Reactions Involving the Nitrogen Atoms

Azaindoles are readily acylated on the pyrrole nitrogen by warming on a water bath with acid anhydrides or with acid chlorides in the presence of carbonate or pyridine. Good yields were obtained by this procedure for the following compounds l-acetyl-7-azaindole, 1-benzoyl- and l-benzenesulfonyl-7-azaindole, l-benzoyl-2-methyl-7-azaindole, 1-ethoxycarbonyl- and l-chloroacetyl-7-azaindole, l-acetyl-3-cyano-7-azaindole, 1-benzoyl-4-azindole, and 1-acetyl- and l-benzoyl-2,5-dimethyl-4-azaindole. The only reported failure was with 5-methyl-2-phenyl-4-azaindole, which failed to react with acetic anhydride or benzoyl chloride. 2-Methyl-7-azaindole-3-acetic acid was acylated by treatment of its ierGbutyl ester with sodium hydride in dimethylformamide, followed by p-chlorobenzoyl chloride.  

No example of N-acylation of 5- or 6-azaindoles appears to have been recorded. 

The 1-acylazaindoles are hydrolyzed easily with alkali and are relatively stable to acids at low temperatures. At least in one case, the 3-cyano compound, hydrolysis proceeds readily with water. 

Protiva et alA formed the sodium salt of 2-methyl-5-phenyl-4-azaindole with sodamide in xylene and refluxed it with j3-dimethyl-aminoethyl chloride to obtain the 1-alkylated compound. Robison et al. found with 7-azaindole that use of sodium hydride in xylene, followed by refluxing with methyl iodide, gave l-methyl-7-azaindole in 62% yield, compared with only 19% when sodamide was used. Also, in the latter case, they isolated a small amount of 7-azaskatole and suspected traces of the 7-methyl compound to be present. 

Several 1-alkanonitriles of 4-, 5-, 6-, and 7-azaindole were prepared in a similar manner.  

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When the reaction products of the reaction involve the nitrogen atoms of nucleophiles in the formation of heterocyclic derivatives, the formation of 1,1-diamino derivatives is usually used to prepare polyazacyclic derivatives221. Scheme 48 shows222 the formation of fused polyazapolycyclic compounds through a condensation between 1,3-diaminopropane and glyoxal to prepare the 1,1-diamino derivative 161. The subsequent reaction of 161 with formaldehyde forms fused addition products (162). 

This section will be limited to reactions involving the nitrogen atom, specifically N protonation and isocyanate formation. 

In acid solution aromatic amines form resins with formaldehyde. This reaction in olves the formation of nuclear methylene linkages similar to those which occur in phenol-formaldehyde resins. The reaction type characteristic of the aromatic nucleus rather than of the activating amine group, whose presence merely facilitates reaction. As a result, resins can be obtained even with tertiary amines such as dimethylaniline. Under these conditions the amine reacts as an ammono-phenol. Studies of the mechanism by which formaldehyde reacU with X-alkyl anilines in acid elution indicate that the primary reaction involves the nitrogen atom. 

Ring-closure reactions that involve a /-amino group on a 1,2-diazine skeleton and a vinyl moiety in its t>/// t>-position occur via the so-called /-amino effect. Although this reaction does not involve reaction at the nitrogen atom itself, it is a very specific reaction that can only occur on /-amines and is therefore incorporated in this section. The reaction... 

Since the discovery of the very remarkable 100% endo selectivity of the reactions of nitronic esters with dimethyl maleate, maleic anhydride and maleimides secondary orbital interactions involving the nitrogen atom of the 1,3-dipole and the substituents on the dipolarophile have been postulated as strong endo-orienting factors, able to overwhelm the contrasting steric factors (Figure 1). 

Assuming that this initial disassembly could handle the selective formation of the C-9 stereocenter, the Hoffmann-La Roche group then anticipated that they could install the C-8 stereocenter in 29 in a controlled manner upon application of a cyclization reaction between the nitrogen atom in 30 and a neighboring group that could be suitably displaced. Although this disconnection involved... 

As the exchange reactions which involve the nitrogen atom of the various amino derivatives strongly depend on the medium, the borderline between intermolecular effects and chemical reactions may become blurred. This is particularly so for proton exchange reactions which occur as a function of pH in >N-H derivatives. However, such processes will be considered in Sect. 8, and only conventional medium effects along with protonation effects will be dealt with now. 

Among the substitution reactions involving the ring nitrogen atoms of the pteridine nucleus, alkylations of amide functions are preeminent. Under base-catalyzed conditions it is usually the nitrogen atom adjacent to the carbonyl function which is substituted... 

The 1-azirine ring also undergoes a number of reactions in which the heterocycle plays the role of the nucleophile. Although the basicity of the nitrogen atom in the azirine ring is much lower than in simple aliphatic amines, this system can still function as a nucleophilic reagent. One example of this involves the acid-catalyzed hydrolysis of 1-azirines to a-aminoketones (200) which represents a well-established reaction. In fact, in many reactions of 1-azirines where acid catalysis is used, formation of a-aminoketones is difficult to avoid (67JA44S6). 

Reaction of the pyrrolidine enamine of cyclohexanone with phenyl vinyl sulfone afforded a 9 1 mixture of the tri- and tetrasubstituted isomers (2(5). The preference of the less substituted isomer in this case is in keeping with the greater overlap requirement between the n electrons of the double bond and the electron pair on the nitrogen atom, since the double bond exo to the five-membered ring is much more favored than the double bond exo to the six-membered ring. It is, however, hard to explain the formation of largely the trisubstituted isomer with the piperidine enamine of cyclohexanone, where both of the rings involved are six-membered. 

Charton has recently examined substituent effects in the ortho position in benzene derivatives and in the a-position in pyridines, quinolines, and isoquinolines. He concludes that, in benzene derivatives, the effects in the ortho position are proportional to the effects in the para position op). However, he finds that effects of a-sub-stituents on reactions involving the sp lone pair of the nitrogen atoms in pyridine, quinoline, and isoquinoline are approximately proportional to CT -values, or possibly to inductive effects (Taft s a ). He also notes that the effects of substituents on proton-deuterium exchange in the ortho position of substituted benzenes are comparable to the effects of the same substituents in the a-position of the heterocycles. 

When methyl 2-(indol-2-yl)acrylate derivative (22a) reacted with A-methoxy-carbonyl-l,2-dihydropyridine (8a) in refluxing toluene, in addition to the dimer of 22a (25%), a mixture of the expected isoquinculidine 23a and the product 24a (two isomers) was obtained in 7% and 45% yields, respectively (81CC37). The formation of 24a indicates the involvement of the 3,4-double bond of dihydropyridine. Similarly, Diels-Alder reaction of methyl l-methyl-2-(indol-2-yl)acrylate (22b) with 8a gave, in addition to dimer of 22b, a mixture of adducts 23b and 24b. However, in this case, product 23b was obtained as a major product in a 3 2 mixture of two isomers (with a- and (3-COOMe). The major isomer shows an a-conhguration. The yields of the dimer, 23b, and 24b were 25%, 30%, and 6%, respectively. Thus, a substituent on the nitrogen atom or at the 3-position of indole favors the formation of the isoquinuclidine adduct 23. 

The diaziridines arc somewhat more stable than the oxaziranes. The three-membered ring of the oxaziranes is decomposed in all of its reactions, but with the diaziridines substitution on the nitrogen atoms can be effected and reactions involving fission and expansion of the ring to a five-membered ring are i)ossiblc,... 

Acid-catalyzed hydrolysis of a nitrile to give a carboxylic acid occurs by initial protonation of the nitrogen atom, followed by nucleophilic addition of water. Review the mechanism of base-catalyzed nitrile hydrolysis in Section 20.7, and then write all the steps involved in the acicl-catalyzed reaction, using curved arrows to represent electron flow in each step. 

Furthermore, the strongly metallic character of selenium weakens the C-Se bond and thus favors reactions involving opening of the ring. The basicity of the three heterocycles is approximately in the same order, the nitrogen atom of selenazole and thiazole possessing much the same properties as the heteroatom of pyridine. Of the two carbon atoms ortho to nitrogen, that is, the 2-carbon and the 4-carbon, only the one in the 2-position is fairly active as a result of its interaction with selenium or sulfur. The 4- and 5-positions of thiazole and selenazole are more susceptible to electrophilic substitution than the 3- and 5-positions of pyridine. This is particularly true of the 5-position of selenazole. Thus it can be said that the 2- and 5-positions of the selenazoles and thiazoles... 

Pyridones have not been considered previously because the reaction site can undergo resonance effects involving more than one type of interaction. Localized effects, assuming they are field effects, will not be affected. If the localized effect were an inductive effect, which seems very unlikely, then there would be two paths to the reaction site. Consider the pyridones for which data are available. Three sets are extant. They are the 3-substituted 4-pyridones, 33 the 5-substituted 2-pyridones, 34 and the 3-substituted 2-pyridones, 35. In each of these systems, the substituent is conjugated with the nitrogen atom by one path and in... 

Kostic el al. discovered that Pd11 complexes, when attached to tryptophan residues, can rapidly cleave peptides in acetone solutions to which a stoichiometric amount of water is added, for hydrolysis.436 The indole tautomer in which a hydrogen has moved from the nitrogen to C(3) is named indolenine. Its palladium(II) complexes that are coordinated via the nitrogen atom have been characterized by X-ray crystallography and spectroscopic methods.451 Binuclear dimeric complexes between palladium(II) and indole-3-acetate involve cyclopalladation.452 Bidentate coordination to palladium(II) through the N(l) and the C(2) atoms occurs in binuclear complexes.453 Reactions of palladium(II) complexes with indole-3-acetamide and its derivatives produced new complexes of unusual structure. Various NMR, UV, IR, and mass spectral analyses have revealed bidentate coordination via the indole carbon C(3) and the amide oxygen.437... 

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