CN116924940A - 一种邻碘代苯胺衍生物的合成方法 - Google Patents
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- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical class NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- -1 diacetic acid iodo arene Chemical class 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 13
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical group FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 230000009435 amidation Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 88
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 25
- 239000011734 sodium Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 11
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000007055 electrophilic iodination reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PBQZQTQFQFYBNJ-UHFFFAOYSA-N n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1 PBQZQTQFQFYBNJ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
本发明公开了一种邻碘代苯胺衍生物的合成方法，属于有机合成技术领域。以二乙酸碘代芳烃1为反应原料，以N‑甲氧基酰胺2以酰胺化试剂，在有机溶剂中室温反应，得到邻碘代苯胺衍生物3。该发明合成方法操作方便，反应条件温和，底物官能团适用范围广泛，反应化学选择性、区域选择性好，收率良好。
Description
技术领域
本发明涉及一种邻碘代苯胺衍生物的合成方法，属于有机合成技术领域。
背景技术
苯胺衍生物和碘代芳烃化合物是有机合成领域中一类重要的合成中间体，用于构筑芳香杂环化合物和联芳烃化合物。
目前，关于一步合成邻碘代芳胺衍生物的方法未见报道，基于逆合成分析策略，传统合成方法一般使用芳胺衍生物作为起始原料，然而在接下来的芳香亲电碘代反应这一步很容易生成多种碘代混合物，即对位碘代芳胺衍生物、邻位碘代物和邻、对位-二碘代物，并且因邻位空间位阻较大，一般主产物为对位碘代芳胺衍生物，反应的区域选择性较差，进而也导致了后提纯困难。再者，芳胺衍生物的芳环上一般不能带有强吸电子基团如酯基等，否者很难再发生芳香亲电碘代反应。
基于以上方法的不足，本发明以简单易得的N-甲氧基酰胺作为酰胺基化试剂通过与二乙酸碘代芳烃的选择性直接酰胺化反应实现邻碘代苯胺衍生物的温和高效便捷合成。
发明内容
为了解决现有合成方法的不足，本发明提供了一种温和、操作简便、高产率及高区域选择性的碘代苯胺衍生物的合成方法。以二乙酸碘代芳烃为反应原料，以N-甲氧基酰胺为酰胺基化试剂，在有机溶剂中搅拌反应，得到邻碘代苯胺衍生物。该发明合成方法操作方便，条件温和、工艺简单，底物官能团适用范围广泛，反应区域选择性好，收率高。
本发明所述一种邻碘代苯胺衍生物的合成方法，包括以下步骤：以二乙酸碘代芳烃1与N-甲氧基酰胺2为原料，在有机溶剂中反应，得到邻碘代苯胺衍生物3；反应方程式如下：
其中：R1选自氢、C1-C4烷基、苯基、卤素、酯基；R2选自氢、C1-C4烷基、C1-C4烷氧基、卤素；R2选自C1-C4烷基、苯基、取代苯基，取代苯基中取代基为卤素、三氟甲基、酯基、C1-C4烷基、C1-C4烷氧基。
进一步地，在上述技术方案中，所述有机溶剂选自六氟异丙醇、三氟甲基苯或三氟乙醇。优选自六氟异丙醇。
进一步地，在上述技术方案中，二乙酸碘代芳烃与N-甲氧基酰胺摩尔比为1-2:1。
进一步地，在上述技术方案中，反应温度为20～25℃。
发明有益效果：
本发明反应条件温和，反应通用性强，可以适用于各种取代基取代的底物，均得到了邻位高区域选择性；与现有技术中得到对位产物形成了很好的技术互补性。
具体实施方式
反应条件优化实验，具体结果如下：
a氨化试剂(0.5mmol)、PhI(OAc)2(0.6mmol)和HFIP(3mL)，室温20分钟；b以CH2Br2为内标1H NMR收率，括号内为分离收率；c0℃.d 1.0eq PhI(OAc)2.ePhI(1.5eq)and AcOOH(1.5eq).fPhI(1.5eq)and mCPBA(1.5eq).gPhI(1.5eq)and mCPBA(1.5eq).
实施例1
在50mL带有磁力搅拌的反应瓶内，加入N-甲氧基苯酰胺(0.5mmol)、PhI(OAc)2(0.75mmol,1.5eq)和HFIP(3mL)。接着反应混合物密封，室温搅拌20分钟。反应完毕，将溶剂蒸干，柱层析纯化得到产物。反应结果如下：
代表性产品表征数据：
N-(2-Iodophenyl)-N-methoxybenzamide(1aa)黄色固体，熔点61-63℃；1H NMR(600MHz,CDCl3)δ7.92(d,J＝7.8Hz,1H),7.69(s,2H),7.48-7.22(m,5H),7.07(t,J＝7.2Hz,1H),3.79(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.8(1C),140.4(1C),134.3(1C),131.1(1C),130.6(1C),130.1(1C),129.3(1C),128.6(2C),128.1(3C),99.7(1C),61.9(1C).HR MS(ESI/QTOF)m/z:calcd for C14H12INNaO2[M+Na]+ 375.9805,found 375.9800.
N-(4-Iodophenyl)-N-methoxybenzamide(1aa’)黄色油状物；1H NMR(600MHz,CDCl3)δ7.74-7.67(m,2H),7.66-7.60(m,2H),7.49-7.43(m,1H),7.42-7.35(m,2H),7.35-7.22(m,2H),3.65(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.3,139.1,138.1,134.3,131.1,128.5,128.22,125.2,91.3,62.0.HRMS(ESI/QTOF)m/z:calcd for C14H12INNaO2[M+Na]+375.9805,found 375.9799.
2-Chloro-N-(2-iodophenyl)-N-methoxybenzamide(2aa)类白色固体；熔点109-111℃；1H NMR(600MHz,DMSO-d6)δ7.99(d,J＝7.8Hz,1H),7.60(d,J＝7.2Hz,1H),7.50(s,3H),7.48-7.29(m,2H),7.28-7.02(m,1H),3.60(s,3H).13C{1H}NMR(150MHz,DMSO-d6)δ141.1,140.4,135.6,131.6,131.5,130.5,130.4,130.0,129.8,128.3,127.3,99.9,62.0.HRMS(ESI/QTOF)m/z):calcd for C14H11ClINNaO2[M+Na]+ 409.9415,found409.9404.
2-Chloro-N-(4-iodophenyl)-N-methoxybenzamide(2aa’)黄色油状物；1H NMR(600MHz,CDCl3)δ7.71(d,J＝7.8Hz,2H),7.41-7.29(m,6H),3.59(s,3H).13C{1H}NMR(150MHz,CDCl3)δ138.1,131.0,130.6,129.7,127.9,126.6,124.6,62.10.HRMS(ESI/QTOF)m/z:calcd for C14H11ClINNaO2[M+Na]+ 409.9415,found 409.9405.
N-(2-Iodophenyl)-N-methoxy-2-methylbenzamide(3aa)浅黄色油状物；1H NMR(600MHz,CDCl3)δ7.93(d,J＝7.8Hz,1H),7.55-7.42(m,1H),7.38(s,2H),7.30-7.24(m,1H),7.22(d,J＝7.4Hz,1H),7.16(s,1H),7.06(t,J＝6.6Hz,1H),3.63(s,3H),2.52(s,3H).13C{1H}NMR(150MHz,CDCl3)δ169.4,143.6,141.7,140.2,135.9,135.1,130.5,130.5,129.6,129.2,128.5,126.7,125.2,119.7,99.1,61.9,19.8.HRMS(ESI/QTOF)m/z:calcdfor C15H14INNaO2[M+Na]+ 389.9961,found 389.9953.
N-(4-iodophenyl)-N-methoxy-2-methylbenzamide(3aa’)浅黄色油状物；1H NMR(600MHz,CDCl3)δ7.69(d,J＝9.0Hz,2H),7.32-7.28(m,4H),7.20(d,J＝8.4Hz,2H),3.55(s,3H),2.36(s,3H).13C{1H}NMR(150MHz,CDCl3)δ169.3,138.7,138.2,135.6,135.3,130.4,129.7,126.7,125.5,124.5,90.9,62.2,19.4.HRMS(ESI/QTOF)m/z:calcd forC15H14INNaO2[M+Na]+ 389.9961,found 389.9958.
2-Ethyl-N-(2-iodophenyl)-N-methoxybenzamide(4aa)浅黄色固体，熔点92-93℃；1H NMR(600MHz,CDCl3)δ7.93(d,J＝7.8Hz,1H),7.49(s,1H),7.39(s,2H),7.36-7.31(m,1H),7.29(d,J＝7.6Hz,1H),7.20(s,1H),7.06(t,J＝6.6Hz,1H),3.60(s,3H),2.87(q,J＝7.8Hz,2H),1.32(t,J＝7.8Hz,3H).13C{1H}NMR(150MHz,CDCl3)δ169.6,142.1,141.8,140.2,134.8,130.4,129.8,129.3,128.9,126.7,125.2,99.2,61.8,26.6,15.6.HRMS(ESI/QTOF)m/z:calcd for C16H16INNaO2[M+Na]+ 404.0118,found 404.0113.
N-(2-Iodophenyl)-N,2-dimethoxybenzamide(5aa)深黄色油状物；1H NMR(600MHz,DMSO-d6)δ7.89(d,J＝7.8Hz,1H),7.39(t,J＝9.0Hz,2H),7.32(t,J＝7.2Hz,1H),7.09(t,J＝7.2Hz,1H),6.97(d,J＝7.2Hz,1H),6.92(t,J＝7.2Hz,1H),3.79(s,3H),3.59(s,3H).13C{1H}NMR(150MHz,DMSO-d6)δ156.3,141.9,140.2,131.4,131.2,130.6,129.4,128.2,126.0,120.5,112.4,100.0,79.2,61.8,56.3.HRMS(ESI/QTOF)m/z:calcd forC15H14INNaO3[M+Na]+ 405.9911,found 405.9902.
3-Fluoro-N-(2-iodophenyl)-N-methoxybenzamide(6aa)浅黄色油状物；1H NMR(600MHz,CDCl3)δ7.94(d,J＝7.8Hz,1H),7.49(d,J＝7.2Hz,1H),7.44(d,J＝8.4Hz,1H),7.40(t,J＝7.8Hz,1H),7.37(d,J＝7.2Hz,1H),7.35-7.30(m,1H),7.13(t,J＝7.2Hz,1H),7.08(td,J＝7.8,1.8Hz,1H),3.77(s,3H).13C{1H}NMR(150MHz,CDCl3)δ167.3,162.4(d,J＝245.7Hz,1C),142.04,140.52,136.5(d,J＝7.2Hz,1C),130.78,130.08,129.8(d,J＝8.0Hz,1C),129.32,124.4(d,J＝2.3Hz,1C),118.0(d,J＝21.0Hz,1C),115.8(d,J＝23.3Hz,1C),99.5,61.9.19F NMR(565MHz,CDCl3)δ-112.3.HRMS(ESI/QTOF)m/z:calcd forC14H11FINNaO2[M+Na]+ 393.9711,found 393.9704.
3-Fluoro-N-(4-iodophenyl)-N-methoxybenzamide(6aa’)发粘油状物；1H NMR(600MHz,CDCl3)δ7.76-7.68(m,2H),7.45(d,J＝7.8Hz,1H),7.40(d,J＝10.2Hz,1H),7.37-7.35(m,1H),7.29(d,J＝8.4Hz,2H),7.19-7.14(m,1H),3.64(s,3H).13C{1H}NMR(150MHz,CDCl3)δ166.98,162.3(d,J＝246Hz,1C),138.8,138.19,136.5(d,J＝7.1Hz,1C),129.8(d,J＝7.8Hz,1C),125.0,124.2(d,J＝2.6Hz,1C),117.9(d,J＝21.2Hz,1C),115.7(d,J＝23.1Hz,1C),91.3,62.1.19F NMR(565MHz,CDCl3)δ-112.2.HRMS(ESI/QTOF)m/z:calcd forC14H11FINNaO2[M+Na]+ 393.9711,found 393.9708.
3-Chloro-N-(2-iodophenyl)-N-methoxybenzamide(7aa)浅黄色油状物；1H NMR(600MHz,CDCl3)δ7.94(d,J＝7.8Hz,1H),7.72(s,1H),7.58(d,J＝6.6Hz,1H),7.40(d,J＝7.8Hz,2H),7.37(d,J＝7.2Hz,1H),7.29(t,J＝7.8Hz,1H),7.09(t,J＝7.8Hz,1H),3.77(s,3H).13C{1H}NMR(150MHz,CDCl3)δ167.3,142.0,140.6,136.3,134.3,131.2,130.8,130.1,129.5,129.4,128.9,126.8,99.5,62.0.HRMS(ESI/QTOF)m/z:calcd for C14H11ClINNaO2[M+Na]+ 409.9415,found 409.9402.
N-(2-Iodophenyl)-N-methoxy-3-methylbenzamide(8aa)类白色固体，熔点78-80℃；1H NMR(600MHz,CDCl3)δ7.91(d,J＝7.9Hz,1H),7.52(s,1H),7.44(s,1H),7.37(d,J＝7.2Hz,2H),7.22(s,2H),7.06(t,J＝7.2Hz,1H),3.78(s,3H),2.34(s,3H).At 328K,13C{1H}NMR(150MHz,CDCl3)δ169.0,142.6,140.4,137.9,134.5,131.8,130.5,130.1,129.3,129.2,127.9,125.6,99.6,61.9,21.4.HRMS(ESI/QTOF)m/z:calcdfor C15H14INNaO2[M+Na]+389.9961,found 389.9954.
N-(4-iodophenyl)-N-methoxy-3-methylbenzamide(8aa’)黄色油状物；1H NMR(600MHz,CDCl3)δ7.69(d,J＝9.0Hz,2H),7.48(s,1H),7.42-7.41(m,1H),7.30-7.23(m,4H),3.64(s,3H),2.37(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.6,139.4,138.1,137.9,134.5,131.63129.0,127.9,125.44125.1,90.9,61.9,21.3.HRMS(ESI/QTOF)m/z:calcdfor C15H14INNaO2[M+Na]+ 389.9961,found 389.9952.
实施例2
按照实施例1中反应条件，仅仅改变反应底物，反应结果如下：
代表性产品表征数据：
N-(2/3-chloro-5-iodophenyl)-N-methoxybenzamide(1ab)1H NMR(600MHz,DMSO-d6)δ8.02-7.91(m,0.89H),7.82-7.73(m,0.22H),7.68(d,J＝7.4Hz,1.46H),7.64-7.57(m,1.09H),7.50(t,J＝7.4Hz,0.96H),7.47-7.38(m,1.94H),7.35(d,J＝8.4Hz,0.2H),7.31-7.19(m,0.73H),3.70(s,3H).13C{1H}NMR(150MHz,DMSO-d6)δ168.7,168.3,144.0,141.5,139.9,139.4,139.0,135.0,134.7,134.3,133.2,132.4,131.3,131.1,130.3,128.5,128.5,128.4,128.3,97.8,91.8,62.3,62.2.HRMS(ESI/QTOF)m/z:calcd forC14H11ClINNaO2[M+Na]+ 409.9415,found 409.9413.
N-(5/2-bromo-2/5-iodophenyl)-N-methoxybenzamide(1ac)1H NMR(600MHz,CDCl3)δ7.82-7.71(m,2.55H),7.69(d,J＝7.2Hz,0.43H),7.54(d,J＝1.8Hz,0.8H),7.51(d,J＝7.2Hz,0.27H),7.46-7.42(m,1.11H),7.40-7.34(m,2.2H),7.19(d,J＝8.4Hz,0.76H),3.73(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.9,168.9,143.7,141.1,140.4,139.4,138.9,135.1,134.1,134.0,133.5,132.5,131.3,128.6,128.5,128.2,123.7,122.6,97.6,91.9,62.2,62.1.HRMS(ESI/QTOF)m/z:calcd for C14H11BrINNaO2[M+Na]+453.8910,found 453.8915.
Methyl 4-iodo-3-(N-methoxybenzamido)benzoate(1ae)类白色固体，熔点107-109℃；1H NMR(600MHz,CDCl3)δ8.01(dd,J＝4.8,3.6Hz,2H),7.74(d,J＝7.8Hz,2H),7.70(dd,J＝8.4,1.8Hz,1H),7.44(d,J＝7.2Hz,1H),7.38(t,J＝7.8Hz,2H),3.92(s,3H),3.76(s,3H).13C{1H}NMR(150MHz,CDCl3)δ169.0,165.7,143.0,140.6,134.3,131.9,131.3,130.9,130.5,128.6,128.2,105.7,62.1,52.6.HRMS(ESI/QTOF)m/z:calcd forC16H14INNaO4[M+Na]+ 433.9860,found 433.9846.
N-(4-iodo-[1,1'-biphenyl]-3-yl)-N-methoxybenzamide(1af)39％，白色固体，熔点116-118℃；1H NMR(600MHz,CDCl3)δ7.91(d,J＝1.8Hz,1H),7.75(dd,J＝8.4,1.8Hz,1H),7.39-7.35(m,3H),7.33(dt,J＝8.4,4.8Hz,1H),7.30-7.26(m,2H),7.21(d,J＝4.8Hz,4H),7.09(d,J＝8.4Hz,1H),3.70(s,3H).13C{1H}NMR(150MHz,CDCl3)δ169.2,141.0,139.0,138.6,137.9,134.2,132.8,130.8,129.0,128.5,128.4,128.1,127.9,92.4,62.2.HRMS(ESI/QTOF)m/z:calcd for C20H16INNaO2[M+Na]+ 452.0118,found 452.0110.
N-(4'-iodo-[1,1'-biphenyl]-2-yl)-N-methoxybenzamide(1af’)13％，白色固体，熔点129-131℃.1H NMR(600MHz,CDCl3)δ7.74-7.69(m,2H),7.54(dd,J＝7.8,1.8Hz,1H),7.44(dtd,J＝16.2,7.2,1.8Hz,2H),7.35-7.30(m,2H),7.25-7.15(m,4H),7.05(d,J＝8.4Hz,2H),3.73(s,3H).13C{1H}NMR(150MHz,CDCl3)δ169.1,140.3,138.4,137.6,134.3,131.2,131.1,130.7,129.7,129.6,128.9,128.5,127.8,93.8,62.0.HRMS(ESI/QTOF)m/z:calcd for C20H16INNaO2[M+Na]+ 452.0118,found 452.0112.
N-(4'-iodo-[1,1'-biphenyl]-4-yl)-N-methoxybenzamide(1af”)13％，白色固体，熔点78-80℃.1H NMR(600MHz,CDCl3)δ7.77(d,J＝8.4Hz,2H),7.68(d,J＝8.4Hz,2H),7.56(s,4H),7.44(d,J＝7.2Hz,1H),7.38(t,J＝7.8Hz,2H),7.32(d,J＝8.4Hz,2H),3.71(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.5,140.0,139.2,138.7,138.2,135.0,130.9,129.0,128.7,128.2,127.5,124.3,93.4,62.0.HRMS(ESI/QTOF)m/z:calcd forC20H16INNaO2[M+Na]+ 452.0118,found 452.0110.N-(2-iodo-3-methylphenyl)-N-methoxybenzamide(1ag)，类白色固体，熔点83-85℃.1H NMR(600MHz,CDCl3)δ7.72(d,J＝6.6Hz,2H),7.41(t,J＝7.2Hz,1H),7.34(t,J＝7.8Hz,2H),7.24(d,J＝7.8Hz,1H),7.23-7.20(m,1H),7.15(d,J＝7.2Hz,1H),3.77(s,3H),2.53(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.7,144.5,142.7,134.7,130.9,130.2,128.6,128.1,127.4,106.9,61.7,29.5.HRMS(ESI/QTOF)m/z:calcd for C15H14INNaO2[M+Na]+ 389.9961,found 389.9952.
N-(4/2-fluoro-2/4-iodophenyl)-N-methoxybenzamide(1ah)43％，黄色油状物；1H NMR(600MHz,DMSO-d6)δ7.76(d,J＝8.4Hz,0.55H),7.64-7.60(m,1.81H),7.55(d,J＝7.8Hz,1.41H),7.45-7.42(m,2.32H),7.38-7.35(m,1.88H),7.27(q,J＝8.4,7.8Hz,0.92H),7.20(q,J＝7.8Hz,0.54H),3.73(s,1.8H),3.68(s,1.2H).13C{1H}NMR(150MHz,DMSO-d6)δ168.8,168.4,158.8(d,J＝253.7Hz,1C),157.4(d,J＝255.8Hz,1C),136.15(d,J＝2.7Hz,1C),134.8(d,J＝3.8Hz,1C),134.5(d,J＝7.4Hz,1C),133.4(d,J＝8.9Hz,1C),131.6,131.4,128.6,128.5,128.3,128.1,126.1(d,J＝22.7Hz,1C),117.2(d,J＝21.2Hz,1C),101.9,94.7,62.4,62.3.19F NMR(565MHz,CDCl3)δ-112.0,-115.4.HRMS(ESI/QTOF)m/z:calcd for C14H11FINNaO2[M+Na]+ 393.9711,found 393.9708.
N-(2-fluoro-6-iodophenyl)-N-methoxybenzamide(1ah”)22％，黄色油状物；1HNMR(600MHz,CDCl3)δ7.69(d,J＝7.8Hz,2H),7.62(dd,J＝7.8,3.0Hz,1H),7.45-7.40(m,1H),7.35(t,J＝7.8Hz,2H),7.32(dd,J＝9.0,5.4Hz,1H),7.13-7.06(m,1H),3.75(s,3H).13C{1H}NMR(150MHz,CDCl3)δ169.0,161.9(d,J＝253.5Hz,1C),138.9,134.4,131.2,130.9(d,J＝9.0Hz,1C),128.6,128.2,127.3(d,J＝25.5Hz,1C),116.4(d,J＝22.5Hz,1C),99.7(d,J＝9.0Hz,1C),61.9.19F NMR(565MHz,CDCl3)δ-119.2.HRMS(ESI/QTOF)m/z:calcd forC14H11FINNaO2[M+Na]+ 393.9711,found 393.9708.
N-(4-chloro-2-iodophenyl)-N-methoxybenzamide(1ai)49％，黄色油状物；1HNMR(600MHz,DMSO-d6)δ7.99(d,J＝2.4Hz,1H),7.66(d,J＝8.2Hz,2H),7.52(dd,J＝8.5,2.2Hz,1H),7.47(d,J＝8.4Hz,2H),7.42(t,J＝7.4Hz,2H),3.71(s,3H).13C{1H}NMR(150MHz,DMSO-d6)δ168.3,141.8,139.4,137.7,135.0,134.8,132.6,131.6,131.3,131.1,129.7,129.6,128.5,128.5,128.4,128.3,100.6,62.0.HRMS(ESI/QTOF)m/z:calcd forC14H11ClINNaO2[M+Na]+ 409.9415,found 409.9406.
N-(2-chloro-6/4-iodophenyl)-N-methoxybenzamide(1ai’)and(1ai”)19％，类白色固体；1H NMR(600MHz,CDCl3)δ7.96-7.89(m,2H),7.87(dd,J＝8.4,1.2Hz,1H),7.77(dd,J＝8.4,1.2Hz,1H),7.56(dd,J＝8.4,1.2Hz,2H),7.54-7.50(m,2H),7.50-7.45(m,2H),7.37-7.30(m,2H),7.24-7.17(m,2H),7.08(t,J＝8.0Hz,1H),6.93(t,J＝8.4Hz,1H),4.10(s,3H),3.66(s,3H).13C{1H}NMR(150MHz,CDCl3)δ168.7,168.3,140.9,139.3,139.1,138.6,134.9,134.9,133.9,131.8,131.2,131.1,130.8,130.7,128.4,128.2,127.9,102.2,101.4,63.1,62.8.HRMS(ESI/QTOF)m/z:calcd for C14H11ClINNaO2[M+Na]+409.9415,found 409.9411.
实施例3
产品1aa可进行多样性衍生，采用反应方程式表示如下:
实施例4
氮气保护下，向Schlenk管内加入Pd(Ph3P)2Cl2(28mg,0.04mmol)、化合物1aa(141mg,0.4mmol)、、KOAc(118mg,1.2mmol)和DMF(4.0mL)，密封并加热至80℃反应12小时，混合物冷却至室温，乙酸乙酯30mL稀释，水洗，无水硫酸钠干燥。过滤浓缩，硅胶柱层析得到68mg产品1aq，白色固体，收率76％，熔点96-98℃。1H NMR(600MHz,CDCl3)δ8.60-8.49(m,1H),8.22(t,J＝7.1Hz,2H),7.78-7.71(m,1H),7.69-7.61(m,1H),7.60-7.51(m,2H),7.37-7.28(m,1H),4.12(s,3H).13C{1H}NMR(150MHz,CDCl3)δ157.3,135.8,133.0,132.7,130.0,128.5,128.1,126.3,123.3,122.0,118.6,112.7,62.8.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (5)
1.一种邻碘代苯胺衍生物的合成方法，其特征在于，包括以下步骤：以二乙酸碘代芳烃1与N-甲氧基酰胺2为原料，在有机溶剂中反应，得到邻碘代苯胺衍生物3；反应方程式如下：
其中：R1选自氢、C1-C4烷基、苯基、卤素、酯基；R2选自氢、C1-C4烷基、C1-C4烷氧基、卤素；R2选自C1-C4烷基、苯基、取代苯基，取代苯基中取代基为卤素、三氟甲基、酯基、C1-C4烷基、C1-C4烷氧基。
2.根据权利要求1所述邻碘代苯胺衍生物的合成方法，其特征在于：所述有机溶剂选自六氟异丙醇、三氟甲基苯或三氟乙醇。
3.根据权利要求2所述邻碘代苯胺衍生物的合成方法，其特征在于：所述有机溶剂选自六氟异丙醇。
4.根据权利要求1所述邻碘代苯胺衍生物的合成方法，其特征在于：所述二乙酸碘代芳烃与N-甲氧基酰胺摩尔比为1-2:1。
5.根据权利要求1所述邻碘代苯胺衍生物的合成方法，其特征在于：反应温度为20～25℃。
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