Microwave-Assisted One-Pot Synthesis of Pyrazolone Derivatives under Solvent-Free Conditions

An efficient one-pot method to generate structurally diverse and medicinally interesting pyrazolone derivatives in good to excellent yields of 51–98% under microwave irradiation and solvent-free conditions has been developed.


Introduction
Pyrazolone derivatives are an important class of heterocyclic compounds that occur in many drugs and synthetic products [1]. These compounds exhibit remarkable antitubercular [2,3], antifungal [4,5], antibacterial [6], anti-inflammatory [7], and antitumor activities [8]. In our effort to identify new farnesoid X receptor (FXR) ligands [9], we recently found by virtual screening that a 4-arylidenepyrazolone derivative 1a (Figure 1) was a FXR antagonist (unpublished data). Consequently, to explore the structure activity relationships (SAR) for this family of compounds, a facile and practical approach for synthesizing 4-arylidenepyrazolone-containing derivatives 1 (Figure 1) became desirable. Generally, 4-arylidenepyrazolone derivatives 1 are synthesized using as starting materials substituted aldehydes 5 [10][11][12] (or their their acetal [13,14] or imine [15,16] precursors) and 2pyrazolin-5-ones 4, the latter generally being obtained by the Knorr condensation [17,18] of βketoesters 2 with substituted hydrazines 3 (Scheme 1). It is obvious that all described methods involve multiple step reactions and most of them produce equimolar amounts of unwanted by-products. In this respect, the development of a one-pot reaction using readily available chemicals would be of considerable significance due to its synthetic efficiency and atom economy.

Optimization of the reaction conditions
Initially we selected ethyl acetoacetate (2a), 3-nitrophenylhydrazine (3b) and 3-methoxy-4-ethoxybenzaldehyde (5a) as the model substrates for the optimization of the reaction conditions, which included microwave oven power, time of irradiation, solid supports and reactant ratios. The results are summarized in Tables 1-2. The preliminary investigations revealed that the one-pot reaction occurred, as designed. Nevertheless, the reaction efficiency was highly microwave oven power dependent (entries 1-3, Table 1), with a good yield being achieved at 420 W. We then compared the synthesis of 1b with irradiation times of 5 min, 10 min, and 15 min at 420 W, and the corresponding yields were 54%, 71%, and 62%, respectively (entries 2 and 4,5, Table 1).  Encouraged by the promising results, we further optimized the reactant ratio (entries 1-7, Table 2) and solid support (entries 8,9, Table 2). The optimum results were obtained when the reactants were mixed is a ratio of 2a/3b/5a = 1.5/1/1 without solid support and irradiated at 420 W for 10 min (entry 4, Table 2). Solid supports such as aluminium oxides and silica gel have been widely used in microwave-assisted organic synthesis to enhance substrates absorption of microwave energy. However, solid supports appeared to offer no advantages in our one-pot reaction (entries 4, and 8,9, Table 2).

Scope of microwave-assisted one-pot synthesis of 4-arylidenepyrazolone derivatives
Having established the optimal reaction conditions, we subjected a series of β-ketoesters, hydrazines, and aldehydes to them to explore the generality and scope of the one-pot process. As shown in Table 3, we were pleased to find that this method was applicable to a broad range substrate of substituted β-ketoester (2a-b), hydrazine (3a-j), and aldehyde (5a-h) substrates.   The target products 1a-r were prepared in good to excellent yields (51-98%). A variety of substituents on the aryl ring including halogens, -CO 2 H, -NO 2 , -CF 3 , alkoxy, etc. were well tolerated. These outcomes imply that electronic features have a marginal effect on the process. Examination of the results also revealed that the steric effects also play a minimal role in governing the reaction efficiency, as all para-(such as compound 1c), meta-(such as compound 1e), and ortho-(such as compound 1g) substituted substrates were smoothly transformed into the desired products. Heterocycles (compound 1l) could efficiently participate in the one-pot reaction as well. Finally, it is noteworthy that the process features simple operation and purification, and all target products could be directly obtained by simple suction filtration and washing with ethyl acetate.

General
The reagents were purchased from Shanghai Chemical Reagent Company, Lancaster, and Acros, and used without further purification. Yields were not optimized. Nuclear magnetic resonance (NMR) spectra were recorded on a Brucker AMX-400 NMR instrument ( 1 H at 400 MHz and 13 C at 100 MHz, respectively). Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane (TMS) used as internal standard. Proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low-and high-resolution mass spectra (LRMS and HRMS) were obtained by electron ionization (EI) on a Finnigan MAT-95 instrument. Microwave experiments were carried out in a domestic microwave oven (Midea MM721AAU-PW).

Conclusions
We have developed a simple, rapid, and efficient one-pot protocol for the preparation of the 4-arylidenepyrazolone derivatives by a solvent-free, microwave-assisted reaction. Furthermore, the procedure used commercially available reagents, giving the desired compounds in good to excellent yields (51-98%). The versatility of this methodology makes it suitable for library synthesis in drug discovery efforts.