CN110437068B - 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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CN110437068B
CN110437068B CN201910695981.9A CN201910695981A CN110437068B CN 110437068 B CN110437068 B CN 110437068B CN 201910695981 A CN201910695981 A CN 201910695981A CN 110437068 B CN110437068 B CN 110437068B
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周强辉
高倩文
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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；
Figure DDA0002149382420000011
式I；
Figure DDA0002149382420000012
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；
Figure BDA0002149382410000011
Figure BDA0002149382410000021
其中，底物A为芳基碘化物，结构式为
Figure BDA0002149382410000022
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：
Figure BDA0002149382410000023
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
Figure BDA0002149382410000024
磺酸氘代甲酯的结构式为
Figure BDA0002149382410000025
碳13标记的磺酸甲酯的结构式为
Figure BDA0002149382410000026
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
Figure BDA0002149382410000031
ArBR5R6、
Figure BDA0002149382410000032
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
Figure BDA0002149382410000033
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
Figure BDA0002149382410000034
和/或
Figure BDA0002149382410000035
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
Figure BDA0002149382410000036
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、乙醚、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
Figure BDA0002149382410000041
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
Figure BDA0002149382410000042
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
Figure BDA0002149382410000051
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
Figure BDA0002149382410000061
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
Figure BDA0002149382410000062
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
Figure BDA0002149382410000071
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
Figure BDA0002149382410000072
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
Figure BDA0002149382410000081
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
Figure BDA0002149382410000082
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
Figure BDA0002149382410000091
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
Figure BDA0002149382410000092
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
Figure BDA0002149382410000093
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
Figure BDA0002149382410000101
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
Figure BDA0002149382410000102
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
Figure BDA0002149382410000111
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
Figure BDA0002149382410000112
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
Figure BDA0002149382410000121
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
Figure BDA0002149382410000131
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
Figure BDA0002149382410000132
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
Figure BDA0002149382410000141
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
Figure BDA0002149382410000151
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
Figure BDA0002149382410000152
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
Figure BDA0002149382410000161
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
Figure BDA0002149382410000162
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
Figure BDA0002149382410000171
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
Figure BDA0002149382410000172
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
Figure BDA0002149382410000181
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
Figure BDA0002149382410000182
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
Figure BDA0002149382410000191
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
Figure BDA0002149382410000201
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
Figure BDA0002149382410000202
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
Figure BDA0002149382410000211
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
Figure BDA0002149382410000221
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
Figure BDA0002149382410000222
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
Figure BDA0002149382410000231
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
Figure BDA0002149382410000232
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
Figure BDA0002149382410000241
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
Figure BDA0002149382410000242
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
Figure BDA0002149382410000251
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
Figure BDA0002149382410000252
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
Figure BDA0002149382410000261
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
Figure BDA0002149382410000262
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 (6)

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-XVII任一项所示的芳烃甲基化的产物；
Figure FDA0002681841030000011
式I；
Figure FDA0002681841030000012
式Ⅱ；
Figure FDA0002681841030000013
式Ⅲ；
Figure FDA0002681841030000014
式IV；
Figure FDA0002681841030000015
式V；
Figure FDA0002681841030000016
式VI；
Figure FDA0002681841030000017
式VII；
Figure FDA0002681841030000021
式VIII；
Figure FDA0002681841030000022
式IX；
Figure FDA0002681841030000023
式X；
Figure FDA0002681841030000024
式XI；
Figure FDA0002681841030000025
式XII；
Figure FDA0002681841030000031
式XIII；
Figure FDA0002681841030000032
式XIV；
Figure FDA0002681841030000033
式XV；
Figure FDA0002681841030000034
式XVI；
Figure FDA0002681841030000035
式XVII；
其中，底物A为芳基碘化物，结构式为
Figure FDA0002681841030000041
R1为氢、芳基、杂环芳基、烷基、取代烷基、取代烯基、取代炔基、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、对甲苯磺酸甲酯、磷酸氘代三甲酯、对甲苯磺酸氘代甲酯、碳13标记的对甲苯磺酸甲酯、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、质子源中的任意一种；
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；
所述降冰片烯衍生物G，其结构式表示为
Figure FDA0002681841030000042
其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、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，其中M为碱金属离子或碱土金属离子；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。
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R1中，取代烯基为
Figure FDA0002681841030000043
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
Figure FDA0002681841030000044
其中R7为烷基、芳基、取代芳基、硅基中的任意一种。
3.根据权利要求1或2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
Figure FDA0002681841030000051
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。
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。
5.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)。
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、乙醚、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。
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