Stereocontrolled synthesis of heterocycles from unactivated alkynes by photoredox/nickel dual-catalyzed cyclization

Abstract

We introduce an innovative nickel/photoredox dual catalytic sulfonyl-arylation method for synthesizing heterocyclic compounds directly from unactivated alkynes and aryl iodides. This green chemistry approach sidesteps traditional Heck reactions, eliminating reliance on excess metal catalysts and reagents. The method ensures high chemical selectivity, curbing side reactions and facilitating the stereoselective 6-exo-dig cyclization. It simplifies the production of nitrogen- or oxygen-containing heterocyclics, such as 3,4-dihydroisoquinolin-1(2H)-ones, tetrahydroisoquinolines, and isochroman derivatives, with potential applications in medicinal chemistry. The dual catalytic system enhances reactivity with unactivated substrates, marking a significant step in synthetic chemistry.

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Innovative synthetic routes for constructing heterocycles, known for their atom economy and step efficiency, have garnered significant interest from academia and industry due to their potential to enhance drug optimization, including biological activity and pharmacokinetics.^1,2 The dehalogenation carbon cyclization reaction, which fuses aromatic halides with unsaturated carbon–carbon bonds, is particularly effective for creating monocyclic and polycyclic systems.³ This strategy has been adeptly applied to aromatic halide dehalogenation carbon cyclization with alkenes or alkynes through cascade reactions initiated by Heck-type reactions (Scheme 1a).⁴ The advent of visible-light-mediated photochemistry has transformed the field, with photoredox reagents acting as synergistic catalysts in transition-metal catalytic cycles, expanding the range of accessible reaction pathways.⁵ Notably, the metal/photoredox dual catalytic system has been successfully developed for aryl halide dehalogenation carbon cyclization with olefins, combining high efficiency with mild reaction conditions and aligning with green chemistry principles. Xia's group has notably pioneered a nickel/photoredox dual catalytic cyclization process for the aryl alkylation of aryl halides with non-activated olefins, yielding valuable indanethylamine derivatives, marking a significant advancement in catalytic technology (Scheme 1b).⁶ Despite breakthroughs in the cyclization and difunctionalization of unactivated alkynes with aryl halides, these processes still predominantly rely on Heck-type reactions, necessitating metal catalysts and stoichiometric oxidants or reducing agents.⁷

Scheme 1 The catalyzed cyclization/difunctionalization of unsaturated carbon–carbon bonds.

Drawing inspiration from recent advancements, we propose a nickel/photocatalytic intramolecular cyclization strategy as an efficient and direct alternative for synthesizing heterocyclic frameworks with nitrogen or oxygen (Scheme 1c). This innovative method promises a one-step synthesis under mild conditions. However, foreseeable competitive side reactions pose a challenge in the intramolecular cyclization of unactivated alkynes catalyzed by nickel/photoredox dual catalysts. The lower affinity and reactivity of these alkynes towards nickel catalysts could impede the migration–insertion process, potentially leading to the reduction hydrogenation of halogenated benzenes⁸ or direct cross-coupling of sulfonyl radicals with aryl halides.⁹ Furthermore, in the photosensitizer-catalyzed dehalogenation cyclization of aryl halides and alkynes, the formation of undesired cyclization hydrogenation byproducts is a common issue.^8,10 Additionally, the hydrosulfonation reaction between sulfonyl radicals and alkynes presents an alternative, competing pathway.¹¹ In this research, we introduce an innovative nickel/photoredox dual catalytic sulfonyl-arylation method for the cross-coupling cyclization of aryl iodides with unactivated alkynes. This method excels in chemical selectivity, adeptly curbing side reactions and facilitating the stereoselective 6-exo-dig cyclization. It provides a potent synthetic strategy for the preparation of biologically significant heterocyclic compounds, such as 3,4-dihydroisoquinolin-1(2H)-ones, tetrahydroisoquinolines, and isochroman derivatives.

Our study began by selecting 2-iodo-N-methyl-N-(2-methylbut-3-yn-2-yl)benzamide (1a) and sodium p-tolylsulfinate (2a) as model substrates, as detailed in Table 1. Through a systematic experimental approach, we discovered a potent photocatalytic system that includes fac-Ir(ppy)₃ at 5 mol% to serve as the photocatalyst, NiCl₂·6H₂O at 10 mol% as the nickel catalyst, and 4,4′-di-tert-butyl-2,2′-dipyridyl (L1) at 10 mol% as the ligand. Applying this system and irradiating with 465 nm blue LEDs in a DMSO solvent, we successfully synthesized 3,4-dihydroisoquinolin-1(2H)-one, achieving a yield of 35% (entry 1). Building on this initial success, we proceeded to scrutinize a range of alternative photosensitizers, such as Ru(bpy)₃Cl₂·6H₂O, 4-CzIPN, Eosin Y, and Na₂-Eosin Y, in our quest to improve the reaction's conversion rate (entries 2–5). The implementation of Na₂-Eosin Y as the photocatalyst significantly enhanced the yield of our target product to 70% (entry 5). An exhaustive evaluation of various nickel catalysts and ligands underscored that the pairing of NiCl₂·6H₂O with L1 was optimal for the stereoselective transformation of the substrates (entries 6–11). In our solvent screening, DMSO proved to be more effective than DMA or DMF, offering higher reaction efficiency (entries 12 and 13). Control experiments were instrumental in confirming the essential roles of both the nickel catalyst and the photoredox catalyst under visible light irradiation, which were found to be crucial for the reaction's progress (entries 15 and 16).

Table 1 Optimization of the reaction conditions^a

Entry	Variations from conditions	Yield^c (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol, 2.0 equiv.), fac-Ir(ppy)3 (5 mol%), NiCl2·6H2O (10 mol%), and L1 (10 mol%) in DMSO (2.0 mL) at room temperature under N2 with 465 nm blue LEDs for 12 h. b Na2-Eosin Y instead of fac-Ir(ppy)3. c Yield of the isolated product.
1	None	35
2	Ru(bpy)3Cl2·6H2O instead of fac-Ir(ppy)3	43
3	4-CzIPN instead of fac-Ir(ppy)3	50
4	Eosin Y instead of fac-Ir(ppy)3	41
5	Na2-Eosin Y instead of fac-Ir(ppy)3	70
6^b	Ni(OAc)2·4H2O instead of NiCl2·6H2O	31
7^b	NiBr2·DME instead of NiCl2·6H2O	44
8^b	Ni(PPh3)2Cl2 instead of NiCl2·6H2O	67
9^b	L2 instead of L1	39
10^b	L3 instead of L1	46
11^b	L4 instead of L1	37
12^b	DMF instead of DMSO	59
13^b	DMA instead of DMSO	65
14^b	Without light	N.D.
15^b	Without Na2-Eosin Y	N.D.
16^b	Without [Ni] and ligand	N.D.

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With the optimal reaction conditions determined, we explored the versatility of our nickel/photoredox dual catalytic sulfonyl-arylation method for the synthesis of 3,4-dihydroisoquinolin-1(2H)-one from nonactivated alkynes (Scheme 2). A diverse set of substituents, including electron-withdrawing (F, Cl, Br) and electron-donating (Me) groups at the 4-, 5-, and 6-positions, were well-tolerated, affording sulfonylated products with excellent stereoselectivity (3a–3i, yields: 34%–79%). Notably, electron-withdrawing substitutions at the 5-position on the arene led to higher yields than those with electron-donating groups. The method's applicability was further expanded using N-alkyl-protected substrates, such as ethyl and n-pentyl, yielding the corresponding products with 34%–48% yields (3j–3k). Subsequently, a survey of sodium aryl sulfinate (2) was conducted with 1a, revealing that a variety of sodium aryl sulfinate, irrespective of the electronic nature of their substituents (methoxy, tert-butyl, fluoro, chloro, trifluoromethyl), successfully participated in the photocatalytic process, yielding 3,4-dihydroisoquinolin-1(2H)-ones (3l–3q) with yields ranging from 35–75%. Sodium aryl sulfinates bearing ortho or meta substituents also underwent smooth photochemical transformation, producing the corresponding products (3r–3s) with yields of 53% to 83%. Additionally, sodium 2-thiophene sulfinate emerged as a viable coupling partner, providing the target product 3t in a 34% yield. Lastly, we investigated the influence of gem-dimethyl groups on the reactivity of substrates within our reaction system. We found that these groups are not strictly required for achieving successful reaction outcomes. The product 3u, which lacks gem-dimethyl groups, can be synthesized with moderate yields under standard conditions. This finding indicates that our strategy may be more flexible than initially presumed. However, internal alkynes with terminal phenyl substitutions are not compatible with this approach.

Scheme 2 Substrate scope of 3,4-dihydroisoquinolin-1(2H)-ones. Reaction conditions: 1 (0.2 mmol), 2 (2.0 equiv.), Na₂-Eosin Y (5 mol%), NiCl₂·6H₂O (10 mol%), and L1 (10 mol%) in DMSO (2.0 mL) at room temperature under N₂ with 465 nm blue LEDs for 12 h. Isolated yields based on 1.

In our quest to enhance the practical applicability of our photoredox/nickel dual-catalyzed cross-coupling cyclization approach, we conducted a thorough assessment to determine the feasibility of stereoselectively constructing 4-(arylsulfonyl methylene)-1,2,3,4-tetrahydroisoquinolines using unactivated alkynes and sodium sulfinate as starting materials (Scheme 3). A diverse series of structurally distinct sodium aryl sulfinates, including those with electron-donating and electron-withdrawing functional groups, underwent the reaction smoothly, yielding products 4a–4d. Notably, substrates adorned with adjacent methyl groups encountered significant steric hindrance, potentially leading to a substantial decrease in reaction yield, as exemplified by compound 4e. Furthermore, sodium alkyl sulfinates, with methyl and ethyl substituents, integrated well within the photoredox/nickel dual-catalyzed system, displaying commendable reactivity and affording the desired products 4f–4g with yields ranging from 53% to 75%. Additionally, both N-sulfonyl protected and N-unprotected substrates have been shown to be compatible, expanding the synthetic repertoire with yields ranging from 48% to 58% for compounds 4h and 4i. It is also noteworthy that while substrate 1j′ proved to be a viable substrate, it displayed reduced stereoselectivity for the desired product 4j. This reduction in stereoselectivity is likely attributable to the diminished influence of the Thorpe–Ingold effect.

Scheme 3 Substrate scope of tetrahydroisoquinolines. Reaction conditions: 1 (0.2 mmol), 2 (2.0 equiv.), Ru(bpy)₃Cl₂·6H₂O (5 mol%), NiCl₂·6H₂O (10 mol%), and L1 (10 mol%) in DMF (2.0 mL) at room temperature under N₂ with 465 nm blue LEDs for 12 h. Isolated yields based on 1.

The isochromane motif, characterized by the 3,4-dihydro-1H-2-benzopyran core, is a prevalent structural element in numerous natural products and synthetic bioactive molecules.¹² These compounds are celebrated for their diverse pharmacological profiles and are extensively utilized as therapeutic agents, particularly for central nervous system disorders, antitumor treatments, antibacterial applications, and anti-inflammatory therapies. In this study, we introduce an innovative photoredox/nickel dual-catalyzed approach for the synthesis of polysubstituted isochromane derivatives (Scheme 4). This method employs aliphatic terminal alkynes and sodium sulfinates as starting materials, offering a novel pathway to access these biologically relevant scaffolds. Under the photo-catalytic conditions, the reaction yielded polysubstituted isochromanes with satisfactory results, with yields ranging from 36% to 83% (5a–5m). We successfully applied a range of aryl sodium sulfinates, bearing both electron-donating groups (e.g., methyl, tert-butyl) and electron-withdrawing groups (e.g., fluorine, chlorine, bromine, trifluoromethyl), in the cross-coupling cyclization reaction with unactivated alkynes. This resulted in the formation of the corresponding isochromanes with yields between 37% and 83% (5a–5h). Notably, the method showed tolerance to steric hindrance with substrates bearing adjacent methyl groups, although this modification led to a modest reduction in yield (5i). Furthermore, we expanded the substrate scope to include sodium thiophene-2-sulfinate and sodium alkyl sulfinates, which also provided access to 4-(sulfonylmethylene) isochromanes with acceptable yields (5j–5l). Moreover, the α-methyl-substituted ether substrate was found to be readily compatible with this transformation, under scoring the versatility of our approach (5m). Additionally, this strategy is also applicable to the synthesis of product 5n, which lacks geminal dimethyl groups. However, it encounters challenges with the reaction of internal alkynes that have terminal phenyl groups. Notably, when the terminal position of the alkyne is substituted with a methyl group, the formation of trace product 5p can be observed. Moreover, the resulting sulfonyl heterocycles serve as valuable building blocks in organic synthesis (Scheme 5). We successfully alkylated the synthesized product 5a with N,N-dimethylaniline, yielding alkyl-substituted isochromanes (5aa). Furthermore, the oxidation of 5a with KMnO₄ led to the formation of ketone 5ab. Additionally, product 3a can be readily converted into an alkoxy-substituted heterocyclic ring (3aa) through a simple substitution reaction with 2-iodobenzyl alcohol, highlighting its synthetic versatility.

Scheme 4 Substrate scope of isochromanes. Reaction conditions: 1 (0.2 mmol), 2 (2.0 equiv.), Ru(bpy)₃Cl₂·6H₂O (5 mol%), NiCl₂·6H₂O (10 mol%), and L1 (10 mol%) in DMF (2.0 mL) at room temperature under N₂ with 465 nm blue LEDs for 12 h. Isolated yields based on 1. Optimization of the reaction conditions see ESI.†

Scheme 5 Synthetic applications.

To clarify the mechanistic pathway of our catalytic protocol, we conducted a thorough series of control experiments with precision (Scheme 6). Initially, we aimed to confirm the sequence of radical addition by subjecting compound 1a to standard reaction conditions in the absence of reagent 2a. The absence of product 3a′ formation highlights the essential role of reagent 2a in this process (Scheme 6a). Subsequently, we placed compounds 1aa′ and 2a under standard reaction conditions, omitting NiCl₂·6H₂O and L1, to capture the addition products of sulfonyl radicals to alkynes. The failure to form products 3a or 3aa′, with the majority of starting material 1aa′ remaining unreacted, underscores the pivotal function of the Ni catalyst in facilitating the addition reaction of alkynes through highly active sulfonyl free radical nickel intermediates. Further exploration of the radical-mediated process included the strategic use of radical inhibitors and intermediate trapping agents. The introduction of 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) in a 3.0 equivalent ratio to the reaction mixture resulted in a complete suppression of the reaction. High-resolution mass spectrometry (HRMS) analysis confirmed the formation of TEMPO adducts, specifically identifying compound 4, which corroborates the involvement of a radical mechanism.

Scheme 6 Control experiments.

Additionally, employing 1,1-diphenylethylene as an intermediate trapping reagent under standard conditions, HRMS analysis enabled the identification of vinyl-trapped products 5 and the radical addition complex 6. These findings substantiate the proposed radical pathway and the sequence of addition, as illustrated in Scheme 6b. Concurrently, the photocatalytic aspect was examined through a series of visible-light irradiation on/off experiments, which decisively demonstrated the reaction's reliance on light (Scheme 6c). The reaction ceased in the absence of illumination and proceeded significantly faster under continuous visible light, underscoring the indispensable role of photocatalysis. Furthermore, a Stern–Volmer quenching experiment was performed, showing that the fluorescence intensity of Na₂-Eosin Y was efficiently quenched with an increasing concentration of 2a, as depicted in Scheme 6d. In stark contrast, compound 1a showed no quenching effect on the excited state of the photosensitizer. This observation further elucidates the differential interactions between the photosensitizer and the substrates within the photocatalytic process.

Drawing from our mechanistic investigations and relevant literature,^5–11 we propose a plausible mechanism for the photoredox/nickel dual-catalyzed cross-coupling cyclization, as depicted in Scheme 7. The photocatalytic cycle commences with the absorption of visible light by Na₂-Eosin Y, leading to the formation of a long-lived EY* triplet excited state. This state is instrumental in oxidizing sodium p-tolylsulfinate (2a) to the sulfonyl radical A, while concurrently generating the Eosin Y radical anion, which acts as a reductant. The sulfonyl radical A is then incorporated into the nickel catalytic cycle, where it adds to a NiI complex B, yielding the Ts–Ni^II intermediate C. A single electron transfer (SET) event between the Ni^II intermediate C and the Eosin Y radical anion ensues, effectively regenerating the EY photoredox catalyst and restoring the Ts–Ni^I intermediate D. Following this, a 1,2 migratory insertion involving the unactivated alkyne and intermediate D takes place, culminating in the formation of intermediate E. This intermediate then undergoes an intramolecular oxidative addition cyclization with the aryl halide, succeeded by a reductive elimination step, ultimately affording the cyclization product 3a.

Scheme 7 Proposed mechanistic pathway.

Conclusions

In summary, we introduce a novel and environmentally friendly nickel/photoredox dual catalytic sulfonyl-arylation method for the synthesis of heterocyclic compounds. The method's innovative approach allows for the direct transformation of unactivated alkynes and aryl iodides into a variety of biologically significant heterocyclics, such as 3,4-dihydroisoquinolin-1(2H)-ones, tetrahydroisoquinolines, and isochroman derivatives. By bypassing traditional Heck reactions, this green chemistry technique minimizes the use of excess metal catalysts and reagents, enhancing chemical selectivity and curbing side reactions. The dual catalytic system's high reactivity with unactivated substrates and its ability to forge both C(sp²)–C(sp²) and C(sp²)–S bonds highlight its potential to advance synthetic chemistry. The method's operational simplicity, mild reaction conditions, and use of visible light as an energy source further underscore its ecofriendly and efficient nature, making it a promising tool for constructing heterocyclic frameworks in pharmaceuticals and biologically active compounds.

Author contributions

In our collaborative research endeavor, every team member played an essential role in achieving the success of our project. B.-R. Leng and F. Yang were instrumental in optimizing the reaction conditions and expanding the scope of the reaction, ensuring the robustness of our synthetic methodology. J.-L. Bai, Y.-W. Huang, and P. Wei were responsible for experimental management, a task crucial for evaluating the reproducibility and reliability of our synthesis method. Y.-L. Zhu and D.-C. Wang provided expert guidance and strategic direction throughout the project, ensuring that our research remained on track and aligned with our scientific objectives. Y.-L. Zhu and Q.-Q. Liu were the intellectual architects of the project's conception and were also responsible for drafting the manuscript. All authors have contributed insightful comments on the manuscript and have approved the final version submitted for consideration.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data for 3a has been deposited at the CCDC under 2368219† and can be obtained from The Cambridge Crystallographic Data Centre viahttps://www.ccdc.cam.ac.uk/structures/.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21801130), and the Discipline Fund of the School of Pharmaceutical Sciences, Nanjing Tech University (Natural Science).

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2368219. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01627k

‡ These authors contributed equally.

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