Aminopyridines electrophilic substitution

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... 

Acetamido-4-phenylthiazole is nitrated at position 5 of the thiazole ring [232], in contrast to 2-amino-4-phenylthiazole, which is nitrated in the phenyl ring [233], This agrees with existing data on the reactivity of thiazoles during electrophilic substitution. N-(2-Thiazolyl)-2-aminopyridine is nitrated exclusively in the thiazole ring [222],... 

The charge distribution in pyridine leads to deactivation for electrophilic substitution, the least for the position 3 (formation of 3-bromopyridine) at higher temperatures mainly 2-bromo-pyridine is produced by radical substitution. With sodium amide 2-aminopyridine is produced as a nucleophilic substitution reaction. 

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. ... 

Activating substitutents, i.e. groups which can release electrons either inductively or mesomerically, make the electrophilic substitution of pyridine rings to which they are attached faster, for example 4-pyridone nitrates at the 3-position via the O-protonated salt. In order to understand the activation, it is helpful to view the species attacked as a (protonated) phenol-like substrate. Electrophilic attack on neutral pyridones is best visualised as attack on an enamide. Dimethoxypyridines also undergo nitration via their cations, but the balance is often delicate, for example 2-aminopyridine brominates at C-5, in acidic solution, via the free base. ... 

As in benzene chemistry, electron-releasing groups facilitate electrophilic substitution, so that, for example, 2-aminopyridine undergoes 5-bromination in acetic acid even at room temperature this product can then can be nitrated, at room temperature, forming 2-amino-5-bromo-3-nitropyridine. Chlorination of 3-ami-... 

Figure 2. Approaches to 1,X-Naphthyridines A - Electrophilic Substitution of Aminopyridines B - Friedlander-type Condensation...

Pyridine is too unreactive to suffer electrophilic attack by a carbonyl group. However, a form of electrophilic substitution occurs when picolinic and isonicotinic acids are decarboxylated in the presence of carbonyl compounds. These acids undergo decarboxylation in the zwitterionic forms (p. 319), and when decarboxylation occurs in the presence of carbonyl compounds, carbinols are formedi37-9, Jt is not certain whether the reaction proceeds by electrophilic attack by the carbonyl compound on the product of decarboxylation (process A) or whether the carbonyl compound is involved in the decarboxylation (process B), The reaction has preparative value . See also the discussion of the reactions of aminopyridines with aldehydes (p. 359). 

Several thiazolo[4,5- >]pyridines, which may be considered as 2-protected-3-aminopyridines, undergo 4-deprotonation and provide, by reaction with a variety of electrophiles, good yields of functionalized products 231 (Scheme 68) (89TL183). In the case of the 6-chloro derivative 230, exclusive formation of the 4-substituted product 231 was observed. 

The almost exclusive ring closure at the a-position carries over to other electrophilic reactions of substituted 3 -aminopyridine derivatives. For example, the condensation of 3-aminopyridine with ethoxy-methylenemalonic ester (EMME) in dilute solution in boiling Dowtherm A gave the 1,5-naphthyridine 190.425,426 The only exception to date is that of 3-aminopyridine A -oxide which, as expected,... 

Ghosez et al. have recently prepared so-called push-pull dienes (Scheme 6-II).7 These dienes are sufficiently electrophilic to react at relatively low temperatures with unactivated, electron-rich nitriles, affording initial [4 + 2] adducts which tautomerize to 2-aminopyridines. This method would seem to offer a potentially efficient approach to synthesis of certain substituted pyridines. An s-tetrazine dicarboxylate is also a sufficiently electrophilic diene to combine with an N-substituted cyana-mide to afford a triazene in good yield [Eq. (5)].8... 

Although pyridine is resistant to electrophilic aromatic substitution, it is susceptible to nucleophilic aromatic substitution. The reaction of 2-bromopyridine (44) and ammonia, for example, leads to 2-aminopyridine, 46. This is a nucleophilic aromatic substitution reaction (see Chapter 21, Section 21.10), where NHg attacks the ipso carbon to generate a carbanionic intermediate (45), which loses bromine to give 46. Pyridine (10) also reacts directly with sodium amide (NaNHg) at 100°C to give 46 in what is known as the Chichibabin reaction, after Aleksei E. Chichibabin (Russia 1871-1945). 

The first retrosynthetic step introduces a great simplification of TM 8.3 by disconnection of the C-N bond in a refro-Michael mode resulting in 3-aminopyridine TM 8.3a and ethyl methacrylate. The heterocyclic amine is not available by either the nitration of pyridine and reduction or bromination and ammonolysis. In both cases the pyridine nucleus proves resistant to electrophilic aromatic substitution. 

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