Dimethyl -1,2,4,5 -tetrazine- 3,6-dicarboxylate

Equimolecular amounts of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate and 1,2-diphenylcyclopropene in CH2C12 at 20 LC gave the diazanorcaradiene la (72% mp 172— 174CC), a toluene solution of which was refluxed to afford the diazepinc 2a (50% mp 177-178T7). 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

Preparation and Diels-Alder Reaction of a Reactive, Electron-Deficient Heterocyclic Azadiene Dimethyl 1,2,4,5-Tetrazine-3,6-Dicarboxylate. 1,2-Diazine and Pyrrole Introduction. 

Dimethoxy-l-trimethylsilyloxy-l, 3-butadiene. 1,2-Dimethoxy-1 -trimethylsily-loxy-l,3-pentadiene. Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate. 1 -Methoxy-... 

Substituted 1,2,4-triazines and 1,2,4,5-tetrazines are known to undergo [2-1-4] cycloaddition with inverse electron demand when reacted with alkenes. The primary bicyclic product loses nitrogen to give dihydropyridines and dihydropyridazines, respectively. The reaction of methylenecyclopropane with dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate at room temperature gave the spiro-dihydropyridazine 2 in 80% yield. ... 

This approach to 1,2-diazine and pyrrole introduction based on the inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate complements the [4 + 2] cycloaddition reactions of a range of electron-deficient heterocyclic azadienes which permits the divergent preparation of a range of heterocyclic agents employing a common dienophile precursor, Scheme I. 

PREPARATION AND DIELS-ALDER REACTION OF A REACTIVE, ELECTRON-DEFICIENT HETEROCYCLIC AZADIENE DIMETHYL 1,2,4,5-TETRAZINE-3,6-DICARBOXYLATE. 1,2-DIAZINE AND PYRROLE INTRODUCTION... 

The procedure describes the preparation and use of a reactive, electron-deficient heterocyclic azadiene suitable for Diels-Alder reactions with electron-rich, unactivated, and electron-deficient dienophiles. Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, because of its electron-deficient character, is ideally suited for use in inverse electron demand (LUMOdiene-controlled) Diels-Alder reactions. Table I and Table II detail representative examples of the reaction of dimethyl 1,2,4,5-tetrazine-3.6-... 

Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (10a 0.99 g, 5 mmol) and ethyl thioformate (0.45 g, 5 mmol) were heated at reflux in toluene until the red color of the tetrazine disappeared (ca. 110 h). The solvent was then distilled off, the residue boiled several times with hexane, and filtered hot. Lemon-yellow crystals separated on cooling and were recrystallized (anhyd hexane) yield 0.65 g (50%) mp 90-91CC. 

To a suspension of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (2.0 g, 10 mmol) in anhyd PhCl (50 raL) was added A -,A -dimethy 1 cyanamide (700 mg, 10 mmol) and the mixture heated under reflux with exclusion of moisture until the solution became colorless. The solvent was removed and the residue dissolved in EtOAc. Cooling in a refrigerator afforded the product yield 1.78 g (78%) mp 130°C. 

Pyridazino annelated biyclic endoperoxides 197-202 were prepared by cycloadditions of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 150 to unsaturated endoperoxides 191-196 in dichloromethane (Scheme 51) <1996TL921, 2000H(53)761, 2003JHC529, 2003JOC7009>. 

OT / -Phenylene- and ra-phenylene-bis(dienamines) 315 and 316 were transformed with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 150 into the corresponding phenylene-bis(triazolylvinylpyridazines) 317 and 318 in 59-90% yields. Cycloadditions took place selectively at the enamine C=C bond (Scheme 75) <2004T3421>. 

Tetrazines have been frequently used as electron-deficient dienes in IDA reactions with electron-rich dienophiles [12], Uriarte and coworkers [13] reported the reaction of the pyrrolocoumarin 1 with 2 equivalent of either dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (2a) or 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine (2b), followed by the release of nitrogen and aromatization, to produce the corresponding pyridazinepyrrolocoumarins 3 (Scheme 1). 

Boger DL, Panek JS et al (1992) Preparation and Diels-Alder reaction of a reactive, electron-deficient heterocyclic azadiene dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate. 1,2-Diazine (dimethyl 4-phenyl-l, 2-diazine-3, 6-dicarboxylate) and pyrrole (dimethyl 3-phenylpyrrole-2, 5-dicarboxylate) introduction. Organic Synth 70 335... 

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