Combining a Click–Multicomponent Reaction: One-Pot Synthesis of 1,2,3-Triazol-4-ylmethyl 3-Amino-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carboxylate Derivatives

Abstract (1,2,3-Triazol-4-yl)methyl-3-amino-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carboxylate derivatives were synthesized by a four-component, one-pot condensation reaction of benzaldehyde derivatives, an active methylene compound (prop-2-ynyl-2-cyanoacetate), azides, and phthalhydrazide in the presence of Cu(OAc)2/sodium ascorbate as catalysts and 1-methyl-1H-imidazolium trifluoroacetate ([Hmim]TFA) as an ionic liquid medium in good to excellent yields. GRAPHICAL ABSTRACT


INTRODUCTION
Multicomponent reactions (MCRs) have emerged as an efficient synthetic strategy over conventional linear-type synthesis because of their flexible, atomefficient nature and ability to create several new bonds in a one-pot reaction. Therefore, they can achieve combinatorial synthesis of heterocyclic compounds. [1] Nitrogen-containing heterocyclic compounds play an important role in biological systems. Among them, phthalazine derivatives are important targets in synthetic and medicinal chemistry, because of their biological properties. [2,3] Phthalazine derivatives that have two bridgehead nitrogen atoms possess cytotoxic, [4] antimicrobial, [5] anticonvulsant, [6] antifungal, [7] anticancer, [8] and antiinflammatory [9] activities.

RESULTS AND DISCUSSION
In our initial research, we studied the treatment of 4-chlorobenzaldehyde (1a) with 3-nitrophenyl azide (2a), prop-2-ynyl 2-cyanoacetate (3), and phthalhydrazide (4) under different conditions (Table 1). By using Cu(OAc) 2 =sodium ascorbate as the catalyst, the reaction was tested employing various solvents such as CH 3 CN, CH 2 Cl 2 , water, and ethanol. It is worth mentioning that in the absence of catalyst as a Brønsted acid under reflux conditions the target compound was not formed at all (Table 1, entries 1-3). In the presence of p-TsOH as a Brønsted acid in water or ethanol as solvent the reaction was very slow and the product was obtained in poor yield ( Table 1, entries 4 and 5). After several attempts, it was found that by changing the solvent to [Hmim]TFA as an ionic liquid (IL) at 100 C, the desired product 5a was isolated in 81% yield ( Reaction conditions: 4-chlorobenzaldehyde 1a (0.14 g, 1 mmol), 1-azido-3-nitrobenzene 2a (0.16 g, 1 mmol), prop-2-ynyl 2-cyanoacetate 3 (0.14 g, 1.2 mmol), phthalhydrazide 4 (0.16 g, 1 mmol), Cu(OAC) 2 (0.02 g, 10 mol%), sodium ascorbate (0.04 g, 20 mol%), solvent (10 mL), 4 h. Cu(OAC) 2 (0.02 g, 10 mol%), sodium ascorbate (0.04 g, 20 mol%), and p-TSA (0.34 g, 20 mol%).   (Table 1, entry 7). Additionally, different copper sources such as CuI, CuCl 2 , and CuSO 4 were screened in the model reaction using IL catalyst and gave product in poor to moderate yields (Table 1, entries 8-10). It was found that when the amount of the Cu decreased from 10 to 5 mol%, the yields decreased from 81 to 51%, respectively (Table 1, entry 11). It is noteworthy that compound 5a was not produced at lower reaction temperature (60 C) ( Table 1, entry 12) but compound 7a was isolated instead. Apparently, 7a is an intermediate of this reaction and higher temperature was needed for completion of the reaction (Scheme 2). To check the correctness of this hypothesis, compound 7a was synthesized and treated with compound 4 in the presence of [Hmim]TFA at 100 C; after 5 h, the desired product 5a was obtained in 80% yield.
With this optimized procedure in hand, the scope of the four-component reaction was examined by using other aromatic aldehydes 1a-1n, azides 2a-2e, prop-2-ynyl 2-cyanoacetate (3), and phthalhydrazide (4) in the presence of catalytic amounts of Cu(OAc) 2 (10 mol%), sodium ascorbate (20 mol%) and [Hmim]TFA at 100 C for 5-6 h. The results are summarized in Table 2. As can be seen, this transformation is very general for a variety of benzaldehyde derivatives and azides. As shown in Table 2, it was found that this procedure works with a wide variety of substrates. Both electron-rich and electron-deficient groups on the aromatic aldehydes can be used with equal success and five different types of azides were used in this reaction.
Although the exact mechanism of this transformation is not completely clear, a possible pathway for this four-component reaction could be proposed in three steps. First, formation of intermediate 6 by Knoevenagel condensation was followed by the 1,3-dipolar cycloaddition reaction between 6 and azide 2, leading to triazole derivative 7 as an intermediate produced from the click reaction. Then, the subsequent Michael-type addition of phthalhydrazide (4) would give the intermediate 8, followed by cyclization to afford the corresponding product 5 (Scheme 2).
The structures of the products 5a-5p were characterized by their spectroscopic data. The 1 H NMR spectra of these compounds in dimethylsulfoxide (DMSO-d 6 ) Scheme 2. Proposed reaction mechanism.
consisted of a characteristic peak belonging to the triazole H-atom in the region of d ¼ 8. 25-8.85 ppm. In addition, the distinguishing peak for H-C(1) of the 1Hpyrazolo [1,2,b]phthalazine-2-carboxylate moiety was observed at d ¼ 6.05- 6.44 ppm. Another characteristic feature of the 1 H NMR spectra was the appearance of an AB signal at d ¼ 5.08-5.61 ppm, which arises from the (triazol-4-yl)CH 2 unit. Additionally, we checked the recycling of the ionic liquid. In the preparation of 5a, the [Hmim]TFA was reused for five runs. Second and third reactions using recovered ionic liquid afforded similar yields to those obtained in the first run. In the fourth and fifth runs, the yields were decreased (the yields of the product 5a were 81%, 80%, 78%, 72%, and 64%, respectively).

EXPERIMENTAL
Chemicals were purchased from commercial suppliers and were used without purification. Melting points were measured on an Electrothermal 9100 apparatus and were not corrected. High-resolution electrospray ionization-mass spectrometry (HR-ESIMS) spectra were acquired on a Bruker MicroTOF ESI-MS system. 1 H NMR and 13 C NMR spectra were recorded on a Bruker DRX-300 Avance spectrometer at 300.13 and 75.47 MHz, respectively, or a Varian Unity 400 spectrometer at 400 and 100.6 MHz, respectively. Infrared (IR) spectra were recorded on a Bomem MB-Series FT-IR spectrometer.

FUNDING
We gratefully acknowledge financial support from the Research Council of Shahid Beheshti University and Catalyst Centre of Excellence (CCE). Support from the University of New Brunswick is also gratefully acknowledged.

SUPPLEMENTARY MATERIAL
Experimental details and full characterization of compounds 5a-5p, 6a, and 7a, including 1 H and 13 C spectra, can be accessed on the publisher's website.