Metasubstituties bij inwerking van sterke basen op gesubstitueerde 2-halogeenpyridinen

H. Boer

Research output: Thesisinternal PhD, WU


In this thesis an investigation is described on the mechanisms of aminations of derivatives of 2-halogenopyridines with potassium amide in which part of the reaction products contain the amino group occupying the position meta to the leaving halogen atom. Special attention is paid to the possibility that 2,4-didehydropyridine derivatives occur as reaction intermediates.

In the introduction a survey is given of all types of reactions recorded in the literature, occurring when halogenopyridines are treated with strong bases. From stability calculations of the various didehydropyridines the conclusion can be drawn that in some reactions 2,4-didehydropyridines might act as intermediates (Chapter 1).

Subsequently the various procedures for carrying out reactions and the analytical methods used are described (Chapter 2).

First results are given of experiments on the amination of some monohalogenopyridines with potassium amide in liquid ammonia, occurring via 3,4-didehydropyridine as an intermediate, in the presence of other nucleophiles in order to test whether these substances might act as 'didehydro scavengers' (Chapter 3).

Thereupon results of reactions of a series of 2-halogeno-6-ethoxypyridines with potassium amide in liquid ammonia with or without didehydro scavengers are reported. 2-Chloro-6-ethoxypyridine reacts very slowly with potassium amide producing about equal amounts of 2-amino-6-ethoxypyridine and 4-ethoxy-2- methylpyrimidine. This pyrimidine derivative is obviously formed analogous to 4-phenoxy-2-methylpyrimidine from 2-bromo-6-phenoxypyridine with potassium amide: the amide ion attacks the substrate at carbon atom 4, then the ring is opened between carbon atoms 3 and 4 to an intermediate which by ring closure turns into a pyrimidine derivative. From 2-bromo- and 2-iodo-6-ethoxypyridine 2-amino- and 4-amino-6-ethoxypyridine were obtained as main products. The aminations of the bromo and the iodo compounds mentioned above were also carried out in different reaction conditions i.e. various concentrations of potassium amide and in the presence of several didehydro scavengers. From the results obtained, the probability of a route via 6-ethoxy-2,4-didehydropyridine as intermediate is discussed (Chapter 4).

Amination reactions of several 3-substituted 2-bromo-6-ethoxypyridines are described in the next chapter. In some experiments didehydro scavengers were used.

When reacting 2-bromo-3,6-diethoxypyridine and 2-bromo-3-N,N-dimethyl-amino-6-ethoxypyridine with potassium amide in liquid ammonia the product with the amino group on carbon atom 4 appeared to be formed together with the 2-amino compound. In the presence of a didehydro scavenger products containing the substituent derived from this scavenger at the 2- and the 4-position are formed from these substrates together with the amino derivatives. It is likely that in these aminations 2,4-didehydropyridines are involved as intermediates. Likewise, on reacting 2-bromo-6-ethoxy-3-fluoropyridine with potassium amide 2- and 4-amino-6-ethoxy-3-fluoropyridine are formed. In the presence of the thiophenoxide ion as a didehydro scavenger no other products are found. Thus, here a combination of addition-elimination processes is supposed to occur (Chapter 5).

In investigations on the aminations of some 5-substituted 2-bromo-6-ethoxypyridines it was established that the 2-amino derivatives and never the 4-amino compounds are formed. From the 5-ethoxy, 5-N,N-dimethylamino and 5-amino derivative in each reaction the 2-amino derivative is obtained as sole product. In the presence of the 3-oxo-2-pentyl anion the following results were obtained:

In 2-bromo-5,6-diethoxypyridine the 3-oxo-2-pentyl group is introduced into the 2-position. Furthermore 1,3-dicyano-1-ethoxy-4-ethyl-1,3-hexadiene is formed as a by-product.

From 2-bromo-5-N,N-dimethylamino-6-ethoxypyridine only 5-N,N-dimethylamino-6-ethoxy-2-(3-oxo-2-pentyl)pyridine results.

5-Amino-2-bromo-6-ethoxypyridine gives in the presence of 3-pentanone no other products than those formed when the ketone is not added to the reaction mixture.

Thus, whereas didehydro reaction intermediates may be involved to a certain extent in the aminations of 2-bromo-5,6-diethoxypyridine and 2-bromo-S-N,N- dimethylamino-6-ethoxypyridine, the reaction of 5-amino-2-bromo-6-ethoxypyridine probably proceeds by an addition-elimination mechanism only.

2-Bromo-6-ethoxy-5-fluoropyridine gives a totally different reaction mixture on amination. The main product in this case is 4-ethoxy-5-fluoro-2-methylpyrimidine, formed according to the mechanism playing a role in the amination of 2-chloro-6-ethoxypyridine (Chapter 6).

The next chapter (7) gives a survey of the aminations of some 3-ethoxy-2-halogenopyridines. Information has been obtained that the reactions of both 2-bromo-3-ethoxy- and 3-ethoxy-2-iodopyridine might occur via 3-ethoxy-2,4-didehydropyridine as an intermediate.

Finally the results mentioned in the preceding chapters are listed and some general conclusions are drawn (Chapter 8).

Original languageDutch
QualificationDoctor of Philosophy
Awarding Institution
  • den Hertog, H.J., Promotor, External person
Award date3 Oct 1973
Place of PublicationWageningen
Publication statusPublished - 1973


  • amines
  • chemical reactions
  • halogenated hydrocarbons
  • organic halogen compounds
  • pyridines

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