CN110857284A - 一种合成n-甲基脂肪胺的方法 - Google Patents

一种合成n-甲基脂肪胺的方法 Download PDF

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CN110857284A
CN110857284A CN201810967988.7A CN201810967988A CN110857284A CN 110857284 A CN110857284 A CN 110857284A CN 201810967988 A CN201810967988 A CN 201810967988A CN 110857284 A CN110857284 A CN 110857284A
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aliphatic amine
methanol
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汤亚文
胥婧
孟冲
李峰
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Nanjing University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms

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Abstract

本发明公开了一种合成N‑甲基脂肪胺的方法，以脂肪胺和甲醇为原料，采用过渡金属铱催化剂催化N‑甲基化反应。本发明使用无毒无害的水做溶剂，避免使用有机试剂；反应只生成水作为副产物，无环境危害；反应原子经济性高，具有广阔的应用前景。

Description

一种合成N-甲基脂肪胺的方法
技术领域
本发明属有机合成化学技术领域，具体涉及一种合成N-甲基脂肪胺的方法。
背景技术
脂肪胺甲基化反应是一类重要的有机合成反应，其广泛应用于医药、染料、颜料和农业领域。(a.K.L.Seim,A.Obermeyer and M.B.Francis,J.Am.Chem.Soc.,2011,133,16970-16976.b.L.G.Xie and Z.X.Wang,Angew.Chem.,Int.Ed.,2011,50,4901-4904.c.D.A.Davis,A.Hamilton,J.Yang,L.D.Cremar,D.Van Gough,S.L.Potisek,M.T.Ong,P.V.Braun,T.J.Martinez,S.R.White,J.S.Moore and N.R.Sottos,Nature,2009,459,68-72.d.A.Yu,Z.Gu,D.Chen,W.He,P.Tan and J.Xiang,Catal.Commun.,2009,11,162-166.)
近年来，通过使用钌，铱，锰等金属催化剂，激活甲醇作为甲基化试剂已经引起了广泛关注。(a.Huh,K.T.；Tsuji,Y.；Kobayashi,M.；Okuda,F.；Watanabe,Y.Chem.Lett.1988,17,449-452；b.Dang,T.T.；Ramalingam,B.；Seayad,M.A.ACSCatal.2015,5,4082-4088.c.Li,F.；Xie,J.J.；Shan,H.；Sun,C.；L.Chen,L.RSC Adv.2012,2,8645-8652.)该类反应的优势：使用价格低廉低毒的甲醇为甲基化试剂，反应的副产物只生成水的生成，对环境友好，反应原子经济性高。但是这类反应仍需较高温度，反应时间长，大量的强碱，氮气保护等苛刻条件。
最近，我们课题组使用金属催化剂作为催化剂实现了利用醇作为甲基化试剂N-甲基化脂肪胺。(RSC Adv.,2012,2,8645-8652；Org.Lett.2017,19,5790-5793).
然而，之前报导的反应都在大量的甲醇作为溶剂中进行，容易造成溶剂的浪费和环境污染。
发明内容
本发明的目的在于提供种合成N-甲基脂肪胺的方法。
本发明通过下述技术方案实现：一种种合成N-甲基脂肪胺(式Ⅰ)的方法，
Figure BDA0001775446720000011
其包含使胺(式Ⅱ)
与甲醇(式III)反应
MeOH
III
反应是在过渡金属铱催化剂存在下发生，其反应通式为
Figure BDA0001775446720000021
其中，R、R’选自C1-C4烷基。
本发明通过下述具体步骤实现：
在反应容器中，加入胺、甲醇、铱络合物催化剂、碱，混合物反应数小时后，冷却到室温，旋转蒸发除去溶剂，然后通过柱分离，得到目标化合物。
其中所述的过渡金属铱催化剂为金属铱络合物[{Ir(Cp*)(OH2)Cl}2(thbpym)][Cl]2，其结构如下所示：
Figure BDA0001775446720000022
碱选用氢氧化钾，碱对于胺的摩尔量为1equiv，过渡金属铱催化剂的用量为胺的1mol％，甲醇与水的体积比为1:3，反应在130℃下反应12小时。
同现有技术相比，本发明使用水溶性过渡金属催铱化剂，反应展现出以下显著的优点，使用水为溶剂，因此避免了使用甲醇作为溶剂，因而该反应符合绿色化学的要求，具有广阔的发展前景。
具体实施方式
展示一下实例来说明本发明的某些实施例，且不应解释为限制本发明的范围。对本发明公开的内容可以同时从材料，方法和反应条件上进行许多改进，变化和改变。所有这些改进，变化和改变均确定地落入本发明的精神和范围之内。
实施例1:2-甲基-1,2,3,4-四氢异喹啉
2-methyl-1,2,3,4-tetrahydroisoquinoline
Figure BDA0001775446720000023
将四氢异喹啉(66.6mg,0.5mmol)、铱催化剂(5.1mg,0.005mmol,1mol％)、氢氧化钾(28mg,0.5mmol,1equiv)、和甲醇(0.3mL)、水(0.9mL)依次加入到10mL克氏管中。反应混合物在反应容器中130℃下反应12小时后，冷却到室温。旋转蒸发除掉溶剂，然后通过柱层析(展开剂：石油醚/乙酸乙酯)得到纯净的目标化合物，产率：87％。
1H NMR(500MHz,CDCL3)δ7.20-7.07(m,3H,ArH),7.06-6.98(m,1H,ArH),3.58(s,2H,CH2),2.93(t,J＝6.0Hz,2H,CH2),2.69(t,J＝6.0Hz,2H,CH2),2.46(s,3H,CH3)；13C{1H}NMR(125MHz,CDCL3)δ134.9,133.9,128.7,126.5,126.2,125.7,58.1,53.1,46.3,29.4.
实施例2:4,4′-三亚甲基双(1-甲基哌啶)
1,3-bis(1-methylpiperidin-4-yl)propane
将1,3-二(4-哌啶基)丙烷(105.2mg,0.5mmol)、铱催化剂(5.1mg,0.005mmol,1mol％)、氢氧化钾(28mg,0.5mmol,1equiv)、和甲醇(0.3mL)、水(0.9mL)依次加入到10mL克氏管中。反应混合物在反应容器中130℃下反应12小时后，冷却到室温。旋转蒸发除掉溶剂，然后通过柱层析(展开剂：石油醚/乙酸乙酯)得到纯净的目标化合物，产率：85％。
1H NMR(500MHz,CDCL3)δ2.67(d,J＝11.6Hz,4H),2.10(s,6H),1.73(t,J＝11.3Hz,4H),1.51(d,J＝11.2Hz,4H),1.20-1.00(m,12H)；13C{1H}NMR(125MHz,CDCL3)δ56.0,46.5,36.7,35.1,32.4,23.8.。
实施例3:1,4-二甲基哌嗪
1,4-dimethylpiperazine
Figure BDA0001775446720000032
将哌嗪(43.1mg,0.5mmol)、铱催化剂(5.1mg,0.005mmol,1mol％)、氢氧化钾(28mg,0.5mmol,1equiv)、和甲醇(0.3mL)、水(0.9mL)依次加入到10mL克氏管中。反应混合物在反应容器中130℃下反应12小时后，冷却到室温。旋转蒸发除掉溶剂，然后通过柱层析(展开剂：石油醚/乙酸乙酯)得到纯净的目标化合物，产率：83％
1H NMR(500MHz,CDCL3)δ3.20-2.00(s,8H),2.25-2.21(m,6H)；13C{1H}NMR(125MHz,CDCl3)δ55.2,46.1.。

Claims (8)

1.合成N-甲基脂肪胺Ⅰ的方法，其特征是，
Figure FDA0001775446710000011
其包含使胺Ⅱ
Figure FDA0001775446710000012
与甲醇III反应
Figure DA00017754467158808
反应是在过渡金属铱催化剂和碱存在下发生，
其中，R、R’选自C1-C4烷基。
2.根据权利要求1所述的方法，其特征是，过渡金属铱催化剂结构如下：
Figure FDA0001775446710000013
3.根据权利要求1所述的方法，其特征是，催化剂用量相对胺摩尔量为1mol％。
4.根据权利要求1所述的方法，其特征是，碱为氢氧化钾。
5.根据权利要求1所述的方法，其特征是，碱摩尔量相对于胺摩尔量为1equiv.。
6.根据权利要求1所述的方法，其特征是，反应体系溶剂为体积比为1:3的甲醇和水的混合溶剂。
7.根据权利要求1所述的方法，其特征是，反应温度为130℃。
8.根据权利要求1所述的方法，其特征是，反应时间为12小时。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103172523A (zh) * 2011-12-23 2013-06-26 南京理工大学 选择性n-甲基化伯胺的方法
CN107778182A (zh) * 2016-08-29 2018-03-09 南京理工大学 一种合成n‑烷基芳胺的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103172523A (zh) * 2011-12-23 2013-06-26 南京理工大学 选择性n-甲基化伯胺的方法
CN107778182A (zh) * 2016-08-29 2018-03-09 南京理工大学 一种合成n‑烷基芳胺的方法

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