Photocatalyzed de novo synthesis of fused tetracyclic skeletons via stepwise formal [3 + 2]/[4 or 5 + 2] cycloadditions

Abstract

We successfully developed an unprecedented visible light-promoted synthesis route to fused tetracyclic skeletons with rich sp³ carbons through stepwise radical cycloadditions and further cyclization of the final radical intermediates with adjacent aromatic rings. This convenient and sustainable protocol features mild reaction conditions, excellent H₂O and air tolerance, good functional group compatibility and wide substrate adaptability. Moreover, based on direct excitation, radical-trapping, radical clock, and EPR experiments, a possible stepwise formal [3 + 2]/[4 or 5 + 2] cycloaddition process was proposed.

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Introduction

Sp³-rich molecules have drawn increased attention from medicinal chemists because more highly complex molecules with fused and saturated carbocyclic systems can be constructed with more stereocenters and higher three-dimensionality, which make them access greater chemical space with greater selectivity and fewer off-target effects.¹ However, they were usually poorly accessible to fused ring structures with cyclopentanes by pericyclic processes, even though multistep prefunctionalization processes were carried out in the presence of metal catalysts, halo-substituted and redox reagents because of the low site-selectivity.²

“Formal” cycloadditions (FCAs) driven by the opening of strained and saturated rings have been recognized as an ideal approach for the de novo construction of another ring with unrivaled site and stereo-selectivity.³ Metallacycles and zwitterions were usually generated from the opening of saturated rings through transition metals⁴ and heterolytic activation,⁵ respectively, and exploited for the reconstruction of ring skeletons via FCAs. Furthermore, many FCAs were developed from homolytic ring openings because of the extensive investigation and significant progress of photochemistry (Scheme 1).⁶ The homolysis of a Π bond gave a radical adjacent to the strained ring, which drove the ring opening to a biradical intermediate from β-scission. The further addition of the generated biradical intermediate with the Π system led to the formation of another ring (Scheme 1a).⁷ The radical adjacent to the strained ring could also be generated from the radical addition of the Π bond and led to the formation of another radical intermediate via the ring opening (Scheme 1b).⁸ F-(3 + 2)-CAs of the generated radical intermediate with another alkene/alkyne gave the corresponding radical intermediate, which was transformed into an elimination product. Moreover, single electron transfer was also performed to produce the radical adjacent to the strained ring and drive the ring opening process (Scheme 1c).⁹ Despite the significant progress of FCAs in the past decades, there has been still an obvious limitation that the reaction diversity is poor and leads to finite structural diversity of target products. Specifically, it was found that the final radicals were usually quenched by elimination,¹⁰ halogenation¹¹ or hydrogen atom abstraction¹² (Scheme 1c-1), which were formed from the addition of ring opening intermediates with exogenous alkenes or alkynes.

Scheme 1 Formal cycloadditions (FCAs) driven by the homolytic opening of strained, saturated rings. (a) Homolysis of the Π bond gave ring-opening intermediates. (b) Radical addition of the Π bond gave ring-opening intermediates. (c) Single electron transfer gave ring-opening intermediates.

To the best of our knowledge, there has been no successful study on the further cyclization or coupling of the final radical intermediates with adjacent aromatic rings or other functional groups, probably due to the instability of the radicals, poor selectivity and the major steric hindrance and ring strain. Despite the odds, we questioned whether further cyclization of the final radical intermediates could be achieved based on the ingenious substrate design and detailed condition optimization. Herein, we report the idea of successfully achieving the cyclization of the final radical with an adjacent aromatic ring to give another 6 or 7-membered ring (Scheme 1c-2).

Results and discussion

Our initial investigation began with 1-(1H-indol-1-yl)-2-methylprop-2-en-1-one 1 and dimethyl 2-(iodomethyl)cyclopropane-1,1-dicarboxylate 2 as the model substrates to determine the optimal reaction conditions (Table 1). To our delight, the desired product 3 was generated in 74% isolated yield under blue LED irradiation for 5 hours in the presence of a fac-Ir(ppy)₃ photocatalyst, with In(OTf)₃ and DIPEA being the optimal Lewis acid and base, respectively (Table 1, entry 1). Notably, other photocatalysts such as Eosin Y, Na₂-Eosin Y, rhodamine B, Eosin B, and [Ir(ppy)₂(dtbbpy)]PF₆ almost completely shut down the radical cyclization (Table 1, entries 2 and 3). The reduction of the Lewis acid led to more raw material surplus (Table 1, entries 4 and 5). The recovery rate experiment of 2 in the presence/absence of a Lewis acid proves the chelate of the Lewis acid and carbonyl groups can stabilize the free radical intermediate, reduce the ring opening rate of 2 and increase the likelihood of stepwise formal cycloadditions (as shown in Table S2†). Using other bases such as TEA, DMAP, Na₂CO₃, or Cs₂CO₃ or replacing In(OTf)₃ with Zn(OAc)₂, ZnCl₂, Yb(OTf)₃, Zn(OTf)₂, or Cu(OTf)₂ were all less efficient (Table 1, entries 7–9). Meanwhile, the absence of bases also blunted the product formation considerably (Table 1, entry 6). Subsequently, a series of other solvents and different ratios of the mixed solvent were screened (Table 1, entries 10–12). Of them, DMSO/H₂O (4 : 1) was found to be the best media. Some other light sources were then investigated, but all seemed to weaken the reaction (Table 1, entries 13 and 14).

Table 1 Optimization of the reaction conditions^a

Entry	Variation from “standard conditions”	Yield^b (%)
a Reaction conditions: 1 (0.3 mmol, 55.6 mg), 2 (0.6 mmol, 178.8 mg), fac-Ir(ppy)3 (2 mmol%, 3.9 mg), In(OTf)3 (0.75 mmol, 421.5 mg), DIPEA (0.3 mmol, 38.8 mg), DMSO/H2O (4 : 1) (3 mL), 5 h, blue light (40 W, LED, wavelength 420 nm–430 nm). TEA: triethylamine, DMAP: 4-N,N-dimethylaminopyridine, DIPEA: N,N-diisopropylethylamine, DMSO: dimethyl sulfoxide, DMF: N,N-dimethylformamide, ACN: acetonitrile, THF: tetrahydrofuran. b Yields were determined by ^1H NMR using dibromomethane as the internal standard. c Isolated yield. d Reaction for 9 h. e Blue light (40 W, LED, wavelength 390 nm–400 nm). f 300 W simulated sunlight.
1	None	74^c
2	Eosin Y, Na2-Eosin Y, rhodamine B or Eosin B instead of fac-Ir(ppy)3	Trace, trace, 0, 0
3^d	[Ir(ppy)2(dtbbpy)]PF6 instead of fac-Ir(ppy)3	Trace
4	1.0 or 1.5 eq. of In(OTf)3 instead of 2.5 eq. of In(OTf)3	34, 50
5	Without In(OTf)3	23
6	Without DIPEA	21
7	TEA or DMAP instead of DIPEA	46, 36
8	Na2CO3 or Cs2CO3 instead of DIPEA	37, 39
9	Zn(OAc)2, ZnCl2, Yb(OTf)3, Zn(OTf)2, or Cu(OTf)2 instead of In(OTf)3	36, 50, 18, 24, 0
10	DMSO : H2O = (6 : 1, 5 : 1, 3 : 1, 2 : 1, v/v)	74, 72, 44, 16
11	DMSO (3 mL) as a solvent	62
12	DMF, ACN, CH2Cl2, or THF instead of DMSO	12, 0, trace, trace
13^e	Blue LEDs	40
14^f	Simulated sunlight	42

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Subsequently, the substrate scope of indoles and iodomethylcyclopropanes with geminal dicarbonyl substitution compounds was investigated (Table 2). Reactions involving substrates containing H, electron-donating groups (Me, OCH₃), halogen groups (F, Cl, Br, I) and electron-withdrawing groups (CF₃, CN, CO₂Me) on the indole ring proceeded smoothly and gave the desired products in moderate to good yields (3–9, 11–21).

Table 2 Substrate scope of indoles and iodomethylcyclopropanes with geminal dicarbonyl substitution compounds^a,b

a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), fac-Ir(ppy)₃ (2 mmol%, 3.9 mg), In(OTf)₃ (0.75 mmol, 421.5 mg), DIPEA (0.3 mmol, 38.8 mg), DMSO/H₂O (4 : 1) (3 mL), 5–10 h, blue light (40 W, LED, wavelength 420 nm–430 nm), isolated yield. b Only one of the diastereomeric products was obtained.

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It seemed that electronic effects and different positions of substitution patterns (C3–C6) on the indole ring showed no great influence (3–7, 12, 14–21). The structure of 12 was confirmed by X-ray crystallographic analysis (12, CCDC = 2312565†). It is worth noting that, due to the difficulty of purification, only one of diastereomeric product was obtained as for the product 9, 13 and 24. Gratifyingly, this strategy was compatible with protecting groups such as –OBn (10). When both the C-5 and C-6 positions of the indole ring possessed halogen substituents, the reaction proceeded well to form the intriguing polycyclic products 22 and 23 in good yields. The good halogen tolerance of these compounds made them amenable for further functionalization by C–C coupling reactions. Then, iodomethylcyclopropanes with geminal dicarbonyl substitution compounds were tested. When R² was replaced by the protecting group –Bn, the desired product 24 was obtained in 40% yield. In addition, the reaction also proceeded smoothly when R³ was substituted by monomethyl (25).

The reaction could also be extended to biphenylacetylene compounds to obtain another 7-membered ring through the cyclization of the final radical with an adjacent aromatic ring (Table 3). Gratifyingly, substrates bearing substituents on the para-position of the phenyl ring proceeded successfully under the procedure (26–30). When 2-ethynyl-4′-fluoro-1,1′-biphenyl was used as a substrate, 33% of iodinated product was obtained (data are shown in the ESI,†28′). Importantly, the arene ring in the substrate was not limited to the benzene system. When 2-(2-ethynylphenyl)thiophene was employed under the reaction conditions, product 31 was isolated in 28% yield.

Table 3 Substrate scope of biphenylacetylene compounds^a

a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), fac-Ir(ppy)₃ (2 mmol%, 3.9 mg), Zn(OAc)₂ (0.75 mmol, 102.2 mg), DIPEA (0.3 mmol, 38.8 mg), DMSO/H₂O (4 : 1) (3 mL), 5–10 h, blue light (40 W, LED, wavelength 420 nm–430 nm), isolated yield.

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To explore the mechanism of this reaction, several experiments were conducted, as shown in Scheme 2. No desired product was detected in the absence of a photocatalyst or light, indicating that the reaction can proceed normally only when visible light and a photocatalyst exist simultaneously (Scheme 2a). The results of the light on/off experiment are shown in Fig. 1. It is found that the reaction stopped immediately when the light was turned off and resumed efficiently with the reintroduction of the light source, indicating that continuous radical generation under light irradiation is essential for this conversion. Moreover, the transformation was strongly inhibited when a radical scavenger TEMPO, 1,1-diphenylethylene or BHT was introduced (Scheme 2b). Among them, part of the introduced 1,1-diphenylethylene was converted to benzophenone under these conditions (see the ESI,†4–3–2).

Scheme 2 Summary of mechanistic findings.

Fig. 1 Light on/off experiments.

In addition, the cyclization product 32 between 1-ethynyl-4-methoxybenzene and 2 was generated in 32% isolated yield (Scheme 2b). Furthermore, in the radical clock experiments, the ring-opening product 33 was detected by HRMS (Scheme 2c). When 2′ was used instead of 2 to react with indole under standard conditions, the corresponding ring-opening product 33′ was confirmed by NMR (Scheme 2c). Moreover, 97.16% alkyl radical (g = 2.03211, A_N = 14.71 G, A_H = 3.26 G) was detected based on an electron paramagnetic resonance study (Fig. 2). The above results revealed that this process might involve a radical pathway and the generation of an alkyl radical.

Fig. 2 The electron paramagnetic resonance spectra of 1 and 2.

According to the mechanism research and related literature, a possible mechanism was proposed (Scheme 3).^11c Initially, Ir(III) was converted to excited *Ir(III) under blue light irradiation. Then *Ir(III) was oxidized to Ir(IV) by giving up an electron to compound 2, generating radical intermediate 2-1 and driving the ring-opening process. The generated homoallylic radical 2-2 then underwent a [3 + 2] cyclization with 1 to provide radical intermediate 3-1. The ensuing intramolecular cyclization gave the radical intermediate 3-2. Finally, the desired product 3 was achieved via further intramolecular cyclization of the final radical intermediate 3-2 under the action of the Ir photocatalyst.

Scheme 3 Plausible reaction mechanism.

Conclusions

In summary, we successfully developed a novel synthesis route to fused tetracyclic skeletons through further cyclization of the final radical intermediates with adjacent aromatic rings. This methodology provides a unique strategy to construct lucrative, functionally decorated sp³-rich ring systems, which has great reference value in the field of drug development and clinical trials. Many kinds of complicated substrates were successfully shown to be suitable for this method, documenting the great compatibility and generality of this protocol.

Author contributions

Chengkou Liu, Zheng Fang and Kai Guo designed the experiments. Wenjing Guan, Jinlin Hang and Guanru Liu performed the experiments. Wenjing Guan, Jinlin Hang, Yaqi Qiao, Chengcheng Yuan, Lufang Liao and Xiaoqing Fan analysed the data. Wenjing Guan and Chengkou Liu drafted the manuscript. All authors contributed to the preparation of the manuscript.

Data availability

The data underlying this study are available in the published article and its ESI.† Detailed experimental procedures, characterization data, and copies of spectra of products (¹H and ¹³C NMR and HRMS) are available in the ESI† for publication. CCDC 2312565† contains the supplementary crystallographic data for this paper.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was supported by the Natural Science Foundation of Jiangsu Province, Frontier Project (BK20212003).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2312565. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01729c

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