Synlett 2019; 30(17): 1988-1994
DOI: 10.1055/s-0039-1690992
cluster
© Georg Thieme Verlag Stuttgart · New York

Trithioorthoester Exchange and Metathesis: New Tools for Dynamic Covalent Chemistry

Michael Bothe
a  Institute of Organic Chemistry I, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany   Email: max.vondelius@uni-ulm.de
,
A. Gastón Orrillo
b  Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario-CONICET, S2002LRK Rosario, Argentina   Email: rfurlan@fbioyf.unr.edu.ar
,
Ricardo L. E. Furlan
b  Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario-CONICET, S2002LRK Rosario, Argentina   Email: rfurlan@fbioyf.unr.edu.ar
,
a  Institute of Organic Chemistry I, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany   Email: max.vondelius@uni-ulm.de
› Author Affiliations
This work was supported by the Deutsche Forschungsgemeinschaft (Emmy-Noether grant DE1830/2-1), Fondo para la Investigación Científica y Tecnológica (FONCYT) (PICT2015-3574) and a CONICET – BAYLAT Bilateral Cooperation Programme, Level I, Res. 733/15.
Further Information

Publication History

Received: 06 September 2019

Accepted: 11 September 2019

Publication Date:
18 September 2019 (online)

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.

Supporting Information

 
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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); Rf = 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). Rf = 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); Rf = 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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