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

• References and Notes

• 1a Lehn J.-M. Angew. Chem. Int. Ed. 2015; 54: 3276
• 1b Jin Y, Wang Q, Taynton P, Zhang W. Acc. Chem. Res. 2014; 47: 1575
• 1c Corbett PT, Leclaire J, Vial L, West KR, Wietor J.-L, Sanders JK. M, Otto S. Chem. Rev. 2006; 106: 3652
• 1d Furlan RL. E, Otto S, Sanders JK. M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4801
• 2a Lehn J.-M. Top. Curr. Chem. 2011; 322: 1
• 2b Lehn J.-M. Chem. Soc. Rev. 2007; 36: 151
• 3 Kölmel DK, Kool ET. Chem. Rev. 2017; 117: 10358
• 4a Black SP, Sanders JK. M, Stefankiewicz AR. Chem. Soc. Rev. 2014; 43: 1861
• 4b Fritze UF, von Delius M. Chem. Commun. 2016; 52: 6363
• 5 Belowich ME, Stoddart JF. Chem. Soc. Rev. 2012; 41: 2003
• 6a Beeren SR, Sanders JK. M. J. Am. Chem. Soc. 2011; 133: 3804
• 6b Lam RT. S, Belenguer A, Roberts SL, Naumann C, Jarrosson T, Otto S, Sanders JK. M. Science 2005; 308: 667
• 6c Furlan RL. E, Ng Y.-F, Otto S, Sanders JK. M. J. Am. Chem. Soc. 2001; 123: 8876
• 7 Ulrich S, Boturyn D, Marra A, Renaudet O, Dumy P. Chem. Eur. J. 2014; 20: 34
• 8a Mastalerz M. Acc. Chem. Res. 2018; 51: 2411
• 8b Ong WJ, Swager TM. Nat. Chem. 2018; 10: 1023
• 8c Guan X, Li H, Ma Y, Xue M, Fang Q, Yan Y, Valtchev V, Qiu S. Nat. Chem. 2019; 11: 587
• 8d Ono K, Iwasawa N. Chem. Eur. J. 2018; 24: 17856
• 8e Ding H, Chen R, Wang C. In Dynamic Covalent Chemistry: Principles, Reactions, and Applications . Zhang W, Jin Y. Wiley; New York: 2018: 165
• 8f Feng X, Ding X, Jiang D. Chem. Soc. Rev. 2012; 41: 6010
• 9a Frei P, Hevey R, Ernst B. Chem. Eur. J. 2019; 25: 60
• 9b Liu Y, Lehn J.-M, Hirsch AK. H. Acc. Chem. Res. 2017; 50: 376
• 9c Mondal M, Hirsch AK. H. Chem. Soc. Rev. 2015; 44: 2455
• 10 Brachvogel R.-C, von Delius M. Chem. Sci. 2015; 6: 1399
• 11 Orrillo AG, Escalante AM, Furlan RL. E. Chem. Eur. J. 2016; 22: 6746
• 12 Brachvogel R.-C, von Delius M. Eur. J. Org. Chem. 2016; 3662
• 13a Greene TW, Wuts PG. M. Protective Groups in Organic Synthesis, 2nd ed. Wiley; New York: 1991
• 13b Kocienski PJ. Protecting Groups, 3rd ed. Thieme; Stuttgart: 1994
• 14 Collins MS, Shear TA, Smith EK, Strain SM, Zakharov LN, Johnson DW. Chem. Eur. J. 2019; DOI: 10.1002/chem.201903854.
• 15a Brachvogel R.-C, Hampel F, von Delius M. Nat. Commun. 2015; 6: 7129
• 15b Brachvogel R.-C, Maid H, von Delius M. Int. J. Mol. Sci. 2015; 16: 20641
• 15c Shyshov O, Brachvogel R.-C, Bachmann T, Srikantharajah R, Segets D, Hampel F, Puchta R, von Delius M. Angew. Chem. Int. Ed. 2017; 56: 776
• 15d Wang X, Shyshov O, Hanževački M, Jäger CM, von Delius M. J. Am. Chem. Soc. 2019; 141: 8868
• 15e Löw H, Mena-Osteritz E, von Delius M. Chem. Sci. 2018; 9: 4785
• 16 Orrillo AG, Escalante AM, Furlan RL. E. Org. Lett. 2017; 19: 1446
• 17a Orrillo AG, La-Venia A, Escalante AM, Furlan RL. E. Chem. Eur. J. 2018; 24: 3141
• 17b Martinez-Amezaga M, Orrillo AG, Furlan RL. E. Chem. Sci. 2019; DOI: 10.1039/C9SC02166C.
• 18 Lebel H, Grenon M. In Science of Synthesis . Vol. 22; Charette AB. Thieme; Stuttgart: 2005: 749
• 19a Seebach D, Geiß K.-H, Beck AK, Graf B, Daum H. Chem. Ber. 1972; 105: 3280
• 19b Barsamian AL, Blakemore PR. Organometallics 2012; 31: 19
• 20 Cao Y.-J, Lai Y.-Y, Cao H, Xing X.-N, Wang X, Xiao W.-J. Can. J. Chem. 2006; 84: 1529
• 21 Seebach D. Angew. Chem. 1967; 79: 468
• 22a Tlach BC, Tomlinson AL, Ryno AG, Knoble DD, Drochner DL, Krager KJ, Jeffries-EL M. J. Org. Chem. 2013; 78: 6570
• 22b Corey EJ, Seebach D. Angew. Chem. 1965; 77: 1134
• 22c Gröbel B.-T, Seebach D. Synthesis 1977; 357

For syntheses of dithioacetals see:
• 23a Firouzabadi H, Iranpoor N, Hazarkhani H. J. Org. Chem. 2001; 66: 7527
• 23b Tazaki M, Takagi M. Chem. Lett. 1979; 8: 767
• 24a Moulin E, Cormos G, Giuseppone N. Chem. Soc. Rev. 2012; 41: 1031
• 24b Li J, Nowak P, Otto S. J. Am. Chem. Soc. 2013; 135: 9222
• 24c Jin Y, Yu C, Denman RJ, Zhang W. Chem. Soc. Rev. 2013; 42: 6634
• 25a Eckert F, Leito I, Kaljurand I, Kütt A, Klamt A, Diedenhofen M. J. Comput. Chem. 2009; 30: 799
• 25b Kütt A, Selberg S, Kaljurand I, Tshepelevitsh S, Heering A, Darnell A, Kaupmees K, Piirsalu M, Leito I. Tetrahedron Lett. 2018; 59: 3738
• 25c Paenurk E, Kaupmees K, Himmel D, Kütt A, Kaljurand I, Koppel IA, Krossing I, Leito I. Chem. Sci. 2017; 8: 6964
• 26 Pruckmayr G, Wu TK. Macromolecules 1978; 11: 662
• 27a Otto S, Furlan RL. E, Sanders JK. M. J. Am. Chem. Soc. 2000; 122: 12063
• 27b Delius M, Geertsema EM, Leigh DA, Slawin AM. Org. Biomol. Chem. 2010; 8: 4617
• 28a Schmittel M, Levis M. Synlett 1996; 315
• 28b Kamal A, Laxman E, Reddy PS. M. M. Synlett 2000; 1476
• 28c Gauthier JY, Martins EO, Young RN, Zamboni RJ. Synlett 2002; 984
• 28d Kumar V, Dev S. Tetrahedron Lett. 1983; 24: 1289
• 28e Patney HK. Tetrahedron Lett. 1991; 32: 2259
• 28f Tamami B, Borujeny KP. Synth. Commun. 2003; 33: 4253
• 29a Rasmussen B, Sørensen A, Gotfredsen H, Pittelkow M. Chem. Commun. 2014; 50: 3716
• 29b Ji S, Cao W, Yu Y, Xu H. Angew. Chem. Int. Ed. 2014; 53: 6781
• 29c Chuard N, Poblador-Bahamonde AI, Zong L, Bartolami E, Hildebrandt J, Weigand W, Sakai N, Matile S. Chem. Sci. 2018; 9: 1860
• 29d Bartolami E, Basagiannis D, Zong L, Martinent R, Okamoto Y, Laurent Q, Ward TR, Gonzalez-Gaitan M, Sakai N, Matile S. Chem. Eur. J. 2019; 25: 4047
• 29e Steinmann D, Nauser T, Koppenol WH. J. Org. Chem. 2010; 75: 6696
• 30a DeWolfe RH. Synthesis 1974; 153
• 30b Mochel WE, Agre CL, Hanford WE. J. Am. Chem. Soc. 1948; 70: 2268
• 31a Cordes EH, Bull HG. Chem. Rev. 1974; 74: 581
• 31b Chiang Y, Kresge AJ, Lahti MO, Weeks DP. J. Am. Chem. Soc. 1983; 105: 6852
• 31c Repetto SL, Costello JF, Butts CP, Lam JK. W, Ratcliffe NM. Beilstein J. Org. Chem. 2016; 12: 1467
• 31d Deslongchamps P, Dory YL, Li S. Tetrahedron 2000; 56: 3533
• 32a Bhawal BN, Morandi B. ACS Catal. 2016; 6: 7528
• 32b Bhawal BN, Morandi B. Chem. Eur. J. 2017; 23: 12004
• 33 Bhawal BN, Morandi B. Angew. Chem. Int. Ed. 2019; 58: 10074
• 34a Otsuka H, Nagano S, Kobashi Y, Maeda T, Takahara A. Chem. Commun. 2010; 46: 1150
• 34b Caraballo R, Sakulsombat M, Ramström O. Chem. Commun. 2010; 46: 8469
• 35 Amamoto Y, Kamada J, Otsuka H, Takahara A, Matyjaszewski K. Angew. Chem. Int. Ed. 2011; 50: 1660
• 36 Saiz C, Wipf P, Manta E, Mahler G. Org. Lett. 2009; 11: 3170
• 37 Cacciapaglia R, Di Stefano S, Mandolini L. J. Am. Chem. Soc. 2005; 127: 13666
• 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.
• 42 In the case of O,O,O-orthoesters, hydrolysis is presumably the source of the free nucleophile, whereas with S,S,S-orthoesters, our observation of a bright-pink color might indicate that a thiol/thionium pair is formed, even without participation of water.
• 43a Fan Y, An Z, Pan X, Liu X, Bao X. Chem. Commun. 2009; 7488
• 43b Node M, Nishide K, Fuji K, Fujita E. J. Org. Chem. 1980; 45: 4275