Reactions with tetrazines

Appropriately substituted azolyldieneamines were found to undergo double inverse electron demand Diels-Alder reactions with tetrazine derivatives, yielding azolylpyridazines and... 

The 2,3-dihydrobenzo[l,2-7 5,4-3 ]difuran 705 can undergo a cycloaddition reaction with tetrazine 706 followed by furan ring opening and lactonizaton to afford the pyridazino-fused coumarin 707 (Scheme 174) <2005T4805>. Similarly, benzo[l,2-3 5,4-7 ]difurans 708 react with tetrazine 706 to form the pyridazino-fused coumarins 709 and 710 (Equation 283) <2005T4805>. 

Diels-Alder cycloaddition reactions with tetrazines provide a useful approach to the preparation of pyrrolo[2,3-d]pyridazines. Thus, the lactam acetal (97), which is in equilibrium with the cyclic ketene A,O-acetal (98), reacts with tetrazines (99) to give the partially reduced product (100) <86CB3600>. The methylthio analogue of the acetal (97) also reacts similarly with tetrazines (Scheme 7) <87JHC545>. 

Cyclic enol ethers give first the intermediate bicyclic dihydro-pyridazine adducts that isomerize by ring cleavage to pyridazines with hydroxyalkyl or alkoxyalkyl substituents. Several other alkenes were also used in the reaction with tetrazines to give pyridazines. ... 

Figure 1 presents a collection of rate constants for cyclic dienophiles in the reaction with tetrazine diester (48). 

Ketone 167 reacted with morpholine and p-TosOH to yield enamine 169, which undergoes Diels-Alder reaction with tetrazine 142 to yield the isolable intermediate 170. Aromatization occurs easily on further treatment of 170 with p-TosOH in boiling benzene leading to N-protected tricyclic pyridazines 171 (2002BMC1 Scheme 30). 

General Discussion. Oxazole functions as an azadiene in the Diels-Alder reaction. The resulting [4 + 2] product is normally not isolated, instead rearranging to pyridines (eq 3). High regios-electivity has been reported for this reaction. Oxazole can also perform as a dienophile, as in the reaction with tetrazines (eq A) ... 

A particularly interesting system where nitrogen is lost cheletropically after formation of the initial [4 + 2] cycloadduct involves the thermal reaction of azirines with tetrazines (82) (74CC45, 74TL2303, 74CC782, 75JHC183). A variety of heterocyclic products are produced depending on the structure of the azirine and tetrazine used and the reaction conditions. 

The Diels-Alder reaction of cyclopropenes with 1,2,4,5-tetrazines (see Vol.E9c, p 904), a reaction with inverse electron demand, gives isolable 3,4-diazanorcaradienes 1, which are converted into 4H-1,2-diazepines 2 on heating. The transformation involves a symmetry allowed [1,5] sigmatropic shift of one of the bonds of the three-membered ring, a so-called walk rearrangement , followed by valence isomerization.106,107... 

Several dihydrotetrazine materials have been promoted as oxygen scavengers, including 3,6-dimethyl,1-2-dihydro,1,2,4,5-tetrazine, and the diethyl- and diphenyl-derivatives. 3,6-Dimethyl,1-2-dihydro,1,2,4,5-tetrazine is a six-sided ring with a formula H3C-CN2C-CH3NHNH its MW equals 102. Its basic reaction with oxygen is shown here ... 

The DA reaction of tetrazines such as 3 was also studied by use of the GS/ MW process [26, 27]. The expected adduct, however, decomposed by nitrogen elimination followed by dehydrogenation, giving a pyridazine or a dihydropyrida-zine [23-25], With 2,3-dimethylbutadiene and cyclopentadiene as dienophiles, SMWI gave dihydropyridazines 8 and 9, as with classical heating [23] (Tab. 7.1, entries 6 and 7). 

Synthetic approaches to representatives of this ring system have been discussed in CHEC-II(1996) <1996CHEC-II(8)496>. Research activity in this area has been considerably extended during the past years. Thus, the basic starting material is a 6,6-disubstituted tetrahydro[l,2,4,5]tetrazin-3-thione 52, which has been converted in three different ways reaction with phenacyl bromides led to 3,3-disubstituted 3,4-dihydro-6-phenyl-2//-thiazolo[3,2-4]-[l,2,4,5]tetrazines 53, reaction of 52 with 1,2-dibromoethane gave 3,4,6,7-tetrahydro-2//-thiazolo[3,2-7][l,2,4,5]tetra-zines 54, whereas transformation of 52 with chloroacetic acid in the presence of sodium acetate yields substituted 3,4-di hydro-1-2//-thiazolo[3,2- 1 [ 1,2,4,5]tctrazin-6(7//)-oncs 55 <2001IJB584> (Scheme 17). Details are shown in Table 2. 

Oxidation of 3,6-diamino-1,2,4,5-tetrazine (198) with oxone in the presence of hydrogen peroxide yields 3,6-diamino-l,2,4,5-tetrazine-2,4-dioxide (201) (LAX-112). The same reaction with 90 % hydrogen peroxide in trifluoroacetic acid yields 3-amino-6-nitro-1,2,4,5-tetrazine-2,4-dioxide (202). Treatment of 3,6-diamino-1,2,4,5-tetrazine (198) with 2,2,2-trinitroethanol and 2,2-dinitro-2-fluoroethanol generates the Mannich condensation products (203) and (204) respectively. 

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). 

The inverse electron demand Diels-Alder [4- -2]-cycloaddition of imidazoles to electron-poor dienes to yield imidazo[4,5-i pyridazines, reported in CHEC-II(1996), has been further developed. It was reported that the reaction of267 with tetrazines 268 was fruitless. However, 267 reacted with excess of 268 to yield aromatic 271 along with 1,4-dihydrotetrazine 270. Most likely, 271 arose from dehydrogenation of first-formed 269 by an extra equivalent of 268 <2001T5497> (Scheme 18). 

The reaction of ring-strained cycloalkcnes with tetrazines often proceeds under mild conditions for example, reaction of trieyclo[4.2.2.0i-5]deca-3,7-dienes with the dipyridyltetrazine 18 at room temperature gave 3,4-diazabicyclo[4.2.0]octa-2,4-diene derivatives 19 after nitrogen extrusion.24... 

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). 

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