Zwitterions as catalytic electron donor species for visible light-induced photoactivation of oxime esters and direct C3-alkylation of quinoxalin-2(1H)-ones

Abstract

A novel ternary EDA complex catalysis strategy has been developed for the photoactivation of oxime esters. By augmenting the electron-donating properties of zwitterions with a base, a ternary EDA complex is formed, facilitating intermolecular charge transfer under visible light. This process enables the single-electron reduction of γ,δ-unsaturated oxime esters, resulting in the homolytic cleavage of the N–O bond. The resulting iminyl radicals then undergo intramolecular cyclization to generate alkyl radicals, enabling C3-alkylation of quinoxalin-2(1H)-ones in good to excellent yields. Additionally, a novel covalent fluorescent labeling method was established using this mild alkylation method.

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Introduction

Zwitterions, molecules that contain both a positive and a negative charge within the same structure, have attracted significant attention in the fields of biochemistry and material science.^1–5 Additionally, the versatility of zwitterionic catalysts, which can act as both nucleophiles and electrophiles, presents opportunities for selective and efficient transformations in organic synthesis. For instance, numerous remarkable accomplishments have been documented in the utilization of zwitterions as ionic nucleophilic catalysts,^6–8 proton transfer catalysts,⁹ and electrophilic bromination catalysts^10,11 (Fig. 1a). The implementation of these catalytic processes heavily depends on the electron-donating properties stemming from the negatively charged center within the zwitterionic structure. In another scenario, harnessing the electron-donating properties of organic catalysts, visible light-induced electron donor–acceptor (EDA) complex catalysis has achieved remarkable success in the past decade.^12–17 Recently, we reported a new catalytic strategy wherein a base is used to in situ transform thioureas into the corresponding anions, which serve as the catalytic electron donor species.¹⁸ We then conceive whether the inherent negative charge in zwitterions could serve as electron donors, triggering single electron transfer under light irradiation as well. In 2022, Gryko introduced pyridine N-oxide as a HAT reagent for the photochemical C–H functionalization of electron-deficient heteroarenes.¹⁹ Despite its stoichiometric use, pyridine N-oxide functions as an electron donor in forming an EDA complex, demonstrating its potential in photocatalysis. To the best of our knowledge, there have been no more reports, as of yet, that combine the electron-donating properties of zwitterions with visible light catalysis.

Fig. 1 (a) Previous accomplishments of zwitterions as organocatalysts. (b) Zwitterions as catalytic electron donor species for ternary EDA complex catalysis.

Here, we present this report on the utilization of zwitterions as catalytic electron donor species in a novel ternary EDA complex catalysis, as shown in Fig. 1b. Distinct from conventional photoactivation approaches involving single-electron transfer (SET) between the excited photocatalyst and oxime ester,^20–23 we discovered the formation of a ternary EDA complex, involving the sulfur-based zwitterionic salt, γ,δ-unsaturated oxime ester, and base, that promoted intermolecular charge transfer under visible light irradiation. This ultimately led to the homolytic cleavage of the N–O bond. The resulting iminyl radicals underwent intramolecular cyclization, yielding alkyl radicals that facilitated the C3-alkylation of quinoxalin-2(1H)-ones, an essential bioactive compound and an important receptor in radical reactions.^24–28 By enhancing the electron-donating properties of the sulfur-based zwitterionic compound, various quinoxalin-2(1H)-ones and heteroaromatic cycles were successfully alkylated with different pyrroline derivatives. This novel developed synthetic protocol was further extended to enable alkynylation labeling of quinoxalin-2(1H)-ones, which were subsequently fluorescence-labeled via CuAAC reactions, thereby demonstrating the practical application of this strategy.

Results and discussion

At the outset of our investigation, the photoactivation of γ,δ-unsaturated oxime ester 1a was studied using various reported photocatalysts and zwitterionic organocatalysts as shown in Table 1. The typical photocatalysts, such as fac-Ir(ppy)₃ and 4CzIPN, were found to catalyze reactions as anticipated in entries 1 and 2. Considering the cost and complexity of synthesizing these photocatalysts, the newly reported thiourea precatalyst T1 ¹⁸ (entry 3) and the cheap N-donor catalyst DABCO²⁹ (entry 4) were utilized for catalysing this reaction. A good yield of 89% of the desired product 3aa was obtained using T1 in cooperation with KHCO₃, whereas DABCO proved to be ineffective under the same reaction conditions. We then redirected our attention to investigating zwitterions as promising electron donor catalysts for EDA complex catalysis. The easily prepared sulfur-based zwitterionic salt^10,11,30 (Z1, entry 5), the readily available, and widely used oxygen-based zwitterionic catalysts (Z2, entry 6 and Z3, entry 7) and the newly reported zwitterion compound with good delocalization of negative charges³¹ (Z4, entry 8) were employed as electron donor catalysts. To our delight, with the application of just a 5 mol% loading of Z1, the reaction proceeded smoothly and led to a clean reaction by employing dimethyl sulfoxide (DMSO) as the solvent at room temperature under white LED irradiation for 6 hours with 1.5 equiv. of KHCO₃, yielding the desired product 3aa in an isolated yield of 96%. The cooperation with KHCO₃ was determined to be crucial in this reaction, and subsequent experimentations with different bases (entries 9–13) did not lead to improved results. Control experiments revealed that both Z1 and light irradiation are essential for this transformation, as indicated by entries 14 and 15. Moreover, only a trace of the product was formed when the reaction was conducted under air (entry 16). To our surprise, this reaction can also be successfully conducted under sunlight irradiation, affording the desired product in 90% yield (entry 17).

Table 1 Catalysts and reaction conditions investigations^a

Entry	Catalyst	Base	Yield^b (%)
a Optimized conditions: 1a (0.20 mmol), 2a (0.30 mmol), catalyst (0.01 mmol), base (0.30 mmol), DMSO (2.0 mL), under the irradiation of 20 W white LED (400–800 nm) for 6 h at room temperature under N2 atmosphere. b Yield of the isolated product 3aa. c Reaction performed with 2 mol% of catalyst. d Reaction performed without base. e Reaction performed in dark. f Reaction performed under air. g Reaction performed under sunlight irradiation.
1^c	fac-Ir(ppy)3	KHCO3	93/87^d
2^c	4CzIPN	KHCO3	83/28^d
3	T1	KHCO3	89/0^d
4	DABCO	KHCO3	8/0^d
5	Z1	KHCO3	96/0^d
6	Z2	KHCO3	7/0^d
7	Z3	KHCO3	75/0^d
8	Z4	KHCO3	51/0^d
9	Z1	K2CO3	90
10	Z1	K3PO4	89
11	Z1	Na2CO3	88
12	Z1	Et3N	15
13	Z1	DMAP	32
14	None	KHCO3	8
15^e	Z1	KHCO3	0
16^f	Z1	K2CO3	Trace
17^g	Z1	K2CO3	90

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After optimizing the conditions, we examined a range of substrates to evaluate this reaction, with the results presented in Fig. 2. We initially explored the substrate scope of γ,δ-unsaturated oxime esters. Notably, the reaction was effective for aryl-substituted oxime esters, regardless of the electronic properties and positions of substituents on the phenyl ring, affording products 3aa–3fa in 89–96% yields. Additionally, 2-naphthyl- and benzothiophene-substituted substrates were compatible with this transformation (3ga and 3ha). The successful incorporation of notoriously challenging pyridine groups (3ia–3ka) underscored the remarkable robustness of this chemistry. Furthermore, oxime substrates bearing α-substituents performed well, delivering the desired products in excellent yields (3la, 3ma). As expected, substituted and cyclic olefin units proved suitable substrates, affording 3na–3qa in 65–94% yields. Pleasingly, aliphatic substituted oxime esters also performed well, yielding 3ra and 3sa in 70% and 84% yields, respectively.

Fig. 2 Scope of oxime esters and quinoxalin-2(1H)-ones under optimized conditions. ^a Reaction performed on a 3.0 mmol scale for 12 h.

We subsequently explored the scope of substituted quinoxalin-2(1H)-ones, and found that both electron-donating (methyl and methoxy) and electron-withdrawing (chloro) substituents at various positions on the benzene ring underwent smooth reactions, yielding the corresponding pyrroline alkylated products (3ab–3af) in excellent yields of 84–94%. The disubstituted quinoxalin-2(1H)-ones (3ag and 3ah) and fused-ring analogue (3ai) were also compatible with this transformation. Notably, the optimized reaction conditions were sufficiently mild to accommodate a broad range of substituents at the N1 position (3aj–3am), including sensitive alkenyl and alkynyl groups, affording the desired products in excellent yields (92–95%). The protocol demonstrates exceptional functional group tolerance, enabling its application to valuable scaffolds, including those derived from natural isolates and drug-like molecules. For instance, quinoxalin-2(1H)-ones bearing α-D-mannofuranose (3an), naproxen (3ao), and vanillin (3ap) moieties were selectively alkylated to afford the desired products in 82–95% yields. To demonstrate the utility of this strategy, reactions were performed on a gram scale (3.0 mmol) to yield 3aa in 92% yield and 3aj in 94% yield, respectively.

Encouraged by these results, we proceeded to investigate the broader applicability of our proposed catalytic strategy by exploring its compatibility with other simple yet significant heteroaryl cycles (Fig. 3a). To our delight, coumarin, ethyl 2-(4-oxocinnolin-1(4H)-yl)acetate, and 2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione were successfully alkylated using Z1 as the catalyst, affording the corresponding products 5a–5c in excellent yields upon optimizing the reaction time. Control experiments corroborated the indispensable roles of Z1, KHCO₃, and light irradiation in facilitating this transformation for these heteroaryl cycles. To further demonstrate the synthetic utility of this reaction, a phenylacetylene-derived oxime ester 1t was used for the C3-alkylation of 2a, affording product 1ta with a terminal alkyne moiety in 81% yield under optimized conditions. This was followed by the successful conjugation of FAM azide 6via the classic CuAAC reaction,^32–34 yielding the fluorescent labeled product 7, thereby establishing a novel covalent fluorescent labeling method (Fig. 3b).

Fig. 3 Further synthetic applications of this strategy: (a) screening of other heteroaromatic cycles; (b) covalent labeling application. ^a Reaction conditions: 3ta (5.0 nmol), 6 (5.0 nmol, cas: 1386385-76-7), CuSO₄·5H₂O (0.50 nmol), sodium ascorbate (1.0 nmol), ^tBuOH/H₂O 1 : 1 (100 μL), 50 °C, 6 h. ^b (ESI+) m/z: calculated for C₄₆H₃₈N₇O₇ [M + H]⁺: 800.2827, found: 800.2823.

To probe for insights into the reaction mechanism and clarify the role of Z1 and KHCO₃ in the reaction, a series of experiments were conducted (see the ESI†). A radical trap experiment and a radical clock experiment were carried out to confirm the radical process of 5-exo-trig cyclization.^18,20,35,36 Further control experiments (Fig. 4a) were conducted to confirm the indispensability of Z1 and KHCO₃ in generating the desired radical intermediates. The possibility that the photochemical reaction is triggered by direct excitation of Z1 was ruled out, as it did not occur in the absence of KHCO₃ (Fig. 4a, entry 2), unlike fac-Ir(ppy)₃ (Fig. 4a, entry 6), even though Z1 is capable of absorbing visible light (Fig. 4b). The slight redshift in absorption indicated the formation of an EDA complex between 1a and Z1, but this complex was unable to effectively drive the reaction under visible light initiation. Only when 1a, Z1, and KHCO₃ are combined, a noticeable absorption redshift occurs (Fig. 4c), allowing for the efficient formation of the desired radical intermediate. Therefore, we speculated that KHCO₃ can enhance the electron-donating capability of Z1, leading to the formation of a ternary EDA complex. In the presence of KHCO₃, a 1 : 1 stoichiometry of 1a and Z1 was evaluated by Job plot (Fig. S3†) in the formation of EDA complex. The results of the On–Off–On experiment (Fig. S4†), which involved alternating irradiation and dark sequences, indicated that the EDA complex functions as a catalytic species in this reaction. A slight reaction occurred in the presence of 2a and KHCO₃ (Fig. 4a, entry 3), suggesting the potential for a catalyst-free reaction,³⁷ but with low efficiency under the current conditions.

Fig. 4 (a)–(c) Mechanism study experiments and (d) plausible full catalytic cycle.

Taken together, a plausible full catalytic cycle of this Z1 induced transformation is outlined in Fig. 4d. The reaction starts with the formation of a ternary EDA complex involving 1a, KHCO₃, and Z1. By enhancing the electron-donating properties of the zwitterion Z1, an intermolecular charge transfer occurs under visible light irradiation, achieving the single-electron reduction of oxime ester 1a to generate the intermediate I. During this process, the zwitterion catalyst Z1 transforms into the cationic radical Z1′. Subsequently, homolytic cleavage of the N–O bond occurs, resulting in the formation of iminyl radical II. Then, II undergoes a radical-type 5-exo-trig cyclization to form alkyl radical intermediate III, which then undergoes radical addition to 2a, resulting in the formation of the C–C bond in IV. The intermediate IV further undergoes a 1,2-H shift^37,38 and leads to intermediate V. Finally, the cationic radical Z1′ oxidizes the carbon radical V to generate the cationic intermediate VI, which subsequently undergoes β-H elimination to afford the target product 3aa under basic conditions.

Conclusions

In conclusion, we present the innovative use of zwitterions as catalytic electron donors within a novel ternary EDA complex catalysis. By enhancing the electron-donating properties of the sulfur-based zwitterionic compound with a base, photoactivation of γ,δ-unsaturated oxime esters was achieved under visible light, leading to the cleavage of the N–O bond. The resulting iminyl radicals subsequently underwent intramolecular cyclization to form alkyl radicals, enabling efficient C3-alkylation of quinoxalin-2(1H)-ones in good to excellent yields. Some other heteroaryl cycles were also alkylated using the developed catalysis system. A novel covalent fluorescent labeling method was established by means of this mild alkylation strategy as well. Mechanism experiments confirmed that the formation of a ternary EDA complex involving zwitterions, oxime esters, and base drove the reaction forward. This discovery broadens the scope of EDA catalysis and offers new avenues for accessing affordable and readily available photocatalysts.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (82473767, 82130103 and 82151525), the Research Project from Ping-Yuan Laboratory (2023PY-ZZ-0204), and the Central Plains Scholars and Scientists Studio Fund (2018002). We also acknowledge financial support from the Henan Key Laboratory of Organic Functional Molecules and Drug Innovation.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01390e

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