Electrosynthesis of Quinoxalines via Intermolecular Cyclization/Dehydrogenation of Ketones with o-Phenylenediamines

Abstract

In this study, we proposed a novel electrochemical dehydrogenative synthetic method for preparing 2-substituted quinoxalines by intermolecular cyclization of aryl alkyl ketones and o-phenylenediamines. This method gave various quinoxalines in yields ranging from 35% to 71%. This novel protocol employs mild reaction conditions and offers moderate to excellent yields, a wide substrate scope, and broad functional-group compatibility. Furthermore, a late-stage functionalization and the wide substrate scope demonstrated the synthetic utility of this protocol.

Key words

quinoxalines - electrochemistry - cyclization - green chemistry - dehydrogenation

Quinoxalines are key structural components of many natural products and exhibit privileged pharmacological and biological activities.[1] For instance, AG1295 (Figure [1]) is a PDGF receptor tyrosine kinase inhibitor[2] and chloroquinoxaline sulfonamide is a halogenated heterocyclic sulfanilamide, identified as an active agent against various human solid tumors in an in vitro human tumor colony-forming assay.[3] Moreover, riboflavin (vitamin B₂) possesses a ribose-derived quinoxaline core fused to a uracil.[4] Several recent studies have demonstrated that incorporating quinoxalines into luminescent materials can provide unique characteristics.[5]

Figure 1 Some important quinoxaline derivatives

Various methods have been developed to exploit the unique biological activities of quinoxalines by employing general, efficient, and sustainable synthetic strategies with readily available building blocks. Despite these advances, challenges persist in synthesizing quinoxaline derivatives, including severe reaction conditions, limited raw-material availability, expensive reagents, multistep synthetic processes, and stoichiometric waste.[6] In 2017, Zhang et al. reported an oxidative synthesis of quinoxalines from primary amines under mild conditions with an ortho-quinone catalyst as the terminal oxidant (Scheme [1a]).[7] In 2022, Guo and co-workers reported a method for the annulation of terminal alkynes and o-phenylenediamines, employing oxygen as the terminal oxidant and a cobalt catalyst (Scheme [1b]).[8] Chaubey et al. developed an iridium-catalyzed [4+2] annulation of β-ketosulfoxonium ylides with o-phenylenediamines to synthesize quinoxaline derivatives (Scheme [1c]).[2a] Nguyen et al. conducted an oxidative condensation of o-phenylenediamines with aryl alkyl ketones in the presence of sulfur to synthesize quinoxaline derivatives (Scheme [1d]).[9] However, there remains a high demand for strategies that permit the high-efficiency synthesis of the quinoxaline skeleton under mild conditions and from readily available starting materials.

Scheme 1 Synthetic strategy and routes to 2-substituted benzoxazoles

Developing novel, metal-free, and versatile synthetic strategies for synthesizing quinoxaline derivatives is crucial in academia and in the pharmaceutical sector to discover bioactive compounds.[10] [11] Electrochemical synthesis has recently emerged as a green and sustainable strategy for preparing nontraditional and innovative molecules, with the advantage of using electrons as traceless reagents instead of dangerous and toxic redox reagents.[12] The cyclization of aryl alkyl ketones and o-phenylenediamines is a direct and convenient method for preparing quinoxalines, considering the availability of the chemicals and its high atom economy.

Table 1 Optimization of the reaction conditions^a

Entry	Variation from the standard conditions	Yieldb (%)
1	none	68
2	HCO2H instead of H2C2O4·2H2O	64
3	AcOH instead of H2C2O4·2H2O	53
4	TFA instead of H2C2O4·2H2O	50
5	TsOH instead of H2C2O4·2H2O	43
6	H2C2O4·2H2O (0.5 equiv)	46
7	H2C2O4·2H2O (1.5 equiv)	57
8	No KI	32
9	KI (1 equiv)	45
10	NaI or NH4I instead of KI	35, 54
11	Temp 50 °C or 120 °C	–, 60
12	Current 10 mA or 18 mA	43, 65
13	DMSO instead of DMA	60
14	nBu4NBF4 instead of nBu4NI	32
15	nBu4NClO4 instead of nBu4NI	26
16	KPF6 instead of nBu4NI	trace
17	no nBu4NI	46
18	nBu4NI (1.0 equiv)	56
19	Ni cathode	trace
20	Pt anode	trace
21	no electric current	–

^a Standard reaction conditions: 1a (1 equiv), 2a (1 equiv), ⁿBu₄NI (0.5 equiv), H₂C₂O₄·2H₂O (1 equiv),

KI (0.5 equiv), graphite felt anode, Pt cathode, constant current (15 mA), DMA, 100 °C, 24 h.

^b Isolated yield.

In 2016, Zeng’s group reported an electrochemical protocol for the synthesis of α-amino ketones through the oxidative cross-dehydrogenative coupling of ketones with secondary amines.[13] The electrochemistry occurs in a simple undivided cell, utilizing NH₄I as a redox catalyst and cheap graphite plates as electrodes under constant-current conditions. The reaction is proposed to proceed through an initial α-iodination of the ketone, followed by a nucleophilic substitution of the amine. Inspired by these works and by our program on electrochemical transformation, we have developed a highly selective intermolecular cyclization and dehydrogenation of o-phenylenediamines with aryl alkyl ketones, facilitating a versatile synthesis of quinoxalines (Scheme [1e]).[14]

Initially, we screened the intermolecular cyclization of acetophenone (1a) with 1,2-phenylenediamine (2a) (Table [1]). The reaction was performed using a graphite felt (GF) anode and a Pt cathode as the supporting electrodes, with 0.5 equivalents each of ⁿBu₄NI and KI in an undivided cell (a Schlenk tube). Treatment 1a and 2a in N,N-dimethylacetamide (DMA) (6 mL) in the presence of oxalic acid dihydrate (H₂C₂O₄·2H₂O; 1 equiv) at 100 °C for 24 hours yielded 2-phenylquinoxaline (3aa) in a 68% isolated yield (Table [1], entry 1). Replacement of H₂C₂O₄·2H₂O with HCOOH, AcOH, TFA, or TsOH decreased the yield to 64, 53, 50, and 43%, respectively (entries 2–5). Changing the concentration of H₂C₂O₄·2H₂O did not increase the yield (entries 6 and 7). Similarly, adjusting the KI dosage did not improve the yield (entries 8 and 9). However, use of the iodide salts NaI and NH₄I resulted in lower yields (entry 10). The best yield was achieved at 100 °C: performing the reaction at different temperatures led to lower yields of 3aa (entry 11). Additionally, decreasing or increasing the constant current negatively influenced the reaction outcome (entry 12). When DMSO was employed as the solvent, the yield decreased to 60% (entry 13). Changing the electrolyte to ⁿBu₄NBF₄ or ⁿBu₄NClO₄ resulted in the formation of the desired products in isolated yields of 32, and 26% respectively, whereas KPF₆ gave only a trace of the product (entries 14–16). Notably, the yield decreased when ⁿBu₄NI was not added or when the dosage of ⁿBu₄NI was decreased (entries 17 and 18). Additionally, Pt as anode and Ni as cathode proved unsuitable for this electrochemical reaction (entries 19 and 20). As expected, the reaction failed to give any product without an electric current (entry 21).

The scope of quinoxaline synthesis was then examined (Scheme [2]). 2-Arylquinoxalines 3aa–be with substituents of varying electronic nature were accessible. Acetophenones 1 bearing either electron-rich groups, such as methyl (3ab–ad, 3ai), methoxy (3ae), ethyl (3af), isopropyl (3ag), or tert-butyl (3ah), or electron-deficient substituents such as halo (3aj and 3am), trifluoromethyl (3an), or cyano (3ao) at various positions were all suitable substrates. Substrates containing an ester group or an amide group also reacted to give the corresponding quinoxalines 3ap and 3aq in moderate yields. Furthermore, substrates containing a 2-naphthyl (3ar), 2-furyl (3as), or 1,3-benzodioxol-5-yl (3at) group were also compatible with the reaction conditions. Subsequently, 1,2-diphenylethanone was found to react with 2a to produce the corresponding 2,3-diphenylquinoxaline (3au). Unfortunately, phenylacetone as a substrate was incompatible with the standard reaction conditions (3av).

Scheme 2 Investigation of the scope of the benzoxazole-2-carboxylate. Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), ⁿBu₄NI (0.25 mmol), KI (0.25 mmol), H₂C₂O₄·H₂O (0.5 mmol), DMA (6 mL), constant current = 15 mA, undivided cell, GF anode (1.5 × 1.0 cm), Pt cathode (1.5 × 1.0 cm), 100 °C, 24 h. The isolated yields are reported.

Next, various reactions of 4,5-dimethylbenzene-1,2-diamine with acetophenone derivatives were investigated under the optimized conditions, and gave moderate to high yields of the corresponding products 3ba and 3bb; remarkably, the anti-PDGF receptor agent AG 1295 (3ba) was obtained in a high yield under the optimized conditions. Notably, significant electronic effects were observed in the case of disubstituted 1,2-diaminoarenes containing electron-donating substituents (3ba), which exhibited a higher compatibility than those with electron-withdrawing substituents, such as a halo group (3bc). Furthermore, asymmetric 1,2-diaminoarenes as substrates gave two isomers of the corresponding product quinoxalines (3bd and 3be). These isomers could not be separated by flash chromatography on a silica gel column because of their similar polarities.

In addition, to further explore the applications of this method in constructing quinoxalines, this electro-redox process was evaluated through a 10 mM scale reaction. A gram-scale synthesis of 3aa was achieved by using 1a (0.6 g, 5.0 mM) and 2a (0.81 g, 7.5 mM), with a yield of 69% (0.71 g) (Scheme [3]A). Moreover, the menthol ester substrate 4 (0.151 g, 0.5 mM) could be dehydrogenated with 2a (0.081 g, 0.75 mM) for intermolecular cyclization, resulting in the formation of the complex molecule 5 in 42% yield (0.081 g) (Scheme [3]B).

Scheme 3 Gram-scale experiment and a derivatization

Cyclic voltammetry (CV) experiments were then conducted to further elucidate the electrochemical oxidation processes for this reaction. As shown in Figure [2], CV measurements for ⁿBu₄NI revealed an oxidative wave at 1.63 V (Curve a), whereas KI showed an oxidative wave at 1.41 V, indicating that KI was oxidized first (Curve b). Moreover, when all raw materials were mixed with KI and a blank, the redox response value was significantly increased. The concentration of proton (addition of acid) might play a role here, because it reduces the nucleophilicity of the amine thereby slowing the first substitution; however, as a tradeoff, it probably helps accelerate the cathodic reaction rate thereby lowering the overall resistance of the cell. (Curve c). Additionally, no obvious redox change was observed when the blank was mixed with the two raw materials. The blanks with 1a and 2a exhibited oxidation waves at 1.02 and 1.49 V, respectively (curves d and e). These results indicated that substrate 1a was initially more susceptible to oxidation.

Figure 2 Cyclic voltammograms of substrates 1a and 2a in 0.1 M ⁿ Bu₄NI/DMA, using a Pt wire working electrode and glassy carbon and Ag/AgCl (0.1 M in DMA) as the counter and reference electrodes at 100 mV s^–1 scan rate: (a) blank (0.1 M ⁿBu₄NI in DMA), (b) blank + KI (20 mM), (c) blank + 1a (20 mM) + 2a (20 mM) + KI (20 mM) + H₂C₂O₄·2H₂O (20 mM), (d) blank + 1a (20 mM), (e) blank + 2a (20 mM).

Scheme 4 Proposed mechanism

Based on these experimental results and previous reports,[15] a plausible mechanism for the reaction of 1a and 2a is shown in Scheme [4]. Initially, the iodide is oxidized to an iodine radical that then reacts with 1a to form 2-iodo-1-(4-methylphenyl)ethanone (C). The presence of an acid facilitates the condensation between the diamine 2a and iodinated intermediate C to form imine D. Subsequently, an intramolecular nucleophilic attack of the amino group on the C–I bond generates a cyclic intermediate E, and anodic oxidation potentially yields the desired aromatization product 3aa. Simultaneously, the reduction of protons at the cathode resulted in the release of hydrogen.

In summary, a practical and atom-economic electrocatalytic strategy has been developed for the intramolecular dehydrogenative cyclization of quinoxaline derivatives. This strategy resulted in the production of various 2-substituted quinoxalines in moderate to good yields.[16] The electrocatalytic approach modulated the reactivity of the starting materials to facilitate complex transformations in a single step. Oxidative dehydrogenation cyclization was performed to achieve this transformation without using transition metals or stoichiometric chemical oxidants, under mild conditions. Notably, the reaction, which releases H₂ as a theoretical byproduct, has a high atom economy. Furthermore, the broad substrate scope and late-stage functionalization features of this method extend its adaptability. We expect that this novel approach will be used to construct complex quinoxaline derivatives as active ingredients.

Conflict of Interest

The authors declare no conflict of interest.

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• 16 Quinoxalines 3aa–be; General Procedure A tube was charged with the appropriate ketone 1 (0.5 mmol, 1.0 equiv), amine 2 (0.75 mmol, 1.5 equiv), KI (0.25 mmol, 0.5 equiv), H₂C₂O₄·2 H₂O (0.5 mmol, 1.0 equiv), ⁿ Bu₄NI (0.25 mmol, 0.5 equiv), and DMA (6 mL). The tube was then equipped with a graphite felt anode and a Pt foam cathode, and its contents were subjected to constant-current (15.0 mA) electrolysis at 100 °C for 24 h. After complete consumption of the starting material, the mixture was extracted with EtOAc, and the organic layer was dried (Na₂SO₄), filtered, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc–hexane). 2-Phenylquinoxaline (3aa)^17a Yellow solid; yield: 70 mg (68%). ¹H NMR (600 MHz, CDCl₃): δ = 9.33 (s, 1 H), 8.22–8.19 (m, 2 H), 8.15 (ddd, J = 22.2, 8.4, 1.8 Hz, 2 H), 7.77 (dddd, J = 23.4, 8.4, 7.2, 1.2 Hz, 2 H), 7.59–7.52 (m, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 152.2, 143.7, 142.7, 141.8, 137.1, 130.7, 130.6, 130.0, 129.9, 129.5, 129.4, 127.9. 2-(4-Bromophenyl)quinoxaline (3ak)^17b Yellow solid; yield: 63 mg (44%). ¹H NMR (600 MHz, CDCl₃): δ = 9.27 (s, 1 H), 8.11 (ddd, J = 8.4, 6.4, 2.0 Hz, 2 H), 8.08–8.04 (m, 2 H), 7.80–7.72 (m, 2 H), 7.70–7.65 (m, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 150.4, 142.6, 142.0, 141.5, 135.4, 132.1, 130.3, 129.6, 129.4, 129.0, 128.8, 124.8.
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Publikationsverlauf

Eingereicht: 15. Mai 2024

Angenommen nach Revision: 29. Mai 2024

Accepted Manuscript online:
05. Juni 2024

Artikel online veröffentlicht:
14. Juni 2024