2-Aminopyridine, formation from pyridine

While the aforementioned reaction works well for aminopyridines and alkoxypyridines, it is not operative for most electron-deficient pyridines as well as 2- and 4-bromopyridines. One of the possible reasons for its failure with 2-halopyridines is the formation of an unreactive dimer complex from the oxidative addition intermediate [130]. 

The corresponding V-nitro derivatives behave similarly306-308 in acid solution the hydrazines are produced in a six-electron reaction, in alkaline medium the first two-electron reduction results in the formation of the A7-nitroso derivatives which at a more negative potential are further reduced. iV-Nitropyrazole behaves slightly differently as the reduction in acid solution also results in a cleavage of the N-N bond with formation of nitrous acid. 2-Nitraminopyri-dine309 in acid solution is reduced to the hydrazine. In alkaline solution the anion is reducible, in contradistinction to most nitramines derived from primary amines. The four-electron reduction yields 2-aminopyridine. Pyridine 1-nitroimide is reduced to pyridine.309... 

No cyclopropane-like product ions, i.e. cyclopropyl cyanide ion (7), were generated from various pyridine precursors. By using collisional activation it was shown that 4-hydroxy-or 4-aminopyridines (129) dissociate via loss of CO or HCN, respectively, to form 3H-pyrrole (130), whereas CO loss from ionized 2-hydroxy pyridine (131) gives rise to the formation of IH-pyrrole (10). In other cases, mixtures of 2H- and either IH- or 3H-pyrroles are generated, depending on the nature of the precursor (Scheme 20). 

One of the typical examples of the Baltz-Schiemann reaction is synthesis of fluoro-substituted pyridines 26 from aminopyridines 25 (Scheme 6.10). In this variation, the Baltz-Schiemann reaction is most often used for the synthesis of 2-fluoropyridines. In the first step, a diazonium tetrafluoroborate is generated from 2-aminopyridine, NaN02, and solution of HF and BF3 (HBF4), while subsequent thermal decomposition of the diazonium salt leads to formation of 2-fluoropyridines. In this chapter, we present several literature examples of synthesis of 2-fluoropyridines and examples of specific use of the Baltz-Schiemann reaction for preparation of biologically active derivatives of 2-fluoropyridines. 

In 1895 Am6 Pictet (1857-1937) published the first nicotine synthesis. [529,530] Key steps are the formation of 3-(lff-pyrrol-l-yl)-pyridine from 3-aminopyridine and mucic acid and its rearrangement to 3-(l//-pyrrol-2-yl)-pyridine at high temperatures. N-Methylation and sequential reduction give eventually racemic nicotine, which can be separated with tartaric acid into its enantiomers. 

Scheme 41 Formation of imidazo[1,2-a]pyridines from aminopyridine and aldehydes.

Because of these issues, alternative conditions were investigated for this SnAt reaction, including neutral conditions at high temperature, weaker amine bases, fluoride catalysis, " and acidic conditions. Through these studies, we found the aminopyrimidine 22 to be a very poor nucleophile and typically observed either competitive SnAt reaction of base/solvent or formation of a product (46, Figure 3) that resulted from addition via the pyridine nitrogen of the aminopyridine. This product did not rearrange to the desired product 20 under neutral, weakly basic, or acidic conditions. 

Aminopyridine gives, with benzoquinone, the cyclic product (72). When reactive methylene compounds are also present, further reaction can occur, as in the formation of (73) from benzoquinone, pyridine and acetylacetone 4 and of (74) from a-naphthoquinone, pyridine and aceto-acetic ester s. 1,4-Naphthoquinonedibenzenesulphonimide behaves like naphthoquinone in forming a quaternary salt with pyridine and hydrochloric acid " . 

Comments on the diazotization of aminopyridines and their 1-oxides have been made in connection with nucleophilic substitutions leading to cyano-(p. 226), halogeno- (p. 229) and hydroxy-pyridines (p. 239). The formation of a diazotate from 2-aminopyridine (p. 229), and of diazo oxides from 3-amino-2- and -4-hydroxypyridine (p. 270) has also been noted. 

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