Synthesis and amination of naphthyridines

H.J.W. van den Haak

Research output: Thesisinternal PhD, WU


In the introduction of this thesis (chapter 1) the reactions of nephthyridines with potassium amide which were known at the start of our research are reviewed. It is shown in chapter 2, that in the amination of 1,X-naphthyridines with potassium amide in liquid ammonia at about -35° to -45°C the initial adduct formation is charge controlled. Thus, at these temperatures the site with the lowest electron density is most susceptible for amide attack (C-2 in 1,5 naphthyridine, C-2 in 1,6-naphthyridine, C-2 and C-8 in 1,7-naphthyridine, C-2 in 1,8-naphthyridine), as proved by NMR spectroscopy. On raising the temperature to about 10°C the site of addition has been found to change for 1,5- and 1,7-naphthyridine (NMR spectroscopy):from C-2 to C-4 in 1,5-naphthyridine and from C-2 and C-8 to C-8 only in 1,7-naphthyridine. Thus, at about 10°C the amination is thermodynamically controlled. The several factors which contribute to the stability of these addition products have been discussed. It has been found that the anionic a adducts (2(4,8)-aminodihydro-l,X-naphthyridinides) can easily be oxidized with potassium permanganate into their corresponding 2(4,8)-amino-1,X-naphthyridines.<br/>In chapter 3 a facile synthesis of 2,6-naphthyridine is described. Both 2,6 and 2,7-naphthyridine undergo with potassium amide under kinetically and thermodynamically controlled conditions a adduct formation at position 1. Chichibabin amination of 2,6-naphthyridine yields 1-amino-2,6-naphthyridine in 54% yield. The conversion of 1-halogeno-2,6-naphthyridines into 1-amino-2,6-naphthyridine is shown in chapter 4 to proceed via an even telesubstitution process [S <sub>N</sub> (AE) <sup>tele</sup> process]. The amination of 2-bromo-1,5-naphthyridine into 2-amino-1,5-naphthyridine is shown to proceed via an S <sub>N</sub> (AE) <sup>ipso</sup> substitution mechanism.<br/>Chapter 5 deals with the reaction of 1-halogeno-2,7-naphthyridines with KNH <sub>2</sub> /NH <sub>3</sub> yielding 1-amino-2,7-naphthyridine. Experiments with deuterated compounds show that these reactions proceed via an S <sub>N</sub> (AE) <sup>ipso</sup> process and not via an S <sub>N</sub> (AE) <sup>tele</sup> process, even though a adduct formation at C-8 takes place, as is shown by NMR spectroscopy.<br/>In chapter 6 the occurrence of an open-chain intermediate in the amination of 8-bromo-1,7-phenanthroline is shown by NMR spectroscopy. The reaction of 3-bromo-2-ethoxy-1,5-naphthyridine with KNH <sub>2</sub> /NH <sub>3</sub> is described in chapter 7. The procedure in the literature for its preparation does not lead to this compound but to the isomeric 3-bromo-1-ethyl-1,5-naphthyridin-2(1H)-one. Reaction of this compound with KNH <sub>2</sub> /NH <sub>3</sub> yields 3- and 4-amino-1-ethyl-1,b- naphthyridin-2(1H)one, the latter being the main product. 3-Bromo-2-ethoxy-1,5-naplithyridine was prepared on reacting 2,3-dibromo-1,5-naphthyridine with sodium ethoxide. A mixture of 3- and 4-amino-2-ethoxy- 1,5-naphthyridine was obtained on amination of 3-bromo-2-ethoxy-1,5-naphthyridine. In both cases the intermediacy of the respective 3,4,-dihydro compounds was proposed.<p/>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
Award date16 Oct 1981
Place of PublicationS.l.
Publication statusPublished - 1981


  • pyridines
  • chemical reactions
  • amines
  • synthesis
  • organic compounds

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