CN116396137A - 一种热力学不稳定的取代环己烷化合物及合成方法 - Google Patents

一种热力学不稳定的取代环己烷化合物及合成方法 Download PDF

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CN116396137A
CN116396137A CN202310336548.2A CN202310336548A CN116396137A CN 116396137 A CN116396137 A CN 116396137A CN 202310336548 A CN202310336548 A CN 202310336548A CN 116396137 A CN116396137 A CN 116396137A
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thermodynamically unstable
substituted cyclohexane
cyclohexane compound
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阴国印
史宏进
王璐锦
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Wuhan University WHU
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Abstract

本发明涉及有机合成的技术领域，具体涉及一种热力学不稳定的取代环己烷化合物及合成方法，包括以下步骤：在惰性氛围中，将金属镍类催化剂、配体、碱和硅氢溶于干燥的有机溶剂中，然后加入取代环外烯烃
Figure DDA0004156629890000011
和烷基卤化物R2X，得到反应混合物，随后将上述反应混合物密封后进行反应，反应完成后，除去有机溶剂，分离纯化得到目标产物1,2‑顺式或1,3‑反式，或1,4‑顺式类化合物。本发明提供一种金属催化环外烯烃和烷基卤化物偶联制备热力学不稳定的取代环己烷化合物的高效方法，该方法操作简便，原料便宜易得，底物官能团兼容性好，具有良好的区域选择性及立体选择性。

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一种热力学不稳定的取代环己烷化合物及合成方法
技术领域
本发明涉及有机合成的技术领域，具体涉及一种热力学不稳定的取代环己烷化合物及合成方法。
背景技术
取代环己烷的合物在医药、材料和有机合成领域有着广泛的应用[a)X.Jiang,R.Wang,Chem.Rev.2013,113,5515–5546；b)S.Reymond,J.Cossy,Chem.Rev.2008,108,5359–5406]。
通过C-C键偶联反应是一种合成取代环己烷化合物的简单有效方法[a)Z.Lu,G.C.Fu,Angew.Chem.Int.Ed.2010,49,6676–6678；b)P.M.Perez Garcia,T.D.Franco,A.Orsino,P.Ren,and X.Hu,Org.Lett.,2012.14,16,4286-4289；c)N.A.Owston,G.C.Fu,J.Am.Chem.Soc.2010,132,11908–11909；d)Z.Lu,A.Wilsily；G.C.Fu,J.Am.Chem.Soc.2011,133,8154–8157；e)S.L.Zultanski；G.C.Fu,J.Am.Chem.Soc.2011,133,15362–15364；f)T.Thaler,B.Haag,A.Gavryushin,K.Schober,E.Hartmann,R.M.Gschwind,H.Zipse,P.Mayer and P.Knochel,Nature Chemistry,2010,2,125–130]。
而对于热力学不稳定的取代环己烷的合成，目前仅有少数几例报道[a)N.S.Keddie,A.M.Z.Slawin,T.Lebl,D.Philp,D.O’Hagan,Nat.Chem.2015,7,483–488；b)M.P.Wiesenfeldt,Z.Nairoukh,W.Li,F.Glorius,Science,2017,357,908–912；c)Y.Li,Y.Li,H.Shi,,H.Wei,H.Li,I.Funes-Ardoiz,G.Yin,Science,2022,376,749–753]。
因此，一种更为可行的思路是研究寻找一种合成热力学不稳定的取代环己烷化合物的高效方法。
发明内容
本发明的目的之一在于提供一种合成热力学不稳定的取代环己烷化合物的方法，该方法操作简便，原料便宜易得，底物官能团兼容性好，具有良好的区域选择性及立体选择性。
本发明的目的之二在于提供一种热力学不稳定的取代环己烷化合物。
本发明实现目的之一所采用的方案是：一种合成热力学不稳定的取代环己烷化合物的方法，包括以下步骤：在惰性氛围中，将金属镍类催化剂、配体、碱和硅氢溶于干燥的有机溶剂中，然后加入取代环外烯烃
Figure BDA0004156629870000011
和烷基卤化物R2X，得到反应混合物，随后将上述反应混合物密封后进行反应，反应完成后，除去有机溶剂，分离纯化得到目标产物1,2-顺式或1,3-反式，或1,4-顺式类化合物，即/>
Figure BDA0004156629870000021
所述的配体为如下的任一种：
Figure BDA0004156629870000022
其中，所述R1为甲基、乙基、丙基、叔丁基、环己基、苄基、苄氧基、酯基、酰胺基、苯基、取代苯基中的任意一种；所述R2为苯甲基、取代苯甲基、长碳链取代烷基、二级烷基取代基中的任意一种，所述取代苯甲基化合物的取代基为氯、溴、三氟甲基、酯基、腈基、苯基、甲氧基中的至少一种，所述长碳链取代烷基的碳链长度为2-5；所述X为氯、溴、碘中的任意一种。
优选地，当X为Cl或Br时，金属镍类催化剂：配体：碱：硅氢：取代环外烯烃：卤代物：有机溶剂的用量比为0.03～0.08mol：0.05～0.06mol：2.0～3.0mol：2.0～3.0mol：1mol：1.5～3.0mol：1.5～3mL；当X为I时，金属镍类催化剂：配体：碱：硅氢：取代环外烯烃：卤代物：有机溶剂的用量比为0.03～0.08mol：0.04～0.06mol：2.0～3.0mol：2.0～3.0mol：1mol：1.5～3.0mol：2～4mL。
优选地，所述金属镍类催化剂的阳离子为Ni+，阴离子为Cl–、Br–、I–、[CH3COO]–、[CF3COO]–、[acac]–、Cl–带1个乙二醇二甲醚、[NO3]–带2个结晶水中的任意一种。
优选地，所述的碱为KF、KOt-Bu、K3PO4、LiF、CsF、Cs2CO3中的任意一种。
优选地，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、乙二醇二乙醚、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、乙酸乙酯、丙酮、乙腈、苯乙腈、C3-C12的饱和烷基腈中的至少一种。
优选地，所述硅氢为R3SiH，R3为甲氧基或乙氧基。
优选地，反应温度为0～50℃。
本发明实现目的之二所采用的方案是：一种热力学不稳定的取代环己烷化合物，由所述的方法合成得到。
本发明的方法合成路线如下：
Figure BDA0004156629870000031
本发明具有以下优点和有益效果：
本发明提供一种金属催化环外烯烃和烷基卤化物偶联制备热力学不稳定的取代环己烷化合物的高效方法，该方法操作简便，原料便宜易得，底物官能团兼容性好，具有良好的区域选择性及立体选择性。
本发明的合成方法合成的热力学不稳定取代环己烷产物骨架存在药物，材料分子中，其可以进一步进行转化，可以简单高效地合成一系列新化合物。
具体实施方式
为更好的理解本发明，下面的实施例是对本发明的进一步说明，但本发明的内容不仅仅局限于下面的实施例。
下述实施例中，rt是指室温，NiBr2是指溴化镍(II)，Ni(CF3COO)2·4H2O是指四水合三氟乙酸镍，KF是指氟化钾，(EtO)3SiH是指三乙氧基硅烷，DMF是指N,N-二甲基甲酰胺。
实施例1
Figure BDA0004156629870000032
在充满氩气的手套箱中，将溴化镍(II)(4.4mg，0.02mmol)、配体L5(0.024mmol)、氟化钾(58.2mg，1.0mmol)溶于0.4mL干燥的N,N-二甲基甲酰胺溶剂中，在室温下搅拌10min，加入三乙氧基硅烷(182μL，1.0mmol)再搅拌5min，然后加入上述烯烃(60.8mg，0.4mmol)和苄氯(70μL，0.6mmol)，将剩余的0.4mL干燥的N,N-二甲基甲酰胺溶剂加入到反应体系中，将反应管密封并从手套箱中取出，在室温下反应36小时。反应结束后，用乙酸乙酯和饱和食盐水萃取，无水硫酸钠干燥，减压浓缩，柱层析分离纯化得到目标产物(无色油，产率92％，cis/trans>95:5)。1H NMR(600MHz,CDCl3)δ7.31(t,J＝7.6Hz,2H),7.25–7.18(m,3H),2.63–2.59(m,2H),1.76–1.65(m,5H),1.55–1.45(m,4H),1.16(qd,J＝12.8,2.9Hz,2H),1.00(tt,J＝12.1,3.2Hz,1H),0.86(s,9H).13C NMR(150MHz,CDCl3)δ143.32,128.54,128.41,128.38,125.70,48.70,34.44,33.18,32.72,32.28,30.73,27.67,21.82.HRMS(ESI/QTOF)m/z:[M+H]+Calcd for C18H29:245.2264,found:245.2262.
实施例2
Figure BDA0004156629870000041
在充满氩气的手套箱中，将四水合三氟乙酸镍(II)(7.0mg，0.02mmol)、配体L5(0.02mmol)、氟化钾(70mg，1.0mmol)溶于0.6mL干燥的N,N-二甲基甲酰胺溶剂中，在室温下搅拌10min，加入三乙氧基硅烷(148μL，0.8mmol)，然后加入上述烯烃(60.8mg，0.4mmol)和苯丙基碘(96μL，0.6mmol)，将剩余的0.6mL干燥的N,N-二甲基甲酰胺溶剂加入到反应体系中，将反应管密封并从手套箱中取出，在室温下反应48小时。反应结束后，用乙酸乙酯和饱和食盐水萃取，无水硫酸钠干燥，减压浓缩，柱层析分离纯化得到目标产物(无色油，产率90％，cis/trans>95:5)。1H NMR(400MHz,CHLOROFORM-D)δ7.28(t,J＝7.5Hz,2H),7.19(d,J＝7.5Hz,3H),2.62(t,J＝7.7Hz,2H),1.62(d,J＝7.4Hz,5H),1.51–1.29(m,8H),1.11(q,J＝12.4Hz,2H),0.95(t,J＝12.0Hz,1H),0.84(s,9H).13C NMR(100MHz,CDCl3)δ143.10,128.55,128.36,125.68,48.70,36.19,32.71,32.52,31.93,30.80,27.79,27.67,21.81.HRMS(ESI/QTOF)m/z:[M+H]+Calcd for C20H33:273.2577,found:273.2576.
以下实施例3～12均以上述实施例1的方法步骤进行，溴化镍(II)、配体L8、氟化钾、三乙氧基硅氢、干燥的N,N-二甲基甲酰胺溶剂，原料环外烯烃
Figure BDA0004156629870000042
烷基卤化物R2-X，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：
Figure BDA0004156629870000043
Figure BDA0004156629870000051
Figure BDA0004156629870000061
Figure BDA0004156629870000071
Figure BDA0004156629870000081
以下实施例13～19均以上述实施例2的方法步骤进行，四水合三氟乙酸镍(II)、配体L6、氟化钾、干燥的N,N-二甲基甲酰胺溶剂、三乙氧基硅烷，原料环外烯烃
Figure BDA0004156629870000082
烷基卤化物R2-X，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：
Figure BDA0004156629870000083
Figure BDA0004156629870000091
Figure BDA0004156629870000101
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 (8)

1.一种合成热力学不稳定的取代环己烷化合物的方法，其特征在于，包括以下步骤：在惰性氛围中，将金属镍类催化剂、配体、碱和硅氢溶于干燥的有机溶剂中，然后加入取代环外烯烃
Figure FDA0004156629850000011
和烷基卤化物R2X，得到反应混合物，随后将上述反应混合物密封后进行反应，反应完成后，除去有机溶剂，分离纯化得到目标产物1,2-顺式或1,3-反式，或1,4-顺式类化合物，即/>
Figure FDA0004156629850000012
所述的配体为如下的任一种：
Figure FDA0004156629850000013
其中，所述R1为甲基、乙基、丙基、叔丁基、环己基、苄基、苄氧基、酯基、酰胺基、苯基、取代苯基中的任意一种；所述R2为苯甲基、取代苯甲基、长碳链取代烷基、二级烷基取代基中的任意一种，所述取代苯甲基化合物的取代基为氯、溴、三氟甲基、酯基、腈基、苯基、甲氧基中的至少一种，所述长碳链取代烷基的碳链长度为2-5；所述X为氯、溴、碘中的任意一种。
2.如权利要求1所述的合成热力学不稳定的取代环己烷化合物的方法，其特征在于：当X为Cl或Br时，金属镍类催化剂：配体：碱：硅氢：取代环外烯烃：卤代物：有机溶剂的用量比为0.03～0.08mol：0.05～0.06mol：2.0～3.0mol：2.0～3.0mol：1mol：1.5～3.0mol：1.5～3mL；当X为I时，金属镍类催化剂：配体：碱：硅氢：取代环外烯烃：卤代物：有机溶剂的用量比为0.03～0.08mol：0.04～0.06mol：2.0～3.0mol：2.0～3.0mol：1mol：1.5～3.0mol：2～4mL。
3.如权利要求1所述的合成热力学不稳定的取代环己烷化合物的方法，其特征在于：所述金属镍类催化剂的阳离子为Ni+，阴离子为Cl–、Br–、I–、[CH3COO]–、[CF3COO]–、[acac]–、Cl–带1个乙二醇二甲醚、[NO3]–带2个结晶水中的任意一种。
4.如权利要求1所述的合成热力学不稳定的取代环己烷化合物的方法，其特征在于：所述的碱为KF、KOt-Bu、K3PO4、LiF、CsF、Cs2CO3中的任意一种。
5.如权利要求1所述的合成热力学不稳定的取代环己烷化合物的方法，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、乙二醇二乙醚、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、乙酸乙酯、丙酮、乙腈、苯乙腈、C3-C12的饱和烷基腈中的至少一种。
6.如权利要求1所述的合成热力学不稳定的取代环己烷化合物的方法，其特征在于：所述硅氢为R3SiH，R3为甲氧基或乙氧基。
7.如权利要求1所述的合成热力学不稳定的取代环己烷化合物的方法，其特征在于：反应温度为0～50℃。
8.一种热力学不稳定的取代环己烷化合物，其特征在于：由如权利要求1-7中任一项所述的方法合成得到。
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