Pyrazolo tetrazines

The reaction of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 353 with aromatic amines gave (82CB683) pyrazolo[3,4-e][l,2,4]triazines 354 (Scheme 75). 

The reaction of thietan-3-one 46 with 1,2,4,5-tetrazines 47 gave 4i/-pyrazolo[5,l-c]thiazines 48 via a rare anti-Michael addition <06TL7893>. 

Eight ring systems pyrazolo[3,2-r/][l,2,3,5]tetrazine 1, imidazo[5,l-r7][l,2,3,5]tetrazine 2, imidazo[l,2-A [l,2,4,5]-tetrazine 3, 4//-imidazo[5,l-r7][l,2,3,5]thiatriazine 4, 4//-pyrazolo[5,l -, whereas research on the other four has appeared only recently. In several cases, partially saturated forms of these rings have been obtained. The most substantial literature relates to derivatives of ring system 2 because of the antitumor activity of these compounds. 

Seitz and co-workers (84AP237) reported that 2-pyrazolines (132) react with tetrazines (133) to yield pyrazolo[l,5-rf]-l,2,4-triazines (135), most likely via intermediate cycloadduct 134 (Scheme 18). Addition of py-razoles to 133 has been reported to also yield pyrazolo[l, 5-[Pg.245]

The reaction of aromatic amines with tetrazine (151) gave either 1,2,4-triazoles (154) or pyrazolo[4,3-e]-l,2,4-triazines (155), depending on the substituents. While aniline, p-toluidine, p-anisidine and p-chloroaniline afford 155, the bromo and p-nitro derivatives give 154. Intermediates 152 and 153 were postulated (Scheme 22) (82CB683). 

Derivatives of two pyrazolotetrazine ring systems have been synthesized. Thus, the pyrazolo[5,l-cT -l,2,3,5-tetrazine derivative (161) was formed up on reacting diazopyrazole (86) with isocyanates (79TL4253). 

Pyrazolo[3,4-e]-l,2,3,4-tetrazine (164) was formed by intramolecular cyclization of 163, prepared viadiazotizationof 162 [79ZN(B)275 80MI1]. The intermediacy of 163 has been established via isolating coupling products of 163 with different CH acidic reagents, yielding 165. 

The pyrazolo[3,4-( ][l,2,3,4]tetrazine derivative 49 has been reported to be formed by treatment of the hydrochloride salt of the amine 48 with sodium nitrite in aqueous ethanol at room temperature. Only a single example was described. Compound 49 was obtained as red crystals (m.p. >300°C). The product is presumed to form from the diazonium cation 50 which cyclizes via the hydrazone tautomer 51 (Scheme 2) <1998MI11>. 

Since 1974 two publications have appeared dealing with the preparation of monocyclic 1,2,3,5-tetrazines (76BCJ1339, 79LA870). Beside these two articles, Ege and his group have published the synthesis of condensed 1,2,3,5-tetrazines such as pyrazolo[5,l-rf]-[l,2,3,5]tetrazin-4-ones (25) and l,2,3,5-tetrazino[5,4-6]indazol-4-ones (26) (79TL4253). 

The reaction of 2-(diphenylmethylene)thietan-3-one with 1,2,4,5-tetrazines in KOH-MeOH-THF gives 4//-pyrazolo[5,l-c]thiazines. This novel condensation reaction proceeds via the intermediacy of an 8-(diphenylmethylene)-2//-l,4,5-thiadiazocin-7(8H)-one, which undergoes a multi-step rearrangement including a rare anti-Michael addition.30... 

Pyrazolo[5,l-d][l,2,3,5]tetrazin-4-ones synthesis, 3, 535 Pyrazolo[ 1,5-d]tetrazole structure, S, 263... 

Novel sulfone-containing pyrazolo[5,l-tfl[l,2,3,5]tetrazines and pyrazolo[l,5-ajpyrimidines have been synthesized <05JHC609>. 

Derivatives of pyrazolo[l,2-a]benzo[l,2,3,4]tetrazin-5-ones 66 designed as novel alkylating agents have been synthesized and showed antiproliferative activity <05JMC2859>. Reactions of 2-diazoindoles with alkyl or aryl isocyanates afforded derivatives of the new ring system [l,2,3,5]tetrazino[5,4-a]indole 67, some of which showed antiproliferative activity <05BMC295>... 

The pyrazolo[5,l-f,]-l,2,3,5-tetrazin-4(3//)-one 12 is stable in concentrated sulfuric acid at room temperature but gives the triazene 13 when treated with morpholine.36... 

Dimethylcyanamide reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (485) to give dimethyl 5-dimethylamino-l,2,4-triazine-3,6-dicarboxylate (486) <90JOC3257>. The diester (485) with dimethylamine yields methyl 5-methylamino-l,2,4-triazine-3-carboxylate (487) and its reaction with arylamines gives pyrazolo[3,4-e]l,2,4-triazine derivatives (488). (Scheme 89). Mechanisms for the formation of (487) and (488) were suggested <89CB1381>. 

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