Water‐Catalytic Deconstructive and Proton Transfer Cyclopropanation of Sulfoxonium Ylide with Olefin

Abstract

Cyclopropane rings, with their distinct structure and reactivity, have long been a focus in organic chemistry and are significant pharmacophores in medicinal chemistry. Conventional direct cyclopropanation methods for olefins do not modify the functional groups on the α‐ or β‐carbon of olefins. Herein, a novel deconstructive cyclopropanation reaction is designed for olefins using a close–open–close ring strategy. This enables the migration of functional groups to the α‐ or β‐carbon of olefins, leading to the formation of regioselective cyclopropane compounds, which is a previously unreported approach. By exploiting the zwitterionic property of sulfoxonium ylides and combining them with Density Functional Theory (DFT) computations, the reaction is proposed to proceed via a [2 + 2] cycloaddition to form a strained cyclobutene intermediate, followed by cyclobutane ring‐opening and nucleophilic substitution through a water‐involved proton‐shuttle process for ring closure. Hydrogen‐bonding interactions play a significant role in controlling the regioselectivity.

Water‐catalytic deconstructive and proton transfer cyclopropanation of sulfoxonium ylide with olefin is developed through a sequential water‐mediated ring‐closing/opening reaction. This atom‐economical, environmentally friendly methodology offers easy access to a range of cyclopropyl ketones with moderate to good yields.

1. Introduction

The unique structure and reactivity of cyclopropane rings have long been the focus of attention for organic chemists. This strained three‐membered carbon ring can react with nucleophilic reagents, electrophilic reagents, and radical compounds.^{[ 1 ]} In addition, the conformational rigidity of cyclopropane and the highly directional spatial arrangement of its substituents make it an important pharmacophore in medicinal chemistry.^{[ 2 ]}

Popular methods for the direct cyclopropanation of olefins can be divided into three main groups: 1) halomethylmetal‐mediated cyclopropanation, e.g. Simmons–Smith reaction; 2) transition‐metal catalyzed decomposition of carbene precursors (diazo compounds, ketones, etc); 3) Michael reaction‐initiated ring closure (MIRC).^{[ 3 ]} Direct cyclopropanation does not alter the functional groups on the α‐ or β‐carbon of olefins. Recently, the deconstruction of cycloalkane derivatives by ring‐opening constitutes a highly attractive scaffold hopping strategy in organic synthesis.^{[ 4 ]} Herein, we propose a deconstructive cyclopropanation reaction that employs the close‐open‐close ring strategy for the cyclopropanation of olefins. This enables the migration of functional groups from one carbon skeleton to the α‐ or β‐carbon of olefins, thereby achieving regioselective synthesis of cyclopropane compounds. To date, such a cyclopropanation strategy has remained unreported (Scheme 1a).

Scheme 1.

Cyclopropanation Strategies.

Sulfoxonium ylides have been widely employed as one‐carbon synthons in numerous classical transformation reactions.^{[ 5 ]} Sulfoxonium ylides can serve either as a carbene precursor for the cyclopropanation of olefins catalyzed by transition metals, or as a nucleophilic 1,1‐dipolar species to undergo cyclopropanation with olefins^{[ 6 ]} (Scheme 1b). All the obtained products are direct cyclopropanation products where the functional groups remain at their original positions on the olefins, without migration from other carbon skeletons.

Sulfoxonium ylides are a class of zwitterionic compounds characterized by a carbanion adjacent to a positively charged sulfur atom.^{[ 5 ]} Leveraging this property, we designed a strategy of closing‐opening‐closing the ring for the cyclopropanation of olefins, enabling the migration of functional groups and regioselectively obtaining cyclopropane compounds. The specific process is as follows: 1) Olefins undergo [2 + 2] cycloaddition to form highly strained cyclobutanes,^{[ 7 ]} which provides the driving force for subsequent reactions; 2) The ring strain prompts the ring‐opening of the cyclobutane; during this process, bond reorganization triggers the migration of functional groups, and the regioselectivity is further regulated to determine the direction of functional‐group migration^{[ 8 ]}; 3) The ring‐opened intermediate undergoes nucleophilic substitution to regenerate the cyclic structure via a water‐mediated proton‐shuttle process, ultimately directing the functional group to the α‐ or β‐carbon of the olefin with high regioselectivity. Notably, H₂O serves as a proton‐transfer reagent to achieve proton transfer within the deconstructive intermediate (Scheme 1c).^{[ 9 ]}

2. Results and Discussion

Our initial attempt involved the deconstructive and proton transfer cyclopropanation reaction of sulfoxonium ylide 1a and alkene 2a by using H₂O in DMSO. When the reaction was performed at 100 °C for 12 h (Table 1 , entry 1), the envisioned 1,1‐disubstituted cyclopropyl ketone 3a was obtained in 50% isolated yield. Based on these results, we continued to optimize the reaction conditions. Increasing the amount of water significantly improved the product yield, when DMSO/H₂O (1/1) as solvent, product 3a was obtained in 78% isolated yield (Table 1, entries 2–4). Solvent screening revealed that DMSO/H₂O (1/1) was the best solvent; by contrast, using only H₂O (0.5 mL) as the solvent still afforded a 75% isolated yield. DMSO not only elevated the boiling point of the reaction solvent but also enabled homogeneous reaction conditions. And product 3a could not be obtained in the absence of H₂O (entry 9). The optimum temperature was confirmed as 100°C (entries 13–17). Extending sulfoxonium ylide 1a to 1.2 equivalents did not increase the yield of 3a (entry 18). Substitution of H₂O with CH₃COOH or CH₃CH₂OH afforded the target product with reduced yields (entry 19–20).

Table 1.

Optimized Reaction Conditions. ^a) , ^b) , ^c) , ^d) , ^e) , ^f)

				Yield (%) b)
Entry	Solvent	H2O (X equiv.)	T (°C)	3a	3a’
1	DMSO	10	100	50	40
2	DMSO	100	100	60	37
3	DMSO/ H2O (4/1)	—	100	65	26
4	DMSO/ H2O (1/1)	—	100	78	15
5	DMF/ H2O (1/1)	—	100	63	35
6	PhCH3/ H2O (1/1)	—	100	35	25
7	DCE/ H2O (1/1)	—	100	20	28
8	CH3CN/ H2O (1/1)	—	100	30	25
9	DMSO	Trace	100	nd c	40
10	H2O	—	100	64	20
11	H2O (0.5 mL)	—	100	75	20
12	H2O (0.2 mL)	—	100	70	20
13	H2O (0.5 mL)	—	90	70	20
14	H2O (0.5 mL)	—	80	64	16
15	H2O (0.5 mL)	—	70	50	15
16	H2O (0.5 mL)	—	60	42	10
17	H2O (0.5 mL)	—	25	nd	nd
18 d)	H2O (0.5 mL)	—	100	73	20
19 e)	DMSO	Trace	100	30	45
20 f)	DMSO	Trace	100	15	40

^a) Reaction conditions: In a 5 mL reaction tube, sulfoxonium ylide 1a (0.2 mmol), olefin 2a (0.2 mmol), solvent 1 mL, under air (1 atm), stirred for 12 h at T °C;

^b) Isolated yield of 3a based on 2a;

^c) nd means not detected;

^d) Addition of sulfoxonium ylide 1a (0.24 mmol);

^e) Addition of CH₃COOH (2.0 mmol);

^f) Addition of CH₃CH₂OH (2.0 mmol).

Under optimized reaction conditions, the scope of sulfoxonium ylides (1) was investigated with a variety of olefins (2). A range of olefins was first examined (Table 2 ). The reaction generally tolerated a broad range of substituted benzyl acrylates (3b–3f: R = p‐F, p‐Br, p‐Cl, p‐Me or p‐OMe) to afford high to better yields of the corresponding cyclopropane. Moreover, the cascade reaction produced equally satisfactory results by using a range of acrylates (3g–3m). A study on the electronic influence of the group indicated that although the alkyl substituents with different carbon numbers groups worked well and resulted in good yields (3i–3m), groups containing benzene achieved a higher yield (3d, 90% yield). Notably, both N,N‐dimethylacrylamide 2n and 3‐Oxo‐3‐phenylpropene 2o can be introduced as substrates in this reaction and showed a good yield. Compared to 3a, the enhanced electron‐withdrawing character of phenoxy and phenyl groups in 3g and 3o relative to the benzyloxy group contributes to their improved yields. Afterwards, electron‐deficient alkenes lacking acyl groups (acrylonitrile 2p and phenyl vinyl sulfone 2q) were introduced as reaction substrates. Fortunately, both obtained their counterparts in acceptable yields. Noteworthy, olefin 2r contains an additional alkene group, the target product still was obtained in a high yield, and no extra olefin was reacted to be detected. This indicates that the reaction exhibits good chemical selectivity. The olefin 2s bearing additional carbonyl group demonstrates a lowered yield of the target product, whereas the olefin 2t containing an additional reactive CH₂ group successfully facilitates the formation of the desired product without transformation of the reactive CH₂ group. Conventional cyclopropanation methods often suffer from regioselectivity issues when multiple CH₂ groups are present, leading to the formation of cyclopropanes at various positions. In contrast, our approach achieves selective cyclopropanation at specific sites while preserving other CH₂ moieties intact.^{[ 10 ]} Olefins containing DL‐menthol and cholesterol efficiently delivered the desired products 3u and 3v in moderate to moderate yields. To verify the structure of the cyclopropyl ketones, 3d ^{[ 11 ]} was selected as the representative compound and was characterized by X‐ray crystallography (Table 2, 3d).

Table 2.

Reaction Scope of Olefins. ^a) , ^b)

^a) Reaction conditions: In a 5 mL reaction tube, sulfoxonium ylide 1a (0.2 mmol), olefins 2 (0.2 mmol), H₂O 0.5 mL, under air (1 atm), stirred for 12 h at 100 °C;

^b) Isolated yield of 3 based on 1a.

Then, a wide range of sulfoxonium ylides were employed for reaction under the optimized conditions (Table 3 ). Single substitution at various positions underwent a smooth reaction under optimal conditions, furnishing the corresponding cyclopropane derivatives 4a–4k in 63–88% yields. Both electron‐donating and electron‐withdrawing sulfoxonium ylides were well tolerated and efficiently converted into the desired cyclopropanes with moderate to good yields. Compared with the electron‐donating group, the electron‐withdrawing group provided higher yields. Notably, nitro‐ and cyano‐substituted sulfoxonium ylides can also afford cyclopropanes in good yields. The disubstituted aryl sulfoxonium ylide gave the products 4l in 72% yield. The reaction condition was tolerant to furan, thiophene‐derived and naphthalene‐derived sulfoxonium ylides, furnishing products 4m, 4n and 4o in 75%, 78% and 81% yield, respectively. The yield of alkyl sulfoxonium ylide is unsatisfactory, afforded the corresponding product 4p in only 59% yield.

Table 3.

Reaction Scope of Sulfoxonium Ylides 1. ^a) , ^b)

^a) Reaction conditions: In a 5 mL reaction tube, sulfoxonium ylide 1 (0.2 mmol), olefin 2a (0.2 mmol), H₂O 0.5 mL, under air (1 atm), stirred for 12 h at 100 °C;

^b) Isolated yield of 4 based on 1.

To gain insights into the reaction mechanism, we first conducted isotopic labeling experiments under the standard conditions (Scheme 2 ).^{[ 12 ]} The ¹H NMR spectrum of 1a in D₂O shows a complete D/H exchange of the carbonyl α C–H bond that reveals the reversible hydration of aqueous sulfoxonium ylides. The D/H ratio is 1/2 in the D₂O/H₂O (1/1) indicating that the reaction is primary kinetic isotope effect (Scheme 2a). When the reaction solvent was replaced with D₂O, deuterated products 3a‐d₂ and 3a'‐d₁ were obtained at 70% and 20% yields, respectively (Scheme 2b). Competitive kinetic isotope effect experiments demonstrated that H₂O addition to the intermediate exhibited a normal secondary kinetic isotope effect, accompanied by an irreversible rehybridization from sp³  to sp² (Scheme 2c). Parallel kinetic isotope effect experiments revealed that the H₂O addition step was not rate‐determining step in this catalytic cycle (Scheme 2d). When 1a and 2a were reacted separately in H₂O and D₂O for one hour, the ¹H NMR spectrum of mixture showed significant D/H exchange at the CH₃ group of 1a (Scheme 2e). Monitoring 3a and the by‐product 3a' under initial conditions revealed that 3a formed prior to 3a', indicating kinetic preference for 3a (Scheme 2f). Replaced sulfoxonium ylide with other sulfur ylides, and the reaction cannot occur (Scheme 2g). Neither sulfoxonium ylides with an α‐C substituent nor non‐terminal alkenes afforded the target product (Scheme 2h).

Scheme 2.

Mechanistic studies.

On the basis of these results and control experiments, we propose a plausible H₂O catalytic cycle for water‐catalytic deconstructive and proton transfer cyclopropanation of sulfoxonium ylide 1 with alkene 2 (Scheme 3 ). To more intuitively illustrate proton transfer in the reaction mechanism, we employed D₂O instead of H₂O for mechanistic diagram construction. The proposed mechanism initiates with a Michael addition between sulfoxonium ylide (1a) and benzyl acrylate (2a), yielding intermediate I. This intermediate subsequently undergoes intramolecular nucleophilic attack on the benzoyl carbonyl group, generating the zwitterionic cyclobutane intermediate II. Compared with cyclopropane, cyclobutane exhibits lower ring strain. Intermediate I preferentially undergoes subsequent transformation to form the less strained cyclobutane intermediate II. Following this, intermediate II participates in a cyclobutane ring‐opening by the alkoxide process to form the intermediate III. The reaction cascade continues through a water‐mediated 1,3‐proton transfer from intermediate III to intermediate IV, which subsequently undergoes a second proton transfer to afford intermediate V.^{[ 13 ]} Eventually, the ring was closed in intramolecular to form the cyclopropyl ketone 3a and release DMSO. The H₂O‐mediated proton transfer facilitates the formation of a carbanion intermediate between the two carbonyl groups, which ultimately drives cyclopropane ring closure rather than promoting dihydrofuran derivative formation through carbonyl group reactivity.^[7a] Deuterated intermediates are captured for the reaction by HRMS.

Scheme 3.

Proposed mechanism.

To further validate the proposed reaction mechanism, density functional theory (DFT) calculations were performed (Figure S3, Supporting Information). The computational results reveals that water‐assisted formation of the cyclobutane intermediate is energetically favored over cyclopropane product formation. The first Michael addition via the transition state TS1 with an activation barrier of 20.8 kcal mol⁻¹ is the rate‐determining step. Subsequently, the intramolecular nucleophilic addition to the carbonyl group of the benzoyl group generates the four‐membered ring cyclic intermediate int3, through a low activation barrier of 13.9 kcal mol⁻¹. Notably, a competing pathway involving a conventional three‐membered ring transition state TS2R produces the by‐product, with a higher activation barrier of 16.8 kcal mol⁻¹ (Scheme 4 ). The preferred cyclobutene pathway can be rationalized by stronger hydrogen‐bonding interactions in the transition state, as supported by the shorter distance between water molecule and carbonyl oxygen (1.7 Å). Intriguingly, Without water, the activation barrier becomes higher for the cyclobutane pathway than for the cyclopropane route (10.0 vs 8.4 kcal mol⁻¹). leading to reversed selectivity that aligns with conventional reaction outcomes. These findings demonstrate that hydrogen‐bonding interactions serve as critical determinants in controlling the reaction.

Scheme 4.

Structures of transition states with water (TS2R and TS‐by) and without water (TS2R‐A and TS‐by‐A). Bond lengths are in angstroms.

In order to further demonstrate the synthetic potential of this method, we performed a gram‐scale flow synthesis of 1‐benzoylcyclopropane‐1‐carbonitrile 3p with the utilization of sulfoxonium ylide (1a) and Acrylonitrile (2p), as shown in Scheme 5 .^{[ 14 ]} By applying a flow rate of 1 mL h⁻¹ and a residence time as short as 12 hours, we were able to scale up the reaction process by 25‐fold. The collected reaction solution, after workup and purification, afforded the corresponding cyclopropyl ketone product 3p in acceptable yield (62%). The subsequent conversion of 1‐benzoylcyclopropane‐1‐carbonitrile, the organocatalytic Cloke–Wilson rearrangement of cyclopropyl ketones 3p to 2,3‐dihydrofurans was exploited utilizing the homoconjugate addition process; selective reduction of 3p with NaBH₄ afforded β‐hydroxynitrile 6; the acid‐promoted alcoholysis of 3p in methanol gave cyclopropyl ketones 3i and the hydrolysis of 3p gave carboxylic acid 7, all proceeded smoothly, which further proved the potential synthetic value of this protocol.

Scheme 5.

Gram‐Scale Reaction in Continuous‐Flow and Functionalizationa: Reaction conditions: ^a) In a 10 mL reaction tube, 3p (0.2 mmol), DABCO (0.1 mmol), DMSO 2 mL, under N₂ (1 atm), stirred for 12 h at 120 °C. ^b) In a 10 mL reaction tube, 3p (0.2 mmol), NaBH₄ (0.6 mmol), MeOH 2 mL, under Air (1 atm), stirred for 2 h at room temperature. ^c) In a 10 mL reaction tube, 3p (0.2 mmol), H₂SO₄ (0.5 mL), MeOH 2 mL, under Air (1 atm), refluxed for 12 h. ^d) In a 10 mL reaction tube, 3p (0.2 mmol), NaOH (0.6 mmol), MeOH/H₂O (3/1) 2 mL, under Air (1 atm), stirred for 12 h at 65 °C. ^e) In a 10 mL reaction tube, 3i (0.2 mmol), NaOH (0.6 mmol), MeOH/H₂O (3/1) 2 mL, under Air (1 atm), stirred for 12 h at 65 °C.

3. Conclusion

In summary, we demonstrated a water‐catalytic deconstructive and proton transfer cyclopropanation of sulfoxonium ylide with olefin. The reaction is performed with the utilization of sulfoxonium ylides and olefins as starting materials under simple and mild reaction conditions, delivering 1,1‐disubstituted cyclopropyl ketones in 57–90% yields. Control experiments and DFT studies provided a plausible reaction mechanism of response in which H₂O was involved in proton transfer. Moreover, this method was suitable for continuous‐flow synthesis, which provides an entry point for the industrial application.

Conflict of Interest

The authors declare no conflict of interest.

Supporting information

Supporting Information

Yu X., Huang L., Yang H., Song L., Jin Y., Water‐Catalytic Deconstructive and Proton Transfer Cyclopropanation of Sulfoxonium Ylide with Olefin. Adv. Sci. 2025, 12, e02430. 10.1002/advs.202502430

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.