2.4- Disubstituted-1,3,5-triazines

Synthesis of 2,4-disubstituted 1,3,5-triazines bearing a single type of substituent 522... 

General synthetic approaches to 2,4-disubstituted 1,3,5-triazines have not been described. Muchowski reported a specific route for the efficient synthesis of 2-dimethylamino-4-(trichloro-methyl)-1,3,5-triazine from trichloroacetonitrile and Af,Af-dimethylformamidine in over 80% yield (see Section 6.12.9.6.1). 

Several classes of ligands have been described such as porphyrins, perylenes, amidoanthracene-9,10-diones, 2,7-disubstituted amidofluoren-ones, acridines, ethidium derivatives,disubstituted triazines, fluoroquinoanthroxazines, indoloquinolines, dibenzophenanthrolines, ... 

The initial products are the often isolable hydrazones 19, which undergo cyclization via the hemiaminal 20. Mixtures of isomeric triazines usually result from unsymmetrical 1,2-dicarbonyl compounds 3,5-disubstituted triazines 21 are predominantly obtained from 1,2-ketoaldehydes because of their different carbonyl reactivity ... 

Masquelin has presented a facile preparation of 2,6-disubstituted triazines 194 through base-catalyzed cyclization of the corresponding thiouronium salts 193 (Scheme 29). 

Since 2-alkylsulfinyl [1,3,5] triazines 194 can be substituted easily in various ways, this approach constitutes a novel and efficient synthesis of 2,6-disubstituted triazines 195 <1998TL5725>. 

The analogous [24] and [2e] cyclophanes (44-47) derived from 2,6-substituted pyrazines and 2,4-disubstituted triazines were prepared in low yields with a two building approach, combining dithiol 14a with electrophilic dichloro heterocyles 42 and 43. Moderate affinity of the [2e] macrocyles 45 and 47 for Cu(I), Cu(II) and Ag (I) was observed (Scheme 16.11) [24]. 

Organic Derivatives. Although numerous mono-, di-, and trisubstituted organic derivatives of cyanuric and isocyanuric acids appear in the hterature, many are not accessible via cyanuric acid. Cyanuric chloride 2,4,6-trichloro-j -triazine [108-77-0], is generally employed as the intermediate to most cyanurates. Trisubstituted isocyanurates can also be produced by trimerization of either aUphatic or aromatic isocyanates with appropriate catalysts (46) (see Isocyanates, organic). Alkylation of CA generally produces trisubstituted isocyanurates even when a deUberate attempt is made to produce mono- or disubstituted derivatives. There are exceptions, as in the production of mono-2-aminoethyl isocyanurate [18503-66-7] in nearly quantitative yield by reaction of CA and azitidine in DMF (47). 

Other derivatives of s-triazine, in particular the 2,4-disubstituted ones, are usually prepared by total synthesis and are therefore not closely linked with the chemistry of 5-azauracil unlike the analogous derivatives of 1,2,4-triazine. 2,4-Dimethoxy-l,3,5-triazine was mentioned earlier (e.g., Section II,A,2,a), the other substances are not related to the present subject. 

Dichloro-s-triazine and its 6-alkyl analogs are as easily hydrolyzed by water as trichloro-s-triazine and, on suspension in aqueous ammonia (25°, 16 hr), the first is diaminated in good yield. 2,4-Bistrichloromethyl-6-methyl- and -6-phenyl-s-triazines (321) require a special procedure for mono-alkoxylation (0-20°, 16 hr, alcoholic triethylamine) disubstitution occurs at reflux temperature (8 hr). Aqueous triethylamine (100°, 3 hr) causes complete hydroxy-lation of 2,4,6-tris-trichloromethyl-s-triazine which can be mono-substituted with ammonia, methylamine, or phenoxide ion at 20°. 

Other oxygen nucleophiles demonstrating high reactivity toward 2,4,6-trichloro-s-triazine are A, A -dimethylformamide (10° > 0.5 hr) giving rapid disubstitution (325) A -alkylformamide (20°, 4 hr) in... 

Several 5,6-disubstituted-3-azido[l,2,4]triazine-l-oxides 1021 were prepared (77JHC1221) by treatment of 1020 with nitrous acid. 3-Azido[l, 2,4]-triazine-2-oxide 1023 was prepared by reacting the corresponding 3-bromo derivative 1022 with either tetramethylguanidinium azide in chloroform or sodium azide in aqueous acetone. These azido derivatives were proven to exist in the open-chain form by H- and l3C-NMR and 1R spectra (77JHC1221) (Scheme 191). 

Disubstituted pyridines [86] 87 have been prepared by catalyzed cycloaddition of 4-methyl-1,2,3-triazine 85 with aldehyde enamines 86 (Equation 3.29). The best yields were obtained when ZnBr2 was used as catalyst. 

Several new 2,4-disubstituted pyrrolo[2,l- [l,2,4]triazines, which can be further elaborated, and pyrrolo[5,1 -c]pyrimido[4,5-e] [ 1,2,4]triazines have been made by the reaction of iV,Af-dimethyl-dichloromethyleniminium chloride with l-aminopyrrole-2-carbonitrile and ethyl 4-aniino-3-cyanopyrazolo 5,l-c][l,2,4]triazine-8-carboxylate respectively (Scheme 7) <9613037 >. 

Ferricyanide oxidation of 1,5-disubstituted thiocarbazones (116) give the mesoionic tetrazolium salts (117) under mild conditions (Eq. 21).190 This is in contrast to the strongly alkaline oxidation of carbazides leading to mercapto formazans as shown in Eq. 8 (Section 7.3.1.4). The heterocyclic triazine (118), obtained by the action of a diazonium salt on 2-... 

Triazinethiones have been used frequently for the syntheses of triazino-triazines in the literature. Reaction of 6-methyl-5-[substituted styryl]-2/7-[l,2,4]triazine-3-thiones 39 with thiourea or acetylthiourea in dimethylformamide (DMF) led to the formation of N,N -disubstituted thioureas 40. Heating the compound 40b with glacial acetic acid and fused sodium acetate under reflux led to the formation of the compounds 4,7-dimethyl-8-[2-ethenylfuran]-2-thioxo-l,3,5-triazino[5,6- ][l,2,4]triazine 22 (Scheme 6) <2003PS279>. 

Electrochemical reduction of various 3,4-disubstituted-l,2,5-thiadiazole 1,1-dioxides (3,4-diphenyl- 10, phenanthro[9,10]- 51, and acenaphtho[l,2]- 53) gave the corresponding thiadiazoline 1,1-dioxides <1999CJC511>. Voltammetric and bulk electrolysis electroreduction of 3,4-diphenyl-l,2,5-thiadiazole 1-oxide 9 at ca. —1.5 V, in acetonitrile, gave 3,4-diphenyl-l,2,5-thiadiazole 8 (50%) and 2,4,6-triphenyl-l,3,5-triazine 54 (30%) (Equation 3) <2000TL3531>. 

Condensation of N-perchloroethenylbenzimidoyl chlorides 13 with S-alkylisothiuronium iodides leads to the formation of 4,6-disubstituted 2-alkylthio-l,3,5-triazines 14 in high yields. Their TV-alkyl isomers 15 are synthesized by successive treatment of chlorides 13 with strong basic primary amines and sodium thiocyanate <99MI996>. 

A novel route to synthesize l,3 -triazine-2,4(l//,3//)-diones through the desulfurization of thiocarboamides, such as 1,3-disubstituted 2-thioureas, trisubstituted thioureas and N-substituted thioamides by silver cyanate has been reported <00H(53)929>. Treatment of urazole 23 with one equivalent of sodium hydride under anhydrous conditions, followed by addition of dimethyl sulfate, leads to l,3,5-triazine-2,4-dione 24 in 80% yield . 

JPR269>. 1,3,5-TriaIIyl-hexahydro-l,3,5-triazine has been used in the preparation of a C-4 unsubstituted azetidinone which is the starting material for the synthesis of penems and cephams <00S289>. A novel method for the preparation of AfW-disubstituted-Af"-nitroguanidines via 2-nitroimino-hexahydro-1,3,5-triazine derivatives has been studied <00TL7187>. 

Chloro-4,6-dimethoxy-l,3,5-triazine (100) reacts with iV-methylmorpholine at 20 °C to yield an isolable quaternary triazinylammonium salt (101 R = Me, R, R = C4H8O). This salt can then be reacted with a carboxylic acid to yield a 2-acyloxy-4,6-dimethoxy-l,3,5-triazine (102), which, in turn, can be reacted with an amine to yield an amide (103). This sequence of reactions provides an explanation for the activation (formation of reactive ester) of the carboxylic acid function by 2-chloro-4,6-disubstituted-l,3,5-triazines (100) in the presence of hindered amines. Several other hindered amines may replace iV-methylmorpholine in the process, but unhindered amines such as triethylamine and tributylamine were inactive. ... 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

The 3-phenylpyrimido[5,4-( ]-l,2,4-triazines 29 (also known as 3-phenylreumycins where R = Me) can be transformed into the corresponding 1,6-disubstituted analogues 30 upon selective alkylation with dialkyl sulfates or alkyl halides in DME in the presence of potassium carbonate as shown in Equation (2) <2001J(P1)130, 1997H(45)643>. 

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