CN110372544B - 一种铁催化的联芳烃及其衍生物的合成方法 - Google Patents

一种铁催化的联芳烃及其衍生物的合成方法 Download PDF

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CN110372544B
CN110372544B CN201810325423.9A CN201810325423A CN110372544B CN 110372544 B CN110372544 B CN 110372544B CN 201810325423 A CN201810325423 A CN 201810325423A CN 110372544 B CN110372544 B CN 110372544B
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段新方
张锐
赵岩
刘昆明
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Abstract

本发明涉及一种铁催化的联芳烃及其衍生物的合成方法，所述合成方法是在由铁盐及配体与钛酸酯、酚或酚盐组成的催化体系协同催化下，卤代芳烃或类卤物与芳基格氏试剂在溶剂中混合加热偶联而获得联芳烃及其衍生物。本发明的优点在于：(1)无需采用价格高的钯或毒性大的镍为催化金属，同时也无需使用锌试剂、锡试剂、硼试剂、铜试剂、硅试剂等，仅需使用低毒、富产且价廉的铁盐和钛酸酯，因而成本低且环境友好；(2)适用范围广，收率高，化学选择性高；(3)操作简便，条件温和，易于放大，适合工业化生产。

Description

一种铁催化的联芳烃及其衍生物的合成方法
技术领域
本发明涉及有机化合物制备以及催化合成领域，具体涉及一种铁催化的联芳烃化合物的合成方法。
背景技术
联芳烃化合物在药物、天然产物、功能材料、农药等领域中有着极其广泛的应用。例如下列结构式所示：
Figure BDA0001626423480000011
Losartan为一类常用的临床降压药物；Nantenine是一种重要的阿朴啡类天然产物；而NCB 807则是一种重要的液晶材料。
正是因为联芳烃结构单元的重要性，研究者在这类化合物的合成方面进行了不懈的努力，而上世纪七十年代兴起的过渡金属偶联反应目前已成为合成此类化合物的主要合成手段[Metal-Catalyzed Cross-Coupling Reactions,2nd ed.；de Meijere,A.,Diederich,F.,Eds.；Wiley-VCH:Weinheim,2004]。如反应式(1)所示，通过偶联反应，芳族卤代物或类卤物在钯或镍催化剂的作用下，与芳族金属试剂反应，即可获得联芳烃化合物。
Figure BDA0001626423480000012
尽管上述偶联反应已成为有机合成中重要的工具，却存在着明显的不足。首先，当前主要使用的催化金属是Pd或Ni，其中Pd为贵金属，价格昂贵，加之催化剂绝大多数为均相催化剂，很难回收利用，这已成为限制Pd催化反应工业化的重要瓶颈；而Ni虽然价格低，但毒性大，使用后Ni残留带来的毒性问题也严重限制了Ni催化反应在药物大规模制备中的使用。其次，在这类偶联中，芳基金属试剂一般使用硼试剂、锌试剂、锡试剂等，很难直接使用易得、廉价的格氏试剂，这是因为格氏试剂较活泼，比较敏感的官能团如酯基、酰胺基、氰基、酮基等容易在反应中被破坏[Johansson Seechurn,C.C.C.；Kitching,M.O.；Colacot,T.J.；Snieckus,V.Angew.Chem.,Int.Ed.2012,51,5062]；而硼试剂、锌试剂、锡试剂、铜试剂等往往需要由格氏试剂制备如反应式(2)所示，这不但使这些偶联反应在原子收率及反应步骤上都不经济，而且还由于使用锌、锡、铜等盐而带来了大量有毒废料，造成了严重的环境问题。
发明内容
本发明的目的在于，提供一种铁催化的联芳烃及其衍生物的合成方法，该合成方法采用毒性小、价格低的铁元素和钛元素协同催化，建立一种适用范围广，选择性高，成本低且环境友好的新合成方法。
为达到上述目的，本发明采用了如下的技术方案：
一种铁催化的联芳烃及其衍生物的合成方法，所述合成方法是在由铁盐及配体与钛酸酯、酚或酚盐组成的催化体系协同催化下，卤代芳烃或类卤物与芳基格氏试剂在溶剂中混合加热偶联而获得联芳烃及其衍生物。
本发明所述的方法的反应机理如下式所示：
Figure BDA0001626423480000021
优选地，所述卤代芳烃包括芳烃氯代物、芳烃溴代物、芳烃碘代物、一取代的卤代芳烃、二取代的卤代芳烃或多取代的卤代芳烃；
其中，一取代的卤代芳烃、二取代的卤代芳烃或多取代的卤代芳烃的取代基为烷基、烷氧基、烯基、苯基、酮基、酯基、氰基、酰胺基、酚羟基、羧基的一种或多种。
优选地，所述卤代芳烃包括杂环芳烃的氯代物、杂环芳烃的溴代物、杂环芳烃的碘代物、一取代的卤代杂环芳烃、二取代的卤代杂环芳烃或多取代的卤代杂环芳烃；
其中，杂环芳烃或卤代杂环芳烃中的杂环包括吡啶、喹啉、异喹啉、噻吩、呋喃、吡咯、噻唑、苯并呋喃、苯并噻吩和吲哚中的一种或多种；
一取代、二取代或多取代的取代基为烷基、烷氧基、烯基、苯基、酮基、酯基、氰基、酰胺基、酚羟基、羧基的一种或多种。
优选地，所述的类卤物为芳烃酚类化合物的磺酸酯、芳烃酚类化合物的碳酸酯、杂环芳烃酚类化合物的磺酸酯或杂环芳烃酚类化合物的碳酸酯；其中，磺酸酯包括三氟甲磺酸酯、苯磺酸酯、对甲苯磺酸酯或N,N-二甲基氨基磺酸酯；碳酸酯包括N,N-二甲基氨基碳酸酯。
所述的磺酸酯、碳酸酯等类卤物可由相应的酚类化合物按以下示例所示，通过文献方法制备[Kubota,Y.；Nakada,S.；Sugi,Y.Synlett 1988,183]:
Figure BDA0001626423480000031
优选地，所述芳基格氏试剂包括芳烃格氏试剂、杂环芳烃格氏试剂、一取代的芳烃格氏试剂、二取代的芳烃格氏试剂、多取代的芳烃格氏试剂、一取代的杂环芳烃格氏试剂、二取代的杂环芳烃格氏试剂或多取代的杂环芳烃格氏试剂；
其中，一取代、二取代或多取代的取代基为烷基、烷氧基、烯基、苯基、酮基、酯基、氰基、酰胺基的一种或多种。
所述芳基格氏试剂可用三种方法制备，其中普通格氏试剂(不含酮基、酯基、氰基、酰胺基等官能团)可由氯代物或溴代物与镁屑在无水四氢呋喃中按标准方法制备。含官能团的格氏试剂可依照文献方法[Piller,F.M.；Appukkuttan,P.；Gavryushin,A.；Helm,M.；Knochel,P.Angew.Chem.,Int.Ed.2008,47,6802；Krasovskiy,A.；Knochel,P.Angew.Chem.,Int.Ed.2004,43,3333]通过下面两个示例所示的方法制备：
Figure BDA0001626423480000041
优选地，所述铁盐包括溴化铁、氯化铁、氟化铁、溴化亚铁、氯化亚铁、氟化亚铁、醋酸亚铁、乙酰丙酮铁和乙酰丙酮亚铁的任一种或多种，进一步优选地，所述铁盐为氯化铁、氯化亚铁和乙酰丙酮铁中的任一种或多种。
优选地，所述的配体包括四甲基乙二胺、1,2-四甲基环己二胺、三烃基膦、氮杂卡宾(NHC)，三烃基膦包括三甲膦、三丁基膦、三环己膦、三叔丁基膦、1,3-二(二乙基膦)丙烷、1,3-二(二环己基膦)丙烷、三苯基膦、1,3-二(二苯基膦)丙烷中的任一种或多种；氮杂卡宾(NHC)包括N,N′-二烃基咪唑
Figure BDA0001626423480000042
盐或二氢咪唑
Figure BDA0001626423480000043
盐，其中烃基包括异丙基、环己基、叔丁基、2,4,6-三甲苯基、2,6-二异丙基苯基的一种或两种，优选1,2-四甲基环己二胺、三丁基膦、N,N′-二(2,4,6-三甲苯基)咪唑
Figure BDA0001626423480000044
盐或二氢咪唑
Figure BDA0001626423480000045
盐以及N,N′-二(2,6-二异丙基苯基)咪唑
Figure BDA0001626423480000046
盐或二氢咪唑
Figure BDA0001626423480000047
盐。
优选地，所述钛酸酯具有Ti(OR)4或Ti(OR)2(OR′)2的通式，其中ROH包括C1至C6的各种饱和醇；R′OH为二醇，包括乙二醇、1,3-丙二醇、频哪醇、二缩乙二醇、二乙醇胺或N-甲基二乙醇胺。
优选地，所述酚或酚盐中的酚指的是苯酚、邻苯二酚、间苯二酚、对苯二酚、一取代的苯酚、二取代的苯酚、一取代的邻苯二酚、一取代的间苯二酚、一取代的对苯二酚、二取代的邻苯二酚、二取代的间苯二酚、二取代的对苯二酚；其中，一取代、二取代或多取代的取代基为烷基、烷氧基、苯基、酮基、酯基、酰胺基的一种或多种；
酚盐为酚的锂盐、钠盐、镁盐、钾盐、钙盐或铯盐。
优选地，所述溶剂为溶剂为四氢呋喃或四氢呋喃与甲苯、二甲苯、氯苯中一种或几种的混合溶剂。
优选地，加热温度为35～110℃。
优选地，所述铁盐及配体的使用量为：5mol％～30mol％。
优选地，所述钛酸酯及酚盐的使用量为：20mol％～100mol％。
本发明通过对铁催化性能和反应机制的突破、对催化体系和反应条件的改变，从而得到了一种实施性强、成本低且环境友好型的制备工艺路线。在目前常用的方法中，最为常用的方法多采用贵金属钯或有毒金属镍做催化元素，而采用铁催化的联芳型偶联，不但报道很少，而且存在明显的局限，如很难抑制自身偶联、无法耐受敏感基团和仅适用于氯代物等。本发明经过不断的探索和反复的总结，提出了新的机制和措施，即利用铁与钛的协同催化，从而突破了目前铁催化反应的限制，使铁催化反应变得温和、官能团耐受性强、适用范围广，从而建立了一种高效，成本低和环保的制备方法。
本发明建立一种成本低且环境友好的制备联芳烃的偶联反应。选用低毒、廉价的催化金属，其中铁元素是非常理想的选择，因为铁在地壳中含量高，且毒性低，是生命体所必需的元素(铁元素是血红蛋白的中心金属元素)。再者，为了避免产生大量有毒废料(如锌盐、锡盐、铜盐等)，应直接使用芳族格氏试剂或者使用价格低、毒性小的金属试剂替代锌试剂、锡试剂、铜试剂。钛元素为地壳中含量很高的富产元素，同时毒性很小(人体也可耐受，不少人造关节器件可为钛钢)。值得注意的是，大多数钛试剂水解后可转化为二氧化钛，可制备成钛白粉而被再利用。为此，使用钛试剂替代锌试剂、锡试剂或铜试剂显然可以避免由此产生的大量有毒废料。
本发明的偶联反应，即在毒性小、地壳含量高、价格低的铁元素和钛元素协同作用下，芳族格氏试剂与芳族卤代物或类卤物进行反应，获得偶联产物，为联芳烃类化合物的合成提高了一种成本低且环境友好的合成方法。
本发明提供的联芳烃的新合成方法，是以常见的、廉价的且低毒的铁盐和钛酸酯为共催化金属，与酚盐及适当配体构成催化体系，催化卤代芳烃或类卤物与芳基格氏试剂反应，一步合成出目标产物，其具有如下的优点：
1)不需要价格高的贵金属Pd或毒性大的镍做催化元素。
2)不需要使用锌试剂、锡试剂、硼试剂、铜试剂、硅试剂；从而避免了大量有毒废料的排放。
3)催化金属铁和钛均为廉价、低毒且环境友好型过渡元素。
4)适用范围广，官能团耐受性强，收率高，成本低。
5)操作简单，且条件温和，易于放大，特别适合工业化生产。
具体实施方式
本说明书中公开得任一特征，除非特别叙述，均可被其他等效或具有类似目的的替代特征加以替换。除非特别叙述，每个特征只是一系列等效或者类似特征中的一个例子而已。所述仅仅是为了帮助理解本发明，不应该视为对本发明的具体限制。
以下结合实施例对本发明进行进一步详细的描述，但需要指出的是本发明不仅仅局限于以下实施例。
实施例1、4-(4′-氟苯基)-N,N-二甲基苯磺酰胺的合成
Figure BDA0001626423480000061
在氩气保护下，于25mL干燥的三口瓶中加入Ti(OEt)4(91.2mg,0.4mmol)和苯酚(37.7mg，0.4mmol)和3mL四氢呋喃，室温下滴加3.2mL对溴氟苯的格氏试剂(1M in THF,3.2mmol)，滴毕后继续搅拌30min，制得的溶液备用。
在氩气保护下，N,N-二甲基-4-溴苯磺酰胺(528mg,2mmol)和2mL THF，搅拌使其溶解，随后加入FeCl3(32.5mg,0.2mmol)，TMEDA(92.8mg,0.8mmol)，搅拌10分钟，缓慢滴入上述制备好的金属试剂，再加入3mL甲苯，搅拌回流6至8小时至反应结束(反应进展可用TLC跟踪)。加入30mL蒸馏水终止反应，过滤除去固体，固体用二氯甲烷反复打浆洗涤，滤液用CH2Cl2萃取，合并二氯甲烷提取液，无水Na2SO4干燥，旋蒸除去溶剂得粗品，经柱层析分离得纯产物486mg，产率为87％。
产物呈白色固体，m.p.132-134℃；IR(cm-1,KBr):1600,1487,1338,1162,833,701；1H NMR(CDCl3,400MHz)δ(ppm)7.83(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.56-7.60(m,2H),7.18(t,J＝8.6Hz,2H),2.75(s,6H)；13C NMR(CDCl3,100MHz)δ(ppm)164.4,161.9,144.6,135.5(d),129.0(d),128.4,127.5,116.1(d),38.0；Anal.Calcd for C14H14FNO2S:C,60.20；H,5.05；N,5.01；Found:C,60.54；H,4.78；N,4.89；MS(ESI):[M+H]+(m/z 280)。
实施例2、4-(4′-氟苯基)-N,N-二甲基苯磺酰胺的合成
Figure BDA0001626423480000071
在氩气保护下，于25mL干燥的三口瓶中加入Ti(OEt)4(91.2mg,0.4mmol)和3mL四氢呋喃，室温下滴加2.8mL对溴氟苯的格氏试剂(1M in THF,3.2mmol)，滴毕后继续搅拌30min，制得的溶液备用。
在氩气保护下，N,N-二甲基-4-溴苯磺酰胺(528mg,2mmol)和2mL THF，搅拌使其溶解，随后加入FeCl3(32.5mg,0.2mmol)，TMEDA(92.8mg,0.8mmol)和苯酚钠(由苯酚与乙醇钠制备，46.4mg,0.4mmol),搅拌30分钟，缓慢滴入上述制备好的金属试剂。其他操作与实施例完全相同。经柱层析分离得纯产物475mg，产率为85％。
实施例3、4-(4′-甲基苯基)-N,N-二甲基苯胺的合成
Figure BDA0001626423480000072
在氩气保护下，于25mL干燥的三口瓶中依次加入Ti(OEt)4(91.2mg,0.4mmol)，苯酚(37.7mg，0.4mmol)和3mL无水THF，室温下滴加3.6mL N,N-二甲基4-溴苯胺的格氏试剂(1M in THF,3.2mmol)，滴毕继续搅拌30min，制得钛试剂。
在氩气保护下，于25mL干燥的三口瓶依次加入对甲苯酚的对甲基苯磺酸酯(334mg,2mmol)和2mL无水THF，搅拌使其溶解，再加入FeCl3(32.5mg,0.2mmol)，TMEDA(92.8mg,0.8mmol)和SIPr·HCl(85mg,0.2mmol)，搅拌30分钟，缓慢滴加上述已制备钛试剂，再加入2mL无水甲苯，搅拌回流8小时，加入30mL蒸馏水终止反应，过滤除去固体，固体用二氯甲烷反复打浆洗涤，滤液用CH2Cl2萃取，合并二氯甲烷提取液，无水Na2SO4干燥，旋蒸除去溶剂得粗品，经柱层析分离得纯产物270mg，产率为64％。
产物为浅色低熔点固体，IR(cm-1,KBr):2877,1612,1500,1363,1276,1251,1181,1043,810；1H NMR(CDCl3,400MHz)δ(ppm)7.74-7.72(m,1H),7.53-7.50(m,4H),7.29-7.25(m,1H),6.82(d,J＝8.8Hz,2H),3.02(s,6H),2.37(s,3H)；13C NMR(CDCl3,100MHz)δ(ppm)150.4,142.0,129.4,129.1,127.8,127.4,116.8,112.7,40.4。
实施例4、4-(4′-甲氧基苯基)苯甲酸乙酯的合成
Figure BDA0001626423480000081
氩气保护下，向25mL干燥的三口瓶中加入4-碘苯甲酸乙酯(883.1mg，3.2mmol)和3mL无水THF，冷却至–40℃。该温度下，向反应瓶中缓慢滴加i-PrMgCl·LiCl(3.2mmol,1.0Min THF)。滴毕，在该温度下保温搅拌反应小时。
在氩气保护下，在25mL干燥的三口瓶中依次加入Ti(OEt)4(91.2mg,0.4mmol)苯酚(37.7mg，0.4mmol)和3mL无水THF。将所得溶液搅拌下冷却至–40℃，缓慢滴加上述所获得的格氏试剂，滴毕自然升温至室温，继续搅拌30分钟。控温在20～25℃，减压蒸出THF及交换产生的碘代异丙烷，至体系呈粘稠状，后再加入6mL无水THF，室温搅拌均匀备用。
在氩气保护下，在另外一个25mL干燥的三口瓶中依次加入对溴苯甲醚(371.9mg,2mmol)和3mL THF，搅拌溶解，随后加入FeCl3(32.5mg,0.2mmol)，TMEDA(92.8mg,0.8mmol)，搅拌十分钟后，缓慢滴加上述已制备好的钛试剂，加入3mL甲苯，搅拌下缓慢加热至回流，反应约8小时至反应结束。加入20mL蒸馏水终止反应，过滤除去固体，固体用二氯甲烷反复打浆洗涤，滤液用二氯甲烷萃取，合并二氯甲烷提取液，无水Na2SO4干燥，旋蒸除去溶剂得粗品，经柱层析分离得纯产物384mg，收率为75％。
产物为白色固体；m.p.85℃(lit.,81-82℃)；IR(cm-1,KBr):2398,2311,1714,1645；1H NMR(CDCl3,400MHz)δ(ppm)8.04(d,J＝8.04Hz,2H),7.55(dd,J＝16.5Hz,J＝7.6Hz,4H),6,95(d,J＝8.28Hz,2H),4.35(q,J＝4.4Hz,2H),3.82(s,3H),1.37(t,J＝4.4Hz,3H)；13CNMR(CDCl3,125MHz)δ(ppm)166.6,159.8,145.1,132.5,130.1,128.6,128.4,126.4,114.4,60.9,55.4,14.4。
按照以上实施例，一系列类似的联芳烃化合物以高产率方便地合成，一些典型实例结果总结如下表1。
表1联芳烃及其衍生物的合成结果
Figure BDA0001626423480000091
Figure BDA0001626423480000101
Figure BDA0001626423480000111
最后所应说明的是，以上实施例仅用以说明本发明的技术方案而非限制。尽管参照实施例对本发明进行了详细说明，本领域的普通技术人员应该理解，对本发明的技术方案进行修改或者等同替换，都不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。

Claims (5)

1.一种铁催化的联芳烃类化合物的合成方法，所述合成方法是在由铁盐及配体与钛酸酯、酚或酚盐组成的催化体系协同催化下，芳族卤代物或类卤物与芳族格氏试剂在溶剂中混合加热偶联而获得联芳烃类化合物；
所述铁盐为溴化铁、氯化铁、氟化铁、溴化亚铁、氯化亚铁、氟化亚铁、醋酸亚铁、乙酰丙酮铁和乙酰丙酮亚铁的任一种或多种；
所述配体为四甲基乙二胺、1,2-四甲基环己二胺、三烃基膦或氮杂卡宾；
所述三烃基膦为三甲膦、三丁基膦、三环己膦、三叔丁基膦、1,3-二(二乙基膦)丙烷、1,3-二(二环己基膦)丙烷、三苯基膦、1,3-二(二苯基膦)丙烷中的任一种或多种；
所述氮杂卡宾为N,N′-二烃基咪唑
Figure FDA0002473196040000011
盐或二氢咪唑
Figure FDA0002473196040000012
盐，其中烃基为异丙基、环己基、叔丁基、2,4,6-三甲苯基、2,6-二异丙基苯基的一种或两种；
所述钛酸酯具有Ti(OR)4或Ti(OR)2(OR′)2的通式，其中RO-为C1至C6的饱和醇基；R′O-为二醇基，二醇基中的二醇为乙二醇、1,3-丙二醇、频哪醇、二缩乙二醇、二乙醇胺或N-甲基二乙醇胺；
所述酚或酚盐中的酚指的是苯酚、邻苯二酚、间苯二酚、对苯二酚、一取代的苯酚、二取代的苯酚、一取代的邻苯二酚、一取代的间苯二酚、一取代的对苯二酚、二取代的邻苯二酚、二取代的间苯二酚或二取代的对苯二酚；其中，一取代、二取代的取代基为烷基、烷氧基、苯基、酮基、酯基、酰胺基的一种或多种；
酚盐为酚的锂盐、钠盐、镁盐、钾盐、钙盐或铯盐；
所述的类卤物为芳烃酚类化合物的磺酸酯、芳烃酚类化合物的碳酸酯、杂环芳烃酚类化合物的磺酸酯或杂环芳烃酚类化合物的碳酸酯；其中，磺酸酯为三氟甲磺酸酯、苯磺酸酯、对甲苯磺酸酯或N,N-二甲基氨基磺酸酯；碳酸酯为N,N-二甲基氨基碳酸酯。
2.根据权利要求1所述的铁催化的联芳烃类化合物的合成方法，其特征在于，所述芳族卤代物为芳烃氯代物、芳烃溴代物、芳烃碘代物、一取代的卤代芳烃、二取代的卤代芳烃或多取代的卤代芳烃；
其中，一取代的卤代芳烃、二取代的卤代芳烃或多取代的卤代芳烃的取代基为烷基、烷氧基、烯基、苯基、酮基、酯基、氰基、酰胺基、酚羟基、羧基的一种或多种。
3.根据权利要求1所述的铁催化的联芳烃类化合物的合成方法，其特征在于，所述芳族卤代物为杂环芳烃的氯代物、杂环芳烃的溴代物、杂环芳烃的碘代物、一取代的卤代杂环芳烃、二取代的卤代杂环芳烃或多取代的卤代杂环芳烃；
其中，杂环芳烃或卤代杂环芳烃中的杂环为吡啶、喹啉、异喹啉、噻吩、呋喃、吡咯、噻唑、苯并呋喃、苯并噻吩和吲哚中的一种或多种；
一取代、二取代或多取代的取代基为烷基、烷氧基、烯基、苯基、酮基、酯基、氰基、酰胺基、酚羟基、羧基的一种或多种。
4.根据权利要求1-3任一项所述的铁催化的联芳烃类化合物的合成方法，其特征在于，所述芳族格氏试剂为芳烃格氏试剂、杂环芳烃格氏试剂、一取代的芳烃格氏试剂、二取代的芳烃格氏试剂、多取代的芳烃格氏试剂、一取代的杂环芳烃格氏试剂、二取代的杂环芳烃格氏试剂或多取代的杂环芳烃格氏试剂；
其中，一取代、二取代或多取代的取代基为烷基、烷氧基、烯基、苯基、酮基、酯基、氰基、酰胺基的一种或多种。
5.根据权利要求1所述的铁催化的联芳烃类化合物的合成方法，其特征在于，溶剂为四氢呋喃或四氢呋喃与甲苯、二甲苯、氯苯中一种或几种的混合溶剂；加热温度为35～110℃；所述铁盐及配体的使用量为：5mol％～30mol％；所述钛酸酯及酚盐的使用量为：20mol％～100mol％。
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