[7+2]- and [11+2]-cycloaddition reactions of diazo-azoles with isocyanates to azolo[5,1-d] [1,2,3,5] tetrazine-4-ones

Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3‐b]pyridine

“…3‐Amino‐8‐methyl‐6‐phenyl‐2 H ‐pyrazolo[3′,4′:4,5]thieno[2,3‐ b ]pyridine 18 was diazotized with cold 4M hydrochloric acid and saturated aqueous solution of sodium nitrite in the presence of dichloromethane and sodium carbonate to produce pyrazolo[3′,4′:4,5]thieno[2,3‐ b ]pyridine‐3‐diazonium chloride intermediate 29 , which was further stirred with phenyl isocyanate at room temperature to afford the corresponding fused pyrazolo[5,1‐ d ][1,2,3,5]terazinone derivative 36 . The mechanism for the synthesis of pyrazolo[5,l‐ d ][1,2,3,5]tetrazinone analogs was reported via 7 + 2 cycloaddition reaction . It was indicated to proceed first through the addition of ring nitrogen of diazotized pyrazole to the electron‐deficient C═N double bond of phenyl isocyanate to give 1,9‐dipole followed by intramolecular coupling, which is outlined in Figure .…”

“…The mechanism for the synthesis of pyrazolo[5,l-d] [1,2,3,5] tetrazinone analogs was reported via 7 + 2 cycloaddition reaction. [60][61][62] It was indicated to proceed first through the addition of ring nitrogen of diazotized pyrazole to the electron-deficient C═N double bond of phenyl isocyanate to give 1,9-dipole followed by intramolecular coupling, [60] which is outlined in Figure 7. Compound 36 was identified on the basis of its spectral data; its IR declared an absorption band at 1707 cm −1 corresponding to carbonyl function, while its electron impact mass spectrum revealed a peak at m/z 410 corresponding to (M +• +1, 0.08), in addition to the base peak, which appeared at m/z 57 (100).…”

The Medicinal Chemistry of Imidazotetrazine Prodrugs

“…The original synthetic strategy towards TMZ and other imidazotetrazines is based on a general method for azolotetrazines [ 39 ], and involves the coupling of 5-diazoimidazole-4-carboxamide (diazo-IC, 10 ) or its analogues with the relevant isocyanate ( Scheme 5 ). Evidence suggests this occurs in a stepwise rather than a concerted mechanism [ 20 , 25 ].…”

Pyrido[4′,3′:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazines, a new class of Temozolomide heteroanalogues

“…Through this reaction the pyrazolotetrazinones 2a, the 1,2,3-triazolotetrazinones 2b and indazolotetrazinones 2c were obtained. 11 Later, several comprehensive reports describing the synthesis and the antineoplastic activity of many imidazo-tetrazinones 2d appeared, and further pyrazolo-and indazolo-tetrazinone derivatives were prepared using the same synthetic pathway (Scheme 1). 1,[12][13][14][15] The mechanism of this cycloaddition is not completely clarified.…”

“…1,[12][13][14][15] The mechanism of this cycloaddition is not completely clarified. A fully concerted [4+2] mechanism, formerly proposed, 11 seems unlikely since concerted mechanisms where heterocumulenes act as dipolarophiles have generally been discarded. 16 A stepwise ionic pathway might involve either an initial nucleophilic attack at the isocyanate carbon, to give a dipolar intermediate which spontaneously undergoes ring closure or a [3+2] cycloaddition leading to a spiro compound which by a [1,5] sigmatropic rearrangement affords the bicyclic system (Scheme 2).…”