Novel and Efficient Synthesis of 4-Indazolyl-1,3,4-trisubstituted Pyrazole Derivatives

Abstract In the present study, 1-(4,5-dihydro-3,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-3aH-indazol-5-yl)methanone derivatives (9–12) and isoxazoleyl (13–16) have been synthesized by the condensation of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (1–4) with acetyl acetone via Knoevenagel/Michael/aldol reactions in a sequential manner to yield intermediate cyclohexanone (5–8). The intermediates (5–8) treated with NH2NH2 · H2O/NH2OH · HCl afforded 4-indazolyl-1,3,4-trisubstituted pyrazole and isoxazoleyl derivatives. All of these compounds are reported for the first time, and the structures of these compounds were confirmed by means of infrared, 1H NMR, 13C NMR, and mass spectroscopy. GRAPHICAL ABSTRACT


INTRODUCTION
Development of rapid access to N-heterocycles with complexity and diversity stemming from their wide occurrence in nature and broad applications in chemistry, biology, and material sciences has attracted considerable attention in the studies of chemical genetics. [1] In this respect, pyrazoles and indazoles are important synthetic targets in biologically active molecules, synthetic drugs, and drug candidates, and in addition, they can be used as ligands for generating metallic complexes. [2,3] The importance of these heterocyclic moieties has prompted the development of many practical synthetic routes to construct their derivatives. [4,5] Substituted pyrazoles are rarely found in nature but serve as important synthetic targets in medicinal chemistry and pharmaceutical industries. [6] Both 1,3,5-tri-and 1,3,4,5-tetrasubstituted pyrazoles constitute the useful structure of several commercial drugs such as celebrex, [7] Viagra, [8] acomplia, and the insecticide fipronil as well as numerous other compounds that exhibit a wide spectrum of biological and pharmacological properties such as antifungal, [9] antimicrobial, [10] antidiabetic, [11] herbicidal, [12,13] antitumor [14] and antianxiety, [15] activities and serve as active pharmacophores in celecoxib (COX-2 inhibitor) [16] and slidenafil citrate [17] (cGMP specific phosphodiesterase type 5) inhibitors. Substituted pyrazole derivatives play essential roles in biologically active compounds and therefore are an interesting template for medicinal chemistry.
There are several reactions reported for the preparation of pyrazole derivatives. Among them, the Knorr pyrazole synthesis is considered one of the standard methods because of its generality. The reaction leads to the pyrazole derivatives via the condensation of substituted hydrazine with 1,3-dicarbonyl compounds or their derivatives. [18][19][20][21] The other method is the 1,3-dipolar cycloaddition of diazoalkanes or nitrile imines with olefins or alkynes. [19] Recently, a novel regioselective synthesis of 1,3,4-trisubstituted pyrazoles has been successfully employed. [22] As successful as these two methods are in preparing pyrazoles with various substitution patterns, both are not particularly suitable for the regioselective synthesis of 1,3,4-trisubstituted pyrazole in neutral condition.
The 7 0 -H proton in 4-substituted indazolyl derivatives appears as a singlet at d 4.913, but in isoxazolyl derivatives, the same proton appears as a singlet at d 6.126, with formation of olefinic double bond due to dehydration. In isoxazoleyl derivatives 13, 4 0 -H proton shows a doublet at d 4.462, J ¼ 11.1 Hz, coupled with 5 0 -H. It is a useful tool to confirm that there is no 9 0 -H proton.
In 13 C NMR spectrum of the cyclohexanone intermediates 5-8, C-2 appears downfield at d 71.0 ppm due to CH 3 CO and C = O substitution, whereas in indazolyl and isoxazoleyl it shows upfield at d 40.2 ppm. It is important to notice the absence of C = O group. The C-5 in 5-8 appears to peak in the range of d 60.8-60.4 ppm, and in C-7 derivatives 9-16 appears as a signal at d 121.9-107.0. This deshielding effect is due to the conjugation between five-membered heterocyclic and cyclohexene rings.
Considering first the cyclohexanone derivatives, the large coupling constants J 2-3 (J ¼ 12.3 Hz) and J 3-4 (J ¼ 12.3 Hz) are clearly indicative of trans diaxial protons. The large substituents at the neighboring carbon C-3 then must occupy the preferred equatorial positions. The hydroxyl proton was observed to be a doublet, J ¼ 2.4 Hz, coupled to the axial proton 6 Ha , the resonance of which appeared as a doublet of doublets. This is one of the few instances known of long-range coupling to hydroxyl group (Fig. 1). [31] Addition of deuterium oxide caused the disappearance of the hydroxyl doublet and concurrent simplification of the 6 Ha pattern. It is suggested that strong hydrogen bonding of the hydroxyl proton with the neighboring 6 Ha and carbomethoxy function holds the hydroxyl proton in a conformation favorable for long-range coupling.

CONCLUSIONS
In conclusion, we have demonstrated a simple, convenient, efficient method for the preparation of functionalized 4-indazolyl and isoxazolyl substituted of 1,3,4trisubstituted pyrazole derivatives via domino Knoevenagel, Michael and intramolecular aldol reactions to give cyclohexanone derivatives, followed by treatment with NH 2 NH 2 Á H 2 O=NH 2 OH Á HCl. The procedure offers several advantages such as easy workup process, excellent yield of products, operational simplicity, and minimum environmental impact, making the technology practical, easy to perform, and facile.

EXPERIMENTAL
All chemicals and reagents used in the current study were of analytical grade. Melting points were determined with a digital thermometer and were uncorrected. The IR absorption spectra were scanned on Perkin-Elmer Spectrum, BX II FTIR spectrometer using potassium bromide (KBr) pellets, and the wave numbers are given in cm À1 . All the 1 H NMR spectra were recorded on a Bruker DPX300 model spectrometer in CDCl 3 using tetramethylsilane (TMS) as an internal standard, the chemical shifts are reported in d units, and the coupling constants (J) are reported in hertz. Mul- and mass spectra were recorded. Thin-layer chromatography (TLC) was performed on silica-gel sheets (silica gel 60 F 254 , Merck) and visualized in ultraviolet light (254 nm). Column chromatography was performed using silica gel (100-200 mesh), eluting with ethyl acetate and petroleum ether solvent.