- Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding
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An unprecedented 1,4-cycloaddition (vs 3,6-cycloaddition) of 1,2,4,5-tetrazines is described with preformed or in situ generated aryl-conjugated enamines promoted by the solvent hydrogen bonding of hexafluoroisopropanol (HFIP) that is conducted under mild reaction conditions (0.1 M HFIP, 25 °C, 12 h). The reaction constitutes a formal [4 + 2] cycloaddition across the two nitrogen atoms (N1/N4) of the 1,2,4,5-tetrazine followed by a formal retro [4 + 2] cycloaddition loss of a nitrile and aromatization to generate a 1,2,4-triazine derivative. The factors that impact the remarkable change in the reaction mode, optimization of reaction parameters, the scope and simplification of its implementation through in situ enamine generation from aldehydes and ketones, the reaction scope for 3,6-bis(thiomethyl)-1,2,4,5-tetrazine, a survey of participating 1,2,4,5-tetrazines, and key mechanistic insights into this reaction are detailed. Given its simplicity and breath, the study establishes a novel method for the simple and efficient one-step synthesis of 1,2,4-triazines under mild conditions from readily accessible starting materials. Whereas alternative protic solvents (e.g., MeOH vs HFIP) provide products of the conventional 3,6-cycoladdition, the enhanced hydrogen bonding capability of HFIP uniquely results in promotion of the unprecedented formal 1,4-cycloaddition. As such, the studies represent an example of not just an enhancement in the rate or efficiency of a heterocyclic azadiene cycloaddition by hydrogen bonding catalysis but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddition.
- Zhu, Zixi,Glinkerman, Christopher M.,Boger, Dale L.
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supporting information
p. 20778 - 20787
(2020/12/22)
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- Spontaneous resolution of a triple-stranded dinickel(II) helicate generated via intermolecular transamination reaction of S-methylisothiocarbohydrazide in the presence of Ni2+
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The reaction of S-methylisothiocarbohydrazide hydroiodide [H 2NNHC(SCH3)NNH2·HI] with NiCl 2·6H2O in water at room temperature yielded a triple-stranded dinickel(II) helicate [NiII(L1-L 1)3NiII]I4·4H2O (14+·4I-·4H2O), where L 1-L1 = H2NNHC(SCH3)NNC(SCH 3)NHNH2, in 35% yield, which spontaneously separates in enantiomers upon crystallization. The enantiomers do not racemize at room temperature, even not after 15 h of heating at 90 °C. X-ray diffraction structures of both enantiomers, chiroptical and magnetic properties of 1 4+·4I-·4H2O are reported. Demetallation of the complex by treatment with S2- resulted in 3,6-bis(methylthio)-1,4-dihydro-1,2,4,5-tetrazine (2). Compound 2 undergoes 2-e- oxidation in air to give the known 3,6-bis(methylthio)-1,2,4,5- tetrazine (3). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Dobrov, Anatoly,Arion, Vladimir B.,Shova, Sergiu,Roller, Alexander,Rentschler, Eva,Keppler, Bernhard K.
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experimental part
p. 4140 - 4145
(2009/02/07)
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- Radical Cations and Anions of 1,2,4,5-Tetrazines: an Electron Spin Resonance and Cyclic Voltammetric Study
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Exposure to (60)Co γ-ray of dilute solutions of a range of s-tetrazines in fluorotrichloromethane at 77 K gave the corresponding radical cations, identified by their e.s.r. spectra.Two distinct types of spectra were obtained, one showing large hyperfine coupling to four equivalent (14)N nuclei is assigned to n(?)-radical cations, and the other, only found for -NR2 substituents, with strong coupling to two nitrogen nuclei, is assigned to ?-radical cations.The former include the parent s-tetrazine and the 3,6-dimethyl, -diphenyl, dichloro, dimethoxy, bis(methylthio), and di(aziridin-1-yl) derivatives.The latter were also prepared in fluid solution, and showed reversible behaviour in their cyclic voltammograms, in contrast with the former group.The corresponding radical anions have been studied in both fluid and solid solution, all derivatives showing major hyperfine coupling to the four ring (14)N nuclei.Total spin densities have been estimated for both types of radical cations and for the radical anions, and in all cases the total is in the 1.05-1.2 range.This deviation from unity is interpreted in terms of spin polarisation giving rise to considerable negative spin densities.
- Fischer, Hans,Mueller, Thomas,Umminger, Irmgard,Neugebauer, Franz A.,Chandra, Harish,Symons, Martyn C. R.
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p. 413 - 422
(2007/10/02)
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- A Study of 1,4-Dihydro-1,2,4,5-tetrazines
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X-ray structure analysis of the primary compound 1 and the derivatives 9 and 13 yields a 1,4-dihydro structure.Detailed studies of the electronic spectra of 1-16 show that also in solution the 1,4-dihydro form is thermodynamicly favoured.A series of new 1,4-dihydro-1,2,4,5-tetrazine radical cations was studied by e.s.r.
- Neugebauer, Franz Alfred,Krieger, Claus,Fischer, Hans,Siegel, Rolf
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p. 2261 - 2274
(2007/10/02)
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