Metal-Free Regioselective Thiocyanation of (Hetero) Aromatic C-H Bonds using Ammonium Thiocyanate: An Overview

Document Type : Review article


1 College of Health Sciences, University of Human Development, Sulaimaniyah, Kurdistan region of Iraq

2 Department of Chemistry, Qatar University, Qatar

3 Department of Chemistry, Payame Noor University, Tehran, Iran.

4 Miyandoab Branch , Islamic Azad University, Miyandoab, Iran


(Hetero)aryl thiocyanates have been extensively used as dyes, insecticides, vulcanization accelerators, and building blocks in the synthesis of diverse organosulfur compounds. Therefore, development of novel, efficient, and practical methods for their synthesis has always been the important topic in organic synthesis. Recently, direct thiocyanation of (hetero)aromatic C-H bonds using inexpensive and easily available ammonium thiocyanate has attracted considerable attention from the organic synthesis community, because no pre-functionalization of the starting materials is required and therefore the hazardous waste streams are significantly reduced. In this review, we summarize the recent discoveries and developments in this interesting field by hoping it will inspire and stimulate further research on the topic.

Graphical Abstract

Metal-Free Regioselective Thiocyanation of (Hetero) Aromatic C-H Bonds using Ammonium Thiocyanate: An Overview


[1] S. Petropoulos, F. Di Gioia, G. Ntatsi, Vegetable organosulfur compounds and their health promoting effects, Curr. Pharm. Des., 23 (2017) 2850-2875.
[2] M. Feng, B. Tang, S. H Liang, X. Jiang, Sulfur containing scaffolds in drugs: synthesis and application in medicinal chemistry, Curr. Top. Med. Chem., 16 (2016) 1200-1216.
[3] K.A. Scott, J.T. Njardarson, Analysis of US FDA-approved drugs containing sulfur atoms, Top. Curr. Chem., 376 (2018) 5.
[4] T. Castanheiro, J. Suffert, M. Donnard, M. Gulea, Recent advances in the chemistry of organic thiocyanates, Chem. Soci. Rev., 45 (2016) 494-505.
[5] C. Shen, P. Zhang, Q. Sun, S. Bai, T.A. Hor, X. Liu, Recent advances in C–S bond formation via C–H bond functionalization and decarboxylation, Chem. Soci. Rev., 44 (2015) 291-314.
[6] (a) S. Jana, S. Chattopadhyay, Efficient and novel method for nucleophilic thiocyanation of activated aromatic compounds using sodium thiocyanate at ambient condition, Inorg. Chem. Commun., 35 (2013) 160-163; (b) F. Wang, X. Yu, Z. Qi, X. Li, Rhodium‐catalyzed C-S and C-N functionalization of arenes: Combination of C-H activation and hypervalent iodine chemistry, Chem. Eur. J., 22 (2016) 511-516.
[7] (a) N. Muniraj, J. Dhineshkumar, K.R. Prabhu, N‐Iodosuccinimide catalyzed oxidative selenocyanation and thiocyanation of electron rich arenes, ChemistrySelect, 1 (2016) 1033-1038; (b) D. Khalili, Graphene oxide: a promising carbocatalyst for the regioselective thiocyanation of aromatic amines, phenols, anisols and enolizable ketones by hydrogen peroxide/KSCN in water, New J. Chem., 40 (2016) 2547-2553.
[8] (a) K. Nikoofar, S. Gorji, Oxidant-free thiocyanation of phenols and carbonyl compounds under solvent-free conditions by AlCl3/NH4SCN, J. Sulfur Chem., 37 (2016) 80-88; (b) V.A. Kokorekin, R.R. Yaubasarova, S.V. Neverov, V.A. Petrosyan, Electrooxidative C–H functionalization of heteroarenes. thiocyanation of pyrazolo [1, 5‐a] pyrimidines, Eur. J. Org. Chem., (2019) 4233-4238.
[9] (a) T. Nagamachi, P. Torrence, J. Waters, B. Witkop, An easy access to 5-mercaptopyrimidine nucleosides through one-step synthesis of 5-thiocyanato-uridine and-2′-deoxyuridine, Chem. Commun., (1972) 1025-1026; (b) S.-I. Watanabe, T. Ueda, Thiocyanation of tubercidin and its derivatization to 6-propyl-and 6-cyano derivatives, Nucleos. Nucleot. Nucl., 1 (1982) 191-203.
[10] (a) Y. Kita, T. Takada, S. Mihara, B.A. Whelan, H. Tohma, Novel and direct nucleophilic sulfenylation and thiocyanation of phenol ethers using a hypervalent iodine (III) reagent, J. Org. Chem., 60 (1995) 7144-7148; (b) C. Feng, Y. Peng, G. Ding, X. Li, C. Cui, Y. Yan, Catalyst and additive-free regioselective oxidative C–H thio/selenocyanation of arenes and heteroarenes with elemental sulfur/selenium and TMSCN, Chem. Commun., 54 (2018) 13367-13370.
[11] D. Wu, J. Qiu, P.G. Karmaker, H. Yin, F.-X. Chen, N-Thiocyanatosaccharin: a “sweet” electrophilic thiocyanation reagent and the synthetic applications, J. Org. Chem., 83 (2018) 1576-1583.
[12] (a) K. Jouvin, C. Matheis, L.J. Goossen, Synthesis of aryl tri‐and difluoromethyl thioethers via a C-H‐thiocyanation/fluoroalkylation cascade, Chem. Eur. J., 21 (2015) 14324-14327; (b) S.N. Kadam, A.N. Ambhore, M.J. Hebade, R.D. Kamble, S.V. Hese, M.V. Gaikwad, P.D. Gavhane, B.S. Dawane, Metal-Free One-Pot Chemoselective thiocyanation of imidazothiazoles and 2-aminothiazoles with in situ generated N-thiocyanatosuccinimide, Synlett, 29 (2018) 1902-1908.
[13] J. Wang, P. Su, S. Abdolmohammadi, E. Vessally, A walk around the application of nanocatalysts for cross-dehydrogenative coupling of C–H bonds, RSC Adv., 9 (2019) 41684-41702; (b) S. Ebrahimiasl, F. Behmagham, S. Abdolmohammadi, R.N. Kojabad, E. Vessally, Recent advances in the application of nanometal catalysts for Glaser coupling, Curr. Org. Chem., 23 (2019) 2489-2503; (c) M. Li, S. Abdolmohammadi, M.S. Hoseininezhad-Namin, F. Behmagham, E. Vessally, Carboxylative cyclization of propargylic alcohols with carbon dioxide: A facile and green route to α-methylene cyclic carbonates, J. CO2 Util., 38 (2020) 220-231; (d) Y. Yang, D. Zhang, E. Vessally, Direct amination of aromatic CH bonds with free amines, Top. Curr. Chem., 378 (2020) 37.
[14] J. Yadav, B. Reddy, S. Shubashree, K. Sadashiv, Iodine/MeOH: a novel and efficient reagent system for thiocyanation of aromatics and heteroaromatics, Tetrahedron Lett., 45 (2004) 2951-2954.
[15] J.S. Yadav, B.V.S. Reddy, B.B.M. Krishna, IBX: a novel and versatile oxidant for electrophilic thiocyanation of indoles, pyrrole and arylamines, Synthesis, 2008 (2008) 3779-3782.
[16] U.S. Mahajan, K.G. Akamanchi, Facile method for thiocyanation of activated arenes using iodic acid in combination with ammonium thiocyanate, Synth. Commun. 39 (2009) 2674-2682.
[17] H.R. Memarian, I. Mohammadpoor-Baltork, K. Nikoofar, DDQ-promoted thiocyanation of aromatic and heteroaromatic compounds, Can. J. Chem., 85 (2007) 930-937.
[18] H.R. Memarian, I. Mohammadpoor-Baltork, K. Nikoofar, Ultrasound-assisted thiocyanation of aromatic and heteroaromatic compounds using ammonium thiocyanate and DDQ, Ultrason. Sonochem., 15 (2008) 456-462.
[19] L.C.D. de Rezende, S.M.G. de Melo, S. Boodts, B. Verbelen, W. Dehaen, F. da Silva Emery, Thiocyanation of BODIPY dyes and their conversion to thioalkylated derivatives, Org. Biomol. Chem., 13 (2015) 6031-6038.
[20] L.C. Rezende, S.M. Melo, S. Boodts, B. Verbelen, F.S. Emery, W. Dehaen, Thiocyanation of 3-substituted and 3,5-disubstituted BODIPYs and its application for the synthesis of new fluorescent sensors, Dyes Pigm., 154 (2018) 155-163.
[21] W. Fan, Q. Yang, F. Xu, P. Li, A visible-light-promoted aerobic metal-free C-3 thiocyanation of indoles, J. Org. Chem., 79 (2014) 10588-10592.
[22] Y. Gao, Y. Liu, J.-P. Wan, Visible light-induced thiocyanation of enaminone C–H bond to access polyfunctionalized alkenes and thiocyano chromones, J. Org. Chem., 84 (2019) 2243-2251.
[23] S. Mitra, M. Ghosh, S. Mishra, A. Hajra, Metal-free thiocyanation of imidazoheterocycles through visible light photoredox catalysis, J. Org. Chem., 80 (2015) 8275-8281.
[24] G. Li, Q. Yan, X. Gong, X. Dou, D. Yang, Photocatalyst-free regioselective C–H thiocyanation of 4-anilinocoumarins under visible light, ACS Sustain. Chem. Eng., 7 (2019) 14009-14015.
[25] M. Chakrabarty, S. Sarkar, A clay-mediated eco-friendly thiocyanation of indoles and carbazoles, Tetrahedron Lett., 44 (2003) 8131-8133.
[26] J. Yadav, B.S. Reddy, Y.J. Reddy, 1-Chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2, 2, 2] octane bis (tetrafluoroborate) as novel and versatile reagent for the rapid thiocyanation of indoles, azaindole, and carbazole, Chem. Lett., 37 (2008) 652-653.
[27] B. Das, A.S. Kumar, Efficient thiocyanation of indoles using para-toluene sulfonic acid, Synth. Commun., 40 (2010) 337-341.
[28] C. Wang, Z. Wang, L. Wang, Q. Chen, M. He, Catalytic thiourea promoted electrophilic thiocyanation of indoles and aromatic amines with NCS/NH4SCN, Chin. J. Chem., 34 (2016) 1081-1085.
[29] B. Akhlaghinia, A.-R. Pourali, M. Rahmani, Efficient and novel method for thiocyanation of aromatic compounds using trichloroisocyanuric acid/ammonium thiocyanate/wet SiO2, Synth. Commun., 42 (2012) 1184-1191.
[30] N. Iranpoor, H. Firouzabadi, R. Shahin, D. Khalili, 2, 2′-Azobenzothiazole as a new recyclable oxidant for heterogeneous thiocyanation of aromatic compounds with ammonium thiocyanate, Synth. Commun., 42 (2012) 2040-2047.
[31] K. Nikoofar, S. Gorji, Determination of the promoting effect of nano SiO2 and H3PO4@ nano SiO2 in the thiocyanation of N-containing aromatic compounds under solvent-free conditions, J. Sulfur Chem., 36 (2015) 178-186.
[32] Y.L. Ren, W. Wang, B. Zhao, X. Tian, S. Zhao, J. Wang, F. Li, Nitrogen dioxide catalyzed oxidative thiocyanation of arenes with ambient air as the terminal oxidant, ChemCatChem, 8 (2016) 3361-3366.
[33] T.B. Mete, T.M. Khopade, R.G. Bhat, Transition-metal-free regioselective thiocyanation of phenols, anilines and heterocycles, Tetrahedron Lett., 58 (2017) 415-418.