Synthesis of Air‐stable, Odorless Thiophenol Surrogates via Ni‐Catalyzed C−S Cross‐Coupling

Abstract

Thiophenols are versatile synthetic intermediates whose practical appeal is marred by their air sensitivity,t oxicity and extreme malodor.H erein we report an efficient catalytic method for the preparation of S-aryl isothiouronium salts, and demonstrate that these air-stable, odorless solids serve as user-friendly sources of thiophenols in synthesis. Diverse isothiouroniums alts featuring synthetically useful functionality are readily accessible by nickel-catalyzed CÀS cross-coupling of (hetero)aryl iodides and thiourea. Convenient, chromatography-free isolation of these salts is achieved by precipitation, allowing the methodology to be appliedd irectly to large scales. Thiophenols are liberated from the corresponding isothiouronium salts upon treatment with a weak base, enabling an in situ release/S-functionalization strategy that entirely negates the need to isolate, purify or manipulate these noxiousreagents.[a] Dr.

Electro-organic synthesis: an environmentally benign alternative for heterocycle synthesis

“…The construction of the C-S bond is one the most significant transformations in modern organic synthesis, as molecules containing the C-S bond are mostly found in abundance in biomolecules, pharmaceutical drugs, 104 dyes 105 and many more significant materials. Drugs like vortioxetine 106,107 (antidepressant), sertaconazole 108 (anti-fungal) and organic semiconductors like BTBT, DNT 109 are also important sulphur-containing compounds. Conventional methods for C-S bond construction include dehydrogenative coupling, oxidative/photoredox-catalysed tandem cyclization and pre-functionalization.…”

The electrochemically selective C3-thiolation of quinolines

“…The formation of the C–S bond is also an important transformation in organic synthesis applications, especially as a method to rapidly increase the complexity of molecules to be used in biomedicine and materials science. 10 Therefore, efforts at searching for efficient methods that enable rapid construction of these structures are still highly appreciated. 11 One of the most conventional methods used for constructing quinoline compounds containing sulfide groups is based on the transition-metal-catalyzed cross-coupling reactions of quinoline halides or of those bearing other leaving groups with thiols/thiophenols (Scheme 1b).…”

Generation of Thiyl Radicals from Air-Stable, Odorless Thiophenol Surrogates: Application to Visible-Light-Promoted C–S Cross-Coupling

“…In seeking to address these manifold challenges, we recently reported a convenient and scalable method for the synthesis of S-aryl isothiouronium salts, which serve as airstable, odorless surrogates to thiophenols (Scheme 1). 6 Inspired by the work of Takagi, 7 we showed that Ni-catalyzed C-S coupling of thiourea and diverse (hetero)aryl iodides proceeds under mild, base-free conditions to afford the cor-Scheme 1 Air-stable, odorless S-aryl isothiouronium salts are readily accessible via Ni-catalyzed C-S cross-coupling/precipitation and serve as convenient surrogates for thiophenols in synthesis. 6 DNB: 3,5-dinitrobenzoate.…”

“…6 Inspired by the work of Takagi, 7 we showed that Ni-catalyzed C-S coupling of thiourea and diverse (hetero)aryl iodides proceeds under mild, base-free conditions to afford the cor-Scheme 1 Air-stable, odorless S-aryl isothiouronium salts are readily accessible via Ni-catalyzed C-S cross-coupling/precipitation and serve as convenient surrogates for thiophenols in synthesis. 6 DNB: 3,5-dinitrobenzoate. es 16 that could interfere with the proposed mechanism of Miyake's S-arylation.…”

“…For this study, the initial Ni-catalyzed cross-coupling was performed in isopropyl alcohol rather than NMP (cf. Scheme 1), 6 which is listed under REACH legislation as a Substance of Very High Concern and a candidate for authorization. 17 Although the inorganic anions sulfate and bisulfate provided high levels of precipitation (Scheme 3, entries 1 and 2), the recovered isothiouronium salts proved sparingly soluble in organic media, precluding their characterization or subsequent use as thiophenol precursors in even very polar organic solvents.…”