Triazin-2-yl Derivatives

With the l,3,5-triazin-2-yl derivatives of 4,4 -diaminostilbene-2,2 -disulfonic acid proposed by B. Wendt in 1940 [25], optical brighteners came into full-scale industrial use. In 1941, 4,4 -bis (4-anilino-6-hydroxy-l,3,5-triazin-2-yl)aminoJstil-bene-2,2 -disulfonic acid disodium salt was introduced commercially under the trade name Blankophor B (3) [1264-32-0],... 

The unusual reaction of cyanoacetic acid esters with s-triazine monoazides afforded derivatives of a novel coupled heterocyclic system 2-[l,3,5]triazin-2-yl-l,2-dihydro[l,2,3,4]tetrazine-5-carboxylic acid esters <06CHE965>. 

In order to obviate the formation of a formic ester, the reaction of l,2 3,4-di-0-isopropylidene-a-D-galactopyranose (42) was performed in p-dioxane. The 6-chloro-6-deoxy derivative (45) was again obtained, but only in low yield the major product was assigned the novel structure of 6-0-(4,6-dichloro-l,3,5-triazin-2-yl)-l,2 3,4-di-0-isopropylidene-a-D-galactopyranose (54). 

The encapsulation of a fluorescent pyrenyl derivative, l-(4,6-dichloro-l,3,5-triazin-2-yl)pyrene (pyrene-R), has provided direct evidence for the release of a hydrophobic molecule from the metalla-cage [ (p v C6 A Me)Ru 6(p-dhbq)3 (tpt)2]6+> following uptake into cancer cells [61]. The fluorescence of pyrene-R has allowed monitoring of cellular uptake and accumulation, as well as an estimation of the efficiency of the [pyrene-Rc (/tPr C6H4Me)Ru 6((i-dhbq)3(tpt)2]6+ system to transport and release its cargo (Fig. 17). 

Similarly prepared from l,2-diamino-3-chlorocyclopropenylium ions 9 and 4,6-disubstituted 5-dialkylamino-l,2,3-triazincs 10 were the derivatives of l,2-diamino-3-(l,2,3-triazinium-2-yl)cyclopropcnylium dications 11, which upon hydrolysis gave the 1,2-diamino-3-(5-oxo-2,5-dihydro-l,2,3-triazin-2-yl)cyclopropenylium ions 12. " °... 

The other members of this family of compounds are phosphorodithioic acid derivatives. Of these, menazon, 0,0-dimethyl-S-(4,6-diamino-l,3,5-triazin-2-yl)-methyl phosphorodithioate (78), distinguishes itself by its low toxicity to warmblooded animals. It is prepared by cyclisation of biguanide and ethyl chloroacetate, upon which the 2-chloromethyl-4,6 iaminotriazine formed is reacted with sodium 0,0-dimethyl phosphorodithioate (Anonym, 1958). 

The strategy was chosen to (1) link the amino acid derivative to a polystyrene-supported hydroxylamine, (2) carry out the cyclization under Mitsunobu conditions, and (3) assemble a short peptide on the free amino group present in the ring. This approach has been shown to be suitable particularly for solid-phase synthesis, as the supported (3-lactam could be easily separated from the by-products of the Mitsunobu reaction. The linker employed was a polystyrene resin carrying 0-trityl-hydroxylamine linker, prepared according to the literature procedure [151]. After the deprotection of Fmoc group carried out with 20% piperidine in DMF, the L-cbz-serine (or L-cbz-threonine) was coupled using (4,6-Dimethoxy-[l, 3, 5]-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) [152] in M-methylpyrrolidone (NMP) in the presence of M,M-diisopropylethylamine (DIPEA) (Schemes 42 45). 

The reaction of bis(mercaptothioformylhydrazido)phthalate 4 with cyanamide yielded the bis-l,2,4-triazin-6-yl derivative 5 <01PS65>. 

The synthesis, crystal structure and anticancer activity of derivatives of ethyl and methyl (tetrahydroimidazo[2,l-c][l,2,4]triazin-3-yl) formate and acetate have been reported <06EJM539 06EJM1373>. 

Substituted derivatives of l-(tetrahydrobenzo[b]thiophen-2-yl-3-carboxylate)-5-phenyl-6-thio-l,2,4-triazin-4-one have been synthesized by heterocyclization reactions of different hydrazones obtained from 2-amino-tetrahydrobenzo[b]thiophene-3-carboxylate with phenyl isothiocyanate <00PS275>. Reaction of 5-methyl isothiosemicarbazide with a-amino acid vicinal tricarbonyl reactive substrates 1 and 2 yields 1,2,4-triazine substituted a-amino acids, as an equimolar mixture of regioisomers 3a/3b and 4a /4b, respectively <00JCS(P1)299>. 

Some new bactericidal and fungicidal derivatives of purine and pyrazolo[l,2,4]triazine have been synthesized by the reaction of 4-arylidene-2-phenyl-S-oxazolones with different nucleophilic reagents <99IJC(B)445>. A variety of pyrazolo[3,2-c][l,2,4]-triazin-3-yl 55, 59 and l,2,4-triazolo[33-c][l,2,4]-triazin-3-yl-phosphonic acid dialkyl esters 56, 60 have been synthesized from diazobetaines of pyrazoles 57 and ttiazoles 58 and monocarbanions of certain phosphonates, respectively <99H513>. 

In a study involving 3-methylfervenulin 50 (R = Me) <1996JHC949>, shown in Scheme 4, it was found that reaction with methanolic methylamine or ethylamine at room temperature gave the imidazo[4,5-i ]-l,2,4-triazines 52a and 52b, respectively. This transformation is believed to proceed via the intermediate l,2,4-triazin-6-yl urea derivatives 51. The same investigation showed that the reaction of a range of 3-alkylfervenulins 50 with ethanolic sodium hydroxide gave the 3-alkyl imidazo[4,5-i ]-l,2,4-triazines 53. 

The first work in this field was probably that of Piletsky et al. [84] that described a competitive FILA for the analysis of triazine using the fluorescent derivative 5-[(4,6-dichlorotriazin-2-yl)amino]fluorescein. The fluorescence of the supernatant after incubation was proportional to the triazine concentration and the assay was selective to triazine over atrazine and simazine. The same fluorescent triazine derivative was applied to competitive assays using atrazine-imprinted films [70]. To this end an oxidative polymerization was performed in the presence of the template, the monomer(s) 3-thiopheneboronic acid (TBA) or mixtures of 3-amino-phenylboronic acid (APBA) and TBA (10 1) in ethanol-water (1 1 v/v) where the template is more soluble. The polymers were grafted onto the surface of polystyrene microplates. The poly-TBA polymers yielded a detection limit of 8 pM atrazine whereas for the poly-TBA-APBA plates it was lowered to 0.7 pM after 5 h of incubation. However, a 10-20% decrease in the polymer affinity was observed after 2 months. 

The coupling of the 4,4,4-trifluoro-l-(thien-2-yl) butane-1,3-dione with azole diazonium salts gives the pyrazolo [5,1-c] triazine (xi), benzimidazo [5-1-c] 1,2,4-triazine (xii) and triazolo [3,3-c] 1,2,4-triazine (xiii) derivatives incorporating trifluoromethyl group [25]. 

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