A survey is given of investigations on the reactions of halogeno-azahetarenes in strongly basic media, especially towards potassium amide and lithium piperidide, which were found to comprise direct and cine substitutions, ring openings and ring transformations, halogen migrations and several other processes. In this connection we studied reactions of 4-substituted halogenopyridines with potassium amide, involving cine substitutions and halogen migrations (chapter 1).
Reaction procedures and methods of analysis applied are described in chapter 2.
First we investigated the amination of 3-bromo-4-ethoxypyridine, a substrate previously supposed to be converted at -33° into 2-amino-4-ethoxypyridine, 4-ethoxypyridine and 2-amino-5-bromo-4-ethoxypyridine via a mechanism involving 4-ethoxy-2,3-didehydropyridine as an intermediate and a bromine migration (PIETERSE and DEN HERTOG, 1962). By varying reaction conditions and applying 2
H-labelling it was established that 3-bromo-4-ethoxypyridine is transformed into 4-ethoxypyridine and 3,5-dibromo-4-ethoxypyridine by an intermolecular trans-bromination, that 4-ethoxypyridine is formed at the same time by potassium-bromine exchange and that 2(=6)-amino-4-ethoxypyridine does not originate from a didehydropyridine derivative as an intermediate but results from an abnormal-addition-elimination reaction (AE a
) starting with an attack on the nucleus at C-6 by the amide ion. In a base-catalyzed reaction the 3,5-dibromo derivative is converted into 2,5-dibromo-4-ethoxypyridine, which at -33° is aminated to yield 2-amino-5- bromo-4-ethoxypyridine.
Action of potassium amide on 3-bromo-2,4-diethoxypyridine results in a bromine shift to C-5 and subsequent formation of 2,4-diethoxypyridine, 6-amino-2,4- diethoxypyridine and 6-amino-3-bromo-2,4-diethoxypyridine (chapter 3).
Variation of the substituent at C-4 and the halogen atom at C-3 gave the following results.
3-Chloro-4-ethoxypyridine is converted into 4-amino-3-chloropyridine (AE-mechanism). The 3-iodo derivative yields 4-ethoxypyridine and 3-amino-4-ethoxypyridine at -33° whereas at -75° only deiodination takes place.
3-Chloro-, 3-bromo- and 3-iodo-4-piperidinopyridine give the 3-amino derivative according to the S N
- or AE-mechanism, this strongly temperature dependent process being favoured by the voluminosity of the substituent. Evidence for a nucleophilic substitution via radical anions as a side-reaction is obtained in the conversion of 3-iodo- into 3-amino-4-piperidinopyridine. Only 3-bromo-4-piperidinopyridine yields the 2-amino compound through the AE a
-pathway with initial attack of the amide ion at C-2 and C-6. Dehalogenation was found to occur in the aminations of 3-bromo- and 3-iodo-4-piperidino pyridine (potassium-halogen exchange).
3-Bromo-4-(4'-pyridyl)pyridine containing a -I, -M substituent is rapidly transformed into 2-amino- and 3-amino-4-(4'-pyridyl)pyridine and into debrominated material. In a mixture of liquid ammonia and ether some 2-bromo-4-(4'- pyridyl)pyridine is formed together with 4-(4'-pyridyl)pyridine; a result indicating that possibly in both media bromine migration takes place, in liquid ammonia followed by a rapid amination.
3-Bromo-4-cyanopyridine, the second compound with a -I, -M group studied, yields 4-aminopyridine, 3-bromo-4-aminopyridine, 3,5-dibromo-4-aminopyridine and 2-bromo-4-aminopyridine. Thus in this case bromine migrations occur and subsequently replacements of the cyano by the amino group (chapter 4).
In connection with the results described above the reactivities of dibromo- and tribromo-4-ethoxypyridines in liquid ammonia and in a mixture of liquid ammonia and ether were studied.
In liquid ammonia 2,3-dibromo-4-ethoxypyridine yields 2,5-dibromo-4-ethoxypyridine and 2-amino-5-bromo-4-ethoxypyridine; 2,5-dibromo-4-ethoxypyridine also gives 2-amino-5-bromo-4-ethoxypyridine, while 3,5-dibromo-4-ethoxypyridine is converted into the 2,5-dibromo- and 2-amino-5-bromo derivative as well, together with substances resulting from side and subsequent reactions. It is supposed that all the reactions start with the abstraction of the most acidic proton. The formed carbanion then abstracts a bromonium ion from a molecule of the starting material yielding 2,3,5-tribromo-4-ethoxypyridine and the anion of the 2- or 5-bromo derivative. From these products by a second migration of a bromonium ion 2,5-dibromo-4-ethoxypyridyl-3-anion and the starting substance are obtained.
In the mixture of liquid ammonia and ether the same disproportionation products are formed. In this medium however, they react independently according to different routes. Thus 2,3-dibromo- and 2,5-dibromo-4-ethoxypyridine give mixtures of 2-amino-4-ethoxypyridine, 2,6-dibromo-4-ethoxypyridine and 2,3,6-tribromo-4-ethoxypyridine of the same composition, whereas 3,5-dibromo-4-ethoxypyridine is converted into 3-bromo-4-ethoxypyridine as main product, together with 2,3,6-tribromo-4-ethoxypyridine.
2,3,5-Tribromo-4-ethoxypyridine is transformed in both media into 2,3,6-tribromo-4-ethoxypyridine and in liquid ammonia also debrominated to 2,5-dibromo-4-ethoxypyridine.
In order to check the validity of the mechanisms proposed several experiments were carried out, viz. the action of potassium amide on mixtures of two substrates. The results are in good agreement with the schemes given and corroborate the introduced reaction mechanisms. Although in nearly all the reactions studied the bromine migration is an intermolecular process, there is an indication of an intramolecular transformation in the isomerization of 3,5-dibromo-6-deutero-4-ethoxypyridine into 2,5-dibromo-6-deutero-4-ethoxypyridine of nearly the same deuterium content.
The above was an incentive to investigate the base-catalyzed bromine shift in bromo-chloro-4-ethoxypyridines in both media. The reaction of 3-bromo-2-chloro-4-ethoxypyridine proceeds analogously to that of 2,3-dibromo-4-ethoxypyridine. 2-Bromo-3-chloro-4-ethoxypyridine was found to be the only example of a substrate from which a bromonium ion is abstracted from C-2 in the pyridine nucleus, producing 3-chloro-4-ethoxypyridine and 2,6-dibromo-3-chloro-4-ethoxypyridine. From 3-bromo-5-chloro-4-ethoxypyridine together with the last-mentioned products 2-bromo-5-chloro-4-ethoxypyridine is formed.
Finally it is emphasized that several isomerizations described may be used for the synthesis of compounds otherwise not easily accessible (chapter 5).