N-(3,4,5-trimethoxybenzylidene)methanamine | 73608-65-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(3,4,5-trimethoxybenzylidene)methanamine
• 英文别名: 3,4,5-trimethoxybenzylidenemethylamine；N-(3,4,5-Trimethoxybenzylidene)methylamine；N-methyl-1-(3,4,5-trimethoxyphenyl)methanimine
• CAS: 73608-65-8
• 化学式: C₁₁H₁₅NO₃
• 分子量: 209.245
• InChiKey: BUHXDRJIZKOEFB-UHFFFAOYSA-N

物化性质

• 沸点：
  181-192 °C(Press: 14 Torr)
• 密度：
  1.03±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  40
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(3,4,5-trimethoxybenzylidene)methanamine 在 氯化亚砜 作用下， 以 氯仿 为溶剂， 反应 4.75h， 生成 5,6-Dihydro-5,11-diketo-6-methyl-8,9,10-trimethoxy-11H-indeno[1,2-c]isoquinoline
  参考文献：
  名称：

  Synthesis of Cytotoxic Indenoisoquinoline Topoisomerase I Poisons

  摘要：

  A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-6,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2, Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most-cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.

  DOI：

  10.1021/jm9803323
• 作为产物：
  描述：

  盐酸甲胺 、 3,4,5-三甲氧基苯甲醛 在 碳酸氢钠 作用下， 以 neat (no solvent) 为溶剂， 以80%的产率得到N-(3,4,5-trimethoxybenzylidene)methanamine
  参考文献：
  名称：

  Simple and efficient one-pot solvent-free synthesis of N-methyl imines of aromatic aldehydes

  摘要：

  简述 在碱存在下，通过将芳香醛和盐酸甲胺研磨在一起，实现了 N-甲基亚胺的单锅无溶剂合成，收率从良好到极佳。当使用过量的盐酸甲胺和廉价的碳酸氢钠时（通常摩尔比 ArCHO/CH3NH2-HCl/NaHCO3 = 1:5:5），让反应进行 1 小时（如果是含有抽电子取代基的芳香醛）或过夜（如果是电子丰富的醛），可获得最佳收率。经过简单的处理（用二乙醚萃取）后，得到的产物大多纯度很高，足以进行光谱鉴定。通过这种方法，共制备出 31 种 N-甲基亚胺，其中 8 种是首次合成。在可能的情况下，通过光谱手段（1H-和 13C-NMR、IR、MS）阐明了它们的结构。对于水杨醛和 4-氯苯甲醛，也在克级规模上合成了相应的亚胺，分离收率分别为 72% 和 84%。本方法不仅产量高，而且消除了传统合成 N-甲基亚胺的缺点，如使用有害溶剂和或多或少昂贵的催化剂，以及必须在加压容器中使用无水气体工作/处理。

  DOI：

  10.1016/j.crci.2013.01.010

文献信息

• Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues:  Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation
  作者：Le Wang、Keith W. Woods、Qun Li、Kenneth J. Barr、Richard W. McCroskey、Steven M. Hannick、Laura Gherke、R. Bruce Credo、Yu-Hua Hui、Kennan Marsh、Robert Warner、Jang Y. Lee、Nicolette Zielinski-Mozng、David Frost、Saul H. Rosenberg、Hing L. Sham

  DOI：10.1021/jm010523x

  日期：2002.4.1

  The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines

  描述了一系列具有杂环取代康维他汀A-4（CA-4）中的顺式双键的化合物的合成和构效关系研究。发现取代的甲苯磺酰基甲基异氰化物是构建杂环的关键中间体。评价了基于杂环的CA-4类似物对NCI-H460和HCT-15癌细胞系的细胞毒性。3-氨基-4-甲氧基苯基和N-甲基-吲哚-5-基是CA-4中3-羟基-4-甲氧基苯基的最佳替代品。发现4，5-二取代的咪唑是替代CA-4中的顺式双键的最佳选择。药物化学的努力导致发现化合物24h和25f在大鼠中的生物利用度分别为32％和82％。
• Application of Sequential Cu(I)/Pd(0)-Catalysis to Solution-Phase Parallel Synthesis of Combinatorial Libraries of Dihydroindeno[1,2-<i>c</i>]isoquinolines
  作者：Sarvesh Kumar、Thomas O. Painter、Benoy K. Pal、Benjamin Neuenswander、Helena C. Malinakova

  DOI：10.1021/co200027c

  日期：2011.9.12

  methodology is compatible with a wide-range of aliphatic linear, branched, and ester functionalized N-substituents. Unexpectedly, the formation of regioisomers featuring a 1,2,3-contiguous substitution pattern in the aromatic ring of the indene core was observed. Three distinct combinatorial libraries with a total of 111 of members were synthesized, and 80 highly substituted dihydroindenoisoquinolines structurally

  实现了并行的溶液相合成二氢茚并异喹啉组合库的顺序Cu（I）/ Pd（0）催化的多组分耦合和环空协议。关于茚核的芳基环上的取代图案以及N-取代基的方案范围和局限性已经定义，这表明该方法与各种脂族直链，支链，和酯官能化氮-取代基。出乎意料的是，观察到在茚核的芳环中形成具有1,2,3-连续取代图案的区域异构体。合成了三个不同的组合文库，共有111个成员，并且提供了80种与已知药物结构相关的高度取代的二氢茚并异喹啉，包括一些由两种区域异构体的混合物组成的混合物，可用于生物活性测试。
• Radical Mediated Aza‐ <i>Pauson‐Khand</i> Reaction of Acetylenes, Imines, and CO Leading to Five‐Membered Unsaturated Lactams
  作者：Takahide Fukuyama、Takuma Okada、Nao Nakashima、Ilhyong Ryu

  DOI：10.1002/hlca.201900186

  日期：2019.10

  Formal [2+2+1] cycloaddition reaction involving acetylenes, aromatic imines, and CO was achieved by radical chain reaction, which gave five‐membered unsaturated lactams in modest to good yields. When we used 5‐chloropentyne, sequential carbonylation took place accompanied with double annulation events to give a cyclohexanone‐fused lactam in excellent stereoselectivity.

  通过自由基链反应可实现涉及乙炔，芳族亚胺和CO的正式[2 + 2 + 1]环加成反应，从而适度地获得良好收率的五元不饱和内酰胺。当我们使用5-氯戊炔时，发生了连续的羰基化并伴有两次环化反应，从而以极好的立体选择性生成了环己酮融合的内酰胺。
• Synthesis of Cytotoxic Indenoisoquinoline Topoisomerase I Poisons
  作者：Dirk Strumberg、Yves Pommier、Kenneth Paull、Muthusamy Jayaraman、Pamela Nagafuji、Mark Cushman

  DOI：10.1021/jm9803323

  日期：1999.2.1

  A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-6,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2, Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most-cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.
• Simple and efficient one-pot solvent-free synthesis of N-methyl imines of aromatic aldehydes
  作者：Niko S. Radulović、Ana B. Miltojević、Rastko D. Vukićević

  DOI：10.1016/j.crci.2013.01.010

  日期：2013.3

  Résumé A one-pot solvent-free synthesis of N-methyl imines in good to excellent yields was performed by grinding together aromatic aldehydes and methylamine hydrochloride in the presence of a base. The best yields were achieved when an excess of methylamine hydrochloride and inexpensive sodium hydrogen carbonate was used (usually in a molar ratio ArCHO/CH3NH2·HCl/NaHCO3 = 1:5:5), allowing the reaction to proceed for 1 h (in the case of aromatic aldehydes containing electron-withdrawing substituents) or overnight (in the case of electron-rich aldehydes). After a simple work-up (extraction with diethyl ether) the obtained products were mostly pure enough for spectral characterization. In this way, 31 N-methyl imines were prepared, among which eight were synthesized for the first time. Their structures were elucidated by spectral means (1H- and 13C-NMR, IR, MS) whenever it was possible. In the case of salicylaldehyde and 4-chlorobenzaldehyde, the synthesis of the corresponding imines was also conducted on a gram-scale with a 72% and 84% isolated yield, respectively. The present approach not only provides good to high yields, but also eliminates the disadvantages of the traditional synthesis of N-methyl imines, such as the use of hazardous solvents and more or less expensive catalysts and the necessity of work/handling with an anhydrous gas in pressurized containers.

  简述 在碱存在下，通过将芳香醛和盐酸甲胺研磨在一起，实现了 N-甲基亚胺的单锅无溶剂合成，收率从良好到极佳。当使用过量的盐酸甲胺和廉价的碳酸氢钠时（通常摩尔比 ArCHO/CH3NH2-HCl/NaHCO3 = 1:5:5），让反应进行 1 小时（如果是含有抽电子取代基的芳香醛）或过夜（如果是电子丰富的醛），可获得最佳收率。经过简单的处理（用二乙醚萃取）后，得到的产物大多纯度很高，足以进行光谱鉴定。通过这种方法，共制备出 31 种 N-甲基亚胺，其中 8 种是首次合成。在可能的情况下，通过光谱手段（1H-和 13C-NMR、IR、MS）阐明了它们的结构。对于水杨醛和 4-氯苯甲醛，也在克级规模上合成了相应的亚胺，分离收率分别为 72% 和 84%。本方法不仅产量高，而且消除了传统合成 N-甲基亚胺的缺点，如使用有害溶剂和或多或少昂贵的催化剂，以及必须在加压容器中使用无水气体工作/处理。