Reactions of Amino-Pyridines

The three amino-pyridines are all more basic than pyridine itself and form crystalline salts by protonation at the ring nitrogen. The a- and y-isomers are monobasic only, because charge delocalisation over both nitrogen atoms, in the manner of an amidinium cation, prevents the addition of a second proton. The effect of the delocalisation is strongest in 4-aminopyridine 9.1) and much weaker in 2-aminopyridine (p/ aH 7.2). Delocalisation is not possible for the P-isomer, which thus can form a di-cation in strong acid (p/faHS 6.6 and -1.5).  

As in benzene chemistry, electron-releasing amino groups facilitate electrophilic substitution, so that, for example, 2-aminopyridine undergoes 5-bromination in acetic acid even at room temperature this product can then be nitrated, at room temperature, forming 2-amino-5-bromo-3-nitropyridine. Bromina-tion of all three amino-pyridines is best achieved with iV-bromosuccinimide at room temperature, products being 2-amino-5-bromo-, 3-amino-2-bromo- and 4-amino-3-bromopyridines. Similarly, chlorination of 3-amino-pyridines affords 3-amino-2-chloro-pyridines. Nitration of amino-pyridines in acid solution is also relatively easy, with selective attack of 2- and 4-isomers at P-positions. A mechanistic study of dialkylamino-pyridines showed nitration to involve attack on the salts.  

A limited number of examples of C-alkylations of aminopyridines have been reported. With 1-hydroxymethylbenzotriazole (29.3) in the presence of acid, 2-aminopyridine reacts at C-5. 4-Dimethylaminopyridine is trifluoroacetylated at C-3 with trifluoroacetic anhydride the example shows the subsequent intramolecular nucleophilic displacement of the dimethylamino group and thence formation of a pyrazolo[4,3-c]pyridine. ° 

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The synthesis of zolpidem began with an alkylation/condensation reaction of amino-pyridine 5 and bromide 6 to give imidazopyridine 7 (Scheme 15.1). Mannich-type reaction with formaldehyde and dimethylamine provided 8. Treatment of 8 with methyliodide to form the quaternary salt 9, followed by reaction with sodium cyanide, gave 10. Acidic hydrolysis followed by reaction of the resultant acid 11 with carbonyldiimidazole (GDI) and dimethylamine afforded zolpidem (1) in 46% overall yield (George et al., 1991 Rossey and Long, 1988). 

Orientation of reactions of amino-pyridines and -azines with electrophiles... 

Another series of macrocydic complexes has been prepared by Busch and co-workers by the condensation reaction of either pyridine-2,6-dicarboxaldehyde or 2,6-diacetylpyridine with various polyamines (Scheme 38). 24,2628,2640 2645 Other examples of template reactions leading to different types of macrocydic complexes are reported in Schemes 39-44.2628 2646 2650 The selfcondensation of l-amino-2-carboxaldehyde in the presence of nickel(II) gives two types of macrocycle (Scheme 45), M51... 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

Reaction of the pyridine derivative (303 R = CH(Ph)2) with ethyl orthoformate afforded only the imidazo[4,5-c]pyridine (304) in good yield <73JMC292>. A later study <87JMC1746> has reported the isolation of mixtures of both imidazo[4,5-c]pyridines (304) and imidazo[4,5-6]pyridines (305) (Equation (23)) with the isomeric ratio being dependent on the steric bulk of the 4-amino substituent. When compound (303 R = phenyl) was cyclized with ethyl orthoformate a mixture of both isomers (304) and (305) was isolated in a 1 2 ratio. However, if compound (303 R = benzyl) is used a 1 10 ratio of the products (304) and (305) is obtained. When a phenethylamino group is positioned at C-4 only the isomer (304) is formed in the reaction. Interestingly, the reaction of the derivatives (306) or (308) with benzaldehyde at room temperature for 64 h furnished only modest yields of the products (307) and (309), respectively (Equation (24)). No imidazo[4,5-c]pyridine isomer was detected in these reactions. 

The reaction of amino acids with ninhydrin can detect amino acids on a wide variety of substrates. For example, if a kidnapper touches a ransom note with his fingers, the dermal ridges on his fingers leave traces of amino acids from skin secretions. Treatment of the paper with ninhydrin and pyridine causes these secretions to turn purple, forming a visible fingerprint. 

Reaction of amino-3(2If)-pyridazinones and 4-amino-3,6-dimeth-oxypyridazine with tosyl chloride has been investigated recently. Thus, 4-amino-3(2.ff)-pyridazinone (or its 6-methoxy analog) (99) when treated with tosyl chloride in pyridine at room temperature for several days yielded a mixture of 100 (R = OMe, 30%) and 101 (R = OMe, 24% R = H, 1-2%). That 100 is formed by rearrangement... 

Vitamin Bg exists as six separate forms in the pyridine group of water-soluble vitamins. The common forms are pyridoxal and pyri-doxamine together with their corresponding phosphate esters and pyridoxine forms. These compounds function as cofactors in a wide variety of enzyme reactions, but most notably in the transamination reaction of amino acid biosynthetic pathways. Extraction of this group of vitamins can be performed by the same methods as those described for the B2 vitamins (Section 11.8.3.3). 

The high reactivity of the exocyclic 4-NH- group is again illustrated by the reaction of 2-imino-3-phenyl-4-amino-5-(ethoxycarbonyl)-4-thiazoline with EtOjCCH SCN, which yields 134 (296), and by the intramolecular preparation of the dihydrothiazolo[4,5-h]pyridine derivative 136 (297) (Scheme 89). 

Much of the development of the chemistry of sulfanilamidoselenazole derivatives is a result of the important role played by sulfonamides in chemotherapy and more particularly the good activity of sulfathiazoie against bacterial infections. Backer and De Jonge (441 prepared these derivatives by reaction of 2-amino-4-methyl- and 2-aminO-4-phenyl-selenazoles with A -acetylsulfanilic acid chloride in pyridine.. Alkaline... 

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