Dipolar Cycloaddition Reactions with Quinazolinones: A New Route for the Synthesis of Several Annelated Pyrrolo- and Pyridazinoquinazoline Derivatives

The novel 2-aryl-3a,4,12,12a-tetrahydropyrrolo[3',4':4,3]-pyridazino[6,1-b]-quinazoline-1,3,6-triones (6a–d), 2-aryl-10-oxopyridazino[6,1-b]-quinazoline-3-thio-carboxamides (10a–d) and 2-aryl-3-nitro-1,2,3,4-tetrahydro-pyridazino[6,1-b]quinazolin-10-ones (12a–d) were synthesized via a new, facile one step route involving the reactions of the zwitterion 4, formed in situ, with a variety of N-arylmaleimides 5, 3-aryl-2-cyano-thioacrylamides 8 and ω-nitrostyrenes 11. Dehydrogenation of the tetrahydro derivatives 6a–d and 12a–d in nitrobenzene resulted in the formation of 2-arylpyrrolo[3',4':4,3]-pyridazino[6,1-b]quinazoline-1,3,6-triones (7a–d) and 2-aryl-3-nitropyridazino[6,1-b]quinazolin-10-ones (13a–d), respectively. The structures of the products were confirmed by elemental analysis and spectral data.


Results and Discussion
The starting material 3-amino-2-methyl-4(3H)-quinazolinone (2) was prepared by condensation of 2-methyl-3,1-benzoxazin-4-one (1) with hydrazine hydrate as described in the literature [25]. It was then reacted with NCS to yield in situ the respective 3-amino-2-chloromethyl-4(3H)-quinazolinone (3), which was isolated and its structure confirmed on the basis of analytical and spectral data. This reaction constitutes a new and facile procedure for the synthesis of this reactive compound [26]. Compound 3 was then treated with triethylamine (TEA) to afford the zwitterion 4, created by the loss of HCl (Scheme 1). This zwitterionic species 4 was used as the key intermediate for the present study. Thus, the behavior of 4 towards the N-arylmaleimides 5a-d was investigated with regards to the synthesis of annelated quinazolines. It was found that compound 2 reacted with N-phenylmaleimide (5a) in the presence of NCS and TEA in dry chloroform with stirring for 1 h at room temperature to give a reaction product of molecular formula C 19 H 14 N 4 O 3 which corresponds to the addition of one molecule of 2 to one molecule of 5a, with subsequent elimination of a HCl molecule. The IR spectrum of this product showed the presence of NH (3340 cm -1 ), C=O (1680 cm -1 ), saturated CH 2 and CH (2980 cm -1 ) and C=N groups (1635 cm -1 ), in addition to the CO-NAr-CO group, which appears as two widely separated bands [27] at 1780 and 1710 cm -1 . Its 1 H-NMR spectrum revealed the presence of signals for the pyridazine H-3 and H-4, pyridazine-CH 2 , NH and aromatic protons in their proper positions (cf. Experimental). Based on the above data, this product was formulated as 2-phenyl-3a,4,12,12a-tetrahydropyrrolo[3',4':4,3]-pyridazino[6,1-b]quinazoline-1,3,6-trione (6a). The formation of 6a is assumed to proceed via the initial reaction of 2 with NCS to yield 3-amino-2-chloromethyl-4(3H)-quinazolinone (3), which is not isolated, but rather reacts in situ with TEA to give the zwitterionic intermediate 4, which in turn reacts with 5a via a dipolar cycloaddition to yield the final isolable pyrrolopyridazinoquinazoline derivative 6a. This constitutes a simple and easy one pot reaction leading to a fused heterocyclic derivative which otherwise is difficult to obtain. A similar reaction with maleimides has been described in our earlier communications [23,24]. Similarly, the diionic species 4 reacted with each of the N-arylmaleimides 5b-d, under the same experimental conditions, to afford the corresponding tetrahydropyrrolo [3',4':4,3]pyridazino[6,1-b]quinazolinetrione derivatives 6b-d, respectively, whose structure was based also on correct elemental analyses and spectroscopic data studies (cf. Experimental Additional confirmation of the structures of 6a-d came from their dehydrogenation using boiling nitrobenzene to yield the corresponding pyrrolo[3',4':4,3]pyridazino[6,1-b]quinazoline-1,3,6-triones 7a-d, respectively (Scheme 1). The structure of the latter products was also confirmed by their elemental analyses and spectral data. Thus, the IR spectra of compounds 7a-d displayed bands assignable to NH and saturated CH 2 groups, while their 1 H-NMR spectra revealed only the presence of signals for pyridazine H-5 and aromatic protons (and for CH 3 or OCH 3 if present). No pyridazine H-3 or H-4 signals were detected in these spectra which were found to be in accordance with the expected outcome of the proposed dehydrogenation reaction (cf. Experimental).
As a continuation of our studies aimed at synthesizing pyridazinoquinazoline derivatives with potential biological activity, the behavior of the zwitterionic species 4 towards a variety of 3-aryl-2cyanothioacrylamides 8a-d was also examined. Thus, 4 reacted in chloroform with 3-phenyl-2cyanothioacrylamide (8a) to give the respective 10-oxopyridazino[6,1-b]quinazoline-3thiocarboxamide structure 10a (Scheme 2). Formation of 10a is assumed to proceed via addition of the NH in 4 to the activated α,βunsaturated center in 8a, affording the cyclic adduct 9a which spontaneously aromatizes to the final product 10a via elimination of a HCN molecule and subsequent dehydrogenation. The IR spectrum of this product showed the bands of NH 2 , C=O and C=S groups. Moreover, its 1 H-NMR spectrum revealed the presence of signals corresponding to the presence of NH 2 function, in addition to the pyridazine CH and aromatic protons in their proper positions (cf. Experimental). In the same way, each of 8b-d also reacted with 4 to yield the corresponding pyridazinoquinazolines 10b-d, respectively, whose structures was similarly established based on elemental analysis and spectral data.

Scheme
As an extension of this synthetic route, the behavior of 4 towards various ω-nitrostyrenes 11a-d was also studied. Thus, compound 2 and NCS in chloroform and TEA (i.e. 4) reacted with 11a-d to yield the corresponding 3-nitrotetrahydropyridazino[6,1-b]quinazolin-10-ones 12a-d, respectively (Scheme 2). Both elemental analyses and spectral data of the latter products were consistent with the assigned structures. Bands of NH and saturated CH 2 groups appeared in their IR spectra, while their 1 H-NMR spectra confirmed the presence of these groups, in addition to two pyridazine-CH and aromatic protons, in each case (cf. Experimental).
The 1,2,3,4-tetrahydro derivatives 12a-d could also be dehydrogenated by the action of boiling nitrobenzene to afford the corresponding 2-aryl-3-nitropyridazino[6,1-b]quinazolin-10-ones 13a-d (Scheme 2). No absorption bands for NH groups were detected in the IR spectra of 13a-d. Additionally, their 1 H-NMR spectra revealed the complete absence of pyridazine-CH, pyridazine-CH 2 and NH signals while they revealed only the presence of signals for pyridazine H-5 and aromatic protons (and for OCH 3 if present).

Acknowledgements
Thanks are due to Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida, USA, for providing some facilities during the progress of this work.

General
All melting points are uncorrected. IR (KBr discs) were recorded on Perkin Elmer FT-IR type 4 spectrophotometer. 1 H-NMR Spectra were recorded on Gemini 200 MHz Spectrometer using TMS as an internal standard. 13 C-NMR spectra were recorded using a Varian Mercuy 300 NMR Spectrometer. Mass spectra were recorded on AEI MS 30 mass spectrometer operating at 70eV. Compounds 1 [28], 2 [25], 5 [29] and 11 [30] were prepared according to the reported literature procedures.