Synthesis of furoquinolines from 2-alkenylanilines via anodic dearomatization and cascade cyclization

Abstract

Herein, we report an anodic dearomatization reaction followed by a one-pot nucleophilic cycloaddition/Bischler–Napieralski reaction of 2-alkenylanilines for the construction of structurally diverse dihydrofuro[2,3-g]quinolinones. These compounds represent an understudied subclass of furoquinoline scaffolds. This metal-free protocol features high atom economy and good functional group tolerance, providing a practical route to dihydrofuro[2,3-g]quinolinones. Notably, these products can be readily oxidized to furo[2,3-g]quinolines, which hold potential for the preparation of bioactive compounds.

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Furoquinoline derivatives constitute core structural motifs in numerous natural products and other biologically active compounds.¹ Owing to their broad spectrum of biological activities, including antimalarial,² anticancer,³ and antibacterial activities,⁴ as well as applications in materials science such as cyanine dyes and metal corrosion inhibitors,^5,6 the efficient construction of furoquinoline frameworks has attracted considerable attention from synthetic chemists. Furoquinoline compounds can be classified into furo[2,3-b]quinolines,⁷ furo[2,3-c]quinolines,⁸ and furo[2,3-g]quinolines (Fig. 1).⁹ While a variety of synthetic strategies have been developed for the construction of furo[2,3-b]- and furo[2,3-c]quinoline scaffolds, methods for the synthesis of furo[2,3-g]quinoline frameworks remain scarce. In view of their unique structural features and potential biological activities, the development of efficient synthetic methods to further expand the chemical space of furoquinoline derivatives is therefore of significant scientific interest.

Fig. 1 Furoquinolines: their skeleton types.

Electrochemical reactions represent an emerging and promising technique for sustainable organic synthesis, enabling efficient and green construction of molecular frameworks under mild reaction conditions.¹⁰ Recently, we achieved the anodic dearomatization of 2-alkynylanilines, and the resulting intermediates were converted into a variety of multifunctionalized benzenoid indoles through simple chemical transformations.¹¹ As illustrated in Scheme 1, we envision that the electrochemical oxidative dearomatization of 2-alkenylanilines would generate intermediate I, which possesses multiple reactive sites. With an appropriately designed alkene as the nucleophile, nucleophilic attack is anticipated to occur at the C-6 position owing to steric hindrance at the C-4 position, thereby facilitating intramolecular nucleophilic cycloaddition with the alkene to construct a dihydrofuran ring and form intermediate II. Additionally, intermediate II contains the requisite functional groups for a Bischler–Napieralski reaction,¹² which can undergo cyclization to form a quinoline ring, ultimately affording dihydrofuro[2,3-g]quinolinones.

Scheme 1 Construction of dihydrofuro[2,3-g]quinolones from 2-alkenylanilines.

To commence our study, N-(4-methoxy-2-vinylphenyl)acetamide (1a) was employed as a model substrate to screen suitable reaction conditions. After systematic screening, the optimal conditions were established as follows: electrolysis was conducted at a constant current of 2 mA using a graphite anode and a platinum cathode in an undivided cell, with 4.0 equiv. of LiClO₄·3H₂O as the electrolyte in a mixed solvent of MeOH/H₂O (6 : 1, v/v) for 4 h, affording the desired dearomatized product 2a in an excellent isolated yield of 92% (Table 1, entry 1).

Table 1 Optimization of reaction conditions^a

Entry	Variation from standard conditions	Yield^b (%)
a Standard conditions: 1a (0.1 mmol, 1.0 equiv.), LiClO4·3H2O (4.0 equiv.), MeOH (3 mL), H2O (0.5 mL), undivided cell equipped with a carbon plate anode (0.1 cm^2) and a platinum plate cathode (0.1 cm^2), 2 mA, rt, 4 h.b Isolated yields.
1	None, 4 h	92
2	3 mA	81
3	1 mA, 14 h	85
4	n-Bu4NClO4 instead of LiClO4·3H2O	81
5	n-Bu4NBF4 instead of LiClO4·3H2O	71
6	n-Bu4NPF6 instead of LiClO4·3H2O	64
7	LiCl instead of LiClO4·3H2O	54
8	MeOH : H2O = 3 : 1	53
9	MeOH : H2O = 9 : 1	72
10	MeOH as solvent	68
11	C (+), C (−)	78
12	Pt (+), Pt (−)	65
13	Steel (+), Pt (−)	60
14	GC (+), Pt (−)	38
15	RVC (+), Pt (−)	58
16	No electric current	0

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Increasing the current to 3 mA or decreasing it to 1 mA, even with the reaction time extended to 14 h, resulted in a noticeable decrease in product yield (entries 2 and 3). Electrolyte screening experiments demonstrated that ammonium salts and other lithium salts led to diminished yields compared with lithium perchlorate (entries 4–7). In addition, adjusting the volume ratio of MeOH to H₂O—either increasing or decreasing the proportion of methanol—compromised the reaction yield (entries 8–10). Moreover, replacing the electrode combination with alternative configurations (e.g., carbon plate anode and cathode, platinum plate anode and cathode, steel anode and platinum cathode, glassy carbon (GC) anode and platinum cathode, or reticulated vitreous carbon (RVC) anode and platinum cathode) failed to improve the yield (entries 11–15). Notably, the target product 2a could not be detected in the absence of an applied current (entry 16).

With the optimal reaction conditions in hand, the substrate scope of 2-alkenylanilines was systematically examined (Scheme 2). We first assessed the influence of different protecting groups (PGs) on the anodic oxidation process. When the acetyl group was replaced with other protecting groups (2b–2j), a decrease in the reaction yield was observed (68–84%). Subsequently, the effect of the R² substituent was investigated. When R² was a phenyl group, only moderate yields were obtained, irrespective of the presence of electron-donating or electron-withdrawing substituents at the para position (2k and 2l, 71–75%). In contrast, variation of the R³ substituent revealed that a methyl group was optimal, affording the highest yield (2m, 84%), whereas replacement with a phenyl group or substituted phenyl groups led to diminished yields (2n–2q, 67–78%). Furthermore, substrates in which the 2-alkenyl moiety was incorporated into endocyclic double bonds—such as those within phenyl, thiophene, furan, benzofuran, and carbazole frameworks—were also compatible, reacting smoothly to give the corresponding products in good to excellent yields (2r–2v, 81–93%). Similarly, a decrease in yield was also observed when the PG group was replaced with butyryl (2w, 86%) or benzoyl groups (2x, 52%).

Scheme 2 The scope of 2-alkenylanilines for anodic oxidative dearomatization. Reactions were carried out using standard conditions of Table 1, entry 1. ^a Gram-scale experiment: 1a (1.0 g).

To explore the nucleophilic cycloaddition reaction, intermediate 2a was selected as the model substrate, with 4-methoxystyrene employed as the nucleophile. Gratifyingly, the reaction displayed excellent regioselectivity, exclusively delivering the C-6-selective cyclization product as the sole regioisomer. The cyclization proceeded smoothly to generate the corresponding dihydrofuran intermediate. Notably, this intermediate could be directly subjected to a subsequent transformation without isolation or purification. Treatment with trifluoromethanesulfonic anhydride (Tf₂O) and 2-chloropyridine enabled a Bischler–Napieralski cyclization, efficiently constructing the quinoline ring and affording 2-(4-methoxyphenyl)-6-methyl-2,3-dihydrofuro[2,3-g]quinoline (3a) in an 87% overall yield over two steps. The structure of 3a was unambiguously confirmed by single-crystal X-ray diffraction (CCDC 2529801, SI for details).¹³

Encouraged by this result, we next systematically examined the substrate scope of the cyclization reaction (Scheme 3). Initially, the compatibility of various alkenes with the model substrate 2a was evaluated. Both monosubstituted alkenes, including styrene, 1-naphthylethylene, and 2-vinylthiophene, as well as sterically hindered gem-disubstituted alkenes, underwent smooth cyclization to furnish the corresponding products 3b–3s in moderate to good yields. The nature and position of substituents on the styrene ring were found to exert a pronounced influence on the reaction outcome. For example, p-methylstyrene (e.g., 3d) afforded higher yields than its meta- or ortho-substituted counterparts (3b and 3c). Halogen-substituted styrenes (3h–3k) were inert in TMSOTf/CH₃CN; instead, the reaction proceeded smoothly only when using the stronger acid pentafluorobenzoic acid in the highly polar solvent hexafluoroisopropanol, affording the corresponding products in moderate yields. Notably, the use of indene as the nucleophile led to the formation of the pentacyclic fused-ring system 3t, albeit in a diminished yield of 11%. Subsequently, using 4-methoxystyrene as the model nucleophile, the generality of the reaction with different dearomatized intermediates 2 was investigated. The nature of the N-acyl protecting group was found to have a negligible impact on the reaction efficiency, as substrates bearing either aliphatic or aromatic formyl protecting groups smoothly delivered the desired heterocycles 3u–3y in yields ranging from 73% to 86%. Furthermore, styrene derivatives bearing a methyl group or substituted phenyl groups at the R³ position were also well tolerated, affording the corresponding dihydrofuro[2,3-g]quinoline products 3z–3ad in moderate yields (63–75%).

Scheme 3 The substrate scope of the cyclization reaction. ^a Isolated yields in two steps. ^b Reactions were performed in pentafluorobenzoic acid and hexafluoroisopropanol at room temperature.

Finally, incorporation of the styrene C=C double bond into cyclic frameworks including benzene, indole, thiophene, and benzofuran moieties allowed for the efficient construction of tetra- to hexacyclic fused furo[2,3-g]quinoline architectures 4a–4g (Scheme 4) in 79–92% yields.

Scheme 4 The substrate scope of the cyclization reaction with cyclic frameworks.

A plausible mechanism for the overall two-ring construction process is proposed in Fig. 2. Initially, substrate 1 undergoes single-electron oxidation at the anode to form Int-1, which is then subjected to nucleophilic addition with methanol to afford Int-2. Int-2 is further oxidized via single-electron transfer at the anode to generate Int-3, followed by hydrolysis to give intermediate 2. Under the promotion of TMSOTf, intermediate 2 undergoes nucleophilic cycloaddition with an alkene to yield Int-6. After coordination with TMSOTf, Int-6 is activated by 2-chloropyridine to form the corresponding onium salt, which finally undergoes intramolecular nucleophilic cycloaddition and aromatization to furnish product 3.

Fig. 2 Plausible mechanism.

As shown in Fig. 3, the dihydrofuro[2,3-g]quinoline products are readily amenable to oxidation to afford the corresponding furo[2,3-g]quinolines.¹⁴ For instance, 3o and 4f undergo oxidation upon treatment with DDQ to yield the respective furo[2,3-g]quinolones 5a and 5b in 89% and 86% yields, respectively.

Fig. 3 Oxidation of dihydrofuro[2,3-g]quinoline derivatives to the corresponding furo[2,3-g]quinolines.

In summary, we report a method to synthesize structurally diverse dihydrofuro[2,3-g]quinolinones via an anodic dearomatization reaction and a one-pot nucleophilic cycloaddition/Bischler–Napieralski reaction of 2-alkenylanilines. Furthermore, the resulting dihydrofuro[2,3-g]quinolinone products are readily oxidized to the corresponding furo[2,3-g]quinolines, which have potential applications in bioactive molecule synthesis.

Author contributions

X. Feng primarily conducted the experiments and analyzed the experimental data. R. Fan and Q. He conceived and designed the project and wrote the paper. All authors contributed to the discussion and revision of the paper.

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: supplementary figures, synthetic protocols and characterisation data for all compounds. See DOI: https://doi.org/10.1039/d6ob00390g.

CCDC 2529801 contains the supplementary crystallographic data for this paper.¹³

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 22371051) and the Natural Science Foundation of Shanghai Municipality (No. 24ZR1404700) for support of this research.

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