Trifluoromethyl-substituted 1,2,4-triazines

Kawase and Koiwai have developed an unusual ring-transformation methodology for the synthesis of trifluoromethyl-substituted 1,2,4-triazine derivatives (08CPB433). Mesoionic 4-trifluoroacetyl-l,3-oxazolium-5-olates... 

Two main synthetic approaches to trifluoromethyl substituted 1,2,4-triazines are known. They are cyclocondensation process based on (trifluoromethyl)carbonyl derivatives and transformation of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine ring. 

Scheme 15 Synthetic approaches to trifluoromethyl substituted 1,2,4-triazines...

Examples of synthesis of trifluoromethyl-substituted 1,2,4-triazines by transformation of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 49 ring are presented at Scheme 20. The anomeric C-glycosyl precursors 50, functionalized by an imidate group and appropriate for C-nucleoside synthesis were utilized as heterodienophiles in a Diels-Alder reaction with inverse electron demand to yield the 0-benzyl protected 5-( 3-D-ribofuranozyl)- and 5-(a-D-ribofuranosyl)-1,2,4-triazines 51 (Scheme 20) [30]. 

Imino-l,3-thiazetidine 83 was used as precursor in the synthesis of triazine 85 (Scheme 36) [74], Reaction of 83 with hifluoroacetic anhydride leads to 2-trifluoromethylimino-3-(4-chlorophenyl)-l,3-thiazetidine 84, the treatment of 84 with S-methylisothiourea sulfate results in trifluoromethyl substituted triazine 85. 

Certain trifluoromethyl-substituted 1,2,4,5 tetrazines [260, 26i] and 1,2,4 triazines [i06] can be used as cyclic hetero-1,3-dienes and provide efficient preparative routes to partially fluorinated heterocycles (equations 55 and 56)... 

The main synthetic approaches to trifluoromethyl substituted 1,3,5-triazines are trimerization of CF3CN [58], cyclocondensation process based on imidoylamidines [59], cyanoguanidines [60] or biguanides [61 ] and also fluorination of trichloromethyl-1,3,5-triazines [47,62],... 

A (1/7-imidazol-l-yl) silver species (55) has been postulated as the key intermediate in the 3-l-2-cycloaddition reaction of diazoalkanes (54) with benzynes yielding 2-aryl-2H-indazoles (56) (Scheme 18). The 3-I-2-cycloaddition reaction of 3-trifluoromethyl-4-diazopyrazolinones with dialkyl acetylene dicarboxylates, in refluxing toluene, produced spiro 3/f-pyrazole adducts that rearranged to the trifluoromethyl-substituted pyrazolo[l,5-fi(][l,2,4]triazin-7-ones. ° The 1,3-dipolar cycloaddition reaction of aromatic thioketones (58) with 2-aza-1,3-dicarbonyl compounds (57), at 20-50 C, yielded thiadiazoline adducts (59) that readily eliminate nitrogen to produce oxathioles (60) in moderate yields (up to 70%) (Scheme 19). ... 

In comparison with the diazines, the inductive effects of the extra nitrogen(s) leads to an even greater susceptibility to nucleophilic attack and, as a result, all the parent systems and many derivatives react with water, in acidic or basic solution. Similarly, simple electrophilic substitutions do not occur some apparent electrophilic substitutions, such as the bromination of 1,3,5-triazine, probably take place via bromide nucleophilic addition to an N -Br triazinium salt. Attempted direct A-oxidation of simple tetrazines with the usual reagents generally results in ring cleavage, however it can be achieved satisfactorily with methyl(trifluoromethyl)dioxirane. ... 

A-Substituted cyanamides undergo cycloaddition exclusively across the 2- and 5-position in 3-(methylsulfanyl)-5,6-bis(trifluoromethyl)-l,2,4-triazine to yield the bicyclic compound as a nonisolable intermediate. Elimination of trifluoroacetonitrile affords 1,3,5-triazincs 31 while elimination of methyl thiocyanate yields 1,2,4-triazines 32202 (see Section 2.2.1.3.). 

Into a solution of 3-(methylsulfanyl)-5,6-bis(trifluoromethyl)-l,2,4-triazine (1.3 g, 5.0 mmol) in nitrobenzene (5 mL) was added the A-substituted eyanamide (6.0 mmol). This mixture was heated to 190°C with stirring under N2 for 2 d, then chromatographed on silica gel (benzene). 

Reaction pathway for substitution of fluorine atom in 2,4,6-trifluoro-l,3,5-triazine 55 under the action of trifluoromethyl anion has been studied [4] (Scheme 53). Since C3NjF4" can act as a potential fluoride donor, initial reaction takes place between C3N3F4" (A) and MesSiCFs forming a reactive silane, a source of the elusive CF3 anion, which can then attack the neutral triazine (Scheme 53). Through A rearrangement, elimination, and further addition reactions the observed. As a result products 132,133 and 134 are formed (Scheme 53). 

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