Pyridines nitrogen

The pyrazole molecule resembles both pyridine (the N(2)—C(3) part) and pyrrole (the N(l)—C(5)—C(4) part) and its reactivity reflects also this duality of behaviour. The pyridinic N-2 atom is susceptible to electrophilic attack (Section 4.04.2.1.3) and the pyrrolic N-1 atom is unreactive, but the N-1 proton can be removed by nucleophiles. However, N-2 is less nucleophilic than the pyridine nitrogen atom and N(1)H more acidic than the corresponding pyrrolic NH group. Electrophilic attack on C-4 is generally preferred, contrary to pyrrole which reacts often on C-2 (a attack). When position 3 is unsubstituted, powerful nucleophiles can abstract the proton with a concomitant ring opening of the anion. 

Bonati has classified the pyrazole complexes into two groups compounds containing neutral pyrazoles (HPz), called 2-monohaptopyrazoles since it is the N-2 pyridinic nitrogen lone pair which confers on them the ligand properties and compounds containing pyrazole anions (Pz) which can act as monodentate or, more often, as exobidentate ligands (72CRV497). 

Clearly, the proportion of substitution occurring adjacent to the pyridinic nitrogen atom is increased by protonation. Also noteworthy are the high proportion of ortho substitution product and the selective attack at C-3 in the iV-phenyl derivative. 

The analogy between a substituent linked to a carbonyl group and a substituent in an a or, to a lesser extent, a y-position to a pyridinic nitrogen has been discussed in Section 4.02.3.1.2). The conclusions hold for pyrazoles and indazoles. 

The 3-pyridylcarboxamide, prepared from the anhydride (Pyr, 99% yield), is cleaved (55-86% yield) by basic hydrolysis (0.5 M NaOH, rt) after quatemization of the pyridine nitrogen with methyl iodide. ... 

How does the Hiickel ff-electron model deal with pyridine Nitrogen is more electronegative than carbon, so the N atom ought to have a higher (more negative) T-electron charge than a carbon atom in benzene. It is conventional to write the heteroatom (X and Y are used to denote heteroatoms such as N and O) parameters in terms of the standard ac and yScc... 

An alternative scheme which has parallels with several reactions described in Section II can also account for the production of Kashi-moto s compound and is outlined in the following. Initial attack of the pyridine nitrogen atom on the ester group with the expulsion of... 

The corresponding [5,4-6]-compound (107) was prepared similarly and treated with methyl iodide to give a quaternary salt which was shown to have structure 108, because mild alkaline hydrolysis gave 3-acetamido-l-methyl-2-pyridone. Again, quaternization took place on the pyridine-nitrogen, which is different from the behavior of the corresponding 1,4-diazaindene mentioned above. 

Halopyridines undergo self-quaternization on standing while the less reactive 2-halo isomers do not. However, more is involved here than the relative reactivity at the ring-positions. The reaction rate will depend on the relative riucleophilicity of the attack-ing pyridine-nitrogens (4-chloropyridine is more basic) and on the much lower steric hindrance at the 4-position. Related to this self-quatemization are the reactions of pyridine and picolines as nucleophiles with 4-chloro- and 2-chloro-3-nitropyridines. The 4-isomer (289) is. again the more reactive by 10-30-fold (Table VII, p. 276). 

Tile pyridine nitrogen atom remains the center for predominant protonation of both imidazo[4,5-h]- and imidazo[4,5-c]-pyridines 40 and 41, respectively [88JCS(P2)1839 90MRC573]. 

The 2-methyl-4,9-dioxo-4,9-dihydrothiazolo[4,5-.g]quinoline was first quar-temized with methyl iodide on pyridine nitrogen and then treated with IV-methyl-quinolinium-4-yl salt, affording monomethine cyanine dyes 41 to study solva-tochromism, acid-base properties, and antimicrobial activities (95MI1). 

Random incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. For example, treatment of ethyl acetoacetate with ammonia gives the corresponding P-aminocrotonate 32. The aldehyde (34) required for preparation of such an unsymmetrical compound is prepared by reaction of the product from direct metallation of 33 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate and the p-aminocrotonate from isopropyl acetoacetate leads to isradipine (35) [9]. The same aldehyde with ethyl acetoacetate and the P-aminocrotonate from ethyl acetoacetate gives darodipine (36) [10]. In much the same vein, condensation of the ben-zaldehyde 37 with methyl acetoacetate and its P-aminocrotonate derivative affords riodipine (38) [11]. 

The methyl groups adjacent to the pyridine nitrogens can also be modified without changing calcium channel blocking activity. The most significant change involves replacement of methyl by a nitrile group. Hantsch type condensation of the nitrobenzaldehyde 43 with methyl acetoacetate and the vinyl amine 44 from isopropyl 3-cyano-3-ketopropionate leads directly to nilvadipine (45) [13]. 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

Primary, secondary, and tertiary amines can be aminated by chloramine also, but pyridine nitrogens have been aminated only by hydrovylamine-O-sulfonic acid. 

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