Olefin isomerization-Michael addition cascade in aqueous micelles: a new piperazine-based antifungal chemotype

Abstract

Advancing sustainability and catalysis in synthetic organic processes has emerged as a central theme, driven by pressing environmental challenges associated with the manufacture of fine chemicals, pharmaceuticals, agrochemicals, and functional materials. At the core of this shift is the growing use of alternative reaction media, particularly water, and the adoption of energy-efficient processes, owing to their inherent advantages and superior environmental performance. In this context, we report a water-assisted olefin isomerization-Michael addition cascade reaction of functionalized β,γ-unsaturated olefins with amines in aqueous SDS micelles (2% w/w). The reaction proceeds at room temperature without the need for additional catalysts, additives, or activators, and demonstrates a broad substrate scope with excellent yields and functional group tolerance. Process scalability, recyclability of the aqueous micelles, 100% atom economy, and a low E factor further underscore the sustainability and efficiency of this methodology. Mechanistic studies establish that water plays a central role in enabling the amine-assisted olefin isomerization (β,γ → α,β) followed by Michael addition, likely through stabilization of reactive intermediates via water-mediated hydrogen-bonding networking. The resulting nitrile-containing piperazine derivatives were evaluated for antifungal activity. Compounds 3g and 3h demonstrated promising antifungal activity, showing molecular synergy with fluconazole and inducing ROS-mediated fungal growth inhibition, an important mechanistic strategy for combating fungal infections. Furthermore, these compounds demonstrated efficacy against a rapidly growing, drug-resistant clinical strain of Candida auris, a pathogen ranked as a critical priority by the WHO. Overall, our findings reaffirm the growing importance of sustainable chemistry in shaping the future of drug discovery and development.

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Green foundation

1. This work advances green chemistry by establishing a metal-free, additive-free, room-temperature synthesis of antifungal chemotypes using micellar catalysis in water. The hydrogen-bond-driven olefin isomerization-Michael addition cascade avoids harmful solvents, precious metals, and harsh reagents, thereby enhancing atom economy and energy efficiency. This sustainable approach delivers bioactive molecules effective against drug-resistant Candida auris, underscoring its environmental advantages and therapeutic potential in antifungal drug discovery.

2. The reaction proceeds under ambient conditions with a low E-factor, indicating minimal waste generation. The process is scalable and conducted in recyclable aqueous micelles, eliminating the need for organic solvents. No external base, additive, or metal catalyst is required, reducing environmental and safety hazards.

3. While the methodology is already highly sustainable, it could be further enhanced by switching to bio-derived surfactants for micelle formation, thereby improving biodegradability and reducing reliance on petroleum-based components.

Introduction

The integration of green chemistry into organic synthesis and medicinal chemistry is revolutionizing both academia and industry by fostering innovation in drug discovery and development while advancing sustainability and environmental stewardship.¹ At the core of this shift is the increasing use of alternative reaction media and energy-efficient processes, which enhance both productivity and environmental performance.² In this context, the use of water as a non-classical solvent is gaining significant attention owing to its safety, non-flammability, abundance, and low cost.³ Moreover, water's unique chemical and physical properties often enable reactivity and selectivity that are difficult to achieve in conventional organic solvents.⁴ Consequently, aqueous-phase organic transformations have been increasingly applied in the synthesis of fine chemicals (pharmaceuticals, agrochemicals), functional materials, and biomolecular synthesis as well as their modifications.⁵

While conducting organic reactions in water is highly attractive, it presents several challenges, including the poor solubility of organic substrates, reagents, and catalysts, which limits overall efficiency and productivity. In addition, many substrates and catalytic systems are susceptible to degradation or deactivation in aqueous media, often resulting in reduced yields.⁶ Water itself may also promote side reactions that compromise both the reactivity and selectivity of the process.

To overcome these limitations, surfactant-based systems have been developed in which surfactants (amphiphiles) self-assemble in water to form micelles, which enables the reactions in aqueous media efficiently (micellar catalysis).⁷ These nanosized aggregates possess hydrophobic interiors that solubilize organic substrates, concentrate reactants, and often accelerate transformations through nano-confinement and unique micro-environmental effects. As a result, micellar catalysis has emerged as a powerful strategy, facilitating organic reactions in water with improved yields, selectivity, and sustainability.⁷ In this direction, current research is increasingly directed toward designing new surfactants that not only rival but often surpass traditional organic-solvent-based methodologies in both efficiency and scope.⁸

In this context, we report a water-assisted olefin isomerization-Michael addition cascade of functionalized β,γ-unsaturated olefins with amines in aqueous SDS micelles (2% w/w). The reaction proceeds at room temperature without the need of additional catalysts, additives, or activators, and exhibits broad substrate scope with excellent yields and functional group tolerance. Process scalability, recyclability of the aqueous micelles, 100% atom economy, and a low E factor further underscore the sustainability and efficiency of this methodology. Mechanistic investigations reveal that water plays a central role in enabling amine-assisted olefin isomerization (β,γ → α,β) followed by Michael addition, likely through stabilization of reactive intermediates via water-mediated hydrogen-bonding networks. This conclusion is supported by control reactions in organic solvents, isotopic substitution experiments (H₂O vs. D₂O), and NMR monitoring of reaction progress.

The resulting nitrile-containing piperazine derivatives were evaluated for antifungal activity. The selected compounds (3g & 3h) displayed promising anti-fungal effects, synergistic interactions with fluconazole, and ROS-mediated mechanisms of action, an important strategy to combat fungal infections. Notably, these compounds were effective against a rapidly growing, drug-resistant clinical strain of Candida auris, a WHO-designated “critical priority” pathogen. This outcome highlights the potential of sustainable chemistry to drive the discovery of new antifungal agents. This finding also underscores the transformative potential of sustainable chemistry to positively impact modern drug discovery and development.

Results and discussion

Reaction development and substrate scope

The study began by evaluating different aqueous micelles (2% w/w) for the model reaction between phenyl piperazine 1a and allyl nitrile 2a under catalyst- and additive-free conditions at room temperature (25–28 °C). A range of anionic, cationic, and non-ionic surfactants were tested, including vitamin E-derived PTS, TPGS-750-M, phytosterol-based SPGS-550-M, and cellulose-derived HPMC (hydrophobic polymer). While most aqueous micelles produced the desired product 3a in promising yields, the anionic surfactant sodium dodecyl sulfate (SDS) performed best, affording an isolated yield of 44% of 3a after 5 h, followed by SDOSS (39%). A control reaction conducted in pure water afforded a markedly lower yield (17%), underscoring the essential role of aqueous micelles in enhancing reaction efficiency (Fig. 1).

Fig. 1 (A) Evaluation of aqueous micellar systems for the cascade olefin isomerization-Michael addition reaction. (B) Summary of the final optimized reaction conditions. (C) Chemical structure of the selected surfactant, sodium dodecyl sulfate (SDS). The reaction temperature rt corresponds to 25–28 °C.

To further validate the selection of SDS, the surfactants were re-examined with a second representative substrate pair (allyl phenyl sulfone 4a and piperazine 1a). The results were consistent with the initial findings: SDS again outperformed all other surfactants under identical conditions, providing the highest yield of desired product 5a (41%) (Fig. 1). Additionally, SDS offers advantages of low cost, wide availability, and a well-characterized micellar environment. Thus, from both affordability and sustainability perspectives, SDS represents the most practical choice.⁹

With identified amphiphile, further optimization revealed that using aqueous SDS (2% w/w) at room temperature was optimal, leading to an 81% isolated yield of 3a after 24 hours (Fig. 1 and SI). Reactions performed at elevated temperatures (60–80 °C) showed modestly improved conversions, with yields reaching up to ∼86%, indicating that heating can be advantageous for less reactive substrate combinations.

Under the optimized conditions, the scope of the developed in-water protocol was systematically explored to assess its generality and potential for sustainable library synthesis (Fig. 2). Using compound 2a as a representative olefin, a wide range of piperazines were examined. Differently substituted phenyl piperazines underwent smooth reaction to the corresponding adducts (3a–3h) with excellent yields ranging (80–88%). The N-heteroaryl piperazines also furnished the desired products (3i, 3j) equally well with excellent yields. N-Benzyl (3k–3m) and N-benzhydryl (3n, 3o) analogues were efficient, affording the target compounds in high conversions and yields. These conversions demonstrated remarkable tolerance toward both electron-donating (–Me, –OMe) and electron-withdrawing (–NO₂, –CF₃, –CN) substituents, as well as halogens (–Cl, –F), underscoring the compatibility of diverse functional groups under mild, environmentally benign conditions. Functionalized derivatives such as N-benzoyl (3q), N-acetyl (3r), and N-Boc (3s) piperazines were well tolerated, highlighting the protocol's adaptability to electronically sensitive functionalities.

Fig. 2 Synthesis of structurally diverse library compounds was carried out under the optimized reaction conditions, and the reported yields correspond to isolated, purified products. Reaction scale: 0.2 mmol. Amount of olefin used: 0.3 mmol (1.5 equiv.). ^a 0.6 mmol (3 equiv.) of 2a was used. ^b Reactions were performed at 80 °C.

Next, the compatibility of allyl sulfones was examined using a series of functionalized piperazines. Under the optimized micellar conditions, allyl phenyl sulfone (4a) efficiently reacted with various substituted piperazines (16 examples) to afford the target adducts (5a–5p) in isolated yields of 68–82%. Other activated olefins such as allyl methyl sulfone (5q), butadiene sulfone (6a), and 3-butenoate (6b), also proved compatible, yielding the corresponding products in promising yields.

Towards the end, we extended the scope to other amines including morpholine (6c), thiomorpholine (6d), pyrrolidine (6e), amantadine (6f), cyclohexylamine (6g), ethanolamine (6h), propargylamine (6i), and others (6j & 6k). All these substrates participated readily, delivering the corresponding products in excellent yields.

Collectively, these results highlight the broad applicability, mildness, efficiency, and environmental compatibility of the developed in-water protocol (Fig. 2). Notably, some olefins such as allyl phosphonate (7a), allyl isocyanate (7b), and allyl isothiocyanate (7c) were non-productive under the standard conditions. While no reaction occurred with 7a, substrates such as 7b and 7c furnished the corresponding urea (8a, 85%) and thiourea (8b, 82%) derivatives in excellent yields (SI).

To the best of our knowledge, this work represents the first catalyst-free Michael addition of piperazine to β,γ-unsaturated nitriles or sulfones performed in water under mild conditions. Existing methods for constructing such scaffolds typically require Ru- or Mn-based catalysts,¹⁰ organic solvents,¹¹ or the use of the nucleophile as the reaction medium,¹⁰ and often involve strongly basic¹² or high-pressure thermal conditions (200–220 °C).¹³ In contrast, our protocol eliminates metal catalysts and harsh conditions, provides broad substrate scope with excellent functional-group tolerance, and offers a more sustainable alternative.

Process's scalability, recycling study, and green metrics calculations (sustainability assessment)

To evaluate the scalability of the protocol, gram-scale reactions (1 g) were conducted using the model substrate, yielding satisfactory results (Fig. 3 & SI). The recyclability of the spent SDS-containing aqueous medium was also assessed. After each reaction, a minimal volume of ethyl acetate was added, vortexed, and the supernatant containing the product and organic residues was carefully removed. The aqueous SDS layer was reused for three consecutive reaction cycles without any significant loss in 3a yield. However, a modest decline in yield was observed after the third cycle.

Fig. 3 Demonstration of (A) recyclability of the reaction system, (B) scale-up experimentation, and (C) calculation of green chemistry metrics.

Several factors appear to contribute to this effect. First, accumulation of ionic byproducts, possibly from leftover amines, reduces the solubility of SDS in water, resulting in a change in the extent of micelles’ aggregation and decreasing the availability of the hydrophobic core where the reaction occurs.¹⁴ This was confirmed by the particle size distribution analysis of the recycled aqueous SDS micelles after the 4^th run using a Zetasizer. The analysis revealed a substantial increase in average hydrodynamic diameter (2707 nm) compared to the reference SDS micelles (66 nm), indicating the change in the aggregation behavior of SDS surfactant, which likely contributed to the yield reduction. Second, residual organic impurities remaining after product extraction may accumulate within the hydrophobic core, altering the polarity and packing of the micelles and thereby diminishing their reaction efficiency. Finally, minor losses of surfactant during extraction and transfer steps inevitably lower the effective SDS concentration, further perturbing the micellar environment. Taken together, these factors likely account for the observed decrease in yield during repeated reuse of the micellar medium.

The assessment of key green chemistry metrics quantitatively substantiates the sustainability of the developed protocol.¹⁵ The reaction exhibits a 100% atom economy, indicating complete incorporation of all reactant atoms into the final product. Complementary parameters, including atom efficiency (81%), reaction mass efficiency (RME, 80.75%), E factor (24.61), and a process mass intensity (PMI) of 53.18, further highlight the resource-efficient and waste-minimizing nature of the transformation. These values collectively affirm the environmental compatibility and operational simplicity of the present in-water methodology (Fig. 3 and SI).

Investigation of water’ role

To delineate the role of water and micelles in the olefin isomerization/Michael addition cascade, we conducted a series of experiments under optimized conditions across a range of solvents with varying properties. In non-hydrogen-bond-donating solvents such as toluene, THF, DCE, and 1,4-dioxane (α = 0.00), the reaction was non-productive. In contrast, methanol (α = 0.97) gave 3a in 21% yield, indicating a modest benefit from hydrogen-bond donor capacity. Notably, water alone or D₂O alone did enable product formation, but in very low yields compared to aqueous SDS micelles (H₂O: 12% vs. SDS/H₂O: 81%). These findings highlight that while water is necessary, the aqueous micellar environment is critical to efficient reaction progression.

Additional insights come from solvent comparisons: trifluoroethanol (TFE, α = 1.51) failed to yield product despite being a stronger hydrogen-bond donor than water (α = 1.17). This contrast points to the importance of water's dual hydrogen-bond donor (HBD) and hydrogen-bond acceptor (HBA, β = 0.18) properties, which TFE lacks (β = 0.00)¹⁶ (Fig. 4A). Kinetic isotope effects further support this interpretation: the reaction was significantly slower in D₂O-based micelles than in H₂O micelles, and product formation in MeOH contrasted with the absence of product in CD₃OD.¹⁷ These results underscore the critical role of hydrogen-bonding networks in enabling the cascade reaction¹⁸ (Fig. 4B).

Fig. 4 Investigation of the role of water and the plausible reaction pathway leading to the product: (A) Reactions performed in organic solvents with varying α and β values. (B) Reaction kinetics showing differential isotopic rates. (C) D₂O-labeling experiment. (D) Examination of amine-assisted “in-water” olefin isomerization. (E) Evaluation of water-assisted Michael addition. (F) Proposed reaction mechanism leading to the final product.

To further elucidate the specific role of water in olefin isomerization, additional studies were performed. Allyl nitrile (2a) was stirred separately in aqueous micelles and in toluene at room temperature for varying time intervals (1, 2, and 3 h), and the reaction progress was monitored by ¹H NMR spectroscopy. No isomerized product (2b) was detected under either condition, suggesting that the presence of an amine (piperazine) is required to initiate the process. To confirm this, the isomerization of 2a was examined in the presence of the co-substrate, piperazine (1d), in aqueous micelles and in toluene over the same time intervals. In water, the isomerized product (2b) was observed by ¹H NMR at each time point along with the product (3d), whereas no formation of 2b occurred in toluene even after 3 h (Fig. 4D). This contrast strongly supports a base-assisted anionic pathway for olefin isomerization and rule out the possibility of electrophilic isomerization of olefin.¹⁹

Further evidence was obtained from C–H/D exchange experiments and pH monitoring of the reaction. The model reaction was conducted in D₂O-derived SDS micelles, and deuterium incorporation at the α-position of the nitrile was confirmed in the isolated product by ¹H and ²H NMR, consistent with an α-deprotonation-initiated isomerization pathway (Fig. 4C). Monitoring the pH of the reaction medium (2 wt% SDS in water, room temperature, unbuffered, standard reactant loading) revealed mildly basic conditions (initial pH = 11.54; final pH = 8.71), attributable to the amine substrate. Such conditions disfavor the carbocationic pathway (electrophilic isomerization) for olefin isomerization and instead support a base-mediated anionic pathway. Further, the absence of isomerization or product formation in toluene highlights the importance of water and the micellar environment. Stabilization of the transient α-cyanocarbanion is likely achieved through hydrogen-bonding networks provided by water molecules. In contrast, in nonpolar solvents such as toluene, the absence of hydrogen-bond donors/acceptors and the low dielectric constant preclude effective charge stabilization, rendering the anionic pathway unfavorable in toluene.

Next, we examined water's role in the Michael addition of piperazine (1d) to isomerized allyl nitrile (2b). Separate reactions were conducted in aqueous micelles and toluene, with progress monitored via¹H NMR spectroscopy at 1 h, 2 h, and 3 h intervals. In aqueous micelles, the formation of the desired product 3d was consistently observed, whereas no product formation was detected in toluene. These findings confirm that water plays a pivotal role in both the isomerization of olefin and the subsequent Michael addition, enabling the complete reaction sequence (Fig. 4E).

Based on literature precedents and our experimental observations, the plausible reaction pathway leading to the formation of 3a is outlined as follows. The initial olefin isomerization proceeds via an amine-assisted anionic pathway involving reversible α-deprotonation of 2a, transient α-cyanocarbanion formation, allylic rearrangement, and subsequent protonation by the corresponding conjugate acid (or water) to generate the isomerized olefin 2b (the Michael acceptor). Water-mediated hydrogen-bonding networks are proposed to stabilize the high-energy carbanion intermediate, thereby lowering the activation barrier and accelerating the isomerization process.²⁰ In the subsequent Michael addition, water is proposed to act as a dual activator, engaging in hydrogen-bonding interactions with both the electrophile (α,β-unsaturated nitrile 2b) and the nucleophile (piperazine 1). This dual activation enhances the reactivity of both partners, promoting favorable orbital alignment and charge stabilization that facilitate nucleophilic addition²¹ (Fig. 4F).

Key experimental observations supporting the critical role of water include: (i) the absence of product formation in organic solvents that are poor hydrogen-bond donors (low α) or acceptors (low β); (ii) the lack of requirement for external catalysts or acid/base additives; and (iii) the distinct reaction kinetics observed in H₂O compared to D₂O. Collectively, these findings highlight the unique role of water in driving the overall cascade.

Anti-fungal activity of library compounds

Fungal infections pose a significant global health burden, affecting over one billion people and causing an estimated 1.5 million deaths each year.²² The emergence of drug-resistant pathogens, particularly Candida auris, further underscores the urgent need for novel antifungal agents.²³ Among various organic frameworks, piperazine scaffolds are widely employed in antifungal drug discovery for their ability to overcome resistance, enhance target interactions, and improve pharmacokinetic properties,²⁴ while nitriles provide complementary benefits through increased lipophilicity and potential covalent interactions.²⁵ Consequently, the development of nitrile-containing piperazine-based scaffolds holds great promise as a new class of potential antifungal therapeutics, particularly those incorporating a methyl group, due to its significant impact on drug-likeness.²⁶ Accordingly, subsequent studies were designed to evaluate the antifungal potential of the synthesized nitrile-containing piperazines (3a–3t).

To evaluate antifungal activity, the nitrile-containing piperazine library (3a–3t) was screened against three clinically significant fungal pathogens, Candida albicans, C. glabrata, and C. tropicalis, which are designated as “critical” or “high” priority organisms in the WHO Fungal Priority Pathogens List.²⁷ Primary screening was performed using the NCCLS M27-A2 protocol in RPMI medium incubated at 37 °C for 24, 48, and 72 hours. The growth was compared to the solvent control (DMSO), with fluconazole used as the positive control. Although the compounds were broadly active, variation in potency across species was noted: in C. albicans, compound 3q showed moderate inhibition (53.1%); in C. glabrata, 3g (73.6%) and 3h (69.8%) were most effective; and in C. tropicalis, 3g (76.6%) and 3h (67.9%) exhibited the highest inhibition. Three compounds (3q, 3g, and 3h) were selected for MIC₅₀ determination, with 3g and 3h consistently demonstrating the lowest MIC₅₀ values across all three Candida species (Fig. 5 and SI).

Fig. 5 Exploration of antifungal activity of library compounds: (A) MIC₅₀ values of compounds (3g and 3h) against fungal species. (B) Inhibitory activity of compounds (3g and 3h) against drug-resistant clinical strains. (C) Synergistic effects of compounds (3g and 3h) in combination with fluconazole (FLC) against C. tropicalis. (D) ROS assay using 3g and 3h in C. glabrata.

Analyzing the synergistic effects of promising compounds in combination with commonly used antifungal agents offers a promising strategy to enhance the efficacy of the limited arsenal of antifungal treatments available for combating fungal infections.²³ This approach not only has the potential to improve therapeutic outcomes but may also help mitigate the toxic side effects associated with current antifungal drugs. In this context, synergy studies revealed that 3g and 3h enhanced the efficacy of fluconazole against C. glabrata and C. tropicalis, suggesting potential for combination therapy.

We next evaluated their activity against a drug-resistant clinical strain of Candida auris isolated from a bloodstream infection (BSI). At 100 μg mL⁻¹, 3g and 3h inhibited growth by 67.6% and 60.7%, respectively, demonstrating promising activity against drug-resistant pathogens. The preliminary mechanistic investigations indicated that compound 3h induced significant ROS generation in C. glabrata, an effect that was reversed by co-treatment with ascorbic acid, confirming ROS involvement in antifungal activity.²⁸ Finally, mammalian cytotoxicity testing using HEK293 cells showed that 3h exhibited no detectable toxicity up to 59.7 μg mL⁻¹, highlighting its potential as a safe and effective antifungal agent for therapeutic use.

Conclusions

In conclusion, we have developed a sustainable olefin isomerization-Michael addition cascade that operates in aqueous SDS micelles at room temperature without the need for catalysts, additives, or external activators. The method features a broad substrate scope, delivers high yields, and demonstrates excellent functional-group tolerance. The process employs recyclable aqueous micelles, achieves 100% atom economy, maintains a low E factor, and demonstrates successful execution on a 1 g scale, suggesting good potential for further scalability and reinforcing its strong sustainability profile. Comprehensive mechanistic studies reveal the crucial role of water in promoting both olefin isomerization (β,γ → α,β) and the subsequent Michael addition, likely through water-mediated hydrogen-bond-assisted stabilization of charged intermediates. The nitrile-containing piperazine derivatives (3g and 3h) exhibit potent antifungal activity, display synergistic interactions with fluconazole, and act through ROS-mediated mechanisms. Notably, both compounds were effective against drug-resistant Candida auris, a WHO-designated “critical priority” pathogen, highlighting the therapeutic promise of this sustainable chemistry approach.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information includes the optimization table, procedure, NMR, green metrics calculations, mechanistic insights, biological evaluation, and HPLC analysis. See DOI: https://doi.org/10.1039/d5gc06424d.

Acknowledgements

The authors thank the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Government of India, and NIPER Ahmedabad for financial support. D. K. gratefully acknowledges funding from the ANRF (CRG/2022/004057) and the ICMR (Intermediate Grant IRPGI-2025-01-00800). S. B. acknowledges financial support from the Gujarat State Biotechnology Mission (Project ID: 20242505) and the Prime Minister’s Early Career Research Grant (ANRF/ECRG/2024/004160/LS).

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Footnote

† These authors contributed equally.

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