2- Aryl-1,2,4-triazin-3-ones

New 2-aryl-l,2,4-triazin-3-ones and 2-aryl-l,2,4-tri-azepin-3-ones were prepared in a three step reaction sequence from readily available aryl isocyanates and aminoacetals or ketals. The key step in the reaction scheme was the formation of 2-arylsemicarbazides by the treatment of arylureas with the aminating reagent 0-(4-nitrophenyl)hydroxylamine. 2-Aryl-1,2,4-triazin-3-ones... 

A new synthesis of 2-aryl-1,2,4-triazin-3-ones and 2-aryl-l,2,4-triazepin-3-ones from convenient starting materials has been demonstrated. Of these compounds, the triazin-3-ones were found to have herbicidal properties and with appropriate aromatic substituents, weed control can be obtained at low application rates. However, the weed control/crop tolerance ratio may limit the commercial application of the more active triazinones. 

The increase in thermodynamic stability of 85 is achieved by easy ring opening (01H127). This knowledge allows one to control the regioselectivity of the oxidative amination of the 6-aryl-l,2,4-tiiazine 4-oxides 53, obtaining either (i) the 5-amino-1,2,4-triazine 4-oxides 56 in the reaction of 53 with amines at low temperature in the presence of the oxidant or (ii) the 3-amino-1,2,4-triazine 4-oxides 88, provided the reaction is carried out in two steps (addition and oxidation) at room temperature or higher. 

The first case of the use of amino acids as chiral auxiliaries in nucleophilic addition to triazinones was employed in the reaction of C-nucleophiles with 3-aryl-l,2,4-triazin-5(4 )-ones 16 and A-protected amino acids 17, to form l-acyl-6-Nu-3-aryl-l,6-dihydro-l,2,4-triazin-5(4A)-ones 18 in high diastereomeric excess <06TL7485>. 

The triazine ring could be formed by reaction [82S853 83BSF(2)226] of alkyl (2-aryl-4-thioxo-3,4-dihydro-2//-quinazolin-3-yl)acetates 477, prepared from 476, with hydrazine to yield 6-aryl-2,4-dihydro[l,2,4]tria-zino[4,3-c]quinazolin-3-ones 478. 

Hydrolytic cleavage of condensed 1,2,3-triazine derivatives is normally a straightforward, high-jneld process which results in production of one or other of several distinct types of product. 3-Alkyl- and 3-aryl-3,4-dihydro-l,2,3-benzotriazines, for example, undergo facile hydrolysis in concentrated hydrochloric acid to give, via the diazonium compound, A(-alkyl- and W-aryl-substituted o-chlorobenzylamines (100, R = Cl). If the reaction is carried out in water or in dilute mineral acid, the corresponding -alkyl and iV-aryl-substituted o-hydroxybenzylamines (100, R = OH) are obtained. 

As mentioned above, condensed 1,2,3-triazine derivatives can be arylated by treatment with nitro-activated aryl halides. The only other report of direct arylation of the 1,2,3-triazine system is due to McKillop and Kobylecki, who studied the reaction of l,2,3-benzotriazin-4-one (10, R = H) with diaryliodonium salts in the presence of base. Treatment of 10, R = H, with diphenyl- and di-p-bromophenyliodonium chloride results in exclusive arylation at N2 and gives the corresponding triazinium betaines (77, R = Ph, p-BrCjH4) in good yield. When di-p-tolyliodonium chloride is used, a mixture of the Nj-, Nj-, and 0-arylated... 

NMR spectroscopy has been little used in the 1,2,3-triazine field and, like IR spectroscopy, is useful only for confirmation of the presence of specific substituent groups. °- - Attempts to extend this technique to more demanding problems, such as the site of alkylation or arylation " of l,2,3-benzotriazin-4(3/0-one, have been unsuccessful. 

The UV spectra of other types of 1,2,3-triazine derivatives are generally more complicated than those of the 3-alkyl- and 3-aryl-1,2,3-benzotriazin-4(3if)-ones, and in most cases data are available for only a small number of compounds of each type. Consequently, the utility of this information in diagnostic and structural elucidation work is not very... 

Aryl-substituted amides 39, when treated with triethyl orthoformate, give the corresponding N-arylated pyrimidine-fused rings 40 (Scheme 4) <2000PS(164)299> as well as one example of the triazine 41 <2000PS(164)299>. 

Reaction of 4-aryl-3-methylthio-l,2,4-triazin-5-ones (342) with hydrazine led to 4-amino-3-arylamino-l,2,4-triazin-5-ones (343) instead of the expected 4-aryl-3-hydrazino derivatives (344). This is explained by nucleophilic attack of the hydrazine at the 5-position, ring opening and subsequent reclosure. The same result was obtained when 4-aryl-3-thioxo-... 

The reaction of 1,2-dicarbonyl compounds (452) with amidrazones (453) is the best method for the synthesis of alkyl, aryl or hetaryl substituted 1,2,4-triazines (78HC(33)189, p. 195). No limitation of this synthetic principle is reported, except that it is, of course, preferable for the dione (452) to be symmetrical. The best reaction procedure is to add the dicarbonyl compound to a solution of the free amidrazone, or amidrazonium salt in the presence of one mole of base, and allow a reaction time of about 12 h. Since the first step of this reaction, i.e. condensation of the hydrazono group with one carbonyl group, is fast, while the second, i.e. condensation of the amide group with the other carbonyl, is slow, the intermediate (454) has been isolated in a few cases. This method has been used also for the synthesis of compounds containing more than one 1,2,4-triazine nucleus, and for the parent 1,2,4-triazine (1) (68CB3952). 

Hydrolysis in acid of compounds assigned the a-cyanoazoacetophenone structures (681) affords arylglyoxal semicarbazones (682). These can be cyclized in hot sodium hydroxide to 5-aryl-l,2,4-triazin-3-ones (683) <02LA(325)129). 

The reaction of a-amino ketones (508d) with thiosemicarbazides (761) affords 3-amino-4,5-dihydro-l,2,4-triazines (762) and the dihydrotriazine-3-thiones (763) (57MI21900). 2,2-Dimethyl-3-dimethylamino-2i/-azirine (764) reacts with benzohydrazides (765 R = Ar) via the open-chain intermediates (766) to give 3-aryl-6-dimethyIamino-2,5-dihydro-l,2,4-triazines (767 R = Ar). With ethyl carbazidate (765 R = OEt) the corresponding triazin-3-one (768) is formed (78HCA2419,78C332). 

Triazines with three different substituents are formed by variations on the above methods. There is no efficient route to trialkyl or triaryl derivatives, although the reaction of acylimidates and amidines has met with some success (see Section 2.20.4.6.2). In general the best routes available are as follows, (a) Substitution reactions of cyanuric chloride, (b) The condensation of Af-cyanoamidine with chloromethyliminium salts, (c) 2-Aryl-1,3,5-triazin-2-ones may be efficiently prepared by ring closure reactions on AT-(a-chloroalky-lidene)carbamoyl chloride and amidines (see Section 2.20.4.4.1). 

Other claims are the isothiazolo[4,5-d][l,2,3]triazine-4-ones (170) for the treatment of gout and eschemia <86EUP274654>, the 3-aryl[l,2,5]thiadiazolo[3,4-d]pyrimidine-7-ones as antiallergics <90EUP349239>, 3-dialkylaminoethyl-l,2,3-triazolo[4,5-d]pyrimidine-5,7-diones as bronchodilators <88EUP272226>, and the 5-aryl-1,2,3-triazolo[4,5-d]pyrimidines as antihypertensives <88USP4923874>. 

A number of 8-aryl substituted pyrido[3,4-t/]-l,2,3-triazin-4(3//)-ones have been found to be most efficacious as inhibitors of xanthine oxidase, potential compounds for the treatment of ischemia and gout <88EUP274654>. A number of 3//,4//-pyrido[3,2-e]-l,2,4-triazine and 3/f,4//-pyrido[3,4-e]-1,2,4-triazine 3-acetamides have shown antiinflammatory, diuretic, antihypertensive, and psychotropic effects <89FES279>. During a search for potential antidepressant compounds, the pyrido-1,2,3-triazinone (399) was found to be more active than its isomer (400) <87EJM337>. 

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