A convenient approach for the electrochemical bromination and iodination of pyrazoles

1 Introduction

Versatile biological and wide pharmaceutical activities of pyrazoles show that they have ubiquitous scaffolds in bioactive heterocyclic compounds [1], [2], [3], [4]. 4-Halopyrazoles especially 4-bromo and 4-iodopyrazoles have been proven to strengthen the biological activities [5], [6], [7]. They are also used as both starting materials and reactive intermediates in highly active compounds synthesis [8, 9] and they are used in organic synthesis for e.g., cross-coupling reactions [10], [11], [12], [13], [14], [15], [16]. Pyrazoles are electron-rich aromatic heterocycles that are halogenated at 4-position with various reagents [17, 18]. Effective protocols have been reported in the literature for bromination [19, 20] and iodination [21, 22] of pyrazoles, however, some of the reaction conditions or the used reagents are not safe.

Eco-friendly methods for utility compounds synthesis are broadly interesting in chemistry and electrochemistry, by replacing electrons as clean reactants instead of hazardous, dangerous, or expensive chemical oxidants and reductants reagents can be used for processes development to improve our environment quality [23, 24]. Also, electrosynthesis is an attractive method in industrial and biological applicable compound synthesis [25], [26], [27], [28], [29]. Electrochemical halogenation of aromatic compounds has been cited in the literature [30], [31], [32], [33], [34]. Electrochemical halogenation of pyrazole derivatives has been noted by Lyalin [35], [36], [37], [38], [39], [40], in which, a hetero-phase system in a divided electrochemical cell [35], [36], [37] or two different stages [38] were used to carry out the halogenation (Scheme 1).

Scheme 1:

Electrochemical halogenation of pyrazoles.

Electrolysis conditions:

1. Divided cell, platinum anode, copper cathode, constant-current (CC) = 0.2–3.0 А cm⁻², a two-phase (7:3 vol/vol) mixture of an aqueous M-X and CHCl₃ as supporting electrolyte, Qт = 2 F per 1 mol of pyrazole [35, 36].

2. Divided cell, platinum anode, copper cathode, CC = 7.5–44.5 mА cm⁻², an aqueous solution (70 mL) containing NaNO₃ (0.021 mol), KI (0.01 mol), NaHCO₃ (0.015 mol), pyrazole (0.01 mol), and CHCl₃ (30 mL) as supporting electrolyte, Qт = 2 F per 1 mol of pyrazole [37].

3. Divided cell, platinum anode, copper cathode, CC = 0.1–0.3 А cm⁻², 1 M KOH, pyrazole (0.09 mol), molar ratio Pz/KIO₃/KI/H₂SO₄ = 3:1:2:4, hetero-phase system H₂O/CHCl₃ (CCl₄) (5:1 vol/vol) as supporting electrolyte, Qт = 2 F per 1 mol of pyrazole [38].

4. Undivided cell, carbon rod anode, platinum plate cathode, CC = 12 mA cm⁻², pyrazole (0.3 mmol), Na-X (2.0 equiv.), DMF (10.5 mL)/H₂O (0.5 mL), 80 °C (or CH₃CN [10.5 mL]/H₂O [0.5 mL], 75 °C), N₂, Qт = 5.2 F per 1 mol of pyrazole [34].

Due to the high utility of 4-halopyrazoles, we were encouraged to investigate a safe and convenient procedure for 4-bromo and 4-iodopyrazoles synthesis under simple and mild electrolysis conditions.

2 Results and discussion

Herein, bromination and iodination of some pyrazole derivatives were carried out in the presence of KBr and KI as halogen sources under CC electrolysis using a simple one-compartment cell assembled with two graphite sheets as working electrodes and a large stainless-steel sheet as stable, available and inexpensive electrodes. Reaction conditions are mild and environmentally compatible and the halogenated pyrazoles were obtained without the need to use any catalysts and unsafe reagents (Scheme 2).

Scheme 2:

Electrochemical 4-bromination and 4-iodination of pyrazoles.

In order to find the suitable electrolyte, electrosynthesis was carried out in different solutions such as H₂O (NaH₂PO₄·H₂O (0.2 M), pH = 7)/EtOH, AcONa/EtOH, H₂O (NaH₂PO₄·H₂O (0.2 M), pH = 7)/MeOH, AcONa/MeOH, ClO₄Na/MeCN and H₂O (NaH₂PO₄·H₂O (0.2 M), pH = 7)/MeCN (Table 1). When AcONa/EtOH (Table 1, entries 2, 3) were used as an appropriate electrolyte, the final products were obtained with easier work-up and higher efficiency. In the absence of a supporting electrolyte, the reaction progression and the product yields were unsuitable (Table 1, entry 13). In these conditions, the obtained products have good purity without a need to perform chromatography or even recrystallization.

Investigation of current density variations on electrolysis efficiency showed that, when parameters such as electrolyte consistency, reaction temperature, and electrode areas were fixed, the best conclusion for electrolyzing a solution consisting of 1a (1.0 mmol) and KX (2.0 mmol) was achieved with a current range of 1–4 mA cm⁻² (Table 1, entries 2, 3, and 8–12). In these stipulations, the used charges were limited in the range 92–110 °C (Table 2). In this range, the essential potential for selective oxidation of KX to X₂ is made available. Appling current densities lower than 1 mA cm⁻² resulted in decreasing the yields because the oxidation of KX to X₂ is difficult to achieve. Increasing the current densities to 4 mA cm⁻² was ineffective and exertion of current densities more than 4 mA cm⁻² resulted in side-reactions such as solvent oxidation and products degradation.

The reaction mechanisms have been proposed in Scheme 3. Pyrazoles as electron-rich aromatic compounds are halogenated at 4-position under aromatic electrophilic substitution although, a reversible lone electron pair coordination of the tertiary nitrogen with halogen (pathway A, intermediate I) is suggested [41]. Herein, the reaction begins with anodic oxidation of KBr or KI salts on the surface of the electrode. Then, the in-situ produced X₂ molecules can rapidly be attacked by pyrazoles 1 as the nucleophile. Finally, the produced intermediates II are aromatized by removing H-X molecules in the presence of Et₃N to produce the 4-halogenated pyrazoles 2.

Scheme 3:

Proposed mechanisms for electrochemical bromination and iodination of pyrazoles.

The proposed mechanism via pathway A is a known and general mechanism for aromatic electrophilic substitution, which has been reported for the halogenation of pyrazoles [34], [35], [36], [37], [38], [39], [40]. Moreover, based on our recently reported research on electrocatalyzed pyrazole N–N coupling reactions [42], since the reaction conditions here are similar to the electrocatalyzed pyrazole coupling reactions, we anticipate the synthesis of compounds 2 might have been carried out via pathway B. Herein, the in-situ produced X₂ in reaction with electrochemically catalyzed pyrazoles_ox III gives intermediate IV which is in equilibrium with V. Fast removing an HX molecule in the presence of Et₃N gives the intermediate VI which by accepting an electron from the starting pyrazole 1 leads to the final product 2 and the next cycle of the reaction begins with the electrochemically produced X₂. Preliminary theoretical calculations and structure optimizations of intermediates I–VI (compiled in the Supplementary Material) show that the electrosynthesis of 4-halopyrazoles 2 through the intermediates III–VI can be possible according to the content energy and stability viewpoint.

3 Conclusions

In summary, bromination and iodination of some pyrazole derivatives were done in a one-compartment cell under CC electrolysis. The significant advantage of this procedure is the usage of KX salt instead of hazardous X₂ and producing the low concentrations of X₂ in-situ which are rapidly attacked by pyrazoles. Moreover, mild reaction conditions, easy work-up, remarkable yields, and environmentally compatible reaction conditions are notable. Also, in addition to the general and known reported mechanism for halogenation of pyrazoles, it is anticipated the synthesis of compounds 2 might have been carried out via electrocatalyzed single-electron oxidation of pyrazoles.

4 Experimental

A potentiostat/galvanostat apparatus (BEHPAJOOH PGS 2065, Isfahan, Iran), a stirrer, and a one-compartment electrochemical cell containing two working electrodes (graphite sheets: 70 × 30 × 3 mm³) and a stainless-steel sheet (70 × 5 mm²) as counter were used for preparative electrolysis under CC coulometry. Starting materials and solvents were prepared commercially and applied without purification. Melting points were registered using an Electrothermal 9100 apparatus (Rochford, UK). IR spectra (KBr plate or liquid film) were recorded using an IR-460 Shimadzu spectrometer. NMR Bruker apparatuses (DRX-400 AVANCE and DRX-250 AVANCE, Rhein-stetten, Germany) were applied to record NMR spectra.

General reaction procedure: A solution of KI (2.0 mmol) in NaOAc (1.0 mmol)/EtOH (50 mL) or KBr in NaOAc (1.0 mmol)/EtOH:H₂O (49:1, 50 mL), a pyrazole derivative 1 (1.0 mmol) and Et₃N (1.0 mmol), were electrolyzed in a one-compartment cell. A 1 mA cm⁻² current density at 25 °C was applied for electrolysis. The electrosynthesis was stopped based on consumed charges (Table 2) or the consumed starting pyrazole (Thin Layer Chromatography (TLC) monitoring). For the re-activation of the graphite electrodes during electrosynthesis, the electrolysis was halted and the working electrodes were cleaned with acetone. When the electrosynthesis was finished, the reaction dissolvent was detached and recovered for the next reactions. The residue mixture was rinsed with H₂O several times and dried in the air. In the cases of compounds 2g and 2f, the residue mixtures were worked-up with TLC (n-hexane/ethyl acetate, 5:1) for more purification.

4-Bromo-3-methyl-1H-pyrazole (2a): Yellowish solid, M. p. 74–76 °C (76–77 °C [43]); Isolated yield: 132 mg (82%); ¹H NMR, δ (ppm) (250 MHz in CDCl₃): 11.70 (brs, 1H, NH, was disappeared by adding D₂O), 7.50 (s, 1H, =CH), 2.29 (s, 3H, CH₃); ¹³C NMR, δ (ppm) (62.9 MHz in CDCl₃): 141.7, 135.6, 93.7, 10.5.

4-Iodo-3-methyl-1H-pyrazole (2b): Pale yellow crystalline powder, M. p. 109–110 °C (110.5 °C [43]); Isolated yield: 185 mg (89%); ¹H NMR, δ (ppm) (250 MHz in CDCl₃): 12.06 (brs, 1H, NH, was disappeared by adding D₂O), 7.53 (s, 1H, =CH), 2.31 (s, 3H, CH₃); ¹³C NMR, δ (ppm) (62.9 MHz in CDCl₃): 145.0, 140.2, 59.4, 12.1.

4-Bromo-3,5-dimethyl-1H-pyrazole (2c): Yellowish solid, M. p. 122–124 °C (124–125 °C [20]); Isolated yield: 165 mg (94%); ¹H NMR, δ (ppm) (400 MHz in CDCl₃): 11.79 (brs, 1H, NH, was disappeared by adding D₂O), 2.31 (s, 6H, CH₃); ¹³C NMR, δ (ppm) (100 MHz in CDCl₃): 142.6, 94.0, 11.2.

3,5-Dimethyl-4-iodo-1H-pyrazole (2d): White solid, M. p. 136–139 °C (136–138 °C [20]); Isolated yield: mg 196 (88%); ¹H NMR, δ (ppm) (400 MHz in CDCl₃): 10.81 (brs, 1H, NH, was disappeared by adding D₂O), 2.29 (s, 6H, CH₃); ¹³C NMR, δ (ppm) (100 MHz in CDCl₃): 146.3, 62.5, 12.9.

4-Bromo-3-methyl-5-phenyl-1H-pyrazole (2e) [44]: Yellowish solid, M. p. 90–93 °C (87–92 °C [45]); Isolated yield: 182 mg (77%); ¹H NMR, δ (ppm) (400 MHz in CDCl₃): 11.52 (brs, 1H, NH, was disappeared by adding D₂O), 7.78–7.76 (m, 2H, Ar-H), 7.45–7.41 (m, 3H, Ar-H), 2.15 (s, 3H, CH₃); ¹³C NMR, δ (ppm) (100 MHz in CDCl₃): 145.6, 143.2, 130.7, 128.6, 128.5, 127.5, 92.6, 11.0.

4-Iodo-3-methyl-5-phenyl-1H-pyrazole (2f): Yellowish solid, M. p. 114–116 °C (113–115 °C [46]); Isolated yield: 242 mg (85%); ¹H NMR, δ (ppm) (400 MHz in CDCl₃): 11.00 (brs, 1H, NH, was disappeared by adding D₂O), 7.74–7.72 (m, 2H, Ar-H), 7.45–7.43 (m, 3H, Ar-H), 2.17 (s, 3H, CH₃); ¹³C NMR, δ (ppm) (100 MHz in CDCl₃): 131.6, 128.6, 128.5, 128.4, 128.2, 128.1, 60.4, 12.9.

4-Bromo-3,5-dimethyl-1-phenylpyrazole (2g): Yellowish oil [20], Isolated yield: 181 mg (72%); ¹H NMR, δ (ppm) (250 MHz in CDCl₃): 7.45–7.40 (m, 5H, Ar-H), 2.30 (s, 6H, CH₃); ¹³C NMR, δ (ppm) (62.9 MHz in CDCl₃): 147.6, 139.9, 137.5, 129.2, 127.8, 124.7, 97.4, 12.4, 11.8.

3,5-Dimethyl-4-iodo-1-phenylpyrazole (2h): Yellowish oil [20], Isolated yield: 209 mg (70%); ¹H NMR, δ (ppm) (250 MHz in CDCl₃): 7.40 (s, 5H, Ar-H), 2.35 (s, 3H, CH₃), 2.32 (s, 3H, CH₃); ¹³C NMR, δ (ppm) (62.9 MHz in CDCl₃): 147.4, 139.2, 137.0, 129.4, 128.8, 125.4, 59.4, 12.6, 11.8.