Synthesis of a new tricylic ring system: [1,2,3]triazolo[1,5-b ]cinnolinium salt

Synthesis of the first representative of the linearly fused [1,2,3]triazolo[1,5-b ]cinnolinium heteroaromatic cation as a quaternary salt is reported. Improved reaction conditions for preparation of some precursors have been elaborated. Reaction of the new heteroaromatic salt with nucleophiles resulted in regioselective formation of zwitterionic products.


Introduction
In the frame of our investigations on bridge-head nitrogen containing fused azolium salts we reported the synthesis of the linearly fused [1,2,3]triazolo [1,5-b]isoquinolinium salt (1, R 1 = alkyl and aryl group, Ar = phenyl or substituted phenyl group) 1 .Study of the reactivity of this quaternary salt (1) revealed that in reactions with various nucleophiles (e.g. with NuH = morpholine) regioselective addition at C-9 takes place to yield stable pseudobase-type products (2).This finding prompted us to extend the investigations to an aza-derivative of 1 containing a nitrogen atom in position 9.This structural change excludes the possibility of an attack of the nucleophile in this particular position.In this paper we report our efforts to synthesize this designed [1,2,3]triazolo [1,5-b]cinnolinium salt and to explore its reactivity with nucleophilic reagents.

Results and Discussion
According to the earlier established protocol 2 , the synthesis of the desired model compound was planned by oxidative cyclization of cinnoline-3-ketones.Our literature survey indicated that very few procedures leading to such ketones were published 3,4 , among which the method described by Al-Alwadi et al. 4 a few years ago seemed the most suitable for our purpose.These authors found that such ketones (6) can be obtained via a 3-step pathway starting from substituted benzophenones (3).Thus, 3 was reacted first with dimethylformamide dimethylacetal to give an aminoenone (4), this compound was then reacted with phenyldiazonium salt to afford the hydrazone 5 and, finally, cyclization reaction under strongly acidic conditions resulted in formation of the cinnoline ketone (6).
While reproduction of the first reaction step (i.e. 3 → 4) took place in excellent yield, 5 we had to encounter some difficulties with the subsequent two reaction steps: rather low yields and intensive decompositions were experienced.As a result of an ongoing search for suitable reaction conditions for the desired synthesis, however, we have found that by the help of two modifications both transformations can be carried out in satisfactory and well reproducible yields.
The first modification was that instead of in situ preparation of the diazonium salt in the second reaction step, crystalline phenyldiazonium fluoroborate (A = BF 4 ) 6 was used and, thus, hydrazones 5a-d were obtained in high yields.As to the final ring closure reaction we have found, furthermore, that extenstion of the reaction time to 40 min and exclusive application of polyphosphoric acid results in a dramatic increase of the yields of 6a-d.This successful preparative result allowed also the synthesis of two new compounds: the p-bromo substituted 5e and 6e.Some data (yield, mp) of the products prepared by the improved methodology are compiled in Table 1., whereas the modified reaction conditions are described in the Experimental Section for the new derivatives 5e and 6e Treatment of p-nitrophenyl ketone (6d) with p-bromophenylhydrazine hydrochloride in ethanolic hydrochloric acid afforded arylhydrazone 7 as orange crystals.Oxidative cyclization of other related hydrazones to triazolium salts are generally carried out by N-bromosuccinimide 2 .While application of this reagent in the present case, unfortunately, failed, treatment of 7 with 2,4,4,6-tetrabromocyclohexa-2,5-dienone (8) -easily obtainable by bromination of 1,3,5tribromophenol and also commercially available -successfully resulted in the desired cyclization and gave the fused triazolium bromide 9 as yellow crystals in modest yield.Comparison of the UV spectra of 7 and 9 revealed that a significant change of the absorbances occurred (blue shift of the first maximum by 35 nm) which clearly indicates the substantial change of the chromophore.Appearance of the downfield 1 H-NMR shift (singlet at 10.64 ppm) is also in accordance with the presence of the positively charged heteroaromatic pyridazine moiety.
Two nucleophilic reagents: pyrrolidine and sodium methoxide have been selected for investigation of reactivity of the new heteroaromatic salt 9.These reactions have been carried out in acetonitrile at room temperature.In both cases a zwitterionic addition product (10 and 11, respectively) separated from the reaction mixture.The most significant spectral property of these products was the presence of a proton attached to the saturated carbon atom in position 4 appearing at 5.8 and 6.6 ppm, respectively, whereas all routine analytical data (elemental analysis, MS) were in entire agreement with these structures.An interesting spectroscopic feature of zwitterionic compounds is the negative solvatochromy 7 , i.e. a significant red shift of the first maximum in UV/VIS when changing a polar solvent for an apolar one.This has also been detected for derivative 10 as shown in Fig 1.
The interesting finding of this regioselective addition reveals that position 4 as indicated by the strongly downfield NMR shift of the attached proton is electron-withdrawn enough to accept the nucleophilic heteroatom and to form a new sigma bond.The addition is obviously facilitated by the presence of N-9 atom which is able to bear two lone electron pairs and, thus, to become negatively charged.In other words, it is the C4-C3a-N10-N9 1,2-diazadiene structural moiety in records that 1,2-diazadienes easily react with nucleophiles at the terminal C4 atom 8 .Although the title new tricyclic heteroaromatic salt has been synthesized successfully, extenstion of this methodology to ketones bearing substituents other than nitro group on the phenyl moiety failed.In these cases the hydrazones related to 7 can not be isolated from the reaction mixture because subsequent rapid spontaneous conversions.Study of these transformations is in progress and the results will be published later.

Experimental Section
General Procedures.Melting Points were determined on a Kofler apparatus and are uncorrected.The IR spectra were recorded on a Thermo Nicolet Avatar 320 FT-IR spectrometer and the UV spectra were measured on a ThermoSpectronic Unicam UV 500 spectrophotometer.The NMR spectra were determined on a Varian Unity Inova spectrometer (200 MHz and 400 MHz for 1 H and 100 MHz for 13 C).The elemental analysis has been carried out with an Elementar Vario EL III apparatus.

Figure 1 .
Figure 1.UV spectrum of 10: a red shift of 29 nm, approximately appears in the spectrum recorded in a dichloromethane solution ( ----) compared to that of the acetonitrile solution (──).

Table 1 .
Improved reaction conditions and yields with the synthesis of the hydrazones 5 and ketones 6