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CN107298650B - 杂环羧酸酰胺配体及其在铜催化芳基卤代物偶联反应中的用途 - Google Patents

杂环羧酸酰胺配体及其在铜催化芳基卤代物偶联反应中的用途 Download PDF

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CN107298650B
CN107298650B CN201710247202.XA CN201710247202A CN107298650B CN 107298650 B CN107298650 B CN 107298650B CN 201710247202 A CN201710247202 A CN 201710247202A CN 107298650 B CN107298650 B CN 107298650B
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CN107298650A (zh
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马大为
樊梦阳
伍海波
周伟
殷俊力
蒋西
翟运通
牛松涛
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Zhejiang Zhongke Chuangyue Medicine Co ltd
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Abstract

本发明提供了杂环羧酸酰胺配体及其在铜催化的偶联反应中的应用，具体地，本发明提供了一种如下式I所示的化合物的用途；其中，各基团的定义如说明书中所述。所述的式I化合物可以用作为铜催化芳基卤代物偶联反应中的配体，用于催化形成C‑N、C‑O、C‑S键等芳基卤代物的偶联反应。

Description

杂环羧酸酰胺配体及其在铜催化芳基卤代物偶联反应中的 用途
技术领域
本发明涉及有机合成领域，具体地，本发明提供了一种杂环羧酸酰胺配体促进的铜催化芳基卤代物偶联反应，特别是偶联生成C-N、C-O、C-S键的反应。
背景技术
过渡金属催化的芳基卤代物与合适的亲核试剂如有机胺、活泼亚甲基化合物、炔、苯酚、醇、苯硫酚、亚磺酸钠、硫化钠、磷酸酯等发生相应的偶联反应是非常有效的生成C-N、C-C、C-O、C-S、C-P键的方法。通常，芳基碘、芳基溴的反应活性较高，在钯、铜、镍等过渡金属的催化下能较好的实现相应的偶联反应；和溴(碘)代芳烃相比，氯代芳烃便宜易得，更具有应用前景；然而C-Cl键键能高(Grushin，V.V.；Alper，H.Chem.Rev.1994，94，1047.)，过渡金属与之氧化加成就很难发生，反应不如溴代物和碘代物高效。钯和镍催化的芳基氯代物的C-N偶联反应已有相关报道，采用大位阻的磷配体促进反应是一个有效的手段，2005年Hartwig小组使用具有二茂铁结构的大位阻膦配体，顺利完成了芳环和芳杂环氯代物与一级胺的偶联反应，该体系中催化剂和配体的当量甚至可以降低到十万分之一的摩尔当量，对于个别芳杂环底物在室温条件下就可以完成此类反应，充分显示了该催化体系的高效；此外，该反应对于苯环上的取代基团也有着很好的兼容性(Shen，Q.；Shekhar，S.；Stambuli，J.P.；Hartwig，J.F.Angew.Chem.Int.Ed.2005，44，1371.)。
Figure BDA0001270570570000011
FG＝-OH，-CH2OH，-COOH，-CONH2，-NHCOCH3
2011年，Buchwald小组发现利用不同的膦配体，可以使氯代芳烃分别和一级胺、二级胺发生偶联，该体系对于底物具有很广的兼容性，除了一股脂肪胺，带有杂环的芳香胺也能顺利发生偶联(Maiti，D.；Fors，B.P.；Henderson，J.L.；Nakamura，Y.；Buchwald，S.L.Chem.Sci.2011，2，57.)。
Figure BDA0001270570570000012
虽然金属钯和镍在催化的氯代芳烃的氨基化反应中有着很高的效率，但是在大规模应用上存在一些问题：1、体系中需要加入大位阻、结构较复杂的膦配体或氮杂卡宾配体来促进反应；2、钯催化剂的价格昂贵，且零价镍所需的反应操作相当苛刻，这在一定程度上限制了其应用。相比而言，铜催化剂廉价、稳定、易得，所使用的配体结构简单，可以明显避免这些缺陷。然而目前所报道的铜催化的偶联反应底物大多局限在碘代物和溴代物。
2007年，Pellón小组利用2-氯苯甲酸邻位羧基的促进作用，在超声作用下，实现了和脂肪胺的偶联反应，一级胺和二级胺都能以较好的收率得到偶联产物，然而该方法只对邻位羧基取代底物有效，不具普遍性(Docampo，M.L.；Pellón，R.F.；Estevez-Braun，A.；Ravelo，A.G.Eur.J.Org.Chem.2007，4111.)。这个反应本质上还是一个亲核取代反应而不是偶联反应，且反应温度非常高。
Figure BDA0001270570570000021
另外一篇关于氯代芳烃的Ullmann偶联反应的报道来自Taillefer小组，他们利用2，2，6，6-四甲基-3，5-庚二酮为配体，实现了氯苯和酚类化合物的C-O偶联，该体系的主要缺点是需要在反应中加入高达0.8当量的配体，因而降低了反应的经济性(Xia，N.；Taillefer，M.Chem.Eur.J.2008，14，6037.)。
Figure BDA0001270570570000022
R＝Me，OMe，COCH3，NO2，CN；R′＝Me，OMe，F，tBu
2012年，马大为课题组将草酸2，6-二甲基苯基单酰胺羧酸作为配体用于铜催化的芳基碘代物、溴代物与有机胺的C-N偶联反应(Org.Lett.2012，14，3056-3059)。最近，他们将在此基础上设计的草酸双酰胺类配体成功用于芳基氯代物的偶联反应，多类亲核试剂如伯胺、环状仲胺、氨水、苯酚等都能用于该反应，并以较好的收率得到偶联产物(J.Am.Chem.Soc.2015，137，11942-11945；Org.Lett.2015，77，5934-5937.)。
综上所述，铜催化的芳基氯代物的偶联反应具有非常重要的应用前景，合适的配体是该类反应能够发生的关键。本领域仍然缺乏一种制备简单、适合工业化应用，能够使反应高效进行的铜催化的芳基氯代物偶联反应的催化体系。
发明内容
本发明的目的是提供一种能够用于铜催化的芳基卤代物(特别是芳基氯代物)偶联反应的催化体系。
本发明的第一方面，提供了一种如下式I所示的化合物的用途：
Figure BDA0001270570570000023
其中，R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R2选自下组：取代或未取代的Cl-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R3选自下组：H、取代或未取代的C1-C6烷基；
或者，R2和R3以及与其相邻的N原子一起形成3-至20-元的饱和或不饱和的环(如取代或未取代的吡咯、吲哚、唑类、苯并唑以及芳杂环)；
其特征在于，作为配体用于铜催化的芳基卤代物偶联反应；其中，所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物，或其组合。
在另一优选例中，所述的R1选自下组：取代或未取代的含有1-3个杂原子的饱和或不饱和的3-15元(优选为5-9元)杂环基，所述杂原子选自N、O或S，所述杂环基为饱和或不饱和的。
在另一优选例中，所述的R1选自下组：取代或未取代的吲哚基，取代或未取代的吡咯基、取代或未取代的苯并咪唑基、取代或未取代的咪唑基、取代或未取代的噻唑基、取代或未取代的苯并噻唑基、取代或未取代的含有1或2个N原子的饱和或不饱和的6元杂环基(如吡啶基、吡嗪基、嘧啶基)、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的苄基、取代或未取代的喹啉基、取代或未取代的
Figure BDA0001270570570000031
取代或未取代的金刚烷基、取代或未取代的C1-C6烷基、取代或未取代的
Figure BDA0001270570570000032
在另一优选例中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、甲基、三氟甲基、乙基、异丙基、叔丁基、二甲胺基、甲氧基、叔丁氧基、-Ac、CH3NHC(O)-、苯基、苯氧基、-COOH、酯基、硝基、氰基、羟基、甲硫基。
在另一优选例中，所述的芳基卤代物为芳基氯代物。
在另一优选例中，所述化合物的结构如下式II所示：
Figure BDA0001270570570000033
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R4选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R4取代基的数量为1-4个，取代位置可以为邻位或间位，各R4可以相同或不同，当R4取代基的数量≥2时，相邻的R4可以连接成环(优选为3-20元的环，可以为饱和、不饱和或芳香性的碳环或杂环)。
在另一优选例中，所述化合物的结构如下式III所示：
Figure BDA0001270570570000041
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R5选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R5取代基的数量为1-3个，取代位置可以为邻位或间位，各R5可以相同或不同，当R5取代基的数量≥2时，相邻的R5可以连接成环(优选为3-20元的环，可以为饱和、不饱和或芳香性的碳环或杂环)。
在另一优选例中，所述化合物的结构如下式IV所示：
Figure BDA0001270570570000042
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R6选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R6取代基的数量为1-4个，取代位置可以为邻位或间位，各R6可以相同或不同，当R6取代基的数量≥2时，相邻的R6可以连接成环(优选为3-20元的环，可以为饱和、不饱和或芳香性的碳环或杂环)。
在另一优选例中，所述化合物的结构如下式Va、Vb、或Vc所示：
Figure BDA0001270570570000051
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R7选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R7取代基的数量为1或2个，各R7可以相同或不同，当R7取代基的数量为2时，相邻的R7可以连接成环(优选为6-20元芳香环，如苯环)。
在另一优选例中，所述化合物的结构如下式VIa、VIb、或VIc所示：
Figure BDA0001270570570000052
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R8选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R8取代基的数量为1-3个，各R8可以相同或不同，当R8取代基的数量≥2时，相邻的R8可以连接成环(优选为6-20元饱和或不饱和环)。
在另一优选例中，所述化合物的结构如下式VII所示：
Figure BDA0001270570570000061
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R9选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
A为3-至12-元饱和或不饱和的杂环基，其中，所述的杂环含有1-4个各自独立地选自N、O、S的杂原子。
在另一优选例中，A为含有一个N原子的5元杂环。
在另一优选例中，A为呋喃、噻吩或吡咯。
在另一优选例中，R9取代基的数量为1-3个，各R9可以相同或不同，当R9取代基的数量≥2时，相邻的两个R9可以连接成环(优选为6-20元饱和或不饱和环，如苯环)。
在另一优选例中，所述化合物选自下组：
Figure BDA0001270570570000062
Figure BDA0001270570570000071
Figure BDA0001270570570000081
Figure BDA0001270570570000091
Figure BDA0001270570570000101
本发明的第二方面，提供了一种芳基卤代物偶联反应方法，所述的方法包括：用铜作为催化剂，用如下式I所示的化合物作为配体，进行所述的偶联反应：
Figure BDA0001270570570000111
其中，R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R3选自下组：H、取代或未取代的C1-C6烷基；
或者，R2和R3以及与其相邻的N原子一起形成3-至20-元的饱和或不饱和的环(如取代或未取代的吡咯、吲哚、唑类、苯并唑以及芳杂环)；
其中，所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物，或其组合。
在另一优选例中，所述的铜催化剂选自下组：CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，或其组合；优选CuI。
在另一优选例中，所述的反应在碱存在下进行。
在另一优选例中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸氢钠、碳酸氢钾、碳酸钠、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠，或其组合；优选为磷酸钾、碳酸铯；最优选为磷酸钾。
在另一优选例中，在所述反应中，所述配体与反应物芳基卤代物的摩尔比为1～50∶100，优选为5～20∶100；所述配体与铜催化剂的摩尔比为1～5∶1，优选为1～2∶1。
在另一优选例中，所述的反应包括：
Figure BDA0001270570570000112
在惰性溶剂中，用
Figure BDA0001270570570000113
与偶联试剂反应，得到
Figure BDA0001270570570000114
化合物；
其中，X选自下组：N、O或S；
Y选自下组：Cl、Br、I；
Figure BDA0001270570570000115
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、未取代或被1个或2个C1-C6的烷基或C2-C10的酰基(烷基-CO-)取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、3-至20-元的杂芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；其中，所述芳基上的两个相邻的碳原子上的两个氢原子可以被-(CH2)n-取代(n为1、2、3、4、5或6)；
所述的偶联试剂选自下组：氨水、氨气、铵盐(优选为氯化铵、碳酸铵、硫酸铵、磷酸氢铵，或其组合)/氢氧化物溶液(优选为氢氧化钾溶液)、
Figure BDA0001270570570000121
ReC(O)NHRd、RcSO2M(优选地，M为钠、钾)、叠氮化钠、NHRcRd、RcOH、RcSH、氢氧化物及能够水解出氢氧根的盐；
Rc、Rd、Re各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C5烷基-C3-C20的环烷基、取代或未取代的3-至20-元的杂环基，或取代或未取代的C1-C5烷基-3-至20-元的杂环基；
或Rc和Rd共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
或Re和Rd共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氰基、氧(即基团上同一个碳原子上的两个氢原子被＝O取代)、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基、C1-C6烷基-S-。
在另一优选例中，所述的惰性溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇，或其组合；优选为DMSO和/或DMF。
在另一优选例中，所述的反应温度在50-180℃，优选100-130℃。
在另一优选例中，所述的反应包括以下(1)、(2)、(3)或(4)：
(1)在惰性溶剂中，用
Figure BDA0001270570570000122
与NHRcRd反应，得到
Figure BDA0001270570570000123
Figure BDA0001270570570000124
其中，各基团的定义如上文中所述；
(2)在惰性溶剂中，用
Figure BDA0001270570570000125
与氨源反应，得到
Figure BDA0001270570570000126
Figure BDA0001270570570000131
其中，各基团的定义如上文中所述；
所述的氨源选自下组：氨气、氨水、氯化铵、碳酸铵、碳酸氢铵、硫酸铵、硝酸铵、磷酸铵、磷酸氢二铵、叠氮化钠，优选氨气、氨水、氯化铵和磷酸氢二铵。
(3)在惰性溶剂中，用
Figure BDA0001270570570000132
与RcOH反应，得到
Figure BDA0001270570570000133
Figure BDA0001270570570000134
其中，各基团的定义如上文中所述；
(4)在惰性溶剂中，用
Figure BDA0001270570570000135
与RcSO2M反应，得到
Figure BDA0001270570570000136
Figure BDA0001270570570000137
其中，各基团的定义如上文中所述。
(5)在惰性溶剂中，用
Figure BDA0001270570570000138
与RcSH反应，得到
Figure BDA0001270570570000139
Figure BDA00012705705700001310
其中，各基团的定义如上文中所述。
在另一优选例中，在反应(1)中，所述的配体优选：L-53或L-103。
在另一优选例中，在反应(1)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(1)中，所述的惰性溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO、DMF，最优选DMSO。
在另一优选例中，在反应(1)中，所述的反应温度在50-180℃，优选100-130℃。
在另一优选例中，在反应(2)中，所述的配体优选：L-13、L-15或L-31。
在另一优选例中，在反应(2)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(2)中，当所述的氨源为铵盐时，所述的反应在强碱存在下进行(优选为在KOH存在下进行)。
在另一优选例中，在反应(2)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO、DMF，最优选DMSO。
在另一优选例中，在反应(2)中，所述的反应温度在50-180℃，优选100-130℃。
在另一优选例中，在反应(3)中，所述的配体优选：L-13、L-15或L-35。
在另一优选例中，在反应(3)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(3)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO。
在另一优选例中，在反应(3)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(4)中，所述的配体优选为：L-92，和/或L-105。
在另一优选例中，在反应(4)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(4)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，或其组合；优选DMSO。
在另一优选例中，在反应(4)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(5)中，所述的配体优选：L-13，L-112，L-114。
在另一优选例中，在反应(5)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(5)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环、DME，或其组合；优选DME。
在另一优选例中，在反应(5)中，所述的反应温度为25-180℃，优选50-120℃。
本发明的第三方面，提供了一种芳基偶联反应的催化体系，所述的反应体系包括：铜催化剂、配体、碱、有机溶剂；
其中，所述的铜催化剂选自下组：CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，或其组合；优选为CuI；
所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸氢钠、碳酸氢钾、碳酸钠、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠，或其组合；优选为磷酸钾、碳酸铯；
所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、1，4-二氧六环、四氢呋喃、DME、甲苯，或其组合；优选为DMSO和/或DMF和/或DME；
所述的配体具有以下式(I)所示的结构：
Figure BDA0001270570570000141
其中，各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的催化体系用于进行芳基卤代物的偶联反应；所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物。
在另一优选例中，所述的催化体系用于进行芳基氯代物的偶联反应。
本发明的第四方面，提供了一种如下式(I)所示的化合物：
Figure BDA0001270570570000142
其中，R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R3选自下组：H、取代或未取代的C1-C6烷基；
或者，R2和R3以及与其相邻的N原子一起形成3-至20-元的饱和或不饱和的环(如取代或未取代的吡咯、吲哚、唑类、苯并唑以及芳杂环)。
在另一优选例中，所述的化合物中，R1、R2、R3中任一个分别为本申请中相应的具体化合物中所对应的基团。
在另一优选例中，所述化合物的结构如下式II所示：
Figure BDA0001270570570000151
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的Cl-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R4选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R4取代基的数量为1-4个，取代位置可以为邻位或间位，各R4可以相同或不同，当R4取代基的数量≥2时，相邻的R4可以连接成环。
在另一优选例中，所述化合物的结构如下式III所示：
Figure BDA0001270570570000152
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R5选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R5取代基的数量为1-3个，取代位置可以为邻位或间位，各R5可以相同或不同，当R5取代基的数量≥2时，相邻的R5可以连接成环。
在另一优选例中，所述化合物的结构如下式VI所示：
Figure BDA0001270570570000161
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R6选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R6取代基的数量为1-4个，取代位置可以为邻位或间位，各R6可以相同或不同，当R6取代基的数量≥2时，相邻的R6可以连接成环。
在另一优选例中，所述化合物的结构如下式Va、Vb、或Vc所示：
Figure BDA0001270570570000162
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R7选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R7取代基的数量为1或2个，各R7可以相同或不同，当R7取代基的数量为2时，相邻的R7可以连接成环(优选为6-20元芳香环，如苯环)。
在另一优选例中，所述化合物的结构如下式VIa、VIb、或VIc所示：
Figure BDA0001270570570000171
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R8选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R8取代基的数量为1-3个，各R8可以相同或不同，当R8取代基的数量≥2时，相邻的R8可以连接成环(优选为6-20元饱和或不饱和环)。
存另一优选例中，所述化合物的结构如下式VII所示：
Figure BDA0001270570570000172
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R9选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
A为3-至12-元饱和或不饱和的杂环基，其中，所述的杂环含有1-4个各自独立地选自N、O、S的杂原子。
在另一优选例中，A为含有一个N原子的5元杂环。
在另一优选例中，A为呋喃、噻吩或吡咯。
在另一优选例中，R9取代基的数量为1-3个，各R9可以相同或不同，当R9取代基的数量≥2时，相邻的两个R9可以连接成环(优选为6-20元饱和或不饱和环，如苯环)。
在另一优选例中，所述的式(I)化合物选自下组：
Figure BDA0001270570570000181
Figure BDA0001270570570000191
Figure BDA0001270570570000201
Figure BDA0001270570570000211
Figure BDA0001270570570000221
本发明的第五方面，提供了一种如本发明第四方面所述的化合物的制备方法，通过选自方法(i)或(ii)的方法进行：
方法(i)包括步骤：
Figure BDA0001270570570000222
在惰性溶剂中，用R2-NH-R3和
Figure BDA0001270570570000223
进行反应，得到式(I)化合物；
方法(ii)包括步骤：
Figure BDA0001270570570000231
在惰性溶剂中，用R2-NH-R3和
Figure BDA0001270570570000232
进行反应，得到式(I)化合物；
其中，各基团的定义如本发明第四方面中所述。
在另一优选例中，所述的方法(i)中，所述的惰性溶剂选自下组：四氢呋喃、二氯甲烷、DMF。
在另一优选例中，所述的方法(i)中，所述的反应在三乙胺存在下进行。
在另一优选例中，所述的方法(i)中，所述的反应在10℃～80℃(优选为室温，即10-40℃)下进行。
在另一优选例中，所述的方法(ii)中，所述的惰性溶剂选自下组：四氢呋喃、二氯甲烷、DMF。
在另一优选例中，所述的方法(ii)中，所述的反应在-5℃～80℃(优选为室温，即10-40℃)下进行。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，提供了一类适合用于铜催化芳基氯代物偶联反应的草酸(单、双)酰胺配体，通过该类配体与铜试剂、碱、溶剂组成的合适催化体系，可以用于芳基卤代物的铜催化偶联反应，特别是能够有效促进常规条件下难以发生的铜催化的芳基氯代物与多种亲核试剂的偶联，生成C-N、C-O、C-S键，合成众多有用的小分子化合物。该方法反应条件温和，适用范围广，具有很好的工业应用前景。
术语
如本文所用，术语“卤素”指氟、氯、溴、碘。
术语“卤代”指基团上的一个或多个氢原子被卤素所取代。
术语“烷基”指直链或支链烷基。当烷基前具有碳原子数限定(如C1-C6)时，指所述的烷基含有1-6个碳原子，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“环烷基”指具有饱和的或部分饱和的单元，二环或三环(并环、桥环或螺环)环系。所述的环烷基可以具有3-20个碳原子。当某个环烷基前具有碳原子数限定(如C3-C20)时，指所述的环烷基含有3-20个碳原子，例如环丙基、环丁基、环戊基、环庚基、或类似基团。所述的环烷基可以是单环、多环、螺环或桥环形式。
如本文所用，术语“烷氧基”指通过氧原子相连的烷基(例如，-O-烷基，其中烷基如上所述)，例如(但并不限于)甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。当烷氧基前具有碳原子数限定(如C1-C6)时，指所述的环烷基含有1-6个碳原子。
术语“芳基”指单环，二环或稠环的芳香族碳氢基团，所述的芳基可以是取代或未取代的。当一个芳基前具有碳原子数限定(如C6-C20)时，指所述的芳基含有6-20个碳原子。芳基的例子例如(但并不限于)：苯基、联苯基、萘基、或类似基团(其中的每个碳原子均可以被任意取代)。
术语“杂芳基”指单环，二环或稠环的芳香族基团，所述基团包括至少一个选自N、O或S的杂原子。所述的杂芳基可以是3-至20-元的，具有1-5个各自独立地选自N、O或S的杂原子的芳香环基。杂芳基的例子例如(但并不限于)：吡啶、嘧啶、吡咯、吲唑、吲哚、呋喃、苯并呋喃、噻吩，或类似基团。
术语“杂环基”指单环或稠环的饱和或部分饱和取代基，所述基团包括至少一个相同或不同的选自N、O或S的杂原子。所述的杂环基可以是3-至20-元的，具有1-5个各自独立地选自N、O或S的杂原子的杂环基。杂环基的例子例如(但并不限于)：氮杂环基、氧杂环基、硫杂环基、氮氧杂环基等。
术语“酯基”指具有“烷基-COO-”结构的基团，其中，烷基定义如上所述。
术语“酰基”指具有“烷基-CO-”结构的基团，其中，烷基定义如上所述。
术语“酰胺基”指具有“烷基NHC(O)-”或者“芳基NHC(O)-”结构的基团，其中，烷基、芳基定义如上所述。
配体
除非特别说明，本文中所提到的配体指用于铜催化的芳基氯代物偶联反应中的配体。
本发明中可用的配体具有如前文式(I)所示的结构，在本发明的一个优选实施方式中，配体具有以下的结构(各基团的定义同上文中所述)：
Figure BDA0001270570570000241
其中，R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R3选自下组：H、取代或未取代的C1-C6烷基；
或者，R2和R3以及与其相邻的N原子一起形成3-至20-元的饱和或不饱和的环(如取代或未取代的吡咯、吲哚、唑类、苯并唑以及芳杂环)。
在另一优选例中，所述的化合物中，R1、R2、R3中任一个分别为本申请中相应的具体化合物中所对应的基团。
在另一优选例中，所述配体的结构如下式II所示：
Figure BDA0001270570570000251
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R4选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R4取代基的数量为1-4个，取代位置可以为邻位或间位，各R4可以相同或不同，当R4取代基的数量≥2时，相邻的R4可以连接成环。
在另一优选例中，所述配体的结构如下式III所示：
Figure BDA0001270570570000252
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R5选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R5取代基的数量为1-3个，取代位置可以为邻位或间位，各R5可以相同或不同，当R5取代基的数量≥2时，相邻的R5可以连接成环。
在另一优选例中，所述配体的结构如下式VI所示：
Figure BDA0001270570570000261
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R6选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R6取代基的数量为1-4个，取代位置可以为邻位或间位，各R6可以相同或不同，当R6取代基的数量≥2时，相邻的R6可以连接成环。
在另一优选例中，所述配体的结构如下式Va、Vb、或Vc所示：
Figure BDA0001270570570000262
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R7选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R7取代基的数量为1或2个，各R7可以相同或不同，当R7取代基的数量为2时，相邻的R7可以连接成环(优选为6-20元芳香环，如苯环)。
在另一优选例中，所述化合物的结构如下式VIa、VIb、或VIc所示：
Figure BDA0001270570570000271
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R8选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，R8取代基的数量为1-3个，各R8可以相同或不同，当R8取代基的数量≥2时，相邻的R8可以连接成环(优选为6-20元饱和或不饱和环)。
在另一优选例中，所述配体的结构如下式VII所示：
Figure BDA0001270570570000272
其中，R2选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
R9选自下组：H、硝基、卤素、取代或未取代的C1-C6烷基、烷氧基(如C1-C6烷基氧基)、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
A为3-至12-元饱和或不饱和的杂环基，其中，所述的杂环含有1-4个各自独立地选自N、O、S的杂原子。
在另一优选例中，A为含有一个N原子的5元杂环。
在另一优选例中，A为呋喃、噻吩或吡咯。
在另一优选例中，R9取代基的数量为1-3个，各R9可以相同或不同，当R9取代基的数量≥2时，相邻的两个R9可以连接成环(优选为6-20元饱和或不饱和环，如苯环)。
各个上述的配体可以是通过市售途径获得，或按照本发明所提供的优选方法制备得到。
应理解，由于C-Br和C-I键的键能小于C-Cl键，在同等条件下，芳基溴代物、芳基碘代物的偶联反应相较于芳基氯代物而言更易发生。因此，上述配体除了可以用于芳基氯代物的偶联反应之外，也可以用于本领域常规的芳基溴代物、芳基碘代物的偶联反应。
铜催化的芳基氯代物的偶联反应
本发明还提供了一类铜催化的芳基氯代物的偶联反应方法，所述的方法包括使用如前文所述的式(I)化合物作为配体进行上述反应。
通常，芳基碘、芳基溴的反应活性较高，在钯、铜、镍等过渡金属的催化下能较好的实现相应的偶联反应；和溴(碘)代芳烃相比，氯代芳烃便宜易得，更具有应用前景；然而C-Cl键键能高，这导致芳基氯代物在常规的芳基溴代物、芳基碘代物的催化条件下很难发生反应。
对于不同的反应物可以在本发明的公开范围内对配体和反应条件进行优化，从而选用最合适的配体种类和反应条件(如温度、溶剂、反应物比例和反应时间等)，在阅读了本申请的公开内容之后，上述优化是本领域技术人员的技能范围之内的。
几种最为优选的铜催化芳基氯代物偶联反应如下所示：
1.杂环羧酸酰胺配体促进的铜催化的芳基氯代物的C-N偶联反应
上述反应中，偶联试剂的选择没有特别的限制，可以为相应的伯胺或仲胺，也可以为其他氨源如氨气、氨水乃至铵盐、叠氮化钠等。具体反应过程如下所示：
偶联试剂为伯胺或仲胺的情况中，反应如下式所示：
Figure BDA0001270570570000281
其中各基团的定义如上文中所述，
Figure BDA0001270570570000282
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
Rc、Rd各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH。
上述反应过程中，铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
所述的配体没有特别的限制，可以为上文中所述的任意一种配体，优选为L53或L103。
优选的碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾、碳酸铯，最优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO、DMF，最优选DMSO。
反应温度在50-180℃，优选100-130℃。
偶联试剂为其他氨源的情况中，反应如下所示：
Figure BDA0001270570570000291
其中各基团的定义如上文中所述，
Figure BDA0001270570570000292
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-、芳基NHC(O)-)、C2-C10的酰胺基(烷基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
所述的氨源选自下组：氨气、氨水、氯化铵、碳酸铵、碳酸氢铵、硫酸铵、硝酸铵、磷酸铵、磷酸氢二铵、叠氮化钠，优选氨气、氨水、氯化铵和磷酸氢二铵。
当所述的氨源为铵盐时，所述的反应在强碱存在下进行(优选为在KOH存在下进行)。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
配体为所述的任意一种，优选L13、L15或L31。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸铯、磷酸钾，最优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO、DMF，最优选DMSO。
反应温度在50-180℃，优选100-130℃。
2.杂环羧酸酰胺配体促进的铜催化的芳基氯代物的C-O偶联反应
Figure BDA0001270570570000293
其中各基团的定义如上文中所述，
Figure BDA0001270570570000294
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
Rc选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、-CN、MeS-、砜基、磺酰胺基。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
配体为所述的任意一种，优选L13、L15或L35。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO。
反应温度在50-180度，优选100-130度。
3.杂环羧酸酰胺配体促进的铜催化的芳基氯代物的C-S偶联反应
Figure BDA0001270570570000301
其中各基团的定义如上文中所述，
Figure BDA0001270570570000302
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
Rc选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、-CN、MeS-、砜基、磺酰胺基。
配体为1所述的任意一种，优选L-92，L-105。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1，4-二氧六环，优选DMSO。
反应温度在50-180度，优选100-130度。
与现有技术相比，本发明的主要优点包括：
1.提供了一类能够高效率地进行铜催化的芳基氯代物偶联反应的催化体系，所述的催化体系能够使在常规的芳基溴代物和芳基碘代物偶联体系下难以进行的芳基氯代物偶联反应顺利进行，且底物兼容性好，催化体系适用范围广。
2.相较于现有技术中的芳基氯代物偶联反应方法，本发明的方法采用成本较低的铜催化剂体系，且配体结构简单，制备方便，用量少，反应经济。
3.本发明的催化体系所使用的原料芳基氯代物与其他芳基卤代物相比，原料成本低，来源广泛，具有很好的大规模应用前景。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：配体类型1～4用酰氯法制备：
Figure BDA0001270570570000311
将苯并咪唑-2-甲酸或吲哚-2-甲酸(1.0eq)置于单口瓶中，加入DCM(0.5M)和1～2滴DMF，搅拌(部分底物不溶解)，橡胶塞塞住瓶口，插上气球，向体系中滴加草酰氯(3.0eq)，滴加过程中有大量气体放出(气球膨胀，是HCl、CO2、CO气体)，滴加完后室温下搅拌2～3小时，停止搅拌后取出搅拌子，旋蒸除去DCM和过量草酰氯，抽干，所得固体即为酰氯(可能有部分与盐酸成盐，因此下一步和胺反应时需要加过量的三乙胺)，以上反应式中R’即相当于本发明式I中的R2。
将苄胺或取代芳香胺溶于THF，加入三乙胺，搅拌下将上述酰氯加入到体系中(可直接将固体刮下来分批加进去，也可以溶于THF滴加进去)，加完后室温下搅拌至反应完全。旋蒸除去THF，抽干，加水，抽滤，冷乙醚洗涤，得固体。
Figure BDA0001270570570000312
Figure BDA0001270570570000321
Figure BDA0001270570570000331
Figure BDA0001270570570000341
Figure BDA0001270570570000351
Figure BDA0001270570570000361
实施例2、配体类型5～8用活性酸酐法制备：
Figure BDA0001270570570000362
将杂环-2-羧酸(1.0eq.)溶于THF(0.2M)中，加入N-乙基吗啉(NEM，2.5eq.)，冰水浴冷却下滴加氯甲酸异丁酯(1.0eq.)。加完后保持冰水浴搅拌15分钟，再将相应的胺(1.2eq.)缓慢加入到体系中，加完后撤去冰水浴，升至室温后搅拌过夜(部分亲核性弱、反应活性差的胺需要加热回流)。将得到的悬浊液减压浓缩，然后加水，再加乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，最后减压浓缩，硅胶柱层析，即可得到相应的杂环-2-羧酸的酰胺，以上反应式中R’即相当于本发明式I中的R2。(注：部分配体需进一步脱除N上的Boc保护基，脱除保护基的方法为本领域常规的脱Boc保护基方法，如TFA脱除保护基)
Figure BDA0001270570570000363
Figure BDA0001270570570000371
Figure BDA0001270570570000381
Figure BDA0001270570570000391
实施例3、对甲基氯苯与苄胺偶联反应合成N-对甲基苯基苄胺
Figure BDA0001270570570000392
在10mL封管中加入碘化亚铜(0.05mmol)，配体(0.1mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次，再加入对甲基氯苯(0.5mmol)，苄胺(0.75mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析(石油醚∶乙酸乙酯＝50∶1)，得产品N-对甲基苯基苄胺。1H NMR(400MHz，CDCl3)δ7.34-7.21(m，5H)，6.96(d，J＝8.0Hz，2H)，6.54(d，J＝8.4Hz，2H)，4.28(s，2H)，3.88(br s，1H)，2.22(s，3H)；13C NMR(100MHz，CDCl3)δ20.6，48.8，113.2，126.9，127.3，127.7，128.8，130.0，139.8，146.1；HRMS(ESI)calcd.for C14H16N(M+H)+：198.1283，Found：198.1287.
不同杂环羧酸酰胺配体实验结果列于下表。
配体编号 产率/％ 配体编号 产率/％ 配体编号 产率/％
L-1 17 L-2 12 L-3 21
L-7 21 L-32 23 L-53 24
L-54 10 L-55 5 L-96 9
L-103 31 L-102 26 L-106 34
L-107 29
实施例4、对甲基氯苯与各类伯胺、仲胺偶联反应合成相应的苯胺衍生物
Figure BDA0001270570570000401
在10mL封管中加入碘化亚铜(0.05mmol)，配体L-103(0.05或0.1mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次，再加入对甲基氯苯(1.0mmol)，胺(1.5mmol)和1mL DMSO，反应在120℃下均匀搅拌24或48小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品N-对甲基苯基胺。
本实施例使用不同的胺，所得结果列于下表。
Figure BDA0001270570570000402
Figure BDA0001270570570000411
实施例5、对氨基苄醇的合成
Figure BDA0001270570570000412
在10mL封管中加入对氯苄醇(0.5mmol)，氨源(0.75mmol)，铜盐催化剂(0.05mmol)，配体(0.05mmol)，碱(0.5mmol)，抽真空置换氩气3次，再加入0.5mL溶剂，反应在110℃下均匀搅拌24小时，冷却后用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品对氨基苄醇(淡黄色固体)。
1H NMR(400MHz，CDCl3)δ7.11(d，J＝8.3Hz，2H)，6.62(d，J＝8.3Hz，2H)，4.49(s，2H)，3.22(br s，2H)；13C NMR(100MHz，CDCl3)δ145.9，131.0，128.7，115.1，65.1；LC-MS(ESI，m/z)：124.1(M+H)+.
本实施例采用不同的氨源、铜盐催化剂、配体、碱和溶剂，所得结果列于下表。
Figure BDA0001270570570000413
Figure BDA0001270570570000421
实施例6、芳香胺的合成
在10mL封管中加入碘化亚铜(0.05mmol)，配体L-15(0.05或0.1mmol)，磷酸钾(1.1mmol)，抽真空置换氩气3次，再加入氯代芳烃(1.0mmol)，1mL DMSO和氨水(2.0mmol)，反应在110℃或120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品芳香胺。
本实施例使用不同的氯代芳烃，所得结果列于下表。
Figure BDA0001270570570000422
Figure BDA0001270570570000423
Figure BDA0001270570570000431
Figure BDA0001270570570000441
实施例7、4-甲基二苯醚的合成
Figure BDA0001270570570000442
在10mL封管中加入苯酚(1.5mmol)，碘化亚铜(0.1mmol)，配体(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对甲基氯苯(1.0mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品4-甲基二苯醚。
1H NMR(400MHz，CDCl3)δ7.40-7.31(m，2H)，7.21-7.15(m，2H)，7.14-7.08(m，1H)，7.06-7.01(m，2H)，7.00-6.93(m，2H)，2.38(s，3H)；13C NMR(100MHz，CDCl3)δ158.02，154.91，133.06，130.45，129.83，122.98，119.32，118.53，20.89
采用不同的配体所得结果列于下表。
配体编号 产率/％ 配体编号 产率/％ 配体编号 产率/％
L-1 19 L-2 38 L-3 30
L-6 58 L-7 45 L-10 44
L-13 68 L-14 62 L-15 64
L-17 44 L-21 26 L-29 42
L-30 32 L-31 29 L-32 22
L-35 69 L-37 59 L-40 48
L-57 37 L-96 26 L-103 19
L-16 14 L-18 10 L-19 7
L-22 21 L-23 32 L-24 11
L-27 8 L-34 17 L-36 58
L-50 11 L-52 28 L-56 54
L-58 10 L-59 9 L-60 19
实施例8、芳基氯代物和RcOH偶联反应合成二芳基醚和芳基烷基醚
Figure BDA0001270570570000451
在10mL封管中加入卤代芳烃底物(1.0mmol)，酚(1.2mmol)，碘化亚铜(0.05mmol)，配体L-13(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次后加入1mL DMSO，反应在120℃下均匀搅30小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产物二芳基醚。所得结果列于下表。
Figure BDA0001270570570000452
实施例9、对氯苯甲醚与甲基亚磺酸钠的偶联
Figure BDA0001270570570000453
在10mL封管中加入甲基亚磺酸钠(0.6mmol)，碘化亚铜(0.05mmol)，配体(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对氯苯甲醚(0.5mmol)和1mLDMSO，反应在120℃下均匀搅拌24小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品对甲氧基苯基甲基砜。
1H NMR(400MHz，CDCl3)δ3.05(s，3H)，3.90(s，3H)，7.04(dd，J＝7.5，2.1Hz，2H)，7.88(dd，J＝7.5，2.1Hz，2H)；EI-MS(m/z)186(M+)
采用不同的配体所得结果列于下表。
配体 产率/％ 配体 产率/％ 配体 产率/％
L-54 24 L-88 50 L-89 52
L-90 31 L-91 26 L-92 80
L-95 45 L-96 40 L-104 47
L-105 50 L-108 36 L-109 44
L-115 53 L-35 52
实施例10、对氯苯甲醚与甲基亚磺酸钠的偶联
Figure BDA0001270570570000461
操作同实施例9，采用不同的铜催化剂、碱、溶剂、反应温度，实验结果如下：
编号 铜盐 碱 溶剂 温度 产率/％
1 CuI Cs<sub>2</sub>CO<sub>3</sub> DMSO 120 31
2 CuI K<sub>2</sub>CO<sub>3</sub> DMSO 120 60
3 CuI K<sub>3</sub>PO<sub>4</sub> DMSO 120 80
4 CuBr K<sub>3</sub>PO<sub>4</sub> DMSO 120 50
5 CuCl2 K<sub>3</sub>PO<sub>4</sub> DMSO 120 18
6 Cu<sub>2</sub>O K<sub>3</sub>PO<sub>4</sub> DMSO 120 22
7 CuCl K<sub>3</sub>PO<sub>4</sub> DMSO 120 45
8 CuSCN K<sub>3</sub>PO<sub>4</sub> DMSO 120 35
9 Cu<sub>2</sub>S K<sub>3</sub>PO<sub>4</sub> DMSO 120 18
10 CuI K<sub>3</sub>PO<sub>4</sub> DMF 120 65
11 CuI K<sub>3</sub>PO<sub>4</sub> NMP 120 73
12 CuI K<sub>3</sub>PO<sub>4</sub> 甲苯 120 36
实施例11、芳基氯与烷基或芳基亚磺酸钠的偶联
Figure BDA0001270570570000462
在10mL封管中加入烷基或芳基亚磺酸钠(0.6mmol)，碘化亚铜(0.05mmol)，配体(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入芳基氯(0.5mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得相应的产品。
Figure BDA0001270570570000463
Figure BDA0001270570570000471
实施例12、溴/碘代芳烃和胺反应合成芳香胺
在10mL封管中加入溴/碘代芳烃底物(1.0mmol)，胺(1.2mmol)，碘化亚铜(0.05mmol)，配体(0.05mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次后加入1mL DMSO，反应在80℃下均匀搅48小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产物芳香胺。所得结果列于下表。
Figure BDA0001270570570000472
实施例13、对甲基碘苯和对甲氧基苯硫酚反应合成芳香硫醚
Figure BDA0001270570570000473
在10mL封管中加入碘化亚铜(0.05mmol)，配体(0.1mmol)，碳酸钾(1.0mmol)，抽真空置换氩气3次，再加入对甲基碘苯(0.5mmol)，对甲氧基苯硫酚(0.6mmol)和1mL DME，反应在80℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品(4-甲氧基苯基)-对甲苯基硫醚。
1H NMR(500MHz，CDCl3)δ7.38(d，J＝8.6Hz，2H)，7.16(d，J＝8.1Hz，2H)，7.08(d，J＝8.0Hz，2H)，6.88(d，J＝8.6Hz，2H)，3.81(s，2H)，2.32(s，2H).13C NMR(126MHz，CDCl3)δ159.47，136.12，134.34，129.79，129.39，125.63，114.89，55.35，45.84，21.01，8.66.ESI-MS m/z231.4(M+H)+
采用不同的配体所得结果列于下表。
配体 产率/％ 配体 产率/％ 配体 产率/％
L-13 70 L-62 50 L-63 56
L-65 65 L-54 60 L-71 56
L-79 48 L-82 50 L-84 44
L-96 63 L-112 72 L-113 61
L-114 70 L-74 31 L-75 42
L-76 36 L-61 37 L-64 57
L-68 39 L-69 53 L-70 61
L-66 36 L-67 45 L-77 71
L-78 65 L-86 31 L-80 43
L-81 52 L-83 54 L-85 43
L-87 26
实施例14、碘代芳烃和苯硫酚反应合成芳香硫醚
Figure BDA0001270570570000481
在10mL封管中加入碘化亚铜(0.05mmol)，配体(0.1mmol)，碳酸钾(1.0mmol)，抽真空置换氩气3次，再加入取代碘苯(0.5mmol)，取代苯硫酚(0.6mmol)和1mL DME，反应在80℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品芳香硫醚。
Figure BDA0001270570570000482
Figure BDA0001270570570000491
实施例15、对甲氧基溴苯与其他偶联试剂的反应
Figure BDA0001270570570000492
在10mL封管中加入铜盐催化剂(0.1mmol)，配体(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次，再加入氯代芳烃(1.0mmol)，1mL DMSO和亲核试剂(2.0mmol)，反应在90℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得相应的偶联产物。
Figure BDA0001270570570000493
实施例16、芳基氯与烷基或芳基亚磺酸钠的偶联(克级反应)
Figure BDA0001270570570000494
在10mL封管中加入烷基或芳基亚磺酸钠(6.5mmol)，碘化亚铜(0.5mmol)，配体(0.5mmol)，磷酸钾(5.0mmol)，抽真空置换氩气3次，再加入芳基氯(5mmol)和3mL DMSO，反应在120℃下均匀搅拌24-36小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得相应的产品。
Figure BDA0001270570570000495
Figure BDA0001270570570000501
Figure BDA0001270570570000511
实施例17、芳基碘或芳基溴与烷基或芳基亚磺酸钠的偶联(克级反应)
Figure BDA0001270570570000512
在10mL封管中加入烷基或芳基亚磺酸钠(6.5mmol)，碘化亚铜(具体用量见下表)，配体(具体用量见下表)，磷酸钾(5.0mmol)，抽真空置换氩气3次，再加入芳基氯(5mmol)和4mL DMSO，反应在相应温度下均匀搅拌24小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得相应的产品。
Figure BDA0001270570570000513
Figure BDA0001270570570000521
Figure BDA0001270570570000531
Figure BDA0001270570570000541
Figure BDA0001270570570000551
在本发明提及的所有文献都在本申请中引用作为参考，就如同每i篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

1.一种式II所示的化合物的用途：
其特征在于，作为配体用于铜催化的芳基卤代物偶联反应；其中，所述的芳基卤代物为芳基氯代物；
Figure FDA0003638371910000011
其中，
R2选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、苄基；其中，所述C6-C20的芳基选自下组：苯基、联苯基和萘基；所述3-至20-元的杂芳基选自下组：吡啶、嘧啶；
R2中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、未取代或被1个或2个C1-C6的烷基取代的氨基、羟基、C1-C6烷基、C1-C6烷氧基、C6芳基、C6芳基-氧基、C1-C6烷基-S-；
R4选自下组：H、硝基、卤素、C1-C6烷基、C1-C6烷基氧基。
2.如权利要求1所述的用途，其特征在于，R2选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述C6-C20的芳基选自下组：苯基、联苯基和萘基。
3.如权利要求1或2所述的用途，其特征在于，所述卤素为F；和/或C1-C6烷基-S-为MeS-。
4.如权利要求1所述的用途，其特征在于，所述的化合物选自：
Figure FDA0003638371910000012
Figure FDA0003638371910000021
Figure FDA0003638371910000031
。
5.一种芳基卤代物偶联反应方法，其特征在于，所述的方法包括：用铜催化剂，用如权利要求1中所述的式II所示的化合物作为配体，进行所述的偶联反应：
Figure FDA0003638371910000032
其中，所述的芳基卤代物为芳基氯代物；
并且，所述的偶联反应如下：
Figure FDA0003638371910000033
在惰性溶剂中，用
Figure FDA0003638371910000034
与偶联试剂反应，得到
Figure FDA0003638371910000035
化合物；
其中，X选自下组：N、O或S；
Y选自下组：Cl；
Figure FDA0003638371910000036
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基或杂芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、未取代或被1个或2个C1-C6的烷基或C2-C10的酰基取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、3-至20-元的杂芳基、C6-C10的芳基-氧基、C2-C10的酯基、C2-C10的酰基、C2-C10的酰基-烷氧基、C2-C10的烷基NHC(O)-、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；其中，所述芳基上的两个相邻的碳原子上的两个氢原子可以被-(CH2)n-取代，其中n为1、2、3、4、5或6；
所述的偶联试剂选自下组：氨水、氨气、铵盐/氢氧化物溶液、碳原子数为2-20的
Figure FDA0003638371910000041
ReC(O)NHRd、RcSO2M、叠氮化钠、NHRcRd、RcOH、RcSH、氢氧化物及能够水解出氢氧根的盐；其中，M为钠、和/或钾；
Rc、Rd、Re各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
或Rc和Rd共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
或Re和Rd共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氰基、氧、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基、C2-C10的酰基-烷氧基、C2-C10的酰基、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基、C1-C6烷基-S-。
6.如权利要求5所述的方法，其特征在于，在所述偶联反应中，所述配体与反应物芳基卤代物的摩尔比为1～50:100；和/或
所述配体与铜催化剂的摩尔比为1～5:1。
7.如权利要求5所述的方法，其特征在于，在所述偶联反应中，所述配体与反应物芳基卤代物的摩尔比为5～20:100；和/或
所述配体与铜催化剂的摩尔比为1～2:1。
8.如权利要求5所述的方法，其特征在于，所述铵盐选自下组：氯化铵、碳酸铵、硫酸铵、磷酸氢铵，或其组合；和/或
所述氢氧化物溶液为氢氧化钾溶液。
9.如权利要求5所述的方法，其特征在于，所述的偶联反应的反应温度在50-180℃。
10.如权利要求5所述的方法，其特征在于，所述的偶联反应的反应温度在100-130℃。
11.如权利要求5所述的方法，其特征在于，所述的偶联反应选自以下(1)、(2)、(3)、(4)或(5)：
(1)在惰性溶剂中，用
Figure FDA0003638371910000042
与NHRcRd反应，得到
Figure FDA0003638371910000043
Figure FDA0003638371910000051
其中，各基团的定义如权利要求5中定义；
(2)在惰性溶剂中，用
Figure FDA0003638371910000052
与氨源反应，得到
Figure FDA0003638371910000053
Figure FDA0003638371910000054
其中，各基团的定义如权利要求5中定义；
所述的氨源选自下组：氨气、氨水、氯化铵、碳酸铵、碳酸氢铵、硫酸铵、硝酸铵、磷酸铵、磷酸氢二铵、叠氮化钠；
(3)在惰性溶剂中，用
Figure FDA0003638371910000055
与RcOH反应，得到
Figure FDA0003638371910000056
Figure FDA0003638371910000057
其中，各基团的定义如权利要求5中定义；
(4)在惰性溶剂中，用
Figure FDA0003638371910000058
与RcSO2M反应，得到
Figure FDA0003638371910000059
Figure FDA00036383719100000510
其中，各基团的定义如权利要求5中定义，M为钠、和/或钾；
(5)在惰性溶剂中，用
Figure FDA00036383719100000511
与RcSH反应，得到
Figure FDA00036383719100000512
Figure FDA00036383719100000513
其中，各基团的定义如权利要求5中定义。
12.如权利要求11所述的方法，其特征在于，所述的氨源选自下组：氨气、氨水、氯化铵和磷酸氢二铵。
13.一种芳基偶联反应的催化体系，其特征在于，所述的反应体系包括：铜催化剂、配体、碱、和有机溶剂；
其中，所述的铜催化剂选自下组：CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，或其组合；
所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸氢钠、碳酸氢钾、碳酸钠、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠，或其组合；
所述的有机溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、1,4-二氧六环、四氢呋喃、DME、甲苯，或其组合；
所述的配体为如权利要求1中所述的式II所示的化合物：
Figure FDA0003638371910000061
并且，所述芳基偶联反应如下：
Figure FDA0003638371910000062
在惰性溶剂中，用
Figure FDA0003638371910000063
与偶联试剂反应，得到
Figure FDA0003638371910000064
化合物；
其中，X选自下组：N、O或S；
Y选自下组：Cl；
Figure FDA0003638371910000065
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基或杂芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、未取代或被1个或2个C1-C6的烷基或C2-C10的酰基取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、3-至20-元的杂芳基、C6-C10的芳基-氧基、C2-C10的酯基、C2-C10的酰基、C2-C10的酰基-烷氧基、C2-C10的烷基NHC(O)-、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；其中，所述芳基上的两个相邻的碳原子上的两个氢原子可以被-(CH2)n-取代，其中n为1、2、3、4、5或6；
所述的偶联试剂选自下组：氨水、氨气、铵盐/氢氧化物溶液、碳原子数为2-20的
Figure FDA0003638371910000066
ReC(O)NHRd、RcSO2M、叠氮化钠、NHRcRd、RcOH、RcSH、氢氧化物及能够水解出氢氧根的盐；其中，M为钠、和/或钾；
Rc、Rd、Re各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
或Rc和Rd共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
或Re和Rd共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基；
其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氰基、氧、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基、C2-C10的酰基-烷氧基、C2-C10的酰基、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基、C1-C6烷基-S-。
14.如权利要求13所述的催化体系，其特征在于，所述铜催化剂为CuI；所述的碱选自下组：磷酸钾、碳酸铯；和/或所述的有机溶剂为：DMSO和/或DMF和/或DME。
15.一种化合物：
其中，所述的化合物选自下组：
Figure FDA0003638371910000071
。
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