Inwerking van basen op N-oxiden van pyridine en pyrimidine

R. Peereboom

Research output: Thesisinternal PhD, WU


A survey is given of investigations on reactions of halogeno- azahetarenes in basic media as described to date in the literature, chiefly of those on the behaviour of N-oxides of halogeno-azahetarenes and in some cases those of otherwise N-quaternised azahetarenes towards liquid ammonia and towards potassium amide in liquid ammonia. The reactions were found to proceed according to S N (AE)-, S N (EA)- and S N (AE a )-mechanisms and/or ring openings. The open-chain compounds formed in the latter process close either to the same (S N (ANRORC)- mechanism) or a new ring system (ring transformation) (Chapter

In this connection we studied reactions of 3-bromopyridine 1-oxides with potassium amide in liquid ammonia and reactions of 4-X-6-methyl-(phenyl)pyrimidine 1-oxides with liquid ammonia and potassium amide in liquid ammonia.

It was found that the reaction of 3-bromopyridine 1-oxide with potassium amide in liquid ammonia in the presence of isopropylamine affords 3-amino- and 3-(isopropylamino)pyridine 1-oxide whereas 3-bromopyridine 1-oxide remains unchanged in a mixture of liquid ammonia and isopro pylamine alone. These results affirm the previous hypothesis, that the amination of 3-bromopyridine 1-oxide with potassium amide in liquid ammonia proceeds by the S N (EA)-mechanism via 2,3-didehydropyridine 1-oxide (Chapter 2).

3-Bromo-6-methylpyridine 1-oxide was converted into 4-amino- (main product), 3-amino- and 2-amino-6-methylpyridine 1-oxide by potassium amide in liquid ammonia, whereas 3-bromo-6-ethoxypyridine 1-oxide when treated with the same reagent only yielded 3-amino-6-ethoxypyridine 1-oxide Thus the methyl group occupying the 6-position changes the pathway of the amination of 3-bromopyridine 1-oxide, whereas the ethoxy group at the C(6)-atom does not. This difference can be explained by assuming that the methyl derivative is partly deprotonated yielding an anionic group which has a strong mesomeric interaction with the N-oxide group leading to a change of the charge distribution in the ring of the substrate. This causes the occurrence of a second reaction pathway, an S N (EA)-mechanism via 3,4-didehydro-6-methylpyridine 1-oxide (Chapter 2).

The reaction of 3-bromoquinoline 1-oxide with potassium amide in liquid ammonia affords 3-hydroxy-4-[3-amino-2-quinolyl]quinoline 1-oxide together with 3- and 4-aminoquinoline 1-oxide. These products must be formed via 3,4-didehydroquinoline 1-oxide as an intermediate. That 3-bromoquinoline 1-oxide reacts differently from 3-bromopyridine 1-oxide is caused by the fused benzogroup which changes the charge distribution in the substrate considerably and enhances the stability of the intermediary 3,4-didehydroquinoline 1-oxide compared to that of 2,3-didehydroquinoline 1-oxide (Chapter 2).

The oxidation of 4-X-6-methyl(phenyl)pyrimidines (X=Cl, Br and OC 6 H 5 can theoretically give two isomeric N-oxides (N(1)- and N(3)-oxide). The structure determination of the formed 4-X-6- methyl(phenyl)pyrimidine N-oxides was based on the structure of 4- chloro-6-methyl(phenyl)pyrimidine 1-oxide which was established by means of PMR spectroscopy on the dechlorinated compound (Chapter 3).

The reactions of 4-chloro-6-methyl(phenyl)pyrimidine 1-oxide with liquid ammonia and with potassium amide in liquid ammonia yield a compound formed by amino-dechlorination, 4-amino-6-methyl(phenyl)pyrimidine 1-oxide and a ringtransformation product, 5-amino-3-methyl(phenyl)isoxazole.

The results of the reactions of 4-chloro-6-methyl- and 4-chloro-6-phenyl-[l(3)- 15N]pyrimidine 1-oxide with liquid ammonia and with pot assium amide in liquid ammonia indicate that an S N (ANRORC)-mechanism is not operative in the conversion to the 4-amino-6-methyl- and 4-amino-6-phenylpyrimidine 1-oxide respectively. Furthermore it could be established that the dechlorination in liquid ammonia does not take place via a 4,5-didehydropyrimidine 1-oxide as intermediate, but according to an S N (AE)-process. This is based on the results of the reaction of 4-chloro-5-deutero-6-phenylpyrimidine 1-oxide The amino-dechlorination of the same substrate with potassium amide in liquid ammonia presumably takes place via the same pathway. This result is supported by studying the reactions of 4-chloro-5,6-diphenylpyrimidine 1-oxide in both media. 4-Amino-5,6-diphenylpyrimidine 1-oxide as well as 5-amino-3,4-diphenyl-isoxazole are formed. Since an S N (EA)-mechanism is prohibited because of the presence of a phenylgroup on position 5, this result is good evidence for the occurrence of an S N (AE)-mechanism in the nucleophilic displacement of the halogen atom in the 4-halogenopyrimidine 1-oxides (Chapter 4).

The results of the reactions of 4-chloro-6-methyl-[l(3)- 15N]pyrimidine 1-oxide with liquid ammonia and with pot de in liquid ammonia have established two concurrent pathways for the formation of 5-amino-3-methylisoxazole. The first pathway involves addition of the nucleophile to the C(2)-atom, resulting in an isoxazole compound with the same 15N-enrichment as present in the substrate. In the second route addition to the C(4)-atom occurs leading to amino-dechlorination, as well as ring transformation to 5-amino-3-methylisoxazole with 15N enrichment at the ring nitrogen only . 6-Methyl-4-phenoxypyrimidine 1-oxide forms 5-amino-3-methylisoxazole but no 4-amino-6-methylpyrimidine 1-oxide in the reaction with potassium amide in liquid ammonia. In good accordance with these data it has been found that in this reaction the isoxazole formation only takes place via an addition of the amide ion to the C(2)-atom (Chapter 5).

Variation of the substituent X of the 4-X-6-methyl(phenyl)pyrimidine 1-oxides influences the competition between the amination and the ring contraction. The substrates, in which X=Cl, Br and I, yield 4- aminopyrimidine 1-oxides, as well as 5-aminoisoxazoles, in both media. The addition of the amide ion or ammonia to the C(4)-atom is the principal reaction pathway. In the cases where X=OC 6 H 5 and X=SC 6 H 5 the activation by the substituent at the 4-position must be low, because these substrates only react with potassium amide in liquid ammonia at -33°C. The addition of the amide ion at the C(2)-atom is strongly favoured to the addition at the C(4)-atom. 6-Methyl-4-(trimethylammonio)pyrimidine 1-oxide affords 4-amino-6-methylpyrimidine 1-oxide as sole product in the reaction with liquid ammonia. The trimethylammonio group, a good leaving group, strongly activates the 4- position for the direct nucleophilic substitution and prohibits the addition of ammonia at the C(4)-atom (Chapter 6).

Original languageDutch
QualificationDoctor of Philosophy
Awarding Institution
  • den Hertog, H.J., Promotor, External person
  • van der Plas, H.C., Co-promotor
Award date24 Jan 1975
Place of PublicationWageningen
Publication statusPublished - 1975


  • piperidines
  • pyridines
  • pyrimidines
  • nitrogen oxides
  • chemical reactions
  • bases
  • alkalinity

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