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

Abstract

The synthetic versatility of thiophenols is offset by their air-sensitivity and foul odor. It is demonstrated that S-aryl isothiouronium salts can be used as precursors to thiyl radicals, extending the practical benefits of these air-stable, odorless salts from ionic to single electron manifolds. The isothiouronium salts are accessed via Ni-catalyzed cross-coupling of (hetero)aryl iodides and thiourea and are isolated as free-flowing solids following anion exchange. Judicious choice of a redox-innocent counteranion enables use of these convenient thiophenol surrogates in radical processes, as is exemplified by the synthesis of non-symmetrical diaryl thioethers via light-promoted S-arylation.

The aryl-sulfur motif is common to a vast array of drugs, agrochemicals, materials, and high impact odorants.[1] [2] Regardless of the substitution pattern or oxidation state at sulfur, all aryl-sulfur species can ultimately be derived from thiophenols via established synthetic protocols.[3–5] However, the direct use of thiophenols in synthesis is often rendered impractical due to their relatively low commercial availability, challenging syntheses, air-sensitivity, toxicity, and pungent malodor.

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 air-stable, 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 corresponding isothiouronium iodides in excellent yields. These salts can be isolated without column chromatography simply by precipitation upon anion metathesis with sodium 3,5-dinitrobenzoate (Na[DNB]). The corresponding thiophenol is released in situ under the basic conditions typically employed for established ionic and metal-catalyzed S-functionalization protocols, including S_N2, conjugate addition, S_NAr, Ullmann arylation, and oxidation (Scheme [1]).[6] In this way, our methodology eliminates the need for experimentalists to isolate or otherwise manipulate noxious thiophenols en route to the target aryl-sulfur species.

However, attempts to employ these isothiouronium salts in single electron chemistry proved unsuccessful, precluding their use not only in conventional radical chemistry, but also in photoredox catalysis. We recognized that this apparent restriction to ionic S-functionalization processes represents a significant limitation in the applicability of isothiouronium salts, especially given the ease of formation of thiyl radicals from thiophenols and their versatile reactivity.[8] Here, we seek to address this shortcoming such that the practical benefits of isothiouronium salts can be extended to single electron chemistry.

The visible-light-mediated C–S coupling of thiophenols and aryl halides was selected as an archetypal radical process in which to test the isothiouronium salts. Recently reported by Miyake,[9] [10] this methodology provides facile access to non-symmetrical diaryl thioethers under mild conditions and in the absence of a transition-metal catalyst (Scheme [2]A); the ability to replace the thiophenol with an isothiouronium salt would therefore provide a practical improvement to this already powerful methodology. Moreover, combined experimental and computational studies suggest that the reaction proceeds via photo-stimulated electron transfer within a transient thiophenolate/aryl halide electron donor–acceptor (EDA) complex,[11] confirming that it is an appropriate testbed for the development of redox-compatible isothiouronium salts.

We found that, while Miyake’s chemistry could be reproduced in excellent yield with isothiouronium iodide salts in place of thiophenols, it could not be extended to the corresponding DNB salts (Scheme [2]B).[12] These results demonstrate the de facto suitability of isothiouronium salts as thiophenol surrogates in radical chemistry, but also reveal a sensitivity to the counteranion that prevents exploitation of the easily isolated DNB salts. We hypothesized that the failure of our DNB salts to engage in Miyake’s methodology is likely due to the electron accepting ability of (poly)nitrobenzenes,[13] which are commonly employed as radical traps.[14] Of particular relevance, methyl 3,5-dinitrobenzoate readily undergoes two reversible single electron reductions [E _1/2(I) = –1.215 V vs Fc/Fc⁺, E _1/2(II) = –1.620 V vs Fc/Fc⁺],[15] and the free acid is known to form EDA complexes[16] that could interfere with the proposed mechanism of Miyake’s S-arylation.[9] Replacing DNB with an alternative, redox-innocent counteranion would avoid competing electron transfer processes and would ultimately enable the general use of isothiouronium salts in radical-based reactions.

Different counteranions were therefore assessed for their ability to precipitate the isothiouronium salt (Scheme [3]). 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. Metathesis with sodium tosylate failed to afford a precipitate (entry 3). In contrast, exchange of iodide for a benzoate counteranion generally resulted in high levels of precipitation (entries 4–12). While the majority of the isothiouronium benzoates formed gels or fine powders that prevented efficient isolation, salts of chloro- or trifluoromethyl-substituted benzoates (entries 7, 8, 11, and 12) afforded free-flowing plate-like crystals amenable to filtration. The chlorobenzoates were ultimately rejected due to the potential reactivity of the C–Cl bond, and the trifluoromethylbenzoate salts were selected for further investigation.

To ascertain their compatibility with single electron processes, the redox properties of the different benzoate counteranions were investigated (Figure [1]). Cyclic voltammetry was conducted in DMSO to ensure relevance to Miyake­’s methodology. As anticipated, sodium DNB readily undergoes two chemically-reversible single electron reductions [Figure [1]A; E _1/2(I) = –1.321 V vs Fc/Fc⁺, E _1/2(II) = –1.702 V vs Fc/Fc⁺], whereas sodium 4-trifluoromethylbenzoate (TB) and sodium 3,5-bis(trifluoromethyl)benzoate (BTB) each undergo a single, irreversible reduction event at much lower potentials (Figure [1]B and 1C; E _red = –2.487 V vs Fc/Fc⁺ and E _red = –2.570 V vs Fc/Fc⁺, respectively). The resistance of the trifluoromethylbenzoates to reduction suggests that both would be compatible with typical single electron processes, and therefore that they would be suitable as redox-innocent counterions in both photoredox and conventional radical reactions.

Further evaluation indicated that both TB and BTB confer low solubility in apolar solvents (Table [1]), facilitating purification of the precipitated isothiouronium salt simply by washing. However, although the isothiouronium salts of both TB and BTB are stable in the solid state, the TB salts undergo slow decomposition in solution (13% over 72 hours at 0.05 M in DMSO, RT; see SI for full details). As such, the BTB counteranion was employed in subsequent studies.

Table 1 Solubilities of Isothiouronium Salts

Entry	Solvent	Solubility at 25 °C (mg mL–1)
		TB	BTB
1	i-PrOH	5.8	3.9
2	MTBE	1.0	2.5
3	i-PrOAc	3.6	7.2
4	MeCN	4.1	2.5
5	PhMe	0.20	0.19
6	THF	83	45
7	CyH	0.15	0.18

Both the Ni-catalyzed coupling in isopropyl alcohol, and precipitation of the isothiouronium salt by exchange of iodide for BTB, proved general (Scheme [4]). Thus, excellent isolated yields are obtained for couplings of aryl iodides featuring electron-donating (1a–d,m,o) and -withdrawing (1f–l) functionality, acidic protons (1b,l,o,s,t), and Lewis basic heteroatoms (1l,s–u). Couplings of ortho-substituted or very electron-rich aryl iodides required NMP as the reaction solvent, but still provided excellent isolated yields upon anion metathesis (1b,p–r). The reaction efficiency is maintained or improved at multigram scales (1a,c,d,f,g,i), and all products proved stable to air, moisture and ambient light for over 18 months.

Pleasingly, the isothiouronium BTB salts proved entirely compatible with Miyake’s S-arylation (Scheme [5]),[9] [12] with yields equivalent to or better than those obtained from thiophenols. In this way it is therefore possible to access non-symmetrical diaryl sulfides without the use of transition-metal catalysts or the need to handle malodorous thiophenols. Moreover, these results illustrate that – by judicious choice of a redox-innocent counteranion – S-aryl isothiouronium salts can be exploited more generally as convenient and user-friendly surrogates for thiophenols in single electron chemistry.

In summary, we have demonstrated that S-aryl isothiouronium salts can be employed as convenient thiophenol surrogates in single electron chemistry. The practical benefits of these salts – their ease of preparation and isolation, stability to air and moisture, and odorlessness – can therefore now be extended to a wide range of additional transformations. Crucial to achieving compatibility with radical processes has been identification of an alternative counteranion that is not only redox-innocent, but that also confers stability in solution and facilitates high-yielding isolation of the products.

The utility of the new isothiouronium salts is showcased by their application to Miyake’s light-promoted S-arylation methodology, thereby giving concise access to non-symmetrical diaryl sulfides without the need to handle free thiophenols. We anticipate that the practicality and convenience of our redox-compatible isothiouronium salts will be of broad utility within photoredox catalysis, electrosynthesis and conventional single electron chemistries.

Procedures employing O₂- and/or moisture-sensitive materials were performed with anhydrous solvents (vide infra) using standard inert-atmosphere techniques (atmosphere of dry N₂). Analytical TLC was performed on precoated Al-backed plates (Silica Gel 60 F254; Merck), and visualized using a combination of UV light (254 nm) and acidic ethanolic vanillin, aqueous basic KMnO₄ or I₂ stains. Manual flash column chromatography was performed using Scharlab 60 silica gel (35–70 mesh); automated flash column chromatography was performed on disposable columns pre-packed with 50 μm spherical silica gel using a Büchi C-850 equipped with a UV/Vis DAD (200–800 nm) and an ELSD detector. NMR spectra were recorded at 25 °C on a Bruker Avance 500 or 400 spectrometer (¹H, 500/400 MHz; ¹³C{¹H}, 125/100 MHz; ¹⁹F NMR, 471/376 MHz). Chemical shifts are reported in ppm; coupling constants (J) are reported in Hz and are uncorrected for digitization. Standard abbreviations are used to label the multiplicities. ¹H and ¹³C{¹H} chemical shifts are reported relative to TMS, and are referenced to the appropriate residual solvent peaks; CDCl₃: δ_H = 7.26, δ_C = 77.16, DMSO-d ₆: δ_H = 2.50, δ_C = 39.52. ¹⁹F chemical shifts are reported relative to BF₃·OEt₂. IR spectra of neat compounds were recorded over the range 4000–600 cm^–1 using either a PerkinElmer Spectrum 1000 Series FTIR spectrophotometer with an ATR diamond cell, or a Bruker Alpha FTIR spectrophotometer fitted with a Bruker Platinum ATR Quicksnap™ diamond cell. Melting points were measured using Stuart SMP10 or Gallenkamp melting point apparatus in open capillaries. High-resolution electrospray ionization mass spectra (HRMS) were recorded using a Bruker ESI-TOF MicroTOF II spectrometer. Cyclic voltammetry measurements were made using a three-electrode potentiostat galvanostat (Metrohm Autolab) with a glassy carbon working electrode, a Pt wire counter electrode, and an Ag wire reference electrode. Solutions of sodium benzoate salts ([]₀ = 1 mM) were prepared in DMSO (electrolyte: 0.1 M [nBu₄N][PF₆]; reference: ferrocene) under an atmosphere of argon. Measurements were made with a scan rate of 0.1 V/s. Light-promoted C–S couplings were performed in standard borosilicate glassware using a HepatoChem PhotoRedOx Box [https://www.hepatochem.com/photoreactors-leds-accessories/photoredox-box/]; internal reaction temperatures were maintained below 30 °C using the integrated cooling fan. Irradiation was achieved using 18 W CREE XTE LEDs (‘cold white’; 6200 K) with an average relative irradiance of 29 mW/cm² [https://www.hepatochem.com/photoreactors-leds-accessories/ledevoluchem/]. Reagent grade solvents (Fisher Technical) were employed. n-Hexane, MeCN, THF, toluene, and Et₂O were dried using an Inert PureSolv Grubbs-type system (alumina columns, argon atmosphere). CH₂Cl₂ was distilled from CaH₂ under an atmosphere of dry N₂. Unless stated otherwise, all reagents were used as received from commercial sources.

Preparation of starting materials used is provided in the Supporting Information.

S-Aryl Isothiouronium 3,5-Bis(trifluoromethyl)benzoate Salts in i-PrOH; General Procedure 1 (GP1)

A microwave vial containing (Cy₃P)₂NiCl₂ (5.5 mg, 0.0080 mmol), picoline-borane (1.6 mg, 0.015 mmol), thiourea (110 mg, 1.5 mmol), and solid aryl iodide (1.0 mmol) was evacuated and back-filled with dry N₂ (3 ×). Liquid aryl iodides (1.0 mmol) were added subsequent to evacuation and back-filling. Anhydrous, degassed i-PrOH (1.0 mL) was added, and the reaction mixture was stirred at 60 °C for 18 h. After cooling to RT, the extent of conversion was determined by ¹H NMR spectroscopic analysis of a 15 μL aliquot of the mixture diluted with DMSO-d ₆. The mixture was then transferred to a vial and residual mixture was transferred from the microwave vial with H₂O washes (2 × 2 mL). An aqueous solution of sodium 3,5-bis(trifluoromethyl)benzoate (1.2 M; 1.0 mL, 1.2 mmol) was added to the stirred reaction mixture. The resulting suspension was allowed to stand at 4 °C for 1 h before the solid was collected by filtration using a Büchner funnel fitted with glass filter paper. The filter cake was dried by suction for 10 min, then washed with ice-cold methyl tert-butyl ether (2 × 1.5 mL). Drying in vacuo afforded the S-aryl isothiouronium 3,5-bis(trifluoromethyl)benzoate salt as a free-flowing, non-hygroscopic solid.

S-Aryl Isothiouronium 3,5-Bis(trifluoromethyl)benzoate Salts in NMP; General Procedure 2 (GP2)

A microwave vial containing (Cy₃P)₂NiCl₂ (13.8 mg, 0.020 mmol), picoline-borane (4.3 mg, 0.04 mmol), thiourea (110 mg, 1.5 mmol), and solid aryl iodide (1.0 mmol) was evacuated and back-filled with dry N₂ (3 ×). Liquid aryl iodides (1.0 mmol) were added subsequent to evacuation and back-filling. Anhydrous, degassed NMP (1.0 mL) was added, and the reaction mixture was stirred at 60 °C for 18 h. After cooling to RT, the extent of conversion was determined by ¹H NMR spectroscopic analysis of a 15 μL aliquot of the reaction mixture diluted with DMSO-d ₆. The mixture was then transferred to a vial and residual mixture was transferred from the microwave vial with H₂O washes (2 × 2 mL). An aqueous solution of sodium 3,5-bis(trifluoromethyl)benzoate (1.2 M; 1.0 mL, 1.2 mmol) was added to the stirred reaction mixture. The resulting suspension was allowed to stand at 4 °C for 1 h before the solid was collected by filtration using a Büchner funnel fitted with glass filter paper. The filter cake was dried by suction for 10 minutes, then washed with ice-cold methyl tert-butyl ether (2 × 1.5 mL). Drying in vacuo afforded the S-aryl isothiouronium 3,5-bis(trifluoromethyl)benzoate salt as a free-flowing, non-hygroscopic solid.

S-(4-Aminophenyl)isothiouronium 3,5-Bis(trifluoromethyl)benz­oate (1a)

Using 4-iodoaniline (2.19 mg, 10.0 mmol) in GP1; white solid; yield: 3.15 g (7.4 mmol, 74%); mp 172–174 °C (dec.).

IR (neat): 3399, 3247, 2930, 2753, 1626, 1596, 1498, 1443, 1410, 1337, 1275, 1179, 1128, 913, 843, 820, 792, 762, 697, 680, 489, 436 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.95 (br s, 4 H), 8.38 (s, 2 H), 8.12 (s, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 6.66 (d, J = 8.2 Hz, 2 H), 5.89 (s, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 171.4, 167.5, 152.2, 141.2, 137.7, 129.8 (q, J = 32.6 Hz), 129.1, 123.4 (q, J = 278.0 Hz), 123.2, 115.0, 105.2.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.38.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₇H₁₀N₃S⁺: 168.0590; found: 168.0598.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0045.

S-(4-Hydroxyphenyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1b)

Using 4-iodophenol (220 mg, 1.0 mmol) in GP2; white solid; yield: 303 mg (0.71 mmol, 71%); mp 150–152 °C.

IR (neat): 3606, 3354, 3285, 3027, 1712, 1672, 1651, 1635, 1600, 1582, 1496, 1427, 1338, 1274, 1232, 1171, 1130, 914, 832, 794, 773, 699, 680, 523, 491, 436 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 9.70 (br, 4 H), 8.38 (d, J = 1.8 Hz, 2 H), 8.13 (s, 1 H), 7.54–7.36 (m, 2 H), 6.99–6.86 (m, 2 H).

¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 170.4, 167.2, 161.2, 141.7, 138.7, 130.2 (q, J = 32.8 Hz), 129.6 (d, J = 4.0 Hz), 123.9 (q, J = 272.6 Hz), 123.61 (hept, J = 4.1 Hz), 117.96, 111.7.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.38.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₇H₉N₂OS⁺: 169.0430; found: 169.0435.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-(4-Methoxyphenyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1c)

Using 4-iodoanisole (2.30 g, 10.0 mmol) in GP1; white solid; yield: 3.70 g (8.40 mmol, 84%); mp 177–180 °C.

IR (neat): 2947, 1626, 1591, 1494, 1410, 1337, 1276, 1257, 1167, 1128, 1027, 909, 834, 793, 761, 718, 697, 680, 536, 490, 435 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.71 (br s, 4 H), 8.38 (s, 2 H), 8.13 (s, 1 H), 7.65–7.56 (m, 2 H), 7.15–7.07 (m, 2 H), 3.83 (s, 3 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 170.8, 168.2, 162.4, 140.8, 138.6, 130.4 (q, J = 32.7 Hz), 129.6, 124.0, 123.8 (q, J = 272.8 Hz), 116.6, 113.7, 56.0.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.36.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₁₁N₂OS⁺: 183.0592; found: 183.0585.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0053.

S-(p-Tolyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1d)

Using 4-iodotoluene (2.18 g, 10.0 mmol) in GP1; white solid; yield: 3.18 g (7.5 mmol, 75%); mp 196–198 °C.

IR (neat): 3292, 2924, 1626, 1591, 1442, 1407, 1335, 1275, 1179, 1131, 913, 843, 792, 761, 714, 701, 679, 486, 436 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.07 (br s, 4 H), 8.37 (s, 2 H), 8.13 (s, 1 H), 7.59–7.51 (m, 2 H), 7.41–7.34 (m, 2 H), 2.38 (s, 3 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 169.0, 167.0, 141.6, 140.8, 136.0, 131.1, 129.8 (q, J = 32.8 Hz), 129.1, 123.92, 123.90 (q, J = 272 Hz), 120.3, 20.9.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.31

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₁₁N₂S⁺: 167.0643; found: 167.0648.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0049.

S-Phenylisothiouronium 3,5-Bis(trifluoromethyl)benzoate (1e)

Using iodobenzene (112 μL, 1.0 mmol) in GP1; off-white solid; yield: 389 mg (0.94 mmol, 94%); mp 165–167 °C.

IR (neat): 2926, 1627, 1593, 1442, 1412, 1336, 1275, 1176, 1129, 1023, 913, 844, 792, 761, 749, 715, 696, 680, 536, 493, 438 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.39 (s, 2 H), 8.14 (s, 1 H), 7.69 (d, J = 7.4 Hz, 2 H), 7.60–7.55 (m, 3 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 169.6, 168.0, 141.0, 136.4, 131.9, 130.9, 130.4 (q, J = 32.6 Hz), 129.6, 124.3, 123.9, 123.9 (q, J = 272.7 Hz).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.39.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₇H₉N₂S⁺: 153.0481; found: 153.0475.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-(4-Fluorophenyl)isothiouronium 3,5-Bis(trifluoromethyl)benz­oate (1f)

Using 4-fluoroiodobenzene (3.46 mL, 30.0 mmol) in GP1; cream solid; yield: 12.2 g (28.5 mmol, 95%); mp 175–177 °C (dec.).

IR (neat): 3258, 2924, 2763, 1626, 1591, 1492, 1412, 1338, 1276, 1240, 1181, 1158, 1133, 913, 836, 793, 718, 697, 680, 526, 492, 436 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.86 (br s, 4 H), 8.38 (s, 2 H), 8.12 (s, 1 H), 7.80–7.71 (m, 2 H), 7.45–7.35 (m, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 170.0, 168.0, 164.7 (d, J = 249.5 Hz), 141.1, 139.4 (d, J = 9.3 Hz), 130.5 (q, J = 35.1 Hz), 130.0 (d, J = 63.2 Hz), 123.8 (q, J = 272.6 Hz), 123.9, 119.7 (d, J = 3.1 Hz), 118.1 (d, J = 22.4 Hz).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.41 (s, 6 F), –108.79 (tt, J = 9.2, 5.2 Hz, 1 F).

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₇H₈FN₂S⁺: 171.0387; found: 171.0404.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0057.

S-(4-Chlorophenyl)isothiouronium 3,5-Bis(trifluoromethyl)benz­oate (1g)

Using 1-chloro-4-iodobenzene (2.38 g, 10.0 mmol) in GP1; white solid; yield: 3.11 g (7.0 mmol, 70%); mp 180–183 °C.

IR (neat): 3278, 2921, 1626, 1590, 1477, 1443, 1410, 1335, 1275, 1183, 1131, 1093, 1014, 914, 843, 823, 791, 761, 749, 716, 700, 679, 480, 438 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.02 (br s, 4 H), 8.38 (s, 2 H), 8.14 (s, 1 H), 7.74–7.67 (m, 2 H), 7.65–7.57 (m, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 169.5, 168.1, 140.8, 138.2, 137.2, 130.9, 130.2 (q, J = 33.3 Hz), 129.6, 123.9, 123.8 (q, J = 272.7 Hz), 123.1.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.44.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₇H₈ClN₂S⁺: 187.0097; found: 187.0074.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0072.

S-(4-{[(Trifluoromethyl)sulfonyl]oxy}phenyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1h)

Using 4-iodophenyl trifluoromethanesulfonate[1] (350 mg, 1.0 mmol) in GP1; white solid; yield: 410 mg (0.74 mmol, 74%); mp 158–160 °C.

IR (neat): 2936, 1626, 1585, 1483, 1432, 1337, 1275, 1211, 1186, 1128, 1016, 908, 882, 842, 790, 756, 714, 697, 680, 629, 609, 579, 547, 495, 466, 437 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.13 (br s, 4 H), 8.38 (s, 2 H), 8.13 (s, 1 H), 7.94–7.84 (m, 2 H), 7.72–7.63 (m, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 169.1, 167.7, 151.5, 138.8, 130.7 (q, J = 33.1 Hz), 129.6, 125.6, 124.3, 123.9, 123.8 (q, J = 272.6 Hz), 123.1, 117.1 (q, J = 321.5 Hz).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.47 (s, 6 F), –72.77 (s, 3 F).

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₈F₃N₂O₃S₂ ⁺: 300.9928; found: 300.9939.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0054.

S-[4-(Trifluoromethyl)phenyl]isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1i)

Using 4-iodobenzotrifluoride (1.47 mL, 10.0 mmol) in GP1; off-white solid; yield: 3.78 g (7.90 mmol, 79%); mp 158–161 °C.

IR (neat): 3290, 2933, 2750 1672, 1626, 1589, 1516, 1442, 1411, 1336, 1317, 1275, 1178, 1131, 1102, 1061, 1018, 914, 841, 792, 761, 735, 715, 698, 680, 597, 536, 508, 482, 438, 413 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.20 (br s, 4 H), 8.38 (s, 2 H), 8.15 (s, 1 H), 7.91 (d, J = 9.1, 2 H), 7.88 (d, J = 9.1 Hz, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 168.8, 167.5, 139.7, 136.7, 131.5 (q, J = 32.2 Hz), 130.5 (q, J = 32.7 Hz), 129.9, 129.6, 127.5 (q, J = 3.8 Hz), 124.4, 124.3 (q, J = 272.6 Hz), 123.8 (q, J = 272.9 Hz).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.42 (s, 6 F), –61.60 (s, 3 F).

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₈F₃N₂S⁺: 221.0355; found: 221.0363.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-(4-Cyanophenyl)isothiouronium 3,5-Bis(trifluoromethyl)benz­oate (1j)

Using 4-iodobenzonitrile (229 mg, 1.0 mmol) in GP1; cream solid; yield: 396 mg (0.91 mmol, 91%); mp 157–159 °C (dec.).

IR (neat): 3307, 2918, 2738, 2234, 1627, 1591, 1485, 1414, 1337, 1276, 1170, 1122, 910, 844, 789, 763, 724, 713, 698, 680, 551, 503, 462, 436 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.32 (br s, 4 H), 8.38 (s, 2 H), 8.16 (s, 1 H), 8.00 (d, J = 8.1 Hz, 2 H), 7.88 (d, J = 8.11 Hz, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 168.1, 166.7, 138.1, 136.0, 133.8, 130.5, 130.2 (q, J = 32.9 Hz), 129.3, 124.4, 123.2 (q, J = 272.5 Hz), 118.1, 113.6.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.45.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₈N₃S⁺: 178.0433; found: 178.0436.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043 ; found: 257.0049.

S-(3,5-Dichlorophenyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1k)

Using 3,5-dichloroiodobenzene (270 mg, 1.0 mmol) in GP1; white solid; yield: 379 mg (0.79 mmol, 79%); mp 158–160 °C.

IR (neat): 2927, 1626, 1591, 1561, 1404, 1336, 1275, 1172, 1134, 1104, 912, 865, 845, 791, 761, 716, 697, 680, 669, 536, 494, 435 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.00 (br s, 4 H), 8.43–8.34 (m, 2 H), 8.17 (s, 1 H), 7.87 (t, J = 1.9 Hz, 1 H), 7.83 (d, J = 1.9 Hz, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 184.3, 168.9, 167.1, 135.7, 134.7, 131.7, 130.7 (q, J = 32.9 Hz), 129.7, 127.6, 126.1, 123.7 (q, J = 272.8 Hz).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.41.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₇H₇Cl₂N₂S⁺: 220.9707; found: 220.9707.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0054.

S-(2-{6-[(1-hydroxy-3-methylbutan-2-yl)carbamoyl]phenyl})isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1l)

Using N-(1-hydroxy-3-methylbutan-2-yl)-4-iodobenzamide (344 mg, 1.0 mmol) in GP1; white solid; yield: 351 mg (0.65 mmol, 65%); mp 142–144 °C (dec.).

IR (neat): 3284, 2958, 1633, 1540, 1417, 1339, 1285, 1169, 1128, 1062, 1017, 907, 842, 790, 763, 698, 682, 488, 438 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.84 (br s, 4 H), 8.38 (s, 2 H), 8.22 (d, J = 8.8 Hz, 1 H), 8.13 (s, 1 H), 8.04 (d, J = 8.1 Hz, 2 H), 7.76 (d, J = 8.1 Hz, 2 H), 3.87–3.78 (m, 1 H), 3.57–3.48 (m, 2 H), 1.99–1.87 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 168.9, 167.5, 165.3, 140.4, 137.2, 137.0, 135.5, 130.0 (q, J = 32.2 Hz), 129.0, 126.7, 123.5, 123.2 (q, J = 268.8 Hz), 61.3, 56.9, 28.7, 19.7, 18.7.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.42.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₁₃H₂₀N₃O₂S⁺: 282.1271; found: 282.1275.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0052.

S-[3-(2-Methoxy-2-oxoethoxy)phenyl]isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1m)

Using methyl 2-(3-iodophenoxy)acetate[2] (292 mg, 1.0 mmol) in GP1; off-white solid; yield: 273 mg (0.55 mmol, 55%); mp 110–112 °C.

IR (neat): 2944, 1763, 1626, 1591, 1481, 1442, 1412, 1379, 1336, 1275, 1211, 1189, 1172, 1128, 1083, 983, 911, 845, 789, 716, 697, 680, 594, 537, 496, 435 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.92 (br s, 4 H), 8.39 (s, 2 H), 8.13 (s, 1 H), 7.47 (app t, J = 7.9 Hz, 1 H), 7.29–7.26 (m, 2 H), 7.20–7.12 (m, 2 H), 4.88 (s, 2 H), 3.71 (s, 3 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 184.3, 169.4, 167.6, 159.0, 141.3, 131.8, 130.3 (q, J = 33.5 Hz), 129.6, 129.1, 125.2, 123.9 (q, J = 272.8 Hz), 123.7, 121.9, 118.7, 65.4, 52.3.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.35.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₁₀H₁₃N₂O₃S⁺: 241.0641; found: 241.0667.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-[2-(5,5-Dimethyl-9H-fluorenyl)]isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1n)

Using 2-iodo-9,9-dimethyl-9H-fluorene (324 mg, 1.0 mmol) in GP1; white solid; yield: 353 mg (0.67 mmol, 67%); mp 175–177 (dec.).

IR (neat): 3297, 2963, 2740, 1626, 1589, 1443, 1409, 1334, 1274, 1170, 1123, 910, 844, 793, 779, 760, 735, 696, 680, 663, 568, 493, 448 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.69 (s, 4 H), 8.38 (s, 2 H), 8.15 (s, 1 H), 8.02 (d, J = 7.9 Hz, 1 H), 7.97–7.92 (m, 1 H), 7.89 (s, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.62–7.57 (m, 1 H), 7.43–7.37 (m, 2 H), 1.47 (s, 6 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 170.0, 167.8, 156.3, 153.9, 142.0, 140.2, 137.2, 135.2, 130.6, 129.9 (q, J = 33.0 Hz), 129.1, 128.6, 127.3, 123.6, 123.3 (q, J = 272.9 Hz), 123.0, 121.9, 121.2, 121.0, 46.9, 26.4.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.40.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₁₆H₁₇N₂S⁺: 269.1107; found: 269.1125.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0048.

S-(6-Hydroxynaphthalen-2-yl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1o)

Using 6 iodonaphthalen-2-ol (270 mg, 1.0 mmol) in GP1; off-white solid; yield: 348 mg (0.73 mmol, 73%); mp 168–170 °C.

IR (neat): 3378, 3269, 2931, 2775, 1681, 1625, 1587, 1516, 1469, 1426, 1414, 1393, 1336, 1283, 1241, 1213, 1160, 1142, 1122, 912, 896, 858, 845, 796, 764, 723, 697, 681, 617, 558, 539, 493, 471, 439 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.10 (br s, 4 H), 8.39 (s, 2 H), 8.21 (d, J = 1.9 Hz, 1 H), 8.12 (s, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 8.7 Hz, 1 H), 7.51 (dd, J = 8.6, 1.9 Hz, 1 H), 7.24–7.15 (m, 2 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 184.4, 170.4, 167.8, 158.1, 137.6, 136.3, 131.9, 130.6, 130.1 (q, J = 29.8 Hz), 129.6, 128.8, 128.6, 123.9 (q, J = 272.7 Hz), 123.7, 120.3, 116.7, 109.3.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.38.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₁₁H₁₁N₂OS⁺: 219.0587; found: 219.0592.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-(2,4-Dimethylphenyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1p)

Using 4-iodo-m-xylene (464 mg, 2.0 mmol) in GP2; white solid; yield: 750 mg (1.71 mmol, 86%); mp 169–170 °C.

IR (neat): 3287, 2922, 1630, 1591, 1440, 1408, 1333, 1275, 1172, 1129, 913, 843, 765, 711 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 8.38 (br, 4 H), 8.14 (s, 2 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 2.0 Hz, 1 H), 7.19 (dd, J = 7.9, 2.0 Hz, 1 H), 2.38 (s, 3 H), 2.35 (s, 3 H).

¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 169.0, 167.4, 143.5, 142.6, 141.5, 137.8, 132.9, 130.3 (q, J = 32.5 Hz), 129.6–129.4 (m), 129.0, 123.9 (q, J = 272.7 Hz), 123.7 (dd, J = 5.3, 2.8 Hz), 120.2, 21.4, 20.7.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.38.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₉H₁₃N₂S⁺: 181.0794; found: 181.0801.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0050.

S-(2-Ethylphenyl)isothiouronium 3,5-Bis(trifluoromethyl)benz­oate (1q)

Using 1-iodo-2-ethylbenzene (232 mg, 1.0 mmol) in GP2; white solid; yield: 320 mg (0.73 mmol, 73%); mp 181–183 °C.

IR (neat): 3301, 2925, 1623, 1587, 1446, 1404, 1341, 1275, 1176, 1134, 907, 843, 788, 761, 723, 693, 679, 483 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 9.36 (s, 4 H), 8.38 (s, 2 H), 8.14 (s, 1 H), 7.63 (dd, J = 7.8, 1.4 Hz, 1 H), 7.58 (td, J = 7.5, 1.4 Hz, 1 H), 7.51 (dd, J = 7.8, 1.6 Hz, 1 H), 7.38 (td, J = 7.5, 1.6 Hz, 1 H), 2.78 (q, J = 7.5 Hz, 1 H), 1.19 (t, J = 7.5 Hz, 2 H).

¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 168.6, 166.9, 149.2, 141.4, 138.23, 132.7, 130.7, 130.27 (q, J = 32.9 Hz), 129.7–129.4 (m), 128.4, 123.9 (q, J = 272.5 Hz), 124.0–123.6 (m), 123.3, 27.3, 15.6.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.41.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₉H₁₃N₂S⁺: 181.0794; found: 181.0804.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-(2-Methoxyphenyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1r)

Using 2-iodoanisole (234 mg, 1.0 mmol) in GP2; white solid; yield: 355 mg (0.81 mmol, 81%); mp 147–149 °C.

IR (neat): 2942, 1688, 1625, 1590, 1480, 1434, 1410, 1336, 1274, 1175, 1126, 1067, 1025, 909, 845, 793, 750, 698, 680, 539, 490, 435 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 9.39 (br, 4 H), 8.38 (d, J = 1.7 Hz, 2 H), 8.13 (s, 1 H), 7.66–7.57 (m, 2 H), 7.25 (dd, J = 8.5, 1.2 Hz, 1 H), 7.10 (td, J = 7.5, 1.1 Hz, 1 H), 3.88 (s, 3 H).

¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 168.6, 167.0, 160.3, 141.8, 138.2, 134.5, 130.2 (q, J = 32.6 Hz), 129.6 (t, J = 3.9 Hz), 123.9 (q, J = 272.5 Hz), 122.2, 113.4, 111.5, 56.7.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.40.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₁₁N₂OS⁺: 183.0587; found: 183.0593.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

S-[2-(6-Aminopyridin-3-yl)]isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1s)

Using 2-amino-5-iodopyridine (225 mg, 1.0 mmol) in GP1; white solid; yield: 183 mg (0.42 mmol, 42%); mp 168–170 °C (dec.).

IR (neat): 3502, 3246, 3087, 2960, 1646, 1626, 1594, 1497, 1442, 1401, 1336, 1273, 1180, 1128, 908, 843, 792, 761, 711, 696, 679, 531, 493, 455, 436 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.92 (br s, 4 H), 8.38 (s, 2 H), 8.14–8.06 (m, 2 H), 7.53 (d, J = 8.7 Hz, 1 H), 6.75 (s, 2 H), 6.54 (d, J = 8.7 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 170.9, 167.5, 161.6, 155.9, 144.0, 140.8, 130.0 (q, J = 32.59 Hz), 129.1, 123.4 (q, J = 277.2 Hz), 123.3, 109.5, 104.0.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.40.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₆H₉N₄S⁺: 169.0542; found: 169.0550.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0046.

S-(4-Hydroxyquinazolin-6-yl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1t)

Using 6-iodoquinazolin-4-one (270 mg, 1.0 mmol) in GP1; white solid; yield: 310 mg (0.65 mmol, 65%); 137–140 °C.

IR (neat): 3074, 1651, 1614, 1550, 1411, 1346, 1273, 1167, 1123, 1065, 940, 909, 859, 845, 793, 757, 697, 679, 623, 581, 535, 507, 478, 432 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.52 (br s, 4 H), 8.39–8.36 (m, 2 H), 8.34 (d, J = 2.2 Hz, 1 H), 8.25 (s, 1 H), 8.14–8.10 (m, 1 H), 8.01 (dd, J = 8.5, 2.3 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H). The single hydroxyl/amine proton was not observed.

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 169.7, 168.1, 160.6, 151.1, 148.0, 141.2, 140.7 (q, J = 4.2 Hz), 134.9, 130.6 (q, J = 32.1 Hz), 129.9, 129.6 (q, J = 3.9 Hz), 124.4, 124.0, 123.8 (q, J = 272.7 Hz), 122.1.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.42.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₉H₉N₄OS⁺: 221.0497; found: 221.0500.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0049.

S-(5-Indazolyl)isothiouronium 3,5-Bis(trifluoromethyl)benzoate (1u)

Using 5-iodo-1H-indazole (244 mg, 1.0 mmol) in GP2; white solid; yield: 366 mg (0.81 mmol, 81%); 210–212 °C.

IR (neat): 3274, 2935, 2749, 1671, 1627, 1592, 1518, 1441, 1410, 1337, 1275, 1180, 1133, 1096, 1068, 944, 915, 894, 843, 793, 762, 713, 697, 680, 619, 536, 495, 471, 437, 425 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 13.49 (br, 1 H), 9.55 (br, 4 H), 8.38 (s, 2 H), 8.23 (s, 1 H), 8.22 (d, J = 1.7 Hz, 1 H), 8.14 (s, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.52 (dd, J = 8.6, 1.7 Hz, 1 H).

¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 170.4, 167.3, 141.5, 141.2, 134.8, 133.0, 131.4, 130.3 (q, J = 32.1 Hz), 129.6, 124.6, 123.9 (q, J = 271.5 Hz), 123.7, 114.2, 112.8.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –61.41.

HRMS (ESI+): m/z [M – BTB]⁺ calcd for C₈H₉N₄S⁺: 193.0542; found: 193.0547.

HRMS (ESI–): m/z [BTB]^– calcd for C₉H₃F₆O₂ ^–: 257.0043; found: 257.0051.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr. Alexander Kibler (University of Nottingham) for assistance with cyclic voltammetry measurements.

• References

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Corresponding Author

Publication History

Received: 13 October 2021

Accepted after revision: 10 January 2022

Article published online:
10 February 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Ilardi EA, Vitaku E, Njardarson JT. J. Med. Chem. 2013; 57: 2832
  CrossrefPubMedSearch in Google Scholar
• 2 Feng M, Tang B, Liang SH, Jiang X. Curr. Top. Med. Chem. 2016; 16: 1200
  CrossrefPubMedSearch in Google Scholar
• 3 Lee C.-F, Liu Y.-C, Badsara SS. Chem. Asian J. 2014; 9: 706
  CrossrefPubMedSearch in Google Scholar
• 4 Liu H, Jiang X. Chem. Asian J. 2013; 8: 2546
  CrossrefPubMedSearch in Google Scholar
• 5 Kondo T, Mitsudo T. Chem. Rev. 2000; 100: 3205
  Search in Google Scholar
• 6 Magné V, Ball LT. Chem. Eur. J. 2019; 25: 8903
  CrossrefPubMedSearch in Google Scholar
• 7 Takagi K. Chem. Lett. 1985; 14: 1307
  CrossrefSearch in Google Scholar
• 8 Dénès F, Pichowicz M, Povie G, Renaud P. Chem. Rev. 2014; 114: 2587
  CrossrefPubMedSearch in Google Scholar
• 9 Liu B, Lim C.-H, Miyake GM. J. Am. Chem. Soc. 2017; 139: 13616
  CrossrefPubMedSearch in Google Scholar
• 10 Liu B, Lim C.-H, Miyake GM. Synlett 2018; 29: 2449
  Thieme ConnectPubMedSearch in Google Scholar
• 11 Crisenza GE. M, Mazzarella D, Melchiorre P. J. Am. Chem. Soc. 2020; 142: 5461
  CrossrefPubMedSearch in Google Scholar
• 12 It should be noted that relative to Miyake’s conditions, additional base was included to account for the initial deprotonation that enables thiophenol liberation from a neutral isothiourea. For mechanistic studies of isothiouronium decomposition, see: Pratt RF, Bruice TC. J. Am. Chem. Soc. 1972; 94: 2823
  CrossrefSearch in Google Scholar
• 13 Hammerich O. In Organic Electrochemistry, 5th ed. CRC Press; Boca Raton: 2015: 1149
  CrossrefSearch in Google Scholar
• 14 Rossi RA, Pierini AB, Peñéñory AB. Chem. Rev. 2003; 103: 71
  CrossrefPubMedSearch in Google Scholar
• 15 Hernández-Muñoz LS, González FJ, González I, Goulart MO. F, de Abreu FC, Ribeiro AS, Ribeiro RT, Longo RL, Navarro M, Frontana C. Electrochim. Acta 2010; 55: 8325
  CrossrefSearch in Google Scholar
• 16 Mandal A, Rissanen K, Mal P. CrystEngComm 2019; 21: 4401
  CrossrefSearch in Google Scholar
• 17 ECHA substance infocard for NMP (accessed October 2021). https://echa.europa.eu/substance-information/-/substanceinfo/100.011.662

• Supplementary Material