Polystyrene-supported aminobenzenesulfonic acids as bifunctional heterogeneous catalysts for the synthesis of isoxazoline skeletons

Abstract

The isoxazoline skeleton is a pivotal structural motif in pharmaceuticals and agrochemicals, necessitating the development of efficient synthetic methodologies. Conventional synthesis via 1,3-dipolar cycloaddition often requires multiple steps to prepare nitrile oxide precursors. While acid–base catalysis offers a more direct route from α,β-unsaturated aldehydes and ketoximes, catalyst recovery remains a significant challenge. In this study, we developed robust heterogeneous acid–base catalysts by immobilizing aminobenzenesulfonic acids—inexpensive dye precursors—onto polystyrene. These catalysts effectively promote the synthesis of isoxazolines from α,β-unsaturated aldehydes and acetoximes. Notably, the catalyst system is highly compatible with continuous flow reactions, maintaining yields above 70% for over 50 hours of operation. Mechanistic investigations, supported by DFT calculations, reveal two distinct, isomer-dependent pathways: (i) an iminium-mediated 1,4-addition for the 2-aminobenzenesulfonic acid-immobilized catalyst, and (ii) a concerted acid–base activation enabling direct 1,4-addition for the 3-amino isomer.

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The isoxazoline core is a versatile structural motif widely utilized in pharmaceuticals and agrochemicals.¹ Notable examples include the insecticide Fluxametamide² (Nissan Chemical Corporation) and the herbicide Pyroxasulfone³ (Kumiai Chemical Industry Co., Ltd.) (Scheme 1a). Traditionally, the isoxazoline framework is synthesized via 1,3-dipolar cycloaddition using nitrile oxides (Scheme 1b, (1)).⁴ However, this approach is often hampered by the need for multi-step synthesis of the nitrile oxide precursors. To address this challenge, Pihko and co-workers reported an alternative methodology using readily available α,β-unsaturated aldehydes and ketoximes (Scheme 1b, (2)).⁵ Their approach employs a homogeneous catalyst system comprising N-methylaniline and diphenyl phosphate. The proposed mechanism involves the formation of an iminium cation, followed by 1,4-addition of the oxime and subsequent intramolecular cyclization via hydrolysis. Despite its utility, the separation of these homogeneous acid–base catalysts from the reaction mixture can be problematic. Consequently, catalyst immobilization presents a highly attractive alternative.^6,7 However, the co-immobilization of both acidic and basic functionalities onto a single solid support is inherently complex.^8,9 Such processes typically require multiple synthetic steps and frequently suffer from poor reproducibility. To overcome these hurdles, we focused on the aminobenzenesulfonic acid scaffold. These bifunctional molecules are highly cost-effective, as they are widely produced as precursors for azo dyes.¹⁰ Crucially, they possess both acidic (sulfonic acid) and basic (aniline) functionalities within the same molecule.¹¹ We hypothesized that these bifunctional scaffolds could serve as effective catalysts for the transformation reported by Pihko's group.⁵ Furthermore, we reasoned that the amino group could be readily alkylated to facilitate stable immobilization. Herein, we demonstrate that polystyrene-supported aminobenzenesulfonic acids effectively catalyze the 1,4-addition and cyclization of α,β-unsaturated aldehydes with ketoximes, providing a robust and efficient route to isoxazolines (Scheme 1c). We also successfully demonstrate the applicability of this heterogeneous catalyst in a continuous flow system.

Scheme 1 The use and synthesis of isoxazoline skeleton.

Initially, the synthesis of polystyrene-supported aminobenzenesulfonic acid catalysts was performed (Scheme 2). Aminobenzenesulfonic acid derivatives were reacted with Merrifield resin 1 (1.8 mmol g⁻¹ Cl, 200–400 mesh, 1% DVB) in the presence of potassium carbonate in N,N-dimethylacetamide (DMA) at 60 °C for 16 hours. Subsequent acidification with 1.0 M hydrochloric acid, followed by filtration and washing, afforded the immobilized catalysts C1–C5. The catalyst loading was confirmed via energy dispersive X-ray spectroscopy (EDX).

Scheme 2 The synthesis of aminobenzenesulfonic acid catalysts C1–C5.

The catalytic activity was evaluated using the synthesis of isoxazoline 4a as a model reaction (Table 1). Specifically, 3-methyl-2-butenal (2a) and acetoxime (3) were reacted in butyl acetate at 60 °C for 3 hours in the presence of catalysts C1–C5. Among the candidates, catalyst C2 exhibited the highest reactivity (entries 1–5). Solvent screening was subsequently conducted using C1, as it demonstrated a smaller discrepancy between conversion and yield compared to C2. Nonpolar solvents such as toluene and chloroform yielded superior results. In contrast, polar solvents like acetonitrile and methanol led to significantly lower conversions and yields. Notably, when methanol was employed, the byproduct 3-methoxy-3-methyl-1-butanal was observed, resulting from the 1,4-addition of the solvent to the aldehyde. Consequently, toluene was identified as the optimal solvent. Applying these optimized conditions to the highly active C2 catalyst resulted in nearly complete conversion and a 90% yield of 4a within 3 hours (entry 10).

Table 1 Investigation the optimal condition for the synthesis of 4a

Entry	Catalyst	Solvent	Conv. (%)	4a^a (%)
a The conversion and yield were determined by gas chromatography analysis with biphenyl was used as an internal standard.
1	C1	AcO^nBu	71	47
2	C2	AcO^nBu	95	64
3	C3	AcO^nBu	70	43
4	C4	AcO^nBu	76	47
5	C5	AcO^nBu	50	23
6	C1	Toluene	87	76
7	C1	CHCl3	85	74
8	C1	MeCN	40	26
9	C1	MeOH	73	18
10	C2	Toluene	98	90

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With the optimized conditions established, the substrate scope was investigated (Table 2). Citral (2b), which possesses an external olefin, reacted selectively to afford the desired product 4b in 81% yield. Aromatic rings were well-tolerated, providing the corresponding isoxazoline 4c in high yield. Additionally, 2-cyclohexylideneacetaldehyde (2d) underwent the transformation efficiently. However, substrates with a single substituent at the β-position generally exhibited lower yields despite achieving full conversion (>99%). For example, the reaction of 2-octenal (2e) yielded only 60% of 4e (see SI for details). This reduced yield is attributed to the high reactivity of β-monosubstituted substrates toward 1,4-addition, which facilitates substrate polymerization.¹² Other β-monosubstituted substrates similarly provided only moderate yields (4f–4h).

Table 2 Substrate scope

a The yield was determined by gas chromatography analysis because 4a was highly volatile. Biphenyl was used as an internal standard.b 5.0 eq. of acetoxime 3 were used and the reaction was carried out at 30 °C.

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Finally, continuous-flow reaction conditions were investigated using 2a as the substrate.¹³ A catalyst column was prepared by charging a stainless-steel cylinder with a mixture of the catalyst and a diluent. A toluene solution of 2a and 3 was then passed through the column to evaluate the catalytic performance. When using Celite 545 as the diluent, C2 was more active but showed lower durability than C1. Based on long-term stability, C1 was selected as the optimal catalyst for flow operations. The choice of diluent proved to be critical; the use of carboxylic acid silica gel significantly improved both durability and reactivity. Under these conditions, a turnover frequency (TOF) of 2.9 h⁻¹ was achieved, and the yield of 4a remained above 70% for over 50 hours of continuous operation. Although the precise mechanism for this improvement remains under investigation, the efficient removal of free hydroxylamine by the acidic silica gel is likely a key contributing factor to the enhanced catalytic stability (Fig. 1).

Fig. 1 The result in the continuous-flow condition. ^aDetermined by GC analysis.

To elucidate the reaction mechanism, we first performed a control experiment using α,β-unsaturated oxime 5 with catalyst C1 in toluene at 60 °C (Scheme 3a).¹⁴ The reaction yielded the isoxazoline 4a in only 12%, suggesting that the pathway involving direct cyclization of the oximated intermediate is unlikely. According to Baldwin's rules, the cyclization of 5 would require a 5-endo-trig pathway, which is electronically disfavored and kinetically slow.¹⁵ We subsequently investigated the formation of an iminium intermediate. Mixing 3-methyl-2-butenal (2a) with aniline 6 in DMSO-d₆ at 60 °C led to the appearance of new signals in the ¹H-NMR spectrum (Scheme 3b). Further characterization by COSY and NOESY revealed a distinct cross-peak between the benzylic protons and the alkene protons, confirming their spatial proximity and the formation of an iminium cation.

Scheme 3 The mechanistic study of 2-aminobenzenesulfonic acid catalyst C1.

Based on these observations, the proposed catalytic cycle for C1 is illustrated in Scheme 4. The α,β-unsaturated aldehyde initially reacts with the aniline moiety to generate an iminium cation, which then undergoes 1,4-addition by the oxime.¹⁶ Subsequent hydrolysis of the resulting adduct triggers an intramolecular cyclization to afford the isoxazoline. Notably, this pathway bypasses the α,β-unsaturated oxime intermediate 5, allowing the cyclization to proceed via a favored 5-exo-trig ring closure, which accounts for the rapid reaction rate.

Scheme 4 Plausible reaction mechanism using C1.

The mechanistic pathway for catalyst C2 was investigated under identical conditions. Interestingly, unlike the case with C1, no iminium cation formation was detected by NMR when 2a was treated with aniline derivative 7 (Schemes 3b and 5). This striking difference suggests that C2 operates via a fundamentally distinct catalytic cycle that does not involve an iminium intermediate.

Scheme 5 The mechanistic study of 3-aminobenzenesulfonic acid derivative.

Despite the absence of iminium formation, the catalytic reaction using C2 (Table 2) proceeds efficiently at 60 °C to deliver the desired isoxazolines. This observation suggests that C2 operates via a mechanistic pathway distinct from that of C1. In catalyst C1, the sulfonic acid group is positioned ortho to the aniline nitrogen, allowing it to act as an internal Brønsted acid that protonates the α,β-unsaturated aldehyde, thereby facilitating nucleophilic attack by the nitrogen to generate an iminium ion. Conversely, in catalyst C2, the sulfonic acid moiety is meta-connected to the aniline nitrogen. This spatial arrangement precludes the promotion of iminium formation, which is consistent with the absence of iminium signals in the NMR experiments (Scheme 5). To explore alternative pathways, we performed density functional theory (DFT) calculations to map the reaction coordinate. The calculations revealed a concerted reaction pathway involving the cooperative participation of three species: the α,β-unsaturated aldehyde, the oxime, and the C2 catalyst (Fig. 2).¹⁷ In this bifunctional model, the sulfonic acid group of C2 acts as a Brønsted acid to activate the aldehyde, while the aniline nitrogen serves as a Brønsted base by forming a hydrogen bond with the oxime O–H. This dual activation significantly lowers the energy barrier for the 1,4-addition of the oxime, furnishing a 1,4-adduct without prior iminium formation. The calculated activation free energy (ΔG^‡) for the 1,4-addition transition state is 21.5 kcal mol⁻¹ at 25 °C.¹⁸ This indicates that at the experimental temperature of 60 °C, the 1,4-addition step is energetically accessible and potentially reversible. Subsequent hydrolysis of the oxime moiety and intramolecular cyclization are highly exergonic (ΔG ≈ −10.1 kcal mol⁻¹), driving the transformation rapidly toward the final isoxazoline product. While this scenario suggests the 1,4-adduct exists as a transient intermediate, analysis of reaction aliquots by GC and NMR failed to detect its presence. This lack of accumulation supports the conclusion that the subsequent hydrolysis and cyclization steps proceed smoothly and rapidly.

Fig. 2 1,4-Addition of an oxime to an α,β-unsaturated aldehyde via acid–base cooperative activation by 3-aminobenzenesulfonic acid.

In summary, we have developed a novel class of heterogeneous catalysts by immobilizing aminobenzenesulfonic acids onto a polystyrene resin. These catalysts effectively promote the synthesis of isoxazoline skeletons from readily available α,β-unsaturated aldehydes and acetoximes. Specifically, catalysts C1 and C2 exhibited high catalytic activity and demonstrated compatibility with a broad range of substrates, including those bearing aromatic rings and external olefins. Furthermore, the practical utility of these catalysts was underscored by their successful application in continuous-flow reactions. By employing carboxylic acid silica gel as a diluent, the system achieved a turnover frequency (TOF) of 2.9 h⁻¹ and maintained stable product yields above 70% for over 50 hours of operation. Mechanistic investigations revealed two distinct, isomer-dependent pathways: (i) the C1-catalyzed reaction proceeds via an iminium-cation-mediated 1,4-addition. (ii) DFT calculations indicated that C2 operates through a concerted acid–base activation of both the aldehyde and the oxime, enabling a direct 1,4-addition pathway without the formation of an iminium intermediate. These findings highlight the potential of bifunctionalized solid-supported catalysts for sustainable chemical processes. Our laboratory is currently focused on the design and exploration of even more highly active acid–base catalyst systems.

Author contributions

Kai Takizawa, Shun-ya Onozawa and Shū Kobayashi conceived the idea and were in charge of overall direction and planning. Kai Takizawa and Takuma Ishihara performed the experiments. Shinki Tani and Yusuke Hamada supervised Kai Takizawa and Takuma Ishihara. Kazuhiko Sato was also in charge of planning. Tadafumi Uchimaru and Akira Yada performed the computational investigation.

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 is available. See DOI: https://doi.org/10.1039/d6re00067c.

Acknowledgements

The authors thank Dr. Kwihwan Kobayashi (Catalytic Chemistry Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)) for helpful discussions. This study is based on the results obtained from project JPNP19004, subsidized by the New Energy and Industrial Technology Development Organization (NEDO) of Japan. This paper is dedicated to the memory of Dr. Kazuhiko Sato.

Notes and references

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Footnote

† Deceased February 10, 2026.

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