Aminopyridines formation

In 2014, Odom and coworkers reported a titanium-catalyzed synthesis of 2-amino-3-cyanopyridines (Scheme 3.41) [89]. The reactions were performed in a one-pot manner with two manipulation steps. Firstly, titanium-catalyzed alkyne iminoamination and generation tautomers of 1,3-diimines. Then, 2-amino-3-cyanopyridines were formed in good to modest yields after treatment with base (DBU) and malononitrile. A Dimroth rearrangement mechanism for 2-aminopyridine formation was proposed based on the isolation of a 2-imino-l,2-dihydropyridine intermediate which undergoes rearrangement under the reaction conditions. 

Recently H. L. Jones and D. L. Beveridge have presented molecular orbital calculations on the electronic structure of 2,3-pyrid5me explaining the exclusive formation of 2-aminopyridine from this intermediate [Tetrahedron Letters No. 24, 1577 (1964)]. 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

The formation of 1-aminopyridinium chloride has been accomplished by the acid hydrolysis of N- ( -acetaminobenzene-sulfonimido)pyridine.4 Also, the rearrangement of a substituted diazepine has been observed to give a 1-aminopyridine derivative.5 The present procedure is an adaptation of that described by GosI and Meuwsen.1... 

The reaction of 2-aminopyridine with 2-chloropyridine 102 furnishes pyrido[l,2- 3,2- ]pyrimidine derivative 104 in good yield (Scheme 10) <1998T5775, 2003CHE328>. The first step is quaternization with the formation of salt 103. Then 103 undergoes intramolecular cyclization with participation of cyano and amino groups. 

When treated with DBU at elevated temperature, l-[(benzotriazol-l-yl)methyl -2-aminopyridine salts 741 eliminate rather the N-H proton than the C-H one. Intermediates 742 can be trapped with aromatic aldehydes to create betaines 743. The consecutive cyclocondensation and elimination of benzotriazole results in formation of imidazolo[l,2-rz]pyridines 744 in good yields (Scheme 117) <2000JOC9201>. Aldehydes with enolizable a-protons fail to give bicyclic systems 744, producing corresponding enamines instead. 

Stable 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide reacts with 2- and 4-aminopyridines in their imino forms, if acids are present to promote the formation of imine, to give cycloadducts such as 168 (337). 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

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]. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

If di(tcrt-butyl)nitroxide (a radical trap) is present, the reaction with phenylacetonitrile-potassium does not proceed entirely. Acetonitrile-potassium (which is in equilibrium with potassium amide) forms only aminopyridine in the presence of the trap (Moon et al. 1983). Consequently, amination is a classical nucleophile reaction, and the formation of pyridyl acetonitrile is a reaction of the typs- These two reactions are quite different. A stronger CH acid leads to a well-defined synthesis. 

Similar 1,2,3-diheterocyclizations have been performed by addition of other Af, N- or Al,5-dinucleophiles, such as pyridine-2-thiol, 2-aminopyridine, 2-aminothia-zole, thioisonicotinamide, and l//-benzotriazole, to complexes 6 and 46 giving rise to the formation of the five- and six-membered cyclic alkenyl derivatives 96-100 (Fig. 19) [289, 291,292],... 

There is a complication if the nucleophile used in reactions with halopyridines is also a strong base for now the formation of a pyridyne is possible, and with sodamide in liquid ammonia (providing the NH2 ion , B), for example, both 3-aminopyridine and 4-aminopyridine are formed from 4-bromopyridine (Scheme 2.16). 

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