Sigma-Adducts of pyrimidines and pteridines : an NMR study

This thesis deals with the results obtained by an NMR investigation on anionic σ-adducts that are formed between a number of pyrimidines and potassium amide in liquid ammonia and the covalent addition complexes that are formed between a number of pteridines and liquid ammonia or water.<sup><font size="-1">1</font></SUP>H-NMR spectra of some 5-bromo-4-R-pyrimidines (R = Ph, t Bu, OMe, PhMeN, MeNH, Me) in KNH _{<font size="-1">2</font>} /liquid NH _{<font size="-1">3</font>} are described. Evidence is presented for the formation of stable σ-adducts by attack of an amide ion to C-6 of the pyrimidinering in the cases of R = Ph, t Bu, OMe, PhMeN. When the substituent in position 4 contains an acidic hydrogen atom αto the aromatic nucleus (R = MeNH, Me), deprotonation occurs and in the case of R = CH _{<font size="-1">3</font>} also adduct formation has been observed. The ratio of anion to σ-complex is found to change from 3:1 to 1:2 for R = CH _{<font size="-1">3</font>} compared with R = CH _{<font size="-1">3</font>} . This dramatic increase in a-complex formation has been ascribed to a deuterium isotope effect.<sup><font size="-1">1</font></SUP>H and/or <sup><font size="-1">13</font></SUP>C-NMR spectral information is presented concerning the σ-addition complexes between amide ion and some 2-R-pyrimidines, 4-chloro-2-R-pyrimidines (R = Me _{<font size="-1">2</font>} N, PhMeN, piperidino, morpholino, Ph), 5-bromo-2-piperidinopyrimidine and pyrimidine itself. It was proven that in the ring interconversion that occurs when 4-chloro-2-R-pyrimidines are treated with potassium amide in liquid ammonia in first instance a 1:1 anionic σ-complex is formed in which the amide ion has attacked position 6 of the substrate. Furthermore it was established for R = Me _{<font size="-1">2</font>} N that the next step of this reaction is fission of the pyrimidine ring between C-5 and C-6 yielding the 6-amino-3,5-diaza-4-dimethylamino-3,5-hexadiene-1-yne anion. This species appeared to be stable under the reaction conditions. However, when the reaction was quenched by the addition of ammonium chloride cyclization took place to give the final reaction product 2-dimethylamino-4-methyl-s-triazine. For comparison we examined the influence of a phenyl group substituted in position 5. By means of <sup><font size="-1">13</font></SUP>C-NMR spectroscopy it was established that when 4-chloro-2-dimethylamino-5-phenylpyrimidine is reacted with KNH _{<font size="-1">2</font>} /NH _{<font size="-1">3</font>} , the final product 4-benzyl-2-dimethylamino-s-triazine is formed via addition of the amide ion to position 6. This addition is followed by a ring fission process yielding the 6-amino- 3,5-diaza-4-dimethylamino-l-phenyl-3,5-haxadiene-1-yne anion. Interestingly it was further observed, that in this species a hydride ion is transferred from C- 6 to C-2. This hydride shift could be unequivocally established using 4-chloro-6-deutero-2-dimethylamino-5-phenylpyrimidine as starting material. The 5-cyano-3,5-diaza-4-dimethylamino-l-phenyl-1,3-pentadiene anion formed in this internal disproportionation mechanism cyclizes into the 4-benzyl-2-dimethylamino-striazine that is ultimately formed upon work up.<sup><font size="-1">13</font></SUP>C-NMR spectral data of the biologically important pteridine and nineteen of its derivatives (containing one or more Cl, MeS, Me, t Bu or Ph substituents) are reported. The <sup><font size="-1">13</font></SUP>C-NMR spectrum of the title compound has been assigned conclusively. <sup><font size="-1">13</font></SUP>C-NMR substituent effects are shown to be very useful in discerning between 6- and 7-substituted pteridines. Additionally, the <sup><font size="-1">13</font></SUP>C-NMR spectra of several covalent amination products, i.e. the 3,4-dihydro-4-amino- and the 5,6,7,8-tetrahydro-6,7-diaminopteridine derivatives have been recorded. The <sup><font size="-1">13</font></SUP>C-NMR spectra of the corresponding covalent hydrates are also reported