Electricity-Controlled Divergent Synthesis of CF₃‑Tethered Pyrazolines and Pyrazoles via Tandem Radical Trifluoromethylation and Annulation

Abstract

Electricity-controlled, diversity-oriented selective synthesis is a powerful strategy for accessing structurally distinct potential organic molecules. However, achieving this transformation remains a significant challenge in synthetic chemistry. Herein, we report a metal- and external-oxidant-free electrochemical strategy that enables the highly selective synthesis of CF₃-tethered pyrazolines and pyrazoles (>45 examples) from readily available N-allyl-N’-benzylidenesulfonohydrazides and CF₃SO₂Na. This protocol operates via a tandem sequence involving regioselective radical trifluoromethylation, annulation, and oxidation. Notably, precise control over product selectivity is achieved simply by modulating the applied current under constant-current electrolysis conditions. As a result, N-sulfonyl pyrazolines, N-sulfonyl pyrazoles, and N–H pyrazoles are selectively synthesized from the same starting materials. The method features broad substrate scope and functional-group tolerance, including derivatives of fragrances, pharmaceuticals, and natural products. Electricity serves as the sole reagent, with H₂ as a benign byproduct, demonstrating the protocol’s high sustainability. Mechanistic investigations support a radical-mediated pathway involving a ^•CF₃-radical. Interestingly, electron-rich heteroaryl-substituted sulfonohydrazides preferentially undergo C–H trifluoromethylation of the heteroaryl moiety rather than annulation. This observation highlights the differential reactivity of the ^•CF₃ radical toward (hetero)­aryl-substituted N-allylsulfonohydrazides.

N-Heterocycles constitute the major structural class in modern medicinal chemistry, contributing 82% of small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) since 2013. − Among these, pyrazole is a particularly significant scaffold, ranking 44th in frequency among 351 ring systems identified in marketed pharmaceuticals, and is the most frequently occurring pharmacophore among its analogues, such as pyrazolines and pyrazolones (Scheme A,B). Over the past decade, 20 unique small-molecule drugs have been approved by the FDA that contain pyrazole as the core unit and are used for the treatment of cancer, arthritis, HIV/AIDS, and glaucoma (Scheme A). − On the other hand, the incorporation of fluoroalkyl groups into organic molecules has become a powerful strategy for modulating bioavailability, lipophilicity, metabolic stability, and binding affinity, thereby improving biological potency. − In this context, the combination of a pyrazole core with a fluoroalkyl substituent offers an attractive strategy for novel drug design and development. A few examples of fluoroalkyl, in particular, β-fluoroalkyl-substituted drug molecules are known, such as ubrogepant and silodosin (Scheme C). Following this rationale, the development of novel synthetic strategies to access β-fluoroalkylated pyrazoles is highly relevant in the context of medicinal chemistry and fluoroalkyl drug-discovery. Although numerous synthetic strategies have been developed so far for the synthesis of α-fluoroalkyl, in particular trifluoromethyl-substituted pyrazoles, − only a few general synthetic strategies have been developed to date for the synthesis of 4-(β-fluoroalkyl)­pyrazoles. − Altman et al. reported only one example of the synthesis of 4-(β-fluoroalkyl)­pyrazole via a Pd-catalyzed decarboxylative benzylation reaction at high temperature (120 °C). Moreover, a couple of transition-metal-catalyzed, decarboxylative fluoroalkylation strategies, involving either one-step or one-pot, two-step, have been reported for the synthesis of only 4-trifluoroethyl-1H-pyrazole (1 example). ,

1. Examples of (A) Pyrazole-Based Drugs and (B) Bioactive Pyrazoline, (C) Fluoroethyl Containing Drugs, (D) Previous Work on the Synthesis of 4-Fluoroethylpyrazoles, (E) Previous Work on the Electrochemical Synthesis of 4-Fluoroethylpyrazolones, (F) Substrate Design and the Challenges, (G) Analogies to Overcome the Challenges, (H) Retrosynthesis of the Designed Substrate, and its Easy Accessibility, (I) Electricity-Controlled, Highly Selective, and Divergent Synthesis of 4-Fluoroalkyl Pyrazolines, N-Sulfonyl Pyrazoles, and N-H Pyrazoles (This Work).

The serious limitations of these strategies include the need for toxic or hazardous transition-metal catalysts, including some special and expensive metal complexes, ligands, reagents, as well as additives in (sub)­stoichiometric amounts; the need for prefunctionalized pyrazoles or other acyclic reactants/reagents, which require multiple steps for synthesis involving hazardous catalysts and reagents; the need for expensive fluoroalkyl sources; harsh reaction conditions (high temperature); and poor substrate scope, generality, and product yield. Hence, the development of a metal-free, sustainable, and practical synthetic strategy for the preparation of 4-(β-fluoroalkyl)­pyrazoles is highly desirable.

Electrochemical organic transformations have received tremendous attention from synthetic organic chemists owing to their unique features and notable advantages, such as their high sustainability, as electrons serve as clean reagents that eliminate the need for toxic or hazardous oxidants, reductants, or other reagents. , Consequently, several important reaction classes have been developed under electrochemical conditions, including trifluoromethylation. For example, the Cho group disclosed a couple of electrochemical trifluoromethylation strategies, including hydrotrifluoromethylation of alkynes and aminotrifluoromethylation with alkynes, followed by cyclization to access CF₃-functionalized alkenes and oxazoles, respectively. , The Sarkar group reported electro-oxidative generation of CF₃-radicals, followed by a cascade cyclization strategy using β,γ-unsaturated oximes for the construction of β-fluoroalkyl-substituted isoxazolines. Wang et al. reported an electrochemical trifluoromethylation/cyclization strategy for the synthesis of isoquinoline-1,3-diones and oxindoles. A few synthetic strategies have been developed so far for the electrochemical construction of a pyrazoline or pyrazole core from an acyclic substrate, − and an electrochemical trifluoromethylative annulation strategy has been reported using an activated alkene, i.e., N′-arylidene-N-acryloyltosylhydrazides, to access 4-(β-fluoroalkyl)­pyrazolones (Scheme E). However, the electrochemical synthesis of 4-(β-fluoroalkyl)­pyrazolines or pyrazoles is challenging as it requires the trifluoromethylative annulation with an unactivated alkene (Scheme E). Despite notable advancements in the trifluoromethylative annulation for the construction of N-heterocycles and also 4-(β-fluoroalkyl)­pyrazolones, the highly selective, electricity-controlled, divergent synthesis of 4-(β-fluoroalkyl)-substituted pyrazoles and/or pyrazoline synthesis is elusive but highly desirable, as different classes of biologically active N-heterocycles can be accessed from the same starting material by controlling the applied current or potential during electrolysis.

We aimed to develop a practical strategy for the direct synthesis of 4-trifluoroethylpyrazoles from easily accessible N-allylhydrazones, involving radical chemistry via the in situ generation of the ^•CF₃ radical from CF₃SO₂Na. However, the challenge associated with this strategy was the availability of three potential sites in the substrate for the addition of an electrophilic ^•CF₃ radical, leading to three different competitive pathways such as trifluoromethylative annulation (path a, desired pathway), C–H trifluoromethylation of electron-rich (hetero)­aromatics (path b), , and C–H trifluoromethylation of hydrazone unit (path c), − (Scheme F). To overcome this challenge, we reasoned that an alkyl or a relatively electron-poor (hetero)­aryl group-substituted N-allylhydrazones would not undergo path b; however, the feasibility of path c remains questionable (Scheme G). But path c could be shut down by introducing an electron-withdrawing group on the nitrogen atom bearing the allyl group, thereby decreasing electron density on the CN carbon. Thus, we designed (E)-N-allyl-N’-benzylidenebenzenesulfonohydrazide as the general substrate class to explore regioselective fluoroalkylative annulation reaction (Scheme G). The substrate could be easily accessed via a metal-free, one-pot, two-step column-free synthetic route using commercially available, inexpensive starting materials and reagents (Scheme H). Thus, with this strategy, the challenges associated with the previously developed methods could be overcome.

As a part of our continued interest in electrosynthesis, − and trifluoromethylation reactions, − herein, we report an electricity-controlled, highly selective oxidative di- and trifluoromethylation and annulation of (E)-N-allyl-N′-benzylidene-4-methylbenzenesulfonohydrazides, using CF₂HSO₂Na or CF₃SO₂Na as the inexpensive fluoromethylating agent, which afforded the 4-fluoroethyl N-sulfonyl pyrazolines and pyrazoles, selectively, under constant-current electrolysis (CCE) using 7 mA and 4 mA, respectively (Scheme G). Interestingly, when N-sulfonyl pyrazolines were treated with aqueous NaOH solution in the same pot and heated at 50 °C, the corresponding N-H pyrazoles were formed. Thus, two different classes of biologically active pyrazoles, i.e., 4-fluoroethyl N-sulfonyl pyrazoles and N-H pyrazoles, were synthesized directly and selectively from (E)-N-allyl-N′-benzylidene-4-methylbenzenesulfonohydrazides just by regulating the applied electricity during the electrolysis (Scheme G).

We commenced our investigation by selecting (E)-N-allyl-N′-benzylidene-4-methylbenzenesulfonohydrazide (1a) and CF₃SO₂Na (2a) as the model substrates (Figure ). When the reaction was conducted in an undivided cell equipped with a carbon graphite (C_gr) anode and a platinum cathode, using CF₃SO₂Na 2a (2 equiv) and LiClO₄ (1 equiv) in CH₃CN (0.03 M) under constant-current electrolysis applying 7 mA current for 2 h (5.22 F/mol), gratifyingly, the desired product 3-phenyl-1-tosyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (3a) was formed exclusively with an excellent yield of 90% (Figure a). The ¹H NMR analysis of the crude reaction mixture revealed that no corresponding pyrazoline product 4a or other side product was formed (SI). Changing the cathode material from platinum to graphite or copper or stainless steel had little effect on the reaction outcome (Figure a). In contrast, exchanging the electrodes led to inconsistent results. Modifying the anode material from carbon graphite to stainless steel or copper drastically reduced the yield of 3a (Figure a). Replacing LiClO₄ with alternative electrolytes, such as Et₄NBr, ⁿ Bu₄NClO₄, or ⁿ Bu₄NPF₆, resulted in 3a in lower yields; however, KI and ⁿ Bu₄NBr furnished the corresponding pyrazoline product 4a in 10% and 25% yield, respectively (Figure b). Notably, replacing CH₃CN with EtOH or ⁱ PrOH furnished no product (Figure c). While the reaction went well in anhydrous CH₃CN, it was gradually affected with the addition of water to CH₃CN. However, when DMF was used as the solvent, 4a was formed only in 20% yield, and the solvent concentration had little effect on the reaction outcome (Figure c). Screening of reagent stoichiometry revealed that 1 equiv of LiClO₄ and 2 equiv of CF₃SO₂Na 2a were optimal (Figure d). Interestingly, the reaction proceeded efficiently even in the absence of an electrolyte, delivering 3a in 72% yield (Figure d), possibly because the solution conductance of 1a with CF₃SO₂Na or LiClO₄ was comparable (Figure S2). These results revealed that CF₃SO₂Na also served as an electrolyte, facilitating charge transport during electrolysis.

1.

Optimization of the reaction conditions by conducting the reaction between 1a and 2a on a 0.1 mmol scale and determining the yield of 3a and 4a by the ¹H NMR of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard. Bar graphs comparing percent yields of 3a (blue) and 4a (yellow) under systematically varied parameters: (a) electrode material screening, identifying carbon graphite (C_gr) anode, and platinum cathode as optimal; (b) electrolyte screening, with LiClO₄ affording superior performance; (c) solvent and solvent concentration effects, with 0.05 M CH₃CN as the optimal medium; (d) electrolyte/reagent stoichiometry, evaluating varying equivalents of LiClO₄ and CF₃SO₂Na (2a); (e) additive effects on reaction outcome, including acetic acid, Na₂CO₃, and excess Na₂CO₃; and (f) variation of constant current and reaction time, with 4 mA for 2 h identified as optimal. All reactions were conducted in an undivided cell at room temperature. Optimal conditions are highlighted with a box in each panel.

However, scale-up under electrolyte-free conditions was found challenging, and LiClO₄ was therefore used as a supporting electrolyte. An acid or a base was found not to have any effect on the reaction outcome (Figure e). Notably, when the reaction was conducted for 1 h rather than 2 h, the corresponding pyrazoline 4a was the major product (3a:4a = 10:62), indicating that prolonged electrolysis promotes the conversion of 3a to 4a (Figure f). We then reasoned that if electricity is supplied to the reaction mixture in a controlled manner, both 3a and 4a could be synthesized selectively. To selectively obtain 4a, the reaction mixture was electrolyzed at a lower current (4 mA) for 2 h, and interestingly, 4a was formed in 83% yield along with the formation of a very small amount (5%) of 3a; however, prolonged electrolysis until 4 h furnished 3a exclusively in 90% yield (Figure f). Conversely, increasing the current from 7 mA to 10 mA led to partial decomposition of both the starting material and the product, underscoring the system’s sensitivity to current density (Figure f). The blank experiment without electricity furnished no desired product (Figure f). Thus, constant-current electrolysis (CCE) of the reaction mixture of 1a and 2a (2 equiv) in the presence of LiClO₄ (1 equiv) as the supporting electrolyte in MeCN (0.03 M) using 7 mA current for 2 h (conditions 1), furnished 3a as the sole product selectively in 90% yield, while by applying 4 mA current for 2h (conditions 2), 4a was formed as the major product with 83% yield, exclusively. We examined the substrate scope for the selective synthesis of 4-trifluoroethyl N-sulfonyl pyrazoles 3 under conditions 1 (Scheme ). The model substrates 1a and 2a reacted smoothly on a 0.5 mmol scale and in the gram scale, affording 3a in 85% and 65% yield, respectively.

2. Substrate Scope for the Synthesis of 4-Fluoroethyl N-Sulfonyl Pyrazoles .

^a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), LiClO₄ (0.5 mmol), CH₃CN (7 mL), graphite anode and Pt cathode, CCE (7 mA), rt, 8–12 h.

Next, the scope of the benzylidene part of 1 was explored, and a wide variety of substituents (Me, Br, Cl, F, CF₃, CHO, NO₂) at the para position of the benzene ring was tolerated, furnishing 3-aryl-1-tosyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (3a–3h) in moderate to good yield up to 80%. Interestingly, when 1-naphthyl-substituted substrate 1i reacted with 2a under conditions 1, along with the trifluoromethylative annulation, C–H trifluoromethylation of the naphthalene ring occurred, resulting in 3i in 73% yield, possibly because of the relatively high electron density of the naphthalene ring.

A couple of heteroaryl (2-thienyl and 2-thiazolyl)-substituted, 1-tosyl-4-(2,2,2-trifluoroethyl)-1H-pyrazoles, i.e., 3j and 3k, were synthesized successfully in 77% yield. When CF₂HSO₂Na 2b was employed instead of 2a, the desired difluoroalkylated product 3a′ was obtained in 57% yield, demonstrating that the developed protocol is applicable to difluoromethylative annulation reactions too. A couple of N-sulfonyl-substituted substrates (phenylsulfonyl and 4-nitrophenylsulfonyl) were explored, and the desired products 3l–3m were formed. Various aliphatic hydrazones, including cyclopropane-, cyclopentane-, and cyclohexane-substituted substrates, furnished the desired products 3n–3p in 70–80% yield. The molecular structures of 3h and 3n were confirmed by single X-ray crystallographic determination (Figures S10 and S11 and Table S1).

Next, the scope of the electricity-controlled selective synthesis of pyrazolines was explored under conditions 2 (Scheme ). The model substrates 1a and 2a reacted smoothly on a 0.5 mmol scale and in the gram scale, affording the desired product 4a in 80% and 60% yield, respectively. Various electron-donating (OMe and Me), halogen (Br, Cl, and F), and strong electro-withdrawing (4-NO₂) group–substituted substrates smoothly underwent the reaction to furnish the desired pyrazolines 4a, 4q, 4b–4e, 4h, up to 85% yield. The molecular structure of 4c was confirmed by a single X-ray crystallographic determination (Figure S12 and Table S1). (E)-N-Allyl-N’-((2,3-dihydrobenzo­[b]­[1,4]­dioxin-5-yl)­methylene)-4-methylbenzenesulfonohydrazide 1r smoothly underwent the electrochemical trifluoromethylative annulation to furnish 4r in 60% yield. 2-Thienyl- and 2-thiazolyl-substituted substrates also furnished the corresponding pyrazolines (4j and 4k) under conditions 2 in 62% and 80% yield, respectively. Various aliphatic groups, including cyclopropane-, cyclopentane-, and cyclohexane-substituted substrates, reacted well with 2a, furnishing the corresponding pyrazolines 4n–4p in 74–82% yield. Notably, when a 2-methylallyl-substituted substrate, 1s, reacted with 2a, the desired product, 4s, bearing a quaternary carbon, was formed in 66% yield.

3. Substrate Scope for the Synthesis of 4-Trifluoroethyl N-Sulfonyl Pyrazolines .

^a Reaction Conditions: 1 (0.5 mmol), 2 (1 mmol), LiClO₄ (0.5 mmol), CH₃CN (7 mL), graphite anode and Pt cathode, CCE (4 mA), rt, 8–12 h.

Interestingly, the homoallyl group-substituted substrate, 1t, afforded a new class of six-membered N-heterocycle, i.e., 3-phenyl-1-tosyl-4-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyridazine 4t in 75% yield. Unfortunately, 1u, 1v, and 1w did not participate in the reaction with 2a. Notably, the scope to access fully substituted pyrazoles or pyrazolines by this strategy is limited, as the synthesis of the corresponding starting material, i.e., N-allylsulfonohydrazides bearing a substituent on the α-carbon of the allyl group, is challenging.

Since the 4-trifluoroethyl N-sulfonyl pyrazolines 4 were successfully and selectively synthesized from 1 and 2a, next we became interested in converting 4 to N–H pyrazoles via the elimination reaction followed by tautomerization. Interestingly, when the in situ-generated 4a was treated with NaOH (5 equiv) and the reaction mixture was heated at 50 °C, the corresponding N–H pyrazole, i.e., 3-phenyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole 5a was formed in good overall yield (76%) starting from 1a. The scope of the reaction was found to be broad as various electron-donating (4-OMe, 4-Me) halogens (4-Br, 4-Cl, and 4-F) and strong electron-withdrawing (4-CF₃ and 4-NO₂) group–substituted substrates 1 smoothly underwent the one-pot, two-step trifluoromethylative annulation followed by elimination and tautomerization (aromatization) for the direct synthesis of the corresponding CF₃-tethered N–H pyrazoles (5a, 5q, 5b–5f, 5h) in moderate to good yield (62–78%). A couple of heteroaryl-substituted substrates also furnished the desired N–H pyrazoles (5j and 5k) in good yield. Thus, this strategy enabled direct access to both N-sulfonyl pyrazoles and N–H pyrazoles starting from 1 by controlling the applied electricity and subsequent conditions.

When the solution of 4a was heated at 50 °C in the absence of NaOH, no 5a was formed, but in the presence of 1 equiv of NaOH, 5a was formed quantitatively (99%) (Scheme B). To understand why an excess (5 equiv) of base is required for the one-pot synthesis of 5a from 1a, we studied the pH of the reaction mixture after the addition of NaOH at varying stoichiometries and the yield of 5a (Scheme C). This study demonstrated that 3 equiv of NaOH was utilized to neutralize the reaction mixture after the conversion of 1a to 4a; hence, 2 more equivalents (total 5 equiv) were required to make the medium suitably basic [apparent pH (pH_app) = 13] for the quantitative conversion of 4a to 5a and thus leading to the formation of 5a in 76% overall yield from 1a in one-pot via two steps.

4. (A) Scope for the Direct Synthesis of 4-Trifluoroethyl N–H Pyrazoles 5 from 1; (B) Control Experiments for the Conversion of 4a to 5a; and (C) the Effect of NaOH Stoichiometries on the pH_app of the Reaction Mixture after the Formation of 4a and the Yield of 5a from 1a .

Next, we explored our strategy for the late-stage functionalization (LSF) of fragrance ingredients, drug molecules, and natural products. At first, vanillin was converted to 1x in three steps via methylation, condensation, and allylation reactions, which were then treated with 2a. Interestingly, trifluoromethylative annulation along with C–H trifluoromethylation of the aryl ring occurred under both the standard electrochemical conditions 1 or 2, leading to the synthesis of 4x. No corresponding pyrazole product 3x was formed under conditions 1, even after prolonged electrolysis. A similar result was obtained when another fragrance ingredient, i.e., eudesmicaldehyde, which was converted to 1y in two steps and then subjected to reaction with 2a under the standard conditions 1 and 2, afforded only 4y, and no corresponding pyrazole product 3y was formed under conditions 1, even after prolonged electrolysis (Scheme A).

5. (A) Scope of Fragrance Ingredients, (B) Late-Stage Functionalization of Drug and Natural Products, and (C) Synthesis of the Lonazolac Analogue.

A drug molecule, i.e., ibuprofen, was converted to the corresponding starting material 1z in four steps and reacted with 2a to furnish the corresponding pyrazoline product 4z under conditions 2. However, when menthol was converted to 1A in three steps and reacted with 2a under standard conditions 1, the corresponding N-sulfonylpyrazole product, 3A, was formed (Scheme B). These results revealed that while an electron-withdrawing group–substituted substrate facilitates the trifluoromethylative C–H annulation followed by oxidation, leading to the formation of the corresponding N-sulfonyl pyrazoles under the standard conditions 1, the electron-donating group-substituted substrate retarded the oxidation of the in situ-generated pyrazolines to the corresponding pyrazoles under standard conditions 2, even after prolonged electrolysis. The application of the developed protocol was further demonstrated by synthesizing an analogue (3B) of a nonsteroidal anti-inflammatory drug (NSAID), lonazolac 6, − from commercially available molecules in three steps (1B) without requiring any metal or stoichiometric oxidant or reductant (Scheme C).

For an electron-rich heteroaryl such as indole, pyrrole, furan and thiophene-substituted substrates, there was a question of chemoselective addition of the in situ-generated ^•CF₃ radical to either the allyl group (path a), leading to trifluoromethylative C–H annulation or to the heteroaryl ring (path b), leading to the C–H functionalization of the heteroarenes (Scheme ). Interestingly, when the relatively less electron-dense heteroaryl, i.e., thiophene-substituted substrate, was employed, it preferred the path a, leading to the synthesis of the corresponding pyrazoline 4j (under conditions 2) and pyrazole 3j (under conditions 1) via a chemoselective trifluoromethylative C–H annulation over C–H trifluoromethylation of thiophene. However, more electron-dense heteroaryls, i.e., furan, pyrrole, and indole, preferred C–H trifluoromethylation of the heteroaryl (path b) over the trifluoromethylative C–H annulation, leading to the chemoselective synthesis of the corresponding products 7C–7F under conditions 1 or 2; notably, When thiophene was introduced in the sulfonyl part of the molecule, i.e., 1G was employed to react with one equivalent of 2a, it underwent the usual trifluoromethylative C–H annulation and furnished the desired pyrazoline product 4G’ under conditions 2 and the desired pyrazole product 3G’ under conditions 1. Surprisingly, when two equivalents of 2a were used under conditions 1, the substrate underwent trifluoromethylative C–H annulation and C–H trifluoromethylation of the thiophene ring to afford 3-phenyl-4-(2,2,2-trifluoroethyl)-1-((5-(trifluoromethyl)­thiophen-2-yl)­sulfonyl)-4,5-dihydro-1H-pyrazole 4G, and it did not undergo further oxidation to the corresponding pyrazole even after prolonged electrolysis (Scheme ). Trifluoromethylative C–H annulation did not occur at all, even with 2-substituted indole (1H).

6. Substrate-Controlled C–H Trifluoromethylation vs Trifluoromethylative Annulation.

To gain insights into the reaction mechanism, several experiments were conducted. Cyclic voltammetry studies revealed that the oxidation potential of CF₃SO₂Na (E _ox = 1.5 V vs SCE) is much lower than that of the starting material, 1a (E _ox = 2.28 V vs SCE), suggesting that 2a would be preferentially oxidized at the anode relative to 1a (Scheme A). Radical-quenching experiments of the model reaction between 1a and 2a in the presence of radical quenchers, such as 1,1-diphenylethene and BHT, completely quenched the reaction, suggesting a radical pathway for this transformation. Moreover, the corresponding adduct of ^•CF₃ radical and 1,1-diphenylethene was formed, which was isolated in 70% yield (Scheme B­(i)). When 4a was subjected to electrochemical conditions in the presence of LiClO₄ as the supporting electrolyte under a constant current of 7 mA, it furnished 3a in 95% yield (Scheme B­(ii)).

7. (A) Cyclic Voltammetry, (B) Radical-Quenching Experiments and Control Experiments, (C) XPS-Survey Spectra of the Cathode Surface before and after the Reaction, (D) Plausible Reaction Mechanism.

Based on these results, we proposed a plausible reaction mechanism as outlined in Scheme D. Under standard conditions 2 (I = 4 mA), CF₃SO₂Na (2a) underwent preferential oxidation over 1a at the anode to form ^•CF₃ radical as the key intermediate, which then chemo- and regioselectively added to the terminal position of the CC double bond of 1a to form a relatively stable 2 ° alkyl radical intermediate (I). Being nucleophilic in nature, the alkyl radical underwent an intramolecular radical cyclization to the electrophilic imine carbon (CN), resulting in a N-centered radical (II), which after oxidation, being assisted by the adjacent N, and deprotonation furnished the desired N-sulfonyl pyrazoline 4a. The intermediate II could also undergo a 1,2-H atom transfer to form a C-centered radical; however, this pathway is ruled out, as we did not observe the formation of the corresponding ring-opened product from the cyclopropyl-substituted substrate 1n. Under standard condition 1 (I = 7 mA), the in situ-generated 4a underwent two-electron oxidation and two-proton elimination, furnishing the corresponding pyrazole 3a. The liberated protons were reduced at the cathode, producing hydrogen gas as an innocuous byproduct, which was detected in situ with a H₂-gas detector (Figure S9). We observed that after completion of the reaction from 1a to 3a, a white solid precipitate formed on the cathode. The XPS (Figure S6) and EPR analyses (Figure S7) revealed the deposition of sodium metal as the major component, along with lithium as a very minor (negligible) component (Scheme C). However, the XPS-survey spectra of the cathode’s deposition for the synthesis of 4a from 1a showed no lithium peak, suggesting that lithium deposition occurred only for the synthesis of 3a from 1a, which could be because of the higher applied charge (Figure S6). Based on these results, we proposed that after the oxidation of 2a, the counter sodium cation was reduced at the cathode, leading to the deposition of sodium metal there. Moreover, lithium cations from the electrolyte was also reduced at the cathode, generating perchloric acid and making the reaction mixture highly acidic (pH_app = −1.28). When NaOH was added after the formation of 4a, it underwent base-mediated elimination of sodium tosylate and water, followed by tautomerization to furnish 5a.

In conclusion, we report a metal- and external-oxidant-free, electricity-governed divergent synthesis of CF₃-tethered N-sulfonyl pyrazoles and pyrazolines, in which simple modulation of the applied current during constant-current electrolysis dictates product selectivity. This strategy further enables direct access to N–H pyrazoles from readily available N-allylsulfonohydrazides. Using electricity as the sole green reagent, the protocol delivers three distinct classes of pyrazoles/pyrazolines in moderate to high yields with broad functional-group tolerance, encompassing motifs derived from fragrances, pharmaceuticals, and natural products.

Notably, an analogue of the marketed drug lonazolac was efficiently synthesized, underscoring the practical utility of the method. Mechanistic investigations support a chemo- and regioselective CF₃ radical addition followed by annulation and oxidation to furnish N-sulfonyl pyrazolines and pyrazoles. Remarkably, heteroaryl substrates such as pyrrole, furan, and indole preferentially undergo C–H trifluoromethylation over annulation, whereas thiophene derivatives exhibit the opposite chemoselectivity. To the best of our knowledge, this represents the first example of electricity-controlled divergent synthesis enabling access to three classes of biologically relevant heterocycles, and it is anticipated that this sustainable platform will stimulate further developments in diversity-oriented electrosynthesis.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c00788.

• EExperimental procedures, characterization data for all products, including ¹H, ¹³C, and ¹⁹F NMR spectra, and HRMS data, and more detailed information on the optimization of the reaction conditions and mechanistic studies. (PDF)

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.