Introduction

Cyclopropanes have received extensive attention interest as a result of their high ring strain and unique bonding pattern1,2. These strained cyclopropyl moieties constitute not only privileged motifs in natural products, agrochemicals, and pharmaceuticals (Fig. 1A)3,4,5,6,7,8, but also highly versatile intermediates in synthetic chemistry9,10,11,12,13,14. Owing to these pivotal roles, great effort has been devoted to the cyclopropane construction15,16,17,18,19. Conventionally, cyclopropanes are prepared via transition metal-catalyzed carbene insertion into alkenes20,21. This strategy typically relies on metal carbenoids derived from hazardous diazo compounds. As such, alternative carbene precursors have been developed, such as ylides, hydrazones, 1,2-diketones, gem-dihaloalkanes, and others22,23,24,25,26,27,28,29,30,31,32,33,34.

Fig. 1: Context of the work.
figure 1

A Cyclopropanes in natural products and durgs. B Intramolecular organoelectrocatalytic cyclopropanation. C Cyclopropanation with alkenyl thianthrenium salts. D This work: intermolecular organoelectrocatalytic cyclopropanation.

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The non-carbenoid approach, such as Kulinkovich reaction35, Corey–Chaykovsky cyclopropanation36, represents an attractive alternative for the synthesis of cyclopropanes. In this context, only a limited number of novel C1 reagents have emerged to undergo [2 + 1] cyclopropanation of alkenes37,38,39,40,41,42,43,44. Among them, methylene compounds are the ideal C1 components for cyclopropyl ring construction, which are safe, abundant, and bench-stable. However, this ideal approach is still challenging. In 2022, Xu discovered an intramolecular electrocatalytic cyclopropanation of alkenes with active methylene compounds using a phenothiazine catalyst (Fig. 1B)45. However, the intermolecular cyclopropanation cannot achieve using this electrocatalytic system. Subsequently, an intermolecular cyclopropanation of alkenes with alkenyl thianthrenium salts in the presence of base was reported by Shu46 and Wickens47, independently (Fig. 1C). These thianthrenium salts have to be pre-made by thianthrenation of olefins using Ritter’s conditions48,49 or electrolysis50 in a divided cell. In 2023, Carreira and co-workers used α-bromo-β-ketoesters and α-bromomalonates as C1 reagents for the intermolecular photocatalytic cyclopropanation of alkenes with α-bromo-β-ketoesters51. Recently, Giri and co-workers disclosed an elegant intermolecular cyclopropanation of olefins with active methylene compounds bearing two electron-withdrawing groups enabled by photosensitized O2 (Fig. 1D)52. Despite these advances, novel catalytic methods for cyclopropanation with two abundant substrates, mild conditions, high functional group tolerance, and broad scope are still highly desirable.

Herein, we detail the discovery on the use of organic electrochemistry53,54,55,56,57,58 as a sustainable synthetic tool for the intermolecular cyclopropanation of alkenyl trifluoroborates with methylene compounds (Fig. 1D). Notably, this approach uses cheap diphenyl sulfide as the electrocatalyst under base-free conditions. In contrast to previous reports, this method allows for cyclopropanation of challenging substrates, such as styrenes, 1,3-dienes, base-sensitive substrates, and methylene compounds bearing a single electron-withdrawing group.

Results

Optimization of the reaction conditions

We chose two commercially available reagents, benzoylacetonitrile 1 and vinyltrifluoroborate 2, as the model substrates to investigate the electrochemical conditions. As illustrated in Table 1, we determined that 1 reacted efficiently with 2 when performed in an undivided cell in CH3CN/H2O (50/1) at room temperature using PhSPh as the catalyst, nBu4NPF6 (1.0 equiv) as the electrolyte, and C(+)/Pt(-) as the electrodes (entry 1). Other electrode materials also worked for this transformation giving cyclopropane 3 in diminished yields (entries 2–4). Notably, switching from Pt to Ni cathodes allowed for a 90% yield of product 3 to be obtained (entry 5). Other solvents such as CH3OH, DMF, DMSO, or CH2Cl2 failed to provide any desired product 3 (entry 6). Using nBu4NBF4 as the electrolyte instead resulted in a reduced yield (entry 7). The desired product 3 could be isolated in 76% yield in the absence of nBu4NPF6 (entry 8), indicating that the vinyltrifluoroborate salt 2 can act as the supporting electrolyte as well. In addition, the optimal loading of vinyltrifluoroborate 2 was determined to be 2.0 equiv (entries 9&10 vs entry 1), since the amounts of trifluoroborate salt could affect the pH of the reaction medium59 and thus further influence the reaction performance. While shorting the reaction time led to incomplete conversion (entry 11), extending the reaction time resulted in a reduced yield probably due to product decomposition (entry 12). Further optimizing the applied current proved that lower yields were observed with a reduced or increased current (entries 13&14). Finally, several control experiments revealed that water, PhSPh, and electricity were all crucial for the success of this cyclopropanation (entries 15–17).

Table 1 Optimization of the reaction conditions
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Substrate scope

With the optimized conditions in hand, the scope of this electrochemical cyclopropanation was explored, as outline in Fig. 2. A variety of β‑ketonitriles readily underwent the desired cyclopropanation with vinyltrifluoroborate 2 (Fig. 2A). Pleasingly, aryl halides including para-fluorophenyl, para-chlorophenyl, ortho-bromophenyl were inert under these electrochemical oxidative conditions, providing the desired cyclopropanes 4–6 in good to high yields. β‑Ketonitriles bearing electron-deficient and electron-rich arenes showed similar reactivity, providing the desired products 7–12 in good to excellent yields. Sterically hindered ortho-substituted aryl β‑ketonitriles were less reactive, but 6 and 12 could still be obtained in 68% and 64% yield, respectively. Alkyne and alkene functional groups remained intact under the standard conditions to afford cyclopropanes 13–16 in reasonable yields. Notably, no intramolecular cyclopropanation was observed (15), indicating that the reaction may proceed in a different pathway from Xu’s previous report45. Aryl β‑ketonitriles bearing naphthyl ring, quinoline, pyridine, indole, thiophene, and furan were amenable, leading to the desired products 17–23. In addition, alkyl-substituted β‑ketonitriles also worked smoothly, affording cyclopropanes 24 and 25 in moderate yields.

Fig. 2: Substrate scope.
figure 2

A Scope of β‑ketonitriles. B Scope of methylene compounds with two EWGs. C Scope of methylene compounds with one EWG. D Scope of cyclic methylene compounds. E Scope of vinyl trifluoroborates. aPhSPh (0.2 mmol 1.0 equiv), 2.5 h, air. bPhSPh (0.2 mmol 1.0 equiv), 4.0 h, under N2. cPhSPh (0.3 mmol 1.5 equiv), 3.0 h, air.

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Besides these β‑ketonitriles, the cyclopropanation reaction could be also extended to other active methylene compounds with two electron-withdrawing groups (Fig. 2B). To our delight, a variety of methylene compounds including cyanoacetates (26–28), cyanoacetamides (29 and 30), 2-sulfonyl acetonitriles (31), 2-tosyl acetates (32), bis(sulfonyl)methanes (33), β-ketosulfones (34), 1,3-diketones (35 and 36), β-ketoesters (37), malonates (38), β-ketoamides (39), α-nitroketones (40), and β-keto sulfonyl fluorides (41) reacted smoothly with vinyltrifluoroborate 2 to generate the expected cyclopropanes 26–41. Of note, highly base-sensitive benzyl chlorides (27) were well-tolerated. Moreover, olefins (28, 32), esters (37, 38), ketones (35, 36), amides (29, 30), nitro groups (40), and sulfonyl fluorides (41) survived under our conditions, allowing further diversification of these cyclopropane products via known protocols, such as sulfur(VI)−fluoride exchange (SuFEx) click chemistry60,61,62,63,64,65.

Subsequently, we evaluated the scope with respect to methylene compounds with only one electron-withdrawing group (Fig. 2C). Arylacetonitriles (42), arylacetones (43), and α‑aryl esters (44 and 45) could react successfully with 2. A pyridinyl-substituted acetonitrile was also successfully converted to the desired product 46 in 57% yield. Interestingly, phenylmethanesulfonyl fluoride (PMSF), a well-known serine protease inhibitor, was well-accommodated under the standard conditions to give cyclopropyl sulfonyl fluoride 47. The α‑aminoacetonitriles afforded the 3-membered adduct 48 in 59% yield. Notably, an amino acid Schiff base, which was shown to be unsuitable for previous method47, was also compatible under our electrochemical conditions, leading to cyclopropyl-substituted α‑amino acid derivative 49. Moreover, α-(N-pyrrolyl)ketones were suitable substrates, as illustrated by the isolation of cyclopropane product 50 in 67% yield.

Cyclic methylene compounds would be interesting substrates for our electrocatalytic cyclopropanation, as the resulting spirocyclic molecules may find applications in medicinal chemistry and agrochemical discovery. As shown in Fig. 2D, a variety of cycylic methylenes including 5,5-dimethylcyclohexane-1,3-dione, 1,3-indandione, 4-hydroxycoumarin, benzo[b]thiophen-3(2H)-one 1,1-dioxide, edaravone, 2,4-dihydro-3H-pyrazol-3-ones, 3-phenylisoxazol-5(4H)-one, 2-phenyloxazol-5(4H)-one, 2-coumaranone, 3-coumaranone, 1-indanone, and 2-oxindole were subjected to the electrochemical conditions and delivered the desired spirocyclopropanes 51–62 in moderate to good yields.

We then explored the scope of this electrocatalytic cyclopropanation with respect to alkenyltrifluoroborates (Fig. 2E). Various styrenyl trifluoroborates bearing either electron-donating (-Me) or electron-withdrawing (-Cl, -F, -CF3, -CO2Me) groups furnished the desired cyclopropanes 63–69 in reasonable yields. In addition, thiophene and pyridine motifs were also tolerated to afford the corresponding cycylopropanes 70 and 71. Notably, 1,3-dienyl trifluoroborates were also appropriate coupling partners to give 72 and 73. Alkyl-substituted vinyltrifluoroborates underwent the desired process to provide 74–78. It is worth highlighting that sterically challenging trisubstituted olefins were also applicable to this electrochemical cyclopropanation affording tetrasubstituted cyclopropane 76 and spirocyclopropane 77. Overall, synthetically useful yields could be obtained for most challenging substrates with a catalytic amount of PhSPh, the use of stoichiometric mediator is typically required to achieve better reaction performance.

Mechanistic studies

We envisioned two reaction pathways for the possible mechanism of this electrocatalytic cyclopropanation (Fig. 3A). The first commences by formation of the radical cation from the anodic oxidation of PhSPh (Fig. 3A, pathway A). This sulfide radical cation undergoes a single electron transfer with benzoylacetonitrile 1 to generate electrophilic C-radical I. Radical ipso-addition to vinyltrifluoroborate 2 forms radical intermediate II, which is known under photoredox conditions66. Under the electrochemical conditions, the intermediate II is then trapped by sulfide radical cation via a radical-radical coupling process. The resultant sulfonium intermediate III sets the stage for a subsequent nucleophilic substitution reaction. The intramolecular substitution delivers cyclopropyl trifluoroborate IV, which can be facilely converted to radical V through a one-electron oxidation process. After the C–B bond cleavage, a hydrogen atom transfer (HAT) from water to the alkyl radical V eventually furnishes the final product 3. An alternative reaction pathway involving the formation of a vinyl sulfonium salt intermediate must be considered (Fig. 3A, pathway B). Reaction of sulfide radical cation with vinyltrifluoroborate 2 generates a β-boron radical i, which undergoes a single electron oxidation and C–B bond cleavage to form vinyl sulfonium salt ii and BF366,67, The intermediate ii, a known Michael acceptor, reacts with nucleophile 1 to give sulfur ylide iii. Subsequently, a proton transfer from water produces sulfonium iv. Cyclization of intermediate iv eventually delivers the desired cyclopropane 3.

Fig. 3: Mechanistic studies and proposal.
figure 3

A Mechanistic proposal. B Control experiment. C Radical clock expriment. D Cyclic voltammogram experiments. E Isolation of the possible intermediate. F Deuterium incorporation experiments.

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In this regard, a mixture of alkene-tethered substrate 79 and trifluoroborate 2 was subjected to the electrolysis conditions to trap a putative intermediate 80 on the pathway A (Fig. 3B). No intramolecular cyclopropanation was observed and 15 was obtained instead, indicating the carbon radical intermediate 80 was not formed. A radical clock reaction using cyclopropylethenyl trifluoroborate 81 as radical acceptor further confirmed α-carbon radical I could not be generated from benzoylacetonitrile 1, as no ring-opened product was detected (Fig. 3C). Cyclic voltammetry (CV) experiments displayed no oxidation peak of benzoylacetonitrile 1 at 0–3.0 V (Fig. 3D), ensuring that benzoylacetonitrile 1 could not be oxidized under the standard conditions. Taken together, the pathway A, proceeding via oxidation of benzoylacetonitrile 1 and subsequent radical addition with α-carbon radical I, is unlikely.

On the other hand, pathway B accounts for these experimental studies. CV studies revealed the addition of 2 to the PhSPh solution resulted in the disappearance of the oxidation peak of PhSPh (Fig. 3D), suggesting that the electrochemical generated [PhSPh]•+ was trapped by vinyltrifluoroborate 2. Furthermore, the key intermediate, diphenyl vinyl sulfonium salt 82, was successfully isolated in 45% yield, when the counter anion was switched from PF6– to TfO– (Fig. 3E, eq 1). When this intermediate 82 was subjected to the electrolysis conditions or stoichiometric Cs2CO3, the desired product 3 was isolated in 27% or 90% yield, respectively (Fig. 3E, eq 2). When D2O was used in place of H2O, the deuterated product 52-D was isolated in 57% yield with 96% deuterium incorporation from the cyclopropanation of 1,3-indandione 83 (Fig. 3F, eq 1). In a parallel experiment using CD3CN instead of CH3CN, product 52 was obtained in 60% yield without deuterium incorporation (Fig. 3F, eq 1). When we subjected deuterated 1,3-indandione 83-D to the cyclopropanation conditions, no deuterium was detected in the product 52 (Fig. 3F, eq 2). These outcomes support that water is involved in the reaction process as the terminal hydrogen atom source. Whereas HAT from water is challenging due to the high bond dissociation energy68, deprotonation of water can be feasible with the intermediate iii. These mechanistic studies strongly supported that the electrochemical cyclopropanation followed reaction pathway B, as illustrated in Fig. 3A.

In conclusion, we have developed an electrochemical cyclopropanation of alkenyl trifluoroborates with methylene compounds. This transformation utilizes simple diphenyl sulfide as the electrocatalyst under base-free conditions, and thus shows broad scope with various methylene compounds as well as substituted vinyltrifluoroborates. Notably, challenging substrates, such as styrenyl, 1,3-dienyl, fluorosulfonyl, and base-sensitive substrates, have been successfully employed in this approach.

Methods

General procedure for the cyclopropanation

General procedure A

A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with the methylene substrate (0.2 mmol, 1.0 equiv.), potassium alkenyl trifluoroborate (0.4 mmol, 2 equiv), PhSPh (0.04 mmol, 20% mmol) and nBu4NPF6 (0.2 mmol, 1 equiv.). The Schlenk tube was equipped with graphite plate (10 mm × 10 mm × 2 mm) as the anode and Pt plate (10 mm × 10 mm × 0.1 mm) as the cathode. CH3CN (5.0 mL) and H2O (0.1 mL) were added. The mixture was electrolyzed at a constant current of 8 mA at room temperature for 2.5 h. The solvent was then removed under vacuum to give a residue, which was purified by flash column chromatography on silica gel (eluent, petroleum ether/ethyl acetate = 50:1 − 4:1 V/V) to afford desired products 3–12, 17–18, 21–27, 30–31, 33–35, 40, 43, 51–52, 54, 74.

General Procedure B

A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with the methylene substrate (0.2 mmol, 1.0 equiv.), potassium alkenyl trifluoroborate (0.4 mmol, 2 equiv), PhSPh (0.2 mmol, 100% mmol) and nBu4NPF6 (0.2 mmol, 1 equiv.). The Schlenk tube was equipped with graphite plate (10 mm × 10 mm × 2 mm) as the anode and Pt plate (10 mm × 10 mm × 0.1 mm) as the cathode. CH3CN (5.0 mL) and H2O (0.1 mL) were added. The mixture was electrolyzed at a constant current of 8 mA at room temperature for 2.5 h. The solvent was then removed under vacuum to give a residue, which was purified by flash column chromatography on silica gel (eluent, petroleum ether/ethyl acetate = 50:1 − 4:1 V/V) to afford desired products 13–16, 19–20, 29, 32, 37–39, 41, 46, 50, 53, 57–58, 60, 64–69, 71, 73–75, 77–78.

General procedure C

A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with the methylene substrate (0.2 mmol, 1.0 equiv.), potassium alkenyl trifluoroborate (0.4 mmol, 2 equiv), PhSPh (0.3 mmol, 150% mmol) and nBu4NPF6 (0.2 mmol, 1 equiv.). The Schlenk tube was equipped with graphite plate (10 mm × 10 mm × 2 mm) as the anode and Pt plate (10 mm × 10 mm × 0.1 mm) as the cathode. CH3CN (5.0 mL) and H2O (0.1 mL) were added. The mixture was electrolyzed at a constant current of 8 mA at room temperature for 3 h. The solvent was then removed under vacuum to give a residue, which was purified by flash column chromatography on silica gel (eluent, petroleum ether/ethyl acetate = 50:1 − 4:1 V/V) to afford desired products 28, 32, 36, 41–42, 44–45, 47–49, 53, 56, 59, 61–63, 70, 72, 76.