Access to SCN-containing thiazolines via electrochemical regioselective thiocyanothiocyclization of N-allylthioamides

Yan-An Zhang , Zhong Ding , Peng Liu , Wei-Si Guo *, Li-Rong Wen * and Ming Li
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China. E-mail:;

Received 6th March 2020 , Accepted 8th April 2020

First published on 9th April 2020

An electrochemical thiocyanothiocyclization of N-allylthioamides has been developed for the synthesis of SCN-containing 2-thiazolines. This method provides a green and efficient approach to generate 5-exo-cyclization 2-thiazolines with a broad substrate scope and good yields. In addition, 6-endo-cyclization isothiocyanato thiazines are formed regioselectively when cyclic thioamides are used as reactants. The reaction is easy to proceed under catalyst-, additive- and oxidant-free conditions.


Electrochemical synthesis, which is atom economical and sustainable, has attracted much attention in the past decade.1 It provides a green and efficient approach for the generation of radical intermediates using electrons as traceless reagents, and could avoid the use of toxic oxidants and expensive catalysts. Recently, electrochemical difunctionalization of alkenes has been utilized to synthesize a variety of functionalized heterocycles.2 Anodic oxidation can be used to form C–C and C–heteroatom bonds under environmentally friendly conditions. However, an electrochemical approach for the synthesis of 2-thiazolines has not yet been explored.

The 2-thiazoline scaffold is a privileged heterocycle found in natural products and bioactive molecules.3 In addition, thiazolines are representative chiral ligands in asymmetric synthesis.4 Therefore, various approaches have been developed in the past decade for the synthesis of thiazoline derivatives.5 The cyclization based on the toxic β-aminothiols remains the most frequently used approach.6 Furthermore, these reactions usually accompanied by harsh conditions, limited substrate scope and stoichiometric waste formation. Compared to the intramolecular cyclization of N-allylcarboxamides to form oxazolines,7 a similar strategy for the synthesis of thiazolines using N-allylthioamides has rarely been reported, possibly because thioamides are easily oxidized and prone to desulfurization to form amides under traditional oxidative conditions.8 Recently, the Hong group developed a hypervalent iodine-mediated aminothiolation reaction for the synthesis of 5-amino-thiazolines using excess N-allylthioamides as starting materials (Scheme 1a).9 The Nicewicz group developed a photocatalyzed intramolecular hydrothiolation reaction for the synthesis of thiazolines (6 examples) using thiophenol as a hydrogen atom donor (Scheme 1b).10 Despite this progress, the synthesis of functionalized thiazolines from N-allylthioamides under mild reaction conditions is still challenging.

image file: d0qo00300j-s1.tif
Scheme 1 Synthesis of 2-thiazolines from N-allylthioamides.

Organothiocyanates have versatile functionality in natural products and biologically active compounds.11 They are also useful precursors to transform into thiocarbamates, thiotetrazoles, and other sulfur-containing derivatives.12 Thus, a variety of synthetic protocols have been established for the synthesis of SCN-containing compounds.13 Recently, various SCN-containing heterocycles have been constructed by the intramolecular cyclization of alkenes with thiocyanate salts, such as pyrazolines,14 dihydrofurans,15 and oxazines.16 However, the synthetic method for thiocyanato-substituted thiazolines remains undeveloped.17 We speculated that the SCN anion could be transformed into (SCN)2 under mild electrochemical conditions to trigger intramolecular cyclization, as shown in Scheme 1c. Although the proposed strategy seems reasonable, its realization remains challenging. First, the desulfurization of N-allylthioamides should be avoided under electrochemical oxidative conditions.18 Second, thioamides might also be oxidized under electrochemical conditions, resulting in a less regioselective cyclization.10 With our continued interest in thioamide chemistry and electrocatalysis,19 we developed the first example of an electrochemical synthesis of 5-thiocyanatomethyl-2-thiazolines using readily available N-allylthioamides under catalyst- and oxidant-free conditions. When cyclic thioamides were used as starting materials, 6-endo-cyclization isothiocyanato thiazines were formed regioselectively. Moreover, the cheap thiocyanate salt play a dual role, and an additional supporting electrolyte is not required for the reaction.

Results and discussion

Initially, N-allylthioamide 1a and NH4SCN 2 were selected as starting materials to investigate the optimized reaction conditions. The best yield (85%) of the desired thiazoline 3a was obtained by using a graphite rod as both an anode and a cathode at room temperature in CH3CN with a constant voltage of 2.0 V in an undivided cell for 5 h (Table 1, entry 1). A similar yield (81%) was obtained with a platinum plate as a cathode (Table 1, entry 2). However, graphite felt gave a low yield (Table 1, entry 3). The addition of the electrolyte nBu4NPF6 and LiClO4 did not promote the yield of 3a (Table 1, entries 4 and 5). Both an increase and a decrease in the constant voltage than 2.0 V were less efficient, while the use of 5 mA constant current also failed to improve the reaction yield (Table 1, entries 6–8). Moreover, different solvents were screened, CH3OH gave a 59% yield and THF led to a trace amount of 3a (Table 1, entries 9 and 10). Instead of NH4SCN, KSCN resulted in a relatively close yield (Table 1, entry 11). Not surprisingly, no product 3a was detected without electricity (Table 1, entry 12).
Table 1 Optimization of the reaction conditionsa

image file: d0qo00300j-u1.tif

Entry Deviation from standard conditions Yieldb (%)
a Standard conditions: C (Φ 5 mm) anode, C (Φ 5 mm) cathode, constant voltage = 2.0 V, 1a (0.2 mmol), 2 (0.4 mmol), CH3CN (4.0 mL), RT, air, 5 h. b Isolated yields; n.d. = not detected.
1 None 85
2 C (+)|Pt (−) instead of C (+)|C (−) 81
3 C felt instead of C (+)|C (−) 36
4 Add nBu4NPF6 (1 equiv.) 83
5 Add LiClO4 (1 equiv.) 44
6 3.0 V instead of 2.0 V 77
7 1.5 V instead of 2.0 V 73
8 5.0 mA instead of 2.0 V 75
9 THF instead of CH3CN Trace
10 MeOH instead of CH3CN 59
11 KSCN instead of NH4SCN 80
12 Without electricity n.d.

Having established the optimal reaction conditions, the substrate scope of N-allylthioamides 1 was explored (Table 2). The reactions were compatible with different substituted groups (e.g., Me, MeO, Ph, Cl, Br, CF3, and COOMe) on the phenyl ring (R1) regardless of the electronic nature and substitution position, products 3a–j were obtained in 70–88% yields. Thioamides containing 3,5-dimethyl groups on the phenyl ring were also compatible, affording 3k in moderate yield. In addition, a substrate with a naphthyl group furnished thiazoline 3l in 63% yield. Gratifyingly, substrates bearing furan, thiophene, and pyridine moieties were also tolerated to generate products 3m–o in good yields. N-Allylcinnamide was also a good substrate, and the desired product 3p was obtained in 44% yield. Subsequently, 1,1-disubstituted alkenes were performed under the optimized reaction conditions, and the desired thiazolines 3q–aa were also obtained regioselectively, regardless of the electronic properties of the functional group on the two aryl rings (4-OMe, 4-Cl, 4-Br, 2-pyridyl, and 4-CF3). Steric hindrance may influence the transformation, and the corresponding products were obtained in moderate yields. The reaction of 1,2-disubstituted alkenes also proceeded successfully to generate the desired thiazolines 3ab and 3ac in 66% and 63% yields, respectively. Alkyl- and alkene-substituted substrates were also cyclized smoothly, albeit they gave 3ad and 3ae in low yields. It is noteworthy that trisubstituted alkenes were well tolerated, and the desired product 3af was obtained in 58% yield. The structures of compounds 3 were undoubtedly confirmed by the X-ray crystallographic structure of 3ab (see ESI, Fig. S1).

Table 2 Substrate scope of thioamide 1 with 2a,b
a Standard conditions: C (Φ 5 mm) anode, C (Φ 5 mm) cathode, constant voltage = 2.0 V, 1 (0.2 mmol), 2 (0.4 mmol), CH3CN (4.0 mL), RT, air, 5 h. b Isolated yields. c The reaction time was 8 h. d The diastereoselectivity ratio is >19[thin space (1/6-em)]:[thin space (1/6-em)]1.
image file: d0qo00300j-u2.tif

1,2-Dihydronaphthalene substrates were synthesized to test the tolerance of the reaction under the optimized reaction conditions (Table 3). The 6-endo-cyclization products 4a–c were isolated regioselectively in moderate yields, and no 5-exo-cyclization products were detected. Although the explanation for the regioselectivity is unclear, we speculate that the reactions of the substrates bearing cyclic alkenes are prone to occur through 6-endo-cyclization with less steric hindrance. Interestingly, only the C–N bond forming isothiocyanates were generated selectively.20 The structure of compound 4b was confirmed by X-ray crystallography analysis (see ESI, Fig. S2). In addition, the reactions with dihydrochromene- and dihydrothiochromene-derived substrates proceeded smoothly, the corresponding tricyclic isothiocyanates 4d and 4e were obtained in 58% and 60% yields, respectively. Indene thioamide was also tolerated to produce the desired product 4f, albeit in a low yield.

Table 3 Substrate scope of thioamide 1 with 2a,b
a Standard conditions: C (Φ 5 mm) anode, C (Φ 5 mm) cathode, constant voltage = 2.0 V, 1 (0.2 mmol), 2 (0.4 mmol), CH3CN (4.0 mL), RT, air, 8 h. b Isolated yields; all the products were obtained with a >19[thin space (1/6-em)]:[thin space (1/6-em)]1 diastereoselectivity ratio.
image file: d0qo00300j-u3.tif

To demonstrate the practicality of this method, a gram-scale experiment was performed using substrate 1a. The desired product 3a was formed in 71% yield (1.66 g). Furthermore, the synthetic applications of 3 were also explored. As shown in Scheme 2, hydrolyzed thiocarbamate 5 was obtained in 87% yield using sulfuric acid. The thiocyanate group could react with NaN3 through cycloaddition to give tetrazole 6 in 91% yield. Phosphonothioate 7 was obtained in a good yield when diphenylphosphine oxide was used as a nucleophile. The trifluoromethylthio group is widely used in pharmaceuticals and agrochemicals. Similarly, the reaction of 3a with TMSCF3 at room temperature afforded trifluoromethylthio derivative 8 in 78% yield. In addition, 3a can be oxidized to thiazole 9 smoothly in the presence of DDQ.

image file: d0qo00300j-s2.tif
Scheme 2 Gram-scale and follow-up reactions.

Several control experiments were carried out to elucidate the reaction mechanism. A radical scavenger 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) was added into the reaction mixture under standard conditions. The reaction was not inhibited and 3a was obtained in 68% or 57% yield, respectively (Scheme 3, eqn (1)). Furthermore, a radical clock experiment was also carried out using 1ag as the starting material. Product 3ag was obtained in 72% yield with the cyclopropyl group retained, which excluded the formation of a thiyl radical intermediate (Scheme 3, eqn (2)).10 Meanwhile, the cyclic voltammetry experiments of 1a and 2 were performed, and the oxidation peaks were observed at 1.67 V and 1.15 V, respectively (see the ESI, Fig. S3). This result indicated that NH4SCN was easier to oxidize under electrochemical conditions.

image file: d0qo00300j-s3.tif
Scheme 3 Control experiments.

On the basis of the above experimental results and literature reports, a possible mechanism for the tandem reaction is shown in Scheme 4. Initially, the anode oxidation of the SCN anion generates (SCN)2,21 which reacts with N-allylthioamide 1 to form sulfonium intermediate A.22 Subsequently, intramolecular regioselective nucleophilic ring-opening by thioamides, followed by deprotonation, affords thiazoline 3 or thiazine 4. Meanwhile, protons were reduced to hydrogen at the cathode.

image file: d0qo00300j-s4.tif
Scheme 4 Proposed reaction mechanism.


In conclusion, we have developed an efficient tandem reaction for the synthesis of thiocyanato-substituted thiazoline derivatives. This environmentally benign electrochemical strategy is performed under catalyst-, additive-, and oxidant-free conditions with a constant voltage at room temperature. The reaction also features a broad substrate scope, high regioselectivity, and easily scaled-up and simple operation. Furthermore, isothiocyanato-fused thiazines were obtained when cyclic thioamides were used as reactants. Further application of the electrochemical tandem reactions with thioamides is currently under investigation.

Conflicts of interest

There are no conflicts to declare.


This work was financially supported by the National Natural Science Foundation of China (21572110) and the Natural Science Foundation of Shandong Province (ZR2019MB010).

Notes and references

  1. For selected reviews, see: (a) Y. Yuan and A. Lei, Electrochemical oxidative cross-coupling with hydrogen evolution reactions, Acc. Chem. Res., 2019, 52, 3309 CrossRef CAS PubMed; (b) P. Xiong and H.-C. Xu, Chemistry with electrochemically generated N–centered radicals, Acc. Chem. Res., 2019, 52, 3339 CrossRef CAS PubMed; (c) C. Kingston, M. D. Palkowitz, Y. Takahira, J. C. Vantourout, B. K. Peters, Y. Kawamata and P. S. Baran, A survival guide for the “electro-curious”, Acc. Chem. Res., 2020, 53, 72 CrossRef CAS PubMed; (d) G. S. Sauer and S. Lin, An electrocatalytic approach to the radical difunctionalization of alkenes, ACS Catal., 2018, 8, 5175 CrossRef CAS; (e) C. Ma, P. Fang and T.-S. Mei, Recent advances in C-H functionalization using electrochemical transition metal catalysis, ACS Catal., 2018, 8, 7179 CrossRef CAS; (f) Y. Jiang, K. Xu and C.-C. Zeng, Use of electrochemistry in the synthesis of heterocyclic structures, Chem. Rev., 2018, 118, 4485 CrossRef CAS PubMed; (g) P. Wang, X. Gao, P. Huang and A. Lei, Recent advances in electrochemical oxidative cross-coupling of alkenes with H2 evolution, ChemCatChem, 2020, 12, 27 CrossRef CAS; (h) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes and S. R. Waldvogel, Electrochemical allylic oxidation of olefins: sustainable and safe, Angew. Chem., Int. Ed., 2018, 57, 5594 CrossRef CAS PubMed.
  2. (a) Y.-Y. Jiang, S. Liang, C.-C. Zeng, L.-M. Hu and B.-G. Sun, Electrochemically initiated formation of sulfonyl radicals: synthesis of oxindoles via difunctionalization of acrylamides mediated by bromide ion, Green Chem., 2016, 18, 6311 RSC; (b) S. Liang, C.-C. Zeng, X.-G. Luo, F.-Z. Ren, H.-Y. Tian, B.-G. Sun and R. Daniel Little, Electrochemically catalyzed amino-oxygenation of styrenes: a n-Bu4NI induced C-N followed by C-O bond formation cascade for the synthesis of indolines, Green Chem., 2016, 18, 2222 RSC; (c) X.-J. Meng, P.-F. Zhong, Y.-M. Wang, H.-S. Wang, H.-T. Tang and Y.-M. Pan, Electrochemical difunctionalization of olefines: access to selenomethyl-substituted cyclic ethers or lactones, Adv. Synth. Catal., 2020, 362, 506 CrossRef CAS; (d) Z. Guan, Y. Wang, H. Wang, Y. Huang, S. Wang, H. Tang, H. Zhang and A. Lei, Electrochemical oxidative cyclization of olefinic carbonyls with diselenides, Green Chem., 2019, 21, 4976 RSC; (e) Z. Ruan, Z. Huang, Z. Xu, G. Mo, X. Tian, X.-Y. Yu and L. Ackermann, Catalyst-free, direct electrochemical tri- and difluoroalkylation/cyclization: access to functionalized oxindoles and quinolinones, Org. Lett., 2019, 21, 1237 CrossRef CAS PubMed; (f) S. Mallick, M. Baidya, K. Mahanty, D. Maiti and S. D. Sarkar, Electrochemical chalcogenation of β,γ-unsaturated amides and oximes to corresponding oxazolines and isoxazolines, Adv. Synth. Catal., 2020, 362, 1046 CrossRef CAS; (g) Z. Yang, Y. Wang, L. Hu, J. Yu, A. Li, L. Li, T. Yang and C. Zhou, Electrochemically induced thiocyanation of enaminones: synthesis of functionalized alkenes and chromones, Synthesis, 2020, 52, 711 CrossRef CAS.
  3. (a) J. J. Gehret, L. Gu, W. H. Gerwick, P. Wipf, D. H. Sherman and J. L. Smith, Terminal alkene formation by the thioesterase of curacin A biosynthesis, J. Biol. Chem., 2011, 286, 14445 CrossRef CAS PubMed; (b) N. R. Conley, A. D. Andrasi, J. Rao and W. E. Moerner, A selenium analogue of firefly d-Luciferin with red-shifted bioluminescence emission, Angew. Chem., Int. Ed., 2012, 51, 3350 CrossRef CAS PubMed; (c) C. M. Marson, C. J. Matthews, E. Yiannaki, S. J. Atkinson, P. E. Soden, L. Shukla, N. Lamadema and N. S. B. Thomas, Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N–(2-aminophenyl)benzamide binding unit, J. Med. Chem., 2013, 56, 6156 CrossRef CAS PubMed; (d) K. C. Nicolaou, D. E. Lizos, D. W. Kim, D. Schlawe, R. G. de Noronha, D. A. Longbottom, M. Rodriquez, M. Bucci and G. Cirino, Total synthesis and biological evaluation of halipeptins A and D and analogues, J. Am. Chem. Soc., 2006, 128, 4460 CrossRef CAS PubMed; (e) J. M. Macdonald, C. A. Tarling, E. J. Taylor, R. J. Dennis, D. S. Myers, S. Knapp, G. J. Davies and S. G. Withers, Chitinase inhibition by chitobiose and chitotriose thiazolines, Angew. Chem., Int. Ed., 2010, 49, 2599 CrossRef CAS PubMed.
  4. (a) A. Betz, L. Yu, M. Reiher, A.-C. Gaumont, P.-A. Jaffrès and M. Gulea, (N,N) vs. (N,S) chelation of palladium in asymmetric allylic substitution using bis(thiazoline) ligands: A theoretical and experimental study, J. Organomet. Chem., 2008, 693, 2499 CrossRef CAS; (b) D.-M. Du, S.-F. Lu, T. Fang and J. Xu, Asymmetric henry reaction catalyzed by C2-symmetric tridentate bis(oxazoline) and bis(thiazoline) complexes: metal-controlled reversal of enantioselectivity, J. Org. Chem., 2005, 70, 3712 CrossRef CAS PubMed; (c) M. Mellah, A. Voituriez and E. Schulz, Chiral sulfur ligands for asymmetric catalysis, Chem. Rev., 2007, 107, 5133 CrossRef CAS PubMed.
  5. For selected reviews, see: (a) A.-C. Gaumont, M. Gulea and J. Levillain, Overview of the chemistry of 2-thiazolines, Chem. Rev., 2009, 109, 1371 CrossRef CAS PubMed; (b) N.-E. Alom, F. Wu and W. Li, One-pot strategy for thiazoline synthesis from alkenes and thioamides, Org. Lett., 2017, 19, 930 CrossRef CAS PubMed; (c) U. Pathak, S. Bhattacharyya, V. Dhruwansh, L. Kumar Pandey, R. Tank and M. V. S. Suryanarayana, Easy access to thiazolines and thiazines via tandem S-alkylation-cyclodeamination of thioamides/haloamines, Green Chem., 2011, 13, 1648 RSC; (d) B. C. Lemercier and J. G. Pierce, Synthesis of thiazolines by copper catalyzed aminobromination of thiohydroximic acids, Org. Lett., 2014, 16, 2074 CrossRef CAS PubMed; (e) G.-Q. Liu, C.-H. Yang and Y.-M. Li, Modular preparation of 5–Halomethyl-2-oxazolines via PhI(OAc)2–p romoted intramolecular halooxygenation of N–allylcarboxamides, J. Org. Chem., 2015, 80, 11339 CrossRef CAS PubMed.
  6. (a) M. Trose, F. Lazreg, M. Lesieur and C. S. J. Cazin, A straightforward metal-free synthesis of 2-substituted thiazolines in air, Green Chem., 2015, 17, 3090 RSC; (b) R. Zhao, M. Yan, R. Zhang, Y. Ma and J. Chen, CuBr2-promoted cyclocondensation of amidines with aminoalcohols/aminothiols for the synthesis of 2-oxazolines, 2-oxazines and 2-thiazolines under solvent-free conditions, ChemistrySelect, 2019, 4, 10907 CrossRef CAS; (c) O. V. Maltsev, V. Walter, M. J. Brandl and L. Hintermann, Medium buffer effects on the condensation of L-cysteine and aryl nitriles to (R)-2-Aryl-4,5-dihydrothiazole-4-carboxylic acids, Synthesis, 2013, 45, 2763 CrossRef CAS.
  7. (a) J. D. Haupt, M. Berger and S. R. Waldvogel, Electrochemical fluorocyclization of N–allylcarboxamides to 2–oxazolines by hypervalent iodine mediator, Org. Lett., 2019, 21, 242 CrossRef CAS PubMed; (b) J. Yu, H. Yang and H. Fu, Transition metal-free trifluoromethylation of N-allylamides with sodium trifluoromethanesulfinate: synthesis of trifluoromethyl-containing oxazolines, Adv. Synth. Catal., 2014, 356, 3669 CrossRef CAS; (c) Q.-B. Zhang, P.-F. Yuan, L.-L. Kai, K. Liu, Y.-L. Ban, X.-Y. Wang, L.-Z. Wu and Q. Liu, Preparation of heterocycles via visible-light-driven aerobic selenation of olefins with diselenides, Org. Lett., 2019, 21, 885 CrossRef CAS PubMed.
  8. (a) H. Wang, L. Wang, J. Shang, X. Li, H. Wang, J. Gui and A. Lei, Fe-catalysed oxidative C–H functionalization/C–S bond formation, Chem. Commun., 2012, 48, 76 RSC; (b) X.-Y. Qian, S.-Q. Li, J. Song and H.-C. Xu, TEMPO-catalyzed electrochemical C-H thiolation: synthesis of benzothiazoles and thiazolopyridines from thioamides, ACS Catal., 2017, 7, 2730 CrossRef CAS; (c) G. Zhang, C. Liu, H. Yi, Q. Meng, C. Bian, H. Chen, J. Jian, L.-Z. Wu and A. Lei, External oxidant-free oxidative cross-coupling: A photoredox cobalt-catalyzed aromatic C-H thiolation for constructing C-S bonds, J. Am. Chem. Soc., 2015, 137, 9273 CrossRef CAS PubMed; (d) L. M. Bouchet, A. A. Heredia, J. E. Argüello and L. C. Schmidt, Riboflavin as photoredox catalyst in the cyclization of thiobenzanilides: synthesis of 2–substituted benzothiazoles, Org. Lett., 2020, 22, 610 CrossRef CAS PubMed; (e) P. Ricci, T. Khotavivattana, L. Pfeifer, M. Medebielle, J. R. Morphyc and V. Gouverneur, The dual role of thiourea in the thiotrifluoromethylation of alkenes, Chem. Sci., 2017, 8, 1195 RSC; (f) Y. Cheng, J. Yang, Y. Qu and P. Li, Aerobic visible-light photoredox radical C-H functionalization: catalytic synthesis of 2-substituted benzothiazoles, Org. Lett., 2011, 14, 98 CrossRef PubMed.
  9. H. Jeon, D. Kim, J. H. Lee, J. Song, W. S. Lee, D. W. Kang, S. Kang, S. B. Lee, S. Choi and K. B. Hong, Hypervalent iodine-mediated alkene functionalization: oxazoline and thiazoline synthesis via inter-/intramolecular aminohydroxylation and thioamination, Adv. Synth. Catal., 2018, 360, 779 CrossRef CAS.
  10. P. D. Morse and D. A. Nicewicz, Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides, Chem. Sci., 2015, 6, 270 RSC.
  11. (a) S. H. Szajnman, W. Yan, B. N. Bailey, R. Docampo, E. Elhalem and J. B. Rodriguez, Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of trypanosoma cruzi proliferation, J. Med. Chem., 2000, 43, 1826 CrossRef CAS PubMed; (b) E. Elhalem, B. N. Bailey, R. Docampo, I. Ujváry, S. H. Szajnman and J. B. Rodriguez, Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against trypanosoma cruzi, J. Med. Chem., 2002, 45, 3984 CrossRef CAS PubMed; (c) S. Dutta, H. Abe, S. Aoyagi, C. Kibayashi and K. S. Gates, DNA damage by fasicularin, J. Am. Chem. Soc., 2005, 127, 15004 CrossRef CAS PubMed.
  12. (a) Q. Chen, Y. Lei, Y. Wang, C. Wang, Y. Wang, Z. Xu, H. Wang and R. Wang, Direct thiocyanation of ketene dithioacetals under transition-metal-free conditions, Org. Chem. Front., 2017, 4, 369 RSC; (b) D.-L. Kong, J.-X. Du, W.-M. Chu, C.-Y. Ma, J.-Y. Tao and W.-H. Feng, Ag/pyridine co-mediated oxidative arylthiocyanation of activated alkenes, Molecules, 2018, 23, 2727 CrossRef PubMed.
  13. For selected reviews, see: (a) T. Castanheiro, J. Suffert, M. Donnard and M. Gulea, Recent advances in the chemistry of organic thiocyanates, Chem. Soc. Rev., 2016, 45, 494 RSC; (b) J. Wen, L. Zhang, X. Yang, C. Niu, S. Wang, W. Wei, X. Sun, J. Yang and H. Wang, H2O-controlled selective thiocyanation and alkenylation of ketene dithioacetals under electrochemical oxidation, Green Chem., 2019, 21, 3597 RSC; (c) P.-F. Yuan, Q.-B. Zhang, X.-L. Jin, W.-L. Lei, L.-Z. Wu and Q. Liu, Visible-light-promoted aerobic metal-free aminothiocyanation of activated ketones, Green Chem., 2018, 20, 5464 RSC; (d) S.-M. Yang, T.-J. He, D.-Z. Lin and J.-M. Huang, Electrosynthesis of (E)–vinyl thiocyanates from cinnamic acids via decarboxylative coupling reaction, Org. Lett., 2019, 21, 1958 CrossRef CAS PubMed; (e) L.-S. Kang, M.-H. Luo, C. M. Lam, L.-M. Hu, R. Daniel Little and C.-C. Zeng, Electrochemical C-H functionalization and subsequent C-S and C-N bond formation: Paired electrosynthesis of 3-amino-2-thiocyanato α,β-unsaturated carbonyl derivatives mediated by bromide ion, Green Chem., 2016, 18, 3767 RSC; (f) X. Zeng, B. Chen, Z. Lu, G. B. Hammond and B. Xu, Homogeneous and nanoparticle gold-catalyzed hydrothiocyanation of haloalkynes, Org. Lett., 2019, 21, 2772 CrossRef CAS PubMed; (g) W. Fan, Q. Yang, F. Xu and P. Li, A visible-light-promoted aerobic metal-free C–3 thiocyanation of indoles, J. Org. Chem., 2014, 79, 10588 CrossRef CAS PubMed; (h) X. Zhang, C. Wang, H. Jiang and L. Sun, A low-cost electrochemical thio- and selenocyanation strategy for electron-rich arenes under catalyst- and oxidant-free conditions, RSC Adv., 2018, 8, 22042 RSC.
  14. F. Meng, H. Zhang, H. He, N. Xu, Q. Fang, K. Guo, S. Cao, Y. Shi and Y. Zhu, Copper-catalyzed domino cyclization/thiocyanation of unactivated olefins: access to SCN-containing pyrazolines, Adv. Synth. Catal., 2020, 362, 248 CrossRef CAS.
  15. A.-H. Ye, Y. Zhang, Y.-Y. Xie, H.-Y. Luo, J.-W. Dong, X.-D. Liu, X.-F. Song, T. Ding and Z.-M. Chen, TMSCl-catalyzed electrophilic thiocyano oxyfunctionalization of alkenes using N–thiocyano-dibenzenesulfonimide, Org. Lett., 2019, 21, 5106 CrossRef CAS PubMed.
  16. H. Yang, X.-H. Duan, J.-F. Zhao and L.-N. Guo, Transition-metal-free tandem radical thiocyanooxygenation of olefinic amides: a new route to SCN-containing heterocycles, Org. Lett., 2015, 17, 1998 CrossRef CAS PubMed.
  17. Qumruddeen, A. Yadav, R. Kant and C. B. Tripathi, Lewis base/Brønsted acid cocatalysis for thiocyanation of amides and thioamides, J. Org. Chem., 2020, 85, 2814 CrossRef CAS PubMed . At the time of getting our manuscript ready for submission, the Tripathi group reported Lewis base/Brønsted acid cocatalysis for the synthesis of thiocyanated thiazolines by an electrophilic thiocyanation of thioamides. Only activated olefins can afford the desired products.
  18. (a) C. Huang, X.-Y. Qian and H.-C. Xu, Continuous-Flow electrosynthesis of benzofused S-heterocycles by dehydrogenative C-S cross-coupling, Angew. Chem., 2019, 58, 6650 CrossRef CAS PubMed; (b) A. A. Folgueiras-Amador, X.-Y. Qian, H.-C. Xu and T. Wirth, Catalyst- and supporting-electrolyte-free electrosynthesis of benzothiazoles and thiazolopyridines in continuous flow, Chem. – Eur. J., 2018, 24, 487 CrossRef CAS PubMed.
  19. (a) W.-S. Guo, H. Gong, Y.-A. Zhang, L.-R. Wen and M. Li, Fast construction of 1,3-benzothiazepines by direct intramolecular dehydrogenative C-S bond formation of thioamides under metal-free conditions, Org. Lett., 2018, 20, 6394 CrossRef CAS PubMed; (b) L.-R. Wen, C.-C. Zhou, M.-Z. Zhu, S.-G. Xie, W.-S. Guo and M. Li, Intramolecular dehydrogenative C-S bond coupling of thioamides to form 1,3-benzothiazines under metal-free conditions, Org. Biomol. Chem., 2019, 17, 3356 RSC; (c) L.-B. Zhang, R.-S. Geng, Z.-C. Wang, G.-Y. Ren, L.-R. Wen and M. Li, Electrochemical intramolecular C–H/N–H functionalization for the synthesis of isoxazolidine-fused isoquinolin-1(2H)-ones, Green Chem., 2020, 22, 16 RSC.
  20. (a) P. S. Smith and D. W. Emerson, The isomerization of alkyl thiocyanates to isothiocyanates, J. Am. Chem. Soc., 1960, 82, 3076 CrossRef CAS; (b) Z. Liang, F. Wang, P. Chen and G. Liu, Copper-catalyzed intermolecular trifluoromethylthiocyanation of alkenes: convenient access to CF3–containing alkyl thiocyanates, Org. Lett., 2015, 17, 2438 CrossRef CAS PubMed.
  21. (a) M. Dyga, D. Hayrapetyan, R. K. Rit and L. J. Gooßen, Electrochemical ipso-thiocyanation of arylboron compounds, Adv. Synth. Catal., 2019, 361, 3548 CrossRef CAS; (b) V. A. Kokorekin, V. L. Sigacheva and V. A. Petrosyan, New data on heteroarene thiocyanation by anodic oxidation of NH4SCN. The processes of electroinduced nucleophilic aromatic substitution of hydrogen, Tetrahedron Lett., 2014, 55, 4306 CrossRef CAS.
  22. W. Wei, L. Liao, T. Qin and X. Zhao, Access to saturated thiocyano-containing azaheterocycles via selenide-catalyzed regio- and stereoselective thiocyanoaminocyclization of alkenes, Org. Lett., 2019, 21, 7846 CrossRef CAS PubMed.


Electronic supplementary information (ESI) available. CCDC 1960652 and 1960653. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0qo00300j

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