Alkenes 1,2,4,5-tetrazine

Rieder U, Luedtke NW (2014) Alkene-Tetrazine ligation for imaging cellular DNA. Angew Chem Int Ed 53(35) 9168-9172. doi 10.1002/anie.201403580... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The preparation of rigid alicyclic molecules bearing effector groups from alkene blocks using s-tetrazines and 1,3,4-triazines as stereoselective coupling agents [67]... 

Another convenient entry to fused cyclobutene-1,2-diesters was via site selective modification of the norbomene rt-bond in Smith s fe-alkene 49, e.g. treatment with 3,6-di(2 -pyridyl)-s-tetrazine 51 followed by DDQ oxidation afforded the cyclobutene-derivative 53 <97AA119>, while direct coupling with 3,5-f> (trifluoromethyl)-l,3,4-oxadiazo]e 54 furnished the tas(cyclobutene-l,2-diester) 55 (Scheme 6) <97SL196>. 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

The reactivity of tetrazines with electron-attracting substituents (e.g. R3 = R6 = C02Me) is particularly high, so it was proposed to use them as titrating agents to determine the purity of liquid alkenes (62CB2248). 

Dihydropyridazines (117) result from Diels-Alder addition of. v-tetrazines (115) with electron-rich alkenes (e.g. 116). Frequently the products aromatize, as in (117) — (118) (see also Section 3.2.1.10.2.iv). 

The first product of the reaction of 1,2,4,5-tetrazines (39) with alkenes (142) is the bicyclic compound (143), which has never been isolated since it loses nitrogen immediately by a retro-Diels-Alder reaction to give 4,5-dihydropyridazine (144). These compounds have been isolated in a few cases but usually a product is obtained which is formed from (144) in one of four different ways ... 

Oxidation of (144) to give the pyridazine (146). For this reaction it is necessary that the alkene has protons at each end of the double bond. Very often an excess of the tetrazine acts as the oxidizing agent. 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

Various fused pyridazine derivatives can be prepared by the inverse-electron-demand DielsAlder cycloadditions of 1,2,4,5-tetrazines with a wide range of alkynes and alkenes . For example, 3,6-bis(trifluor-omethyl)-l,2,4,5-tetrazine 426 cycloadds to benzyne giving a quantitative yield of l,4-bis(trifluoromethyl)phthalazine 427 (Scheme 222) <1987AGE332>. 

By reacting 1,2,4,5-tetrazines with alkynes the initially-formed 2,3,5,6-tetraazabicyclo[2.2.2]oct-2,5,7-triene (148) decomposes without isolation to give the pyridazine (146) by elimination of nitrogen. In most cases the reaction with alkynes requires higher temperatures and longer reaction times than with alkenes (Scheme 8). 

Since the initial demonstrations of the participation of substituted l,2,4,S-tetrazines ° and oxa-zoles ° ° in [4 + 2] cycloaddition reactions with alkene and alkyne dienophiles, the investigation and application of the Diels-Alder reactions of heteroaromatic systems possessing reactive azadienes have been pursued extensively. A number of general reviewshave treated the spectrum of heteroaromatic azadienes that participate in [4 + 2] cycloaddition reactions and many of the individual heteroaromatic systems have been reviewed separatcly. ° ° An extensive account was published recently and should be consulted for descriptions of the [4 + 2] cycloaddition reactions of the common heteroaromatic azadienes that have been observed to date. 

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. ... 

Reaction of l,4-dihydronaphthalene-l,4-imine with di-pyridyl-1,2,4,5-tetrazine, designed to prepare isoindoles, also gives 3,6-di-pyridyl-pyridazine. Other bicyclic alkenes react similarly. Pyridazines are also formed in reactions between 1,2,4,5-tetrazines and dioxene. 

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. ... 

Extensive studies of preparation of 4-mono- and 4,5-disubstituted pyridazines from 1,2,4,5-tetrazines using donor-substituted alkenes, alkynes, ketene aminals, or styrenes were reported by Sauer. Pyridazine itself can be prepared from 1,2,4,5-tetrazine and acetylene (27% yield), ethyl vinyl ether (78% yield), methyl vinyl sulfide (76% yield), or N,jV-dimethylvinyl-... 

Tetrazines 1 are readily reduced by other hydroheterocyclic compounds, such as tetrahydro-1, 2,4,5-tetrazines254 or by dihydropyridazines which are formed by cycloaddition reactions of 1 with alkenes (see Section 5.2.5.), to dihydro-1,2,4,5-tetrazines 2. 

The most intensively studied reactions of 1,2,4,5-tetrazines are cycloaddition reactions with alkenes and alkynes, not only due to theoretical interest but also due to its importance in synthesis. The 1,2,4,5-tetrazines are diene components in this [4 + 2]-cycloaddition reaction while the alkynes and alkenes are the dienophiles. Kinetic studies have shown that these reactions should be classified as Diels Alder reactions with inverse electron demand. Therefore, 1,2,4,5-tetrazines with electron-withdrawing substituents (C02Me, CF3) and dienophiles with electron donating substituents are the most reactive compounds. However, dimethyl... 

Initial work on the reactions of 1,2,4,5-tetrazines with alkenes used 3,6-perfluoroalkyl-... 

In a similar manner the bicyclic intermediates 4, which are formed when 1,2,4,5-tetrazines 1 react with alkenes, also lose nitrogen immediately, affording the dihydropyridazines 5. These compounds have been isolated in a few cases, but usually secondary products are obtained which are formed by one of the following processes ... 

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