Reactivity of 1,2,3-triazole-substituted 1-azabutadienes (vinamidines)

The reactivity of the new 1,2,3-triazole-substituted vinamidines ( i.e. 1-azabutadienes) was investigated. They were used as synthons to obtain new pyrazole, di-1,2,3-triazole as well as 4-amino-1,2,3-triazole derivatives. The Diels-Alder reaction with inverse electronic demand (using dimethyl 1,2,4,5-tetrazin-3,6-dicarboxylate as reagent) resulted in the formation of a new pyridazine derivative.


Introduction
3][4] We studied the reactivity of two new 1-azadienes (1a,b), described by us recently. 1These vinamidines were found to be fairly stable under the conditions of their preparation, although their aminolysis or hydrolysis could theoretically lead to the formation of aminotriazole 2. This compound was isolated in low yield as byproduct in the reaction that gave 1b. 1

Results and Discussion
In order to study the possibility of formation of 2, the 1-azadiene 1b was reacted with an excess of morpholine in the presence of morpholinium perchlorate.A slow reaction took place at room temperature and instead of the expected aminotriazole 2 1 (which was isolated in very low, 2% yield), two other products were obtained: the 2-bromo-2-propenal-3-yl-aminotriazole 3 1 (37%; being formed via the hydrolysis of the morpholine moiety) and the 3-hydroxy-4-morpholino-1aza-1,3-butadien-1-yl derivative 4 (29%; being formed by the hydrolysis of the bromo substituent).

Scheme 1. Aminolysis and hydrolysis of vinamidine 1b.
The structure elucidation of 4 showed that depending on the solvent it can also exist in zwitterionic form.The acidic hydroxy group at position 3 can protonate the N-atom at position 1 (or the N-atom of the morpholine substituent).As a result, the nitrogen atom in question became positively charged, while the oxygen was bearing a negative charge.
The reaction with morpholine showed that the aminolysis of 1b was not a favoured process to give 2, instead the hydrolysis of the morpholino or the bromo substituents took place under influence of traces of water in the solvent.
Under acidic conditions at room temperature the vinamidine 1b is stable.At reflux temperature, however, the reaction of 1b with aq.HCl resulted in (within 1 h) a yellow crystalline product.Its structure elucidation showed that the resulted compound (5) has a salttype character and contains the protonated amine (2) and the hydroxytriazole anion 6 in 1 : 1 ratio.The two components were separated by column chromatography to give the pure 2 as well as 6.This exists in equilibrium of two tautomeric forms, 6a and 6b, the latter being the dominant form (IR: 1644 cm -1 ).
The reduction of vinamidines 1a with tetrabutylammonium borohydride or sodium borohydride gave, as expected, the morpholinopropylamine derivative 10 as major product in 51% yield.Similar reactions are described in the literature: Ch.Jutz et al. 11 carried out the reaction of vinamidines and vinamidinium salts with NaBH4 to get 1,3-diaminopropane derivatives, while W. Schroth et al. 12 reduced vinamidines catalytically on Pd/C to get similarly 1,3diaminopropane derivatives.
In the case of 1b the isomeric derivative 11 was also obtained.Its formation can be explained by the reduction of the intermediate aziridinium salt 14 (Scheme 4), which was formed by an intramolecular attack of the nitrogen atom of morpholine on the -C-atom of the first intermediate (13) of the reduction.As minor products of the reduction, propylamines 12a,b were also isolated.

Scheme 4. Formation of isomeric morpholinopropylamine derivative 11.
The ring opening of activated (like 14) and non-activated aziridines is widely studied.S. Stankovic et al. 13 gave a detailed overview in a recent review about the regioselectivity found in the reaction of 2-substituted aziridines with nucleophiles (see also citations therein).The reaction is dependent on the activation and the nucleophile used.Usually the reaction occurs at the more hindered C-atom when the nucleophile is halogen (except fluoride), azide, and cyanide ion.Alcohols 14 and hydride anion 15 prefer the less hindered C-atom.
We found that the 1-azadienes 1a,b did not react with N-phenylmaleinimide even at elevated temperature if heated for longer time (Scheme 5).The compound 1b didn't react with dimethyl acetylenedicarboxylate at ambient temperature.After prolonged heating at 100 o C a multicomponent mixture was formed, from which no definite product could have been isolated.The less electrondeficiant aminoazabutadiene 1a, however, did react with dimethyl acetylenedicarboxylate but instead of a cycloadduct (17), compound 15 was isolated in low (37%) yield.Its formation can be explained by the hydrolysis of the first intermediate (16a and 16b) of the addition (see Scheme 6).According to the 1 H NMR the configuration of the doublebond of the propenal moiety of 15 is trans ( 3 J HH =13. 4 Hz), while the configuration of the double-bond of the diester could not be determined.
The reaction of 1b with 4-toluenesulfonyl azide (18) led to the formation of 19 in low (15%) yield (Scheme 7).The isolation of this compound was important because it provides a proof for the reaction mechanism of this type of reactions.Earlier it was found 16 that the reaction of related systems, the aminobutadiens with 4-toluenesulfonyl azide (18) led to the formation of triazole-or tetrazole-substituted pyrazoles.An intermediate similar to 23 (Scheme 8) was postulated in that reaction, from which N-(4-toluenesulfonyl)morpholinoformimine (22)  17 could be cleaved to form a diazo intermediate (similar to 25), which gave, after intramolecular cyclization, the isolated pyrazoles.In our case HBr could be easily eliminated from the first intermediate (23, R=Br)  Isothiocyanates are widely used in [4+2] 18,19 or [3+2] 20 cycloaddition reactions.As the further reagent ethoxycarbonyl isothiocyanate was chosen in the reaction with 1a,b.
Contrary to our expectations, this reagent proved to be only an acylating agent that formed in the first step very probably the intermediates 31 and 32 in a slow reaction at room temperature (2 weeks) (see Scheme 10).These intermediates were hydrolysed in two routes: the route a gave 28 while the other possible way (route b) gave 29.In the course of the reaction, morpholine was liberated, which reacted with the reagent ethoxycarbonyl isothiocyanate to give 1-(ethoxycarbonyl)amino-1-morpholinomethanethione (30) 21 .Scheme 10.Proposed intermediates leading to products 28-30.
Although the tetrazine derivative disappeared from the reaction mixture rapidly, the conversion of 1a was only 78.4% (the isolated yield of 37 was 70%, based on the recovered 1a).The repeated reaction with 2.4 equivalents of tetrazine resulted in the isolation of 37 in 91% yield!
The formation of 37 can be explained by the first addition of the activated, electron rich double bond next to the morpholine moiety of 1a to the highly electrondeficiant aromatic ring (in positions 3 and 6) of tetrazine 35 forming the intermediate 36.This bicyclic intermediate aromatizes by loosing N2 and morpholine to give the isolated pyridazine derivative 37.
The attempted reaction of 1b with tetrazinedicarboxylate was unsuccessful.The vinamidine 1b remained unchanged even after prolonged stirring in dichloroethane with 35.

Conclusions
In the present paper we described the synthesis of new representatives of a few important azaheterocyclic ring systems (e.g., pyrazoles, 1,2,3-triazoles and pyridazines).The members of these ring systems have a wide range of applications.
The biological activity of pyrazole derivatives is recognized long ago as reviewed by R. E. Orth in as early as 1968. 24Pyrazoles have been reported as potential anti-obesity agents. 25They are promising scaffolds for the synthesis of antiinflammatory and/or antimicrobial agents 26 and show potential in the crop protection chemistry. 27J.-Y.Yoon et al. 28 recently reviewed the advances in the regioselective synthesis of pyrazole derivatives.
The different 1,2,3-triazole derivatives have also important biological activities as reviewed earlier by R. Boehm and Ch.Karow 29 and recently by I. Pibiri and S. Buscemi. 302][33] The copper-free variations 34,35 enable to perform the click reaction in living animals.

Experimental Section
General.Melting points were determined by a Büchi apparatus.IR spectra (KBr pellet) were recorded on Specord IR-75 and Bruker IFS-28 equipments.The 1 H-NMR spectra were measured on Varian XL-100 (100 MHz), Varian VXR-400 and Bruker DRX-400 instruments (400 MHz) at ambient temperature using TMS as internal standard. 13C NMR spectra were recorded on a Bruker DRX-400 instrument.The yields of the reactions were not optimized.