Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles

The synthesis of novel polycyclic π-conjugated dihydropyridazines, pyridazines, and pyrroles was studied. Dihydropyridazine dyes were synthesized by inverse electron-demand Diels–Alder cycloaddition reactions between a dibenzosuberenone and tetrazines that bear various substituents. The pyridazines were synthesized in high yields by oxidation of dihydropyridazine-appended dibenzosuberenones with PIFA or NO. p-Quinone derivatives of pyridazines were also obtained by H-shift isomerization following the inverse electron-demand Diels–Alder reaction of tetrazines with p-quinone dibenzosuberenone. Then these pyridazines were converted to the corresponding pyrroles by reductive treatment with zinc. It was observed that all the dihydropyridazines obtained gave absorbance and emission at long wavelengths.

On the other hand, many natural compounds that contain a pyrrole core, such as bilirubin, hemoglobin, chlorophyll a, and vitamin B12, are very important for life. In addition to being common in natural products and biological systems, the active ingredient of many top-selling drugs such as atorvastatin, sunitinib, and ketorolac, contains a pyrrole unit ( Figure 1) [49].
Due to these unique features, the synthesis of new dihydropyridazines, pyridazines, and pyrroles, which have the potential to be used in many applications, is very important. inverse electron-demand Diels-Alder cycloaddition reactions of alkenes with tetrazines are commonly used for the synthesis of dihydropyridazines and pyridazines [50][51][52][53][54].
In our previous study, we made a discovery that would form the basis of a new class of dyestuffs with skeletons unlike those of classic organic dyestuffs. In that study, two highly fluorescent dibenzosuberenone-based dihydropyridazine dyes, 3a,b, were synthesized, and it was found that they can be used as a selective and sensitive sensor of fluoride anions (Scheme 1, Table 1) [55]. In another work, we reported the design, synthesis, and structural and photophysical characterization of a new series of 3,7-substituted dihydropyridazine dibenzosuberenone units with electron-withdrawing and electron-donating functional groups [56].
Herein, we report the examined impact of various electronwithdrawing and electron-donating functional groups at the 3and 6-positions of s-tetrazine on inverse electron-demand Diels-Alder cycloaddition reactions with a dibenzosuberenone (1) and the photophysical properties of dihydropyridazines. The corresponding pyridazines and pyrroles were obtained from dihydropyridazines. Finally, we investigated the photophysical properties of dihydropyridazines.
Inverse electron-demand Diels-Alder reactions are cycloadditions between electron-rich dienophiles and electron-poor dienes. EDGs raise the electron density of dienes and, in parallel, raise the LUMO diene -HOMO dienophile energy gap, and consequently the reactivity decreases. Although the tetrazine ring is an electron-poor diene, the dibenzosuberenone (1) dienophile is not electron-rich enough. Therefore, for such cycloaddi- tion reactions, the tetrazine must be substituted by EWGs to decrease the electron density of the diene. Consequently, our results confirm that EDGs and EWGs play a crucial role in the reactivity.
It should be noted that, unlike the other tetrazine derivatives, dichlorotetrazine (2k) afforded the addition product 3k and the oxidation product 4k as a result of its reaction with dibenzosuberenone (1). When dibromotetrazine (2l) was used, on the other hand, the oxidation product 4l and an unexpected product, dibromobenzonorbornadiene 5l, were formed (Scheme 2). The formation of the oxidized products 4k and 4l in these reactions was probably due to the properties of tetrazines because they are known to act, in some cases, as oxidizing agents in Diels-Alder reactions, depending on the structure of the diene and the reaction conditions [64]. A proposed reaction mechanism for the formation of the dibenzosuberenone derivatives 3 and 4 is illustrated in Scheme 3. Although 3k was isolated, 3l could not be detected in the reaction mixture due to its complete conversion to 4l, revealing its ease of oxidation com-Scheme 4: Proposed mechanism for the formation of 5l.
pared to the chloro derivative 3k. In addition, dihydrotetrazines 6k and 6l could not be isolated, as probably compound 6k decomposed completely in the reaction medium and 6l decomposed following a bromine transfer to dibenzosuberenone (1, Scheme 3).
The formation of 5l was also an unexpected result because there has been no precedent reported to date, in which a tetrazine acts as a halogen source in the halogenation of a double bond. Therefore, the formation of 5l constitutes the first example of this unusual behavior. In the proposed mechanism illustrated in Scheme 4, tetrazine 6l first tautomerizes into 7, from which dibenzosuberenone (1) receives bromine to give 5l via bromonium 8. As tetrazine 9 was unstable under the current reaction conditions, it decomposed and could not be observed [65].
In the second part of the study, dihydropyridazines 3a-f were oxidized to pyridazines. In contrast to dihydropyridazineamide 3e, the reaction of dihydropyridazines 3a-d and 3f with PIFA ([bis(trifluoroacetoxy)iodo]benzene) afforded the corresponding pyridazine derivatives 4a-d and 4f in good yields (79-95%). As a result of the reaction of PIFA with dihydropyridazine 3e, the intended pyridazine compound could not be obtained. Alternatively, nitrogen monoxide (NO) gas was used as oxidizer and pyridazineamide 4e was obtained in high yield (83%, Scheme 5).
In another important part of this study, pyridazines were converted into the corresponding pyrroles via a ring contraction under reductive conditions in presence of zinc dust in acetic acid according to the Boger procedure, which is a highly reliable synthetic approach [66][67][68]. For pyrrole conversions, methoxycarbonyl-and 2-pyridylpyridazine derivatives 4a and 4b were used.
When methoxycarbonylpyridazine 4a reacted with 5 equivalents of Zn in acetic acid at room temperature overnight the corresponding pyrrole 10aa was obtained. When using 10 equivalents of Zn instead of 5 equivalents, hydroxypyrrole 10ab was formed, in which the carbonyl group was also reduced to the hydroxy group. Then unsubstituted pyrrole 10ac was synthesized by the reaction of pyrrole 10ab with 4 equivalents of KOH under microwave irradiation (Scheme 6).
The reaction of 2-pyridylpyridazine 4b with Zn did not work at room temperature. Under reflux conditions compound 10ba was obtained, which contained the corresponding pyrrole and acetate structures. The acetate is formed by reducing the carbonyl group to alcohol and then reacting this alcohol with acetic acid. After hydrolysis of the acetate group with sodium hydroxide, alcohol derivate 10bb was formed. Oxidation of alcohol 10bb with MnO 2 led to the formation of the corresponding ketone 10bc. Eventually, pyrrole derivative 10bc, having a carbonyl group, was obtained by these reactions (Scheme 7).
In order to increase the conjugation of dibenzosuberenone 1 for the photophysical aspect, the p-quinone methide derivative of dibenzosuberenone 11 was synthesized according to the method in the literature [69]. The products expected from the reaction of p-quinone methide 11 with tetrazines 2a,b are dihydropyridazines 12a,b, but this molecule could not be obtained. Instead, surprisingly, products 13a,b were obtained, of which the dihydropyridazine part was oxidized to pyridazine and the p-quinone methides part was reduced to phenol. After the phenolic part of 13a,b was oxidized to p-quinone methides with PIFA, 14a and 14b were synthesized in 87% and 91% yields, respectively. Moreover, by submitting 13a,b to reductive conditions in presence of Zn, the pyridazine part of 13a,b was converted to pyrrole 15a,b. Finally, the phenolic parts of 15a,b were oxidized to p-quinone methides 16a,b with PIFA in excellent yield (89-97%, Scheme 8).
For the formation of unexpected compound 13, we propose two different mechanisms. First, following the formation of phenolic tautomer 12A by tautomerization A with a [1,7]-H shift 13 would be formed. Alternatively, in the second mechanism, 13 is thought to occur by tautomerization B and a [1,5]-H shift (Scheme 9).

Photophysical properties
In our previous work, we examined the photophysical and fluoride sensing properties of dihydropyridazine fluorescent dyes 3a,b in detail. In the present study, the effects of functional groups with different conjugations on maximum absorbance (λ max , abs ) and emission (λ max , ems ), and wavelengths of dihydropyridazines 3c-f and 3k were investigated. Compounds 3c,d, with high conjugation, show the highest absorption and emission maxima values and compounds 3f and 3k, with low conjugation, show the lowest absorption and emission maxima values ( Figure 3, Figure 4, and Figure 5). All these molecules (3c-f and 3k) have Stokes shifts greater than 100 nm. The fluorescence quantum yields of 3c-f and 3k were calculated by comparison with a well-known reference, quinine sulfate, in 0.5 M H 2 SO 4 solution (Ф F = 0.546) as the standard dye ( Table 2). When the UV-vis and fluorescence spectra of pyridazines and pyrroles were examined, it was seen that generally, they did not have effective absorbance or emission intensity. Although all π-conjugated pyridazines and pyrroles known in the literature did not show high emission, along with other photophysical properties the excellent coordination ability and especially their importance in biological systems always make these compounds valuable.

Scheme 9:
Proposed mechanism for the formation of 13.

Conclusion
Novel polycyclic π-conjugated dibenzosuberenone-based dihydropyridazine dyes were synthesized by inverse electrondemand Diels-Alder cycloaddition reactions between dibenzosuberenone (1) and tetrazines bearing various substituents. These products showed long absorption wavelengths and emission bands, large Stokes shifts, and good fluorescence quantum yields. The dihydropyridazines were oxidized into pyridazines and then converted to pyrroles. Moreover, p-quinone methide derivatives of dibenzosuberenone-based pyridazines and pyrroles were synthesized. We continue intensively to perform various photochemical and biochemical studies on these compounds, which have the potential to be used in chemosensors, light harvesting, organic optoelectronics, metal coordination complexes and other photophysical applications and in biological systems.

Supporting Information
Supporting Information File 1 Experimental procedures, copies of 1 H NMR, 13 C NMR, and HRMS(Q-TOF) spectra.

Funding
We are grateful to The Scientific and Technological Research Council of Turkey (TUBİTAK) (Project number KBAG-215Z445) for financial support.