CN114956924A - 一种串联/偶联反应合成多氟代联芳烃的方法 - Google Patents

一种串联/偶联反应合成多氟代联芳烃的方法 Download PDF

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CN114956924A
CN114956924A CN202210760782.3A CN202210760782A CN114956924A CN 114956924 A CN114956924 A CN 114956924A CN 202210760782 A CN202210760782 A CN 202210760782A CN 114956924 A CN114956924 A CN 114956924A
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梁磊
李琛
王松林
祝勇
谷永庆
牛红英
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Abstract

本发明公开了一种串联/偶联反应合成多氟代联芳烃的方法，属于有机化学领域。以芳香化合物1为原料，在噻吩硫氧化物和三氟乙酸酐存在下反应；随后向混合物中加入含氟苯甲酸2、钯催化剂和碳酸银；或加入含氟苯硼酸3、钯催化剂、氟化铯和碳酸银；或加入含氟芳香化合物4、钯催化剂、配体L*、氟化铯和碳酸银，升温继续反应，得到多氟代联芳烃化合物5。本发明为氟代联芳烃类化合物的合成提供了一种简便、高效、高选择性的合成方法，反应原料廉价易得，产物结构丰富，产物化学/区域选择性高，反应后得到的氟代联芳烃化合物5，收率中等至优秀。

Description

一种串联/偶联反应合成多氟代联芳烃的方法
技术领域
本发明涉及多氟代联芳烃的合成方法，具体涉及一种钯盐催化的串联/偶联反应合成氟代联芳烃的方法，属于有机化学中的金属催化领域。
背景技术
氟代芳香族化合物在医药化学、有机功能材料和农药中有着广泛的应用。目前，氟代联芳烃类化合物的合成方法主要是通过催化偶联，选用芳香亲电试剂同氟代芳香亲核试剂反应构筑氟代联芳烃。
第一类：预活化芳烃与多氟芳基化试剂偶联
Figure BDA0003720954420000011
LG＝Cl，Br，l，N2BF4，COCl，OTf，OTs and etc.；Y＝CO2H，B(OH)2，Bpin，H and etc.
[TM]＝Pd，Ni and Cu
第二类：非活化芳烃与多氟芳基化试剂偶联
Figure BDA0003720954420000012
Y＝CO2H，B(OH)2，Bpin，H and etc
[TM]＝Pd and Au
第一类：选用预活化的芳烃作为起始原料，如卤代芳烃、芳基重氮盐、苯甲酰氯和芳基磺酸盐等。通常，预活化的芳烃底物局限性较大，原料来源有限，同时对于复杂分子预活化的区域选择性控制难以实现。对于非活化芳香化合物的多氟芳基化反应研究相对较少，且区域选择性难以控制。同时，受限于氟代芳香亲核试剂的反应活性，商业可得性和区域选择性，目前氟代芳基的范围也显示出了很大的局限性。
第二类：选用非活化的芳烃作为起始原料，同氟芳基化试剂偶联。该类反应同样面对区域选择性的挑战，以钯盐作为催化剂时，反应区域选择性较差，且无法实现复杂芳香族化合物的氟芳基化反应。以金盐作为催化剂时，对于结构简单的芳香化合物，具有较好的区域选择性，但是对于结构复杂的分子氟芳基化反应仍无法实现。同时，受限于氟代芳香亲核试剂的反应活性，商业可得性和区域选择性，目前氟代芳基的范围也显示出了很大的局限性。
发明内容
为了克服上述缺陷，本发明采用非活化芳烃和多种廉价易得的多氟芳基化试剂为原料，通过串联策略，在钯/银双金属共同作用下合成氟代联芳烃类化合物。该方法为氟代联芳烃类化合物的合成提供了一种简便、廉价、高效和高选择性的合成方法。
本发明所述一种钯催化偶联反应合成多氟代联芳烃的方法，包括如下步骤：以芳香化合物1为原料，在噻吩硫氧化物和三氟乙酸酐存在下反应；随后向混合物中加入含氟苯甲酸2、钯催化剂和银盐；或加入含氟苯硼酸3、钯催化剂、碱和银盐；或加入含氟芳香化合物4、钯催化剂、配体L*、碱和银盐，升温继续反应，得到多氟代联芳烃化合物5；
进一步地，在上述技术方案中，芳香原料1选自：单取代、双取代、多取代芳烃和芳香族药物分子、芳香族农药分子和芳香族天然产物分子；取代基包括：烷氧基、烷基、环烷基、卤素、腈基、氨基、酯基、醛基和羰基。氟代苯甲酸2选自：五氟苯甲酸、四氟苯甲酸、三氟苯甲酸和二氟苯甲酸。氟代苯硼酸3选自：五氟苯甲酸、四氟苯甲酸、三氟苯甲酸和二氟苯甲酸和单氟苯硼酸。氟代苯4选自：五氟苯、四氟苯、四氟吡啶和三氟吡啶。
进一步地，在上述方案中，所述钯催化剂选自Pd(PPh3)2Cl2、PdCl2、Pd(OAc)2、Pd(PPh3)4或Pd2(dba)3。
所述银盐选自Ag2CO3、Ag2O、AgOTf或AgNO3。优选为Ag2CO3。
进一步地，在上述方案中，所述碱选自CsF、K2CO3、Na2CO3、tBuONa或Cs2CO3。
进一步地，在上述方案中，反应溶剂选自DMSO、DCE、DMA或THF。
进一步地，在上述方案中，所述配体L*选自PPh3、DavePhos、JohnPhos、RuPhos、X-Phos、CyJohnPhos或JohnPhos。
将上述技术方案进一步细化，具体操作条件，采用反应方程式表示如下：方案一
Figure BDA0003720954420000021
含氟苯甲酸2选自：
Figure BDA0003720954420000031
方案二
Figure BDA0003720954420000032
含氟苯硼酸3选自：
Figure BDA0003720954420000033
方案三
Figure BDA0003720954420000034
含氟芳环4选自：
Figure BDA0003720954420000035
上述芳香化合物1均选自：
Figure BDA0003720954420000036
Figure BDA0003720954420000041
本发明上述具体三种操作技术方案，详细分成如下三类：
A、一种钯催化反应合成氟代联芳烃类化合物的方法，包括如下操作：以芳香化合物1为原料，加入噻吩硫氧化物，三氟乙酸酐和乙腈，相应混合物在0℃下反应1小时，随后至于室温下继续反应2小时，反应液体萃取浓缩后，向混合物中加入和氟代甲酸2，钯催化剂、碳酸银和DMSO，经氮气保护后，与80℃继续反应24小时，反应得到多氟代联芳烃化合物5，反应方程式如下：
Figure BDA0003720954420000042
B、一种钯催化偶联反应合成多氟代联芳烃的方法，包括如下步骤：以芳香化合物1为原料，加入噻吩硫氧化物，三氟乙酸酐和乙腈，相应混合物在0℃下反应1小时，随后至于室温下继续反应2小时，反应液体萃取浓缩后，向混合物中加入和氟代硼酸3，钯催化剂、碳酸银和DMSO，经氮气保护后，与80℃继续反应24小时，反应得到多氟代联芳烃化合物5，反应方程式如下：
Figure BDA0003720954420000043
C、一种钯催化偶联反应合成多氟代联芳烃的方法，包括如下步骤：以芳香化合物1为原料，加入噻吩硫氧化物，三氟乙酸酐和乙腈，相应混合物在0℃下反应1小时，随后至于室温下继续反应2小时，反应液体萃取浓缩后，向混合物中加入和氟代苯4，钯催化剂、膦配体、碳酸银和DMA，经氮气保护后，与25度继续反应24小时，反应得到多氟代联芳烃化合物5，反应方程式如下：
Figure BDA0003720954420000051
进一步地，在上述方案中，对于脱羧偶联：所述芳香化合物1、氟代苯甲酸2、Pd(PPh3)2Cl2与Ag2CO3摩尔比为1:1.5:0.05:1。
进一步地，在上述方案中，对于Suzuki偶联：所述芳香化合物1、氟代苯硼酸3、Pd(PPh3)2Cl2、Ag2CO3与CsF摩尔比为1:1.5:0.05:1:2。
进一步地，在上述方案中，对于直接芳基化：所述芳香化合物芳香化合物1、氟代苯4、Pd(PPh3)2Cl2、JohnPhos、Ag2CO3与CsF摩尔比为1:1.5:0.05:0.06:0.5:2。
进一步地，在上述技术方案中，反应温度选自25℃-80℃。
进一步地，在上述技术方案中，钯催化反应过程需要惰性气体保护下操作，惰性气体优选氮气。
在上述反应条件下，经过反应纯化后，对于不同的底物分离收率55％-88％。
发明有益效果：
本发明为氟代联芳烃类化合物的合成提供了一种简便、高效、高选择性的合成方法，反应原料廉价易得，产物结构丰富，产物化学/区域选择性高，反应后得到的氟代联芳烃化合物5，收率中等至优秀。
具体实施方式
Figure BDA0003720954420000052
Figure BDA0003720954420000053
Figure BDA0003720954420000061
Figure BDA0003720954420000062
aGeneral procedure for decarboxylation coupling.In situ activationstep:1(0.3mmol),TTO(0.3mmol),(CF3O)2O(0.9mmol),HBF4·Et2O(1.2equiv.)in MeCN(1.0mL)at 0℃ or-40℃ for 1h,r.t.for another 2-24h；then Condition A:ArF-CO2H2a(0.45mmol),Pd(PPh3)2Cl2(5mol％),Ag2CO3(0.3mmol)in DMSO(1.0mL)at 80℃ for24h.bGeneral procedure for SMC.In situ activation step；then Condition B:ArF-B(OH)23a(0.45mmol),Pd(PPh3)2Cl2(5mol％),CsF(0.6mmol),Ag2CO3(0.3mmol)in DMSO(1.0mL)at 80℃ for 24h.cGeneral procedure for C-H/C-H coupling.In situactivation step；then Condition C:ArF-H 4a(1.2mmol),Pd(PPh3)2Cl2(5mol％),JohnPhos(6mol％),Ag2CO3(0.15mmol),CsF(0.6mmol)in DMA(1.0mL)atr.t.for24h.dYieldofthe isolatedproduct.
在反应条件的筛选中，首先以五氟苯甲酸作为氟芳基化试剂考察了不同的钯盐、溶剂、银盐和溶剂对反应的影响。确定最优条件后，通过对上述最优条件的进一步优化，确定了氟代芳基硼酸和氟代苯作为氟芳基化试剂的最佳条件。
实施例1
Figure BDA0003720954420000063
将苯甲醚1a(0.3mmol)、噻吩-S-氧化物(69.7mg，0.3mmol)和MeCN(1.0mL)加入到10mL反应管中。冷却至0℃后，加入HBF4·Et2O(49μL，0.36mmol)，然后添加三氟乙酸酐(126μL，0.9mmol)，形成深紫色溶液。用螺帽密封小瓶，并在0℃下搅拌混合物1小时，然后在25℃下搅拌2小时。随后，在减压下浓缩所得的棕色反应混合物，用5mL二氯甲烷稀释后，将二氯甲烷溶液倒入饱和NaHCO3水溶液(5mL)中。将混合物倒入分离漏斗中，分离各层。收集二氯甲烷层，并用二氯甲烷(2×5mL)进一步提取水层。用NaBF4水溶液(2×5mL，5％w/w)洗涤合并的二氯甲烷溶液。在Na2SO4上干燥二氯甲烷层，并在减压下去除溶剂得到中间体。然后，将该中间体，五氟苯甲酸2a(0.45mmol，95.4mg)、Pd(PPh3)2Cl2(10.6mg，5mol％)和Ag2CO3(82.7mg，0.3mmol)加入到反应管中。将反应管觅封后氮气置换三次后通过注射器向反应管中加入二甲基亚砜(1.0mL)。将混合物在80℃下搅拌24小时。通过硅胶柱层析或薄层层析(纯PE至PE/EA:5/1)纯化得纯化产物5a，白色固体73.6mg，收率73％。1H NMR(600MHz,CDCl3)δ7.37(d,J＝8.4Hz,2H),7.03–7.01(m,2H),3.87(s,3H).13C NMR(151MHz,CDCl3)δ160.4,145.1(m),143.5(m),141.0(m),139.3(m),138.8(m),137.2(m),131.6,118.52,115.9(m),114.4,77.2,55.5.19F NMR(565MHz,CDCl3)δ-143.68(dd,J＝22.6,5.7Hz),-156.59(t,J＝19.78Hz),-162.62(td,J＝22.6,5.7Hz).
实施例2
Figure BDA0003720954420000071
将苯甲醚1a(0.3mmol)、噻吩-S-氧化物(69.7mg，0.3mmol)和MeCN(1.0mL)加入到10mL反应管中。冷却至0℃后，加入HBF4·Et2O(49μL，0.36mmol)，然后添加三氟乙酸酐(126μL，0.9mmol)，形成深紫色溶液。用螺帽密封小瓶，并在0℃下搅拌混合物1小时，然后在25℃下搅拌2小时。随后，在减压下浓缩所得的棕色反应混合物，用5mL二氯甲烷稀释后，将二氯甲烷溶液倒入饱和NaHCO3水溶液(5mL)中。将混合物倒入分离漏斗中，分离各层。收集二氯甲烷层，并用二氯甲烷(2×5mL)进一步提取水层。用NaBF4水溶液(2×5mL，5％w/w)洗涤合并的二氯甲烷溶液。在Na2SO4上干燥二氯甲烷层，并在减压下去除溶剂得到中间体。然后，将该中间体，2,3,4-三氟苯硼酸3b(0.45mmol，79.2mg)、Pd(PPh3)2Cl2(10.6mg，5mol％)、Ag2CO3(82.7mg，0.3mmol)和CsF(91.1mg,0.6mmol)加入到反应管中。将反应管觅封后氮气置换三次后通过注射器向反应管中加入二甲基亚砜(1.0mL)。将混合物在80℃下搅拌24小时。通过硅胶柱层析或薄层层析(纯PE至PE/EA:5/1)纯化得纯化产物6d，浅黄色固体73.6mg，收率83％。1HNMR(600MHz,CDCl3)δ7.44(dd,J＝9.0,1.8Hz,2H),7.12(m,2.4Hz,1H),7.05–6.98(m,3H),3.87(s,3H).13C NMR(151MHz,CDCl3)δ159.8(s),151.1(dd,J＝9.8,2.3Hz),149.6(dd,J＝10.6,3.0Hz),149.4(dd,J＝10.6,1.5Hz),148.0(dd,J＝10.6,3.0Hz),141.3(t,J＝15.9Hz),139.6(t,J＝15.9Hz),130.1,130.0,126.6(m),123.7(m),114.3(s),112.1(dd,J＝17.3,3.8Hz),77.2,55.4(s).19F NMR(565MHz,CDCl3)δ-136.62(m),-139.18(m),-160.33(td,J＝19.8,7.5Hz).
实施例3
Figure BDA0003720954420000081
将苯甲醚1a(0.3mmol)、噻吩-S-氧化物(69.7mg，0.3mmol)和MeCN(1.0mL)加入到10mL反应管中。冷却至0℃后，加入HBF4·Et2O(49μL，0.36mmol)，然后添加三氟乙酸酐(126μL，0.9mmol)，形成深紫色溶液。用螺帽密封小瓶，并在0℃下搅拌混合物1小时，然后在25℃下搅拌2小时。随后，在减压下浓缩所得的棕色反应混合物，用5mL二氯甲烷稀释后，将二氯甲烷溶液倒入饱和NaHCO3水溶液(5mL)中。将混合物倒入分离漏斗中，分离各层。收集二氯甲烷层，并用二氯甲烷(2×5mL)进一步提取水层。用NaBF4水溶液(2×ca.5mL，5％w/w)洗涤合并的二氯甲烷溶液。在Na2SO4上干燥二氯甲烷层，并在减压下去除溶剂得到中间体。然后，将该中间体，1,2,3,5-四氟苯3b(0.9mmol，135.1mg)、Pd(PPh3)2Cl2(10.6mg，5mol％)、Ag2CO3(82.7mg，0.3mmol)、CsF(91.1mg,0.6mmol)和JohnPhos(5.4mg,6mol％)加入到反应管中。将反应管觅封后氮气置换三次后通过注射器向反应管中加入N,N-二甲基乙酰胺(1.0mL)。将混合物在80℃下搅拌24小时。通过硅胶柱层析或薄层层析(纯PE至PE/EA:5/1)纯化得纯化产物6b，浅黄色固体53.1mg，收率69％。1H NMR(600MHz,CDCl3)δ7.37(d,J＝9.0Hz,2H),7.03–7.00(m,2H),6.88–6.83(m,1H),3.87(s,3H).13C NMR(151MHz,CDCl3)δ160.0,155.2(m),153.6(m),150.4(m),149.9(m),148.7(m),148.2(m),138.5(m),136.8(m),131.5,119.7,115.9(m),114.2,101.0(m),77.2,55.4.19F NMR(565MHz,CDCl3)δ-118.42(dd,J＝17.0,5.7Hz),-134.27(m),-135.82(d,J＝22.6Hz),-165.04(m).
实施例4
Figure BDA0003720954420000091
将吡丙醚1v(3.11mmol，1.0g)、噻吩-S-氧化物(720.2mg，3.11mmol)和MeCN(10mL)加入到25mL反应管中。冷却至0℃后，加入HBF4·Et2O(510μL，3.72mmol)，然后添加三氟乙酸酐(1.3mL，9.3mmol)，形成深紫色溶液。用螺帽密封小瓶，并在0℃下搅拌混合物1小时，然后在25℃下搅拌2小时。随后，在减压下浓缩所得的棕色反应混合物，用50mL二氯甲烷稀释后，将二氯甲烷溶液倒入饱和NaHCO3水溶液(50mL)中。将混合物倒入分离漏斗中，分离各层。收集二氯甲烷层，并用二氯甲烷(2×50mL)进一步提取水层。用NaBF4水溶液(2×50mL，5％w/w)洗涤合并的二氯甲烷溶液。在Na2SO4上干燥二氯甲烷层，并在减压下去除溶剂得到中间体。然后，将该中间体，五氟苯甲酸2a(4.67mmol，0.99g)、Pd(PPh3)2Cl2(109.5mg，5mol％)和Ag2CO3(854.6mg，3.1mmol)加入到反应管中。将反应管觅封后氮气置换三次后通过注射器向反应管中加入二甲基亚砜(10.3mL)。将混合物在80℃下搅拌24小时。通过硅胶柱层析或薄层层析(纯PE至PE/EA:5/1)纯化得纯化产物5v，白色固体1.15g，收率74％。1HNMR(600MHz,CDCl3)δ8.17(m,1H),7.57(m,1H),7.36(m,2H),7.04(d,J＝9.0Hz,4H),7.00–6.96(m,2H),6.86(m,1H),6.76(d,J＝8.4Hz,1H),5.63(m,1H),4.23(dd,J＝9.6,4.8Hz,1H),4.11(dd,J＝9.6,4.8Hz,1H),1.51(d,J＝6.6Hz,3H).13C NMR(151MHz,CDCl3)δ163.3,159.8,155.9,149.3,146.9,145.1(m),143.5(m),141.1(m),139.4(m),138.8,137.1(m),131.7,121.5,112.0,117.3,116.9,116.1,115.6(m),111.8,77.2,71.2,69.34,17.1.19F NMR(565MHz,CDCl3)δ-143.45(dd,J＝19.8,8.5Hz),-156.12(t,J＝22.60Hz),-162.35(td,J＝22.6,11.3Hz).HRMS(ESI-TOF):m/z calcd.For C26H19F5NO3 +[M+H]+488.1280.found m/z488.1276.
实施例5
采用实施例1-3中类似的合成方法，得到产物结构和收率分别如下：
Figure BDA0003720954420000101
实施例6
Figure BDA0003720954420000102
Figure BDA0003720954420000111
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 (8)

1.一种钯催化偶联反应合成多氟代联芳烃的方法，其特征在于，包括如下步骤：以芳香化合物1为原料，在噻吩硫氧化物和三氟乙酸酐存在下反应；随后向混合物中加入含氟苯甲酸2、钯催化剂和碳酸银；或加入含氟苯硼酸3、钯催化剂、氟化铯和碳酸银；或加入含氟芳香化合物4、钯催化剂、配体L*、氟化铯和碳酸银，升温继续反应，得到多氟代联芳烃化合物5；具体分为如下三种方案：
方案一
Figure RE-FDA0003772684080000011
含氟苯甲酸2选自：
Figure RE-FDA0003772684080000012
方案二
Figure RE-FDA0003772684080000013
含氟苯硼酸3选自：
Figure RE-FDA0003772684080000014
方案三
Figure RE-FDA0003772684080000015
含氟芳环4选自：
Figure RE-FDA0003772684080000021
上述芳香化合物1均选自：
Figure RE-FDA0003772684080000022
2.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：所述钯催化剂均选自Pd(PPh3)2Cl2；所述配体L*选自JohnPhos。
3.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：方案一，所述芳香化合物1、氟代苯甲酸2、Pd(PPh3)2Cl2与Ag2CO3摩尔比为：1:1.5:0.05:1。
4.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：方案二，所述芳香化合物1、氟代苯硼酸3、Pd(PPh3)2Cl2、Ag2CO3与CsF摩尔比为：1:1.5:0.05:1:2。
5.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：方案三，所述芳香化合物芳香化合物1、氟代苯4、Pd(PPh3)2Cl2、JohnPhos、Ag2CO3与CsF摩尔比为：1:1.5:0.05:0.06:0.5:2。
6.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：
方案二，反应温度选自25℃-80℃。
7.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：
方案二，偶联反应过程需要在惰性气体保护下操作。
8.根据权利要求1所述钯催化偶联反应合成多氟代联芳烃的方法，其特征在于：
第一步反应溶剂为乙腈；第二步反应溶剂为DMSO或DMA。
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