Reactions with Nitrogen Nucleophiles

Chemical Properties The formation of salts with acids is the most characteristic reaction of amines. Since the amines are soluble in organic solvents and the salts are usually not soluble, acidic products can be conveniendy separated by the reaction with an amine, the unshared electron pair on the amine nitrogen acting as proton acceptor. Amines are good nucleophiles reactions of amines at the nitrogen atom have as a first step the formation of a bond with the unshared electron pair of nitrogen, eg, reactions with acid anhydrides, haUdes, and esters, with carbon dioxide or carbon disulfide, and with isocyanic or isothiocyanic acid derivatives. 

Diamines of varying structure show rate enhancements of 20-200 fold, compared to monofunctional aliphatic amines, in nucleophilic reactions with N-acetylimidazole (Page and Jencks, 1972). These were attributed to intramolecular general base catalysis of proton removal from the attacking nitrogen, viz.. 

Nucleophilic attack at nitrogen is rare in these systems. However, the inorganic trithiazyl trichloride (87) acts as an apparent source of electrophilic nitrogen on reaction with certain organic substrates. Reaction with electron-rich alkenes such as stilbene gives 3,4-diphenyl-1,2,5-thiadiazole (77JCS(Pl)916>. 

In a mechanistically similar process, the neutral palladium(II) dipyridylamine complex (24), obtained by deprotonation of complex (23), underwent reaction with benzoyl chloride to give the substituted complex (25) together with some free ligand (Scheme 8).33 This particular reaction sequence could not be generalized because of the relative instability of other metal complexes related to compound (24). However, a more extensive series of electrophilic substitutions could be carried out on the neutral complex (26), which displayed ambident nucleophilic behaviour by reaction with benzyl chloride and benzoyl chloride at nitrogen and reaction with benzenediazonium fluoroborate at carbon (Scheme 9). 

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

A major distinction for nucleophilic reactions with ambident anions is whether they proceed with kinetic or thermodynamic control.80 N-Substituted saccharins (10) should be thermodynamically more stable because of amide character than the isomeric pseudosaccharin (3) of imidate structure. In fact 3 may be rearranged thermally to 10 in an irreversible reaction.96 The threshold for thermodynamic control appears to be lowered for electrophiles with multiple bonds, e.g., formaldehyde, reactive derivatives of carboxylic acids, but also quaternary salts of N-heterocyclic compounds.80 It will be seen that in those cases substitution indeed occurs at the nitrogen, not necessarily through thermodynamic control. 

The resulting anion can then carry out a nucleophilic reaction with the electrophilic nitrogen of the nitroso group of nitrosobenzene. 

Heteroaromatic N-imines and IV-aminoazonium salts show a variety of reactivities, depending on the nature of the heteroaromatic ring and the substituents on the imino or amino nitrogen. The most important types of the reactions are (i) reactions with electrophiles at the imino or amino nitrogen, (ii) reactions with nucleophiles on the heteroaromatic ring, (iii) 1,3-dipolar cycloaddition, (in) 671-electrocyclic reaction of 1,5-dipoles (mainly thermal reaction), (n) 47t-electrocyclic reaction (mainly photochemical reaction), and (vi) N—N bond cleavage (by thermolysis, photolysis, oxidation, and reduction). 

Functionalization of pyridine. Regioselective reaction with oxygen, sulfur, and nitrogen nucleophiles and with carbon nucleophiles at C-2 occurs via an addition-elimination pathway. 

Methods that rely on alkynes and alkenes for the synthesis of isoquinoline core are based on two basic modes for their cyclization. The first uses electrophilic reagents as activators of alkynes or alkenes for the cyclization process, while the second method uses a nucleophilic atom usually nitrogen in reaction with the alkyne or alkene moiety. 

A -Oxide chemistry in six-membered heterocycles provides considerable scope for synthetic manipulations. One of the very useful transformations is the introduction of halide a to a nitrogen on reaction with phosphorus or sulfur halides, the conversion being initiated by oxygen attack on the phosphorus (sulfur). The power of this transformation can be emphasised by noting that the unsubstituted heterocycle is converted, in the two steps, into a halide with its potential for subsequent displacement by nucleophiles. 

Thus, this chapter focuses on the most investigated classes of metal-catalyzed coupling reactions—namely, reactions of aromatic and aliphatic electrophiles with main group carbon or nitrogen nucleophiles, reactions of aromatic halides with olefins, including enanti-oselective versions of these reactions, and direct coupling processes. The mechanisms of these reactions are presented with reference to the chapters on the stoichiometric steps of these catalytic processes. 

Ammonia, primaiy amines, and related acyclic nitrogen nucleophiles react with a large variety of pyrones to form pyridones. These reactions often have been used to characterize the pyrones or to remove them from mixtures. Under these circumstances, yields are often not reported and experimental conditions are not optimal, and, therefore, in many instances these reactions are difficult to evaluate, particularly as alternative routes to the somewhat more carefully studied direct ring closures to form pyridones. 

The relatively high reactivity of Scm-Cl, however, lowers the selectivity towards substrates with more than one nitrogen nucleophile. Nevertheless, with less reactive nucleophiles, such as the two nitrogens in uns)mimetrically substituted ureas, selectivity is possible. In the reaction shown in eq 18, only the nitrogen adjacent to the oxazole ring reacts with the electrophile Scm-Cl (albeit in low yield, 34%). ... 

Section 4.2 reviewed reactions of oxygen, sulfur, and nitrogen nucleophilic compounds with phosgene equivalents (giving chloroformates, thiochloroformates, and... 

Most syntheses of nitrogen heterocycles involve substitution and/or condensation reactions of nitrogen nucleophiles with difunctional halides or carbonyl compounds. Common nitrogen reagents are ... 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

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