CN114249625A - 一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的方法 - Google Patents

一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的方法 Download PDF

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CN114249625A
CN114249625A CN202111516327.0A CN202111516327A CN114249625A CN 114249625 A CN114249625 A CN 114249625A CN 202111516327 A CN202111516327 A CN 202111516327A CN 114249625 A CN114249625 A CN 114249625A
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冯博雅
陈雨
冯煦
管福琴
张国栋
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Abstract

本发明公开了一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的方法。该方法是在惰性气体氛围下，将(杂)芳基甲酸、三甲基环三氧硼烷、含钯催化剂、膦配体、酸酐添加剂、溶剂混合反应，得甲基(杂)芳烃产物。该方法以稳定且廉价易得的(杂)芳基甲酸作为原料合成甲基(杂)芳烃，可弥补传统过渡金属催化卤代(杂)芳烃与亲核性甲基化试剂的偶联反应中存在的不足，具有以下优点：(1)避免使用较昂贵且难制备的卤代(杂)芳烃，同时避免含卤废弃物的产生；(2)避免甲基格氏试剂、甲基硼酸等不稳定原料的使用，反应具有较好的官能团容忍性；(3)(杂)芳基甲酸原料与产物极性差别较大，易于通过柱层析分离。

Description

一种过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶 联制备甲基(杂)芳烃的方法
技术领域
本发明涉及一种甲基(杂)芳烃的合成方法，特征是以(杂)芳基甲酸为亲电试剂，在过渡金属催化下与三甲基环三氧硼烷进行脱羰偶联，合成甲基(杂)芳烃，属于有机合成中的领域。
背景技术
甲基是有机化合物中最基础，最广泛存在的一类非极性官能团，在化学反应中一般较为惰性。对于药物化学来说，特别是对许多生物活性分子而言，引入一个简单的甲基，会极大改变其溶解性、亲水性以及药物构象等，这也被人们称为“甲基化效应”。在目前最畅销的200种小分子药物里，有超过70％的分子中带有一个以上的甲基。同时，(杂)芳基上的甲基还可以衍生为其他官能团，如醛基、羧基、苄醇、苄卤等，因此甲基化反应在合成化学中也有着广泛的应用。
过渡金属钯或镍催化卤代(杂)芳烃与亲核性甲基化试剂的偶联反应是制备甲基(杂)芳烃最有效的方法之一，但具有以下缺点：(1)卤代(杂)芳烃需要通过较苛刻的反应条件制备，价格昂贵且易产生大量含卤废弃物；(2)亲核性甲基化试剂通常为甲基格氏试剂、甲基硼酸等高活性试剂，反应官能团容忍性较差；(3)卤代原料与甲基化产物极性相近，难以通过柱层析方法分离。
(杂)芳基甲酸类化合物是无毒、廉价、易得且具有较好稳定性的化工原料。近年来，通过将(杂)芳基甲酸预活化为酸酐、酰胺、酯类、酰氯以及酰氟等(杂)芳酰基化合物后，以过渡金属(钯、镍、铑等)催化的方法可以实现(杂)芳基甲酸与不同亲核试剂的脱羰交叉偶联反应，完成C–C、C–O、C–N、C–S等化学键的构筑。
发明内容
针对现有技术存在的缺陷，本发明的目的是在于提供一种以(杂)芳基甲酸为亲电试剂，在过渡金属催化下与温和型亲核甲基化试剂发生脱羰偶联，简洁高效地合成甲基(杂)芳烃的方法，以稳定且廉价易得的(杂)芳基甲酸作为亲电试剂合成甲基(杂)芳烃可弥补传统过渡金属催化甲基化反应存在的不足。
为实现上述目的，本发明提供了一种甲基(杂)芳烃的合成方法，该方法是在惰性气体氛围下，将Ar–COOH、三甲基环三氧硼烷、含钯催化剂、膦配体、酸酐添加剂、溶剂混合反应，得Ar–CH3；其中，所述Ar为芳基或杂芳基，所述芳基或杂芳基任选地被一个或更多个如下取代基取代：烷基、芳基、酰基、硝基、醛基、氰基、三氟甲基、甲氧基、磺酰基、磺胺基、酯基、胺基。“任选地被一个或更多个如下取代基取代”是指可以被一个或更多个指定的取代基取代，也可以为非取代。
可选地，所述芳基选自苯、萘、菲、蒽、芘，所述杂芳基选自喹啉、吡啶、苯并噻吩、苯并呋喃、吲哚、噻唑、咪唑、噁唑。
在本发明的具体实施方式中，所述芳基选自苯、萘，所述杂芳基选自苯并呋喃、喹啉、噻唑。
可选地，所述芳基或杂芳基任选地被1-2个如下取代基取代：苯基、酰基、硝基、氰基、磺胺基、
Figure BDA0003398393340000021
进一步地，在本发明的一个具体实施方式中，所述磺胺基为
Figure BDA0003398393340000022
具体地，在本发明中，所述Ar–COOH选自如下结构：
Figure BDA0003398393340000023
上述合成方法中，含钯催化剂是以下钯(II)化合物之一：二氯化钯(PdCl2)、醋酸钯(Pd(OAc)2)、三氟乙酸钯(Pd(TFA)2)、二(乙酰丙酮)钯(Pd(acac)2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)。
上述合成方法中，膦配体是以下膦化合物之一：双(2-二苯基膦苯基)醚(DPEPhos)、1,2-双(二苯基膦)乙烷(dppe)、1,1’-双(二苯基膦)二茂铁(dppf)、1,4-双(二苯基膦)丁烷(dppb)、4,5-双(二苯基膦)-9,9’-二甲基氧杂蒽(XantPhos)。
上述合成方法中，酸酐添加剂是以下酸酐化合物之一：包括苯甲酸酐(benzoicanhydride)、乙酸酐(Ac2O)、三氟乙酸酐(TFAA)、二碳酸二叔丁酯(Boc2O)、三甲基乙酸酐(Piv2O)。
上述合成方法中，溶剂是以下溶剂之一：THF、1,4-二氧六环、三氟甲苯、正己烷、甲苯。
上述合成方法中，含钯催化剂相对Ar–COOH的摩尔添加量为2.5％～10％，膦配体相对Ar–COOH的摩尔添加量为7.5％～30％，酸酐添加剂相对Ar–COOH的摩尔添加量为100％～300％。
在本发明的一些具体实施方式中，所述含钯催化剂相对Ar–COOH的摩尔添加量为5％；所述膦配体相对Ar–COOH的摩尔添加量为15％；所述酸酐添加剂相对Ar–COOH的摩尔添加量为150％。
上述合成方法中，Ar–COOH与三甲基环三氧硼烷的摩尔比为1:1～1:2。
上述合成方法中，脱羰偶联反应的温度为120～170℃。
上述合成方法中，脱羰偶联反应的时间为6～36小时。
上述合成方法中，反应结束后萃取溶剂为正己烷、二氯甲烷、乙醚、乙酸乙酯中的一种。
本发明所提供的合成方法为过渡金属催化(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃，开发了一条新的甲基(杂)芳烃制备路线，其优点在于：(1)以稳定且廉价易得的(杂)芳基甲酸作为亲电试剂，避免了较为昂贵且难以制备的卤代芳烃的使用，同时避免了含卤废弃物的产生；(2)选取较为廉价稳定的三甲基环三氧硼烷作为亲核甲基化试剂，避免了甲基格氏试剂、甲基硼酸等不稳定原料的使用，反应具有较好的官能团容忍性；(3)(杂)芳基甲酸原料与产物极性差别较大，易于通过柱层析分离。
附图说明
图1所示为本发明提供的(杂)芳基甲酸与三甲基环三氧硼烷脱羰偶联制备甲基(杂)芳烃的合成路径图。
具体实施方式
为使本发明的上述特征、优点和目的更加简明易懂，下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了许多具体细节以便于充分理解本发明。但是本发明能以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
实施例1
目标产物结构式如下：
Figure BDA0003398393340000041
室温下，在装有磁力搅拌子的50mL反应管中加入0.2mmol的2-萘甲酸、0.01mmol的Pd(OAc)2、0.03mmol的XantPhos，将反应管中置换为氮气后，加入0.3mmol的Piv2O、0.4mmol的三甲基环三氧硼烷以及2mL的1,4-二氧六环，将反应体系封闭后，置于带磁力搅拌的油浴加热器中，在160℃下反应24小时。反应完毕后，加入二氯甲烷萃取分离，通过柱层析得到产物。
产物为无色液体，产率为88％
1H NMR(400MHz,CDCl3)δ＝2.53(s,3H),7.33(dd,J＝8.4Hz,1.6,1H),7.39–7.48(m,2H),7.63(s,1H),7.75–7.78(m,2H),7.81(d,J＝8.0Hz,1H)ppm.13C NMR(101MHz,CDCl3)δ＝21.9,125.1,126.0,127.0,127.4,127.7,127.8,128.2,131.8,133.8,135.6ppm.
实施例2
目标产物结构式如下：
Figure BDA0003398393340000042
步骤同实施例1，以邻苯基苯甲酸为原料，反应时间为12小时。
产物为淡黄色液体，产率为82％。
1H NMR(400MHz,CDCl3):δ＝2.27(s,3H),7.22–7.28(m,3H),7.30–7.36(m,3H),7.37–7.62(m,3H)ppm；13C NMR(100MHz,CDCl3):δ＝20.6,125.9,126.9,127.3,127.4,128.2,128.9,129.3,129.9,130.4,135.5ppm.
实施例3
目标产物结构式如下：
Figure BDA0003398393340000043
步骤同实施例1，以邻硝基苯甲酸为原料。
产物为黄色液体，产率为84％。
1H NMR(400MHz,CDCl3):δ＝2.61(s,3H),7.30–7.39(m,2H),7.50(t,J＝7.6Hz,1H),7.97(d,J＝8.4Hz,1H)ppm.13C NMR(100MHz,CDCl3):δ＝20.6,124.8,127.0,132.9,133.1,133.7,149.5ppm.
实施例4
目标产物结构式如下：
Figure BDA0003398393340000051
步骤同实施例1，以对乙酰基苯甲酸为原料。
产物为无色液体，产率为81％。
1H NMR(400MHz,CDCl3):δ＝2.41(s,3H),2.58(s,3H),7.26(d,J＝8.8Hz,2H),7.86(d,J＝8.4Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ＝21.8,26.7,128.6,129.4,134.8,144.0,198.0ppm.
实施例5
目标产物结构式如下：
Figure BDA0003398393340000052
步骤同实施例1，以对氰基苯甲酸为原料。
产物为无色液体，产率为66％。
1H NMR(400MHz,CDCl3)δ＝2.42(s,3H),7.27(d,J＝7.6Hz,2H),7.54(d,J＝8.4Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ＝22.0,109.4,119.3,130.0,132.2,143.8ppm.
实施例6
目标产物结构式如下：
Figure BDA0003398393340000053
步骤同实施例1，以苯并呋喃-2-甲酸为原料，反应在170℃下进行。
产物为无色液体，产率为45％。
1H NMR(400MHz,CDCl3):δ＝2.46(s,3H),6.37(p,J＝1.0Hz,1H),7.15–7.23(m,2H),7.38–7.42(m,1H),7.45–7.49(m,1H)ppm；13C NMR(100MHz,CDCl3):δ＝14.2,102.7,110.7,120.2,122.5,123.2,129.3,154.8,155.5ppm.
实施例7
目标产物结构式如下：
Figure BDA0003398393340000061
步骤同实施例1，以喹啉-6-甲酸为原料。
产物为黄色液体，产率为72％。
1H NMR(400MHz,CDCl3)δ＝2.52(s,3H),7.31–7.37(m,1H),7.51–7.58(m,2H),7.99(d,J＝8.4Hz,1H),8.05(d,J＝8.4Hz,1H),8.83(d,J＝4.4Hz,1H)ppm.13C NMR(100MHz,CDCl3)δ＝21.7,121.2,126.7,128.4,129.2,131.9,135.5,136.5,147.0,149.6ppm.
实施例8
目标产物结构式如下：
Figure BDA0003398393340000062
步骤同实施例1，以丙磺舒为原料。
产物为无色液体，产率为64％。
1H NMR(400MHz,CDCl3)δ＝0.86(td,J＝7.2,1.6Hz,6H),1.49–1.58(m,4H),2.41(s,3H),3.05(td,J＝7.6,1.6Hz,4H),7.23–7.32(m,2H),7.62–7.71(m,2H).13C NMR(100MHz,CDCl3)δ＝11.3,21.6,22.2,50.2,127.2,129.7,137.3,143.0ppm.
实施例9
目标产物结构式如下：
Figure BDA0003398393340000063
步骤同实施例1，以非布索坦为原料。
产物为白色固体，产率为35％。
1H NMR(400MHz,CDCl3)δ＝1.08(d,J＝6.8Hz,6H),2.13–2.24(m,1H),2.36(s,3H),2.39(s,3H),3.86(d,J＝6.4Hz,2H),6.96(d,J＝8.8Hz,1H),7.99(d,J＝8.8Hz,1H),8.04(s,1H)ppm.13C NMR(100MHz,CDCl3)δ＝11.6,14.9,19.2,28.3,75.7,102.7,112.6,116.0,126.9,127.3,131.4,131.9,149.6,160.9,161.5ppm.HRMS(ESI+)calcd for C16H18N2OS[M+H]+287.1213,found 287.1209.
实施例10
目标产物结构式如下：
Figure BDA0003398393340000071
步骤同实施例1，以替米沙坦为原料。
产物为白色固体，产率为80％。
1H NMR(400MHz,CDCl3)δ＝1.01–1.08(m,3H),1.83–1.90(m,2H),2.21(s,3H),2.77(s,3H),2.90–2.98(m,2H),3.80(s,3H),5.45(s,2H),7.10(d,J＝7.6Hz,2H),7.16(d,J＝7.6Hz,1H),7.19–7.25(m,4H),7.27(s,1H),7.28–7.32(m,2H),7.34–7.39(m,1H),7.43(s,1H),7.52(s,1H),7.77–7.83(m,1H)ppm.13C NMR(100MHz,CDCl3)δ＝14.2,17.1,20.6,22.0,30.0,31.9,47.2,109.1,109.6,119.7,122.5,122.7,123.98,124.02,126.0,126.1,127.6,129.6,129.8,130.0,130.5,134.5,135.2,135.4,136.8,141.2,141.8,143.0,143.3,154.9,156.7ppm.HRMS(ESI+)calcd for C33H32N4[M+H]+485.2700,found 485.2696.
实施例11
目标产物结构式如下：
Figure BDA0003398393340000072
步骤同实施例1，以阿达帕林为原料。
产物为白色固体，产率为55％。
1H NMR(400MHz,CDCl3)δ＝1.83(s,6H),2.13(s,3H),2.18–2.25(m,6H),2.54(s,3H),7.00(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,1.6Hz,1H),7.54(dd,J＝8.4,2.4Hz,1H),7.60–7.65(m,2H),7.71(dd,J＝8.4,1.6Hz,1H),7.79–7.83(m,2H),7.96(s,1H)ppm.13C NMR(100MHz,CDCl3)δ＝21.9,29.3,37.3,37.3,40.7,55.3,112.2,124.9,125.6,125.8,126.0,126.7,127.7,128.0,128.6,132.1,132.6,133.4,135.3,138.2,138.9,158.5ppm.

Claims (9)

1.一种制备甲基芳烃或甲基杂芳烃的方法，其特征在于：在惰性气体氛围下，将Ar–COOH、三甲基环三氧硼烷、含钯催化剂、膦配体、酸酐添加剂、溶剂混合反应，得Ar–CH3；其中，所述Ar为芳基或杂芳基，所述芳基或杂芳基任选地被一个或更多个如下取代基取代：烷基、芳基、酰基、硝基、醛基、氰基、三氟甲基、甲氧基、磺酰基、磺胺基、酯基、胺基；
所述含钯催化剂选自二氯化钯、醋酸钯、三氟乙酸钯、二(乙酰丙酮)钯、三(二亚苄基丙酮)二钯中至少一种；所述膦配体选自双(2-二苯基膦苯基)醚、1,2-双(二苯基膦)乙烷、1,1’-双(二苯基膦)二茂铁、1,4-双(二苯基膦)丁烷、4,5-双(二苯基膦)-9,9’-二甲基氧杂蒽中至少一种；所述酸酐添加剂选自苯甲酸酐、乙酸酐、三氟乙酸酐、二碳酸二叔丁酯、三甲基乙酸酐中至少一种；
反应的温度为80～170℃，时间为6～36小时。
2.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述芳基选自苯、萘、菲、蒽、芘，所述杂芳基选自喹啉、吡啶、苯并噻吩、苯并呋喃、吲哚、噻唑、咪唑、噁唑。
3.根据权利要求1或2所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述Ar中的芳基或杂芳基任选地被1-2个如下取代基取代：甲基、苯基、乙酰基、硝基、氰基、磺胺基、
Figure RE-FDA0003491369810000011
4.根据权利要求3所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述磺胺基为
Figure RE-FDA0003491369810000012
5.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述溶剂选自THF、1,4-二氧六环、三氟甲苯、正己烷、甲苯中至少一种。
6.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述含钯催化剂相对Ar–COOH的摩尔添加量为2.5％～10％；所述膦配体相对Ar–COOH的摩尔添加量为7.5％～30％；所述酸酐添加剂相对Ar–COOH的摩尔添加量为100％～300％。
7.根据权利要求5所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述含钯催化剂相对Ar–COOH的摩尔添加量为5％；所述膦配体相对Ar–COOH的摩尔添加量为15％；所述酸酐添加剂相对Ar–COOH的摩尔添加量为150％。
8.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：Ar–COOH与三甲基环三氧硼烷的摩尔比为1:1～1:2。
9.根据权利要求1所述制备甲基芳烃或甲基杂芳烃的方法，其特征在于：所述Ar–COOH选自如下结构：
Figure RE-FDA0003491369810000021
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