Copper(II)-catalyzed synthesis of sulfonyl-functionalized quinone-fused cyclopenta[b]indoles via four-component cascade annulation

Abstract

A copper-catalyzed four-component cascade annulation is realized to access novel sulfonyl-functionalized quinone-fused cyclopenta[b]indoles with high step economy and broad substrate scope, and 34 examples are constructed in one pot with up to 88% yield. This process includes sulfonyl radical triggered tandem cyclization by selective 1,1,2-trifunctionalization of terminal acetylene.

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Introduction

Cyclopenta[b]indoles, a class of the most important carbazole analogues, are common motifs in natural products and biologically active molecules, exhibiting various biological activities (Fig. 1).^1–3 For example, paspaline has good antibacterial and insecticidal activities, MK-0524 was a D2 (PGD2) receptor (DP) antagonist, yeuhchukene has antifertility activity. Fused quinones are also an important class of organic compounds that are widely used in biomedicine, probes, materials and other fields because of their unique biological activity and electron transfer properties.^4,5 However, there are few reports on quinone-fused cyclopenta[b]indole derivatives. Developing practical and scalable synthesis strategies to construct novel quinone-fused cyclopenta[b]indole derivatives is desirable.

Fig. 1 Some representative carbazole polycyclic compounds.

Multi-component reactions can rapidly and selectively realize the synthesis of a single complex structure product from three or more compounds, which plays an important role in pesticide chemistry, natural medicine chemistry, etc.^6,7 Sulfones are an important class of organic compounds due to their unique biological and pharmacological activity.⁸ In recent years, numerous transition-metal-catalyzed/visible-light-mediated sulfonyl radical triggered synthetic methods have been developed for accessing highly functionalized sulfones from sodium sulfinates, sulfonyl chlorides and sulfonic acids.^9–20

Indolyl naphthoquinone is an important synthon for accessing nonclassical conjugated dienes, which can undergo synergistic cyclization, simple mono-functionalization and tandem difunctionalization. In recent years, our group and the Sun group have achieved the Diels–Alder reaction of indolyl naphthoquinone with activated alkenes and alkynes to generate multiple quinone-fused carbazole derivatives (Scheme 1A, (a)–(c)).^21–23 Some of the compounds present high fluorescence quantum yields and could be used as colorimetric sensors to identify carbonates. Through the mono-functionalization of the conjugated diene, Fe(III) catalyzed radical reduction to give dihydronaphthofuran (Scheme 1A, (d)) and merging oxidative coupling and cascade palladium-catalyzed intramolecular oxidative cyclization to give spiro polycyclic N-heterocycles or indolecarbazoles were respectively developed in 2021 and 2024.^24,25 Moreover, successive electrophilic addition/C–N bond coupling or successive electrophilic addition/radical addition were realized to provide various quinone-fused pyrrole[b]indoles or quinone-fused cyclopenta[b]indoles (Scheme 1A, (e) and (f)), and they exhibited good photophysical properties and were promising as fluorescent probes to selectively identify methanesulfonic acid or Type I photosensitizers.^26,27 However, no research on sulfonyl substituted fused-quinones has been reported. Herein, we realized the construction of sulfonyl-functionalized quinone-fused cyclopenta[b]indoles through a four-component reaction from quinone 1a, indole 2a, alkyne 3a and 4-methylbenzenesulfonyl chloride 4a (Scheme 1B).

Scheme 1 Common reaction modes of indolynaphthoquinone and our synthetic strategy.

Results and discussion

We commenced our study in the presence of Cu(acac)₂ (10 mol%) and DPPE (15 mol%), 4-methylbenzenesulfonyl chloride 4a was used as the sulfonyl radical source to to stirred with quinone 1a, indole 2a and alkyne 3a in 2 mL of DCE in a sealed tube at 120 °C for 4 hours, successfully affording sulfonyl-functionalized quinone-fused cyclopenta[b]indole 5 in 49% yield (Table 1, entry 1 and Table S1†). Then the reaction parameters are extensively screened to identify the optimized conditions. The reaction cannot proceed at all without Cu(acac)₂ (Table 1, entry 2), whereas without the addition of DPPE, the yield of the product decreases significantly (Table 1, entry 3). Multiple catalysts were screened (Table S2†), such as copper salts (Table 1, entries 4 and 5), cobalt salts, nickel salts and iron salts, among which Cu(acac)₂ shows better efficiency. A series of ligands were investigated (Table S3†); BINAP provides a higher yield than DPPE (Table 1, entry 6), although other N-, O-, and P-ligands can also give the target product. Among the screening of solvents (Table S4†), only DCE and CH₃CN provided 5 in an acceptable yield, while DCE was better than CH₃CN. The ratio of substrates was also screened (Table S5†). Optimal conditions are as shown in entry 6 in Table 1 and the reaction delivers the product in 56% yield. Moreover, our group is interested in the development of copper-catalyzed asymmetric syntheses of sulfonyl-functionalized quinone-fused cyclopenta[b]indoles, and preliminary exploration of chiral ligands was attempted (Table S6†), but only very low enantioselectivity was realized. Therefore, this work mainly focuses on copper-catalyzed four-component cascade cyclization to rapidly synthesise racemic sulfonyl-functionalized quinone-fused cyclopenta[b]indoles and further experimental exploration of enantioselectivity will be carried out in the laboratory.

Table 1 Optimization of the reaction conditions^a,b,c

Entry	Variation	Yield (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), 3a (0.6 mmol), 4a (0.6 mmol), Cu(acac)2 (10 mol%), DPPE (15 mol%), DCE (2 mL), T = 120 °C, t = 4 h. b Yield refers to the isolated product. c N.D. means not detected.
1	None	49
2	Without Cu(acac)2	N.D.
3	Without DPPE	35
4	CuCl2·2H2O instead of Cu(acac)2	38
5	CuBr2 instead of Cu(acac)2	29
6	BINAP instead of DPPE	56

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After the reaction conditions were optimized, we turned our attention to evaluating the substrate scope of the copper-catalyzed four-component cascade reaction. The transformation features wide functional group tolerance and the results are shown in Scheme 2. Several naphthoquinones such as 5,8-dimethylnaphthalene-1,4-dione, 6,7-dimethylnaphthalene-1,4-dione, 6,7-dibromonaphthalene-1,4-dione and 1,4-anthraquinone were tested, furnishing a variety of fused-quinones in moderate to good yields (5–9). Then, a variety of indoles with a range of functionalities were shown to be compatible. Many valuable functional groups such as methyl, methoxy, chloro, bromo, and allyl at 1-, 4-, 5-, 6-, and 7-positions of indole were well tolerated and afforded the corresponding compounds 10–16 and 19. In particular, the 1H-indole gives the fused-quinone (17) in a significantly reduced yield and the target product (18) of N-acetylindole is not detected by TLC, which may be caused by a decrease in the electron cloud density at the 2-position of indole. Next, various functionalized terminal alkynes were examined. 4-Phenyl-1-butyne can be suitable for this reaction under appropriate conditions, but the product (20) can be obtained only in 23% yield. Phenylacetylene with different substituents, such as methoxy, methyl, chlorine, and bromine, reacts smoothly to afford the target products in 49–88% yields (21–26). Among them, ortho- and meta-substituted ethynyltoluene afford the products in lower yields probably due to steric effects. In addition, this reaction is also suitable for heteroaromatic terminal alkynes, and the product 2-ethynylthiophene 27 is isolated in 25% yield. Finally, a variety of substituted sulfonyl chlorides were tested to probe the efficacy of the four-component reaction. To our delight, alkyl sulfonyl chlorides were readily converted, affording products (28 and 29) in moderate yields. Electron-donating substituents, electron-neutral substituents, and electron-withdrawing functional groups (fluoro, chloro and bromo) were readily converted to the desired compounds (30–36) in 52–80% yields. Moreover, naphthalene sulfonyl chloride and thiophene sulfonyl chloride could also be transformed into products 37 and 38 in good yields. In addition, when the reaction was scaled up to 5 mmol, the yield of compound 24 did not decrease significantly, indicating that the reaction has the prospect of industrialization.

Scheme 2 Substrate scope of the transformation.^{a,b,c,d,e a} Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), 3a (0.6 mmol), 4a (0.6 mmol), Cu(acac)₂ (10 mol%), BINAP (15 mol%), DCE (2 mL), T = 120 °C, t = 4 h. ^b T = 120 °C, t = 12 h. ^c T = 140 °C, t = 12 h.^d Yield refers to the isolated product. ^e N.D. means not detected.

To investigate the mechanism of the four-component annulation, several control experiments were performed (Scheme 3A). Initially, when quinone 1a, indole 2a, alkyne 3a and 4-methylbenzenesulfonyl chloride 4a were stirred under the standard conditions for 3 hours, not only by-products (E)-1-((2-chloro-2-phenylvinyl)sulfonyl)-4-methylbenzene 39 and 5-methyl-7-phenyl-5H-naphtho[2,3-c]carbazole-8,13-dione 42 were isolated, but also (E)-2-(1-methyl-1H-indol-3-yl)-3-(1-phenyl-2-tosylvinyl)naphthalene-1,4-dione 41 was isolated, further confirmed by X-ray crystal structure analysis (eqn (I)), which converts smoothly to the annulation product 5 in good yield in the presence of Cu(acac)₂ (eqn (1) of Scheme 3A). The results of the experiment given in eqn (II) to eqn (V) show that the intramolecular cyclization of the olefin intermediate 41 to the sulfonyl-functionalized quinone-fused cyclopenta[b]indole 5 is a Lewis acid-catalyzed thermodynamic cyclization. The presence of metals and ligands will inhibit this process (eqn (II) and eqn (III)). Only in the presence of a ligand, intermediate 41 is more easily converted into the quinone-fused carbazole 42 (eqn (IV)). The results of the experiment given in eqn (VI) and eqn (VII) suggest that the four-component annulation includes a radical addition process of intermediates 40, 3a and 4a, and not 1a, 3a and 4a.

Scheme 3 Mechanistic study and the proposed mechanism.

On the basis of our mechanistic studies and reported literature,^{9–20,28–36} a plausible mechanism is proposed with substrates 1a, 2a, 3a and 4a (Scheme 3B). Initially, indolylquinone 40 is generated from the Michael addition of quinone 1a and indole 2a with the conversion of [Cu^II] species to [Cu^I] species. Then through a SET pathway, sulfonyl chloride 4a is converted to sulfonyl radical A with the in situ-formed [Cu^IICl] species, which then undergoes selective radical addition of the alkyne to afford the alkene radical intermediate B. Next, a small amount of intermediate B can abstract Cl˙ from [Cu^IICl] species to give the by-product (E)-1-((2-chloro-2-phenylvinyl) sulfonyl)-4-methylbenzene 39, and most of intermediate B follow a radical addition reaction with indolylquinone 40 to afford intermediate F, which is then converted to intermediate 41 through SET by the in situ-formed [Cu^I] species. Finally, driven by [Cu] species, most of intermediate 41 undergoes nucleophilic addition and 1,3-hydrogen migration (HAT) to obtain sulfonyl-functionalized quinone-fused cyclopenta[b]indole 5, while small amounts of quinone-fused carbazole 42 is provided by 6-π electron cyclization and demethylsulfonyl group of intermediate 41.

Conclusion

In summary, we conveniently constructed novel sulfonyl-functionalized quinone-fused cyclopenta[b]indoles by copper-catalyzed four-component cascade cyclization from naphthoquinone, indole, terminal alkyne and sulfonyl chloride. The reaction has good functional group tolerance and can be successfully scaled up to the gram level. Mechanistic studies indicated that this process was sulfonyl radical triggered tandem cyclization through selective 1,1,2-trifunctionalization of terminal acetylene with the construction of four new C–C bonds in one pot. Related photophysical properties and bioactivities of sulfonyl-functionalized quinone-fused cyclopenta[b]indoles will be further explored in the laboratory.

Data availability

Methods and experimental procedures, crystal data, compound characterization data, and NMR spectra can be found in the ESI.† All relevant data are within the manuscript and its ESI.† CCDC experimental crystal structure determination: 2322361, 2322362.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Sichuan Science and Technology Program (No. 2023NSFSC1977 ).

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2322361 and 2322362. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01560f

‡ Hong Xu and Jie Liao contributed equally to this work.

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