CN115572240B - 一种三组分还原交叉偶联构建c-c键的机械力合成方法 - Google Patents
一种三组分还原交叉偶联构建c-c键的机械力合成方法 Download PDFInfo
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- CN115572240B CN115572240B CN202211280805.7A CN202211280805A CN115572240B CN 115572240 B CN115572240 B CN 115572240B CN 202211280805 A CN202211280805 A CN 202211280805A CN 115572240 B CN115572240 B CN 115572240B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
本发明公开了一种三组分还原交叉偶联构建C‑C键的机械力合成方法,涉及有机合成技术领域。合成方法包括以下步骤:将金属与配体的络合物NiBr2·dtbbpy、还原剂、添加剂以及三组分原料和溶剂混合后在机械外力作用下反应,得到所述化合物;所述三组分原料为烷基卤化物、烯烃衍生物和芳基卤化物(或酰氯);所述烷基卤化物为二级或三级烷基卤化物。本发明方法适用于二级或三级烷基溴化物作为亲电试剂的情况,比烷基碘化物更便宜和稳定,且一系列富/缺电子基团取代的芳基碘化物和芳基溴化物均能反应,收率较高,底物范围广、官能团耐受性好,对天然产物和药物分子的后期修饰也同样适用,操作简单,适合工业放大。
Description
技术领域
本发明涉及有机合成技术领域,特别是涉及一种三组分还原交叉偶联构建C-C键的机械力合成方法。
背景技术
过渡金属催化的偶联反应为C-C键的构建提供高效便捷的方法,并广泛应用于天然产物及药物分子的合成。其中镍(II)催化的烯烃双官能团化可以在单个反应中同时构建两个C-C键,实现较高的化学、区域和立体选择性,成为工业上构建C-C键的常用策略之一,如该方法可以应用于临床候选药物(TK-666)及其衍生物的合成,或者可以简化5-脂氧合酶激活蛋白(FLAP)潜在抑制剂的制备等。
目前关于镍催化的三组分还原交叉偶联构建C-C键的合成方法主要是镍催化的分子间烯烃1,2-双官能团化,即在镍催化下,四(二甲氨基)乙烯(TDAE)为还原剂,两种不同的亲电试剂,即Csp2-和Csp3-卤化物同时添加到各种烯烃中直接形成Csp3-Csp3和Csp3-Csp2键。已经对这类三组分还原交叉偶联的合成方法做了详细报道,但是这些方法具有以下局限性:1.在溶液体系中反应,需要加入大量的有机溶剂,成本高,不符合原子经济和绿色化学的标准;2.还原剂为TDAE,而TDAE制备复杂、反应时间长达一周,且试剂质量难以保证,导致反应重复性不好,收率低;3.底物适用性范围狭小,只适用于三级烷基碘化物,而廉价易得的三级烷基溴化物及二级卤化物都不能反应;4.操作复杂,需要严格在氮气保护下进行。
发明内容
本发明的目的是提供一种三组分还原交叉偶联构建C-C键的机械力合成方法(机械化学力方法),以解决上述现有技术存在的问题,本发明方法仅需要少量的溶剂,底物适应范围广,二级/三级烷基溴化物均可参与反应,操作简单,在空气条件下即能获得较高的收率。
为实现上述目的,本发明提供了如下方案:
本发明技术方案之一,一种三组分还原交叉偶联构建C-C键的机械力合成方法,包括以下步骤:
将金属与配体的络合物NiBr2·dtbbpy、还原剂、添加剂以及三组分原料和溶剂混合后在机械外力作用下反应,得到所述化合物;
所述三组分原料为烷基卤化物、烯烃衍生物和芳基卤化物;
所述烷基卤化物为二级或三级烷基卤化物。
反应式如下:
进一步地,所述还原剂为锌或锰;优选的为锌。
所述添加剂为碘化钠、碘化钾和四丁基碘化铵中的一种;优选的为碘化钠。
所述溶剂为四氢呋喃、2-甲基四氢呋喃、乙腈、甲苯、1,4-二氧六环、N,N-二甲基乙酰胺和二甲基亚砜中的一种或多种;优选的为四氢呋喃和1,4-二氧六环,所述四氢呋喃和1,4-二氧六环的体积比经过多次实验尝试,最终确认为10:1(当四氢呋喃和1,4-二氧六环的体积比为10:1时,产物的收率更高)。以上溶剂分析纯即可满足反应要求。溶剂的用量(μL)与体系所有原料,催化剂、配体以及还原剂、添加剂总量(mg)的比例为1:3~4:3。
所述烷基卤化物、烯烃衍生物和芳基卤化物的摩尔比为1-3:1-2:1-2;所述烷基卤化物、烯烃衍生物和酰氯的摩尔比为1-3:1-2:1-2;优选的,烷基卤化物、烯烃衍生物和芳基卤化物(或酰氯)的摩尔比为2:1:2、3:1:2、1:2:2、3:2:2、2:2:1、3:1:1.5、2:1:1.5或1.5:1:2,更优选的,为3:1:1.5。
所述金属与配体的络合物NiBr2·dtbbpy的用量为三组分原料质量的1-10%;优选的,为5%。
所述反应的时间为0-3小时,且不为0;优选的,反应的时间为1.5小时。
进一步地,所述烷基卤化物的结构式为下列结构式中的一种:
进一步地,所述烯烃衍生物的结构式为下列结构式中的一种:
进一步地,所述芳基卤化物的结构式为下列结构式中的一种:
进一步地,所述金属与配体的络合物NiBr2·dtbbpy的制备方法包括以下步骤:
将镍(II)溴化乙烯二醇二甲基醚络合物和4,4’-二叔丁基-2,2’-联吡啶按当量比1:1.2加入溶剂中溶解,除去溶剂,得到所述金属与配体的络合物NiBr2·dtbbpy。
进一步地,所述机械外力通过将混合后的原料密封后置于球磨仪中以10-35Hz的频率研磨来施加;反应结束后还包括从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯的步骤。优选的,研磨的频率为35Hz。
本发明技术方案之二,利用上述的机械力合成方法制备得到的化合物。
本发明技术方案之三,一种拓宽三组分还原交叉偶联构建C-C键过程中底物适用性范围的方法,采用上述的三组分还原交叉偶联构建C-C键的机械力合成方法。
本发明技术方案之四,一种节约三组分还原交叉偶联构建C-C键过程中溶剂用量的方法,采用上述的三组分还原交叉偶联构建C-C键的机械力合成方法。
本发明公开了以下技术效果:
(1)本发明选用(球磨)机械化学代替了传统的溶液体系,避免了大量有机溶剂的使用,废物排放少,节约资源,绿色环保,原子利用率高,并且本发明方法操作简单、反应时间短、效率高,有利于工业级制备。
(2)本发明方法使用的还原剂可以为Zn或Mn粉,较传统文献报道的还原剂TDAE,更稳定易得,成本更低廉。
(3)本发明方法适用于二级或三级烷基溴化物作为亲电试剂的情况,烷基溴化物比烷基碘化物化学性质稳定,便于储存和使用;且一系列富/缺电子基团取代的芳基碘化物和芳基溴化物均能反应,收率较高,底物范围广、官能团耐受性好,对天然产物和药物分子的后期修饰也同样适用。
(4)本发明仅使用少量的分析纯溶剂(四氢呋喃和二氧六环)作为有机溶剂,避免使用超干溶剂,极大的降低了成本。目前三组分还原偶联反应依赖于TDAE作为还原剂。该还原剂对水和氧气高度敏感,使用分析纯试剂以及暴露在空气中会导致反应性大幅度降低,因此现有技术必须使用超干无氧溶剂。而本发明使用化学性质稳定的锌粉作为还原剂,对反应条件兼容性好,对水分和氧气不敏感,因而可以使用分析纯试剂且无需惰性气体保护。本发明中溶剂的用量(μL)与体系所有原料、催化剂、配体以及还原剂、添加剂总量(mg)的比例为1:3~4:3,现有技术中溶剂用量与投料总量的比例一般为10:3~20:3。
(5)本发明方法在空气条件操作,之后在密闭条件下进行反应,就能够获得较高的收率,无需使用大量惰性气体,操作简单,适合工业放大。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
本发明以下实施例中,所用原料均为市场采购,其中溶剂为分析纯试剂。
本发明实施例中所用NiBr2·dtbbpy通过以下步骤制备得到:
将镍(II)溴化乙烯二醇二甲基醚络合物(463.0mg,1.0eq.)和4,4’-二叔丁基-2,2’-联吡啶(442.9mg,1.2eq.)置于250mL的圆底烧瓶中,加入80mL的乙醇使其完全溶解,用旋转蒸发仪除去溶剂,得到浅绿色固体,即为NiBr2·dtbbpy,备用。
本发明实施例1-42制备得到的化合物结构式分别如下所示:
实施例1:N-(3,3-dimethyl-1-phenylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、碘苯(0.15mmol,16.8μL,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体20.7mg,产率73.7%。
1H NMR(400MHz,CDCl3)δ7.68–7.66(m,2H),7.42–7.37(m,1H),7.34–7.21(m,6H),7.19–7.13(m,1H),6.33(d,J=8.0Hz,1H),5.24(m,1H),1.77(d,J=6.5Hz,2H),0.91(s,9H).
13C NMR(101MHz,CDCl3)δ166.3,144.3,134.8,131.5,128.8,128.7,127.2,126.9,126.5,51.5,50.8,31.0,30.1.
实施例2:N-(3,3-dimethyl-1-(p-tolyl)butyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-碘甲苯(0.15mmol,32.7mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体12.5mg,产率42.4%。
1H NMR(400MHz,CDCl3)δ7.67-7.65(m,2H),7.48-7.42(m,1H),7.35–7.31(m,2H),7.18(d,J=8.4Hz,2H),7.06(d,J=8.0Hz,2H),6.20(d,J=8.0Hz,m,1H),5.21(m,1H),2.25(s,1H),1.76(d,J=6.6Hz,2H),0.91(s,9H).
13C NMR(101MHz,CDCl3)δ166.2,141.3,136.9,134.8,131.5,129.5,128.6,126.9,126.4,51.25(s),50.8,30.97,30.2,21.2.
实施例3:N-(1-(4-(tert-butyl)phenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-叔丁基碘苯(0.15mmol,26.7μL,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体21.3mg,产率63.2%。
1H NMR(400MHz,CDCl3)δ7.68–7.66(m,2H),7.42–7.38(m,1H),7.34–7.31(m,2H),7.27–7.25(m,2H),7.21–7.18(m,2H),6.25(d,J=8.2Hz,2H),5.26–5.21(m,1H),1.79–1.74(m,2H),1.22(s,9H),0.92(s,9H).
13C NMR(101MHz,CDCl3)δ166.2,150.1,141.3,134.8,131.5,128.6,126.9,126.1,125.7,51.0,50.8,34.5,31.5,31.0,30.1.
实施例4:N-(3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体28.1mg,产率80.5%。
1H NMR(400MHz,CDCl3)δ7.74(dd,J=5.2,3.3Hz,2H),7.56(d,J=8.2Hz,2H),7.52–7.37(m,5H),6.56(d,J=7.8Hz,1H),5.35–5.30(m,1H),1.86–1.75(m,2H),1.01(s,9H).
13C NMR(101MHz,CDCl3)δ166.5,148.5,134.3,131.7,128.7,126.9,126.7,125.7,51.3,50.9,31.1,30.1.
19F NMR(376MHz,CDCl3)δ-62.32.
LC-MASS m/z calcd for C20H23F3NO[M+H]+350.17,found 350.02;
实施例5:N-(1-(4-fluorophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-氟碘苯(0.15mmol,17.3μL,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体22.9mg,产率76.6%。
1H NMR(400MHz,CDCl3)δ7.75–7.73(m,2H),7.50–7.46(m,1H),7.43–7.38(m,2H),7.33–7.30(m,2H),7.02–6.98(m,2H),6.37(d,J=7.8Hz,1H),5.31–5.26(m,1H),1.82(dd,J=6.5,2.3Hz,2H),0.99(s,9H).
13C NMR(101MHz,CDCl3)δ166.3,163.1,160.7,140.1,134.5,131.6,128.7,128.1,128.0,126.9,115.6,115.4,50.9,50.8,31.0,30.1.
19F NMR(376MHz,CDCl3)δ-115.51.
实施例6:N-(1-(4-bromophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-溴碘苯(0.15mmol,42.4mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体25.9mg,产率73.0%。
1H NMR(400MHz,CDCl3)δ7.73–7.71(m,2H),7.50–7.45(m,1H),7.42–7.37(m,4H),7.22–7.19(m,2H),6.43(d,J=7.9Hz,1H),5.26–5.21(m,1H),1.78(dd,J=6.5,5.0,2H),0.97(s,9).
13C NMR(101MHz,CDCl3)δ166.4,143.5,134.5,131.8,131.7,128.7,128.2,126.97,120.92,51.0,50.7,31.0,30.1.
实施例7:N-(1-(4-iodophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、1,4-二碘苯(0.15mmol,49.5mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmo l,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体32.8mg,产率80.6%。
1H NMR(400MHz,CDCl3)δ7.74–7.72(m,2H),7.63–7.61(m,2H),7.50–7.46(m,1H),7.41-7.37(m,2H),710–7.08(m,2H),6.49(d,J=7.9Hz,1H),5.25-5.20(m,1H),1.81–1.75(m,2H),0.98(s,9H).
13C NMR(101MHz,CDCl3)δ166.4,144.2,137.8,134.5,131.6,128.7,128.5,126.9,92.5,51.1,50.7,31.0,30.1.
实施例8:N-(1-(3-iodophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、1,3-二碘苯(0.15mmol,49.5mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmo l,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体31.0mg,产率76.2%。
1H NMR(400MHz,CDCl3)δ7.77–7.72(m,2H),7.67(d,J=1.5Hz,1H),7.56(d,J=7.8Hz,1H),7.50–7.47(m,1H),7.40(t,J=7.5Hz,2H),7.31(d,J=7.7Hz,1H),7.04(t,J=7.8Hz,1H),6.48(d,J=8.0Hz,1H),5.26–5.20(m,1H),1.80–1.77(m,2H),0.99(s,9H).
13C NMR(101MHz,CDCl3)δ166.4,146.9,136.23,135.3,134.4,131.6,130.6,128.7,127.0,125.9,94.8,51.0,50.8,31.1,30.1.
实施例9:N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、1-氟-4-碘2-(三氟甲基)苯(0.15mmol,43.5mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(RetschMM500,35赫兹,90分钟),结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,10:1),收集并干燥得到白色固体22.4mg,产率61.0%。
1H NMR(400MHz,CDCl3)δ7.75–7.73(m,2H),7.56–7.48(m,3H),7.45–7.39(m,2H),7.17–7.10(m,1H),6.42(d,J=7.5Hz,1H),5.32–5.27(m,1H),1.86–1.74(m,2H),1.01(s,9H).
13C NMR(101MHz,CDCl3)δ166.5,140.9,134.1,132.2,132.1,131.9,128.8,126.9,124.8,117.3,117.1,50.80,50.7,31.1,30.1.
19F NMR(376MHz,CDCl3)δ-116.84,-61.23.
实施例10:N-(3,3-dimethyl-1-(4-(trifluoromethoxy)phenyl)butyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、1-碘-4-(三氟甲基)苯(0.15mmol,43.2mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体25.1mg,产率68.8%。
1H NMR(400MHz,CDCl3)δ7.76–7.73(m,2H),7.52–7.46(m,1H),7.43–7.34(m,4H),7.15(d,J=8.0Hz,2H),6.48(d,J=7.5Hz,1H),5.33–5.28(m,1H),1.82–1.79(m,2H),1.00(s,9H).
13C NMR(101MHz,CDCl3)δ166.4,148.2,143.2,134.4,131.7,128.7,127.8,126.9,121.3,50.9,50.8,31.0,30.1.
19F NMR(376MHz,CDCl3)δ-57.76.
实施例11:N-(1-(3,4-dichlorophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、3,4-二氯碘苯(0.15mmol,40.9mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体26.4mg,产率75.6%。
1H NMR(400MHz,CDCl3)δ7.74(m,2H),7.52–7.47(m,1H),7.42–7.37(m,4H),7.17(dd,J=8.3,2.0Hz,1H),6.50(d,J=7.6Hz,1H),5.25–5.19(m,1H),1.79–1.75(m,2H),1.00(s,9H).
13C NMR(101MHz,CDCl3)δ166.5,144.8,134.2,132.7,131.8,131.0,130.7,128.7,128.4,126.9,126.0,50.8,50.7,31.1,30.1.
LC-MASS m/z calcd for C19H21Cl2NNaO[M+Na]+372.08,found 372.01
实施例12:N-(1-(3-chlorophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、3-氯碘苯(0.15mmol,35.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体22.3mg,产率70.8%。
1H NMR(400MHz,CDCl3)δ7.76–7.73(m,2H),7.52–7.46(m,1H),7.40(t,J=7.5Hz,2H),7.32(s,1H),7.25–7.17(m,3H),6.45(d,J=7.9Hz,1H),5.29–5.24(m,1H),1.80–1.78(m,2H),1.00(s,9H).
13C NMR(101MHz,CDCl3)δ166.4,146.6,134.6,134.4,131.7,130.1,128.7,127.4,126.9),126.5,124.8,51.2,50.8,31.1,30.1.
实施例13:N-(1-(4-cyanophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、3-碘苯腈(0.15mmol,34.4mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体22.9mg,产率74.8%。
1H NMR(400MHz,CDCl3)δ7.76–7.73(m,2H),7.63–7.60(m,2H),7.54–7.50(m,1H),7.46–7.42(m,4H),6.37(d,J=7.5Hz,1H),5.31–5.26(m,1H),1.82–1.76(m,2H),1.02(s,9H).
LC-MASS m/z calcd for C20H22N2NaO[M+Na]+329.16,found 329.04;
实施例14:N-(3,3-dimethyl-1-(naphthalen-2-yl)butyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、2-碘萘(0.15mmol,38.1mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体23.9mg,产率72.2%。
1H NMR(400MHz,CDCl3)δ7.84–7.75(m,6H),7.49–7.40(m,6H),6.41(d,J=8.1Hz,1H),5.52-5.47(m,1H),1.94(dd,J=7.6,6.6Hz,2H),1.03(s,9H).
LC-MASS m/z calcd for C23H25NNaO[M+Na]+354.18,found 354.05;
实施例15:N-(3,3-dimethyl-1-(5-(trifluoromethyl)pyridin-2-yl)butyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、5-三氟甲基-2-碘吡啶(0.15mmol,41.0mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体24.3mg,产率69.4%。
1H NMR(400MHz,CDCl3)δ7.75–7.73(m,3H),7.52–7.39(m,5H),6.68(d,J=7.1Hz,2H),5.37–5.32(m,1H),1.93–1.89(m),1.02(s).
LC-MASS m/z calcd for C19H21F3N2NaO[M+Na]+373.15,found 373.02;
实施例16:N-(3,3-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)butyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-碘苯硼酸频哪酯(0.15mmol,49.5mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体30.8mg,产率75.7%。
1H NMR(400MHz,CDCl3)δ7.75–7.73(m,3H),7.52–7.39(m,5H),6.68(d,J=7.1Hz,2H),5.37–5.32(m,1H),1.93–1.89(m),1.02(s).
LC-MASS m/z calcd for C25H35BNO3[M+H]+408.27,found408.04;
实施例17:N-(1-(4-chlorophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-氯碘苯(0.15mmol,35.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体23.0mg,产率73%。
1H NMR(400MHz,CDCl3)δ7.75–7.73(m,2H),7.51–7.47(m,1H),7.43–7.39(m,2H),7.28(d,J=0.8Hz,4H),6.38(d,J=7.8Hz,1H),5.29–5.23(m,1H),1.81–1.79(m,2H),0.99(s,9H).
实施例18:Methyl 4-(1-benzamido-3,3-dimethylbutyl)benzoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-碘苯甲酸甲酯(0.15mmol,50.9mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体27.7mg,产率81.7%。
1H NMR(400MHz,CDCl3)δ7.98–7.96(m,2H),7.76–7.73(m,2H),7.48–7.46(m,1H),7.41–7.37(m,4H),6.55(d,J=7.6Hz,2H),5.36–5.31(m,1H),3.88(s,3H),1.81(t,J=6.4Hz,2H),0.99(s,9H).
13C NMR(101MHz,CDCl3)δ166.9,166.5,149.67,134.47,131.7,130.1,128.9,128.7,126.9,126.4,52.2,51.4,50.7,31.1,30.1.
实施例19:N-(1-(3,5-difluorophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、3,5-二氟碘苯(0.15mmol,36.0mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体18.7mg,产率59.0%。
1H NMR(400MHz,CDCl3)δ7.76–7.74(m,2H),7.54–7.47(m,1H),7.45–7.39(m,2H),6.88–6.83(m,2H),6.67–6.65(m,1H),6.43(d,J=7.7Hz,1H),5.24(m,1H),1.77–1.75(m,2H),1.01(s,9H).
13C NMR(101MHz,CDCl3)δ166.5,164.5,162.1,148.6,134.2,131.9,128.9,126.9,109.4,109.1,102.6,51.1,50.9,31.1,30.1.
19F NMR(376MHz,CDCl3)δ-109.18.
实施例20:N-(1-(4-bromo-3-fluorophenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、3-氟-4-溴碘苯(0.15mmol,45.0mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体27.8mg,产率73.7%。
1H NMR(400MHz,CDCl3)δ7.75–7.73(m,2H),7.52–7.39(m,4H),7.10(dd,J=9.5,2.0Hz,1H),7.02(dd,J=8.2,2.0Hz,1H),6.42(d,J=7.3Hz,1H),5.25–5.23(m,1H),1.77(dd,J=6.4,2.3Hz,2H),1.00(s,9H).
13C NMR(101MHz,CDCl3)δ166.5,160.4,146.5,146.4,134.2,133.7,131.8,128.8,126.9,123.4,123.9,114.6,114.4,107.4,107.2,50.9,50.7,31.1,30.1.
19F NMR(376MHz,CDCl3)δ-106.68.
实施例21:N-(1-(4-methoxyphenyl)-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-甲氧基碘苯(0.15mmol,35.1mg,1.5eq.)、2-溴-2-甲基丁烷(0.3mmol,37.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体22.5mg,产率72.3%。
1H NMR(400MHz,CDCl3)δ7.77–7.71(m,2H),7.48–7.36(m,3H),7.31–7.25(m,2H),6.88–6.83(m,2H),6.34(d,J=8.0Hz,1H),5.29–5.24(m,1H),3.78(s,3H),1.85–1.83(m,2H),0.97(s,9H).
实施例22:N-(1-(4-chloro-3-(4-ethoxybenyl)phenyl-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-碘-1-氯-2-(4-乙氧基苄基)苯(0.15mmol,55.9mg,1.5eq.)、2-溴-2-甲基丁烷(0.3mmol,37.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,10:1),收集并干燥得到白色固体38.2mg,产率85.0%。
1H NMR(400MHz,CDCl3)δ7.72–7.67(m,2H),7.51–7.46(m,1H),7.40(t,J=7.5Hz,2H),7.30(d,J=8.1Hz,1H),7.14(dt,J=4.7,2.1Hz,2H),7.08–7.04(m,2H),6.81–6.79(m,2H),6.35(d,J=8.0Hz,1H),5.28–5.17(m,1H),4.01(s,2H),1.76–1.74(m,1H),1.40(t,J=7.0Hz,3H),0.96(s,9H).
实施例23:N-(1-(4-(hydroxymethyl)phenyl-3,3-dimethylbutyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-碘苄醇(0.15mmol,35.1mg,1.5eq.)、2-溴-2-甲基丁烷(0.3mmol,37.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体23.5mg,产率75.5%。
1H NMR(400MHz,CDCl3)δ7.76–7.72(m,2H),7.51–7.45(m,H),7.40(t,J=7.5Hz,1H),7.35–7.28(m,2H),6.41(d,J=7.6Hz,1H),5.29(dd,J=14.3,6.8Hz,1H),4.64(s,2H),1.82(d,J=6.9Hz,2H),0.99(s,9H).
LC-MASS m/z calcd for C20H26NO2[M+H]+312.19,found 312.13;
实施例24:N-(3,3-dimethyl-1-(4-trifluoromethyl)phenyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、2-溴-2-甲基丁烷(0.3mmol,37.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体27.4mg,产率75.4%。
1H NMR(400MHz,CDCl3)δ7.76–7.73(m,2H),7.56(d,J=8.2Hz,2H),7.52–7.47(m,1H),7.46–7.38(m,4H),6.52(d,J=7.8Hz,1H),5.35–5.29(m,1H),1.79(t,J=6.1Hz,2H),1.36(q,J=7.5Hz,2H),0.95(d,J=4.1Hz,6H),0.85(t,J=7.5Hz,3H).
13C NMR(101MHz,CDCl3)δ166.5,148.7,134.3,131.7,128.7,126.9,126.7,125.8,125.7,50.9,48.5,34.8,33.6,27.2,8.5.
19F NMR(376MHz,CDCl3)δ-62.28.
实施例25:N-(2-(1-methycyclohexyl)-1-(4-(trifluoromethyl)phenyl)
ethyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、1-溴-1-甲基环己烷(0.3mmol,52.8mg,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),结束后,混合物用乙酸乙酯洗脱出来,减压蒸馏除去溶剂,通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体24.5mg,产率62.9%。
1H NMR(400MHz,CDCl3)δ7.76–7.74(m,2H),7.57(d,J=8.2Hz,2H),7.52–7.48(m,1H),7.47–7.39(m,4H),6.47(d,J=7.7Hz,1H),5.38–5.32(m,1H),1.82(dd,J=6.3,3.7Hz,2H),1.46–1.42(m,5H),1.40–1.36(m,2H),1.33–1.28(m,3H),1.02(s,3H).
13C NMR(101MHz,CDCl3)δ166.4,148.7,134.3,131.8,128.8,126.97,126.7,125.8,125.5,50.5,49.7,38.4,38.2,33.5,26.3,25.3,22.1,22.0.
19F NMR(376MHz,CDCl3)δ-62.35
实施例26:N-(3,3-dimethyl-5-phenyl-1-(4-(trifluoromethyl)phenyl)pentyl)benzamide氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、(3-bromo-3-methylbutyl)benzene(0.3mmol,70.8mg,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),反应结束,混合物用乙酸乙酯洗脱出来,通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体33.9mg,产率77.2%。
1H NMR(400MHz,CDCl3)δ7.73–7.70(m,2H),7.57(d,J=8.2Hz,2H),7.51–7.44(m,3H),7.42–7.36(m,2H),7.27–7.22(m,2H),7.19–7.14(m,1H),7.13–7.09(m,2H),6.48(d,J=7.9Hz,1H),5.40–5.35(m,1H),2.59–2.53(m,2H),1.90–1.88(m,2H),1.61(dd,J=10.1,7.5Hz,2H),1.06(d,J=1.2Hz,3H).
13C NMR(101MHz,CDCl3)δ166.58,148.48,142.78,134.38,131.8,128.8,128.5,128.3,127.0,126.8,125.8,51.1,48.8,44.9,33.8,30.7,27.7.
19F NMR(376MHz,CDCl3)δ-62.32.
实施例27:N-(3,3,7-trimethyl-1-(4-(trifluoromethyl)phenyl)octyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、2-br omo-2,6-dimethylheptane(0.3mmol,61.8mg,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),反应结束,混合物用乙酸乙酯从硅胶中洗脱出来,通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体29.2mg,产率69.6%。
1H NMR(400MHz,CDCl3)δ7.76–7.73(m,2H),7.57(d,J=8.2Hz,2H),7.53–7.47(m,1H),7.47–7.39(m,4H),6.46(d,J=7.7Hz,1H),5.34–5.29(m,1H),1.83–1.79(m,2H),1.53–1.49(m,1H),1.28–1.19(m,4H),1.10–1.05(m,2H),0.98(d,J=2.3Hz,6H),0.84(dd,J=6.6,1.6Hz,6H).
13C NMR(101MHz,CDCl3)δ166.4,148.6),134.3,131.8,128.7,126.9,126.7,125.8,51.0,48.9,42.8,39.8,33.6,28.1,27.9,27.8,22.7,22.6,21.9.
19F NMR(376MHz,CDCl3)δ-62.34.
实施例28:5-benzamido-3,3-dimethyl-5-(4-(trifluoromethyl)phenyl)pentylbenzoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、3-br omo-3-methylbutyl benzoate(0.3mmol,81.0mg,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体37.4mg,产率77.4%。
1H NMR(400MHz,CDCl3)δ7.97–7.95(m,2H),7.76–7.71(m,2H),7.55(t,J=7.4Hz,3H),7.48–7.32(m,7H),6.71(d,J=8.1Hz,1H),5.43(td,J=8.8,3.8Hz,1H),4.47–4.32(m,2H),2.07–1.96(m,2H),1.89–1.80(m,2H),1.09(d,J=12.6Hz,6H).
实施例29:N-(2-(4-methyltetrahydro-2H-pyran-4-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)benzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、4-br omo-4-methyltetrahydro-2H-pyran benzoate(0.3mmol,53.4mg,3.0eq.)、锌(0.2mmo l,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,10:1),收集并干燥得到白色固体36.8mg,产率94.1%。
1H NMR(400MHz,CDCl3)δ7.76–7.71(m,2H),7.57(d,J=8.2Hz,2H),7.53–7.37(m,5H),6.62(d,J=8.2Hz,1H),5.41(td,J=8.3,4.4Hz,1H),3.75–3.52(m,4H),1.98–1.83(m,2H),1.67–1.38(m,4H),1.14(s,3H).
LC-MASS m/z calcd for C22H24F3NO2391.17,found 391.91;
实施例30:Benzyl 4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)pentanoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、丙烯酸苄酯(0.1mmol,15.4μL,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmo l,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到白色固体30.2mg,产率82.9%。
1H NMR(400MHz,CDCl3)δ7.54(d,J=8.2Hz,2H),7.43(d,J=8.2Hz,2H),7.35–7.28(m,3H),7.25–7.21(m,2H),5.12–5.01(m,2H),3.75(dd,J=9.0,3.7Hz,1H),2.36–2.30(m,1H),1.59–1.55(m,1H),0.88(d,J=3.3Hz,9H).
13C NMR(101MHz,CDCl3)δ173.9,144.8,135.6,128.6,128.6,128.3,128.2,125.7,77.4,77.4,67.01,48.2,47.3,31.2,29.5.
19F NMR(376MHz,CDCl3)δ-62.39.
实施例31:tert-butyl 4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)pentanoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、丙烯酸叔丁酯(0.1mmol,14.3μL,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmo l,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到无色油状液体21.5mg,产率65.3%。
1H NMR(400MHz,CDCl3)δ7.55(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,2H),3.59(dd,J=9.2,3.5Hz,1H),2.28(dd,J=14.0,9.2Hz,1H),1.48(dd,J=14.0,3.6Hz,1H),1.37(s,9H),0.91(s,9H).
13C NMR(101MHz,CDCl3)δ173.2,145.7,128.1,125.5,81.0,49.3,47.2,31.2,29.5,27.9.
19F NMR(376MHz,CDCl3)δ-62.34.
实施例32:4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)pentyl benzoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、苯甲酸烯丙酯(0.1mmol,15.5μL,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到白色固体25.4mg,产率69.5%。
1H NMR(400MHz,CDCl3)δ7.91–7.89(m,2H),7.58–7.52(m,3H),7.41(t,J=7.6Hz,4H),4.42(dd,J=10.8,6.4Hz,1H),4.28(dd,J=10.8,8.0Hz,1H),3.26(m,1H),1.76(dd,J=14.2,5.9Hz,2H),0.86(s,9H).
13C NMR(101MHz,CDCl3)δ166.5,148.3,133.1,130.1,129.5,128.6,128.5,125.5,69.8,45.9,41.9,31.4,30.1.
19F NMR(376MHz,CDCl3)δ-62.22.
实施例33:3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl benzoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、苯甲酸乙烯酯(0.1mmol,13.9μL,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到白色固体25.6mg,产率73.1%。
1H NMR(400MHz,CDCl3)δ7.91–7.89(m,2H),7.40–7.36(m,3H),7.30–7.22(m,4H),4.19(t,J=7.3Hz,1H),1.85(dd,J=14.1,5.8Hz,2H),0.83(s,9H).
实施例34:tert-butyl(3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl)carbamate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-Boc-乙烯胺(0.1mmol,14.3mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体22.4mg,产率65.0%。
1H NMR(400MHz,CDCl3)δ7.57(d,J=8.1Hz,2H),7.37(d,J=7.9Hz,2H),4.79(s,2H),1.62(s,2H),1.40(s,9H),0.98(s,9H).
19F NMR(376MHz,CDCl3)δ-62.29.
实施例35:4,4-dimethyl-N-phenyl-2-(4-(trifluoromethyl)phenyl)pentanamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-苯基丙烯酰胺(0.1mmol,14.8μL,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体19.4mg,产率55.3%。
1H NMR(400MHz,CDCl3)δ7.58(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),7.44(d,J=7.7Hz,2H),7.29(d,J=7.5Hz,2H),7.22(s,1H),7.08(t,J=7.4Hz,1H),3.59(dd,J=8.0,4.4Hz,1H),2.49(dd,J=14.1,8.0Hz,1H),1.61(dd,J=14.1,4.4Hz,2H),0.93(s,9H).
13C NMR(101MHz,CDCl3)δ171.2,145.6,137.8,129.1,128.1,125.9,124.6,120.0,51.0,47.3,31.2,29.7.
19F NMR(376MHz,CDCl3)δ-62.41.
实施例36:N-(3,3-dimethyl-1-(trifluoromethyl)phenyl)butyl)3,5-dimethylbenzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、3,5-二甲基-N-乙烯基苯甲酰胺(0.1mmol,17.5mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(RetschMM500,35赫兹,90分钟),结束后,混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体29.8mg,产率79.0%。
1H NMR(400MHz,CDCl3)δ7.56(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.34(s,2H),7.12(s,1H),6.44(d,J=7.8Hz,1H),5.33(m,1H),2.32(s,6H),1.81(dd,J=6.2,5.5Hz,2H),1.01(s,9H).
13C NMR(101MHz,CDCl3)δ166.8,148.6,138.4,134.8,133.3,126.7,125.7,125.6,124.7,51.2,50.8,31.1,30.1,21.3.
19F NMR(376MHz,CDCl3)δ-62.31.
实施例37:N-(3,3-dimethyl-1-(trifluoromethyl)phenyl)butyl)4-methoxybenzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、4-甲氧基-N-乙烯基苯甲酰胺(0.1mmol,17.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),结束后,混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体27.1mg,产率71.5%。
1H NMR(400MHz,CDCl3)δ7.73–7.71(m,2H),7.57(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),6.93–6.89(m,2H),6.25(d,J=7.6Hz,1H),5.34–5.28(m,1H),3.84(s,3H),1.80(d,J=6.5Hz,2H),1.01(s,9H).
19F NMR(376MHz,CDCl3)δ-62.34.
实施例38:N-(3,3-dimethyl-1-(trifluoromethyl)phenyl)butyl)-2-methylbenzamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、2-甲基-N-乙烯基苯甲酰胺(0.1mmol,16.1mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体23.9mg,产率65.8%。
1H NMR(400MHz,CDCl3)δ7.59(d,J=8.1Hz,1H),7.45(d,J=8.1Hz,1H),7.34–7.27(m,2H),7.23–7.14(m,2H),6.13(s,1H),5.33–5.28(m,1H),2.33(s,3H),1.75(d,J=6.4Hz,2H),1.02(s,9H).
13C NMR(101MHz,CDCl3)δ169.1,148.7136.4,136.2,131.2,130.1,126.7,126.3,125.8,125.7,51.0,50.8,31.1,30.1,19.8.
19F NMR(376MHz,CDCl3)δ-62.31.
实施例39:N-(3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl)acetamide
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基乙酰胺(0.1mmol,8.5mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体14.8mg,产率51.6%。
1H NMR(400MHz,CDCl3)δ7.57(d,J=8.2Hz,2H),7.39(d,J=8.1Hz,2H),5.67(d,J=7.2Hz,1H),5.21–5.04(m,1H),1.97(s,3H),1.70(d,J=4.5Hz,2H),0.96(s,9H).
LC-MASS m/z calcd for C15H20F3NNaO[M+H]+310.13,found 310.09;
实施例40:Benzyl 2-benzoyl-4,4-dimethylpentanoate
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、丙烯酸苄酯(0.1mmol,15.4μL,1.0eq.)、苯甲酰氯(0.15mmol,17.3μL,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到白色固体19.7mg,产率60.5%。
1H NMR(400MHz,CDCl3)δ7.99–7.97(m,2H),7.60–7.55(m,1H),7.47–7.43(m,2H),7.29(dd,J=4.3,2.4Hz,3H),7.20(dd,J=6.6,3.0Hz,2H),5.11(d,J=3.5Hz,2H),4.43(t,J=6.0Hz,1H),2.05(d,J=6.0Hz,2H),0.90(s,9H).
实施例41:N-(2-cyclohexyl-1-(4-(trifluoromethyl)phenyl)ethyl)benzamide
氮气保护下,将NiBr2·dtbbpy(4.8mg,0.01mmol,10mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、苯甲酰氯(0.15mmol,17.3μL,1.5eq.)、碘代环己烷(0.3mmol,39.0μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,2.0小时),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到白色固体8.3mg,产率22.1%。
1H NMR(400MHz,CDCl3)δ7.77(d,J=7.8Hz,2H),7.59(d,J=8.2Hz,2H),7.53–7.42(m,5H),6.33(d,J=7.5Hz,1H),5.33–5.27(m,1H),1.85–1.77(m,3H),1.39–1.11(m,8H),1.11–0.93(m,2H).
实施例42:1-(3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl)pyrrolidine-2-one
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.01mmol,5mol%)、N-乙烯基吡咯烷酮(0.1mmol,10.7μL,1.0eq.)、苯甲酰氯(0.15mmol,17.3μL,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚),收集并干燥得到白色固体19.2mg,产率61.4%。
1H NMR(400MHz,CDCl3)δ7.57(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),5.54(dd,J=9.3,4.4Hz,1H),3.46–3.38(m,1H),3.02–2.93(m,1H),2.34(td,J=9.1,7.0Hz,2H),1.99–1.91(m,2H),1.81(dd,J=14.4,4.4Hz,2H),0.96(s,9H).
LC-MASS m/z calcd for C17H22F3NNaO[M+Na]+336.15,found 336.29;
实施例43:N-(3,3-dimethyl-1-(trifluoromethyl)phenyl)butyl)3,5-dimethylbenzamide
空气保护下,将NiBr2·dtbbpy(82.8mg,0.057mmol,3mol%)、3,5-二甲基-N-乙烯基苯甲酰胺(5.7mmol,1.0g,1.0eq.)、4-三氟甲基碘苯(8.55mmol,1.24mL,1.5eq.)、溴代叔丁烷(17.1mmol,1.85mL,3.0eq.)、锌(11.4mmol,748mg,2.0eq.)和碘化钠(11.4mmol,1.7g,2.0eq.)添加到50mL的不锈钢罐中(内置3颗直径为12mm的不锈钢球),再加入分析纯5.7mL四氢呋喃和570μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,2小时),反应结束后,混合物用乙酸乙酯洗脱出来,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,10:1),收集并干燥得到白色固体1.55g,产率72.1%,核磁数据与实施例36一致。
实施例44:N-(3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl)benzamide
空气条件下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体27.3mg,产率78.9%,核磁数据与实施例4一致。
实施例45:N-(3,3-dimethyl-1-(4-(trifluoromethyl)phenyl)butyl)benzamide
空气条件下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)添加到1.5mL的不锈钢罐中(内置一颗直径为5mm的不锈钢球),再加入分析纯0.1mL四氢呋喃和10μL 1,4-二氧六环,拧紧不锈钢罐,置于球磨仪上进行研磨(Retsch MM500,35赫兹,90分钟),待研磨结束后,混合物用乙酸乙酯从硅胶中洗脱出来,减压蒸馏除去溶剂,粗产物通过硅胶柱层析提纯(洗脱剂为石油醚/乙酸乙酯,20:1-10:1),收集并干燥得到白色固体27.7mg,产率79.3%,核磁数据与实施例4一致。
溶液体系参照实验1:
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)置于反应小瓶中,再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,反应1.5h,点板监测并没有产物。
溶液体系参照实验2:
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)置于反应小瓶中,再加入超干0.1mL四氢呋喃和10μL 1,4-二氧六环,反应16h,点板监测并没有产物。
溶液体系参照实验3:
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)置于反应小瓶中,再加入超干0.5mL四氢呋喃和50μL 1,4-二氧六环,反应1.5h,点板监测并没有产物。
溶液体系参照实验4:
氮气保护下,将NiBr2·dtbbpy(2.4mg,0.005mmol,5mol%)、N-乙烯基苯甲酰胺(0.1mmol,14.7mg,1.0eq.)、4-三氟甲基碘苯(0.15mmol,40.8mg,1.5eq.)、溴代叔丁烷(0.3mmol,32.3μL,3.0eq.)、锌(0.2mmol,13.1mg,2.0eq.)和碘化钠(0.2mmol,30.0mg,2.0eq.)置于反应小瓶中,再加入超干0.5mL四氢呋喃和50μL 1,4-二氧六环,反应16h,点板监测并没有产物。
表1为本发明机械化学力合成方法与传统溶液体系的收率对比,具体以实施例4(对应编号1),44(对应编号2),45(对应编号3)以及溶液体系参照实验1-4(依次对应编号4-7)为例。
表1
利用本发明的机械化学力合成方法,可以引入一些生物活性和药物分子的核心结构,例如1-氯-2-(4-乙氧基苄基)-4-碘代苯(实施例22),它是制备治疗2型糖尿病达格列净的关键中间体。此外,还可以应用于合成临床候选药物--革兰氏阳性细菌胸腺甘酸激酶抑制剂的关键中间体(TK-666)及其衍生物;或者可以简化5-脂氧合酶激活蛋白(FLAP)潜在抑制剂的制备过程;以及制备能够抑制乳腺癌细胞增殖的药物。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (4)
1.一种三组分还原交叉偶联构建C-C键的机械力合成方法,其特征在于,包括以下步骤:
将金属与配体的络合物NiBr2·dtbbpy、还原剂、添加剂以及三组分原料和溶剂混合后在机械外力作用下反应,得到所述化合物;
所述三组分原料为烷基卤化物、烯烃衍生物和芳基卤化物,或者,为烷基卤化物、烯烃衍生物和酰氯;
所述还原剂为锌或锰;所述添加剂为碘化钠、碘化钾和四丁基碘化铵中的一种;所述溶剂为四氢呋喃、2-甲基四氢呋喃、乙腈、甲苯、1,4-二氧六环、N,N-二甲基乙酰胺和二甲基亚砜中的一种或多种;所述烷基卤化物、烯烃衍生物和芳基卤化物的摩尔比为1-3:1-2:1-2;所述烷基卤化物、烯烃衍生物和酰氯的摩尔比为1-3:1-2:1-2;所述金属与配体的络合物NiBr2·dtbbpy的用量为三组分原料质量的1-10%;所述反应的时间为0-3小时,且不为0;
所述烷基卤化物的结构式为下列结构式中的一种:
所述机械外力通过将混合后的原料密封后置于球磨仪中以10-35Hz的频率研磨来施加;
所述烯烃衍生物的结构式为下列结构式中的一种:
所述芳基卤化物的结构式为下列结构式中的一种:
所述金属与配体的络合物NiBr2·dtbbpy的结构式为
所述溶剂的用量以μL计,所述金属与配体的络合物NiBr2·dtbbpy、还原剂、添加剂以及三组分原料的用量以mg计,所述溶剂的用量与所述金属与配体的络合物NiBr2·dtbbpy、还原剂、添加剂以及三组分原料的用量之和的比例为1:3~4:3。
2.根据权利要求1所述的三组分还原交叉偶联构建C-C键的机械力合成方法,其特征在于,所述金属与配体的络合物NiBr2·dtbbpy的制备方法包括以下步骤:
将镍(II)溴化乙烯二醇二甲基醚络合物和4,4’-二叔丁基-2,2’-联吡啶按当量比1:1.2加入溶剂中溶解,除去溶剂,得到所述金属与配体的络合物NiBr2·dtbbpy。
3.一种拓宽三组分还原交叉偶联构建C-C键过程中底物适用性范围的方法,其特征在于,采用权利要求1所述的三组分还原交叉偶联构建C-C键的机械力合成方法。
4.一种节约三组分还原交叉偶联构建C-C键过程中溶剂用量的方法,其特征在于,采用权利要求1所述的三组分还原交叉偶联构建C-C键的机械力合成方法。
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