Simple Electrochemical Synthesis of Pyrazolo[4,3-c]quinoline Derivatives

Valuable pyrazolo[4,3-c]quinoline derivatives were synthesized efficiently from the easily available 7-Chloro-4-hydrazinoquinoline through electrochemical synthesis under moderate and scalable electrolytic conditions afforded linear hydrazones (3a-g) then the cyclized one (4a-g). The conduct of the reactions was performed in a simple undivided cell under constant current without oxidizing reagents or transition metal catalysts. The synthesized products of the cyclization reaction have been characterized via UV/Vis spectrophotometry, 1H-NMR and FTIR spectroscopy, the understanding of the mechanism of the reaction, the importance of reactant structure to control the rate of the reaction and equilibria in the process is substantial. The applying of this protocol to the effective synthesis of key intermediates for antidiabetic compounds was done.


1.Introduction
Organic electrosynthesis (OES) is considered a versatile technique since it is a technique which has environmentally friendly nature; moreover, it is classified as a clean and green procedure. OES method overcomes the conventional processes whether organic synthesis or synthetic via many advantages, such as mild reaction conditions, higher yield, higher products selectivity, easy to control process [1][2][3][4]. In recent times, OES has become increasingly popular due to the progress made in the field and development of relevant technology which allows an increasing number of chemical methodologies [5,6]. Besides the increased safety and improvements in multistep synthesis, advantages such as improved mixing and heat management, energy efficiency, scalability, waste generation, access to a wider range of reaction condition, and reproducibility potential benefit of green chemistry [7].
Quinoline and their derivatives are an important category of heterocycles, they used as beneficial dyes and intermediates in organic synthesis. Furthermore, they are used to make rubber and chemicals [11].
Great attention has been concentrated on the synthesis of quinoline derivatives such as their hydrazone derivatives in the last years because they are possessed advantageous biological activities. Quinoline hydrazone derivatives used as antimicrobial [21], antifungal agents [22], anti-tubercular [23], anti-tumoral [24], and anti-leishmanial [25], they can be prepared by traditional methods of synthesis from the reaction of arene aldehydes [26,27] In a continuation of our previous work [28], In 1999, Youssef's group reported the electrochemical reduction of some 2,4-disubstituted pyridines. After a long gap, we report herein for the first time, the design of a novel electrochemical reactor and its application in the cyclic hydrazones formation via the electrochemical reaction of heteroaromatic hydrazines when they react with aromatic aldehydes to give the cyclic heteroaromatic hydrazones, by using an undivided cell.

Cell and electrode design
The controlled potential organic electrosynthesis experiments were conducted in an undivided cell and in constant current of 5 mA and were equipped with two electrodes. They were a graphite electrode (ϕ 6 mm, about 10 mm immersion depth in solution) and a platinum plate electrode (10 mm×10 mm×0.2 mm) as the anode and the cathode, respectively.

Instruments
A Stuart SMP30 apparatus was used to determine melting points via open capillary tubes, and they were uncorrected. Thin-layer chromatography (TLC) was the technique that used to monitor the progress of all reactions and determine the purity of all compounds performed on aluminum foil sheets, and these sheets were precoated by adsorbent material as silica gel 60 F254 with a thickness of 0.20 mm (Merck plates)while the visualization was done via ultraviolet radiation (254 nm). The measurements of 1H NMR spectra were conducted on an NMR spectrometer device (Bruker Avance II, 300 MHz) and were recorded in deuterated solvent that was dimethyl sulfoxide-d6 (DMSO-d6) contained in tetramethylsilane (TMS). Chemical shifts (δ) were reported in ppm downfield proportional to tetramethylsilane (TMS, δ = 0 ppm); moreover, the peak of the residual proton of the solvent (DMSO-d6) appeared at δ = 2.53 ppm. The measurements of mass spectrometric were carried out by the Shimadzu LC-MS/MS 8050 spectrometer operating at 70 eV and were reported in mass/charge (m/z). The measurements of UV-Vis spectra were performed on an Agilent 8453 UV-Vis spectrophotometer using dimethyl formamide (DMF). IR spectra were recorded on an FTIR spectrophotometer (Shimadzu, IR Affinity 1, Tokyo). A Vario MICRO-cube Elementar (Elemental Analyzer, Germany) was used to conduct the microanalysis for C, H, and N. All spectra were recorded in Imam Abdulrahman Bin Faisal University facility.

General procedure for the organic electrosynthesis of 7-chloro-1H-pyrazolo[4,3-c]quinoline derivatives (4a-g)
The crude 7-chloro-4-hydrazinoquinolines (5; 0.6 mmol), aldehydes 2a-g and MeCN (10 mL) were added in a 150 mL undivided cell; moreover, this mixture was stirred at room temperature or heated until TLC showed that condensation was done. Next, Tetrabutylammonium tetrafluoroborate (TBATFB) (0.5 mmol) was added and followed by MeCN (5 mL) and H2O (1 mL). Meanwhile, the cell was equipped with a graphite electrode as the anode (ϕ 6 mm, about 10 mm immersion depth in solution) and a platinum plate electrode as the cathode (10 mm×10 mm×0.2 mm). The entire mixture was stirred and electrolyzed under a constant current of 10 mA for 20-30 min. The reaction mixture was transported to a single-necked flask after the reaction was finished; therefore, the MeCN was removed by rotary evaporation. Then, the remains of the mixture were washed and extracted with water and CH2Cl2 (10 mL x 3), respectively. The organics were combined, dehydrated over Na2SO4, and concentrated. The https://doi.org/10.37358/RC.21.2.8419 obtaining of the desired products 4a-g with high purity was achieved by flash column chromatography on silica gel.

3.Results and discussions
The electrochemical synthesis of hydrazone derivatives (4a-g) through dehydrogenative cyclization was conducted in an undivided cell, and the cell was equipped with a graphite electrode as the anode and a platinum plate electrode as the cathode while Tetrabutylammonium tetrafluoroborate (TBATFB) was used as the supporting electrolyte. The electrochemical reactions proceed without oxidizing reagents or transition metal catalysts (Figure 1).

Figure 1. The controlled potential organic electrosynthesis cell design
As explained previously, the reaction can be carried out in two steps to provide the desired cyclic hydrazones (4a-g) within 20-30 min with 40-84% yields. The first step is chemical condensation of linear hydrazones 7-chloro-4-quinolinylhydrazones derivatives (3a-g) and the second step is the electrochemical cyclization (4a-g) in Scheme 1. All linear hydrazones 7-chloro-4-quinolinylhydrazones derivatives formed during all the reactions did not interfere with the cyclization reaction. Scheme 1. General scope for the synthesis of cyclic hydrazones (4a-g) The substrate scope for the synthesis of cyclic hydrazones (4a-g) was then explored Scheme 1. First, the benzene ring of aldehydes (2a-g) at the para-position could be substituted with electron donating groups such as methyl (2b), methoxy (2c), dimethyl amine (2d) and with electron-withdrawing substituents such as nitro (2e). Second, substituted groups at the ortho-position such as chloro (2f) and trifluoro methoxy (2g) have been used.
The efficiency of the reaction of the electron-deficient substrates was decreased due to the possibility of the difficulty in cyclizing the electrophilic C-radical onto the N-phenyl ring.
Our experiments were carried out in the undivided cell, and the applied potential to the working electrode was 2.5 V. The electrodes were placed in an undivided cell as close to each other as possible to reduce cell resistance. Platinum electrode selected as the working electrode since it has been proven that it has a good activity toward the organic electrosynthesis [29]. The reaction proceeded at the cathode graphite.
For optimal results, stirring can be introduced to increase mass transfer, however, since no laminar flow over the electrode surface is obtained, such setups are not considered hydrodynamic electrodes.
In this setup, the maximum cyclic hydrazones (4a-g) concentration was reached within the first 20 min as described in (Table 1). The course of the reaction was followed up via TLC each ten minutes. After 30 min, the final concentration was already reached. The experiment was repeated and blocking the surface of the electrode was possible.
For further investigation of the resulted cyclic hydrazones (4a-g), the measurements of UV-VIS spectroscopy were performed on the products and were recorded in DMF Figure 2. UV spectra show an absorption band at (361-366) nm in all aldehyde's spectra.  For further verification, the measurements of FT-IR spectra were performed on the cyclic hydrazone derivatives (4a-g) and were recorded in a spectral range between 4000 and 400 cm -1 . The IR spectra displayed a strong band at 3400 cm -1 attributed to the NH stretching vibration. The noticed vibrations in the region 3000 cm -1 were specified to aromatic CH stretching; in addition, the band of phenyl ring was observed at 2000 cm -1 . The C=C aromatic stretching was observed at 1450 cm -1 . The band at 1350 cm -1 can be assigned to CH bending, whereas the band at 1200 cm -1 was observed to C-N stretching. The noticed vibrations in the region 1050-1100 cm -1 were assigned to C=C-H bending. In the IR spectra of all cyclic hydrazone derivatives (4a-g), we observed the apparition of a strong band at 1600 cm -1 and it was assigned to the stretching vibration of C=N.

Mechanism
In the following step, efforts were made to verify the reaction mechanism. Because of previous results and reports [2], a possible mechanism of the electrochemical synthesis of hydrazones through the dehydrogenative cyclization of the linear hydrazones 7-chloro-4-quinolinylhydrazones derivatives was suggested via using the reaction of hydrazine; 7-chloro-3-phenyl-1H-pyrazolo[4,3-c]quinoline (4a) as an example Scheme 3. The structural features and new mechanism have been covered by this work to speed up the reaction. Although the synthesis of hydrazone was a direct condensation Scheme 1, the reaction was not reversible in aqueous media.

4.Conclusions
In conclusion, we have developed an efficient electrochemical system for cyclic hydrazone (4a-g) formation of the linear hydrazones 7-chloro-4-quinolinylhydrazones derivatives (3a-g) by the straightforward dehydrogenative in a simple undivided cell. The electrosynthetic pathway of the cyclic hydrazone formation reaction of hydrazine with aromatic aldehydes has been investigated. The under-standing of the reaction and the improvement of the outcome of the transformation are necessary to avoid the degradation of the formed intermediates, and that is for further verification in the mechanism. This electrochemical process provides access to fused heterocycles in a straightforward and clean way. Since the electrochemical construction of aromatic heterocycles represents a major part of drugs, it deserves more attention.