A Telescopic, Sustainable Synthesis of the Key Starting Materials of Antipsychotic Drugs Quetiapine and Loxapine via Reductive Amidation

Abstract

Quetiapine, a dibenzothiazepine derivative, is an antagonist of serotonin and dopamine. It was approved by the Food Drug and Administration for the treatment of schizophrenia in 1997 and has been used as a commonly prescribed second-generation atypical antipsychotic drug. Loxapine is a dibenzoxazepine tricyclic compound used as an antipsychotic, antagonising dopamine and serotonin receptors for the treatment of acute and chronic schizophrenia. However, the preparation of their Key Starting Materials (KSMs) in the reported synthesis routes suffers from several significant restrictions, such as multistep synthesis, harsh reaction conditions, high cost factors, and the use of reagents that are environmentally unfriendly. In this work, we aimed to explore a telescopic green process for the synthesis of dibenzo[b,f][1,4]thiazepin-11(10H)-one and 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one, the two KSMs required for the commercial production of quetiapine and loxapine. The process involves an intermolecular base-mediated S_NAr reaction of 2-fluoro-1-nitrobenzene and methyl 2-mercaptobenzoate or methyl 2-hydroxybenzoate, followed by intramolecular reductive amidation employing sodium dithionite (Na₂S₂O₄) as the sole reagent. The S_NAr reaction was performed in the presence of K₂CO₃ in DMF at 90°C, followed by workup to give a crude product, which was treated with Na₂S₂O₄ in DMSO without any prepurification to obtain the desired cyclized KSMs. Unlike the commonly used metal/acid reagent for the reduction of nitro compounds, the developed process avoids the use of any metal reagent or acidic conditions. The key features include a reduced number of steps, a telescopic process avoiding purification of the first step product, and reductive amidation of unactivated esters without any externally added activating agent.

Keywords

quetiapine - loxapine - APIs synthesis - nitro reduction - reductive amidation - sodium dithionite (Na₂S₂O₄)

Introduction

Despite an admirable effort being made by numerous pharmaceutical enterprises worldwide to meet the growing demand for generic active pharmaceutical ingredients (APIs), similar research activities in academia are less common. Academic and industry joint involvement is required with the goal of developing a sustainable and cost-effective process that could replace the traditional methods lacking green approaches. Such synthetic approaches for generic APIs eventually could bridge the enormous gap between supply and demand.[1] [2] [3]

Quetiapine, belonging to the dibenzothiazepine class, is a common second-generation atypical antipsychotic drug that has been commonly prescribed for the treatment of schizophrenia. It works to block serotonin and dopamine receptors and was initially approved by the Food and Drug Administration in 1997.[4] [5] Subsequently, it was approved in the treatment of both bipolar depression and mania and in the adjuvant treatment of major depressive disorder. It has dose-dependent effects, accounting for the antipsychotic effect at higher doses.

Loxapine also works to block serotonin and dopamine receptors. Loxapine is a dibenzoxazepine tricyclic antipsychotic agent used to treat both acute and chronic schizophrenia.[6] [7] Loxapine closely resembles the traditional antipsychotic agents with regard to its therapeutic effectiveness and incidence of side effects. From 2024 to 2030, the global market for antipsychotic medications is expected to reach an estimated USD 24.97 billion, growing at a compound annual growth rate of 6.1% from its 2024 valuation of USD 17.53 billion. In 2023, the schizophrenia drugs segment represented the biggest revenue share of 39.2% of the market. Approximately 24 million people worldwide suffer from schizophrenia, whereas the current market for quetiapine is worth US$155.9 million and US$0.13 million for loxapine.[8]

The representative commercial synthetic routes of quetiapine are shown in [Scheme 1].[9] [10] [11] [12] The synthesis consists of multiple steps, including (1) base-mediated S_NAr reaction of 1-chloro-2-nitrobenzene with benzenethiol, (2) reduction of the nitro group, (3) N-carbamate derivatization or isocyanate formation of the resultant 2-(phenylthio)aniline, and (iv) intramolecular cyclization. However, these methods have some disadvantages, such as multiple steps, metal-mediated nitro reduction, and the use of toxic reagents. The major impurities in the synthesis of quetiapine are also shown in the Scheme.[13] They are desethanolquetiapine (impurity I), N-formylpiperazinylthiazepine (impurity II), quetiapine carboxylate (impurity III), N-ethylpiperazinylthiazepine (impurity IV), ethyl quetiapine (impurity V), and bis(dibenzo)piperazine (impurity VI). According to the definition of key starting materials (KSM), dibenzo[b,f][1,4]thiazepin-11(10H)-one (compound 1) is the KSM for quetiapine. Compound 1 contains a significant portion of the quetiapine structure, and it is the point where critical impurities are introduced to warrant regulatory legal oversight.

Scheme 1 Commercial synthesis routes to quetiapine and impurities.

The commercial synthetic routes of loxapine are shown in [Scheme 2].[14] [15] [16] [17] [18] [19] [20] [21] The process begins with an intermolecular base-mediated S_NAr reaction of 1-fluoro-2-nitrobenzene with methyl 5-chloro-2-hydroxybenzoate, then, a reduction of the nitro group with a tin reagent (SnCl₂) to give a 2-aminophenoxy substituted benzoate compound, which is followed by an intramolecular cyclization with a strong acid, H₂SO₄ furnish 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one (compound 2). The low yields of the final product are usually due to the multiple steps in the synthesis of these pathways, which may require the isolation of intermediates and harsh conditions. The impurities of loxapine[22] include loxapine N-oxide (impurity VII), 3-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (impurity VIII), 8-methoxy loxapine-d ₃ (impurity IX), and (bis(dibenzo)piperazine (impurity X). Compound 2 contains a significant portion of the loxapine structure, and the critical impurities are introduced at this stage to warrant regulatory legal oversight.

Scheme 2 Commercial synthesis route to loxapine and impurities.

Other available routes for the synthesis of these KSMs are primarily accomplished through palladium-catalyzed carbonylative synthesis employing various carbonyl surrogates. This process uses hazardous CO gas and requires a specific pressure, which is not in line with greener practices and is likely inconvenient on scale.[23] [24] [25] [26] [27] ortho-Aminophenols are conventionally intermolecularly cyclized with ortho-haloaromatic acids to prepare dibenzoxazepinones and their derivatives.[28] [29] [30] In order to synthesize dibenzothiadiazapinone 1 and dibenzoxazepinone 2 in a novel, widely applicable, and highly efficient manner, it is imperative to develop innovative green and sustainable methods.

Amides can be produced when carboxylic acids react with amines in the amidation process.[31] This method is primarily used as an alternative to the traditional direct amidation technique.[32] [33] [34] The direct amidation of carboxylic acids and amines requires a stoichiometric amount of coupling reagents, whereas the direct amidation of esters requires an activating agent.[35] [36] [37] [38] [39] [40] The reductive amidation of esters with nitroarenes has recently become the focus of new research[41] [42] [43] [44] [45] where the nitro group was used as an alternative to the amino group. The reductive amidation reaction shows notable differences compared with traditional amidation, as it avoids the necessity of reducing nitro compounds to amines and the use of any coupling reagents. This reaction produces minimal waste and maximizes atom efficiency.[46] [47] [48]

Sodium dithionite (Na₂S₂O₄) is a cheap reductant (∼$30/kg) capable of donating one electron and is widely used as a reagent in the clothing and color industries.[49] It is possible to use Na₂S₂O₄ for chemoselective nitro group reduction. Although this alternative to conventional metal-based nitro group reduction is more environmentally friendly,[50] [51] [52] it largely remains underexplored.[53] [54] [55] [56] [57] Furthermore, chemoselective reduction of a nitro group integrated with other synthetic transformations in the presence of other reducible groups remains to be explored.[58] [59] [60] Our group has used Na₂S₂O₄ as the only reagent under mild and neutral conditions for the synthesis of different heterocycles, e.g., dihydrobenzothiadiazine-1,1-dioxides and pyrrole-fused N-heterocycles[61] [62] and also for amidation reactions to the synthesis of 2-indolinones and tetrahydropyrrolo[1,2-a]tetrahydropyridines and pyridoo[1,2-a]quinoxaliones.[63] [64]

Herein, we report a telescopic synthesis of compound 1 and compound 2, which involves an intermolecular base-mediated S_NAr reaction followed by intramolecular reductive amidation of esters ([Scheme 3]). Instead of undergoing purification in the initial stage, the crude product from the S_NAr reaction is subjected to reductive amidation using Na₂S₂O₄ as the sole reagent. The features of the protocol include chemoselective reduction of the nitro group, reductive cyclization of the nitro group to lactam formation, ease of purification, and overall low process mass intensity (PMI) value.

Scheme 3 Our synthesis strategy for the key starting materials (compounds 1 and 2) of quetiapine and loxapine.

Results and Discussion

Our initial investigation to develop a model synthesis of dibenzoxazepinone utilizing 2-fluoro-1-nitrobenzene and methyl 2-hydroxybenzoate as substrates was focused on identifying an optimum condition for a telescopic synthesis. While a base is required for the intermolecular S_NAr reaction, 1.5 equiv. of K₂CO₃ was used as a base, and DMF was used as a solvent. For intramolecular reductive amidation, Na₂S₂O₄ was the reagent of choice. After trying the reaction for 24 hours at 70°C with EtOH as the solvent, no appreciable change was observed ([Table 1], entry 1). Subsequent attempts yielded the same result, even when the solvent system was switched from EtOH to EtOH/H₂O in a 3:1 ratio. We tried increasing the ratio of EtOH/H₂O from 3:1 to 5:1, adjusting the temperature, and adding base sodium hydroxide, but none of these worked to produce the desired result ([Table 1], entries 3–4). In later trials, we used DMF/H₂O at a ratio of 5:1, but there was no product formation ([Table 1], entry 5). However, when DMSO is used as the solvent, the final product was produced in 75% yield ([Table 1], entry 6). The yield was further improved (85%) when we raised the temperature from 80 to 90°C ([Table 1], entry 7). However, continuing to increase the temperature to 100°C afforded the product in inferior yields.

Table 1 Optimization study with model substrates 2-fluoro-1-nitrobenzene and methyl 2-hydroxybenzoate[a]

Entry	Additive (equiv.)	Solvent (mL)	Temperature (°C)	Yield (%)[b]
1	_	EtOH	70°C	n.d.
2	_	EtOH/H2O (3:1)	70°C	n.d.
3	_	EtOH/H2O (5:1)	80°C	n.d.
4	NaOH	EtOH/H2O (5:1)	80°C	n.d.
5	_	DMF/H2O (5:1)	80°C	n.d.
6	_	DMSO	80°C	75%
7	_	DMSO	90°C	85%
8	_	DMSO	100°C	82%

^a Reaction conditions: 2-fluoronitro-1-benzene (1 equiv., 0.250 mmol), methyl 2-hydroxybenzoate (1.5 equiv., 0.375 mmol), base (1.5 equiv., 0.375 mmol), Na₂S₂O₄ (3.5 equiv., 0.875 mmol), solvent (1 mL), at specified temperature for 24 hours.

^b Isolated yields. n.d., not detected.

With the determined optimized condition in hand, the synthesis of KSM 1 is shown in [Scheme 4]. A reaction mixture of 2-fluoro-1-nitrobenzene and methyl 2-mercaptobenzoate in the presence of K₂CO₃ in DMF was heated at 90°C for 6 hours. After completion of the reaction monitored by TLC analysis, the workup of the reaction mixture gave the crude product methyl 2-((2-nitrophenyl)thio)benzoate. The crude product was used further in the next step without any purification (telescopically). The direct reductive amidation of the crude methyl 2-((2-nitrophenyl)thio)benzoate was performed by heating the crude with Na₂S₂O₄ in DMSO at 90°C for 24 hours. In this way, intramolecular lactamization occurred, resulting in the formation of KSM 1 with an overall yield of 84% (two steps). It is important to note that the KSM 1 was isolated simply by crystallization.

Scheme 4 Synthesis route of dibenzothiazapine 1.

The synthesis of KSM 2 is shown in [Scheme 5]. Following a similar procedure as stated above, heating a reaction mixture of 2-fluoro-1-nitrobenzene and methyl 5-chloro-2-hydroxybenzoate using K₂CO₃ as base in DMF at 90°C for 6 hours gave the crude product methyl 5-chloro-2-(2-nitrophenoxy)benzoate, which was used further without any purification. Direct reductive lactamization of the crude product in the presence of Na₂S₂O₄ in DMSO occurred when the reaction mixture was heated at 90°C for 16 hours. The resulting product KSM 2 was isolated by simple crystallization with an overall yield of 84% (two steps). Perhaps most importantly, direct lactamization has remained unexplored in the synthesis of these KSMs, which signifies the novelty of the protocol described in this manuscript.

Scheme 5 Synthesis route of dibenzoxazepinone 2.

To understand the mechanism of the reaction, a control experiment was performed ([Scheme 6]). As the first step reaction gives a stable S_NAr product, the intermediate 2ab was isolated. To make clear whether the reductive amidation follows a radical pathway, 2ab, the pure isolated oxydibenzene product, was exposed to the standard reaction conditions in the presence of TEMPO. It was observed that TEMPO completely inhibited the reaction, proving the existence of a radical pathway. Based on this limited control experiment and our previous experiences,[61] [62] [64] a plausible mechanism for the direct amidation is shown. Na₂S₂O₄ undergoes a homolytic cleavage to produce the sulfoxylate anion radical (SO₂ ^· − ), a strong single-electron reductant that donates an electron to substrate 2ab. The resultant reduced nitroso intermediate 2ac may undergo further reduction to hydroxylamine intermediate 2ad. The intermediate 2ad is further reduced to the amine 2ae. Next, the unactivated ester group in 2ae is proposed to be activated (1,3-chelation) by NaHSO₃ generated in situ from Na₂S₂O₄. Furthermore, the intramolecular nucleophilic substitution of the amine with the activated ester could produce the desired cyclized product 2a.

Scheme 6 Control experiment and plausible reaction mechanism.

A green chemistry analysis of the method for the synthesis of the two KSMs was performed ([Table 2]). The analysis revealed that the PMI values are nearly 25, which indicates the processes are considerably green. However, because of the unavailability of all the information from previous methods, a direct comparison with the previous methods cannot be done at present.

Table 2 Green metrics analysis of the key starting materials that are described herein

Green metrics analysis	1	2
Yield [%]	84	84
Conversion [%]	100	100
Atom economy [%]	69.9	74.9
Reaction mass efficiency [%]	46.5	50
Process mass intensity [Reaction]	27.6	25.4

Conclusion

A telescopic green process to the synthesis of two KSM, i.e., dibenzo[b,f][1,4]thiazepin-11(10H)-one (1) and 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one (2) that are useful for the production of the antipsychotic drugs, quetiapine and loxapine, is reported. The first step involves an intermolecular base-mediated S_NAr reaction of 2-fluoro-1-nitrobenzene and methyl 2-mercaptobenzoate or methyl 2-hydroxybenzoate, which gave a crude diphenyl (thio)ether product. The crude product was used in the next direct lactamization without purification. The second step involves an intramolecular reductive amidation employing Na₂S₂O₄ as a sole reagent, wherein the nitro group was reduced in situ, and the resultant aniline product undergoes ammonolysis with the ester group to form a lactam. Unlike the commonly used metal/acid reagent for the reduction of nitro compounds, the developed process avoids the use of any metal reagent or acidic conditions. The key aspects include a reduced number of steps, a telescopic process avoiding purification of the first step product, and reductive direct amidation of unactivated esters, featuring the novelty of the process.

Experimental Section

Material and Methods

All solvents and reagents were acquired from commercial suppliers. All reactions were carried out in a sealed screw-cap tube, and the round-bottom flask with a stirring bar was used for scale-up. TLC analysis was carried out using Merck precoated silica gel 60 F254 on aluminium sheets. By subjecting the developed TLC plate to UV light, it became visible. ¹H and ¹³C NMR spectra were recorded on a JEOL at a frequency of 600 and 151 MHz, respectively, using CDCl₃ as the solvent and tetramethylsilane as an internal standard. Chemical shifts are reported as δ values in parts per million (ppm), while coupling constants (J values) are reported in Hertz (Hz). The following was the designation for the multiplicity pattern: d, doublet; dd, doublet of doublet; dt, triplet of doublet; t, triplet; m, multiplet; s, singlet; bs, broad singlet. Full proton decoupling was used to record the ¹³C NMR spectra. Silica gel (60-120 mesh, Silica gel-G for TLC, and Silica gel GF-254) was used for column chromatography.

Preparation of Dibenzo[b,f][1,4]oxazepin-11(10H)-one (2a)

An oven-dried screw cap vial equipped with a magnetic stir bar was charged with 2-fluoro-1-nitrobenzene (1.0 equiv., 2 mmol, 282 mg), methyl 2-hydroxybenzoate (1.5 equiv., 3 mmol, 456 mg), and K₂CO₃ (1.5 equiv., 3 mmol, 331 mg) in DMF (4 mL). The resulting reaction mixture was stirred at 90°C in an oil bath for 6 hours. After completion, the reaction mixture was diluted with 20 mL of water. A 1 N HCl solution was added to neutralise the reaction system. The intermediate methyl 2-(2-nitrophenoxy)benzoate was extracted using EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product, which was used further without any purification. The crude was dissolved in DMSO (4 mL). Na₂S₂O₄ (1,218 mg, 7 mmol) was added. The reaction mixture was stirred at 90°C in an oil bath for 16 hours. After completion, the reaction mixture was diluted with ice-cold water/crust ice (20 mL) and extracted using EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The color impurities were removed by a filtration column. The desired product was obtained as a white solid (1.69 mmol, 358 mg, 85% yield).[26] ¹H NMR (600 MHz, CDCl₃) δ 9.25 (s, 1H), 7.98 to 7.95 (m, 1H), 7.53 (td, J = 7.7, 1.8 Hz, 1H), 7.27 to 7.27 (m, 1H), 7.25 (d, J = 7.7 Hz, 2H), 7.14 (dt, J = 4.7, 2.6 Hz, 2H), 7.13 to 7.11 (m, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 167.9, 159.8, 151.1, 134.6, 132.1, 130.8, 126.1, 126.0, 125.4, 125.3, 121.8, 121.5, 121.0.

Preparation of Dibenzo[b,f][1,4]thiazepin-11(10H)-one (1)

An oven-dried screw cap vial equipped with a magnetic stir bar was charged with 2-fluoro-1-nitrobenzene (1.0 equiv., 2 mmol, 282 mg), methyl 2-mercaptobenzoate (1.5 equiv., 3 mmol, 504 mg), and K₂CO₃ (1.5 equiv., 3 mmol, 331 mg) in DMF (4 mL). The resulting reaction mixture was stirred at 90°C in an oil bath for 6 hours. After completion, the reaction mixture was diluted with 20 mL of water. A 1 N HCl solution was added to neutralise the reaction mixture. The intermediate methyl 2-((2-nitrophenyl)thio)benzoate was extracted using EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product, which was used further without any purification. The crude was dissolved in DMSO (4 mL). Na₂S₂O₄ (1,218 mg, 7 mmol) was added. The reaction mixture was stirred at 90°C in an oil bath for 24 hours. After completion, the reaction mixture was diluted with ice-cold water/crust ice (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The color impurities were removed by a filtration column. The desired product was obtained as a white solid (1.67 mmol, 381 mg, 84% yield) according to a reported study.[30] ¹H NMR (600 MHz, CDCl₃) δ 8.89 (s, 1H), 7.85 (dd, J = 7.6, 1.8 Hz, 1H), 7.57 (dd, J = 7.8, 1.5 Hz, 1H), 7.51 (dd, J = 7.6, 1.5 Hz, 1H), 7.41 (td, J = 7.6, 1.8 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 7.6, 1.3 Hz, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 170.2, 139.5, 137.5, 137.0, 133.1, 132.4, 132.0, 130.3, 129.9, 128.9, 126.2, 122.8.

Preparation of 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one (2)

An oven-dried screw cap vial equipped with a magnetic stir bar was charged with 2-fluoro-1-nitrobenzene (1.0 equiv., 2 mmol, 282 mg), methyl 5-chloro-2-hydroxybenzoate (1.5 equiv., 3 mmol, 558 mg), and K₂CO₃ (1.5 equiv., 3 mmol, 331 mg) in DMF (4 mL). The resulting reaction mixture was stirred at 90°C in an oil bath for 6 hours. After completion, the reaction mixture was diluted with 20 mL of water. A 1 N HCl solution was added to neutralise the reaction mixture. The intermediate methyl 5-chloro-2-(2-nitrophenoxy)benzoate was extracted using EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product, which was used further without any purification. The crude product was dissolved in DMSO (4 mL). Na₂S₂O₄ (1,218 mg, 7 mmol) was added. The reaction mixture was stirred at 90°C in an oil bath for 16 hours. After completion, the reaction mixture was diluted with ice–cold water/crust ice (20 mL) and extracted using EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The colour impurities were removed using a filter column. The desired product was obtained as a white solid (1.67 mmol, 411 mg, 84% yield) according to a reported study.[26] ¹H NMR (600 MHz, CDCl₃) δ 8.63 (s, 1H), 7.93 (dd, J = 7.8, 1.6 Hz, 1H), 7.35 (t, J = 6.9 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.1 Hz, 2H), 6.75 (d, J = 8.2 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 169.3, 149.1, 137.9, 134.2, 133.2, 130.7, 129.1, 125.3, 122.6, 122.5, 121.4, 121.0, 119.3.

Preparation of methyl 2-(2-nitrophenoxy)benzoate (2ab)

An oven-dried screw cap vial equipped with a magnetic stir bar was charged with 2-fluoro-1-nitrobenzene (1.0 equiv., 2 mmol, 282 mg), methyl 2-hydroxybenzoate (1.5 equiv., 3 mmol, 456 mg), and K₂CO₃ (1.5 equiv., 3 mmol, 331 mg) in DMF (4 mL). The resulting reaction mixture was stirred at 90°C in an oil bath for 6 hours. After completion, the reaction mixture was diluted with 20 mL of water. A 1 N HCl solution was added to neutralise the reaction mixture. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄, and concentrated under reduced pressure[65] to give methyl 2-(2-nitrophenoxy)benzoate (2ab) as a yellow liquid. ¹H NMR (600 MHz, CDCl₃) δ 8.00 (dd, J = 7.8, 1.8 Hz, 1H), 7.96 (dd, J = 8.2, 1.7 Hz, 1H), 7.56 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (ddd, J = 8.6, 7.4, 1.7 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 165.5, 154.3, 151.6, 140.6, 134.2, 132.6, 125.9, 125.5, 123.6, 122.7, 122.3, 118.6, 118.5, 52.4.

Conflict of Interest

None declared.

Supporting information

Green chemistry metrics of synthesized compounds 2a, 1, and 2 ([Supplementary Table S1]–[S3], available in the online version) and ¹H NMR and ¹³C NMR spectra of compounds 2a, 1, 2, and 2ab ([Supplementary Figs. S1]–[S6], available in the online version) can be found in the “[Supporting Information]” section of this article's webpage.

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Publication History

Received: 14 January 2025

Accepted: 26 September 2025

Article published online:
13 November 2025