Reactions via hetarynes

Very strong bases such as NaNH2 convert unactivated aryl halides into benzyne intermediates which react rapidly with nucleophiles to form the products of an apparently simple nucleophilic substitution. It is now clear that hetarynes are frequent intermediates in reactions of not too highly activated heteroaromatic halides. 

reaction of 3-chloro-, 3-bromo- and 3-iodo-pyridine with potassium amide in liquid ammonia give in each case the same mixture of 3- and 4-aminopyridine, showing the intermediacy of 

4- pyridyne. Under these conditions the corresponding 4-halopyridines react entirely through 

Pyridynes are also formed from ort/m-dihalides and alkali metals. Thus, reaction of 3-bromo-4-chloropyridine (889) with lithium amalgam and furan gives product (891) by trapping of the 3,4-pyridyne (890). Although 2,3-pyridyne is not formed from 3-halopyridines, because of the weaker acidity of the 2- as compared to the 4-hydrogen atom (see Section 3.2.1.8.2), it can be trapped by furan in small yield from the reaction of 3-bromo-2-chloropyridine with lithium amalgam. 

3-Pyridyne 1-oxide (893) is obtained by the action of potassium amide on 2-bromopyridine 1-oxide (892), as shown by the formation of a mixture of the 2- and 3-aminopyridine oxides. Reaction of 5-bromopyrimidine with sodium amide in liquid ammonia involves 4,5-pyrimidyne as an intermediate. 

---