Ring transformations in reactions of pyrimidine and N-alkylpyrimidinium salts with nucleophile

E.A. Oostveen

Research output: Thesisinternal PhD, WU


<p/>Paper I<p/>On treatment with liquid ammonia at -33°C, the quaternary pyrimidinium salts, <em>i.e.</em> 1-methylpyrimidinium methyl sulfate, 1,2-dimethylpyrimidinium iodide, 1,4,6-trimethyl-pyrimidinium iodide and 1,2,4,6-tetramethylpyrimidinium iodide demethylate yielding pyrimidine. 2-methyl-, 4,6-dimethyl- and 2,4.6-trimethylpyrimidine, respectively. It was observed that under these conditions 1-methyl-[1,3- <sup><font size="-1">15</font></SUP>N]-pyriniidiniuni methyl sulfate yields [1- <sup><font size="-1">15</font></SUP>N]-pyrimidine. By measuring the PMR spectra of above- mentioned pyrimidinium salts in liquid ammonia it is shown that these salts undergo covalent amination on the 1,6-azomethin bond. These results indicate that the demethylation reaction occurs <em>via</em> an Addition-NucleophileRing-Opening-Ring Closure mechanism.<p/>Paper II<p/>On treatment with active methylene compounds in basic media the quaternary pyrimidinium salts, <em>i.e.</em> methyl 1-methylpyrimidinium sulfate, 1-methyl-4-phenylpyrimidinium iodide and 1-methyl-5- phenylpyrimidinium iodide are converted into pyridine derivatives. The mechanism of the reaction is discussed.<p/>Paper III<p/>On treatment of the quaternary pyrimidinium salts <em>i.e.</em> 1-methyl-4-phenylpyrimidinium iodide and 1-methyl-5-phenylpyrimidinium iodide with cyanamide, <em>O</em> -methylisouronium chloride or bis[S-methylisothiouronium] sulfate in basic media, 2-amino-4-phenylpyrimidine and 2-amino-5-phenylpyrimidine are formed respectively. A ring transformation is involved in which the two-atom fragment N(1)-C(2) of the pyrimidine ring is replaced by an N-C fragment of the reagent. On reacting 1-methylpyrimidinium iodide with benzamidinium chloride or pivalamidinium chloride in a solution of sodium ethoxide in ethanol, 2-phenylpyrimidine and 2- <em>tert</em> -butylpyrimidine are formed respectively.<p/>It is proved by <sup><font size="-1">15</font></SUP>N-labelling that this nucleophilic substitution occurs <em>via</em> a ring transformation in which the N(1)- C(2)-N(3) fragment of the pyrimidine is replaced by the N-C-N fragment of the amidine. These reactions are new examples of a nucleophilic substitution occurring according to an S <sub><font size="-1">N</font></sub> (ANRORC) mechanism.<p/>Paper IV<p/>Reaction of 4-alkoxy- or 4,6-dialkoxypyrimidines with 1 equivalent of triethyloxonium tetrafluoroborate yields 4-alkoxy-N-ethyl or 4,6-dialkoxy-N-ethylpyrimidinium salts, respectively. With two or more equivalents of this reagent, rearrangement of N-ethyl-alkoxypyrimidinium salts into 1-ethyl-3-alkyl-1,4(3,4)-dihydro-4-oxopyrimidinium salts takes place. These rearrangements can also be performed by heating. The mechanism of these rearrangement reactions is discussed.<p/>Paper V<p/>The crystal and molecular structures of two isomeric compounds, 1-ethyl-4,6-diethoxypyrimidinium tetrafluoroborate and 1,3-diethyl-1,4(3,4)-dihydro-6-ethoxy-4-oxopyrimidinium tetrafluoroborate, reaction products of 4,6-diethoxypyrimidine with Meerwein reagent [O(C <sub><font size="-1">2</font></sub> H <sub><font size="-1">5</font></sub> )<font size="-1"><sub>3</sub><sup>+</SUP></font>BF<font size="-1"><sub>4</sub><sup>-</SUP></font>] , have been determined by means of X-ray diffraction.<br/>1-Ethyl-4,6-diethoxypyrimidinium tetrafluoroborate is monoclinic a=10.794, b=13.361,c=10.892 Å, <em> β</em> =112.6°, space group P2 <sub><font size="-1">1</font></sub> /n, four molecules per unit cell.<br/>1,3-Diethyl-1,4(3,4)-dihydro-6-ethoxy-4-oxopyrimidinium tetrafluoroborate is monoclinic, a=17.637, b=14.054, c=11.501 Å, <em> β</em> =101.7°, space group C2/c, eight molecules per unit cell.<br/>In both structures the fluoroborate ions are disordered. The bond distances in the π-electron systems are reasonably well described in terms of a small number of resonance structures.<p/>Paper VI<p/>Treatment of 1,3-diethyl-1,4(3,4)-dihydro-4-oxopyrimidinium tetrafluoroborate and its 2-phenyl, 6-phenyl, 6-methyl and 6-ethoxy derivatives with aqueous ammonia resulted in the formation of a mixture of open-chain compounds i.e. <em>N</em> -formyl(acetyl,benzoyl)- <em>N</em> -ethyl-3-(ethylamino)acrylamides and <em>N</em> -ethyl-3-[formyl(acetyl,benzoyl)ethylamino]-acrylamides. They are formed by cleavage of the pyrimidine ring between the N(1)-C(2) and N(3)-C(2) bond, respectively. In liquid ammonia the same ring cleavage generally occurs; however, in the case where a 6-ethoxy group is present, recyclisation can take place, leading to 6-(ethylamino)pyrimidine derivatives. This degenerate ring transformation has been observed also with the 2-methyl and 2-phenyl derivative of 1,3-diethyl-1,4(3,4)-dihydro-6-ethoxy-4-oxopyrimidinium tetrafluoroborate. Evidence is presented by means of <sup><font size="-1">1</font></SUP>H-NMR and <sup><font size="-1">13</font></SUP>C-NMR spectroscopy that all these reactions are iniated by attack of NH <sub><font size="-1">3</font></sub> at the C(2)-position. Some of the above-mentioned open-chain compounds underwent a ring closure to the initially used 1,3-diethyl-1,4(3,4)-dihydro-4-oxopyrimidinium tetrafluoroborates on treating them with hydrofluoroboric acid in absolute ethanol.<p/>Paper VII<p/>On treatment with liquid ammonia at -33° the quaternary pyrimidinium salts i.e. 4-ethoxy-1-ethyl- and 4,6-diethoxy-1-ethylpyrimidinium tetrafluoroborate undergo amino-de-ethoxylation, yielding 1,4-dihydro-1-ethyl-4-iminopyrimidine hydrogen tetrafluoroborate and a mixture of 1,4-dihydro-6-ethoxy-1-ethyl-4-imino- and 1,6-dihydro-4-ethoxy-1-ethyl-6-iminopyrimidine hydrogen tetrafluoroberate, respectively. <sup><font size="-1">1</font></SUP>H-NMR and <sup><font size="-1">13</font></SUP>C-NMR spectroscopic evidence is presented for the fact that compounds 1 and 3 easily give σ-adducts at position 2. Using <sup><font size="-1">15</font></SUP>N-labelled ammonia it was shown that in these amino-de-ethoxylation reactions the substitution at C(4) or C(6) does not involve ring opening but probably occurs via an S <sub><font size="-1">N</font></sub> (AE <sub><font size="-1">n</font></sub> ) process. Reaction of 4-ethoxy-1-ethyl-2-phenyl-, 6-ethoxy-1-ethyl-4-phenyl-, 4,6-dimethoxy-1-ethyl-2-phenyl- and 4,6-dimethoxy-1-ethyl-2-methylpyrimidinium tetrafluoroborate with liquid ammonia gives besides the amino-de-ethoxylation product degenerate ring transformations leading to the N-deethylated products 14-16 and 4(6)-ethylaminopyrimidines 17-19. The salt 11 and 1,6-dihydro-1-ethyl-6-imino-4-phenylpyrimidine hydrogen tetrafluoroborate undergo, with potassium hydroxide, a Dimroth rearrangement to pyrimidines 20 and 17, respectively.<br/> <p/>Paper VIII<p/>The mechanism of the conversion of pyrimidine into 5-ethyl-2-methylpyridine has been investigated. It has been proved, using the labelled compounds [1,3- <sup><font size="-1">15</font></SUP>N]pyrimidine, [4,6- <sup><font size="-1">14</font></SUP>C]pyrimidine and [5- <sup><font size="-1">14</font></SUP>C]pyrimidine, that this reaction proceeds <em>via</em> a mechanism, in which the pyrimidine ring is fragmentated into two molecules of HCN and one molecule of <em>N</em> -methylacetaldimine. Four molecules of this imine undergo an aldol type condensation leading to 5-ethyl-2-methylpyridine.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
Award date8 Jun 1977
Place of PublicationWageningen
Publication statusPublished - 1977


  • pyrimidines
  • chemical reactions


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