Aminopyridine, halogenation

The regioselective halogenation of pyridinium-A -(2 -pyridyl)aniinide 7 with N-halosuccinimides, combined with a reduction of the N-N bond, provides a convenient preparation of 5-halo- and 3,5-dihalo-2-aminopyridines 8 <95T(51)8649>. 

Thieno-pyridopyridine isomers were prepared by the coupling of a halogenated aminopyridine derivative and formyl-thienylboronic acid. The coupling of the unprotected reagents led to the concomitant formation of the carbon-nitrogen and carbon-carbon bonds in good yield (4.2.),3... 

When the blocking group is other than a halogen atom or a keto group, only tars are formed. 8-Hydroxy- 1,7-naphthyridine61 is obtained from 3-amino-2-hydroxypyridine, and 1,5-naphthyridine is obtained from the 2-halo-3-aminopyridines when they are subjected to the Skraup reaction. 3-Aminopyridine 1-oxide aifords the parent 1,5-naphthyridine,62 and both 3-amino-6-hydroxypyridine and 3-amino-6-chloropyridine give 2-hydroxy-l,5-naphthyridine.63 Hart64 has applied the Skraup synthesis to 3-amino-4-hydroxypyridine and has obtained the expected 4-hydroxy-l,5-naphthyridine. 

Aminopyridines and the lactone (43) in polyphosphoric acid at 160 C gave 3-(2-hydroxyethyl)-4-oxo-4//-pyrido[l,2-a]pyrimidines (44). At lower temperature (120 C) the furan derivative (46) was formed.65 When effected with phosphoryl halides (POCl3 or POBr3), reaction of 2-aminopyridines and 43 afforded products of type 44 where the hydroxyl group was replaced by a halogen atom.49-83,85... 

By treatment of an amide with sodium hypobromite or sodium hypochlorite solution (or with halogen admixed with aqueous alkali), a primary amine having one less carbon atom is produced. Good yields are obtained when the reaction is applied to most aliphatic and aromatic amides. Examples are provided by the preparation of anthranilic acid and 3-aminopyridine (Expt 6.53). 

Halogenation of the 3-hydroxypyridines follows the pattern set by the 3-aminopyridines in that substitution takes place at the 2-position. Chlorination with hydrochloric acid and hydrogen peroxide,102 bromination with one equivalent of bromine in pyridine,192 and iodination with iodine and sodium carbonate102 all give the 2-halo-3-hydroxypyridine. Chelation and formation of a cyclic transition state does not appear a likely possibility in these reactions. Under more vigorous conditions or with an excess of the halogen, 2,6-disubstitu-tion162,183 and 2,4,6-trisubstitution can occur.162... 

Pyridones, aminopyridines, and diazines with two strongly activating substituents, readily undergo nitration, sulfonation, and halogenation (reactivity approximately that of benzene). 

Halogenation of 3-hydroxy- and 2-, 3-, and 4-aminopyridines proceeds under milder conditions (e.g., CI2, Br2, or I2 in EtOH or H2O, 20100 C) to form the mono- and dihalo derivatives, ortho and para to the activating group. 

Craig method. Introduction of a halogen into the a-position of pyridine by treatment of a solution of a-aminopyridine with sodium nitrite in hydrogen halide, followed by warming. 

A number of halogenated derivatives of 155, 160, and 165 have been prepared.129 For example, the thieno-1,2-thiazine analog 166 has been converted to eneamine derivative 167 which has been acylated (phosgene/ triethylamine) to afford acid chloride 168. Treatment of 168 with 2-aminopyridine gave 169 (Eq. 36). This process is completely analogous to the 1,2-benzothiazine synthesis depicted in Eq. (6). 

Pyridine is attacked directly by powerful nucleophiles. For example, 2-aminopyridine is synthesized by the reaction of pyridine with sodamide, NaNH2, the Tschitschibabin reaction The nitrogen heteroatom acts as a strongly electron-withdrawing group. Displacement of halogen from substituted pyridines is particularly easy, especially when ortho or para to the N heteroatom (see Heterocyclic Chemistry by M. Sainsbury in this series). 

Halogens attached to pyrazine react readily with 2>aminopyridine with the formation of a doubly fused imidazole ring. 2-Aminopyridines carrying alkyl or alkoxy groups react at ambient temperature while two halogen atoms or a nitro group inhibit the cyclization. 

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