External electrolyte-free electrochemical one-pot cascade synthesis of 4-thiocyanato-1H-pyrazoles

Wei-Bao He Sai-Jie Zhao Jing-Yang Chen Jun Jiang Xiang Chen Xinhua Xu Wei-Min He

Citation:  Wei-Bao He, Sai-Jie Zhao, Jing-Yang Chen, Jun Jiang, Xiang Chen, Xinhua Xu, Wei-Min He. External electrolyte-free electrochemical one-pot cascade synthesis of 4-thiocyanato-1H-pyrazoles[J]. Chinese Chemical Letters, 2023, 34(2): 107640. doi: 10.1016/j.cclet.2022.06.063 shu

External electrolyte-free electrochemical one-pot cascade synthesis of 4-thiocyanato-1H-pyrazoles


  • During the past years, green and sustainable chemistry has become increasingly significant in all fields of current chemistry. Along these lines, organic electrochemical synthesis has attracted considerable attention as a powerful and practical tool for constructing new chemical bonds in synthetic chemistry, given their environmental friendliness, high efficiency and sustainability [1-4]. Compared to traditional chemistry that requires a stoichiometric amount of oxidants, electrochemistry with traceless electricity as redox reagents will reduce waste generation and lead to a higher atom utilization. Furthermore, simultaneously cross-de-hydrogenative coupling reactions through H2 evolution were achieved due to anodic oxidation and cathodic proton reduction, obviating the need for stoichiometric electron or proton acceptors. As a consequence, plenty of electrochemical synthesis reactions have been well-developed over the past decade [5-19]. Unfortunately, supporting electrolytes are mandatory for the vast majority of these reactions, which result in production of waste and lead to environmental problems. And to further, tedious purification procedures also enhance economic costs. Therefore, the exploration of external supporting electrolyte-free electrochemical synthesis reaction is highly desirable.

    Organic thiocyanates represent high-value structural units, which are broadly present in many bioactive molecules, synthetic pharmaceuticals and marketed agrochemicals [20, 21]. Moreover, they are also acted as important synthetic intermediates and versatile building blocks for preparing various sulfur-containing compounds [22-26]. According, considerable efforts have been made towards the development of novel methods to synthesize organic thiocyanates [27-31]. Pyrazole and its derivatives, as a kind of important five-membered heterocycles with two adjacent nitrogen atoms, have extensive applications in pharmaceutical discovery and organic synthesis [32-38]. Among various functionalized pyrazoles, diverse biological and pharmacological activities of thiocyanatopyrazoles have driven organic chemists to make effects to synthesize such molecules. Although numerous studies have been published on the synthesis of thiocyanatopyrazoles through thiocyanation of pyrazoles (Scheme 1a) [39-45], an efficient protocol for both the construction of pyrazole scaffold and the incorporation of thiocyanato group in a single-step reaction has not been reported.

    Scheme 1

    Scheme 1.  Multicomponent synthesis of 4-thiocyanato-1H-pyrazoles.

    The multicomponent cascade reaction has emerged as a powerful transformation that allows the rapid assembly of functionalized N-heterocycles from inexpensive and commercial available chemicals in an atom- and step-economic manner [46-55]. However, to the best of our knowledge, the electrochemical cascade synthesis of 4-thiocyanato-1H-pyrazoles has not been reported. Considering the importance of thiocyanatopyrazoles, herein we reported a practical and sustainable method for the synthesis of various 4-thiocyanato-1H-pyrazoles through the electrochemical three-component cascade reaction of hydrazines, 1, 3-diones and NH4SCN at ambient temperature without assistance of additional catalyst or supporting electrolytes (Scheme 1b).

    Initially, the electrochemical three-component reaction of phenylhydrazine (1a), 1, 3-pentanedione (2a) and NH4SCN (3) was selected as the template reaction (Table 1). Using acetonitrile as a solvent, graphite plate (C) as the anode and platinum plate (Pt) as the cathode, 96% GC yield of the target product (4aaa) was obtained under 12 mA constant-current electrolysis at ambient temperature (Table 1, entry 1). In term of electrode synthesis, changing the C(+)/Pt(−) electrode pair to other electrode pairs resulted in a lower reaction efficiency (entries 2-7). A series of reaction solvents were next tested (entries 8-12). The replacement of MeCN with acetone or DMF delivered a trace yield of 4aaa, while markedly inferior yield of 4aaa was detected when using THF, DMSO or EtOH as the reaction medium. However, increasing the operating current to 16 mA did not benefit the product yield (entry 13). Furthermore, decreasing the operating current to 8 mA led to a diminished yield of 4aaa (entry 14). Lower yield of desired product 4aaa was obtained by increasing the concentration of the substrates (entry 15). No improvement in the transformation was observed when the reaction was carried out under nitrogen atmosphere (entry 16). No target product was formed in the absence of electric current (entry 17). Changing the NH4SCN to KSCN or NaSCN, lower yield of 4aaa was obtained (entries 18 and 19).

    Table 1

    Table 1.  Optimization of reaction conditions.a
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    With the optimal reaction conditions in hand, the substrate scopes were next investigated (Scheme 2). Substrates with substituents at the benzene ring at the terminus of the alkyne were investigated firstly. To our delight, good to excellent isolated yields of products (4aaa4maa) were obtained when phenylhydrazines (1) were modified with electron-donating or electron-withdrawing groups at the para-position of phenyl ring. Due to the high reactivity and rich multifunctional conversion of aryl halides they can be used in different synthesis (such as alkylation reactions) and further preparation of other derivatives. Moreover, other functional groups on the aromatic ring (OMe, OCF3 and CN) represent potential chemical versatility and practicality in high-value pharmaceutical synthesis. The meta-, ortho-substituted and di-substituted phenylhydrazines were suitable for the present electrochemical transformation and afford the target products (4naa4raa) in good to excellent yields. These results suggested that this transformation was insensitive to steric effect. Both the naphthalen-2-ylhydrazine and 2-hydrazinopyrazine underwent the reaction smoothly, delivering the corresponding products (4saa and 4taa) with moderate to good yields. Gratifyingly, aliphatic ahydrazines, such as cyclohexylhydrazine, benzylhydrazine, trifluoroethylhydrazine and 3-hydrazineylpropanenitrile were effective in yielding the desired products (4uaa4xaa) with 78%–89% yields. In addition, several 1, 3-dione derivatives including heptane-3, 5-dione, 1-cyclopropylbutane-1, 3-dione, 1-phenylbutane-1, 3-dione were also amenable to the reaction conditions, producing the target products (4aba4ada) in 91%, 86% and 63% yields, respectively.

    Scheme 2

    Scheme 2.  Reaction scope. Conditions: C (15 mm × 15 mm × 3 mm) as the anode, Pt (15 mm × 15 mm × 0.3 mm) as the cathode, constant current = 12 mA, 1 (0.5 mmol), 2 (0.5 mmol), 3 (1.0 mmol), MeCN (10 mL), room temperature, in air, 10 h, undivided cell. Isolated yields.

    Once the substrate scope of this reaction was established, the synthetic practicability of the electrochemical process was investigated. The large-scale synthesis experiment was firstly conducted. In the small-scale experiment, some undesirable products were observed and may result in a slightly decreased yield for the target compound 4 even the concentration of 1 was increased from 0.05 mol/L to 1 mol/L. However, same protocol was performed through increasing the amount of 1a from 0.5 mmol to 5.0 mmol, desirable compound 4aaa was obtained in 89% yield, and besides, and tremendously reduced amount of solvent can make the reaction proceed smoothly in the case of a 12.5 fold-concentration of substrates (Scheme 3a). To our delight, a 3-volt battery can easily bring about the present electrochemical transformation as the sole power supply in spite that the abundant batteries are readily available (Scheme 3b). Compared to most of the electrochemical processes with requirement of silica-gel column chromatographic purification to remove the external supporting electrolyte, catalyst and additives that might restrain subsequent transformations universally, the biggest advantage of the present electrochemical reaction allowed an environmentally benign process and did not employ any external supporting electrolyte or additive. Furthermore, five one-pot transformations starting from 1a confirmed the superiority of this approach. Un-purified thiocyanatopyrazole smoothly underwent the subsequent trifluoromethylation (1a5a) [56], thiomethylation (1a5b) [56], Grignard reaction (1a5c) [57], disulfide formation reaction (1a5d) [58] and tetrazole cyclization (1a5e) [56] in good yields (Scheme 3c). Taken together, the developed electrochemical protocol showed both practicability and simplicity.

    Scheme 3

    Scheme 3.  (a) Gram-scale synthesis of 4aaa. (b) The synthesis of 4aaa with 3.0 V battery. (c) One-pot transformations.

    Given this facile and sustainable electro-synthesis method, we conducted some mechanistic studies to acquire insight into this transformation (Scheme 4). The present electrochemical reaction was largely suppressed with 3 equiv. of radical inhibitor (TEMPO and 1, 1-diphenylethylene) as the additives (Scheme 4). These results suggested that a free-radical mechanism might be involved in the present reaction. Furthermore, the cyclic voltammetry (CV) analysis was also performed to reveal key mechanistic insights into the electrochemical reaction (Fig. S3 in Supporting information, ). It can be found that NH4SCN is the first compound to be oxidized, and the oxidative peak as well as the reduction peak was appeared at 0.78 V and 0.26 V (vs. Ag/AgCl). These results can be assigned to the oxidation of the SCN anion to form SCN radical, which further underwent radical coupling to produce (SCN)2 [59-60]. The oxidative potential of pyrazole 6a (1.85 V vs. Ag/AgCl) was next detected. In addition, the CV analysis revealed that 6a is oxidized preferentially at the surface of anode in the mixture of 3a and 6a.

    Scheme 4

    Scheme 4.  Control experiments.

    According to the above-mentioned investigations and referring to the related studies [43, 59-60], a probable reaction pathway of the electrochemical transformation is proposed in Scheme 5. Initially, the thiocyanate anion underwent anodic oxidation to form the thiocyanate radical, which underwent dimerization to generate a (SCN)2 (A). The cyclo-condensation reaction of hydrazine (1a) and 1, 3-dione (2a) led to the formation of pyrazole 6, which reacted with the intermediate A to produce a pyrazole cation intermediate (B) with the release of a thiocyanate anion. Finally, the target pyrazole product 4 was formed through the deprotonation of B and reproduction of the aromatic system. The by-product hydrogen gas was released while the proton was reduced at the surface of Pt cathode.

    Scheme 5

    Scheme 5.  Plausible reaction mechanism.

    In conclusion, a practical and efficient protocol for constructing 4-thiocyanato-1H-pyrazoles through electrochemical three-component cascade reaction of hydrazines, 1, 3-diones and NH4SCN using undivided electrochemical cells at ambient temperature was well established. This method does not require chemical oxidants, additives or external supporting electrolyte and has an excellent substrate scope as well as operational simplicity, providing an eco-friendly and sustainable access to various 4-thiocyanato-1H-pyrazoles from cheap and readily accessible starting materials. With the simple and clean reaction conditions, both a gram-scale synthesis and several one-pot sequential transformations starting from hydrazine were successfully accomplished. This protocol presents a green, eco-friendly, and low-energy-consumption electro catalytic transformation to avoid multi-steps, allow safety and environmental protection and simplify the operation, and realize high-efficiency atom utilization, which exhibited great significance in pharmaceutical and synthetic chemical industry.

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    We are grateful for financial support from the National Natural Science Foundation of China (No. 21902014) and Hunan Provincial Natural Science Foundation of China (No. 2021JJ40429).

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  • Scheme 1  Multicomponent synthesis of 4-thiocyanato-1H-pyrazoles.

    Scheme 2  Reaction scope. Conditions: C (15 mm × 15 mm × 3 mm) as the anode, Pt (15 mm × 15 mm × 0.3 mm) as the cathode, constant current = 12 mA, 1 (0.5 mmol), 2 (0.5 mmol), 3 (1.0 mmol), MeCN (10 mL), room temperature, in air, 10 h, undivided cell. Isolated yields.

    Scheme 3  (a) Gram-scale synthesis of 4aaa. (b) The synthesis of 4aaa with 3.0 V battery. (c) One-pot transformations.

    Scheme 4  Control experiments.

    Scheme 5  Plausible reaction mechanism.

    Table 1.  Optimization of reaction conditions.a

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  • 发布日期:  2023-02-15
  • 收稿日期:  2022-03-26
  • 接受日期:  2022-06-23
  • 修回日期:  2022-06-22
  • 网络出版日期:  2022-06-30
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