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

C.A.H. Rasmussen

Research output: Thesisinternal PhD, WU


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.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
Award date6 Oct 1978
Place of PublicationWageningen
Publication statusPublished - 6 Oct 1978


  • halogenated hydrocarbons
  • organic halogen compounds
  • pyrimidines


Dive into the research topics of 'Cine and direct aminations of 5- and 6-halogenopyrimidines : a mechanistic study'. Together they form a unique fingerprint.

Cite this