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Chinese Journal of Organic Chemistry >

2020 , Vol. 40 >Issue 4: 1017 - 1027

DOI: https://doi.org/10.6023/cjoc201909026

Synthesis of 1,7-Bis(N-substituted-aminomethyl)-2,8-dihydroxy-Tröger's Bases and Their Application in Aldol-Ullmann Reaction

  • Yuan Rui ,
  • Cui Hao ,
  • Chen Wen ,
  • Ren Xuanxuan ,
  • Zhou Hang ,
  • Xu Hui ,
  • Sun Yawen ,
  • Liang Yanni ,
  • Wan Yu ,
  • Liu Jinjuan ,
  • Wu Hui
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  • a Key Laboratory of Biotechnology for Medicinal Plant of Jiangsu Province, Jiangsu Normal University, Xuzhou, Jiangsu 221116;
    b School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, Jiangsu 221116

Received date: 2019-09-17

  Revised date: 2019-11-06

  Online published: 2020-05-06

Supported by

Project supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Natural Science Research Projects in Universities of Jiangsu Province (No. 19KJB430019), the Science and Technology Foundation of Xuzhou City (No. KC19242), the Aid Project for PhD Faculties in Jiangsu Normal University (No. 17XLR023) and the Graduate Student Scientific Research Innovation Projects in Jiangsu Province (Nos. KYCX18_2111, KYCX18_2116).

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Abstract

1,7-Bis(N-substituted-aminomethyl)-2,8-dihydroxy-Tröger's bases (4) were synthesized and used as efficient organocatalyst for the Aldol reaction of 4-hydroxylcoumarin and 2-benzylidenemalononitrile (or methyl(ethyl)-2-cyano-3-phenylacrylate) to afford 2-amino-4-aryl-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitriles (carboxylates) (8). Subse-quently, they were used as the efficient ligand to promote the Pd-catalyzed Aldol-Ullmann reaction to give 7-aryl-7,12-dihydro-6H-chromeno[3',4':5,6]pyrano[2,3-b]indol-6-one (10) and 5'(or 5',7')-substituted-6H,12H-spiro[chromeno[3',4':5,6]-pyrano[2,3-b]indole-7,3'-indoline]-2',6-dione (12), respectively. The anti-cancer activity on human three positive breast cancer cells (MCF-7), human three negative breast cancer cells (MDA-MB-231), human hepatoma cells (HepG2), human hepatoma cells (MHCC-97H) and cytotoxicity on human hepatocyte cells (LO2) of catalyst 4 and all products in vitro were evaluated. 1,7-Bis((methylamino)methyl)-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazocine-2,8-diol (4b) had selective inhibition (inhi-bition rate>30%) on MCF-7 cells while 1,7-bis(((1-phenylethyl)amino)methyl)-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazo-cine-2,8-diol (4d) and 1,7-bis(((pyridin-2-ylmethyl)amino)methyl)-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazocine-2,8-diol (4e) had selective inhibition on MDA-MB-231 cells. 2-Amino-5-oxo-4-(3,4,5-trimethoxyphenyl)-4H,5H-dihydropyrano[3,2-c]chromene-3-carbonitrile (8q) had strong inhibitory effects on three kinds of cancer cells except MDA-MB-231 while 2-amino-4-(4-bromophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (8a), 2-amino-4-(2,4-dichlorophenyl)-5-oxo-4H,5H-dihydropyrano[3,2-c]chromene-3-carbonitrile (8e), 2-amino-4-(3-fluorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chrome-ne-3-carbonitrile (8m) and 2-amino-4-(3-bromophenyl)-5-oxo-4H,5H-dihydropyrano[3,2-c]chromene-3-carbonitrile (8n) had strong inhibitory effects on four kinds of cancer cells. However, all the compounds showed cytotoxicity to normal LO2 cells which prompts the necessary of structure modification to reduce the toxicity.

Key words： Tröger's base; Aldol-Ullmann reaction; anti-tumor activity

Cite this article

Yuan Rui , Cui Hao , Chen Wen , Ren Xuanxuan , Zhou Hang , Xu Hui , Sun Yawen , Liang Yanni , Wan Yu , Liu Jinjuan , Wu Hui . Synthesis of 1,7-Bis(N-substituted-aminomethyl)-2,8-dihydroxy-Tröger's Bases and Their Application in Aldol-Ullmann Reaction[J]. Chinese Journal of Organic Chemistry, 2020 , 40(4) : 1017 -1027 . DOI: 10.6023/cjoc201909026

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