CN110981900A - 一种金属催化末端烯烃制备1,1-双炔类化合物的方法 - Google Patents
一种金属催化末端烯烃制备1,1-双炔类化合物的方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0805—Compounds with Si-C or Si-Si linkages comprising only Si, C or H atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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Abstract
本发明公开了一种金属催化末端烯烃制备1,1‑双炔类化合物的方法及应用。在金属镍类催化剂NiA、配体、联硼酸频哪醇酯和碱的作用下,将非活化的末端烯烃与三异丙基硅基乙炔溴溶于有机溶剂中并进行反应,经柱层析分离纯化得到上述结构的1,1‑双炔类化合物。本发明方法可高效合成上述结构的1,1‑双炔类化合物,具有优秀的区域选择性,并且产物中含有炔烃基团,可应用于进一步转化,从而产生各种高度官能团化的化合物,为合成复杂药物分子及药物先导化合物提供了新方法。
Description
技术领域
本发明属于有机合成领域,具体涉及一种金属催化末端烯烃1,1-双炔化的方法及应用。
背景技术
含有炔类化合物广泛存在于天然产物及药物分子中[a)P.J.Stang,F.Diederich,Modern Acetylene Chemistry;Wiley-VCH:Weinheim,1995;b)B.M. Trost,C.-J.Li,Modern Alkyne Chemistry:Catalytic and Atom-Economic Transformations;Wiley-VCH:New York,2014]。
目前,前人报道的大部分是活化的烯烃的1,2-炔官能团化[a)X.-Y.Bai,W.-W.Zhang,Q.Li,B.-J.Li,J.Am.Chem.Soc.2018,140,506;b)X.-Y.Bai,Z.-X.Wang, B.-J.Li,Angew.Chem.,Int.Ed.2016,55,9007.]。尽管如此,对于非活化的末端烯烃的1,1-双炔化反应目前为止没人报道。我们的方法操作简便,原料廉价易得,由非活化的末端烯烃制备1,1-双炔类化合物,为后面的分子修饰提供额外的途径。
发明内容
本发明的目的之一在于提供一种金属催化末端烯烃1,1-双炔化的方法,该方法操作简便,原料廉价易得,底物官能团兼容性好,具有优秀的区域选择性。
本发明实现上述目的技术方案如下:
一种金属催化末端烯烃制备1,1-双炔类化合物的方法,所述1,1-双炔类化合物的结构式如下:
所述由末端烯烃制备上述结构式的1,1-双炔类化合物的方法包括以下步骤:在惰性气体氛围下,在金属镍类催化剂NiA、配体、联硼酸频哪醇酯和碱的作用下,将末端烯烃与三异丙基硅基乙炔溴溶于有机溶剂中并进行反应,反应完全后将所得反应混合物过滤,减压浓缩除去有机溶剂,产物经柱层析分离纯化得到 1,1-双炔类化合物,所述金属镍类催化剂NiA:配体:联硼酸频哪醇酯:碱:末端烯烃:炔溴:有机溶剂的用量比为摩尔:摩尔:摩尔:摩尔:摩尔:摩尔:体积mL=0.05:0.05:2.5:2.5:1:3:5;
所述方法合成路线如下:
所述R1为取代的长链全烷基化合物,所述的取代的长链烷基化合物的取代基为任意以下结构的一种或几种:卤素、羟基、腈基、频哪醇硼烷、烷氧基、对甲基苯磺酰胺、烷基或芳基取代的酯类、芳香杂环、取代的芳基任一种。
所述由末端烯烃制备上述结构式的1,1-双炔类化合物的方法的方法具体如下:
在惰性气体中,将金属镍类催化剂NiA、配体、联硼酸频哪醇酯和碱溶于干燥的有机溶剂中,然后加入末端烯烃和三异丙基硅基乙炔溴,得到反应混合物,随后将上述反应混合物密封并从惰性气体中取出,反应完全后,过滤,减压浓缩除去有机溶剂,再经柱层析分离纯化得到目标产物1,1-双炔类化合物。
优选地,所述的金属镍类催化剂NiA中,为NiBr2、NiI2、Ni(ClO4)2·6H2O、 Ni(acac)2、NiBr2·DME中的任一种。
优选地,所述的配体为如下任一种:
所述的碱,其阳离子为Li+、Na+、K+和Cs+中的任一种,阴离子为F–、CO3 2–、 HCO3 –、PO4 3–、HPO4 2–、H2PO4 –、OH–、[CH3COO]–、[CF3COO]–、[OMe]–和[OtBu]–中的任一种。
所述的有机溶剂为甲醇、乙醇、异丙醇、四氢呋喃、2-甲基四氢呋喃、1,4- 二氧六环、乙醚、甲基叔丁基醚、乙二醇二甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、苯、甲苯、二甲苯、三甲苯、氯苯、1,2-二氯苯、丙酮、乙腈、C3-C12的饱和烷基腈中的一种或几种。
本发明还提供由上述方法制备得到的1,1-双炔类化合物。
本发明的目的之二在于提供上述方法制备得到的1,1-双炔类化合物的应用,应用于进行炔烃的转化,产生各种高度官能团化类化合物,为合成复杂药物分子及药物先导化合物提供了新方法。
本发明实现目的之二的技术方案如下:
上述1,1-双炔类化合物在用于制备高度官能团化炔类化合物中的应用,包括以下步骤:
所述应用的路线如下:
所述应用具体步骤如下:
1)在惰性气体中,将金属镍类催化剂NiA、配体、联硼酸频哪醇酯和碱溶于干燥的有机溶剂中,然后加入末端烯烃和三异丙基硅基乙炔溴,得到反应混合物,随后将上述反应混合物密封并从惰性气体中取出,反应完全后得到反应液Ⅰ;
2)将所述反应液Ⅰ用硅藻土过滤,然后用乙酸乙酯洗涤并浓缩,将得到的浓缩混合物溶于二氯甲烷中,得到反应液Ⅱ,然后在室温下,向反应液Ⅱ中加入一定的1M TBAF的四氢呋喃溶液,反应三个小时,TLC检测反应完全后,将反应液减压浓缩除去溶剂,再经柱层析分离纯化得到目标产物
其中,金属镍类催化剂NiA:配体:联硼酸频哪醇酯:碱:末端烯烃:炔溴:有机溶剂:二氯甲烷:1M TBAF四氢呋喃溶液的用量比为摩尔:摩尔:摩尔:摩尔:摩尔:体积mL:体积mL:体积mL=0.05:0.05:2.5:2.5:1:3:5:5: 1。
与现有技术相比,本发明具有以下有益效果:
本发明公开的末端烯烃制备1,1-双炔类化合物的方法,使用非活化的末端烯烃,炔溴在金属镍催化剂作用下,一锅法反应制备1,1-双炔类的有机化合物,该反应方法不但可以高效的合成目标化合物,而且底物适用性强,具有优良的区域选择性,此方法所使用的原料廉价易得,操作简便,底物官能团兼容性好,可以高效的合成1,1-双炔类产物。
具体实施方式
通过以下详细说明可以进一步理解本发明的特点和优点。所提供的实施例仅是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。
下述实施例中,
NiI2是指碘化镍,L是指配体,LiOMe是指甲醇锂,NMP是指N-甲基吡咯烷酮。
实施例1
在充满氩气的手套箱中,将碘化镍(3.1mg,0.01mmol)、配体(L)(0.01 mmol)、甲醇锂(19.0mg,0.5mmol)、联硼酸频哪醇酯(127mg,0.5mmol),加入1mL超干的N-甲基吡咯烷酮溶剂中,然后加入庚烯(28μL,0.2mmol) 和三异丙基硅基乙炔溴(150μL,0.6mmol)将反应管密封并从手套箱中取出,在30℃下反应24小时。反应结束后,用乙酸乙酯萃取,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率86%)。1H NMR(400MHz,Chloroform-d)δ3.41(t,J=6.72Hz,1H),1.72(dt,J=8.85,6.50Hz,2H),1.59- 1.53(m,2H),1.34-1.23(m,8H),1.07-1.04(m,42H),0.88(t,J=6.99Hz,3H) ppm;13C NMR(101MHz,Chloroform-d)δ106.8,81.1,36.1,31.9,28.8,26.8,25.5, 22.7,18.7,14.2,11.4ppm;HRMS(ESI)Calculated for C29H57Si2([M+H]+): 461.3993,measured:461.3992.
实施例2
在充满氩气的手套箱中,将碘化镍(3.1mg,0.01mmol)、配体(L)(0.01 mmol)、甲醇锂(19.0mg,0.5mmol)、联硼酸频哪醇酯(127mg,0.5mmol),然后加入1mL超干的N-甲基吡咯烷酮溶剂中,然后加入6-溴-1-己烯(26.7μL, 0.2mmol)和三异丙基硅基乙炔溴(150μL,0.6mmol)将反应管密封并从手套箱中取出,在30℃下反应24小时。反应结束后,用乙酸乙酯萃取,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率54%)。1H NMR(400 MHz,Chloroform-d)δ3.45-3.39(m,3H),1.91-1.84(m,2H),1.76-1.71(m,2H), 1.63-1.57(m,2H),1.52-1.44(m,2H),1.09-1.02(m,42H)ppm;13C NMR(101 MHz,Chloroform-d)δ106.4,81.4,35.7,33.8,32.8,27.7,26.0,25.4,18.7,11.4ppm; HRMS(ESI)Calculatedfor C28H54Si2([M+H]+):525.2942,measured:525.2943.
实施例3
在充满氩气的手套箱中,将碘化镍(3.1mg,0.01mmol)、配体(L)(0.01 mmol)、甲醇锂(19.0mg,0.5mmol)、联硼酸频哪醇酯(127mg,0.5mmol),然后加入1mL超干的N-甲基吡咯烷酮溶剂中,然后加入上述烯烃(27.0mg, 0.2mmol)和三异丙基硅基乙炔溴(150μL,0.6mmol)将反应管密封并从手套箱中取出,在30℃下反应24小时。反应结束后,用乙酸乙酯萃取,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率67%)。1H NMR(400 MHz,Chloroform-d)δ6.65-6.63(m,2H),6.14-6.12(m,2H),3.87(t,J=7.18Hz, 2H),3.42(t,J=6.65Hz,1H),1.86-1.70(m,4H),1.62-1.57(m,2H),1.09-1.04 (m,42H)ppm;13CNMR(101MHz,Chloroform-d)δ120.5,108.1,106.2,81.6,49.7, 35.5,31.2,25.4,24.2,18.7,11.3ppm;HRMS(ESI)Calculated for C31H56NSi2 ([M+H]+):498.3946,measured:498.3947.
实施例4
在充满氩气的手套箱中,将碘化镍(3.1mg,0.01mmol)、配体(L)(0.01mmol)、甲醇锂(19.0mg,0.5mmol)、联硼酸频哪醇酯(127mg,0.5mmol),然后加入 1mL超干的N-甲基吡咯烷酮溶剂中,然后加入上述烯烃(36.5mg,0.2mmol) 和三异丙基硅基乙炔溴(150μL,0.6mmol)将反应管密封并从手套箱中取出,在30℃下反应24小时。反应结束后,用乙酸乙酯萃取,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率45%)。1H NMR(400MHz, Chloroform-d)δ4.09(t,J=6.09Hz,2H),3.46(t,J=6.41Hz,1H),2.24-2.30(m,1H),1.93-1.85(m,4H),1.82-1.71(m,4H),1.48-1.36(m,2H),1.30-1.19(m,4 H),1.06-1.02(m,42H)ppm;13C NMR(101MHz,Chloroform-d)δ176.3,106.0, 81.8,63.7,43.4,32.7,29.2,26.1,25.9,25.6,25.2,18.7,11.3ppm;HRMS(ESI) Calculated for C33H61O2Si2([M+H]+):545.4205,measured:545.4194.
实施例5
在充满氩气的手套箱中,将碘化镍(3.1mg,0.01mmol)、配体(L)(0.01 mmol)、甲醇锂(19.0mg,0.5mmol)、联硼酸频哪醇酯(127mg,0.5mmol),然后加入1mL超干的N-甲基吡咯烷酮溶剂中,然后加入上述烯烃(36.5mg, 0.2mmol)和三异丙基硅基乙炔溴(150μL,0.6mmol)将反应管密封并从手套箱中取出,在30℃下反应24小时。反应结束后,用乙酸乙酯萃取,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率82%)。1H NMR(400 MHz,Chloroform-d)δ7.75-7.73(m,2H),7.31-7.30(m,2H),4.44(t,J=6.13Hz, 1H),3.35(t,J=6.65Hz,1H),2.95-2.90(m,2H),2.43(s,3H),1.66-1.64(m,2 H),1.54-1.48(m,4H),1.06-1.02(m,42H)ppm;13C NMR(101MHz, Chloroform-d)δ143.5,137.1,129.8,127.3,106.1,81.6,43.2,35.3,29.2,25.3,23.9, 21.6,18.7,11.3ppm;HRMS(ESI)Calculatedfor C34H60NO2SSi2([M+H]+): 602.3878,measured:602.3878.
以下实施例6-实施例12均以上述实施例1-实施例5的方法步骤进行,合成得到的化合物结构和名称、NMR与HRMS数据及产率如下表所示:
表1实施例6~12所得化合物结构及表征
实施例13
将二氯甲烷(0.1M)加入10毫升装有实施例12所得双炔化合物与搅拌子的圆底烧瓶中,最后慢慢滴加四丁基氟化铵溶液(2.0equiv)室温搅拌3小时,点板检测,反应完全后过硅胶柱,得到目标产物(无色油,87%)。1H NMR(400 MHz,Chloroform-d)δ7.30-7.25(m,2H),7.21-7.17(m,3H),4.92-4.89(m,2H), 3.00(t,J=1.51Hz,1H),2.85-2.81(m,2H),2.45-2.40(m,2H)ppm;13C NMR (101MHz,Chloroform-d)δ214.3,141.2,128.6,128.6,126.1,88.2,79.8,79.1,77.6, 35.0,34.0ppm;HRMS(ESI)Calculated for C13H13([M+H]+):169.1012,measured: 169.1012.
以上所述是本发明的优选实施方式而已,当然不能以此来限定本发明之权利范围,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和变动,这些改进和变动也视为本发明的保护范围。
Claims (9)
2.如权利要求1所述的方法,其特征在于,所述R1为取代的长链全烷基化合物,所述的长链全烷基化合物的取代基为以下结构中的任一种或几种:卤素、羟基、腈基、频哪醇硼烷、烷氧基、对甲基苯磺酰胺、烷基或芳基取代的酯类、芳香杂环、取代的芳基。
3.如权利要求1所述的方法,其特征在于,所述的金属镍类催化剂NiA中,为NiBr2、NiI2、Ni(ClO4)2·6H2O、Ni(acac)2、NiBr2·DME中的任一种。
5.如权利要求1所述的方法,其特征在于,所述的碱,其阳离子为Li+、Na+、K+和Cs+中的任一种,阴离子为F–、CO3 2–、HCO3 –、PO4 3–、HPO4 2–、H2PO4 –、OH–、[CH3COO]–、[CF3COO]–、[OMe]–和[OtBu]–中的任一种。
6.如权利要求1所述的方法,其特征在于,所述的有机溶剂为甲醇、乙醇、异丙醇、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙醚、甲基叔丁基醚、乙二醇二甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、苯、甲苯、二甲苯、三甲苯、氯苯、1,2-二氯苯、丙酮、乙腈、C3-C12的饱和烷基腈中的一种或几种。
7.一种1,1-双炔类化合物,其特征在于,由权利要求1~6任一项方法制备得到。
9.如权利要求8所述的应用,其特征在于,所述1,1-双炔类化合物:二氯甲烷:1M TBAF四氢呋喃溶液的用量比为摩尔:体积mL:体积mL=1:5:1。
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