Electrochemical C3-Thiocyanation of Quinolines

Electrochemical C3-Thiocyanation of Quinolines | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Chinese Journal of Chemistry This is a preprint and has not been peer reviewed. Data may be preliminary. 25 March 2025 V1 Latest version Share on Electrochemical C3-Thiocyanation of Quinolines Authors : Ziyun Wang , Runzhao Shi , Jialing Zhang , Lin-Bao Zhang 0000-0002-8334-4188 , Li-Rong Wen , and Weisi Guo 0000-0001-6688-4679 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174287541.14000255/v1 Published Chinese Journal of Chemistry Version of record Peer review timeline 398 views 252 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The site-selective C‒H thiocyanation of quinoline has potential application value but remains undeveloped. We report herein an electrochemical C3-thiocyanation of quinoline derivatives under external oxidant-free conditions. The key to success for this reaction is the in situ formation of activated silylquinolinium salts. This method exhibits mild reaction conditions, broad substrate scope, and excellent site-selectivity. The practicality of this protocol is further demonstrated by a scale-up reaction, follow-up transformations, and late-stage thiocyanation of quinoline-based bioactive molecules. Cite this paper: Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX Electrochemical C3-Thiocyanation of Quinolines Ziyun Wang, Runzhao Shi, Jialing Zhang, Lin-Bao Zhang, Lirong Wen* and Weisi Guo* College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao 266042, China Electrochemical synthesis| Thiocyanation | Quinoline | C‒H functionalization | Green chemistry Comprehensive Summary The site-selective C‒H thiocyanation of quinoline has potential application value but remains undeveloped. We report herein an electrochemical C3-thiocyanation of quinoline derivatives under external oxidant-free conditions. The key to success for this reaction is the in situ formation of activated silylquinolinium salts. This method exhibits mild reaction conditions, broad substrate scope, and excellent site-selectivity. The practicality of this protocol is further demonstrated by a scale-up reaction, follow-up transformations, and late-stage thiocyanation of quinoline-based bioactive molecules. Background and Originality Content Functionalized quinolines are widely existing in pharmaceuticals, natural products, functional materials, and bioactive molecules. [1] Particularly, the quinoline motif is frequently used N-containing heterocycle in FDA-approved drugs. [2] In this context, a range of efficient methods have been developed for the synthesis of functionalized quinoline derivatives. [3] Among them, the direct C‒H bond functionalization is the representative protocol. [4] Due to the electron deficient property of quinoline, site-selective functionalization at the C2 and C4 positions through nucleophilic addition is relatively facile. A variety of approaches has been reported for the C2 or C4 functionalization of quinolines. [5] In contrast, the site-selective C3-functionalization of quinolines has been rarely explored. [6] In the past decades, transition-metal catalyzed C3-functionalization of quinolines have been developed in the presence of Pd, Ir, or Ni (Scheme 1a). [7] An alternative method for the C3-functionalization is the reductive dearomatization protocol, which converts the electron-deficient substrates to electron-rich intermediates (Scheme 1b). [8] The C3-selective cyanation and trifluoromethylation have been achieved through silanes or boranes reduction. In addition, the C3-functionalization of quinolines through radical approaches have also been explored, such as C3-iodinaton and trifluoromethylthiolation (Scheme 1c). [9] Despite these advances, the reaction type and scope for direct C3-functionalization of quinolines are still limited. To our knowledge, a general protocol for the site-selective C3-thiocyanation of quinolines has not been realized. Scheme 1 C3-functionalization of quinolines The thiocyanate group (SCN) is a prevalent functional motif in natural products and bioactive molecules. [10] In addition, thiocyanates are valuable intermediates for the synthesis of N, S-containing derivatives. [11] Therefore, the introduction of a SCN group into quinolines has potential application value. Recently, our group reported a series of electrochemical C(sp 3 )‒H thiocyanation reactions under mild reaction conditions. [12] In light of our continuous interests in C‒H thiocyanation and the sustainable characteristics of organic electrosynthesis, [13] we report herein a site-selective quinoline C3‒H thiocyanation under mild electrochemical conditions (Scheme 1d). This protocol has the following advantages: 1) inexpensive graphite rod and nickel plate as electrodes, 2) external oxidant- and metal-free, 3) TMSNCS plays a dual role as an activation reagent and coupling partner, 4) excellent C3 site-selectivity and broad substrate scope, 5) easily scaled up and suitable for late-stage thiocyanation of bioactive molecules. Results and Discussion The electrochemical thiocyanation of 6-methylquinoline ( 1 ) with trimethylsilyl isothiocyanate (TMSNCS, 2 ) was chosen as a model reaction for the optimization of the reaction conditions. The desired C3-thiocyanation product 3 was obtained in 73% yield when the reaction was carried out in an undivided cell with graphite rod as the anode, nickel plate as the cathode, n Bu 4 NH 2 PO 4 as the electrolyte, MeCN as the solvent under a constant current (10 mA) at room temperature (Table 1, entry 1). The yield of product 3 was decreased obviously using graphite felt as the anode or platinum plate as the cathode (entries 2 and 3). Changing other solvents, such as DCE or HFIP, only gave trace amounts of the product (entry 4). Replacing the electrolyte with n Bu 4 NClO 4 or n Bu 4 NPF 6 resulted in decreased yields (entries 5 and 6). The optimization of the current failed to improve the yield (entry 7). When KSCN or NH 4 SCN was used instead of TMSNCS, the reaction could not proceed (entry 8). A slightly lower yield was observed under an air atmosphere (entry 9). Finally, control experiment indicated the crucial role of electricity, while no product was observed in the absence of current (entry 10). Table 1 Optimisation of the reaction conditions a 1 None 73 2 graphite felt as anode 35 3 platinum plate as cathode 44 4 DCE or HFIP as solvent trace 5 n Bu 4 NClO 4 instead of n Bu 4 NH 2 PO 4 40 6 n Bu 4 NPF 6 instead of n Bu 4 NH 2 PO 4 15 7 8 mA or 12 mA 52 or 50 8 KSCN or NH 4 SCN instead of TMSNCS n.r. 9 under air 56 10 no current n.r. a Conditions: graphite rod anode and nickel plate cathode, 1 (0.2 mmol), 2 (0.3 mmol), n Bu 4 NH 2 PO 4 (0.2 mmol), MeCN (5 mL), undivided cell, constant current (10 mA), N 2 , rt, 4 h (7.5 F/mol). b Isolated yield. With the optimal conditions in hand, the scope of quinolines was explored (Table 2). The C6-substituted quinolines, including methyl, fluoro, methoxy, and ester group, could smoothly generate C3-thiocyanated products 3-6 in 43-73% yields. Unsubstituted quinoline gave the desired product 7 in 46% yield. The C2-substituted substrates (-Me, -Ph, and -CN) exhibited good reactivity, providing products 8-10 in moderate yields. In addition, 4-methylquinoline, 5-methoxyquinoline, 7-chloroquinoline, 8-chloroquinoline, and 8-aminoquinoline were also compatible with the reaction conditions, affording the corresponding products 11-15 in 39-79% yields. Multi-substituted quinolines, including 2,6-, 2,7-, 2,8-, and 6,7-disubstituted substrates, could selectively undergo C-3 thiocyantion to product products 16-21 in moderate yields. To our delight, other benzofused heterocycles, such as isoquinoline and quinoxaline, also led to the desired products 22-24 in moderate yields. Interestingly, when pyrrolo[2,3- b ]pyridine was used as a substrate, the C3-pyrrolo thiocyanate product 25 was obtained selectively in 40% yield. The practicality of this thiocyanation protocol was further demonstrated by late-stage modification of bioactive molecules. The tetra-substituted quinoline derived from antibacterial drug chlorquinaldol could afford the thiocyanate 26 in 42% yield. Cloquintocet-mexyl, which is a herbicide safener, could give the desired compound 27 in 32% yield. In addition, the quinoline derivatives of L-menthol, ibuprofen and probenecid, were all compatible with the reaction to produce the corresponding thiocyanates 28-30 in 34-41% yields. To demonstrate the synthetic utility of this method, the synthesis of thiocyanated quinoline 9 was successfully scaled up to 5 mmol (Scheme 2). As a versatile synthetic intermediate, the follow-up transformations of thiocyanate 9 were next investigated. Thiocyanate 9 could be converted to trifluoromethylthio quinoline 31 in the presence of TMSCF 3 with 79% yield. Treatment of 9 with NaN 3 afforded tetrazole derivative 32 in good yield. In addition, thiocyanate 9 could be readily hydrolyzed to 33 with H 2 SO 4 . Table 2 Substrate scope a a Conditions: substrates (0.2 mmol), TMSNCS 2 (0.3 mmol), n Bu 4 NH 2 PO 4 (0.4 mmol), MeCN (5 mL), undivided cell, 10 mA, N 2 , rt, 4 h. b 3 h. c 3.5 h. d TMSNCS 2 (0.4 mmol), 13 mA. Scheme 2 Follow-up transformations Scheme 3 Control experiments To gain insight into the mechanism of the electrochemical C3-thiocyanation, the oxidation potentials of the substrate 1 and TMSNCS were determined (Figure S3 in the ESI). The results indicate that TMSNCS can be oxidized under the reaction conditions (E = 1.81 V), whereas quinoline 1 has no obvious oxidation signal. As shown in Scheme 3, a series of control experiments were also conducted. Quinoline 1 was rapidly converted to quinolinium salt 34 in the presence of TMSNCS, which could readily transformed to 35 by anion exchange (Scheme 3a). [14] The use of H 2 PO 4 as anion exhibits better solubility and stable voltage. The thiocyanate 3 was obtained in 73% yield when quinolinium salt 35 was subjected to the standard reaction conditions, indicating that 35 was a key intermediate in the transformation (Scheme 3b). Moreover, the product 3 was isolated in 30% yield when the reaction was performed in a divided cell, indicating that the reaction involves anodic oxidation process (Scheme 3c, see the ESI for details). The addition of TEMPO inhibited the formation of product 3 (Scheme 3d). The thiocyanation at other site was not observed when using 3-methylquinoline 36 as a substrate, only starting material was recovered (Scheme 3e). On the basis of control experiments and previous reports, a possible reaction mechanism is described in Scheme 4. Initially, the quinoline substrate is in situ activated to form the silylquinolinium salt 35 . Meanwhile, the SCN anion is oxidized at the anode to generate the electrophilic SCN radical. Subsequently, a regioselective addition of SCN radical to 35 produces the radical cation 37 , which undergoes deprotonation and anodic oxidation to afford the thiocyanated quinolinium salt 38 (detected by HRMS). Finally, the C3-thiocyanated product 3 is obtained by N‒Si bond cleavage. Scheme 4 Mechanistic proposal Conclusions In conclusion, we report a new method for electrochemical C3-thiocyanation of quinolines under external oxidant-free conditions. This protocol provides a general tool for the synthesis of thiocyanated quinolines with broad substrate scope and excellent site-selectivity. Furthermore, the late-stage modification of bioactive molecules, scale-up reaction and follow-up transformations enable valuable synthetic applications. Mechanistic studies reveal that the in situ generation of silylquinolinium salt is the key intermediate for the thiocyanation. Given the broad use of thiocyanates and quinoline derivatives, we believe that the C3-thiocyanated quinolines have great potential for application in synthetic chemistry. Experimental To a 10 mL three-necked flask equipped with carbon rod anode (Φ1.0 cm × 1.0 cm depth in solution) and nickel plate cathode (1.5 cm x 1.0 cm x 0.1 mm) was charged with 1 (0.2 mmol, 1.0 equiv., 29 mg), TMSNCS (0.3 mmol, 1.5 equiv., 39 mg), n Bu 4 NH 2 PO 4 (0.2 mmol, 1.0 equiv., 68 mg) and MeCN (5 mL). The electrolysis was carried out at room temperature using a constant current of 10 mA under N 2 for 4 h (7.5 F/mol). After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired product 3 as a yellow solid (29 mg, 73% yield). Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx. 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Rev. 2017 , 117 , 13230‒13319. 14. The silylquinolinium salts 34 and 35 are new bench-stable compounds. See the ESI for characteristic data and NMR spectra. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 Left to Right: Ziyun Wang, Runzhao Shi, Jialing Zhang, Lin-Bao Zhang, Lirong Wen and Weisi Guo Entry for the Table of Contents Electrochemical C3-thiocyanation of quinolines Ziyun Wang, Runzhao Shi, Jialing Zhang, Lin-Bao Zhang, Lirong Wen* and Weisi Guo* Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX The site-selective C‒H thiocyanation of quinoline has potential application value but remains undeveloped. We report herein an electrochemical C3-thiocyanation of quinoline derivatives under external oxidant-free conditions. The key to success for this reaction is the in situ formation of activated silylquinolinium salts. This method exhibits mild reaction conditions, broad substrate scope, and excellent site-selectivity. The practicality of this protocol is further demonstrated by a scale-up reaction, follow-up transformations, and late-stage thiocyanation of quinoline-based bioactive molecules. Information & Authors Information Version history V1 Version 1 25 March 2025 Peer review timeline Published Chinese Journal of Chemistry Version of Record 29 May 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Chinese Journal of Chemistry Keywords electrochemical synthesis quinoline thiocyanation Authors Affiliations Ziyun Wang Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Runzhao Shi Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Jialing Zhang Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Lin-Bao Zhang 0000-0002-8334-4188 Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Li-Rong Wen Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Weisi Guo 0000-0001-6688-4679 [email protected] Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Metrics & Citations Metrics Article Usage 398 views 252 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ziyun Wang, Runzhao Shi, Jialing Zhang, et al. Electrochemical C3-Thiocyanation of Quinolines. Authorea . 25 March 2025. DOI: https://doi.org/10.22541/au.174287541.14000255/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! 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