Tetrazines, reactions with enamines

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Perhaps through enamine formation from ketones prohne catalyzes a Diels-Alder reaction with 1,2,4,5-tetrazines. ... 

Inverse electron demand Diels-Alder reactions of 3,6-bismethylthio-l,2,4,5-tetrazine with a wide range of dienophiles have been shown to give substituted 3,6-bismethylthiopyridazines (148), generally in yields of 60% to 90% (Scheme 111). The reactivity of electron-rich alkynes and alkenes shows the expected order of ynamines > enamines > ketene acetals > enamides > trimethylsilyl or alkyl enol ethers > enol acetates reaction with ynamines is complete at room temperature in one... 

For stereochemical investigations of the reaction type mentioned above cis-trans isomeric dienophiles (or dienes) are normally used. For the tetrazine reactions in question electron-rich dienophiles are necessary, such as cK-/ra 5-isomeric enamines or enol ethers. C -enamines are extremely sensitive, isomerizing to the more stable trans isomers very quickly <69CB1917>. Hence, it is not surprising that only very few examples are available to prove that the (4 -I- 2) cycloaddition reactions of 1,2,4,5-tetrazines are stereospecific, in accord with concerted bond making. Cis-trans isomeric... 

A bicyclic Diels-Alder adduct is presumably in intermediate in these reactions although it was not actually observed. Interestingly, ketone hydrazones react with the tetrazine via their enamine tautomers, giving diazenes as products. 

Recently, Rusinov et al. reported unexpected formation of cyclopenta[4,5]imidazo[l,2-3]-l,2,4,5-tetrazines 321 in the reactions of r-tetrazine hydrazones 319 with enamines 320 in methanol. When carried out in acetonitrile, these reactions produced the expected cyclopenta[4,5]pyridazines 322 (Scheme 76) <2003HC039>. 

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). 

Wang, et al. reported an organocatalylic direct inverse electron demand Diels-Alder reaction of ketones 140 with l,2,4,5-tetrazinesl41, Scheme 3.46 [62]. Examination of the results of catalyst screening revealed that L-proline seems to be the best organocatalyst tried in this process. Several steps were involved in the cascade reactions inverse electron demand Diels-Alder reaction of 1,2,4,5-tetrazines 141 with the enamines, derived from ketones and L-proline, followed by a subsequent retro-Diels-Alder process to extrude and elimination to afford pyridazines 142. 

An unusual approach to the synthesis of chain-fluorinated diazines relies on the inverse-electron-demand hetero-Zretro-Diels - Alder ihDA/rDA) sequence. The background of this method for the preparation of nitrogen-containing heterocycles in general has been reviewed recently [674], Typical dienes used for the synthesis of chain-fluorinated diazines are given in Fig. 29. Since electron-deficient dienes are necessary for the first step of the sequence - inverse-electron-danand hetero-Diels -Alder reaction, fluoroalkyl substituents of tri- and tetrazines 1111-1112 are favorable for the process. Typical electron-rich dienophiles for the reactions with 1111-1112 are enamines (including amino heterocycles) and alkynes, although other examples are also known. 

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... 

These authors found that the tetrazinylhydrazone derivative 46 when reacted with pyrrolidinoenamine 47 in methanol yields the cyclopenta-fused derivative of the title ring system 48 in 94% yield. A similar transformation was carried out successfully by using morpholine-enamine in somewhat poorer yield. When the transformation was tried in acetonitrile as a solvent, a totally different reaction was observed a regular Diels-Alder reaction between the tetrazine ring and the enamine double bond (of inverse electron demand) took place to yield pyridazines. 

Pyrimidines are expected to be much less reactive in cycloadditions of this type than triazines and tetrazines. Normally, the presence of electron-withdrawing substituents on the pyrimidine ring is essential. The best results are obtained with a nitro group in position 5. Reaction of 5-nitropyrimidine with various enamines affords fused nitropyridines (82TL3965 89T2693) (Scheme 59). The mechanism (89T2693) is in agreement with the usual expectations. 

Since the report by Carboni and Lindsey in 1959 on the cycloaddition reaction of tetrazines to multiple bonded molecules as a route to pyridazines, such reactions have been extensively studied. In addition to acetylenes and ethylenes, enol ethers, ketene acetals, enol esters and enamines, and even aldehydes and ketones have been used as starting materials for pyridazines. A detailed investigation of various 1,2,4, 5-tetrazines in these syntheses revealed the following facts. In [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine with dienophiles, which lead to pyridazines, the following order of reactivity was observed (in parenthesis the reaction temperature is given) ynamines (25°C) > enamines (25-60°C) > ketene acetals (45-100°C) > enamides (80-100°C) > trimethylsilyl or alkyl enol ethers (100-140°C) > enol... 

Two atypical reactions of tetrazines involve a dienatnine and a dihydropyridine. Acyclic diena-mines react with two molecules of 3,6-diaryl-l,2,4,5-tetrazines to give a mixture of 3,6-diaryl-pyridazines and the corresponding 4-dialkylamino derivatives (Scheme 112) reaction proceeds by cycloaddition to the terminal double bond and then to the enamine double bond by a second tetrazine to give the postulated intermediate (149), followed by loss of nitrogen and, finally, aromatization is achieved by an unusual carbon-carbon cleavage to give the two products <87H(26)337>. The expected inverse electron demand Diels-Alder reaction between the Ar-methyl-l,4-dihyropyridine (150) and... 

Even more so than 1,2,4-triazines (see p 441), 1,2,4,5-tetrazines display heterodiene activity in their reactions towards electron-rich, multiply-bonded systems. Enol ethers, enamines, ketene acetals, imido esters, alkynylamines and nitriles undergo [4+2] cycloadditions with inverse electron demand across the ring positions C-3 and C-6 [176]. Olefinic dienophiles lead to diverse products depending on their substituents ... 

L-Pro has been used as an organocatalyst in an inverse-electron-demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines to furnish pyrazines with medicinal interest.The transformation proceeds by the reaction of the diene 1,2,4,5-tetrazine with the enamine formed in situ from the ketone and L-Pro. A retro-Diels-Alder step eliminates nitrogen and forms the pyr-azine product after catalyst elimination. The transformation is, however, not regioselective with unsymmetrical ketones. 

Displacement of Sulphur. The Wittig reaction of resonance-stabilized phosphorus ylides with thioacyl-urethanes gives acylated enamines, e.g. (84), from which )ff-keto-esters are obtained by hydrolysis. Hydrazine displaces sulphur in thioanilides, giving amidrazones, but with two equivalents of arylselenoamides it gives 2,5-diaryl-1,3,4-selenadiazoles. Selenoamides react with an excess of hydrazine to give 1,2,4,5-tetrazines (see also Chap. 6, p. 294). l,2-Bis(thio-benzamido)ethane, when treated with NEt, and HgO, cyclizes to 2-phenyl-... 

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