Non-Kolbe oxidation driven electrochemical C(sp²)–H lactonization towards the synthesis of isocoumarins

Abstract

A novel method for electrochemical C(sp²)–H lactonization was developed. This strategy enabled the synthesis of various isocoumarins in moderate to excellent yields with good functional group tolerance. The gram-scale reaction and derivatizations of the product showed the applicability of this method. Relevant mechanism experiments supported the rare non-Kolbe process. Overall, this work provides a sustainable and cheaper approach for the synthesis of isocoumarins.

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Introduction

Isocoumarins are significant heterocyclic compounds that exhibit unique biological and pharmacological activities, and they are found in numerous natural products (Scheme 1).¹ Recognized for their valuable applications in various fields, including antimicrobial,² anticancer,³ antiallergic⁴ and anti-HIV,⁵ isocoumarins have garnered substantial interest among chemists for their synthesis. To date, numerous methods employing organic catalysts and transition metals have been established.⁶ Among these, the strategy of C–H activation using readily available benzoic acids without complex pre-functionalization could prepare isocoumarins step-economically and efficiently.⁷ Although great progress has been achieved and even green processes have been introduced instead of using external oxidants in some cases,⁸ the dependency on transition metals with potential risk and high cost still restrict their further developments (top of Scheme 2a). Thus, a sustainable method without using any metals and external oxidants to access isocoumarins from benzoic acids is urgently needed.

Scheme 1 Representative natural products containing isocoumarins.

Scheme 2 Traditional oxidative C–H lactonization strategies.

Retrosynthetic analysis of isocoumarins suggests that the oxidative C–H/O–H cross-coupling of 2-vinyl benzoic acids may present an unexplored alternative method (bottom of Scheme 2a). With the assistance of environmentally friendly oxidants, the proposal is possible to be realized. Electrochemical C–H lactonization is an emerging method for the construction of C–O bonds from carboxylic acids.⁹ Using electrons as internal and traceless oxidants, this method precludes the generation of reductive waste during the transformation. In addition, the only by-product hydrogen released at the cathode is clean and risk-free. Accordingly, electrochemical oxidation may be chosen to convert 2-vinyl benzoic acids into isocoumarins sustainably.

The strategy of electrochemical C–H lactonization has played an important role in the synthesis of lactones. Electrochemical lactonization of remote C(sp²)–H bonds in carboxylic acids typically initiates through various mechanisms. Once the C(sp²)–H sources are substituted with EWGs (electron-withdrawing groups) to reduce the electron density, Kolbe oxidation occurs to deliver an electrophilic carboxyl radical, which would undergo cyclization and oxidation to access the products (top of Scheme 2b).¹⁰ However, electrochemical C–H lactonization involving C(sp²)–H bonds with a medium or high electron density has been seldom documented. The enriched electrons contributed to the non-Kolbe oxidation to acquire an unstable intermediate, which could be attacked by nucleophilic carboxylic acids to afford the products (bottom of Scheme 2b).¹⁰ Based on our previous research regarding the electrochemical conversions of carboxylic acids,¹¹ we envisioned that lactonization of 2-vinyl benzoic acids could be achieved in a non-Kolbe way to prepare isocoumarins (Scheme 2c). Nonetheless, two challenges remain: (1) 2-vinyl benzoic acid was usually used as a radical acceptor to obtain phthalide via di-functionalization under electrochemical conditions¹² and (2) the radical cation produced from styrene with poor stability might dimerize on electrodes.¹³

Results and discussion

With 2-(1-(2,5-dimethylphenyl)vinyl)benzoic acid (1a) as a model substrate, we optimized the reaction conditions for electrochemical lactonization (Table 1). The desired product 2a was obtained in 91% yield in an undivided cell with graphite felt electrodes, using MeCN/TFA as a co-solvent and LiClO₄ as an electrolyte (entry 1). A lower voltage of 1.5 V couldn't effectively initiate the oxidation process (entry 2). When the reaction was performed under 2.5 V, an intractable mixture was obtained (entry 3). Replacing LiClO₄ with other electrolytes such as Et₄NBF₄, Bu₄NClO₄, or Bu₄NPF₆ also gave lower yields of 80–87% (entries 4–6). Omitting TFA gave no product (entry 7). Using AcOH instead of TFA did not improve the result, giving a comparable yield of 37% (entry 8). DMF was an unsuitable solvent for the reaction (entry 9). Replacing the graphite electrode with Pt (−) and Ni (−) reduced the yields to 45% and 78% respectively (entries 10 and 11). The transformation couldn't be achieved without electricity (entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	Variation from the standard conditions	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), LiClO4 (0.6 mmol), MeCN (5.5 mL) and TFA (0.5 mL) in an undivided cell (Ecell = 2.0 V) with graphite felt electrodes at RT under air. See the ESI† for more details. b Isolated yields are shown.
1	None	91
2	1.5 V	Trace
3	2.5 V	Messy
4	Et4NBF4 instead of LiClO4	87
5	Bu4NClO4 instead of LiClO4	86
6	Bu4NPF6 instead of LiClO4	80
7	Without TFA	0
8	AcOH instead of TFA	37
9	DMF instead of MeCN	0
10	C(+)|Pt(−)	45
11	C(+)|Ni(−)	78
12	No current	0

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Having established the optimized conditions, we investigated the scope of substituents on 2-vinyl benzoic acids (Scheme 3). ortho-Methyl substituted substrates with 4-methyl or methoxy could furnish the desired products (2b and 2c) in 86% and 66% yields, respectively. Besides, ortho-alkyl and alkoxy substituents were converted into the corresponding isocoumarins (2d–2g) in yields of 65–87%. Notably, the yield decreased to 55% when the substituents were absent (2h). Even with para-methyl and dimethyl groups, the substrates didn't deliver the products in better yields (2i and 2j). Given the similar electron density between 1j and 1a, we hypothesize that the variation in yields was not directly related to the oxidation potentials (Fig. S8-4 and S8-5, see the ESI† for details). The introduction of ortho-methyl may enhance the stability of the key intermediate via σ–π hyperconjugation.¹⁴ Various naphthyl substrates were also amenable in the transformation, furnishing the desired analogues (2k and 2l) in 95% and 65% yields. In addition, more substituted benzoic acid moieties were tested. 2-Naphthoic acid-derived product 2m could be obtained in 70% yield. Halogen-containing substrates were also found to be compatible under the standard conditions, as demonstrated by the conversion of dichloro-substituted benzoic acid to product 2n with a 65% yield. Notably, R-1 with an internal olefin moiety could also deliver product R-2 in 32% yield.

Scheme 3 Scope of substrates 1. Reaction conditions: 1 (0.2 mmol), LiClO₄ (0.6 mmol), MeCN (5.5 mL) and TFA (0.5 mL) in an undivided cell (E_cell = 2.0 V) with graphite felt electrodes at RT under air. See the ESI† for more details.

To further demonstrate the versatility of the electrochemical transformation, we expanded the conjugated system of the substrates to incorporate a variety of substituents (Scheme 4). As expected, the para-phenyl product 4a was obtained in 94% yield, which was due to delocalization of benzene ring electrons. Diverse para-aryl substituents were used to prove the tolerance of functional groups. Isocoumarins with tert-butyl, trifluoromethoxy, ethoxy, dimethyl and phenyl groups were all synthesized in 64–99% yields (4b–4f). Additionally, thienyl substrates were found to be competent in the transformation, affording the corresponding products with 62% and 65% yields (4g and 4h). The absolute configuration of 4g was confirmed by single-crystal X-ray diffraction (CCDC 2360419†). Besides, different naphthyl substrates performed well to give products in 60–77% yields (4i and 4j).

Scheme 4 Scope of substrates 3. Reaction conditions: 3 (0.2 mmol), LiClO₄ (0.6 mmol), MeCN (5.5 mL) and TFA (0.5 mL) in an undivided cell (E_cell = 2.0 V) with graphite felt electrodes at RT under air. See the ESI† for more details.

To further demonstrate the synthetic application of this methodology, a gram-scale reaction of 1a was conducted (Scheme 5a). 1.01 g (4.0 mmol) of 1a was used under the standard conditions to obtain 2a in a slightly reduced 73% yield. Furthermore, some derivatization experiments of 2a were conducted (Scheme 5b). D-1 with an isoquinolinone skeleton was obtained under basic conditions, offering more possibilities for the development of novel pharmaceuticals.¹⁵ Thiolactone D-2, a structural motif prevalent in numerous bioactive molecules,¹⁶ was obtained in 96% yield. Site-selective bromination of 2a took place to produce D-3 in 85% yield.

Scheme 5 Synthetic application.

To elucidate the reaction mechanism, a kinetic isotope study was conducted (Scheme 6a). A KIE value of 0.82 was determined through the intermolecular competition experiment of 1h and 1h-d₂. It could be proved that the cleaving of the C–H bond was not the turnover-determining step, and the oxidation of the substrate appeared to be more critical in the overall reaction. In consideration of the reaction potential measured at about 1.70 V (vs.SCE) in the chronopotentiometry experiment (Fig. S6, see the ESI† for details), CV experiments were performed to determine the oxidative processes (Scheme 6b). Benzoic acid 1hb exhibited no oxidative tendency under the standard conditions. In contrast, an oxidation peak for 1,1-diphenylethylene 1ha was observed at 2.193 V. The oxidation peak for 1h was recorded at 2.189 V, aligning with that of 1ha, which indicates that the initial oxidation of the styrene moiety is likely the driving force of the reaction. A significant reduction current observed may indicate hydrogen evolution at the cathode during the process.

Scheme 6 Considerations of the mechanism.

Based on the above results and previous reports,¹⁰ a mechanism was proposed (Scheme 7). As depicted by the CV curves (Scheme 6b), substrate 1h was oxidized to form the unstable radical cation Avia a SET (single electron transfer) process at the anode. With the assistance of a conjugate base obtained from TFA by reduction at the cathode, A would undergo nucleophilic cyclization to deliver benzyl radical B; meanwhile, TFA was recovered as a “catalyst”. Benzyl cation C was obtained by the oxidation of B. Finally, ortho-hydrogen elimination completed the transformation and offered isocoumarin 2h.

Scheme 7 Proposed mechanism.

Conclusions

In summary, we have successfully established an alternative electrochemical approach for the synthesis of isocoumarins through C(sp²)–H lactonization, eschewing the reliance on transition metals and external oxidants. This method has been demonstrated to yield a range of products in moderate to excellent yields. Our findings diverge from the conventional Kolbe oxidation pathway, as the reaction is initiated through a non-Kolbe oxidation mechanism. Kinetic isotope effect (KIE) and cyclic voltammetry (CV) experiments were conducted and are in alignment with the proposed mechanism. This mild and environmentally benign method, characterized by high atom economy, paves the way for a sustainable and cost-effective synthesis of isocoumarins.

Author contributions

Dr Y. Zhang guided this electrochemical transformation. C. Liu carried out the electrochemical experiments, dealt with all the data and drafted the manuscript. H. Liu and G. Zhang contributed to compound characterization. Y. Liu, P. Liao, and Y. Mei participated in the synthesis of substrates. All the authors discussed the results and commented on the manuscript.

Data availability

The data underlying this study are available in the published article and its ESI.†

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by the Natural Science Foundation of China (No. 22101299) and the Chinese Universities Scientific Fund (No. 2024TC049).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2360419. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01381f

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