Inwerking van stikstofhoudende nucleofielen op enige 15N-gemerkte pyrimidine- en chinazolinederivaten

A.P. Kroon

Research output: Thesisinternal PhD, WU


In this thesis an investigation is described on the mechanism of aminations of pyrimidine- and quinazoline derivatives with nitrogen containing bases.

In the introduction a survey is given of investigations, reported in the literature, concerning σ-complex formation on azahetarenes and their derivatives. The complex forming ability of different carbon atoms in these heterocyclic substrates with nucleophiles is very important for the explanation of the results of many reactions (Chapter I).

On amination of 2-X-4-phenylpyrimidines (X=F, Cl, Br, J) with potassium amide in liquid ammonia at -75 °C, 2-amino-4-phenylpyrimidine is obtained in good yield. A second product, 3-amino-3-phenylacrylonitrile, is isolated in low yield.

The formation of the 2-amino compound occurs to a large extent via a series of reactions, involving an initial Addition of the Nucleophile, to the C 6 atom, Ring-opening and Ring-Closure [S N (ANRORC)- mechanism] (X=F, Cl, Br, J; resp. 82, 88, 88, 73%). Proof for this mechanism is based on studies with 2-halogeno-4-phenyl-[1,3- 15N]-pyrimidines. In the case of the 2-chloro- and 2-bromo compound the open- chain intermediate postulated in the S N (ANRORC)-mechanism can be isolated. This intermediate cyclized slowly at room temperature to the 2- amino compound. Reaction with potassium amide or sodium hydroxide gave the same result. Surprisingly the 3-amino-3-phenylacrylonitrile obtained from the 15N-labelled compounds, contains no excess of 15N. Apparently both N- atoms present in this compound must come from the amide ion. It is proposed that the nitrile is formed by an initial attack of the amide ion on C 4 . Due to steric hindrance this addition is difficult and thus must be only a minor pathway. After ring opening of the C 4 adduct it is assumed that a second amide ion adds across the azomethine bond in this open-chain product. Loss of cyanamide and a subsequent reduction-oxidation process can then give rise to the formation of acrylonitrile. This second S N (ANRORC)- mechanism, via the C 4 adduct, cannot be ruled out but it is considered to be of less importance (Chapter II).

Since there is very little information on the effect of leaving group mobility on the S N (ANRORC)-mechanism the influence of different groups on the occurrence of this mechanism was studied in the reaction of the 2-X- 4-phenylpyrimidines (X=SCH 3 , SO 2 CH 3 , SC 6 H 5 , SO 2 C 6 H 5 , SCN, CN and +N(CH 3 ) 3 ) with potassium amide. Using the [1,3- 15N]-labelled substrates, the corresponding 2-amino compounds are isolated and investigated by mass spectrometry. From the results the conclusion can be drawn that the methylthio-, the thiocyanato- and the methylsulfonyl group show a behaviour nearly identical to the 2-halogeno compounds [%-S N (ANRORC)mechanism resp. 91, 90 and 73] . The trimethylammonio- and the cyanogroup undergo almost exclusively a S N (AE) displacement process (90% and 95% resp.), while the phenylsulfonyl group has no special preference 34% S N (AE). It is very striking that the methylsulfonyl group - in contrast to the phenylsulfonyl group - mainly undergoes a S N (ANRORC)-amination. Deprotonation of the methyl group possibly is the cause of this difference; formation of the C 2 -NH 2 adduct, the first step in the addition-elimination, is then less favourable. 1H-NMR spectrometric measurements of the methylsulfonyl substrate in the amination medium showed the disappearance of the CH 3 signal. The C 6 -NH 2 adduct, postulated in the S N (ANRORC)-amination of the 2-substituted 4-phenylpyrimidines, is proven by measuring 5-deuterio-2-methylthio-4-phenylpyrimidine in its reaction medium with 1H-NMR (Chapter III).

Investigations were carried out as to how the course of the reaction is influenced by the presence of a substituent in position 6, choosing for that purpose the phenyl group. This voluminous group can possibly prevent (or retard) the addition of the amide ion at position 6(4), making the competitive reaction pathway via an addition-elimination reaction more favourable. The results, obtained when aminating 2-X-4- phenyl- [1,3- 15N] -pyrimidine (X=F, Cl, Br) with potassium amide, give evidence that in the amination of the fluoro compound no ring opening occurs, but that 2-chloro- and 2-bromo-4-phenylpyrimidine react for a considerable part (~ 70%) via ring opening into the 2-amino compound. Since in the reaction of the 2-chloro- and 2-bromo-4-phenylpyrimidine about 90% reacts by a S N (ANRORC)-mechanism one has to conclude that the phenyl group in position 4 or 6 does actually influence the addition of the amide ion on that position. The reaction intermediate, postulated for the S N (ANRORC)-mechanism in the 2-halogeno-4,6- diphenylpyrimidines, is isolated for the 2-bromo- and 2-chloro compound in low yield, using short reaction times. (Chapter IV).

In extension of the work on the amination of 2-halogeno-4,6-difenylpyrimidines, the possibility that a ring opening is also involved in the conversion of 2-chloro-4-phenylquinazoline into 2-amino-4- phenylquinazoline with potassium amide was investigated. Mass spectrometric determinations of this product indicate that about 70% of the substrate reacts via ring opening into the 2-amino compound. In this quinazoline substrate attack of amide ion at only one carbon atom can give rise to a S N (ANRORC)-mechanism, so we can conclude that this quinazoline is more vulnerable to the ring opening reaction than the 2-chloro-4,6-diphenyl-pyrimidine. This can be explained with the well-known high reactivity of the 3,4-bond in quinazoline. Experiments with other 2-substituted 4-phenyl-[3- 15N]-pyrimidines showed the same trend in occurrence of the S N (ANRORC)-mechanism as found for the 2-substituted 4- phenylpyrimidines: the 2-fluoro compound was aminated for 55% and the 2-cyano compound for 15% via a ring opening. investigation of (-chloro-4-phenylquinazoline in the amination reaction with ethanolic ammonia, using 15N labelled substrate showed as unexpected result that in the amination the S N (ANRORC)mechanism is operative for 34%. This percentage was found to be dependent on the concentration of the ammonia. The occurrence of the same ring opening reaction was shown in the amination of 2-chloro- and 4-chloroquinazoline with ethanolic ammonia (Chapter V).

It is reported ill the literature that on heating 4-quinazolinone with phenyl phosphorodiamidate 4-aminoquinazoline is formed. It is now shown, using [3- 15N]-4-quinazolinon that the formed 4-amino compound contains a certain amount of 15N-label in the amino group. It is determined that in this reaction a ring opening is partly operative in the amination of the oxo compound. The amino compound however, also undergoes an exchange reaction with PPDA involving a ring opening (Chapter VI).

Original languageDutch
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
Award date15 May 1975
Place of PublicationS.l.
Publication statusPublished - 1974


  • chemical reactions
  • nitrogen
  • pyrimidines
  • derivatives

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