Cine and direct aminations of 5- and 6-halogenopyrimidines : a mechanistic study

This thesis describes investigations into the mechanistic aspects of the cine amination of 4-substituted 5-halogenopyrimidines and the direct amination of 4-substituted 6-halogenopyrimidines by potassium amide in liquid ammonia.PMR spectra of some 4-R-5-bromopyrimidines (R=C ₆ H ₅ , t -Bu, OCH ₃ , H ₃ CNC ₆ H ₅ , HNCH ₃ , CH ₃ ) in liquid ammonia containing potassium amide are reported. Evidence is presented for the formation of stable 1:1 σ-adducts by addition of an amide ion to C-6 of the pyrimidine ring in the cases of R=C ₆ H ₅ , t-Bu, OCH ₃ and H ₃ CNC ₆ H ₅ . When R=HNCH ₃ deprotonation of the substituent occurs. In the case of R=CH ₃ deprotonation is observed alongside adduct formation, the ratio of anion to σ-complex changing from 3:1 when R=CH ₃ to 1:2 for R=CD ₃ . This increase in σ-complex formation is ascribed to a deuterium isotope effect.Evidence is presented that the cine substitution of 5-bromo-4- t -butyl-[1(3)- ¹⁵N] pyrimidine by potassium amide in liquid ammonia takes place to a considerable extent via an S _N (ANRORC) ^cinemechanism. This process involves an addition of an amide ion to C-2 of the pyrimidine ring, ring opening, loss of hydrogen bromide and subsequent ring closure. A deuterium isotope effect of about 2 is observed, indicating that hydrogen (deuterium) loss is a rate-determining step in the cine amination.No S _N (ANRORC) ^cinemechanism, but an S _N (AE) ^cineprocess is observed when the C-2 atom is inaccessible to the attacking amide ion, as in the cine amination of 5-bromo-2,4-di- t -butylpyrimidine.Treatment of 4- t -butyl-5-chloro- and 5-chloro-2,4-di- t -butylpyrimidine with potassium amide in liquid ammonia yields only minor quantities of the cine sub stitution product. The 6-amino-5-chloro derivatives are obtained as main products. It is proved that no S _N (ANRORC) processes are involved in this Chichibabin reaction, the amination products being formed via an S _N (ANRORC) mechanism.The nature of the substituent at C-4 in 4-R-5-bromopyrimidines influences the mechanism of the cine amination. An S _N (ANRORC) ^cinepathway is observed when R= t -Bu, C ₆ H ₅ , OCH ₃ or a piperidino group. If the substituent possesses an acidic proton a to the pyrimidine ring (R=CH ₃ , HNCH ₃ , HNC ₆ H ₅ and NH ₂ ) deprotonation occurs and the resulting anions are converted into the corresponding 6-amino derivatives via an S _N (AE) ^cineprocess. When R=piperidino a small amount of 2-amino-4-piperidinopyrimidine is obtained via an S _N (AE) ^teleroute.The occurrence of an S _N (ANRORC) mechanism in the direct substitutions of 4-R-6-X-pyrimidines (X=Br or Cl) is dependent on the same characteristic structural requirements as shown for the cine amination, unhindered access of the amide ion to C-2 and absence of an acidic proton αto the heterocyclic ring on the substituent at C-4. Ring opening is observed when R= t -Bu, C ₆ H ₅ , OCH ₃ and piperidino. An S _N (AE) process is indicated when R=CH ₃ (X=Br or Cl), when R=HNC ₆ H ₅ , (X=Cl) and in the reactions of 2,4-di- t -butyl-6-X-pyrimidines (X=Br or Cl). It is shown that the temperature can influence the percentage of the reaction that takes place via an S _N (ANRORC) process considerably.The amino-demethoxylation of 5-bromo-4,6-dimethoxypyrimidine and 4,6- dimethoxypyrimidine by potassium amide is shown to occur entirely via an S _N (ANRORC) mechanism to give the corresponding 6-amino derivatives.