2-溴苯乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-溴-2-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(54mg,70％，dr＝10:1)。1H NMR(500MHz,CDCl3)δ7.53(dd,J＝7.9,1.2Hz,1.08H),7.30–7.22(m,4H),7.21–7.15(m,1.4H),7.14–7.04(m,4H),6.49(d,J＝15.7Hz,1.22H),6.01(dd,J＝15.8,8.5Hz,0.11H),5.38(dd,J＝15.7,9.2Hz,1H),2.47(td,J＝8.5,6.7Hz,1H),2.35–2.29(m,0.11H),2.16(qd,J＝8.7,5.4Hz,1H),1.76(ddd,J＝13.5,8.7,5.1Hz,0.1H),1.42(td,J＝8.3,5.4Hz,1H),1.31(dt,J＝8.6,5.6Hz,0.11H),1.17(dt,J＝6.8,5.4Hz,1.1H).13C NMR(126MHz,CDCl3)δ138.5,137.8,132.6,130.2,130.0,129.7,128.5,127.9,127.0,126.7,125.8,25.5,22.9,12.9.IR(KBr,cm-1)2921,1589,1468,1440,1022,957,691,615,430,420.HRMS(ESI)calcd for C17H15BrNa+[M+Na]+:321.0249,found:321.0247.
实施例12
本实施例提供一种2-((1R，2R)-2-((E)-苯乙烯基)环丙基)萘的制备方法，所述制备方法如下：
以2-萘乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到2-((1R，2R)-2-((E)-苯乙烯基)环丙基)萘(53mg,75％，dr>20:1)。1HNMR(500MHz,CDCl3)δ7.87–7.83(m,1H),7.80(d,J＝8.5Hz,1H),7.75(s,1H),7.53–7.42(m,2H),7.19(dd,J＝8.2,6.8Hz,2H),7.13(dd,J＝7.4,1.2Hz,3H),6.59(d,J＝15.7Hz,1H),5.58(dd,J＝15.7,9.5Hz,1H),2.64(td,J＝8.5,6.5Hz,1H),2.14(qd,J＝8.8,5.5Hz,1H),1.52–1.44(m,1H),1.36–1.29(m,1H).13CNMR(126MHz,CDCl3)δ137.7,136.6,133.5,132.3,130.6,129.8,128.4,128.3,127.7,127.6,127.3,126.7,126.0,125.7,125.4,24.3,23.1,12.9.IR(KBr,cm-1)3022,1599,1493,1447,958,857,692,673,615,430.HRMS(ESI)calcd for C21H28Na+[M+Na]+:293.1301,found:293.1302.
实施例13
本实施例提供一种1-氟-4-((1R，2R)-1-甲基-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以1-氟-4-(丙-1-烯-2-基)苯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到1-氟-4-((1R，2R)-1-甲基-2-((E)-苯乙烯基)环丙基)苯(43mg,66％，dr＝4:1)。1H NMR(500MHz,CDCl3)δ7.40–7.36(m,0.5H),7.32(t,J＝7.6Hz,0.6H),7.30–7.27(m,2H),7.22(dd,J＝8.5,6.6Hz,2.4H),7.15–7.11(m,3H),7.00(td,J＝8.8,2.2Hz,2.48H),6.58(d,J＝15.7Hz,0.25H),6.47(d,J＝15.7Hz,1H),6.15(dd,J＝15.7,8.6Hz,0.26H),5.28(dd,J＝15.7,9.7Hz,1H),1.91–1.78(m,1.26H),1.46(s,0.7H),1.43(s,3H),1.17(dd,J＝8.3,4.8Hz,1H),1.12(t,J＝5.0Hz,1H),0.95(t,J＝5.4Hz,0.26H).13C NMR(126MHz,CDCl3)δ161.5(d,J＝244.2Hz),143.4(d,J＝3.1Hz),139.3(d,J＝3.2Hz),137.9,137.8,132.4,131.2(d,J＝8.0Hz),130.4,128.7,128.6,128.5,127.0,126.7,125.9,1257,115.2(d,J＝21.0Hz),115.1(d,J＝21.0Hz),30.1,29.7,28.9,28.8,27.3,22.2,21.7,21.3.19FNMR(471MHz,CDCl3)δ-116.7.-117.4.IR(KBr,cm-1)3025,2954,1510,1217,959,836,691,553,463.HRMS(ESI)calcd for C18H17FNa+[M+Na]+:275.1206,found:275.1207.
实施例14
本实施例提供一种((1R，2R)-1-甲基-2-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以丙-1-烯-2-基苯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到((1R，2R)-1-甲基-2-((E)-苯乙烯基)环丙基)苯(48mg,72％，dr＝2.8：1)。1H NMR(500MHz,CDCl3)δ7.42(d,J＝7.4Hz,0.9H),7.39–7.32(m,5.9H),7.29–7.23(m,0.6H),7.19–7.12(m,2.9H),6.61(d,J＝15.7Hz,0.39H),6.51(d,J＝15.7Hz,1H),6.21(dd,J＝15.7,8.6Hz,0.36H),5.36(dd,J＝15.7,9.8Hz,1H),1.96(td,J＝8.7,5.9Hz,0.39H),1.87(dt,J＝9.8,6.7Hz,1H),1.53(s,1.97H),1.50(s,3H),1.21(d,J＝6.7Hz,1.99H),1.00(t,J＝5.4Hz,0.34H).13C NMR(126MHz,CDCl3)δ147.6,143.6,138.0,137.8,132.78,130.8,130.2,129.7,128.7,128.5,128.5,128.4,128.2,126.9,126.8,126.5,126.3,125.9,125.7,30.5,29.8,29.5,28.8,27.6,22.3,21.3,21.2.IR(KBr,cm-1)3059,3024,2954,1645,1494,1072,959,764,747,696.HRMS(ESI)calcd for C18H18Na+[M+Na]+:257.1301,found:257.1303.
实施例15
本实施例提供一种(1S，1aR，6aR)-1-((E)-苯乙烯基)-1,1a，6,6a-四氢环丙烷[a]茚的制备方法，所述制备方法如下：
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以茚代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到(1S，1aR，6aR)-1-((E)-苯乙烯基)-1,1a，6,6a-四氢环丙烷[a]茚(46mg,77％，dr>20.8：1)。1H NMR(500MHz,CDCl3)δ7.32–7.30(m,1H),7.22–7.15(m,5H),7.15–7.07(m,3H),6.61(d,J＝15.8Hz,1H),5.35(dd,J＝15.8,9.3Hz,1H),3.25(dd,J＝17.4,7.1Hz,1H),2.97(d,J＝17.4Hz,1H),2.86(ddd,J＝7.8,6.0,1.6Hz,1H),2.22(dt,J＝8.1,6.5Hz,1H),2.04(q,J＝8.4Hz,1H).13C NMR(126MHz,CDCl3)δ143.7,142.4,137.9,131.9,128.5,126.7,126.5,126.1,125.9,125.7,124.7,124.2,32.3,31.9,26.2,24.3.IR(KBr,cm-1)3024,2957,1600,1493,961,750,693,440.HRMS(ESI)calcd for C18H16Na+[M+Na]+:255.1144,found:255.1143.
实施例16
本实施例提供一种1-甲氧基-4-((1R，2S，3S)-2-甲基-3-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以1-甲氧基-4-(丙-1-烯-1-基)苯代替实施例1中步骤(2)的4-甲基苯乙烯，洗脱剂为石油醚：乙酸乙酯＝20:1，其余操作一致，得到1-甲氧基-4-((1R，2S，3S)-2-甲基-3-((E)-苯乙烯基)环丙基)苯(57mg,84％，dr＝7.2:1)。1HNMR(500MHz,CDCl3)δ7.40–7.37(m,0.53H),7.36–7.32(m,0.84H),7.27–7.23(m,2.41H),7.21–7.17(m,3.84H),7.16–7.12(m,1.11H),7.07(d,J＝8.7Hz,0.44H),6.88–6.85(m,2.38H),6.59(d,J＝15.7Hz,0.24H),6.51(d,J＝15.7Hz,1H),6.13(d,J＝15.7,0.24H),5.61(d,J＝15.7,1H),3.83(s,3.66H),2.15(dd,J＝8.7,5.7Hz,1H),1.94–1.91(m,0.27H),1.83–1.79(m,0.23H),1.73(td,J＝9.2,4.8Hz,1H),1.56–1.52(m,0.27H),1.50–1.41(m,1.25H),1.37–1.30(m,4.31H).13CNMR(126MHz,CDCl3)δ157.9,157.8,138.0,137.9,134.7,131.2,130.9,130.3,130.1,129.4,129.0,128.6,128.5,126.9,126.8,126.5,125.8,125.7,114.0,113.7,55.3,32.7,32.2,31.9,31.5,23.7,21.2,18.7,14.1.IR(KBr,cm-1)3025,2954,1610,1513,1451,1287,1177,1036,960,832,738,693.HRMS(ESI)calcd for C19H20NaO+[M+Na]+:287.1406,found:287.1403.
实施例17
本实施例提供一种((1S，3R)-2,2-二甲基-3-((E)-苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
以(2-甲基丙-1-烯-1-基)苯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到((1S，3R)-2,2-二甲基-3-((E)-苯乙烯基)环丙基)苯(43mg,67％，dr>20:1)。1HNMR(500MHz,CDCl3)δ7.29–7.25(m,6H),7.24–7.20(m,3H),7.16–7.13(m,1H),6.57(d,J＝15.7Hz,1H),5.77(dd,J＝15.7,10.3Hz,1H),2.22(d,J＝8.9Hz,1H),1.85(dd,J＝10.3,8.9Hz,1H),1.33(s,3H),1.05(s,3H).13C NMR(126MHz,CDCl3)δ138.2,137.8,131.3,129.7,129.4,128.6,128.2,126.6,126.2,125.8,35.1,32.9,29.1,23.7,17.9.IR(KBr,cm-1)3026,2921,1600,1494,1149,964,797,728,615,583,430.HRMS(ESI)calcd for C19H20Na+[M+Na]+:271.1457,found:271.1458.
实施例18
本实施例提供一种(R，E)-(2-苯乙烯基环丙烷-1,1-二苯基的制备方法，所述制备方法如下：
以1,1-二苯基乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到(R，E)-(2-苯乙烯基环丙烷-1,1-二苯基(60mg,78％，dr>20:1)。1HNMR(500MHz,CDCl3)δ7.52(d,J＝7.3Hz,2H),7.43(t,J＝7.3Hz,2H),7.35(m,7H),7.27(m,4H),6.69(d,J＝15.5Hz,1H),5.61(dd,J＝15.7,9.6Hz,1H),2.54(td,J＝9.2,5.7Hz,1H),1.86(dd,J＝8.7,5.0Hz,1H),1.72(t,J＝5.5Hz,1H).13CNMR(126MHz,CDCl3)δ146.5,141.5,137.8,131.7,131.1,129.3(d,J＝1.7Hz),128.6,128.5,128.4,127.3,126.8,126.7,126.0,125.9,37.7,31.2,23.0.IR(KBr,cm-1)3057,3024,1597,1494,1446,1074,956,748,695,550.HRMS(ESI)calcdfor C23H20Na+[M+Na]+:319.1457,found:319.1463.
实施例19
本实施例提供一种((E)-2-((1R，2R)-2-甲基-2-(丙-1-烯-2-基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以2,3-二甲基丁烷-1,3-二烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到((E)-2-((1R，2R)-2-甲基-2-(丙-1-烯-2-基)环丙基)乙烯基)苯(25mg,48％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.37–7.33(m,2H),7.33–7.28(m,2H),7.22–7.17(m,1H),6.52(d,J＝15.7Hz,1H),6.08(dd,J＝15.7,8.6Hz,1H),4.83–4.73(m,2H),1.78(s,3H),1.73–1.68(m,1H),1.26(s,4H),0.68(dd,J＝5.8,4.7Hz,1H).13C NMR(126MHz,CDCl3)δ149.8,137.8,130.4,130.2,128.5,126.7,125.7,109.3,29.1,27.8,20.8,20.1,18.8.IR(KBr,cm-1)2965,1751,1643,1494,1325,1174,1070,692,615,440.HRMS(ESI)calcd forC15H18Na+[M+Na]+:221.1301,found:221.1305.
实施例20
本实施例提供一种((E)-2-((1R，2S)-2-甲基-2-乙烯基环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以异戊二烯代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到((E)-2-((1R，2S)-2-甲基-2-乙烯基环丙基)乙烯基)苯(24mg,50％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.35–7.27(m,4H),7.21–7.17(m,1H),6.50(d,J＝15.7Hz,1H),6.03(dd,J＝15.7,8.6Hz,1H),5.51(dd,J＝17.2,10.5Hz,1H),5.12–4.84(m,2H),1.73–1.67(m,1H),1.24(s,3H),1.12(dd,J＝8.6,4.8Hz,1H),0.85(dd,J＝6.0,4.8Hz,1H).13C NMR(126MHz,CDCl3)δ146.3,137.8,130.7,129.6,128.6,126.9,125.9,110.0,29.8,25.9,22.4,16.4.IR(KBr,cm-1)3001,2925,1744,1643,1441,1325,1174,1070,693,442.HRMS(ESI)calcd for C15H16 +[M+H]+:185.1325,found:185.1328.
实施例21
本实施例提供一种((E)-2-((1R，2R)-2-甲氧基-2-甲基环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以2-甲氧基丙-1-烯代替实施例1中步骤(2)的4-甲基苯乙烯，洗脱剂为石油醚：乙酸乙酯＝20:1，其余操作一致，得到((E)-2-((1R，2R)-2-甲氧基-2-甲基环丙基)乙烯基)苯(25mg,52％，dr＝13.2:1)。1H NMR(500MHz,CDCl3)δ7.33–7.26(m,4H),7.18(ddt,J＝7.5,6.4,1.5Hz,1H),6.47(d,J＝15.7Hz,1H),5.87(dd,J＝15.7,8.4Hz,1H),3.30(s,3H),1.87(dddd,J＝9.8,8.5,6.5,0.9Hz,1H),1.40(s,3H),1.22(dd,J＝10.0,5.5Hz,1H),0.62(dd,J＝6.5,5.5Hz,1H).13C NMR(126MHz,CDCl3)δ137.7,130.4,129.5,128.7,127.0,125.9,63.9,53.9,28.3,21.1,16.1.IR(KBr,cm-1)2932,1739,1448,1265,1092,962,749,695.HRMS(ESI)calcd for C13H16NaO+[M+Na]+:211.1093,found:211.1092.
实施例22
本实施例提供一种((E)-2-((1R，2R)-2-乙氧基环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以乙氧基乙烯代替实施例1中步骤(2)的4-甲基苯乙烯，洗脱剂为石油醚：乙酸乙酯＝20:1，其余操作一致，得到((E)-2-((1R，2R)-2-乙氧基环丙基)乙烯基)苯(22mg,46％，dr＝4.1:1)。1H NMR(500MHz,CDCl3)δ7.35–7.31(m,2H),7.30–7.26(m,3.57H),7.20–7.14(m,1.18H),6.54(d,J＝16.0Hz,1H),6.37(d,J＝15.8Hz,0.25H),6.04(dd,J＝16.0,9.5Hz,1H),5.86(dd,J＝15.8,8.4Hz,0.25H),3.62–3.52(m,2.57H),3.48(td,J＝6.3,3.8Hz,1H),3.26(ddd,J＝6.3,3.6,2.4Hz,0.23H),1.78–1.69(m,0.25H),1.67–1.60(m,1H),1.21(td,J＝7.0,5.3Hz,3.6H),1.37–1.09(m,0.3H),1.04(dt,J＝9.2,6.2Hz,1H),0.82(ddd,J＝6.1,5.0,2.8Hz,1.25H).13C NMR(126MHz,CDCl3)δ138.1,137.6,130.8,129.3,129.2,128.7,128.6,128.4,126.9,126.7,125.8,66.5,66.2,60.8,58.5,22.6,21.8,15.3,14.9,14.4.IR(KBr,cm-1)3026,2974,1725,1599,1447,1204,1059,693,440.HRMS(ESI)calcd forC13H16NaO+[M+Na]+:211.1093,found:211.1092.
实施例23
本实施例提供一种(1R，6R，7S)-7-((E)-苯乙烯基)-2-恶杂环[4.1.0]庚烷的制备方法，所述制备方法如下：
以3,4-二氢-2H-吡喃代替实施例1中步骤(2)的4-甲基苯乙烯，洗脱剂为石油醚：乙酸乙酯＝20:1，其余操作一致，得到y(18mg,34％，dr＝4.5:1)。1H NMR(500MHz,CDCl3)δ7.40–7.35(m,2H),7.33–7.27(m,2H),7.22–7.16(m,1H),6.62(d,J＝16.0Hz,1H),6.26(dd,J＝16.0,8.8Hz,1H),3.81–3.74(m,2H),3.44–3.37(m,1H),2.04–1.95(m,1H),1.87–1.82(m,1H),1.65–1.60(m,1H),1.58–1.50(m,2H),1.23–1.18(m,1H).13C NMR(126MHz,CDCl3)δ138.2,131.9,128.5,126.7,125.9,125.8,64.7,55.4,24.2,23.4,15.9,15.3.IR(KBr,cm-1)3016,2932,1722,1450,1176,1072,975,699.
实施例24
本实施例提供一种三甲基((1S，2R)-1-苯基-2-((E)-苯乙烯基)环丙氧基)硅烷的制备方法，所述制备方法如下：
以三甲基((1-苯基乙烯基)氧基)硅烷代替实施例1中步骤(2)的4-甲基苯乙烯，洗脱剂为石油醚：乙酸乙酯＝20:1，其余操作一致，得到三甲基((1S，2R)-1-苯基-2-((E)-苯乙烯基)环丙氧基)硅烷(54mg,68％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.37–7.27(m,8H),7.25–7.14(m,2H),6.52(d,J＝16.0Hz,1H),6.18(dd,J＝16.0,9.1Hz,1H),1.87(d,J＝6.6Hz,1H),1.68(dd,J＝9.7,6.1Hz,1H),1.32(t,J＝6.3Hz,1H),0.10(s,9H).13C NMR(126MHz,CDCl3)δ144.2,137.8,129.9,129.1,128.5,128.2,126.7,126.5,125.8,125.3,63.1,32.1,22.9,1.1.IR(KBr,cm-1)3412,2929,1733,1441,1250,1072,979,681,440.HRMS(ESI)calcd for C20H24NaOSi+[M+Na]+:331.1489,found:331.1486.
实施例25
本实施例提供一种三甲基(((1R，6S，7S)-7-((E)-苯乙烯基)双环[4.1.0]庚烷-1-基)氧基)硅烷的制备方法，所述制备方法如下：
以(环己基-1-烯-1-氧基)三甲基硅烷代替实施例1中步骤(2)的4-甲基苯乙烯，其余操作一致，得到三甲基(((1R，6S，7S)-7-((E)-苯乙烯基)双环[4.1.0]庚烷-1-基)氧基)硅烷(32mg,43％，dr＝5:1)。1H NMR(500MHz,CDCl3)δ7.38–7.24(m,4.69H),7.22–7.12(m,1.18H),6.57(d,J＝15.7Hz,0.15H),6.44(d,J＝16.0Hz,1H),6.10(dd,J＝15.7,9.3Hz,0.15H),6.03(dd,J＝16.0,9.3Hz,1H),2.20(dt,J＝13.5,5.2Hz,1H),2.09(ddt,J＝14.1,8.3,5.4Hz,1.1H),1.96(ddd,J＝13.5,9.6,5.7Hz,1.1H),1.62–1.50(m,2.3H),1.41(dd,J＝9.3,5.7Hz,1.15H),1.30(dtdd,J＝14.9,7.4,5.6,1.8Hz,3.6H),1.19(ddt,J＝14.5,11.7,5.9Hz,1H),0.19(s,10H).13C NMR(126MHz,CDCl3)δ138.3,132.1,131.0,128.7,128.6,126.9,126.4,125.8,125.6,62.4,60.4,33.5,32.9,32.8,29.8,28.8,25.4,24.2,22.4,22.2,21.8,21.5,10.0,1.6,1.5.IR(KBr,cm-1)3025,2933,1715,1460,1154,1072,975,699.HRMS(ESI)calcd for C18H26NaOSi+[M+Na]+:309.1645,found:309.1649.
实施例26
本实施例提供一种1-甲基-4-((1R，2R)-2-((E)-4-甲基苯乙烯基)环丙基)苯的制备方法，所述制备方法如下：
(1)取干燥的烧瓶，加入4-甲基苯甲醛(500mg,4.2mmol,1.0eq)和干燥的四氢呋喃(20ml)，冷却至0℃。加入乙炔基溴化镁(0.5mol/L in THF,12.6mL,6.3mmol,1.5eq)，缓慢升至室温。反应结束后重新冷却至0℃，加入氯化铵溶液淬灭。有机相用乙酸乙酯萃取，硫酸钠干燥，减压除去溶剂。将残余物加入二氯甲烷(20ml)溶解，冷却至0℃，加入吡啶(1.0mL,12.6mmol,3.0eq)，滴入氯甲酸甲酯(592mg,6.3mmol,1.5eq)。滴加完毕后加入4-二甲氨基吡啶(51mg,0.42mmol,0.1eq)，反应升至室温保温1小时。加入2N盐酸，有机相用二氯甲烷萃取，硫酸钠干燥，减压除去溶剂后柱层析分离(石油醚/乙酸乙酯＝20/1)得到式A26所示化合物(765mg,90％)。1H NMR(500MHz,CDCl3)δ7.46(d,J＝7.9Hz,2H),7.21(d,J＝7.8Hz,2H),6.27(d,J＝2.3Hz,1H),3.81(s,3H),2.72(d,J＝2.1Hz,1H),2.37(s,3H).13C NMR(126MHz,CDCl3)δ154.9,139.4,133.1,129.4,127.8,79.8,76.3,69.3,55.1,21.3.IR(KBr,cm-1)3280,2953,1750,1441,1263,955,790,673.HRMS(ESI)calcd for C12H12NaO3 +[M+Na]+:227.0679,found:227.0674.
(2)取一干燥的带搅拌子的希莱克管加入叔丁醇锂(21mg,0.26mmol,1.0eq)、IPrCuCl(1.2mg，0.026％mmol,1％eq)和三苯基硅烷(82mg,0.31mmol,1.2eq)，氮气置换三次后加入乙二醇二甲醚(2ml)，室温搅拌5分钟。加入式A26所示化合物(50mg,0.26mmol,1.0eq)，继续搅拌5分钟。加入4-甲基苯乙烯(46mg,0.39mmol,1.5eq)，升至40℃保温12小时。加入饱和氯化铵溶液，随后用乙酸乙酯萃取(3×10mL)，有机相饱和食盐水洗，硫酸钠干燥，减压除去多余溶剂，柱层析分离(洗脱剂：石油醚)得到式C26所示化合物1-甲基-4-((1R，2R)-2-((E)-4-甲基苯乙烯基)环丙基)苯(49mg,79％，dr＝18:1)。1H NMR(500MHz,CDCl3)δ7.15(d,J＝8.0Hz,2H),7.09(d,J＝7.8Hz,2H),7.06(d,J＝8.2Hz,2H),7.03–7.01(m,2H),6.49(d,J＝15.7Hz,1H),5.50(dd,J＝15.7,9.4Hz,1H),2.42–2.36(m,1H),2.33(s,3H),2.29(s,3H),1.98(qd,J＝8.8,5.4Hz,1H),1.34(td,J＝8.4,5.1Hz,1H),1.08(dt,J＝6.4,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ136.3,135.8,135.5,135.2,129.8,129.4,129.2,128.9,125.7,23.5,22.7,21.2,21.1,12.7.IR(KBr,cm-1)3053,1517,1442,1265,1012,958,774,738,699.HRMS(ESI)calcd for C19H20Na+[M+Na]+:271.1457,found:271.1456.
实施例27
本实施例提供一种1-氟-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-氟苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-氟-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(44mg,73％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.15(d,J＝8.1Hz,2H),7.10(dt,J＝8.9,2.9Hz,4H),6.89(t,J＝8.7Hz,2H),6.47(d,J＝15.7Hz,1H),5.45(dd,J＝15.7,9.5Hz,1H),2.41(td,J＝8.5,6.5Hz,1H),2.33(s,3H),1.98(tt,J＝8.9,4.4Hz,1H),1.34(td,J＝8.4,5.1Hz,1H),1.09(dt,J＝6.5,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ161.8(d,J＝245.5Hz),135.6,134.1(d,J＝3.3Hz),130.6(d,J＝2.2Hz),129.2,128.9,128.3,127.2,127.1,115.4,115.3(d,J＝21.4Hz),23.6,22.6,21.2,12.7.19F NMR(471MHz,CDCl3)-116.1.IR(KBr,cm-1)2929,1640,1498,1442,1221,1156,966,817,696,561,506.HRMS(ESI)calcd for C18H17FNa+[M+Na]+:275.1206,found:275.1207.
实施例28
本实施例提供一种1-氯-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-氯苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-氯-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(43mg,73％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.21–7.15(m,4H),7.12(d,J＝7.9Hz,2H),7.07(d,J＝8.5Hz,2H),6.47(d,J＝15.7Hz,1H),5.54(dd,J＝15.7,9.5Hz,1H),2.44(td,J＝8.5,6.5Hz,1H),2.35(s,3H),2.04–1.96(m,1H),1.37(td,J＝8.4,5.1Hz,1H),1.12(dt,J＝6.3,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ136.4,135.7,135.5,132.1,131.7,129.2,128.9,128.6,128.2,126.9,23.7,22.7,21.2,12.8.IR(KBr,cm-1)2921,2855,1612,1489,1441,1260,753,695,499.HRMS(ESI)calcd for C18H17ClNa+[M+Na]+:291.0911,found:291.0905.
实施例29
本实施例提供一种1-溴-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-溴苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-溴-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(40mg,71％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.35–7.30(m,2H),7.18–7.08(m,4H),7.05–6.99(m,2H),6.44(d,J＝15.8Hz,1H),5.54(dd,J＝15.7,9.5Hz,1H),2.47–2.40(m,1H),2.34(s,3H),1.99(dd,J＝9.0,5.5Hz,1H),1.36(td,J＝8.4,5.1Hz,1H),1.11(dt,J＝6.6,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ136.8,135.7,135.5,131.9,131.5,129.1,128.9,128.3,127.3,120.2,23.7,22.7,21.2,12.8.IR(KBr,cm-1)3021,2921,1645,1486,1404,1265,1114,1007,960,819,735,440.HRMS(ESI)calcd for C17H15BrNa+[M+Na]+:335.0406,found:335.0408.
实施例30
本实施例提供一种1-叔丁基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-叔丁基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-叔丁基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(36mg,78％，dr>20:1)。1HNMR(500MHz,CDCl3)δ7.31–7.25(m,2H),7.17(d,J＝7.9Hz,2H),7.12(t,J＝7.7Hz,4H),6.52(d,J＝15.7Hz,1H),5.55(dd,J＝15.7,9.4Hz,1H),2.42(td,J＝8.6,6.5Hz,1H),2.36(s,3H),2.01(qd,J＝8.8,5.4Hz,1H),1.40–1.34(m,1H),1.31(s,9H),1.12(dt,J＝6.4,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ149.6,135.8,135.5,135.2,130.1,129.3,129.2,128.9,125.5,125.4,34.5,31.4,23.6,22.7,21.2,12.7.IR(KBr,cm-1)3021,2962,1702,1515,1363,1269,1112,961,850,810,554.HRMS(ESI)calcd for C18H18 +[M+H]+:234.1403,found:234.1397.
实施例31
本实施例提供一种1-甲氧基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-甲氧基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，洗脱剂为石油醚：乙酸乙酯＝20:1，其他操作一致，得到1-甲氧基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(48mg,80％，dr＝20:1)。1H NMR(500MHz,CDCl3)δ7.16(dd,J＝8.0,2.2Hz,2H),7.14–7.08(m,4H),7.05–6.98(m,0.18H),6.87–6.83(m,0.16H),6.80–6.73(m,2H),6.47(dd,J＝15.9,2.1Hz,1.05H),5.80(ddd,J＝15.8,8.7,2.0Hz,0.06H),5.43(ddd,J＝15.9,9.5,2.5Hz,1H),3.81(s,0.19H),3.77(s,3H),2.43–2.36(m,1H),2.34(s,3H),1.98(qdd,J＝8.7,5.5,1.9Hz,1.06H),1.34(tdd,J＝8.4,5.2,1.9Hz,1H),1.08(qd,J＝5.7,2.2Hz,1H).13C NMR(126MHz,CDCl3)δ158.5,135.8,135.5,130.9,129.2,128.9,128.8,128.6,126.9,125.8,113.9,55.4,23.5,22.7,21.2,12.6.
实施例32
本实施例提供一种4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)-1,1'-联苯的制备方法，所述制备方法如下：
以4-苯基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)-1,1'-联苯(44mg,75％，dr＝20>1)。1HNMR(500MHz,CDCl3)δ7.59–7.53(m,2H),7.49–7.38(m,5H),7.25–7.21(m,2H),7.20–7.08(m,4H),6.56(d,J＝15.7Hz,1H),5.61(dd,J＝15.7,9.5Hz,1H),2.44(td,J＝8.5,6.4Hz,1H),2.35(s,3H),2.03(qd,J＝8.7,5.4Hz,1H),1.38(td,J＝8.4,5.1Hz,1H),1.13(dt,J＝6.5,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ140.9,139.3,136.9,135.6,135.5,131.1,129.1,128.9,128.8,128.7,127.1,126.8,126.1,23.7,22.7,21.1,12.7.IR(KBr,cm-1)3053,2921,2002,1515,1485,1265,962,850,733,698,440.HRMS(ESI)calcd for C24H22Na+[M+Na]+:333.1614,found:333.1613.
实施例33
本实施例提供一种1-硝基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-硝基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，洗脱剂为石油醚：乙酸乙酯＝20:1，其他操作一致，得到1-硝基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(22mg,37％，dr＝3:1)。1H NMR(500MHz,CDCl3)δ8.15(dd,J＝9.3,2.3Hz,0.7H),8.08–8.01(m,2H),7.44–7.38(m,0.7H),7.22(dd,J＝9.2,2.2Hz,2H),7.17–7.08(m,4.4H),7.05–6.96(m,0.5H),6.54(dd,J＝15.7,11.5Hz,1.3H),6.09(dd,J＝15.7,9.1Hz,0.3H),5.72(dd,J＝15.7,9.8Hz,1H),2.51(q,J＝8.1Hz,1H),2.33(s,3.6H),2.11(ddd,J＝9.6,6.1,4.2Hz,0.3H),2.03(qd,J＝8.8,5.3Hz,1H),1.84(tt,J＝9.0,5.0Hz,0.3H),1.46–1.36(m,1.3H),1.29–1.25(m,0.3H),1.19(dt,J＝6.6,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ144.3,138.9,138.4,137.1,136.1,135.8,135.1,129.3,129.2,129.1,127.5,126.4,126.1,126.1,125.9,124.2,124.1,27.7,26.2,24.5,23.1,21.2,17.4,13.3.IR(KBr,cm-1)3444,2921,1592,1512,1339,1109,962,813,690.HRMS(ESI)calcd for C18H18NO2 +[M+H]+:280.1332,found:280.1328.
实施例34
本实施例提供一种1-三氟甲基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以4-三氟甲基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-三氟甲基-4-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(37mg,64％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.45(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),7.15(d,J＝7.8Hz,2H),7.11(d,J＝7.9Hz,2H),6.53(d,J＝15.7Hz,1H),5.64(dd,J＝15.7,9.6Hz,1H),2.47(td,J＝8.5,6.4Hz,1H),2.34(s,3H),2.01(qd,J＝8.8,5.4Hz,1H),1.39(td,J＝8.4,5.2Hz,1H),1.15(dt,J＝6.6,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ141.3,135.9,135.4,134.1,129.2,129.0,128.1,125.8,125.46(q,J＝3.9Hz),24.0,22.8,21.2,12.9.19F NMR(471MHz,CDCl3)δ-62.40.IR(KBr,cm-1)3023,1613,1515,1325,1121,810,600,420.HRMS(ESI)calcd for C19H17F3Na+[M+Na]+:325.1175,found:325.1173.
实施例35
本实施例提供一种1-甲基-2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以2-甲基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(50mg,80％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.21(d,J＝7.9Hz,2H),7.17–7.05(m,6H),6.73(d,J＝15.6Hz,1H),5.50(dd,J＝15.6,9.3Hz,1H),2.47(td,J＝8.4,6.3Hz,1H),2.38(s,3H),2.34(s,3H),2.07(qd,J＝8.8,5.5Hz,1H),1.40(td,J＝8.4,5.1Hz,1H),1.17(dt,J＝6.4,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ137.0,135.7,135.5,134.7,132.1,130.2,129.2,128.9,127.4,126.6,126.0,125.4,23.7,22.9,21.1,19.9,12.7.IR(KBr,cm-1)3055,1517,1445,1263,958,774,740,696.HRMS(ESI)calcd for C19H20Na+[M+Na]+:271.1457,found:271.1456.
实施例36
本实施例提供一种1-甲基-3-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
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以3-甲基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-3-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(48mg,78％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.21(d,J＝7.8Hz,2H),7.14(d,J＝7.9Hz,3H),7.04–6.98(m,3H),6.54(d,J＝15.7Hz,1H),5.60(dd,J＝15.7,9.4Hz,1H),2.48–2.41(m,1H),2.38(s,3H),2.33(s,3H),2.04(dd,J＝9.0,5.6Hz,1H),1.39(td,J＝8.5,5.1Hz,1H),1.14(dt,J＝6.4,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ138.0,137.9,135.8,135.5,130.7,129.7,129.2,128.9,128.4,127.4,126.6,122.9,23.6,22.8,21.5,21.1,12.8.IR(KBr,cm-1)3053,1515,1442,1265,958,774,738,705.HRMS(ESI)calcd for C19H20Na+[M+Na]+:271.1457,found:271.1452.
实施例37
本实施例提供一种1-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)萘的制备方法，所述制备方法如下：
以1-萘甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)萘(43mg,73％，dr>20:1)。1H NMR(500MHz,CDCl3)δ8.13–8.06(m,1H),7.91–7.83(m,1H),7.74(d,J＝8.1Hz,1H),7.56–7.48(m,2H),7.39(t,J＝7.6Hz,1H),7.35–7.31(m,1H),7.31–7.26(m,3H),7.18(d,J＝7.8Hz,2H),5.67(dd,J＝15.5,9.3Hz,1H),2.54(dd,J＝8.6,6.7Hz,1H),2.41(s,3H),2.20(dd,J＝8.8,5.5Hz,1H),1.47(td,J＝8.4,5.2Hz,1H),1.25(dt,J＝6.5,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ135.7,135.6,134.1,133.7,131.0,129.3,129.0,128.4,127.1,126.6,125.8,125.6,125.6,124.2,123.5,23.8,22.9,21.2,12.7.IR(KBr,cm-1)3044,2920,1588,1514,1173,961,814,792,430.HRMS(ESI)calcd for C22H21 +[M+H]+:285.1638,found:285.1635.
实施例38
本实施例提供一种1,3-二甲基-2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以2,6-二甲基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1,3-二甲基-2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(42mg,69％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.18(d,J＝7.8Hz,2H),7.10(d,J＝7.8Hz,2H),7.03–6.95(m,3H),6.44(d,J＝16.1Hz,1H),5.05(dd,J＝16.1,9.1Hz,1H),2.46(td,J＝8.5,6.4Hz,1H),2.35(s,3H),2.12(s,6H),2.08–2.02(m,1H),1.35(td,J＝8.4,5.2Hz,1H),1.16(q,J＝5.6Hz,1H).13C NMR(126MHz,CDCl3)δ137.7,136.0,135.8,135.5,135.4,129.1,128.9,127.6,126.8,126.0,23.3,22.8,21.1,20.9,11.7.IR(KBr,cm-1)3016,2920,1516,1466,1265,1165,968,812,768,736.HRMS(ESI)calcd for C20H22Na+[M+Na]+:285.1614,found:285.1612.
实施例39
本实施例提供一种1,3,5-三甲基-2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以2,4,6-三甲基苯甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1,3,5-三甲基-2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(43mg,71％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.17(d,J＝7.9Hz,2H),7.09(d,J＝7.8Hz,2H),6.80(s,2H),6.41(d,J＝16.1Hz,1H),5.02(dd,J＝16.1,9.1Hz,1H),2.44(d,J＝6.5Hz,1H),2.34(s,3H),2.25(s,3H),2.08(s,6H),2.04(dd,J＝8.8,5.5Hz,1H),1.33(td,J＝8.4,5.2Hz,1H),1.15(dt,J＝6.4,5.4Hz,1H).13C NMR(126MHz,CDCl3)δ135.9,135.8,135.5,135.4,135.1,134.7,129.1,128.8,128.4,126.7,23.3,22.8,21.1,20.9,20.8,11.7.IR(KBr,cm-1)3003,2918,1610,1516,1443,969,836,813.HRMS(ESI)calcd for C21H24Na+[M+Na]+:299.1770,found:299.1766.
实施例40
本实施例提供一种2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯并呋喃的制备方法，所述制备方法如下：
以苯并呋喃-2-甲醛代替实施例26步骤(1)的4-甲基苯甲醛，洗脱剂为石油醚：乙酸乙酯＝20:1，其他操作一致，得到2-((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯并呋喃(44mg,73％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.44(dd,J＝7.6,1.4Hz,1H),7.33(d,J＝8.0Hz,1H),7.21–7.10(m,6H),6.44(d,J＝15.6Hz,1H),6.37(s,1H),5.84(dd,J＝15.6,9.8Hz,1H),2.48(q,J＝8.1Hz,1H),2.34(s,3H),2.01(dd,J＝9.2,5.5Hz,1H),1.41(td,J＝8.4,5.2Hz,1H),1.19(q,J＝5.8Hz,1H).13C NMR(126MHz,CDCl3)δ155.3,154.6,135.8,135.3,133.7,129.3,129.2,129.1,123.9,122.7,120.5,118.2,110.8,102.1,24.4,23.1,21.2,13.3.IR(KBr,cm-1)3023,2920,1678,1514,1450,1173,968,792,695.HRMS(ESI)calcd for C20H18NaO+[M+Na]+:297.1250,found:297.1249.
实施例41
本实施例提供一种1-甲基-4-((1R，2R)-2-((1E，3E)-4-苯基丁烷-1,3-二烯-1-基)环丙基)苯的制备方法，所述制备方法如下：
以肉桂醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-4-((1R，2R)-2-((1E，3E)-4-苯基丁烷-1,3-二烯-1-基)环丙基)苯(33mg,55％，dr>20:1)。1HNMR(500MHz,CDCl3)δ7.29(d,J＝7.2Hz,2H),7.25(d,J＝5.7Hz,2H),7.18–7.06(m,5H),6.58(dd,J＝15.5,10.6Hz,1H),6.41–6.29(m,2H),5.13(dd,J＝15.0,9.7Hz,1H),2.39(td,J＝8.5,6.5Hz,1H),2.33(s,3H),1.91(qd,J＝8.8,5.5Hz,1H),1.32(td,J＝8.4,5.1Hz,1H),1.05(q,J＝5.6Hz,1H).13CNMR(126MHz,CDCl3)δ137.9,135.7,135.6,135.5,130.4,129.5,129.3,129.2,129.0,128.6,127.0,126.2,24.0,22.8,21.2,13.0.IR(KBr,cm-1)3024,2922,1678,1516,1450,968,820,750,695.HRMS(ESI)calcd for C20H21 +[M+H]+:261.1638,found:261.1632.
实施例42
本实施例提供一种1,4-双((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯的制备方法，所述制备方法如下：
以对苯二甲醛代替实施例26步骤(1)的4-甲基苯甲醛，其余投料相应增加，其他操作一致，得到1,4-双((E)-2-((1R，2R)-2-(对甲苯基)环丙基)乙烯基)苯(51mg,40％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.11(d,J＝7.9Hz,4H),7.06(d,J＝7.8Hz,4H),6.98(d,J＝1.2Hz,4H),6.42(d,J＝15.8Hz,2H),5.46(dd,J＝15.8,9.5Hz,2H),2.38(td,J＝8.5,6.5Hz,2H),2.31(s,6H),1.95(qd,J＝8.8,5.4Hz,2H),1.32(td,J＝8.4,5.1Hz,2H),1.06(qd,J＝5.4,2.6Hz,2H).13CNMR(126MHz,CDCl3)δ136.3,136.2,135.7,135.6,130.4,130.3,129.3,129.2,128.9,125.8,23.7,22.8,22.8,21.2,12.8.IR(KBr,cm-1)2921,1326,959,810,673,599,553,430,420.HRMS(ESI)calcd for C30H30Na+[M+Na]+:413.2240,found:413.2237.
实施例43
本实施例提供一种1-甲基-4-((1R，2R)-2-((E)-戊-1-烯-1-基)环丙基)苯的制备方法，所述制备方法如下：
以正丁醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-4-((1R，2R)-2-((E)-戊-1-烯-1-基)环丙基)苯(31mg,54％，dr＝5.7:1)。1H NMR(500MHz,CDCl3)δ7.14–7.05(m,4.46H),6.98(td,J＝6.0,2.8Hz,0.36H),5.55(dtd,J＝17.0,6.9,3.3Hz,1.19H),5.22–5.13(m,0.18H),4.79(ddt,J＝15.2,8.8,1.5Hz,1H),2.33(d,J＝7.3Hz,3.71H),2.27–2.20(m,1.07H),2.00(qd,J＝7.1,1.5Hz,0.39H),1.87(qd,J＝7.1,1.5Hz,2.17H),1.80(qt,J＝8.7,4.9Hz,1.17H),1.66–1.59(m,0.19H),1.40(d,J＝7.3Hz,0.46H),1.34–1.24(m,2.30H),1.20(td,J＝8.5,5.0Hz,1.09H),1.12(dt,J＝8.5,5.3Hz,0.2H),1.03(dt,J＝8.6,5.3Hz,0.21H),0.97–0.89(m,1.92H),0.81(t,J＝7.4Hz,3.07H).13C NMR(126MHz,CDCl3)δ139.8,136.2,135.2,135.0,132.4,130.7,129.4,129.2,129.1,128.7,125.7,34.8,34.7,26.4,24.7,22.9,22.6,21.9,21.16,21.1,16.6,13.8,13.7,11.8.IR(KBr,cm-1)3054,2960,1515,1441,1265,963,757,441.HRMS(ESI)calcd for C15H21 +[M+H]+:201.1638,found:201.1635.
实施例44
本实施例提供一种1-甲基-4-((1R，2R)-2-((E)-3-苯基丙-1-烯-1-基)环丙基)苯的制备方法，所述制备方法如下：
以苯乙醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-4-((1R，2R)-2-((E)-3-苯基丙-1-烯-1-基)环丙基)苯(35mg,57％，dr＝6.2:1)。1H NMR(500MHz,CDCl3)δ7.35(q,J＝6.0,3.9Hz,1H),7.31–7.20(m,3H),7.16(s,4.36H),7.10–7.06(m,2H),7.04–6.99(m,0.38H),5.71(dt,J＝14.5,7.0Hz,1.2H),5.34–5.24(m,0.17H),4.97(ddt,J＝15.1,8.8,1.5Hz,1H),3.43–3.39(m,0.4H),3.27(d,J＝7.0Hz,2H),2.41(s,3H),2.36(s,0.5H),2.32(td,J＝8.7,6.3Hz,1.14H),1.88(pd,J＝9.2,8.7,4.7Hz,1.2H),1.70(dt,J＝8.6,3.7Hz,0.17H),1.25(td,J＝8.4,5.0Hz,1H),1.18(dt,J＝8.5,5.3Hz,0.2H),1.11–1.07(m,0.2H),1.02(q,J＝5.7Hz,1H).13C NMR(126MHz,CDCl3)δ141.1,140.9,136.0,135.4,135.1,133.9,131.2,129.3,129.1,129.0,128.8,128.7,128.6,128.5,128.3,127.6,126.1,125.9,125.7,39.2,39.0,26.3,24.8,22.8,21.6,21.2,21.1,16.6,11.6.IR(KBr,cm-1)3025,2920,1678,1516,1451,964,818,747,698.HRMS(ESI)calcd forC19H20Na+[M+Na]+:271.1457,found:271.1460.
实施例45
本实施例提供一种1-((1R，2R)-2-((E)-2-环己基乙烯基)环丙基)-4-甲苯的制备方法，所述制备方法如下：
以环己醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到32mg,51％(32mg,51％，dr＝55.2:1)。1H NMR(500MHz,CDCl3)δ7.12–7.06(m,4H),6.97(d,J＝8.1Hz,0.4H),5.49(dd,J＝15.5,7.1Hz,1.22H),5.12(dd,J＝8.2,1.3Hz,0.24H),4.76(ddd,J＝15.4,8.7,1.2Hz,1H),2.34(s,3H),2.32(s,0.6H),2.23(td,J＝8.6,6.2Hz,1.05H),1.84–1.76(m,2.27H),1.76–1.71(m,1.01H),1.65(dt,J＝12.7,3.6Hz,2.31H),1.61–1.52(m,3.09H),1.24–1.16(m,2.54H),1.16–1.05(m,2.33H),1.04–0.93(m,2.14H),0.90(q,J＝5.7Hz,1.1H).13C NMR(126MHz,CDCl3)δ139.9,137.0,136.2,135.3,135.2,129.7,129.2,129.1,128.7,126.8,125.7,40.9,40.7,33.5,33.4,33.3,33.2,26.5,26.4,26.3,26.2,26.1,24.8,22.6,21.9,21.2,21.1,16.7,11.9.IR(KBr,cm-1)3026,2955,1536,1443,1265,963,857,670.HRMS(ESI)calcd for C18H24Na+[M+Na]+:263.1770,found:263.1767
实施例46
本实施例提供一种1-((1R，2R)-2-((E)-6-氯己-1-烯-1-基)环丙基)-4-甲苯的制备方法，所述制备方法如下：
以5-氯戊醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-((1R，2R)-2-((E)-6-氯己-1-烯-1-基)环丙基)-4-甲苯(34mg,57％，dr＝5:1)。1H NMR(500MHz,CDCl3)δ7.11–7.07(m,4H),5.49(dt,J＝15.3,6.8Hz,1H),4.79(ddt,J＝15.3,8.9,1.4Hz,1H),3.44(t,J＝6.8Hz,2H),2.33(s,3H),2.25(td,J＝8.7,6.3Hz,1H),1.91(qd,J＝7.1,1.4Hz,2H),1.78(qd,J＝8.7,5.6Hz,1H),1.69–1.58(m,2H),1.40(q,J＝7.5Hz,2H),1.19(td,J＝8.4,5.1Hz,1H),0.93(q,J＝5.7Hz,1H).13C NMR(126MHz,CDCl3)δ136.0,135.3,130.2,129.7,129.1,128.8,45.1,31.8,31.7,26.7,22.7,21.7,21.1,11.6.IR(KBr,cm-1)3000,2924,1516,1444,1265,962,819,735,428.HRMS(ESI)calcd for C16H21ClNa+[M+Na]+:271.1224,found:271.1223.
实施例47
本实施例提供一种1-((1R，2R)-2-((E)-2-环丙基乙烯基)环丙基)-4-甲苯的制备方法，所述制备方法如下：
以环丙醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-((1R，2R)-2-((E)-2-环丙基乙烯基)环丙基)-4-甲苯(34mg,54％，dr＝5.5:1)。1H NMR(500MHz,CDCl3)δ7.16(s,4H),5.16(dd,J＝15.2,8.5Hz,1H),4.95(dd,J＝15.2,9.0Hz,1H),2.40(s,3H),2.30(td,J＝8.7,6.3Hz,1H),1.88–1.79(m,1H),1.30–1.22(m,2H),1.01–0.94(m,1H),0.64(ddq,J＝8.3,4.1,2.4,1.9Hz,2H),0.34–0.29(m,2H).13C NMR(126MHz,CDCl3)δ136.0,135.2,134.1,129.0,128.7,127.0,22.7,22.0,21.1,13.8,11.9,6.7,6.6.IR(KBr,cm-1)3003,1515,1449,1190,1042,954,821,737.HRMS(ESI)calcd for C15H18Na+[M+Na]+:221.1301,found:221.1304.
实施例48
本实施例提供一种1-((1R，2R)-2-((E)-十二烷基-1,11-二烯-1-基)环丙基)-4-甲苯的制备方法，所述制备方法如下：
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以10-十一烯醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-((1R，2R)-2-((E)-十二烷基-1,11-二烯-1-基)环丙基)-4-甲苯(35mg,59％，dr＝6.5:1)。1H NMR(500MHz,CDCl3)δ7.14–7.03(m,4H),5.91–5.78(m,1H),5.54(dt,J＝14.4,6.9Hz,1H),5.06–4.91(m,2H),4.83–4.72(m,1H),2.34(s,3H),2.24(q,J＝6.4Hz,1H),2.06(q,J＝7.2Hz,2H),1.87(q,J＝6.7Hz,2H),1.83–1.75(m,1H),1.42–1.34(m,2H),1.33–1.12(m,11H),0.92(q,J＝5.7Hz,1H).13C NMR(126MHz,CDCl3)δ139.4,136.1,135.2,130.9,129.3,129.2,128.7,114.2,34.0,32.7,29.8,29.6,29.5,29.3,29.2,29.1,22.6,21.9,21.2,11.7.IR(KBr,cm-1)2925,2853,1640,1516,1461,961,909,821,722.HRMS(ESI)calcd forC22H32Na+[M+Na]+:319.2396,found:319.2395.
实施例49
本实施例提供一种1-甲基-4-((1R，2R)-2-((E)-3-甲基-1-烯-1-基)环丙基)苯的制备方法，所述制备方法如下：
以异丁醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-4-((1R，2R)-2-((E)-3-甲基-1-烯-1-基)环丙基)苯(33mg,51％，dr＝4.8:1)。1H NMR(500MHz,CDCl3)δ7.13–7.05(m,4.4H),7.00–6.95(m,0.4H),5.51(dt,J＝15.4,6.3Hz,1.2H),5.09(ddd,J＝15.3,8.3,1.3Hz,0.2H),4.75(ddd,J＝15.3,8.7,1.3Hz,1H),2.33(s,3H),2.32(s,0.6H),2.23(td,J＝8.7,6.2Hz,1.4H),2.14(ddd,J＝13.5,6.7,1.3Hz,1H),1.85–1.81(m,0.2H),1.77(qd,J＝8.6,5.6Hz,1H),1.59(d,J＝1.3Hz,0.4H),1.19(td,J＝8.5,5.0Hz,1H),1.14–1.08(m,0.2H),1.05–0.96(m,1.8H),0.93–0.90(m,1.4H),0.87(d,J＝6.7Hz,6H).13CNMR(126MHz,CDCl3)δ139.8,138.1,136.4,136.1,135.2,135.0,129.3,129.2,129.1,128.7,126.3,125.7,31.2,31.0,26.4,24.8,22.9,22.8,22.7,22.6,21.7,21.2,21.1,16.7,11.8.IR(KBr,cm-1)3054,2958,1515,1463,1265,963,737,440.HRMS(ESI)calcd for C15H20Na+[M+Na]+:223.1457,found:223.1458.
实施例50
本实施例提供一种1-甲基-4-((1R，2R)-2-((E)-3-苯基-1-烯-1-基)环丙基)苯的制备方法，所述制备方法如下：
以2-苯丙醛代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-甲基-4-((1R，2R)-2-((E)-3-苯基-1-烯-1-基)环丙基)苯(24mg,38％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.30–7.22(m,2H),7.19–6.98(m,7H),5.17(dd,J＝9.1,1.5Hz,1H),2.42(td,J＝8.5,6.3Hz,1H),2.34(s,3H),2.17(d,J＝1.3Hz,3H),2.10–2.02(m,1H),1.40(td,J＝8.5,4.9Hz,1H),1.04(q,J＝5.6Hz,1H).13C NMR(126MHz,CDCl3)δ143.9,136.0,135.4,135.2,129.1,128.8,128.2,127.9,126.4,125.5,23.4,21.2,19.0,16.4,13.2.IR(KBr,cm-1)3003,2925,1710,1441,1259,948,718,691,450.HRMS(ESI)calcd for C19H21 +[M+H]+:249.1638,found:249.1639.
实施例51
本实施例提供一种1-((1R，2R)-2-(环己基甲基)环丙基)-4-甲苯的制备方法，所述制备方法如下：
以环己酮代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到1-((1R，2R)-2-(环己基甲基)环丙基)-4-甲苯(21mg,35％，dr>20:1)。1HNMR(500MHz,CDCl3)δ7.10(s,4.18H),7.00(d,J＝8.1Hz,0.32H),4.70(d,J＝8.8Hz,0.14H),4.48(dt,J＝8.6,1.3Hz,1H),2.35(s,3.56H),2.29–2.18(m,3.47H),2.13–2.09(m,0.28H),1.98–1.93(m,2.12H),1.89(td,J＝8.7,5.8Hz,1H),1.82(dt,J＝9.0,4.9Hz,0.16H),1.77–1.71(m,0.14H),1.60–1.53(m,4.4H),1.51–1.44(m,2.11H),1.43–1.38(m,1.2H),1.25(td,J＝8.5,4.8Hz,1H),1.16(d,J＝8.5Hz,0.15H),0.96(dt,J＝8.7,5.2Hz,0.17H),0.84(td,J＝6.0,4.8Hz,1H).13C NMR(126MHz,CDCl3)δ141.1,140.1,139.6,136.4,135.0,134.9,129.1,128.6,125.7,124.2,120.1,37.0,36.9,29.4,28.7,28.6,27.8,27.1,27.0,24.8,22.6,22.5,21.2,21.1,17.4,17.3,12.8.IR(KBr,cm-1)3026,2918,1629,1442,1275,975,823.HRMS(ESI)calcd forC17H22Na+[M+Na]+:249.1614,found:249.1616.
实施例52
本实施例提供一种((E)-3-((1R，2R)-2-(对甲苯基)环丙基)丙-2-烯-1,1-二苯基的制备方法，所述制备方法如下：
以二苯甲酮代替实施例26步骤(1)的4-甲基苯甲醛，其他操作一致，得到((E)-3-((1R，2R)-2-(对甲苯基)环丙基)丙-2-烯-1,1-二苯基(24mg,40％，dr>20:1)。1H NMR(500MHz,CDCl3)δ7.43–7.38(m,2H),7.34–7.28(m,3H),7.20–7.09(m,7H),6.98(dd,J＝8.0,1.7Hz,2H),5.35(d,J＝10.1Hz,1H),2.34(s,3H),2.33–2.29(m,1H),1.94–1.86(m,1H),1.32–1.25(m,1H),1.11(dt,J＝6.4,5.1Hz,1H).13C NMR(126MHz,CDCl3)δ142.9,141.4,140.7,135.8,135.6,130.5,130.0,129.2,129.0,128.3,128.1,127.3,127.0,126.7,24.5,21.2,20.5,13.9.IR(KBr,cm-1)3023,2959,2920,1644,1445,1259,957,745,691,446.HRMS(ESI)calcd for C24H22Na+[M+Na]+:333.1614,found:333.1612.
实施例53～60
本实施例提供一系列1-甲基-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(C1)的制备方法，制备方法和原料与实施例1相同，其区别在于采用不同氮杂卡宾铜催化剂，具体见表1。收率用步骤(2)的收率表示：
表1实施例53～60
实施例61～67
本实施例提供一系列1-甲基-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(C1)的制备方法，制备方法和原料与实施例1相同，采用不同硅试剂和碱，具体见表2。收率用步骤(2)的收率表示：
表2实施例61～67
实施例 催化剂 提供氢源的硅试剂 有机碱 收率％
61 IPrCuCl(1％) 苯硅烷 叔丁醇锂 68
62 IPrCuCl(1％) 聚甲基氢硅氧烷 叔丁醇锂 53
63 IPrCuCl(1％) 四甲基二硅氮烷 叔丁醇锂 36
64 IPrCuCl(1％) 三甲氧基硅烷 叔丁醇锂 62
65 IPrCuCl(1％) 三乙基硅烷 叔丁醇锂 10
66 IPrCuCl(1％) 三苯基硅烷 叔丁醇钠 38
67 IPrCuCl(1％) 三苯基硅烷 叔丁醇钾 26
实施例68～79
本实施例提供一系列1-甲基-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(C1)的制备方法，制备方法和原料与实施例1相同，采用不同当量的烯烃、反应温度和溶剂，具体见表3。收率用步骤(2)的收率表示：
表3实施例68～79
实施例 烯烃当量eq. 反应温度℃ 溶剂 收率％
68 1.0 40 乙二醇二甲醚 56
69 2.0 40 乙二醇二甲醚 80
70 3.0 40 乙二醇二甲醚 82
71 5.0 40 乙二醇二甲醚 82
72 1.5 25 乙二醇二甲醚 69
73 1.5 40 乙二醇二甲醚 80
74 1.5 60 乙二醇二甲醚 81
75 1.5 40 四氢呋喃 61
76 1.5 40 甲苯 15
77 1.5 40 二氯甲烷 10
78 1.5 40 乙腈 53
79 1.5 40 1,4-二氧六环 48
实施例80～82
本实施例提供一系列1-甲基-4-((1R，2R)-2-((E)-苯乙烯基)环丙基)苯(C1)的制备方法，制备方法和原料与实施例1相同，其区别在于采用不同的试剂代替氯甲酸甲酯对羟基进行保护，再进一步与烯烃反应，具体见表4。收率用步骤(2)的收率表示：
表4实施例80～82
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (7)

1.一种乙烯基环丙烷化合物的制备方法，其特征在于，包括如下步骤：
式A所示化合物与式B所示化合物，在氮杂卡宾铜催化剂、提供氢源的硅试剂、溶剂和有机碱的条件下，反应生成式C所示乙烯基环丙烷化合物；
其中，R1选自C6-C14芳基、苯并呋喃基、C1-C10烷基或C3-C8环烷基；
R2选自氢原子或C1-C10烷基；
或者R1和R2还可以通过C2-C10烷基链相连成环；
R3选自甲酸甲酯基、乙酰基、对甲苯磺酰基或三氟甲磺酰基；
R4选自氢原子、苯基、C1-C10烷基或三甲基硅氧基；
R5选自氢原子、C6-C14芳基、C1-C10烷基、C1-C6烷氧基或三甲基硅氧基；
R6和R7可以相同或不同，独立选自氢原子或C1-C6烷基；
或者R4和R6还可以通过C2-C10烷基链相连成环；所述烷基链上有一个或多个杂原子；
所述R1、R4、R5上的任意一个或多个氢原子可以被取代基取代，所述取代基独立选自C1～C6直链或支链烷基、C1-C6直链或支链烷氧基、卤素原子、硝基、三氟甲基、苯基或乙烯基；
所述氮杂卡宾铜催化剂为IPrCuCl、SIPrCuCl、IMesCuCl或SIMesCuCl；
所述提供氢源的硅试剂选自苯硅烷、三苯基硅烷、聚甲基氢硅氧烷、四甲基二硅氮烷、三甲氧基硅烷或三乙基硅烷；
所述有机碱选自叔丁醇锂、叔丁醇钾或叔丁醇钠。
2.根据权利要求1所述乙烯基环丙烷化合物的制备方法，其特征在于，
R1选自C6-C10芳基、苯并呋喃基、C1-C8烷基、C3-C6环烷基；
R2选自氢原子或C1-C6烷基；
R3选自甲酸甲酯基、乙酰基、对甲苯磺酰基或三氟甲磺酰基；
R4选自氢原子、苯基、C1-C6烷基、三甲基硅氧基；
R5选自氢原子、C6-C10芳基、C1-C6烷基、C1-C6烷氧基、三甲基硅氧基；
R4和R6还可以通过C2-C10烷基链相连成环；所述烷基链上有一个杂原子。
3.根据权利要求1所述乙烯基环丙烷化合物的制备方法，其特征在于，R1选自C4烷基、R2选自氢原子、R4选自甲基、R5选自C6芳基、R6和R7选自氢原子。
4.根据权利要求1所述乙烯基环丙烷化合物的制备方法，其特征在于，反应中式A所示化合物、式B所示化合物、氮杂卡宾铜催化剂、提供氢源的硅试剂和有机碱的摩尔比例为1.0:(1.0～5.0)：(0.0001～0.1)：(1.0～2.0)：(1.0～2.0)。
5.根据权利要求1所述乙烯基环丙烷化合物的制备方法，其特征在于，所述反应的温度为25～60℃。
6.根据权利要求1所述乙烯基环丙烷化合物的制备方法，其特征在于，所述溶剂选自乙二醇二甲醚、四氢呋喃、甲苯、二氯甲烷、二氯乙烷、乙腈或1,4-二氧六环中的一种。
7.根据权利要求6所述乙烯基环丙烷化合物的制备方法，其特征在于，所述溶剂选自乙二醇二甲醚、四氢呋喃、乙腈或1,4-二氧六环中的一种。
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