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

Benzo[Z)]thiophene reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate in a cyclo-addition-fragmentation reaction to yield (143), whereas benzo[A]furan and N- methylindole yield products (144) arising from ring opening and recyclization (76AP679). 

The reaction of oxepin with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate affords a 2 1 mixture of products 9 a and 10, whose formation can be rationalized by a [4+2] and a [4 + 6] cycloaddition, followed by nitrogen extrusion.235 With 2,7-dimethyloxepin, only dimethyl 6,8-dime-thy 1-2.4a-dihydrooxepino[4,5-c/]pyridazine-l,4-dicarboxy late (9b) as product of the [4 + 2] cycloaddition can be isolated.235 236... 

Cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with EWG-substituted primary ketene N,0-acetals provides a tetrasubstituted pyridazine, methyl 4-amino-5,7-dioxo-6,7-dihydro-5/7-pyrrolo[3,4-4pyridazine-3-carboxylate <200681513>. 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

A facile preparation of pyrrolo 3,4-/ indoles 143 from pyridazino[4,5-fc]indoles 142 using a Zn/AcOH reductive ring contraction has been described [38], Since compounds 142 are easily prepared from the inverse electron demand cycloaddition of indoles 141 with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate, this represents a simple, two-step sequence to prepare the pyrroloindoles 143 (Scheme 26). 

A novel formal inverse-electron-demand hetero-Diels-Alder reaction between 2-aryl-a,/3-unsaturated aldehydes and ketones produces dihydropyran derivatives stereo-specifically.161 The inverse-electron-demand Diels-Alder reaction of 3,4-r-butylthio-phene 1-oxide with electron-rich dienophiles shows vyn-jr-face and endo selectivity.162 (g) The inverse-electron-demand Diels-Alder reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163... 

In order to confirm the stmcture of the tricyclic thietane 60, it underwent several reactions <20040L1313>, which were performed on the substituent of the ring carbon atom. The thietane 60 underwent hydrogenation on palladium-on-charcoal to give the fully saturated compound 61. The presence of a double bond in compound 60 was also confirmed by [4+2] Diels-Alder cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate as well as of diphenyl-isobenzofuran, which led to the formation of cycloadducts 62 and 63, respectively (Scheme 10) <20040L1313>. 

The spiro compound 106 underwent a Diels-Alder cycloaddition with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate to give the condensed 1,2-diazocine 107, presumably via retrograde deazatization of the initial [4+2] cycloadduct with cleavage of the cyclobutane ring (Scheme 22) <20040L1313>. 

The inverse electron demand Diels-Alder (IDA) reactions of 3-substituted indoles as 2rt-components with 1,2,4-triazines and 1,2,4,5-tetrazines proceeded in excellent yields both inter- and intramolecularly <1996TL5061>. The reaction of iT-BOC-tryptamine (1110, R = BOCNH(CH2)2) and indole 1110 (R =Me) with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 1111 in refluxing dioxane (3h) provided cycloadducts 1112 (R2 = B0C) and 1113, respectively, in excellent yields (80% and 82%, Scheme 217). Deprotection of compound 1112 produced derivative 1112 (R = H, >99%). 

Boger et al. developed a common strategy useful for the synthesis of related natural products and analogues <99JA54>. Their approach employs an aza Diels-Alder reaction <86CRV781, 89PHC30> using as diene the dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 25 to... 

Dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate continues to be an important reagent in the inverse Diels-Alder reaction, and has been used in the synthesis of ningalin D <05JA10767>, dihydrodiol and diol epoxide of phthalazine <05T1545> and novel pyridazino-psoralen derivatives <05T4805>. 

Most of the synthetic approaches towards benzoannelated [2.2]paracyclo-phanes use the Diels-Alder reaction to build up the annelated rings [18,22,29]. [2.2]Paracyclophane-l-ene (32) and [2.2]paracyclophane-1,9-diene (42) can be considered as the simplest dienophiles for this purpose. Since the first syntheses of these compounds in 1958 by Cram et al. [32], various attempts have been made to get them to react with dienes in terms of Diels-Alder reactions. However, [2 + 4] cycloadditions were never observed [33], and could not be facilitated either by the application of high pressure, or the presence of Lewis acid catalysts Diels-Alder adducts were not even obtained with dienes such as tetrachloro-thiophene dioxide, known for its high reactivity in [2 + 4] cycloadditions with an inverse electron demand. All the more surprising was the observation that monoene 32 reacts smoothly with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate at room temperature leading to a dihydropyridazine-annelated paracyclophane 39 in high yield [34a]. As reported for other tetrazine Diels-Alder reactions... 

Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with 6-methoxy-l,2,3,4-tetrahy-dropyridine gives dimethyl l,2,3,4-tetrahydropyrido[2,3-<5f]pyridazine-5,8-dicarboxylate. Apparently the lactim ether is in tautomeric equilibrium with the corresponding cyclic ketene A,O-acetal, which acts as the dienophile, the final step being the elimination of methanol.73 For a related synthesis, see ref 74. 

Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with dimethylamine affords methyl 5-(methylamino)-l,2,4-triazinc-3-carboxylate (12), while reaction with arylamines yields pyra-zolo[3,4-( ]-l,2,4-triazines 13. Mechanisms for the formation of the two products have been suggested.231... 

Dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (3) affords the following products when reacted with nucleophiles water affords the hydrazide 4, ammonia and dimethylamine the amidrazone 5, methylamine the 1,2,4-triazine 6 and methanol (X = O) or methanethiol (X = S) the dihy-dropyrazoles 7.288... 

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