CN110437068A - 一种芳烃甲基化的制备方法 - Google Patents

一种芳烃甲基化的制备方法 Download PDF

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CN110437068A
CN110437068A CN201910695981.9A CN201910695981A CN110437068A CN 110437068 A CN110437068 A CN 110437068A CN 201910695981 A CN201910695981 A CN 201910695981A CN 110437068 A CN110437068 A CN 110437068A
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周强辉
高倩文
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Wuhan University WHU
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Abstract

本发明涉及有机合成或药物化学技术领域，具体涉及一种芳烃甲基化的制备方法，在惰性气体保护下，将底物A、甲基化试剂B和终止剂C为起始原料，在催化剂D、配体E、降冰片烯衍生物G、碱F的作用下，在30‑140℃下于有机溶剂H中搅拌反应，反应结束后反应混合物经抽滤、浓缩和纯化制得如式I‑Ⅲ任一项所示的芳烃甲基化的产物；式I；式Ⅱ；

Description

一种芳烃甲基化的制备方法
技术领域
本发明涉及有机合成或药物化学技术领域，具体涉及一种芳烃甲基化的制备方法。
背景技术
许多研究表明，甲基基团的引入可以改变药物分子的溶解性，亲水性和结构，从而对其生物活性，药物活性以及物理性质产生显著的影响，这种现象在药物化学中被称为“神奇的甲基化效应”。此外，氘代甲基的引入也已经成为改变生物活性的策略之一。
目前，在芳烃或者杂芳烃上安装甲基的方法主要有：(1)使用甲基金属有机试剂(2)使用甲基亲电试剂。然而，这些方法大多需要导向基团，反应条件苛刻，而且使用的甲基化试剂对空气和水敏感，极大地限制了这些方法的使用范围。因此发展高效、简洁的新的合成方法显得尤为重要。
发明内容
本发明的目的在于提供一种芳烃甲基化的制备方法，所用的原料廉价易得，反应条件温和，底物普适性好，产率高，制备过程简单。
本发明实现上述目的所采用的方案是：一种芳烃甲基化的制备方法，在惰性气体保护下，将底物A、甲基化试剂B和终止剂C为起始原料，在催化剂D、配体E、降冰片烯衍生物G、碱F的作用下，在30-140℃下于有机溶剂H中搅拌反应，反应结束后反应混合物经抽滤、浓缩和纯化制得如式I-Ⅲ任一项所示的芳烃甲基化的产物；
其中，底物A为芳基碘化物，结构式为
R1为氢、芳基、杂环芳基、烷基、取代烷基、取代烯基、取代炔基、硼酸频那醇酯基、酯基、醛基、羧基、羟基、氰基、乙酰基、硝基、酰胺基、磺酰基、烷氧基、烷硫基和卤素中的任意一种，为相同或不同；其中m表示R1的个数，0≤m≤4；
甲基化试剂B为磷酸三甲酯、磺酸甲酯、磷酸氘代三甲酯、磺酸氘代甲酯、碳13标记的磺酸甲酯、碳13标记磷酸三甲酯中的任意一种；
终止剂C为烯烃化合物、芳基硼类化合物、炔烃化合物、氰化物、联硼酸频那醇酯、质子源中的任意一种。
本发明的制备方法中加热过程可采用油浴，为硅油或石蜡油；所述抽滤过程使用砂芯漏斗，在减压的条件下过滤；所述浓缩过程可采用常压蒸馏、减压蒸馏，优选为用旋转蒸发仪减压浓缩；所述纯化过程是通过柱层析得到纯净的产物。
所述反应的反应式如下式所示：
当芳烃甲基化的产物为式I所示时，甲基化试剂B为磷酸三甲酯或磺酸甲酯；当芳烃甲基化的产物为式Ⅱ所示时，甲基化试剂B为磷酸氘代三甲酯或磺酸氘代甲酯；当芳烃甲基化的产物为式Ⅲ所示时，甲基化试剂B为碳13标记的磺酸甲酯或碳13标记磷酸三甲酯。
优选地，所述甲基化试剂B中磺酸甲酯的结构式为磺酸氘代甲酯的结构式为碳13标记的磺酸甲酯的结构式为
其中，R2为取代的芳基，杂环芳基、烷基、取代烷基、烷氧基中的任意一种。
优选地，所述终止剂C为ArBR5R6、B2Pin2、Zn(CN)2、CuCN、质子源中的任意一种；其中，R3和R4分别为芳基、取代芳基、烷基、酯基、氰基、醛基、硝基、酰胺基中的任意一种，R5，R6分别为羟基或烷氧基，R7，R8，R9分别为烷基、芳基、取代芳基、硅基中的任意一种。
优选地，所述R1中，取代烯基为其中R3和R4分别为芳基、取代芳基、烷基、酯基、氰基、醛基、硝基、酰胺基中的任意一种；取代炔基为和/或其中R7，R8，R9分别为烷基、芳基、取代芳基、硅基中的任意一种。
优选地，所述芳基带有至少一个取代基，所述取代基为芳基、杂环芳基、烷基、酯基、氰基、硝基、酰胺基、磺酰基、烷氧基和卤素中的至少一种。
所述烷基为具有1～20个碳原子的烷基；
所述取代烷基为其中o为0和任意整数，X为OR10、OSi(R10)3、SR10、SSi(R10)3、SeR10、N(R10)2、Si(R10)3中的至少一种，其中R10为氢、芳基、杂环芳基、烷基、酯基、氰基、硝基、酰胺基、磺酰基、卤素中的至少一种。
所述烷氧基为具有1～10个碳原子的烷氧基。
优选地，所述质子源为甲酸钠、异丙醇、苯甲醇、异丙基硼酸、乙二醇二甲醚、水中的任意一种。
优选地，所述底物A、甲基化试剂B、终止试剂C、催化剂D、配体E、碱F、降冰片烯衍生物G的投料摩尔比为(1-10)：(1-10)：(1-10)：(0.05-1)：(0.1-1)：(1-10)：(0.05-3)。
优选地，所述催化剂D为Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2中的至少一种；所述配体E为三芳基膦、三烷基膦、二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-二苯基]-2-基)膦、二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦、2'-(二环己基膦基)-N,N-二甲基-[1,1'-二苯基]-2-胺、二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦、三(呋喃-2-基)膦、(3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦中的至少一种；所述溶剂H为甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、***、二甲基乙二醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的至少一种；所述碱F为碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的至少一种。
本发明的制备方法所涉及的反应使用的催化剂为廉价的金属钯盐，相比于之前的反应使用的催化剂或者络合物等是一个重要的补充。
优选地，所述降冰片烯衍生物G，其结构式表示为其中R11为左边五元环上的取代基，p代表取代基个数，0≤p≤8；R12为双键上的取代基，q代表取代基个数，0≤q≤2；R11的构型可以是内型或外型或两者的混合物。
优选地，结构式中，左边五元环上取代基数目为两个及两个以上时，可以相同，也可以不相同；双键上的取代基数目为两个时，可以相同，也可以不相同；R11和R12取代基的种类可以相同，也可以不相同；所述R11和R12独立地为CO2M，M为碱金属离子、碱土金属离子、酯基、氰基、硝基、酰胺基、磺酰基、烷氧基、芳基、杂环芳基、烷基、取代烷基和卤素中的任意一种；所述芳基带有至少一个取代基，取代基为芳基、烷基、取代烷基、烷氧基、酯基、氰基、硝基、卤素中的至少一种，当具有多个取代基时，这多个取代基可以相同或不同；所述烷基是指具有1～10个碳原子的烷基；所述烷氧基是指具有1～10个碳原子的烷氧基。
本发明的方法可以高效地制备芳烃甲基化的产物，和现有技术相比，本发明具有下列优势：
1、本发明所涉及的主要原料为芳基碘代物，磷酸三甲酯，磺酸甲酯，磺酸氘代甲酯，烯烃，炔烃，芳基硼类化合物，氰化物，联硼酸频哪醇酯，质子源，此原料可用商品化试剂，无需特殊处理，且价格低廉，种类繁多；
2、本发明方法所涉及的反应使用的甲基化试剂是磷酸三甲酯，磺酸甲酯，磷酸氘代三甲酯，磺酸氘代甲酯，碳13标记的磺酸甲酯，碳13标记磷酸三甲酯，相比于之前的反应使用的金属甲基化试剂，对空气和水稳定，且价格廉价；
3、本发明方法所涉及的反应对官能团具有很好的容忍性和普适性，取代基可以为烷基、烷氧基、烯基、氰基、酯基、酰胺、巯基、卤原子(F、Cl、Br)芳基，杂环芳基，硼酸频那醇酯基等；
4、本发明方法可以大量(克级)制备芳烃甲基化的产物，为工业化生产奠定了良好的基础。
具体实施方式
为更好的理解本发明，下面的实施例是对本发明的进一步说明，但本发明的内容不仅仅局限于下面的实施例。
实施例1：化合物I-1的制备
向干燥并装有磁力搅拌子的25.0mL反应瓶中加入Pd2(dba)3(9.2mg,0.01mmol,0.05当量),三(呋喃-2-基)膦(5.2mg,0.022mmol,0.11当量),碳酸铯(163mg,0.5mmol,2.5当量)，在惰性气体保护下，2-氰基-5-降冰片烯(48mg,0.4mmol,2.0当量),1-乙基-2-碘苯(92.9mg,0.4mmol,2.0当量),对甲苯磺酸甲酯(74.5mg,0.4mmol,2.0当量),丙烯酸叔丁酯(25.6mg,0.2mmol,1.0当量)和干燥的乙腈(1.0mL)。反应瓶在室温下搅拌约5分钟，之后将混合物加热到80℃搅拌15小时。反应容器冷却至室温后，用短硅胶柱过滤，用乙酸乙酯(10mL)冲洗，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚:乙酸乙酯＝50:1(v/v)，得到化合物I-1(无色油状液体，产率95％)。1H NMR(400MHz,CDCl3):δ7.78(d,J＝16.3Hz,1H),7.19-7.15(m,1H),7.12-7.03(m,2H),5.97(d,J＝16.3Hz,1H),2.68(q,J＝7.5Hz,2H),2.34(s,3H),1.55(s,9H),1.19(t,J＝7.5Hz,3H).13C NMR(100MHz,CDCl3):δ166.21,142.84,142.34,136.41,133.94,128.29,128.21,126.36,125.94,80.69,28.37,26.92,21.38,15.48.HRMS(ESI-TOF):理论计算值：C16H22NaO2[M+Na+]269.1512,实测值：269.1515。
实施例2：化合物I-2的制备
向干燥并装有磁力搅拌子的25.0mL反应瓶中加入Pd(OAc)2(4.5mg,0.01mmol,0.05当量),三(呋喃-2-基)膦(10.2mg,0.022mmol,0.11当量),碳酸铯(163mg,0.5mmol,2.5当量)，在惰性气体保护下，降冰片烯(37.7mg,0.4mmol,2.0当量),叔丁基((2-碘苄基)氧基)二甲基硅烷(139.3mg，0.4mmol，2.0当量),磷酸三甲酯(56.1mg,0.4mmol,2.0当量)，丙烯酸叔丁酯(25.6mg,0.2mmol,1.0当量)和干燥的N,N-二甲基乙酰胺(1.0mL)。反应瓶在室温下搅拌约5分钟，之后将混合物加热到80℃搅拌15小时。反应容器冷却至室温后，反应容器冷却至室温后，用水(10mL)淬灭，用乙酸乙酯(3×10mL)萃取，Na2SO4干燥，过滤，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚:乙酸乙酯＝50:1(v/v)，得化合物I-2(无色油状液体，产率87％)。1H NMR(400MHz,CDCl3):δ7.77(d,J＝16.2Hz,1H),7.36(d,J＝7.6Hz,1H),7.30-7.24(m,1H),7.18(d,J＝7.5Hz,1H),6.16(d,J＝16.2Hz,1H),4.69(s,2H),2.39(s,3H),1.58(s,9H),0.97(s,9H),0.14(s,6H).13C NMR(100MHz,CDCl3):δ166.19,141.04,139.31,136.69,133.68,129.57,128.29,126.30,126.09,80.66,63.74,28.35,26.09,20.98,18.50,-5.12.HRMS(ESI-TOF):理论计算值：C21H34NaO3Si[M+Na+]385.2169,实测值：385.2170。
实施例3：化合物I-3的制备
所用的芳基碘化物为2,6-双(苄氧基)-3-碘苯甲酸甲酯(189.7mg，0.4mmol)，其他条件同实施例1，得化合物I-3(无色油状液体，产率92％)。1H NMR(400MHz,CDCl3):δ7.73(d,J＝16.3Hz,1H),7.49-7.29(m,10H),6.64(s,1H),6.51(d,J＝16.3Hz,1H),5.13(s,2H),4.86(s,2H),3.85(s,3H),2.42(s,3H),1.52(s,9H).13C NMR(100MHz,CDCl3):δ167.00,166.65,156.36,156.29,142.07,136.77,136.59,136.43,128.87,128.70,128.59,128.45,128.10,127.00,124.54,121.21,117.99,111.15,80.42,76.78,70.54,52.60,28.35,21.82.HRMS(ESI-TOF):理论计算值：C30H32NaO6[M+Na+]511.2091,实测值：511.2094。
实施例4：化合物I-4的制备
所用的芳基碘化物为4-碘-2,3-二氢-1H-茚(97.7mg，0.4mmol)，其他条件同实施例3，得化合物I-4(无色油状液体，产率83％)。1H NMR(400MHz,CDCl3):δ7.84(d,J＝16.3Hz,1H),7.12(d,J＝7.6Hz,1H),7.01(d,J＝7.6Hz,1H),6.12(d,J＝16.3Hz,1H),3.01(t,J＝7.3Hz,2H),2.90(t,J＝7.5Hz,2H),2.40(s,3H),2.12-2.00(m,2H),1.54(s,9H).13C NMR(100MHz,CDCl3):δ166.86,143.87,142.90,141.52,135.40,130.49,128.82,125.04,123.78,80.58,33.86,32.74,28.37,25.69,20.61.HRMS(ESI-TOF):理论计算值：C16H22NaO4[M+Na+]281.1512,实测值：281.1510。
实施例5：化合物I-5的制备
所用的芳基碘化物为1-碘萘(101.6mg，0.4mmol)，其他条件同实施例1，得化合物I-5(无色油状液体，产率95％)。1H NMR(400MHz,CDCl3):δ8.16-8.03(m,2H),7.83-7.80(m,1H),7.73(d,J＝8.4Hz,1H),7.53-7.43(m,2H),7.34(d,J＝8.4Hz,1H),6.17(d,J＝16.3Hz,1H),2.53(s,3H),1.60(s,9H).13C NMR(100MHz,CDCl3):δ166.09,141.50,134.09,132.21,131.63,131.11,129.00,128.49,128.37,127.46,126.56,125.26,124.84,80.85,28.39,21.15.HRMS(ESI-TOF):理论计算值：C18H20NaO2[M+Na+]291.1356,实测值：291.1356。
实施例6：化合物I-6的制备
所用的芳基碘化物为4-碘异喹啉(102.1mg，0.4mmol)，其他条件同实施例3，得化合物I-6(黄色固体，产率41％)。1H NMR(400MHz,CDCl3):δ9.13(s,1H),8.05-8.01(m,2H),7.95(d,J＝8.1Hz,1H),7.72-7.66(m,1H),7.58-7.54(m,1H),6.22(d,J＝16.3Hz,1H),2.73(s,3H),1.58(s,9H).13C NMR(100MHz,CDCl3):δ165.72,152.09,149.68,139.47,134.42,130.99,128.42,128.19,126.98,126.56,124.27,123.78,81.20,28.36,23.53.HRMS(ESI-TOF):理论计算值：C17H20NNaO2[M+H+]270.1489,实测值：270.1488。
实施例7：化合物I-7的制备
所用的芳基碘化物为6-氯-3-碘-2-甲基吡啶(101.4mg，0.4mmol)，其他条件同实施例3，得化合物I-7(白色固体，产率90％)。1H NMR(400MHz,CDCl3):δ7.62(d,J＝16.3Hz,1H),7.05(s,1H),6.03(d,J＝16.3Hz,1H),2.54(s,3H),2.32(s,3H),1.54(s,9H).13C NMR(100MHz,CDCl3):δ165.47,157.27,149.66,148.93,138.81,128.99,127.72,123.26,81.33,28.30,23.79,20.65.HRMS(ESI-TOF):理论计算值：C14H19ClNO2[M+H+]268.1099,实测值：268.1105。
实施例8：化合物I-8的制备
所用的芳基碘化物为5-碘-2,4-二甲氧基嘧啶(106.4mg，0.4mmol)，反应温度为100℃，其他条件同实施例1，得化合物I-8(黄色固体，产率69％)。1H NMR(400MHz,CDCl3):δ7.67(d,J＝16.0Hz,1H),6.54(d,J＝16.0Hz,1H),4.06(s,3H),3.99(s,3H),2.54(s,3H),1.53(s,9H).13C NMR(100MHz,CDCl3):δ169.71,169.52,167.23,163.73,134.07,123.07,108.13,80.57,55.00,54.46,28.36,22.93.HRMS(ESI-TOF):理论计算值：C14H20N2NaO4[M+Na+]303.1315,实测值：303.1319。
实施例9：化合物I-9的制备
所用的芳基碘化物为3-甲氧基碘苯(93.6mg，0.4mmol)，对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，其他条件同实施例1，得化合物I-9(无色油状液体，产率78％)。1H NMR(400MHz,CDCl3):δ7.71(d,J＝16.3Hz,1H),7.00(d,J＝8.3Hz,1H),6.74(d,J＝8.3Hz,1H),5.93(d,J＝16.3Hz,1H),3.81(s,3H),2.26(s,3H),2.21(s,3H),1.54(s,9H).13C NMR(100MHz,CDCl3):δ166.22,156.03,142.67,135.63,128.26,127.98,126.28,125.17,110.13,80.71,55.78,28.36,20.51,13.35.HRMS(ESI-TOF):理论计算值：C16H22NaO3[M+Na+]285.1461,实测值：285.1464。
实施例10：化合物II-1的制备
所用的甲基化试剂为对甲苯磺酸氘代甲酯(75.7mg，0.4mmol)，其他条件同实施例1，得化合物II-1(无色油状液体，产率94％)。1H NMR(400MHz,CDCl3):δ7.78(d,J＝16.3Hz,1H),7.17(t,J＝7.5Hz,1H),7.10-7.05(m,2H),5.98(d,J＝16.3Hz,1H),2.68(q,J＝7.5Hz,2H),1.56(s,9H),1.20(t,J＝7.5Hz,3H).13C NMR(100MHz,CDCl3):δ166.21,142.84,142.32,136.29,133.93,128.29,128.21,126.36,125.90,80.68,28.36,26.92,15.47.HRMS(ESI-TOF):理论计算值：C16H19D3NaO2[M+Na+]272.1700,实测值：272.1702。
实施例11：化合物II-2的制备
所用的芳基碘化物为4-溴碘苯(113.2mg，0.4mmol)，所用的甲基化试剂为对甲苯磺酸氘代甲酯(151.4mg，0.8mmol)，其他条件同实施例1，得化合物II-2(白色固体，产率79％)。1H NMR(400MHz,CDCl3):δ7.63(d,J＝16.3Hz,1H),7.20(s,2H),5.97(d,J＝16.4Hz,1H),1.54(s,9H).13C NMR(100MHz,CDCl3):δ166.02,141.09,138.67,133.26,131.03,126.24,121.99,80.89,28.33.HRMS(ESI-TOF):理论计算值：C15H13D6BrNaO2[M+Na+]339.0837,实测值：339.0835。
实施例12：化合物I-10的制备
所用的芳基碘化物为(R)-2-((叔丁氧基羰基)氨基)-3-(4-碘苯基)丙酸甲酯(162.1mg，0.4mmol)，对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，其他条件同实施例1，得化合物I-10(无色油状液体，产率79％)。1H NMR(400MHz,CDCl3):δ7.70(d,J＝16.3Hz,1H),6.81(s,2H),5.97(d,J＝16.3Hz,1H),4.97(d,J＝8.3Hz,1H),4.54(q,J＝6.7Hz,1H),3.72(s,3H),3.19-2.80(m,2H),2.31(s,6H),1.53(s,9H),1.42(s,9H).13C NMR(100MHz,CDCl3):δ172.50,166.33,155.21,141.86,137.05,136.07,132.94,129.28,125.59,80.69,80.07,54.45,52.35,37.99,28.43,28.35,21.30.HRMS(ESI-TOF):理论计算值：C24H35NNaO6[M+Na+]456.2357,实测值：456.2364。
实施例13：化合物II-3的制备
所用的芳基碘化物为(R)-2-((叔丁氧基羰基)氨基)-3-(4-碘苯基)丙酸甲酯(162.1mg，0.4mmol)，所用的甲基化试剂为对甲苯磺酸氘代甲酯(151.4mg，0.8mmol)，其他条件同实施例1，得化合物II-3(无色油状液体，产率70％)。1H NMR(400MHz,CDCl3):δ7.70(d,J＝16.4Hz,1H),6.81(s,2H),5.97(d,J＝16.3Hz,1H),4.97(d,J＝8.3Hz,1H),4.60-4.45(m,1H),3.72(s,3H),3.03-2.96(m,2H),1.54(s,9H),1.42(s,9H).13C NMR(100MHz,CDCl3):δ172.50,166.35,155.21,141.85,136.97,136.09,132.98,129.31,125.55,80.69,80.08,54.46,52.35,38.01,28.44,28.37.HRMS(ESI-TOF):理论计算值：C24H29D6NNaO6[M+Na+]462.2733,实测值：462.2738。
实施例14：化合物III-1的制备
所用的芳基碘化物为(R)-2-((叔丁氧基羰基)氨基)-3-(4-碘苯基)丙酸甲酯(162.1mg，0.4mmol)，所用的甲基化试剂为碳13标记的对甲苯磺酸甲酯(149.8mg，0.8mmol)，其他条件同实施例1，得化合物III-1(无色油状液体，产率71％)。1H NMR(400MHz,CDCl3):δ7.70(d,J＝16.3Hz,1H),6.81-6.80(m,2H),5.97(d,J＝16.3Hz,1H),4.98(d,J＝8.3Hz,1H),4.57-4.52(m,1H),3.72(s,3H),3.07-2.92(m,2H),2.31(d,J＝126.9Hz,6H),1.53(s,9H),1.42(s,9H).13C NMR(100MHz,CDCl3):δ172.50,166.34,155.20,141.85,137.27,136.83,136.05,136.01,132.92,129.29,129.26,125.56,80.69,80.07,52.36,28.34,21.31.HRMS(ESI-TOF):理论计算值：C22 13C2H35NNaO6[M+Na+]458.2424,实测值：458.2416。
实施例15：化合物I-11的制备
所用的芳基碘化物为2-(4-(4-碘苯甲酰基)苯氧基)-2-甲基丙酸异丙酯(180.9mg，0.4mmol)，所用的甲基化试剂为对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，其他条件同实施例1，得化合物I-11(无色油状液体，产率49％)。所用的芳基碘化物为2-(4-(4-碘苯甲酰基)苯氧基)-2-甲基丙酸异丙酯(180.9mg，0.4mmol)，所用的甲基化试剂为磷酸三甲酯(112.1mg,0.8mmol,4.0当量)，其他条件同实施例3，也可得化合物I-11(无色油状液体，产率44％)。1H NMR(400MHz,CDCl3):δ7.78-7.65(m,3H),7.41(s,2H),6.86(d,J＝8.8Hz,2H),6.04(d,J＝16.4Hz,1H),5.16-5.06(m,1H),2.38(s,6H),1.66(s,6H),1.55(s,9H),1.20(d,J＝6.2Hz,6H).13C NMR(100MHz,CDCl3):δ195.46,173.31,165.91,159.66,141.38,138.10,137.54,136.75,132.14,130.68,129.41,126.86,117.19,81.03,79.46,69.45,28.33,25.51,21.65,21.28.HRMS(ESI-TOF):理论计算值：C29H37O6[M+H+]481.2585,实测值：481.2585。
实施例16：化合物I-12的制备
所用的芳基碘化物为(1S)-1-(4-氟苯基)-3-((3R)-1-(4-氟苯基)-2-(4-碘苯基)-4-氧代氮杂环丁烷-3-基)丙酸乙酯(224.6mg，0.4mmol)，所用的甲基化试剂为对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，其他条件同实施例1，得化合物I-12(黄色油状液体，产率40％)。所用的芳基碘化物为(1S)-1-(4-氟苯基)-3-((3R)-1-(4-氟苯基)-2-(4-碘苯基)-4-氧代氮杂环丁烷-3-基)丙酸乙酯(224.6mg，0.4mmol)，所用的甲基化试剂为磷酸三甲酯(112.1mg,0.8mmol,4.0当量)，其他条件同实施例3，也可得化合物I-12(黄色油状液体，产率61％)。1H NMR(400MHz,CDCl3):δ7.68(d,J＝16.3Hz,1H),7.31-7.16(m,4H),7.05-6.86(m,6H),5.99(d,J＝16.3Hz,1H),5.69(t,J＝6.7Hz,1H),4.48(d,J＝2.3Hz,1H),3.09-3.05(m,1H),2.32(s,6H),2.07-1.97(m,5H),1.89-1.82(m,2H),1.54(s,9H).19F NMR(377MHz,CDCl3)δ-113.77,117.93.13C NMR(100MHz,CDCl3):δ170.35,167.04,166.08,162.54(d,J＝246.8Hz),159.12(d,J＝243.4Hz),141.36,138.00,137.26,135.86(d,J＝3.2Hz),134.83,133.98(d,J＝2.8Hz),128.35(d,J＝8.2Hz),126.30,125.59,118.40(d,J＝7.8Hz),116.00(d,J＝22.6Hz),115.66(d,J＝21.6Hz),80.92,77.48,60.53(d,J＝90.7Hz),33.74,28.34,25.03,21.41,21.35.HRMS(ESI-TOF):理论计算值：C35H38F2NO5[M+H+]590.2713,实测值：590.2721。
实施例17：化合物I-13的制备
向干燥并装有磁力搅拌子的25.0mL反应瓶中加入Pd(OAc)2(4.5mg,0.02mmol,0.1当量),三苯基膦(5.8mg,0.022mmol,0.11当量),碳酸铯(163mg,0.5mmol,2.5当量)，在惰性气体保护下，2-氰基-5-降冰片烯(48mg,0.4mmol,2.0当量),1-碘萘(50.8mg,0.2mmol,1.0当量),对甲苯磺酸甲酯(74.5mg,0.4mmol,2.0当量),苯硼酸频哪醇酯(81.6mg,0.4mmol,2.0当量)和干燥的甲苯(1.0mL)。反应瓶加盖密封并在室温下搅拌约5分钟，之后将混合物加热到80℃搅拌15小时。反应容器冷却至室温后，用短硅胶柱过滤，用乙酸乙酯(10mL)冲洗，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚:乙酸乙酯＝50:1(v/v)，得到化合物I-13(无色油状液体，产率87％)。1H NMR(400MHz,CDCl3):δ7.84-7.82(m,1H),7.78(d,J＝8.4Hz,1H),7.53-7.46(m,2H),7.45-7.35(m,4H),7.33-7.29(m,1H),7.29-7.25(m,2H),2.24(s,3H).13C NMR(100MHz,CDCl3):δ139.93,138.29,133.24,133.06,132.06,130.28,128.74,128.52,127.86,127.34,127.13,126.27,125.91,124.86,20.96.HRMS(ESI-TOF):理论计算值：C17H14Na[M+Na+]241.0988,实测值：241.0997。
实施例18：化合物I-14的制备
所用的芳基硼酸频哪醇酯为4,4,5,5-四甲基-2-(噻吩-2-基)-1,3,2-二氧杂硼烷(84.0mg，0.4mmol)，其他条件同实施例17，得化合物I-14(无色油状液体，产率89％)。1HNMR(400MHz,CDCl3):δ7.82-7.78(m,2H),7.59(d,J＝9.0Hz,1H),7.47(d,J＝5.3Hz,1H),7.44-7.33(m,3H),7.20-7.18(m,1H),6.97(d,J＝2.9Hz,1H),2.34(s,3H).13C NMR(100MHz,CDCl3):δ140.12,136.14,134.27,131.94,130.40,128.51,128.49,127.92,127.80,127.24,126.33,126.03,125.10,21.10.HRMS(ESI-TOF):理论计算值：C15H13S[M+H+]225.0732,实测值：225.0734。
实施例19：化合物I-15的制备
所用的芳基硼酸频哪醇酯为2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(94.1mg，0.4mmol)，其他条件同实施例17，得化合物I-15(无色油状液体，产率83％)。1H NMR(400MHz,CDCl3):δ8.10(d,J＝3.1Hz,1H),7.87-7.84(m,1H),7.81(d,J＝8.4Hz,1H),7.51(dd,J＝8.4,2.4Hz,1H),7.46-7.41(m,3H),7.39-7.33(m,1H),6.92(d,J＝9.2Hz,1H),4.05(s,3H),2.28(s,3H).13C NMR(100MHz,CDCl3):δ163.46,147.70,140.84,134.32,134.29,133.41,132.14,128.74,128.28,128.04,127.91,126.24,125.80,125.07,110.78,53.64,21.07.HRMS(ESI-TOF):理论计算值：C17H16NO[M+H+]250.1226,实测值：250.1228。
实施例20：化合物I-16的制备
所用的芳基硼酸频哪醇酯为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异喹啉(102.1mg，0.4mmol)，其他条件同实施例17，得化合物I-16(无色油状液体，产率47％)。1H NMR(400MHz,CDCl3):δ9.06(d,J＝4.3Hz,1H),8.24(d,J＝8.5Hz,1H),7.92-7.89(m,2H),7.72(t,J＝8.3Hz,1H),7.50(d,J＝8.5Hz,1H),7.42(t,J＝7.5Hz,1H),7.37-7.34(m,2H),7.28-7.21(m,2H),7.07(d,J＝8.5Hz,1H),2.11(s,3H).13C NMR(100MHz,CDCl3):δ150.38,148.64,147.09,133.99,133.34,132.56,131.98,129.91,129.79,128.67,128.50,128.07,128.04,127.01,126.51,126.06,125.74,125.31,122.88,20.59.HRMS(ESI-TOF):理论计算值：C20H16N[M+H+]270.1277,实测值：270.1275。
实施例21：化合物I-17的制备
所用的芳基硼酸频哪醇酯为2-(苯并呋喃-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(97.6mg，0.4mmol)，其他条件同实施例17，得化合物I-17(无色油状液体，产率76％)。1H NMR(400MHz,CDCl3):δ7.88-7.85(m,1H),7.82(d,J＝8.4Hz,1H),7.72(d,J＝2.2Hz,1H),7.65(d,J＝9.3Hz,1H),7.51(d,J＝1.7Hz,1H),7.46-7.38(m,3H),7.34-7.29(m,1H),7.20(dd,J＝8.4,1.7Hz,1H),6.83(dd,J＝2.2,1.0Hz,1H),2.26(s,3H).13C NMR(100MHz,CDCl3):δ154.30,145.50,138.38,134.42,133.67,133.49,132.07,128.73,127.84,127.74,127.30,126.66,126.39,125.88,124.83,122.69,111.41,106.84,21.06.HRMS(ESI-TOF):理论计算值：C19H15O[M+H+]259.1117,实测值：259.1123。
实施例22：化合物I-18的制备
所用的芳基硼酸频哪醇酯为4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚-1-羧酸叔丁酯(137.3mg，0.4mmol)，其他条件同实施例17，得化合物I-18(白色固体，产率85％)。1H NMR(400MHz,CDCl3):δ8.27(d,J＝8.3Hz,1H),7.89-7.84(m,2H),7.54(d,J＝3.8Hz,1H),7.49-7.45(m,2H),7.43-7.38(m,1H),7.32-7.26(m,2H),7.16(d,J＝9.5Hz,1H),6.01(d,J＝3.8Hz,1H),2.20(s,3H),1.72(s,9H).13C NMR(100MHz,CDCl3):δ148.94,134.84,134.33,132.96,132.08,131.53,131.09,129.68,127.75,126.86,126.55,125.30,125.05,124.93,123.88,123.47,113.30,105.93,82.82,27.37,19.68.HRMS(ESI-TOF):理论计算值：C24H23NNaO2[M+Na+]380.1621,实测值：380.1628。
实施例23：化合物I-19的制备
所用的芳基碘化物为1-氯-3-碘-2-甲基苯(50.5mg，0.2mmol)，其他条件同实施例22，得化合物I-19(无色油状液体，产率85％)。1H NMR(400MHz,CDCl3):δ8.17(d,J＝8.3Hz,1H),7.57(d,J＝3.8Hz,1H),7.38(t,J＝7.8Hz,1H),7.31(d,J＝8.2Hz,1H),7.08(d,J＝8.2Hz,1H),6.98(d,J＝7.3Hz,1H),6.09(d,J＝3.7Hz,1H),2.00(s,3H),1.92(s,3H),1.70(s,9H).13C NMR(100MHz,CDCl3):δ149.87,141.13,135.47,135.35,134.65,133.44,132.16,129.58,128.22,128.09,126.22,124.58,123.09,114.26,106.34,83.92,28.35,20.46,17.92.HRMS(ESI-TOF):理论计算值：C21H22Cl NNaO2[M+Na+]378.1231,实测值：378.1240。
实施例24：化合物I-20的制备
所用的芳基碘化物为3-碘-2-甲氧基吡啶(47.1mg，0.2mmol)，其他条件同实施例22，得化合物I-20(无色油状液体，产率42％)。1H NMR(400MHz,CDCl3):δ8.17(d,J＝8.4Hz,1H),8.09(d,J＝5.2Hz,1H),7.57(d,J＝3.7Hz,1H),7.38(t,J＝7.9Hz,1H),7.07(d,J＝7.3Hz,1H),6.87(d,J＝5.2Hz,1H),6.15(d,J＝3.7Hz,1H),3.82(s,3H),2.02(s,3H),1.68(s,9H).13C NMR(100MHz,CDCl3):δ161.96,149.90,148.30,145.34,135.27,130.07,128.54,126.11,124.30,123.99,122.35,119.14,114.64,106.60,83.82,53.80,28.35,19.70.HRMS(ESI-TOF):理论计算值：C20H23N2O3[M+H+]339.1703,实测值：339.1706。
实施例25：化合物II-4的制备
所用的甲基化试剂为对甲苯磺酸氘代甲酯(75.7mg，0.4mmol)，其他条件同实施例22，得化合物II-4(白色固体，产率83％)。1H NMR(400MHz,CDCl3):δ8.25(d,J＝8.3Hz,1H),7.88-7.83(m,2H),7.53(d,J＝3.8Hz,1H),7.48-7.44(m,2H),7.42-7.38(m,1H),7.32-7.23(m,2H),7.15(d,J＝7.3Hz,1H),5.99(d,J＝3.7Hz,1H),1.70(s,9H).13C NMR(100MHz,CDCl3):δ149.95,135.86,135.31,133.87,133.06,132.52,132.09,130.67,128.74,127.87,127.55,126.29,126.05,125.93,124.88,124.46,114.28,106.93,83.83,28.37.HRMS(ESI-TOF):理论计算值：C24H20D3NNaO2[M+Na+]383.1809,实测值：383.1820。
实施例26：化合物I-21的制备
所用的芳基碘化物为(R)-2-((叔丁氧基羰基)氨基)-3-(4-碘苯基)丙酸甲酯(81.1mg，0.,2mmol)，所用的芳基硼酸频哪醇酯为三异丙基((4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)乙炔基)硅烷(153.8mg，0.4mmol)，对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，其他条件同
实施例17，得化合物I-21(黄色油状液体，产率38％)。1H NMR(400MHz,CDCl3):δ7.55(d,J＝8.2Hz,2H),7.07(d,J＝8.0Hz,2H),6.84(s,2H),5.02(d,J＝8.4Hz,1H),4.61-4.56(m,1H),3.76(s,3H),3.11-2.97(m,2H),1.98(s,6H),1.44(s,9H),1.15(s,21H).13CNMR(100MHz,CDCl3):δ172.64,155.29,141.16,140.04,136.14,134.94,132.34,129.21,128.43,121.96,107.17,90.60,80.07,54.53,52.37,37.97,28.45,20.93,18.83,11.46.HRMS(ESI-TOF):理论计算值：C34H49NNaO4Si[M+Na+]586.3323,实测值：586.3314。
实施例27：化合物I-22的制备
所用的芳基碘化物为(R)-2-((叔丁氧基羰基)氨基)-3-(4-碘苯基)丙酸甲酯(81.1mg，0.2mmol)，芳基硼酸频哪醇酯为4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚-1-羧酸叔丁酯(137.3mg，0.4mmol)，对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，其他条件同实施例17，得化合物I-22(无色油状液体，产率58％)。1H NMR(400MHz,CDCl3):δ8.13(d,J＝8.4Hz,1H),7.54(d,J＝3.7Hz,1H),7.36(t,J＝7.9Hz,1H),6.99(d,J＝7.3Hz,1H),6.89(s,2H),6.09(d,J＝3.7Hz,1H),5.06(d,J＝8.4Hz,1H),4.64-4.59(m,1H),3.76(s,3H),3.27-2.86(m,2H),1.93(s,6H),1.68(s,9H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ172.73,155.29,149.92,138.16,136.85,135.29,134.90,133.63,129.73,128.35,128.26,125.95,124.50,123.27,113.92,106.59,83.80,80.03,54.65,52.32,38.24,28.47,28.35,20.56.HRMS(ESI-TOF):理论计算值：C30H38N2NaO6[M+Na+]545.2622,实测值：545.2629。
实施例28：化合物II-5的制备
所用的芳基碘化物为(1S)-1-(4-氟苯基)-3-((3R)-1-(4-氟苯基)-2-(4-碘苯基)-4-氧代氮杂环丁烷-3-基)丙酸乙酯(112.3mg，0.2mmol)，所用的甲基化试剂为对甲苯磺酸氘代甲酯(151.4mg，0.8mmol)，所用的芳基硼酸频哪醇酯为4,4,5,5-四甲基-2-(噻吩-2-基)-1,3,2-二氧杂硼烷(84.0mg，0.4mmol)，其他条件同实施例17，得化合物II-5(黄色油状液体，产率31％)。1H NMR(400MHz,CDCl3):δ7.39(d,J＝5.1Hz,1H),7.29-7.26(m,4H),7.12-7.10(m,1H),7.06-6.92(m,6H),6.81(d,J＝3.3Hz,1H),5.71(t,J＝6.7Hz,1H),4.53(d,J＝2.3Hz,1H),3.14-3.09(m,1H),2.09-2.03(m,5H),1.91-1.86(m,2H).19F NMR(377MHz,CDCl3)δ-113.81,117.99.13C NMR(100MHz,CDCl3):δ170.37,167.15,162.54(d,J＝246.8Hz),159.14(d,J＝243.6Hz),140.57,139.62,137.28,135.91(d,J＝3.1Hz),134.83,134.04(d,J＝2.8Hz),128.35(d,J＝8.2Hz),127.31,126.55,125.72,124.71,118.48(d,J＝7.9Hz),116.02(d,J＝22.7Hz),115.66(d,J＝21.5Hz),74.92,60.61(d,J＝99.0Hz),33.79,25.06,21.37.HRMS(ESI-TOF):理论计算值：C32H23D6F2NNaO3S[M+Na+]574.2105,实测值：574.2115。
实施例29：化合物I-23的制备
所用的芳基碘化物为2-(4-(4-碘苯甲酰基)苯氧基)-2-甲基丙酸异丙酯(90.5mg，0.2mmol)，对甲苯磺酸甲酯(149.0mg,0.8mmol,4.0当量)，芳基硼酸频哪醇酯为4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚-1-羧酸叔丁酯(137.3mg，0.4mmol)，其他条件同实施例17，得化合物I-23(无色油状液体，产率40％)。1H NMR(400MHz,CDCl3):δ8.18(d,J＝8.3Hz,1H),7.85(d,J＝8.8Hz,2H),7.58(d,J＝3.7Hz,1H),7.52(s,2H),7.42-7.37(m,1H),7.02(dd,J＝7.3,0.9Hz,1H),6.91-6.88(m,2H),6.11(d,J＝4.6Hz,1H),5.18-5.02(m,1H),2.01(s,6H),1.69(s,9H),1.68(s,6H),1.22(s,3H),1.20(s,3H).13C NMR(100MHz,CDCl3):δ195.97,173.36,159.57,149.85,143.52,137.20,135.37,136.97,132.99,132.22,130.95,129.25,128.79,126.29,124.61,122.70,117.18,114.30,106.28,83.94,79.45,69.45,28.35,25.53,21.67,20.65.HRMS(ESI-TOF):理论计算值：C35H40NO6[M+H+]570.2850,实测值：570.2857。
实施例30：化合物I-24的制备
向干燥并装有磁力搅拌子的25.0mL反应瓶中加入Pd2(dba)3(9.2mg,0.01mmol,0.05当量),三呋喃基膦(5.2mg,0.022mmol,0.11当量)，碳酸钾(70mg,0.5mmol,2.5当量)，在惰性气体保护下，2-氰基-5-降冰片烯(48mg,0.4mmol,2.0当量),邻甲基碘苯(87.2mg,0.4mmol,2.0当量),对甲苯磺酸甲酯(74.5mg,0.4mmol,2.0当量),乙炔基三异丙基硅烷(36.5mg,0.2mmol,1.0当量)和干燥的乙腈(1.0mL)。反应瓶加盖密封并在室温下搅拌约5分钟，之后将混合物加热到100℃搅拌15小时。反应容器冷却至室温后，用短硅胶柱过滤，用乙酸乙酯(10mL)冲洗，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚:乙酸乙酯＝100:1(v/v)，得到化合物I-24(无色油状液体，产率92％)。1H NMR(400MHz,CDCl3):δ7.13-7.09(m,1H),7.05-7.04(m,2H),2.47(s,6H),1.16(s,21H).13C NMR(100MHz,CDCl3):δ140.84,127.80,126.71,123.55,104.47,99.33,21.44,18.87,11.48.HRMS(ESI-TOF):理论计算值：C19H30NaSi[M+Na+]309.2009,实测值：309.2012。
实施例31：化合物I-25的制备
所用的芳基碘化物为3-碘-2-甲氧基吡啶(94.1mg，0.4mmol)，其他条件同实施例30,得化合物I-25(无色油状液体，产率66％)。1H NMR(400MHz,CDCl3):δ7.94(d,J＝5.3Hz,1H),6.73(d,J＝5.8Hz,1H),3.96(s,3H),2.42(s,3H),1.14(s,21H).13C NMR(100MHz,CDCl3):δ164.75,152.35,145.04,118.07,107.64,101.15,100.15,54.02,20.53,18.82,11.47.HRMS(ESI-TOF):理论计算值：C18H30NOSi[M+H+]304.2091,实测值：304.2091。
实施例32：化合物I-26的制备
所用的芳基碘化物为(R)-2-((叔丁氧基羰基)氨基)-3-(4-碘苯基)丙酸甲酯(162.1mg，0.4mmol)，其他条件同实施例30,得化合物I-26(无色油状液体，产率83％)。1HNMR(400MHz,CDCl3):δ6.79(s,2H),4.94(d,J＝8.2Hz,1H),4.55-4.50(m,1H),3.72(s,3H),3.14-2.86(m,2H),2.42(s,6H),1.42(s,9H),1.13(s,21H).13C NMR(100MHz,CDCl3):δ172.46,155.21,140.99,135.70,127.73,122.32,104.24,99.37,80.08,54.46,52.35,38.14,28.43,21.41,18.84,11.43.HRMS(ESI-TOF):理论计算值：C28H45NNaO4Si[M+Na+]510.3010,实测值：510.3012。
实施例33：化合物I-27的制备
所用碱为碳酸铯(163.0mg,0.5mmol,2.5当量)，所用的炔烃为2-甲基-4-苯基丁-3-炔-2-醇(32.0mg，0.2mmol)，其他条件同实施例30,得化合物I-27(无色油状液体，产率75％)。1H NMR(400MHz,CDCl3):δ7.57-7.52(m,2H),7.40-7.31(m,3H),7.16-7.11(m,1H),7.09-7.07(m,2H),2.52(s,6H).13C NMR(100MHz,CDCl3):δ140.41,131.53,128.50,128.23,127.90,126.83,123.96,123.09,97.96,87.25,21.28.HRMS(ESI-TOF):理论计算值：C16H15[M+H+]207.1168,实测值：207.1176。
实施例34：化合物I-28的制备
在手套箱中，向干燥并装有磁力搅拌子的4.0mL反应瓶中加入Pd(OAc)2(4.5mg,0.02mmol,0.1当量),2-二环己膦基-2'-(N,N-二甲胺)-联苯(8.7mg,0.022mmol,0.11当量)，醋酸钾(49mg,0.5mmol,2.5当量)，2-氰基-5-降冰片烯(72mg,0.6mmol,3.0当量),1-碘萘(25.4mg,0.2mmol,1.0当量),对甲苯磺酸甲酯(111.8mg,0.6mmol,3.0当量),氰化锌(47.0mg,0.4mmol,2.0当量)和干燥的乙二醇二甲醚(1.0mL)。反应瓶加盖密封并在室温下搅拌约5分钟，之后将混合物加热到80℃搅拌15小时。反应容器冷却至室温后，用短硅胶柱过滤，用乙酸乙酯(10mL)冲洗，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚:乙酸乙酯＝30:1(v/v)，得到化合物I-28(白色固体，产率57％)。1H NMR(400MHz,CDCl3):δ8.19(d,J＝8.1Hz,1H),7.95(d,J＝8.5Hz,1H),7.87(d,J＝9.1Hz,1H),7.69-7.63(m,1H),7.57-7.53(m,1H),7.40(d,J＝8.5Hz,1H),2.75(s,3H).13C NMR(100MHz,CDCl3):δ143.11,132.91,132.72,131.32,128.69,128.51,127.79,126.74,125.01,117.23,109.37,21.46.HRMS(ESI-TOF):理论计算值：C12H9NNa[M+Na+]190.0627,实测值：190.0628。
实施例35：化合物I-29的制备
所用的芳基碘化物为2,6-双(苄氧基)-3-碘苯甲酸甲酯(95.0mg，0.2mmol)，其他条件同实施例34，得化合物I-29(白色固体，产率36％)。1H NMR(400MHz,CDCl3):δ7.53-7.45(m,2H),7.44-7.30(m,8H),6.65(s,1H),5.20(s,2H),5.16(s,2H),3.81(s,3H),2.52(s,3H).13C NMR(100MHz,CDCl3):δ165.23,159.82,159.45,146.90,135.87,135.56,128.85,128.78,128.71,128.68,128.42,126.97,117.17,115.68,109.82,100.37,77.73,70.85,52.83,21.47.HRMS(ESI-TOF):理论计算值：C24H21NNaO4[M+Na+]410.1363,实测值：410.1367。
实施例36：化合物I-30的制备
向干燥并装有磁力搅拌子的5.0mL微波反应瓶中加入Pd2(dba)3(9.2mg,0.01mmol,0.05当量),三(4-甲氧苯基)膦(15.5mg,0.044mmol,0.22当量)，醋酸钾(49mg,0.5mmol,2.5当量)，碳酸铯(163mg,0.5mmol,2.5当量)，降冰片烯(38.5mg,0.4mmol,2.0当量),1-碘萘(50.8mg,0.2mmol,1.0当量),对甲苯磺酸甲酯(74.5mg,0.4mmol,2.0当量),联硼酸频哪醇酯(152.4mg,0.6mmol,3.0当量)和干燥的乙腈(2.0mL)。反应瓶加盖密封并在室温下搅拌约5分钟，之后将混合物加热到80℃搅拌15小时。反应容器冷却至室温后，用短硅胶柱过滤，用乙酸乙酯(10mL)冲洗，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚:乙酸乙酯＝30:1(v/v)，得到化合物I-30(白色固体，产率70％)。1H NMR(400MHz,CDCl3):δ8.11(d,J＝8.3Hz,1H),7.77-7.74(m,2H),7.48-7.42(m,1H),7.38(t,J＝7.7Hz,1H),7.28(d,J＝8.4Hz,1H),2.62(s,3H),1.49(s,12H).13C NMR(100MHz,CDCl3):δ141.49,136.73,131.49,129.70,128.61,128.26,127.61,126.14,124.68,84.14,25.24,22.76.HRMS(ESI-TOF):理论计算值：C17H22BO2[M+H+]269.1707,实测值：269.1714。
实施例37：化合物I-31的制备
所用的芳基碘化物为4-碘-N，3-二甲基苯甲酰胺(55.1mg，0.2mmol)，其他条件同实施例36，得化合物I-31(无色油状液体，产率49％)。1H NMR(400MHz,CDCl3):δ7.32(s,2H),6.17(s,1H),2.98(d,J＝4.8Hz,3H),2.41(s,6H),1.39(s,12H).13C NMR(100MHz,CDCl3):δ168.66,142.36,135.13,124.77,84.16,26.90,25.08,22.31.HRMS(ESI-TOF):理论计算值：C16H24BNNaO3[M+Na+]312.1741,实测值：312.1749。
实施例38：化合物I-32的制备
在手套箱中，向干燥并装有磁力搅拌子的10.0mL反应瓶中加入Pd2(dba)3(9.2mg,0.01mmol,0.05当量),三(呋喃-2-基)膦(5.2mg,0.022mmol,0.11当量),碳酸铯(163mg,0.5mmol,2.5当量)，2-邻甲苯基-3a,4,7,7a-四氢-1H-4,7-亚甲异吲哚-1,3(2H)-二酮(101.3mg,0.4mmol,2.0当量),1-碘萘(25.4mg,0.2mmol,1.0当量),对甲苯磺酸甲酯(111.8mg,0.6mmol,3.0当量),甲酸钠(27.2mg,0.4mmol,2.0当量)和干燥的乙二醇二甲醚(1.0mL)。反应瓶加盖密封并在室温下搅拌约5分钟，之后将混合物加热到80℃搅拌15小时。反应容器冷却至室温后，用短硅胶柱过滤，用乙酸乙酯(10mL)冲洗，真空下浓缩。用柱色谱纯化，洗脱剂为石油醚，得到化合物I-32(无色油状液体，产率58％)。1H NMR(400MHz,CDCl3):δ7.82-7.78(m,1H),7.78-7.73(m,2H),7.62(s,1H),7.48-7.37(m,2H),7.32(dd,J＝8.4,1.8Hz,1H),2.52(s,3H).13C NMR(100MHz,CDCl3):δ135.58,133.79,131.82,128.25,127.82,127.73,127.36,126.96,126.00,125.09,21.86.
实施例39：化合物I-33的制备
所用的芳基碘化物为2,6-双(苄氧基)-3-碘苯甲酸甲酯(95.0mg，0.2mmol)，其他条件同实施例38，得化合物I-33(白色固体，产率52％)。1H NMR(400MHz,CDCl3):δ7.44-7.28(m,10H),6.43(s,2H),5.10(s,4H),3.88(s,3H),2.29(s,3H).13C NMR(100MHz,CDCl3):δ167.16,156.58,141.85,137.01,128.60,127.87,126.98,111.70,106.81,70.53,52.38,22.41.HRMS(ESI-TOF):理论计算值：C23H22NaO4[M+Na+]385.1410,实测值：385.1404。
实施例40：化合物II-6的制备
所用的芳基碘化物为1-溴-4-碘萘(66.6mg，0.2mmol)，所用的甲基化试剂为对甲苯磺酸氘代甲酯(75.7mg，0.4mmol)，其他条件同实施例38，得化合物II-5(无色油状液体，产率,53％)。1H NMR(400MHz,CDCl3):δ8.18(d,J＝8.0Hz,1H),7.74(d,J＝7.7Hz,1H),7.65(s,1H),7.58(s,1H),7.54-7.47(m,2H).13C NMR(100MHz,CDCl3):δ136.21,134.82,132.11,130.39,127.77,127.12,126.98,126.86,126.54,122.62.HRMS(ESI-TOF):理论计算值：C11H7D3Br[M+H+]224.1049,实测值：224.1059。
以上所述是本发明的优选实施方式而已，当然不能以此来限定本发明之权利范围，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和变动，这些改进和变动也视为本发明的保护范围。

Claims (10)

1.一种芳烃甲基化的制备方法，其特征在于：在惰性气体保护下，将底物A、甲基化试剂B和终止剂C为起始原料，在催化剂D、配体E、降冰片烯衍生物G、碱F的作用下，在30-140℃下于有机溶剂H中搅拌反应，反应结束后反应混合物经抽滤、浓缩和纯化制得如式I-Ⅲ任一项所示的芳烃甲基化的产物；
其中，底物A为芳基碘化物，结构式为
R1为氢、芳基、杂环芳基、烷基、取代烷基、取代烯基、取代炔基、硼酸频那醇酯基、酯基、醛基、羧基、羟基、氰基、乙酰基、硝基、酰胺基、磺酰基、烷氧基、烷硫基和卤素中的任意一种；其中m表示R1的个数，0≤m≤4；
甲基化试剂B为磷酸三甲酯、磺酸甲酯、磷酸氘代三甲酯、磺酸氘代甲酯、碳13标记的磺酸甲酯、碳13标记磷酸三甲酯中的任意一种；
终止剂C为烯烃化合物、芳基硼类化合物、炔烃化合物、氰化物、联硼酸频那醇酯、质子源中的任意一种。
2.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述甲基化试剂B中磺酸甲酯的结构式为磺酸氘代甲酯的结构式为碳13标记的磺酸甲酯的结构式为
其中，R2为取代的芳基、杂环芳基、烷基、取代烷基、烷氧基中的任意一种。
3.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述终止剂C为ArBR5R6、B2Pin2、Zn(CN)2、CuCN、质子源中的任意一种；其中，R3和R4分别为芳基、取代芳基、烷基、酯基、氰基、醛基、硝基、酰胺基中的任意一种，R5，R6分别为羟基或烷氧基，R7，R8，R9分别为烷基、芳基、取代芳基、硅基中的任意一种。
4.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述R1中，取代烯基为其中R3和R4分别为芳基、取代芳基、烷基、酯基、氰基、醛基、硝基、酰胺基中的任意一种；取代炔基为其中R7，R8，R9分别为烷基、芳基、取代芳基、硅基中的任意一种。
5.根据权利要求1-4任一项所述的芳烃甲基化的制备方法，其特征在于：所述芳基带有至少一个取代基，所述取代基为芳基、杂环芳基、烷基、酯基、氰基、硝基、酰胺基、磺酰基、烷氧基和卤素中的至少一种；
所述烷基为具有1～20个碳原子的烷基；
所述取代烷基为其中o为0和任意整数，X为OR10、OSi(R10)3、SR10、SSi(R10)3、SeR10、N(R10)2、Si(R10)3中的至少一种，其中R10为氢、芳基、杂环芳基、烷基、酯基、氰基、硝基、酰胺基、磺酰基、卤素中的至少一种；
所述烷氧基为具有1～10个碳原子的烷氧基。
6.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述质子源为甲酸钠、异丙醇、苯甲醇、异丙基硼酸、乙二醇二甲醚、水中的任意一种。
7.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述底物A、甲基化试剂B、终止试剂C、催化剂D、配体E、碱F、降冰片烯衍生物G的投料摩尔比为(1-10)：(1-10)：(1-10)：(0.05-1)：(0.1-1)：(1-10)：(0.05-3)。
8.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述催化剂D为Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2中的至少一种；所述配体E为三芳基膦、三烷基膦、二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-二苯基]-2-基)膦、二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦、2'-(二环己基膦基)-N,N-二甲基-[1,1'-二苯基]-2-胺、二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦、三(呋喃-2-基)膦、(3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦中的至少一种；所述溶剂H为甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、***、二甲基乙二醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的至少一种；所述碱F为碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的至少一种。
9.根据权利要求1所述的芳烃甲基化的制备方法，其特征在于：所述降冰片烯衍生物G，其结构式表示为其中R11为左边五元环上的取代基，p代表取代基个数，0≤p≤8；R12为双键上的取代基，q代表取代基个数，0≤q≤2；R11的构型为内型和/或外型。
10.根据权利要求9所述的芳烃甲基化的制备方法，其特征在于：所述R11和R12独立地为CO2M，M为碱金属离子、碱土金属离子、酯基、氰基、硝基、酰胺基、磺酰基、烷氧基、芳基、杂环芳基、烷基、取代烷基和卤素中的任意一种；所述芳基带有至少一个取代基，所述取代基为芳基、烷基、取代烷基、烷氧基、酯基、氰基、硝基、卤素中的至少一种；所述烷基是指具有1～10个碳原子的烷基；所述烷氧基是指具有1～10个碳原子的烷氧基。
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