Nucleophilic addition reactions, diazine

Diazines are considerably more reactive toward nucleophiles than pyridines and as the number of ring nitrogens increases the propensity for nucleophilic addition reactions increases still more. Many 1,2,4-triazines give addition products with various nucleophiles which are formally dihydrotriazines. 

The metallation of diazines, in particular pyrazine and quinoxalines, is extremely difficult due to nucleophilic addition reactions related to the low LUMO energy levels of the rings. The functionalization of these rings was an important synthetic goal due to the many uses of the molecules. 

When radical anions and dianions leads to very slow SET, their nucleophilic properties have to be taken into account. Reactions of electrogenerated species toward CO2, acetic anhydride, acetic chloride, and some classic RX compounds as electrophiles can be explained on the basis of nucleophilic substitutions, but extreme cares have to be taken on the intrinsic nature of the mechanism (Sn vs. radical coupling). Thus reactions involving azo and diazo compounds in the presence of CO2 could be explained by nucleophilic addition (formation of A-functionalized azine and diazines [13]). Several reactions [15,215,229] implying CO2 and acetic anhydride [230] were described. 

Cyclopropyllithium may engage itself in various types of reactions depending on the properties of the aromatic compound. When fluorobenzene is the aromatic substrate, benzyne formation followed by hydride transfer is believed to take place, but if the aromatic compound is a diazine or a substituted or annulated pyridine, the first step is nucleophilic addition of cyclopropyllithium to the nitrogen-containing ring of the aromatic nucleus. The predominance... 

The diazines are very susceptible to nucleophilic addition pyrimidine, for example, is decomposed when heated with aqueous alkali by a process that involves hydroxide addition as a first step. It is converted into pyrazole by reaction with hot hydrazine. 

The examples shown below are illustrative of the many easy nucleophilic additions to the polyaza-azines The reaction of 1,2,4,5-tetrazine with simple amines can be contrasted with the requirement for sodamide (Chichibabin reaction) for the diazines and pyridine. 

The examples shown below are illustrative of the many easy nucleophilic additions to the polyaza-azines the reaction of 1,2,4,5-tetrazine with simple amines can be contrasted with the requirement for sodamide (Chichibabin reaction) for the diazines and pyridine. The easy addition at C-5 of 1,2,4-tri-azines is shown by the VNS reaction of the 3-methylthio-derivatives in the absence of activating groups the ready displacement of methylthio from the same compound is also indicative. ... 

Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions, which compete with the desired DoM process. 

The MCR mechanism to provide dihydropyridine derivatives starting from enamines is similar to the one discussed for the synthesis of 4//-pyrans 10 (Scheme 13.5) [10]. In contrast to the discussed mechanism, the cychzation in the syntheses of dihydropyridine derivatives takes place by addition/dehydration instead of nucleophilic displacement. As an amidine acts like an enamine as well, the reaction pathway for diazine syntheses can be formulated in analogy to the one discussed for the enamine MCR to create N-substituted 2-amino-4//-pyrans 10 (Scheme 13.5) [11],... 

A considerable number of ring-fluorinated diazines undergoes various nucleophilic aromatic substitution reactions. Nucleophilic aromatic substitution reactions follow the well-established two-step addition-elimination mechanism via a Meisenheimer intermediate. The destabilization of sp -C bound fluorine by p-Jt repulsion activates fluorinated aromatic compounds toward nucleophilic attack and subsequent substitution. The susceptibility of the carbon center toward nucleophiles is also enhanced by the negative inductive (-la) effect of fluorine. Therefore the ease of nucleophilic halogen replacement - F>Cl>Br>I - is in the opposite order to that for aliphatic... 

In principle, addition of a nucleophile to the C=N bond of the diazine ring can be accompanied by elimination of fluoroalkyl substituent. Two-step version of this reaction was used in the synthesis of alkaloid rutaecarpine (1210). In particular, reaction of anhydride 1206 with trifluoroacetic anhydride and then - with Irypt-amine led to the formation of quinazoline 1208, which was transformed to 1210 with elimination of trifluoromethane upon acid-catalyzed cycUzation, followed by alkaline hydrolysis (Scheme 260) [744]. 

Despite the widely accepted opinion that fluoroalkyl substituents in aromatic rings are chemically stable and rarely susceptible towards nucleophilic attack, a number of reactions of chain-fluorinated diazines at a-carbon of the fluoroalkyl moiety can be found. In fact, the first examples of such transformations were reported in 1960s [747] they concerned an unusually easy hydrolysis of 5-trifluoromethyluracil and its derivatives upon warming in alkaline media (Scheme 263). Mechanism of the reaction was proposed, which included elimination of fluoride from anionic species 1214 and 1215, formed either by deprotonation of the substrate or addition of hydroxide ion [748], Additional (but similar) reaction pathways were also possible if more acidic NH protons were present in the molecule of the substrate. 

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