A new route to functionally-substituted tetrazines

Ethylthio and isopropylthio chloroacetylenes react with dimethylhydrazine in ether at room temperature to form 1,1,4,4-tetramethyl-3,6-bis-[(alkylythio)methyl]-1,4-dihydro-1,2,4,5-tertazinium-1,4-dichlorides in 67 and 80% yield.


Introduction
(Alkylthio)chloroacetylenes react readily with N-, O-and S-mono-and bifunctional nucleophiles 1 to afford substituted polyfunctional unsaturated compounds including heterocyclic ones.For instance, the reactions with alkylenediamines, 2 2-hydroxyethylamine 3 2-hydroxy-N,Ndimethylamine, 4 thiosemicarbazones, 5 proceed by nucleophilic substitution of the acetylenic chlorine forming ynammonium salts which further undergo cyclization.In this way it was possible to obtain imidazole, oxazolone, oxazolidine, oxazine, and thiazole derivatives which, in certain cases, display effective complex-forming properties or high antimicrobial and antitumor activity.The reactions of (alkylthio)chloroacetylenes with nucleophiles open up new routes to new classes of polyfunctional acyclic and heterocyclic compounds and allow investigation of the nucleophilic substitution at sp-hybridized carbon atoms.

Results and Discussion
The reaction of (alkylthio)chloroacetylenes 1 with dimethylhydrazine, a large-tonnage product within the chemical industry, is not well understood.Prior to our investigation the literature on the reaction of haloacetylenes with hydrazine and its derivatives was limited to a brief note describing the reaction of bromoethynyl(aryl)ketones with N,N-dimethylhydrazine leading to further polymerization and hydrobromination of the intermediate ethynylhydrazines. 6The bidentate nucleophilic character of N,N-dimethylhydrazine (DMH) and the presence of two С sp atoms in the acetylene 1 makes prediction of the product composition difficult.We have shown that (ethylthio) and (iso-propylthio) chloroacetylenes 1а,b react readily with an equimolar amount of DMH in ether at 20-22 о С to afford 1,1,4,4,-tetramethyl-3,6-bis-[(alkylthio)methyl]-1,4-dihydro-1,2,4,5-tetrazinium-1,4-dichlorides 2а,b in 67 and 80% yield, respectively (Scheme 1).

Scheme 1
Compounds 2а,b are white crystalline substances soluble in water, DMSO and ethanol.In the 13 С NMR spectra of 2а,b there are signals of carbon atoms of alkylthio-, CH 3 -N + and exocyclic alkylthiomethylene (SCH 2 ) groups, as well as a signal at 128 ppm, which was assigned to two magnetically equivalent carbon atoms (С=N) in the tetrazine cycle 6,7 Apart from the alkylthio proton signals, the 1   ._

Scheme 2
Thus, the reaction of (ethylthio) and (iso-propylthio) chloroacetylenes with N,Ndimethylhydrazine allows the elaboration of a new synthetic approach to functionally substituted tetrazines.The representatives of this class of compounds have for long time attracted the attention of research chemists due to their high and diverse biological activity. 8

Experimental Section
General Procedures.IR Spectra were recorded on a Specord IR-75 spectrometer in microlayer. 1 H and 13 С NMR spectra were run on a Bruker DPX-400 (400 MHz for 1 H and 100 MHz for 13 C) in DMSO, TMS as internal standard.

1,1,4,4-Tetramethyl-3,6-bis-[(ethylthio)methyl]-1,4-dihydro-1,2,4,5-tetrazinium-1,4dichloride (2а).
To a solution of 2.50 g (0.042 mol) DMH and 100 ml of dry ether a solution of 5.06 g (0.042 mol) of acetylene 1a in 20 ml of dry ether was added drop wise on stirring for 30 min.The reaction proceeded exothermally.The reaction temperature was kept at 20-22°С using external cooling.After the addition of the acetylene solution, the reaction mixture was stirred at 20-22° for further 8 h.Then, the precipitate was filtered off, washed with dry diethyl ether (3×10 ml) and dried in vacuum.5.10 g (67%) of compound 2а was obtained as a white crystalline substance, m.p. 77 H NMR spectra of compounds 2а,b show two singlet signals at ~2.7 and 3.6 ppm corresponding to SCH 2 -and СН 3 N-group protons, respectively.In the IR spectra of the dichlorides 2а,b display absorption bands at 1600 cm -1 from the C=N stretching vibrations .Their ionic character was confirmed by mercurimetric titration which indicated the presence of two chloride-ions per mole of compound.Formation of tetrazines 2a,b in the reaction under consideration (Scheme 1) can be rationalized by Scheme 2 including the nucleophilic attack of the tertiary nitrogen atom of dimethylhydrazine at the С sp carbon atom of chloroacetylenes 1а,b leading to substitution of the halogen atom and formation of ethynylammonium salts 3а,b.The latter dimerize into alkylthiomethylidenetetrazines 4a,b which after prototropic isomerization give tetrazinium-1,4dichlorides 2а,b.