3.5.6- Trisubstituted-l ,2,4-triazines

Zhao et al. [32] applied the microwaves for the synthesis of diverse 3,5,6-trisubstituted-l,2,4-triazines (xx) in excellent yields and purity. The synthetic protocol involved the reaction of benzyl and imidazoyl acyl hydrazide in presence of ammonium acetate and glacial HO Ac. 

Recently, Rauf et al. (07ARK(xvi)137) have developed a microwave-mediated, solvent-free variant of the Neunhoffer chemistry that allows the preparation of 3,5,6-trisubstituted-l,2,4-triazines 13 from 1,2-dicarbonyls 2 and fatty acid hydrazides 12, rather than amidrazones (Scheme 4). In a similar microwave-mediated approach, Nongkhlaw s group utilises 1,2-dicarbonyls, amides and hydrazine to construct 1,2,4-triazines (08ARK(xv)79). 

Rauf and coworkers synthesized the 3,5,6-trisubstituted-l,2,4-triazines from fatty acid hydrazides nnder MW assisted solvent-free conditions [101] (Scheme 3.41). 

Universal method is the cyclocondensation of symmetrical l,2-dicarbonyl compounds with amidrazones, which affords 3,5,6-trisubstituted 1,2,4-triazines 18 ... 

The synthesis of 2,4,6-trisubstituted-l,3,5-triazines has been reviewed <06MI81>. Reaction of an activated form of carboxylic acids 20 with zinc dimethyl imidodicarbonimidate 21 led to 4,6-dimethoxy-l,3,5-triazines 22 in high yields <06S2845>. 

Arya and Dandia [26] presented the HY zeolite promoted, environmentally benign solvent free synthesis of 2,4,6-trisubstituted-l,3,5-triazines (xiv) under microwave irradiation. The synthesized derivatives also showed promising activities when screened for phototoxicity and cytotoxic activities against leukemia and adenocarcinoma derived cell lines in comparison to the normal human keratinocytes. 

Tris(trinitromethyl)-l,3,5-triazine reacts with nucleophiles such as alcohols and amines to give products in which the trinitromethyl groups are displaced in turn to yield mono, di, then trisubstituted compounds. Some of the products which have been obtained are shown in Scheme 12 <95CHE(31)596>. 

Trisubstituted 1,3,5-triazines 1, in general, are more stable to hydrolysis than the parent compound. For example, trialkyl-substituted 1,3,5-triazines require the addition of concentrated hydrochloric acid at 200 X in order to hydrolyze.3 Cyanuric acid (l,3,5-triazine-2,4,6-triol) is only slowly hydrolyzed by hot aqueous alkali and can also be heated under pressure in sulfuric acid solution at 200 °C with minimal decomposition to give carbon dioxide and ammonia.4 One exception is the easy cleavage of l,3,5-triazine-2,4,6-tricarboxylic acid, which on treatment with hot water, yields oxalic acid and ammonia.5... 

Reaction of isothiocyanates with 1,3,5-trisubstituted 2,4-dithiobiurets (155) in the presence of powdered sodium or potassium hydroxide in a polar solvent gave 1,3,5-trisubstituted 6-(substituted-imino)-l,3,5-triazine-2,4-dithiones (156). Condensation of the isothiocyanate did not occur on a nitrogen bearing an aryl substituent. Other modes of cyclization may be envisaged, but only (156) was found. Triazines (156) were sensitive to acid and readily hydrolyzed to 4,6-dithioxotetrahydro-... 

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). 

Trimerization of nitriles, isocyanates, isothiocyanates, imidates, and carbodiimides all lead to symmetrical 2,4,6-trisubstituted 1,3,5-triazines (see Section 6.12.9.5). The use of lanthanide trifluoromethanesulfonate and ammonia as cocatalysts is claimed as a big improvement. The trisaminal of 2,4,6-triformyl-l,3,5-triazine is also useful for further derivatization to unusual structures (see Section 6.12.7.1). Treatment of a 1 1 pyridine/conc. ammonia solution of an aromatic aldehyde with excess Fremy s salt is another development. Separation of the amide coproduct was claimed to be easy. The synthesis fails with aliphatic aldehydes (see Section 6.12.9.5.4). Aminolysis of 2,4,6-triaryl-1,3,5-oxadiazinium salts gives symmetrical 1,3,5-triazines but the reactions are limited in that electron-withdrawing groups in the aromatic rings lead to instability and difficulty in separation of products (see Section 6.12.10.4). 

Using the concept of libraries from libraries , 1,3-disubstituted and 1,3,5-trisubstituted l,3,5-triazine-2,4,6-triones were prepared on two different solid supports from common building blocks such as amino acids, isocyanates, and alkyl halides (see Section 9.03.9.5.2). 

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