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DOI: 10.1039/D5OB01074H (Communication) Org. Biomol. Chem., 2025, Advance Article

Synthesis of 4-(arylthio)isoquinolin-1(2H)-ones via TBHP-mediated sequential amidation/thioetherification of N-alkylisoquinolinium salts

Chuanquan Chua, Jinhui Penga, Lijuan Jina, Yilin Chena, Dahan Wang*a, Jinbing Liua, Junyuan Tanga, Zi Yang*c, Mingming Yud and Jinhui Cai*b
aDepartment of Food and Chemical Engineering, Shaoyang University, Shaoyang, 422100, China. E-mail: syudhwang@163.com
bCollege of Chemistry and Chemical Engineering, University of South China, Hengyang, 421001, China. E-mail: jinhuicai@usc.edu.cn
cHunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha 410219, China. E-mail: yangziycy@163.com
dSchool of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Xiasha West Higher Education District, Hangzhou, 310018, China

Received 2nd July 2025 , Accepted 31st July 2025

First published on 5th August 2025

Abstract

Here, a simple, efficient, and practical method for the assembly of 4-(arylthio)isoquinolin-1(2H)-ones via TBHP-mediated 1,4-difunctionalization of N-alkylisoquinolinium iodide salts under metal-free conditions is reported. This strategy features readily available starting materials, operational simplicity, and metal-free conditions. Remarkably, a variety of (hetero)aryl/alkyl thiols, diphenyl disulfide, diphenyl diselenide, and N-alkylisoquinolinium bromides or chlorides are compatible with this method, which generates the desired 4-(arylthio)isoquinolin-1(2H)-ones in 30–92% yields. The potential synthetic utility is demonstrated by its gram-scale synthesis and derivatizations. The mechanistic experiments indicate that the iodide plays a key role in this transformation.

Isoquinolinones, as privileged skeletons in many natural products, pharmaceuticals, and bioactive molecules,1,2 exhibit unique pharmacological properties, such as treating arthritis, serving as enzyme inhibitors, and acting as anti-allergic agents.3,4 Therefore, tremendous efforts have been devoted to accessing these scaffolds. Among the traditional methods, transition metal-catalyzed [4 + 2] cycloaddition of o-aminobenzamides and unsaturated hydrocarbons is a straightforward strategy for assembling various functionalized isoquinolinones.5 Alternatively, the direct site-selective C–H functionalization of isoquinolinones is feasible for various C4-functionalized N-substituted isoquinolinones (Scheme 1a).6
image file: d5ob01074h-s1.tif
Scheme 1 Strategies for the synthesis of 2,4-disubstituted isoquinolinones.

Given the synthetic complexity of isoquinolinones and to avoid the use of transition metals, developing simple and low-cost methods for functional isoquinolinones is highly desirable. An alternative method involves the oxidation of N-substituted isoquinolinium salts, which was practicable for the synthesis of polysubstituted isoquinolinone scaffolds (Scheme 1b).7 Some research groups applied this strategy to realize the 1,4-difunctionalization of N-alkylisoquinolinium salts, such as iodination/amidation and selenylation/oxidation.8 These cascade strategies have been proven to be powerful and straightforward approaches for all kinds of multi-substituted isoquinolinones.

Organosulfur compounds are extensively found in pharmaceuticals, agrochemicals, functional materials, and natural products.9 To obtain these compounds, introducing sulfur atoms into the backbones of N-heterocycles with simple and efficient synthetic methods is undoubtedly the most direct and efficient method and is still highly in demand.10 To the best of our knowledge, disulfides, sulfonyl chlorides, and ethyl benzenesulfonates are usually employed as the sulfur source for the C4-thioetherification of isoquinolinones.11 Additionally, thiophenols are versatile alternative reagents for the thioetherification, especially for the direct thioetherification of the C(sp2)–H bond in functional molecules, which have been well-developed in recent decades.12 Therefore, we attempted to synthesize 4-(arylthio)isoquinolin-1(2H)-ones 3 via TBHP-mediated sequential amidation/thioetherification of the C(sp2)–H bond in N-alkylisoquinolinium iodide salts 1 with thiophenols 2 as the sulfur source under metal-free conditions (Scheme 1c).

To establish the optimal conditions for this transformation, we commenced the oxidative cross-coupling reaction of N-methylisoquinolinium iodide (1a) and p-tolylthiol (2a) for the synthesis of N-methyl-4-(p-tolylthio)isoquinolin-1(2H)-one (3a) in the presence of oxidants (Table 1). Excitingly, the desired product 3a was successfully obtained in 50% yield when the model reaction utilized 4 equiv. of TBHP (tert-butyl hydroperoxide) as the oxidant and 1 mL of acetonitrile as the solvent with stirring at 80 °C for 16 h (entry 1). Subsequently, other kinds of oxidants were screened. Only trace amounts of the product 3a were furnished when potassium persulfate (K2S2O8) and DTBP (di-tert-butyl peroxide) were used (entries 2 and 3). Additionally, hydrogen peroxide (H2O2) and TBPB (tert-butyl peroxybenzoate) furnished the N-methyl-4-(p-tolylthio)isoquinolin-1(2H)-one 3a in 15% and 10% yields, respectively (entries 4 and 5). Subsequently, an array of solvents, including DCE (dichloroethane), 1,4-dioxane, DMSO, DMAC (dimethylacetamide), NMP (N-methylpyrrolidone), toluene, PhCl, and DMF (N,N-dimethylformamide), was investigated. However, most of them generated compound 3a in low yields (entries 6–13). To our delight, product 3a was provided in 81% yield when the reaction was stirred in DMF (entry 14). To achieve higher yields, the reaction was carried out at higher and lower temperatures. However, both delivered a significant loss in reactivity (entries 15 and 16). Finally, reducing the amount of oxidant to 3 equiv. gave compound 3a in 71% yield (entry 17). Thus, the optimized conditions were established as follows: 1.5 equiv. of p-tolylthiol 2a as the sulfur source, 4 equiv. of TBHP as the oxidant, 1 mL of MeCN as the solvent, reacting at 80 °C for 16 h.

Table 1 Optimization of the reaction conditionsa

image file: d5ob01074h-u1.tif
Entry Solvent Oxidant Yieldb (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), oxidant (4 equiv.), solvent (1 mL), 80 °C for 16 h.b Isolated yield.c 70 °C.d 90 °C.e 3 equiv. of TBHP was used.
1 MeCN TBHP 50
2 MeCN K2S2O8 Trace
3 MeCN DTBP Trace
4 MeCN TBPB 10
5 MeCN H2O2 15
6 DCE TBHP 44
7 1,4-Doixane TBHP 46
8 DMSO TBHP 45
9 DMAC TBHP 38
10 NMP TBHP 46
11 Toluene TBHP 35
12 PhCl TBHP 20
13 H2O TBHP 0
14 DMF TBHP 81
15c DMF TBHP 59
16d DMF TBHP 71
17e DMF TBHP 67

With the optimal conditions in hand, we set out to explore the compatibility of various thiophenol derivatives 2 and N-alkylisoquinolinium iodide salts 1 in Tables 2–4. As shown in Table 2, a wide range of thiols 2 was initially examined under the standard conditions. All of them proceeded smoothly, furnishing the corresponding products 3aa–3ao in moderate to excellent yields. Generally, both electron-rich and electron-deficient arylthiols 2 were well-tolerated in this reaction. Among them, slightly decreased yields were furnished when arylthiols 2 possessing chloro and bromo substituents at the para position were tested. Notably, the congested arylthiols 2g–2h were also compatible with this method, giving compounds 3ag–3ah in 44–76% yields. These results indicated that steric hindrance has no obvious effect in this reaction. Furthermore, this strategy was amenable to multi-substituted thiols 2j–2k, which delivered the expected compounds 3aj–3ak in good yields. Notably, heteroaryl thiols 2, including 3-furyl (2l), 2-thienyl (2m), and benzothiazolyl (2n), were also suitable, producing the corresponding products 3al–3an in moderate yields. Satisfyingly, this approach was expanded to alkyl thiol 2o, which yielded the target product 3ao in 43% yield. Finally, we turned to investigate the compatibility of 2-methylpyridinium iodide in this method; however, no desired product was formed.

Table 2 Substrate scopes of thiols/thiophenolsa
a Conditions: 1a (0.2 mmol), 2 (0.3 mmol), TBHP (4 equiv.), DMF (1 mL), 80 °C for 16 h. Isolated yield is given.
image file: d5ob01074h-u2.tif

Table 3 Substrate scopes of N-alkylisoquinolinium iodide saltsa
a Conditions: 1 (0.2 mmol), 2a (0.3 mmol), TBHP (4 equiv.), DMF (1 mL), 80 °C for 16 h. Isolated yield is given.
image file: d5ob01074h-u3.tif

Table 4 Substrate scopes of N-alkylisoquinoline bromides or chloridesa
a Conditions: 1 (0.2 mmol), 2a (0.3 mmol), TBHP (4 equiv.), DMF (1 mL), 80 °C for 16 h. Isolated yield is given.
image file: d5ob01074h-u4.tif

Next, we turned to examine the substrate scope of N-alkyl isoquinolinium iodides 1 (Table 3). Various substituents, such as bromo, nitro, and methoxy, installed at the skeleton of N-methyl isoquinolinium iodides 1 ran smoothly in this strategy, which generated compounds 3ba–3ca in good to excellent yields. Remarkably, 2-methyl-5-nitroisoquinolinium iodide 1c exhibited outstanding reactivity, providing the desired product 3ca in 92% yield. This result revealed that the electron-withdrawing group substituting on the isoquinoline ring of N-alkylisoquinolinium iodide salt possibly facilitated this transformation. Furthermore, other alkyl substituents, like iso-butyl 1d, iso-propyl 1e, and hydroxylethyl 1f, were also surveyed and proved to be tolerable in this system, generating compounds 3ea–3ga in 50–75% yields. Specifically, alkyl-linked diisoquinolinium iodide 1h was treated with p-tolylthiol (2a) under the standard conditions, which produced the desired product (3ha) via double amidation/thioetherification of substrate 1h in one pot, showing the remarkable synthetic potential of this method.

In addition, we synthesized other kinds of N-alkylisoquinolinium bromides or chlorides 1 and subjected them to the optimal conditions; nevertheless, no desired products 3 were detected. After the slight modification of the standard conditions with the addition of 10 mol% iodine, all of these kinds of substrates successfully underwent the reaction, demonstrating that iodine plays a crucial role in this transformation (Table 4). Comparatively, N-benzylisoquinolinium bromide 1i led to a significant drop in reactivity, giving product 3ia in 57% yield. Disappointingly, N-benzylisoquinolinium chloride 1j gave a poor yield. Other chloride salts 1k–1l were also suitable in this method, albeit in poor yields. Several N-alkylisoquinolinium bromides 1m–1p, containing ethyl, propyl, allyl, and pent-4-en-1-yl, were explored, which smoothly generated the desired products 3ma–3pa in 30–63% yields.

To extend this strategy, we also explored the reactivity of diphenyl disulfide and diphenyl diselenide, which successfully gave the corresponding products 3ap and 3aq in 74% and 71% yields, respectively (Scheme 2a). Furthermore, we performed the model reaction by replacing N-methylisoquinolinium iodide 1a with N-methylquinolinium iodide derivatives 4, and N-methyl-3-(p-tolylthio)quinolin-2(1H)-ones 5a–5c were smoothly obtained in 24–53% yields (Scheme 2b). Notably, this TBHP-mediated amidation/thioetherification of N-alkylisoquinolinium iodide salt 1a with p-tolylthiol 2a was easily scaled up to 6 mmol, whereby 1.26 g of product 3aa was synthesized in 75% yield without a significant loss in reactivity. According to the related reference,13 product 3aa was divergently converted to the corresponding sulfoxide 6a and sulfone 6b in 84% and 90% yields by controlling the amount of m-CPBA (3-chloroperbenzoic acid) and temperature (Scheme 2c).


image file: d5ob01074h-s2.tif
Scheme 2 The strategy was extended to PhSSPh, PhSeSePh, N-methylquinolinium iodide and the gram-scale synthesis of product 3aa and its divergent oxidation.

To gain more information about the mechanism, a series of control experiments was conducted, as shown in Scheme 3. The addition of radical scavengers, such as TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) and BHT (2,6-di-tert-butyl-4-methylphenol), to the model reaction led to the formation of compound 3aa in slightly decreased yields, indicating that a radical pathway was not involved in this work (Scheme 3a). N-Methylisoquinoline iodide salt 1a was successfully converted into N-methylisoquinolinone 6c in 45% yield under the standard conditions, revealing that a possible intermediate 6c was first generated via the oxidation of substrate 1a (Scheme 3b). Furthermore, the oxidative dehydrogenation of N-methylisoquinolinone 6c and p-toluenethiol 2a catalyzed by iodine resulted in product 3aa in 70% yield, while the absence of iodine gave no product, indicating that iodine played a key role in the formation of the C–S bond (Scheme 3c).


image file: d5ob01074h-s3.tif
Scheme 3 Control experiments.

Based on the results of these control experiments and previously related references, a rational mechanism for the oxidative C–S bond formation process is proposed in Scheme 4.11,14 On the one hand, iodide was first oxidized to iodine in the presence of TBHP. Subsequently, iodine was treated with arylthiol 2, which generated an electrophilic species A and hydrogen iodide. On the other hand, the sequential addition of N-methyl isoquinolinium salt 1a with TBHP/deprotonation resulted in the formation of species B. The intermediate B released a tert-butyl alcohol, resulting in the formation of N-alkyl isoquinolinone 6c. Finally, intermediate 6c interacted with species A, leading to the C–S bond formation, which yielded the desired product 3 along with hydrogen iodide. Subsequently, HI regenerated the iodine under the oxidation of TBHP.


image file: d5ob01074h-s4.tif
Scheme 4 Proposed mechanism.

In summary, we developed a versatile platform for the efficient synthesis of 4-(arylthio)isoquinolin-1(2H)-one derivatives via TBHP-mediated oxidative coupling of N-alkylisoquinolinium iodides and thiols. Specifically, iodine is crucial to enabling the C–S bond formation when employing N-alkylisoquinolinium bromides or chlorides as the substrate. Furthermore, PhSSPh, PhSeSePh, and N-methylquinolinium iodide are well-tolerated in this method. The potential synthetic utility of this strategy is underscored by its simple conditions, readily available starting materials, wide substrate scope, excellent functional group tolerance (halides, alkenyl, nitro, and hydroxyl), simplicity of operation, and gram-scale synthesis. The development of simple and efficient methods for C–S bond formation is currently ongoing in our laboratory.

Conflicts of interest

There are no conflicts to declare. The data supporting this article have been included as part of the SI. The data supporting this study are available in the published article and its SI. General information, experimental procedures, characterization data, and copies of NMR spectra are available in the Supporting Information. See DOI: https://doi.org/10.1039/d5ob01074h.

Acknowledgements

This work was supported by the Hunan Provincial Degree and Postgraduate Education Reform Research Project (LXBZZ2024395) and the Graduate Research and Innovation Project of Shaoyang University (CX2024SY07). J. C. thanks the National Natural Science Foundation of China (22301128) for financial support.

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