Regioselective C–H Thiocyanation of Arenes by Iron(III) Chloride Catalysis

Abstract

Aryl thiocyanates are flexible synthetic intermediates that can be used in the preparation of a diverse range of arene building blocks for medicinal chemistry. Here, we report a fast and efficient Lewis acid-catalyzed method for the regioselective thiocyanation of arenes. Iron(III) chloride was found to be an effective Lewis acid for the activation of N-thiocyanatosaccharin and the subsequent thiocyanation of a wide range of activated arenes. The procedure was applicable for the thiocyanation of biologically active compounds such as metaxalone and an estradiol derivative and was used as part of a one-pot tandem iron-catalytic process for the regioselective, dual functionalization of an arene building block.

Trifluoromethylthiolation of Arenes Using Lewis Acid and Lewis Base Dual Catalysis

“…For tyrosine derivative 5o and metaxalone ( 5p ), a 10 mol% catalyst loading allowed completion after 48 h and the isolation of the trifluoromethylthiolation products, 6o and 6p, in 70% and 69% yields, respectively. Our previous studies on C–S bond forming reactions of estradiol ( 5q ) with electrophilic succinimide- or saccharin-based reagents required protection of the hydroxyl groups. , However, reaction of estradiol ( 5q ) using the dual-catalytic method was found to proceed without the requirement of protecting groups. The optimal conditions involved a 5 mol % catalyst loading, which gave a 2:1 mixture of the 2- and 4-trifluoromethylthiolated products.…”

“…Our previous studies on C–S bond forming reactions of estradiol ( 5q ) with electrophilic succinimide- or saccharin-based reagents required protection of the hydroxyl groups. 22b , 23 However, reaction of estradiol ( 5q ) using the dual-catalytic method was found to proceed without the requirement of protecting groups. The optimal conditions involved a 5 mol % catalyst loading, which gave a 2:1 mixture of the 2- and 4-trifluoromethylthiolated products.…”

“…We have shown that iron­(III) salts are effective Lewis acids for the activation of succinimide and saccharin-based reagents and the subsequent regioselective functionalization of arenes. − During our work on the thiocyanation of arenes, trifluoromethylsulfenyl compounds were prepared in two steps by iron­(III)-catalyzed thiocyanation, followed by the reaction with the Ruppert–Prakash reagent under basic conditions. , To circumvent a two-step approach, we proposed that iron­(III)-catalysis could be used to activate CF 3 S-based electrophiles, for the direct, single-step trifluoromethylthiolation of arenes. In 2015, Li and co-workers reported the trifluoromethylthiolation of electron-rich arenes using iron­(III) chloride activation of N -trifluoromethylthiosaccharin ( 4 ) .…”

Highly Diastereoselective Preparation of Tertiary Alkyl Thiocyanates en Route to Thiols by Stereoinvertive Nucleophilic Substitution at Nonclassical Carbocations

“…The first approach involves the reaction of a very reactive sulfur halide derivative with a nucleophilic cyanating agent − (Scheme b, route 1), whereas the alternative method involves the reaction of a thiocyanating reagent with various alkyl or aryl substrates that do not contain sulfur (Scheme b, route 2). , KSCN, NH 4 SCN, N -thiocyanosuccinimide (NTS), N -thiocyanato-dibenzenesulfonimide (NTSI), and TMSNCS are widely used thiocyanating reagents . Complementary strategies using electrophilic thiocyanation, involving CNS + or CN + as reactive species, have been also developed. − Although less commonly encountered, radical thiocyanation has also garnered interest as a method for synthesizing thiocyanates. − Additionally, both electrophilic and nucleophilic thiol cyanation also offer pathways to access thiocyanates . Although the methods mentioned above have been extensively reported in the literature for the incorporation of the thiocyanate functional groups, a new strategy enabling the synthesis of tertiary thiocyanates with complete stereocontrol remains conspicuously absent.…”

Synthesis of Thiazoloindole α-Amino Acids: Chromophores Amenable to One- and Two-Photon Induced Fluorescence

“…Recently, reported methods for the syntheses of [3,2- a ]­thiazoloindoles have typically involved the preparation of N- or C2-alkynyl-substituted indoles, followed by base-mediated cyclization . Instead, we proposed an alternative two-step approach, utilizing a regioselective C2-thioarylation of the tryptophan indole ring via iron­(III) and diphenyl selenide dual-catalyzed activation of N -thiosuccinimide 7 , − followed by a copper-mediated N-arylation reaction between the ortho -bromide substituent and the adjacent indole amine (Scheme ). It was then proposed that the [3,2- a ]­thiazoloindole ring system could be extended, allowing substituent-based tuning of the photophysical properties, by regioselective bromination, followed by a Suzuki–Miyaura cross-coupling reaction.…”