1.2.4- Triazine aromatic nucleophilic substitution

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-... 

Another field of application for active esters is solid-phase synthesis. Some polymer-supported reagents are available commercially (see Fig. 9). The acid is first immobilized on a polymer support as an active ester and the excess reagents are washed away conveniently. Finally, the amide is released by amine treatment. During the cleavage, a limited amount of amine can be used to avoid the presence of excess amine in the final mixture. The acid is loaded onto the resin using classic ester condensation methods for TFP resin 35 (66), HOBt resin 36 (67), and oxime resin 37 (68). In the case of the triazine resin 38, the acid is loaded via an aromatic nucleophilic substitution in the presence of a base (69). 

New aromatic poly(monosulfide)s (10) (34) containing a 1,3,5-triazine ring were readily prepared with moderate yields by the aromatic nucleophilic substitution polymerization of 2,4-dichloro-l,3,5-triazine derivatives with bis(4-mercaptophenyl) sulfide (4,4 -thiodibenzenethiol) [19362-77-7] under mild conditions in the presence of a base in tetrahydrofuran (THF) [109-99-9] solution or in the o-dichlorobenzene/water two-phase system by using phase-transfer catalyst. The resulting polymers showed highly crystalline structures and high thermal stability (Td 330-410). 

Nucleophilic displacement of chlorine, in a stepwise manner, from cyanuric chloride leads to triazines with heteroatom substituents (see Section 6.12.5.2.4) in symmetrical or unsymmetrical substitution patterns. New reactions for introduction of carbon nucleophiles are useful for the preparation of unsymmetrical 2,4,6-trisubstituted 1,3,5-triazines. The reaction of silyl enol ethers with cyanuric chloride replaces only one of the chlorine atoms and the remaining chlorines can be subjected to further nucleophilic substitution, but the ketone produced from the silyl enol ether reaction may need protection or transformation first. Palladium-catalyzed cross-coupling of 2-substituted 4,6-dichloro-l,3,5-triazine with phenylboronic acid gives 2,4-diaryl-6-substituted 1,3,5-triazines <93S33>. Cyanuric fluoride can be used in a similar manner to cyanuric chloride but has the added advantage of the reactions with aromatic amines, which react as carbon nucleophiles. New 2,4,6-trisubstituted 1,3,5-triazines are therefore available with aryl or heteroaryl and fluoro substituents (see Section 6.12.5.2.4). 

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>. 

Small hydrogen isotope effects have been found in a nucleophilic substitution of an aromatic heterocycle, the reaction of cyanuric chloride with aniline-N,N-d2 in benzene solution (Zollinger, 1961a). As the effects are small (5%), it is difficult to draw definite mechanistic conclusions. The reactions of cyanuric chloride and other halogenated triazine derivatives are subject to bifunctional catalysis (e.g. by carboxylic acids and by a -pyridone) and to catalysis by monofunctional bases like pyridine (Bitter and Zollinger, 1961). Reinheimer et al. (1962) measured the solvent isotope effect in the hydrolysis of 2-chloro-5-nitro-pyridine (A h,o/ d.o = 2 36). The result makes it probable, but... 

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). 

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. 

Cycloadditions of 2-cyclopropylidene-l,3-dimethylimidazolidine with different aryl substituted 1,2,4-triazines have been studied. At low temperatures, zwitterions (formed by nucleophilic attack on the triazines) could be detected spectroscopically and, in some cases, isolated <05HCA1491>. Aromatization and ring cyclization of 3-amino-6-hydrazino-l,2,4-triazin-2-one has been studied, including the X-ray analysis of the 3-ethyl derivative of the title compound <05JHC851>. 

Addition of electron-rich aromatic systems to the 1,2,4-triazine ring can easily be achieved by preliminary activation of the heterocyclic system by protonation or alkylation. Addition of the following nucleophiles to the 1,2,4-triazinium ion (129) has been observed indoles, pyrroles, anilines, phenols, and aminothiazoles. The 1,6-dihydro-1,2,4-triazines (130) can be isolated in most cases and oxidized in a second step to the aromatic 1,2,4-triazine system (Scheme 20). 1,2,4-Triazin-5(2i/)-ones also undergo this reaction. 5-Unsubstituted 1,2,4-triazine 4-oxides (131) can be transformed into 5-substituted 1,2,4-triazine 4-oxides (Equation (14)) <86KGS1535, 92H(33)93l, 95UP 611-01>. 

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 SnH reaction of C-nucleophiles with l,2,4-triazine-4-oxides has, in recent years, been extended to many other nucleophiles. For example, Kozhevnikov et al. (06TL869) have used the methodology to introduce aromatic- 50, heteroaromatic- 52 and carborane-substituted 51 triazines (Scheme 18). As discussed in Section 2.3 (Scheme 8) acetone cyanohydrin can be used to introduce a nitrile moiety by SnH (08JMC1703, 05IZV2122). 

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