2- Aminopyridine reactions

Tu et al. (2007) carried out microwave-assisted multicomponent reactions of a, P-unsaturated ketone, methane-1,2-dicarbonitrile, and primary amine under micro-waves to afford N-substituted 2-aminopyridines. Reactions were controlled by the basicity of amine and the nature of solvent. 

Another pharmaceutically important fused-imidazole ring system is the popular sleeping aid medication zolpidem. Bromination of 4-methylacetophenone and condensation with methylated 2-amino pyridine provides the fused-imidazole in good overall yield. Note that the ring nitrogen on the aminopyridine reaction reacts with the bromide carbon. Mannich-type alkylation at the unsubstituted 5-position provides the dimethylaminomethyl substituent in good yield. Further elaboration yields zolpidem. ... 

This reaction, thoroughly studied for 2-aminopyridine (14, 15), has received less attention in the case of the thiazole nucleus. 2-Amino-4-methylthiazole is formed when 4-methylthiazole is heated with sodium amide for 15 hr at 150°C (16). This reaction was used to identify 2-amino-4-butylthiazok (17). 

When carried out in dilute acid, diazotization of 2-aminothia2ole may provide unstable diazohydroxides (164, 335, 336), differing in that respect from 2-aminopyridines which give 2-pyridones when the reaction is carried out in weak acids (337). 

Treating 5.5 g of 2-amino-4,5-dimethylthiazole HCl with 0.66 g of solid sodium hydroxide 15 min at 220°C yields 53% of 4.4. 5.5 -tetramethyT 2,2 -dithiazolylamine, whose structure w as proved by identification with the produa obtained from the reaction between dithiobiuret and 3-bromo-2-butanone (467). This result is comparable to the reaction between 2-aminopyridine and its hydrochloride to yield bis(pyridyl-2)amine (468). Gronowitz applied this reaction to 2-aminothiazole, refluxing it with its hydrochloride 4 hr in benzene and obtained the dimeric 2-aminothiazole (236). He proposed a mechanism (Scheme 143) that involves the addition of a proton to the 5-position of the ring to give 234. The carbocation formed then reacts on the 5-position of a second... 

The reaction of C2S2 with 2-aminopyridine and /V-pbenylbensamidine yields the higher condensed derivatives C2S2 also reacts with p-aminocrotonate to yield H2NC(CH2)=C(COOC2H2)]2S (7). 

In a related reaction the isocyanate from azide (109) cyclized with aminopyridine esters via a ureido intermediate to give (110) (80JHC733). 

One of the most elegant of these involves the reaction of two moles of 2-aminopyridine with two moles of carbon dioxide under high temperature and pressure to give the 3-pyridyl-2,4-dione (279) (54USP2680741). 

In a 5-1, 3-necked flask fitted with a mechanical stirrer (Note 1), a dropping funnel, and a thermometer for reading low temperatures is placed 790 ml. (7 moles) of 48% h drobromic acid. The fl.ask and contents are cooled to 10-20 in an ice-salt bath, and 150 g, (1.59 moles) of 2-aminopyridine (Note 2) is added over a period of about 10 minutes. While the temperature is kept at 0° or lower, 240 ml. (4.7 moles) of bromine is added dropwise (Note 3). A solution of 275 g. (4 moles) of sodium nitrite in 400 ml. of water is added dropwise over a period of 2 hours, the temperature being carefully maintained at 0° or lower (Note 4). After an additional 30 minutes of stirring, a solution of 600 g. (15 moles) of sodium hydroxide in 600 ml. of water is added at such a rate that the temperature does not rise above 20-25° (Note 5). The nearly colorless reaction mixture is extracted with... 

Reaction of 2 or 3 aminopyndine with trifluoronitrosomethane forms the trifluoromethaneazo derivative directly 4-Aminopyridine fails to give the azo product [12] (equation 11)... 

The acetylation of isopropanol by acetic anhydride is catalyzed by 4-dimethyl-aminopyridine (DMAP). The reaction kinetics can be followed titrimetrically by hydrolyzing samples at known times and titrating them with standard NaOH. A blank is carried out with the reagents but no alcohol. 

A variety of aryl systems have been explored as substrates in the Knorr quinoline synthesis. Most notable examples are included in the work of Knorr himself who has demonstrated the high compatibility of substituted anilines as nucleophilic participants in that reaction. In the case of heteroaromatic substrates however, the ease of cyclization is dependent on the nature and relative position of the substituents on the aromatic ring." For example, 3-aminopyridines do not participate in ring closure after forming the anilide... 

Thiophenealdehyde has been used in the reductive alkylation of 2-aminopyridine and 2-aminopyrimidine. 2-Arylamino-4- (2-thienyl )thiazoles have been prepared by the reaction of 2-acetylthio-phene with A-arylthioureas in the presence of iodine, ... 

The second group of chemical methods is based on a comparison of the structure (s) of the reaction product(s) with that of the starting material. These methods can be illustrated by the observation that l-methylpyrid-2-onimine (38) is formed when 2-aminopyridine (37) is allowed to react with methyl iodide followed by treatment with alkali. From these data it was incorrectly concluded that 2-aminopyridine reacted, or existed, in the imino form. Actually, the... 

The chemical reactions of 3-aminopyridines, 3-aminoquinoIines, etc. in which the amino group is beta to the hetero atom or is attached to a benzenoid ring are similar to those of aniline (cf. references 282, 290), and it has been generally accepted that these compounds exist overwhelmingly in the amino form. 2-Aminoacridine was not considered to exist as 231 (R = H), because 231 (R Me) shows reac-... 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

The first amination of a halogenopyridine involving a rearrangement was carried out by Levine and Leake in 1955 in an attempt to prepare 3-phenacylpyridine. When 3-bromopyridine (27, X = Br) was allowed to react with sodium amide in liquid ammonia in the presence of sodio-acetophenone, the reaction mixture obtained consisted chiefly of amorphous nitrogenous material from which only 10% of 4-aminopyridine (34, Y = NH2) and 13.5% of 4-phenacylpyridine were isolated. 

Amination of the various four 2-halogenopyridines (24, X = F, Cl, Br, I) under analogous conditions gave 2-aminopyridine (25, Y = NH2) as the sole reaction product in greater than 85% yield.The mechanism of these reactions is discussed in Section II, A, 3. 

Only rarely is the amino group itself anionized during nucleophilic substitution one instance is the reaction of sodamide with 2-aminopyridine to yield 2,6-dianJnopyridine (cf. structure 74 on p. 185). 

Reaction of an Aminopyridine with an Aliphatic Nitro Compound. 289... 

---