Trithioorthoester Exchange and Metathesis: New Tools for Dynamic Covalent Chemistry

Published as part of the Cluster Metathesis beyond Olefins

Abstract

To expand the toolbox of dynamic covalent and systems chemistry, we investigated the acid-catalyzed exchange reaction of trithioorthoesters with thiols. We found that trithioorthoester exchange occurs readily in various solvents in the presence of stoichiometric amounts of strong Brønsted acids or catalytic amounts of certain Lewis acids. The scope of the exchange reaction was explored with various substrates, and conditions were identified that permit clean metathesis reactions between two different trithioorthoesters. One distinct advantage of S,S,S-orthoester exchange over O,O,O-orthoester exchange is that the exchange reaction can kinetically outcompete hydrolysis, thereby making the process less sensitive to residual moisture. We expect that the relatively high stability of the products might be beneficial in future supramolecular receptors or porous materials.

Key words

transesterification - trithioorthoesters - thiols - exchange ­reaction - metathesis - dynamic covalent chemistry

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• 38 Tris[(4-methylbenzene)thio]methane (A5₃ ), tris(isopropylthio)methane (A4₃ ), and tris[(2-phenylethyl)thio]methane [A(10)₃ ] were synthesized by a modified version of the reported procedure; see Ref. 20. Tris[(4-methylbenzene)thio]methane (A5₃ ); Typical Procedure CHCl₃ (1.48 g, 12.4 mmol, 1.0 equiv), DBU (9.79 g, 64.3 mmol, 5.2 equiv), and 4-methylbenzenethiol (6.14 g, 49.4 mmol, 4.0 equiv) were dissolved in anhyd THF (10 mL), and the mixture was heated to 100 °C for 24 h under N₂ in a pressure tube. The mixture was cooled, H₂O (30 mL) was added, and the resulting mixture was extracted with Et₂O (2 × 50 mL). The combined organic phases were washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentrated on a rotary evaporator. The residue was purified by column chromatography [silica gel, PE–CH₂Cl₂ (100:0 to 80:20)]. Subsequent crystallization (CH₂Cl₂) gave A5₃ as a white solid; yield: 2.10 g (44%, 5.48 mmol); R_f = 0.3 (silica gel, PE–CH₂Cl₂, 80:20, UV₂₅₄). ¹H NMR (400 MHz, 298 K, CDCl₃): δ = 7.43–7.41 (m, 6 H), 7.17–7.15 (m, 6 H). 5.32 (s, 1 H), 2.37 (s, 9 H). ¹³C NMR (100 MHz, 298 K, CDCl₃): δ = 138.5, 133.4, 130.4, 129.6, 65.9, 21.2. Anal. calcd for C₂₂H₂₂S₃: C, 69.07; H, 5.80; S, 25.14. Found: C, 69.00; H, 5.93; S, 25.22.
• 39 Synthesis of 1,1,1-Tris(methylthio)ethane (B8₃) This was synthesized by a modified version of the reported procedure.²¹ Trimethyl trithioorthoformate (A8₃ ; 5.28 g, 34.2 mmol, 1.0 equiv) was dissolved in anhyd THF (50 mL) and cooled to –78 °C under N₂. A 2.5 M solution of BuLi in hexane (20.5 mL, 51.3 mmol, 1.5 equiv) was added dropwise and the mixture was stirred for 80 min. MeI (12.13 g, 85.5 mmol, 2.5 equiv) was added dropwise, and the mixture was allowed to slowly warm to r.t. overnight. Et₂O (100 mL) was added and the mixture washed with aq Na₂S₂O₃ (50 mL). The combined extracted organic phases were washed with brine (50 mL), separated, dried (Na₂SO₄), filtered, and concentrated on a rotary evaporator. Distillation through a short Vigreux column (oil-bath temperature: 120 °C; pressure: 7 mbar; bp 70 °C) gave a colorless oil; yield: 4.55 g (79%, 27.0 mmol); R _f = 0.7 (silica gel, PE–EtOAc, 95:5, UV₂₅₄). ¹H NMR (400 MHz, 298 K, CDCl₃): δ = 2.16 (s, 9 H), 1.87 (s, 3 H). ¹³C NMR (100 MHz, 298 K, CDCl₃): δ = 64.3, 28.3, 13.6. Anal. calcd for C₅H₁₂S₃: C, 35.68; H, 7.19; S, 57.14. Found: C, 37.04; H, 7.26; S, 57.81.
• 40 1-[Bis(phenylthio)methyl]-4-fluorobenzene (CH1₂ ) and 1-[bis(phenylthio)methyl]-4-methoxybenzene (DH1₂ ) were synthesized by a modified version of the reported procedure; see Ref 23a. 1-[Bis(phenylthio)methyl]-4-fluorobenzene (CH1₂); Typical Procedure Iodine (1.29 g, 5.10 mmol, 0.1 equiv) was added to a solution of 4-fluorobenzaldehyde (6.30 g, 50.8 mmol, 1.0 equiv) and benzenethiol (11.7 g, 107 mmol, 2.1 equiv) in CHCl₃ (75 mL), and the resulting solution was stirred overnight at r.t. When the reaction was complete, excess I₂ was quenched with 0.1 M aq Na₂S₂O₃ (100 mL). The organic phase was separated, washed with H₂O (100 mL), dried (Na₂SO₄), filtered, and concentrated on a rotary evaporator. Purification by flash column chromatography [silica gel, PE–CH₂Cl₂ (95:5 to 80:20)] and subsequent crystallization from petroleum ether gave CH1₂ as a white solid; yield: 12.8 g (77%, 39.2 mmol). R_f = 0.30 (silica gel, PE–CH₂Cl₂, 80:20, UV₂₅₄). ¹H NMR (500 MHz, 298 K, CD₂Cl₂): δ = 7.42–7.36 (m, 6 H), 7.34–7.28 (m, 6 H), 7.03–6.99 (m, 2 H), 5.53 (s, 1 H). ¹³C NMR (125 MHz, 298 K, CD₂Cl₂): δ = 162.7 (d, ¹ J _CF = 246.5 Hz), 135.9 (d, ⁴ J _CF = 3.2 Hz), 134.5, 132.9, 131.0 (d, ³ J _CF = 8.3 Hz), 129.3, 128.3, 114.6 (d, ² J _CF = 21.8 Hz), 59.6. Anal. calcd for C₁₉H₁₅FS₂: C, 69.91; H, 4.63; S, 19.64. Found: C, 70.05; H, 4.84; S, 20.05.
• 41 1-Fluoro-4-[tris(phenylthio)methyl]benzene (C1₃ ) and 1-methoxy-4-[tris(phenylthio)methyl]benzene (D1₃ ) were synthesized by a modified version of the reported procedure; see Ref 22a. 1-Fluoro-4-[tris(phenylthio)methyl]benzene (C1₃); Typical Procedure Dithioacetal DH1₂ (2.49 g, 7.66 mmol, 1.0 equiv) and TMEDA (2.49 g. 21.4 mmol, 2.8 equiv) were dissolved in anhyd THF (15 mL) under N₂. The solution was cooled to –78 °C and a 2.5 M solution of BuLi in hexane (4.29 mL, 10.7 mmol, 1.4 equiv) was added dropwise. The mixture was stirred for 80 min at –78 °C, a solution of diphenyl disulfide (5.02 g, 23.0 mmol, 3.0 equiv) in anhyd THF (10 mL) was added slowly, and the mixture was allowed to warm to r.t overnight. The mixture was then cooled to 0 °C and the reaction was carefully quenched with several drops of H₂O. The resulting mixture was extracted with Et₂O (2 × 70 mL), washed with H₂O (100 mL) and brine (100 mL), and the organic layer was separated, dried (Na₂SO₄), filtered, and concentrated on a rotary evaporator. Purification by flash column chromatography [silica gel, PE–CH₂Cl₂ (100:0 to 80:20)] and subsequent crystallization from PE–CH₂Cl₂ gave C1₃ as a white solid; yield: 2.30 g (69%, 5.30 mmol); R_f = 0.32 (silica gel, PE–CH₂Cl₂, 80:20, UV₂₅₄). ¹H NMR (500 MHz, 298 K, CD₂Cl₂): δ = 7.68–7.60 (m, 2 H), 7.34–7.18 (m, 15 H), 6.90–6.82 (m, 2 H). ¹³C NMR (125 MHz, 298 K, CD₂Cl₂): δ = 162.6 (d, ¹ J _CF = 248.0 Hz), 135.7 (d, ⁴ J _CF = 3.1 Hz), 135.0, 133.1, 131.2 (d, ³ J _CF = 8.3 Hz), 129.0, 128.7, 114.9 (d, ² J _CF = 21.6 Hz), 76.7. Anal. calcd for C₂₅H₁₉FS₃: C, 69.09; H, 4.41; S, 22.13. Found: C, 68.96; H, 4.61; S, 22.11.
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