Naphthyridines Chichibabin amination

Naphthyridine undergoes NH2" attachment at position 1 at -30°C. The NMR spectrum of the resulting adduct does not change at 20°C. Accordingly, the amination of the same substrate yields 1-amino-2,6-naphthyridine.110 A similar behavior is displayed by 2,7-naphthyridine, attachment of the reagent occurring at position l.110 Also in this case the Chichibabin amination occurs at room temperature at the same position. 

The mechanism of the Chichibabin amination of pyridine has been discussed in terms of an addition-elimination mechanism via a covalent a-adduct.38 39 The possible formation of 2,3-didehydropyridine (2,3-pyridyne) as intermediate in the Chichibabin amination has been advocated, but this is now definitely rejected.38 39 In this section we discuss the Chichibabin amination of the parent naphthyridines and their derivatives and the products that are obtained in these aminations. The formation of their precursors (the covalent n-adducts) has already been discussed in Section II,A and II,B. 

Chichibabin amination of 1,6-naphthyridine (4) with KNH2/NH3 at room temperature gives 2-amino-l,6-naphthyridine (51) in 33% yield.19 When the... 

However, 3-methyl-1,8-naphthyridine 37b) reacts with KNH2/NH3 in a completely different way than do 37a and 37c. H- and C-NMR spectroscopy unequivocally show the formation of the 1 1 nucleophilic attack (see Section 11,A,4). Similar behavior has been found in the Chichibabin amination of 3-methylpyridine the amide predominantly attacks C-2 and not C-6. This result has been explained by an ion dipole attraction between the incoming amide ion and the methyl substituent. This type of attractive interaction also possibly determines the attack on C-2 in 37b. 

The Chichibabin reaction is exemplified by the amination of 2-methylpyridine (308) by sodium amide in toluene via intermediate 309 to yield 6-amino-2-methylpyridine (310). This reaction has been applied to pyridines, quinolines, isoquinolines, and naphthyridine as well as to benzimidazole, and was reviewed in great detail (66AHC229 78RCRI042 88AHC1). 

Amination of 5-bromo-l,7-naphthyridine with potassium amide in liquid ammonia gave a small yield of a normal Chichibabin product, 8-amino-5-bromo-l,7-naphthyridine, along with tele-aminated products 8-amino- and 2-amino-l,7-naphthyridine. 5-Chloro-I,7-naphthyridine (202) gave a low yield of 8-amino-5-chloro-l,7-naphthyridine (203) and other unidentified products (Scheme 71) (78JHC731). 

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