1,3,5-Triazine-2,4-dione ring

In Scheme 7, ring-opening reactions of some fused pyrazoles are shown. Thus, Baraldi et al. <1999S453> described that the pyrazolo[l,5-<7][l,2,4]triazine-dione derivative 72 is sensitive toward nucleophiles its reaction with benzylamine at room temperature gives rise to the acyl semicarbazide 73 in high yield (78%). 

Thorough studies on this ring system have been carried out by Sztanke et al. during the past decade. The representative cyclization step is shown in Scheme 50 the 2-hydrazinoimidazoline compound 329 when reacted with diethyl oxalate in butanol under reflux conditions gave rise to formation of triazin-diones 330 <2005EJM127>... 

Hexahydro-l,3,5-triazine-2,4-dione ring from 2 isocyanate molecules... 

Formamidinoyl isothiocyanates (157) combine with 2-aminothiazoles the ring nitrogen attacks the spC part of the electrophilic reagent (312) further reaction then yields aza-condensed thiazolo-s-triazines (158) (Scheme 99) (313). Mesoionic S-alkvlthiazolo[3.2-fl]-i-tria2ine-5,7-diones (159) are obtained when 2-alkylaminothiazoles react with phenoxycar-bonyl isocyanate (304). 

The 3-amino-8-oxo derivative of 1,2,4,5,7-pentaazanaphthalene (475) is known as well as various 3-substituted derivatives of the 6,8-dioxo compound. The 3-methylthio- and 3-ethylthio-6,8-dioxo derivatives and their 7-methyl and 5,7-dimethyl analogs were prepared by ring-closure. 3-Ethylthiopyrimido[4,5-e]-as-triazine-6,8-dione was 3-substituted with alkali 2N, 100°, > 30 min) or acid 2N, 100°, < 2 hr, 70% yield) and with ammonia, aniline, piperidine, or monoalkylamines (in pyridine, 115°, 4 hr, 75-85% yield). ... 

The reaction of the fervenulin 1-oxides 100 with secondary amines results in contraction of the 1,2,4-triazine ring to form 2-amino-5,7-dimethylimidazo[4,5-e] pyrimidine-4,6(5/7,7//)-diones 101. The reaction of the same fervenulin 1-oxides 100 with ammonia leads to the 1,2,4-triazine ring cleavage product, 1,3-dimethyl-5-imino-6-isonitrosouracil 102 (94KGS1253). 

The 11 NMR spectrum (500MHz) of 3-(4-chloro-phenyl)-7-ethyl-7,9-dimethyl-2,3,4,9-tetrahydropyrimido[l,2-tf]-[l,3,5]triazine-6,8-dione 49 <2002JHC663> showed the presence of quartets (AB pattern) at 6 4.99 and 6 5.12 corresponding to the methylene protons of the triazine ring. 

Only a limited number of derivatives of this ring system have been reported in literature. The only efficient synthesis utilized azoaroyl-1,2,4-triazines. Thus, condensation of 138 with hydrazines afforded the hydra-zones (139), which give 140 on reflux in acetic acid [85MI2,85PHA(39)504] (Scheme 20). It has been reported that derivatives of 74 were synthesized by cyclization of pyrazoline-4,5-dion-4-isothiosemicarbazones and 4-amidinohydrazones in phenol at 180-200°C (88JPR57). 

The 1,2,4-triazine ring of 3,4-dihydro-2-methyl-1,2,4-triazino[3,2-6]-quinazoline-3,10-dione (622) was formed when 3-amino-2-(substituted amino)quinazolin-4-one (621) was cyclized with ethyl pyruvate in acetic acid (86JHC833). 

Data on the structures of monocyclic dihydro- or hexahydro-1,2,3-triazines, on 1,2,3-triazine tV-oxides and 1,2,3-triazinones are not yet available. From studies on the one-electron reduction of the tetrahydro-l,2,3-triazinium salts (7) it was concluded that the heterocyclic ring is flexible and not planar (80LA285). No detailed information on the structure of 3-benzyl-l,5-diphenyl-l,2-dihydro-l,2,3-triazine-4,6(3//,5f/)-dione (8) or of the 6-hydroxy-4-oxo-l,4-dihydro-l,2,3-triazinium hydroxide inner salts (9) seems to be available. 

Complete destruction of the heterocyclic ring of 1,2,4-triazines on prolonged treatment with aqueous acids is reported for l,2,4-triazin-3-ones (84), l,2,4-triazine-3-thiones (85), 3-thioxo-l,2,4-triazine-5,6-diones (115), 1,2,4-triazine N-oxides, and l,2,4-benzotriazin-3-ones (116). This is a fairly general observation in 1,2,4-triazine systems. 

For the debromination of 6-bromo-l,2,4-triazine-3,5-diones (312), both sodium in ammonia and butyllithium have been used (58JA976,67RRC913). Other methods of obtaining an unsubstituted ring position include desulfurization with Raney nickel of 3-thioxo-1,2,4-triazin-5-ones (187) to the triazin-5-ones (313) (73BSF2126), and treatment of the 3-sulfonylhydrazino-1,2,4-triazines (314) with a base to afford the compounds (107) (55MI21900). 

On the other hand, a proton directly bound to the 1,2,4-triazine ring can be replaced by halogen. This is an electrophilic substitution reaction at carbon, and, as expected for such a heavily aza-substituted ring system, it needs considerable activation by electron-donating substituents. The halogenation reaction is best known in bromination at the 6-position. From the published data it seems that either an amino group in the 3-position or an oxo group in the 5-position is necessary. The formation of 6-halo-substituted compounds has been reported for l,2,4-triazin-5-ones, l,2,4-triazine-3,5-diones, 3-amino-l,2,4-triazines and 3-amino-l,2,4-triazin-5-ones. 

A halogen directly attached to the 1,2,4-triazine ring is very reactive and can be replaced by most other nucleophiles as outlined in Scheme 9. Tlie reactivity toward neutral nucleophiles decreases from the 5-position to the 3- and 6-positions, while that towards anionic nucleophiles decreases from the 5-position to the 6- and 3-positions. Among nucleophiles which displace halogen atoms are water, alcohols, amines, hydrazine, hydroxyl-amine, thiols and hydrogen sulfide. It is also reported that the bromine in 6-bromo-1,2,4-triazine-3,5-dione can be replaced by fluorine (323) or by a cyano group (324). 

Coburn and Bhoosan reported the first synthesis of 1,3-disubstituted l,3,5-triazine-4,6-dione (82) and the corresponding thione derivative. The dione (82) is thermally stable, but forms ring-opened products on exposure to moisture. The reaction of (82) with dimethyl acetylenedicarboxylate gives the 1 1 adduct rather than the expected cycloaddition products (Scheme 50) (75JHC187). The fused system (83) reacts with ethylamine to produce the 1,3,5-triazine (84 equation 41) (81JCS(Pl)33l). 

Dimethylpyrimido[4,5-< ]pyridazine-5,7(6i7,8//)-dione 7V(2)-oxide gives oxidative alkylamination at position 3 (Scheme 35) (88KGS1696) and isofervenulin gives, with ammonia or an alkylamine in the presence of an oxidant, (alkyl)amination at C-3 (Scheme 35) (88KGS1696, 00KGS1403). This C-3 substitution of isofervenuline is claimed to be the first example of amination in the triazine ring at position 3. 

In 1,2,4-triazines it is essential that the 5-position is blocked (cf. pyrimidines without 4- or 6-substituents) to prevent nucleophilic ring opening, oxidation, and ring contractions from competing with N-oxidation (72LA111 86H951). Products include l,2,4-triazin-5-ones and -5,6-diones (72LA111). Whereas... 

The heterocyclic ring in l,2,4-triazine-3,5-dione (12) and its 6-methyl derivative (13) is planar. The data clearly show that in the crystal only the dione structure is present no indication of any other tautomeric structure was found. The methyl group in the 6-position of (13) has an influence on the bond lengths of the two carbonyl groups. While in (12) the two carbonyl groups are equal (1.224 A), in (13) two different distances were found C(3)=0 = 1.213 A and C(5)=0 = 1.242 A. In the ribosides (14) and (15) both carbonyl groups are nearly the same length. 

---