Triazines nucleophilic aromatic

Pyridine A-oxides were converted to tetrazolo[l,5-a]pyridines 172 by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent <06JOC9540>. 3-R-5-Trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-ones 173 have been prepared from the alkylation of 5-trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-one silver salt with different alkylation agents <06CHE417>. The use of 2-fluorophenylisocyanide in the combinatorial Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution afforded tricylic tetrazolo[l,5-a]quinoxaline 174 in good yields and with high diversity <06TL2041>. 

A classic illustration of scaffold decoration is the trisubstituted 1,3,5-triazine. The starting material trichloro-l,3,5-triazine is inexpensive, and the halogens can be displaced by nucleophilic aromatic substitutions one by one. Such chemistry was well precedented in pre-combinatorial days, and used on a large scale for the synthesis of colour-fast reactive dyes. The overall reaction sequence has an appeal in its simplicity, and both academic and industrial practitioners have reported a steady trickle of such triazine-based libraries over the last 20 years. Novelty will come either from the particular set of nucleophiles employed or the assay targets. 

Nucleophilic aromatic substitution reactions follow the well-established two-step addition-elimination mechanism via a Meisenheimer intermediate (Fig. 8.3). Indeed, reaction of fluoride ion with trifluoro- -triazine, gives the corresponding perfluorocarbanion system that has been directly observed by NMR spectroscopy, supporting this mechanistic rationale. This reactivity has been termed mirror-image chemistry, which contrasts the very well-known chemistry of... 

One of the features of the current state of heterocyclic chemistry is a growing interest in the so-called Sn methodology (nucleophilic aromatic substitution of hydrogen) and related processes initiated by a nucleophilic attack at unsubstituted carbon in 7t-deficient azaaromatics addition of nucleophiles (An), oxidative elimination of hydrogen from cr -adducts, or auto -aromatization of cr -adducts, the tandem addition (An-An) or substitution (Sn -Sn ) reactions, and other transformations . All aspects of this relatively new branch of the chemistry of 1,2,4-triazines are discussed in detail in this chapter. 

The displacement of nucleofugal groups is usually realized through the addition-elimination two-step mechanism Sn(AE) . For instance, the trichloromethyl group in 1,2,4-triazines is displaced easily by the action of hydrazine, butylamine, sodium hydroxide, and alkoxides (Scheme 81) <2004SOS(17)357> however, in the reaction of 6-aryl-3-trichloromethyl-l,2,4-triazines with aromatic C-nucleophiles, substitution of hydrogen takes place <2004RCB1295>. 

In addition to electrophilic aromatic substitution reaction and copper salts-mediated or -catalyzed C-H bond functionalization, nucleophilic aromatic substitution reaction has also been explored to introduce the functional groups [60, 61]. One of successful examples is the amination reaction of dichloro-substituted azacalix[2]arene[2]triazine with various amines based on the reactivity of chlorotriazine moiety (Scheme 14.18) [60]. 

All of the general classes of cr -adduct aromatization were found to occur in the reactions of 1,2,4-triazine A-oxides with various nucleophiles. From this point of view, the 1,2,4-triazine A-oxides are a very convenient substrate for the Sj reaction studies. 

The isolated cr -adducts 57 undergo oxidation with KMn04 easily, resulting in the corresponding 5-indolyl-1,2,4-triazine 4-oxides 60 (98ZOR429). Separating the nucleophilic addition step from the oxidative aromatization of the intermediate (T -adducts allows the use of such oxidant-sensitive nucleophiles as indoles. 

The reaction of 1,2,4-triazine 4-oxides 55 with CH-active 1,3-diketones (dime-done, indanedione, iV.iV -dimethylbarbituric acid) in the presence of trifluoroacetic acid (substrate activation by protonation) or KOH (activation of the nucleophile) leads to stable cr -adducts 63, whose oxidative aromatization by the action of KMn04 results in 5-substituted 1,2,4-triazine 4-oxides 64 (98MI). 

Table I details representative examples of the [4 + 2] cycloaddition of triethyl 1,2, 4-triazine-3,5,6-tricarboxylate with pyrrolidine enamines and related electron-rich olefins. Cycloaddition occurs across carbon-3 and carbon-6 of the 1,2,4-triazine nucleus, and the nucleophilic carbon of the dienophile attaches to carbon-3 (eq 1). Loss of nitrogen from the initial adduct and aromatization with loss of pyrrolidine affords pyridine products.

Some heteroarylamines have been prepared by aromatic nucleophilic substitution of suitable support-bound arylating agents with amines (Table 3.27). This technique has been successfully employed in the synthesis of 2-(alkylamino)pyrimidines [507,508], 2-(arylamino)pyrimidines [509], aminopurines [510-512], and 1,3,5-triazines [513]. When the heteroarene is bound to the support as a thioether, nucleophilic clea-... 

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