Improved Protocols for the Synthesis of Precursors of Thiazol-2-ylidene N-Heterocyclic Carbenes

Abstract

We report improved protocols for the synthesis of thiazolium precatalysts from primary amines, carbon disulfide, and α-halo ketones. For N-alkyl-substituted derivatives, yields of the corresponding thiazolethiones can be dramatically improved by isolating the intermediate dithiocarbamates. In most cases, meta-chloroperbenzoic acid can advantageously replace H₂O₂ in acetic acid for the oxidation of thiazolethiones into thiazoliums. This approach was applied to the synthesis of a thiazolium featuring a 2-adamantyl N-substituent, the corresponding persistent carbene, and its dimer.

Key words

thiazolium compounds - carbenes - precatalyst - dithiocarbamates - oxidation

• References and Notes

• 1 A preliminary version of this manuscript has been deposited on the ChemRXiv preprint server, see: Delfau L, Pecaut J, Tomás-Mendivil E, Martin D. ChemRxiv 2024; preprint
• 2a Arduengo AJ. III, Goerlich JR, Marshall WJ. Liebigs Ann./Recl. 1997; 365
• 2b Hopkinson MN, Richter C, Schedler M, Glorius F. Nature 2014; 510: 485
• 2c Ukai T, Tanaka R, Dokawa T. J. Pharm. Soc. Jpn. 1943; 63: 296
• 2d Breslow R. J. Am. Chem. Soc. 1957; 79: 1762
• 2e Breslow R. J. Am. Chem. Soc. 1958; 80: 3719
• 3a Enders D, Niemeier O, Henseler A. Chem. Rev. 2007; 107: 5606
• 3b Bugaut X, Glorius F. Chem. Soc. Rev. 2012; 41: 3511
• 3c De Sarkar S, Biswas A, Samanta RC, Studer A. Chem. Eur. J. 2013; 19: 4664
• 3d Flanigan DM, Romanov-Michailidis F, White NA, Rovis T. Chem. Rev. 2015; 115: 9307
• 3e Wang MH, Scheidt KA. Angew. Chem. Int. Ed. 2016; 55: 14912
• 4a Zhao K, Enders D. Angew. Chem. Int. Ed. 2017; 56: 3754
• 4b Ishii T, Nagao K, Ohmiya H. Chem. Sci. 2020; 11: 5630
• 4c Li Q.-Z, Zeng R, Han B, Li J.-L. Chem. Eur. J. 2021; 27: 3238
• 4d Liu K, Schwenzer M, Studer A. ACS Catal. 2022; 12: 11984
• 5a Götze J. Chem. Ber. 1938; 71: 2289
• 5b Benhamou L, Chardon E, Lavigne G, Bellemin-Laponnaz S, César V. Chem. Rev. 2011; 111: 2705
• 6 An alternative approach based on the thionation of α-formamido ketones, published as a preprint non-peer-reviewed version, was available at the time of our submission; see: Ji T, Rao Garapati VK, Gravel MA. ChemRxiv 2022; preprint
• 7 Deady LW, Stillman DC. Aust. J. Chem. 1976; 29: 1745
• 8 Hantzsch A, Weber JH. Ber. Dtsch. Chem. Ges. 1887; 20: 3118
• 9a Pesch J, Harms K, Bach T. Eur. J. Org. Chem. 2004; 2025
• 9b Lebeuf R, Hirano K, Glorius F. Org. Lett. 2008; 10: 4243
• 9c Vougioukalakis GC, Grubbs RH. J. Am. Chem. Soc. 2008; 130: 2234
• 9d Piel I, Pawelczyk MD, Hirano K, Fröhlich R, Glorius F. Eur. J. Org. Chem. 2011; 5475
• 9e Leopold H, Tronnier A, Wagenblast G, Münster I, Strassneer T. Organometallics 2016; 35: 959
• 9f Draskovits M, Mihovilovic MD. Chem. Commun. 2019; 55: 12144
• 9g Dutta C, Sainaba AB, Choudhury J. Chem. Commun. 2019; 55: 854
• 10a Guo W, Martínez-Rodríguez L, Kuniyil R, Martin E, Escudero-Adań EC, Maseras F, Kleij AW. J. Am. Chem. Soc. 2016; 138: 11970
• 10b Delany EG, Connon SJ. Org. Biomol. Chem. 2018; 16: 780
• 11a Delfau L, Nichilo S, Molton F, Broggi J, Tomás-Mendivil E, Martin D. Angew. Chem. Int. Ed. 2021; 60: 26783
• 11b Delfau L, Assani N, Nichilo S, Pecaut J, Philouze C, Broggi J, Martin D, Tomás-Mendivil E. ACS Org. Inorg. Au 2023; 3: 136
• 12a Kakeno Y, Kusakabe M, Nagao K, Ohmiya H. ACS Catal. 2020; 10: 8524
• 12b Kusakabe M, Nagao K, Ohmiya H. Org. Lett. 2021; 23: 7242

See also:
• 13a Liu M.-S, Shu W. ACS Catal. 2020; 10: 12960
• 13b Ishii T, Nagao K, Ohmiya H. Tetrahedron 2021; 91: 132212
• 13c Liu W.-D, Lee W, Shu H, Xiao C, Xu H, Chen X, Houk KN, Zhao J. J. Am. Chem. Soc. 2022; 144: 22767
• 13d Du H.-W, Liu M.-S, Shu W. Org. Lett. 2022; 24: 5519
• 13e Huang Y, Han Y.-F, Zhang C.-L, Ye S. ACS Catal. 2023; 13: 11033
• 14 Takami F, Wakahara S, Maeda T. Chem. Lett. 1972; 409
• 15a Bellec N, Lorcy D, Boubekeur K, Carlier R, Tallec A, Los S, Pukacki W, Trybula M, Piekara-Sady L, Robert A. Chem. Mater. 1999; 11: 3147
• 15b Bellec N, Guérin D, Lorcy D, Robert A, Carlier R, Tallec A. Acta Chem. Scand. 1999; 53: 861
• 15c Pettersson I, Rang K, Sandström J. Acta Chem. Scand. 1986; 40b: 751
• 15d Aly AA, Brown AB, El-Shaieb KM, Hassan AA, Bedair TM. I. J. Chem. Res. 2009; 689
• 15e Al-Abdullah ES, Al-Tuwaijri HM, Hassan HM, Al-Alshaikh MA, Habib EE, El-Emam AA. Molecules 2015; 20: 8125
• 16 Medvedko S, Ströbele M, Wagner JP. Chem. Eur. J. 2023; 29: e202203005
• 17 Triethylammonium Neopentyldithiocarbamate (1a); Typical Procedure CS₂ (9 mL, 150 mmol) was added to a solution of neopentylamine (3.5 mL, 30 mmol) and Et₃N (4.5 mL, 32 mmol) in Et₂O (50 mL) at 0 °C, and the mixture was stirred for 2 h at r.t. The white precipitate of the dithiocarbamate salt 1a was collected by filtration, washed with Et₂O, dried under vacuum, and used without further purification; yield: 7.09 g (28 mmol, 94%). ¹H NMR (500 MHz, DMSO-d ₆): δ = 9.51 (br s, 1 H), 7.88 (t, J = 6.0 Hz, 1 H), 3.32 (d, J = 6.1 Hz, 2 H), 3.12 (q, J = 7.3 Hz, 6 H), 1.20 (t, J = 7.3 Hz, 9 H), 0.86 (s, 9 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 214.7, 57.8, 45.5, 32.0, 27.6, 8.6. 3-Neopentyl-3,4,5,6,7,8-hexahydro-2H-cyclohepta[d][1,3]thiazole-2-thione (2a); Typical Procedure Dithiocarbamate salt 1a (28 mmol) was dissolved in MeCN (50 mL), and the α-halo ketone MeCOCHClMe (2.8 mL, 28 mmol) was added dropwise. The mixture was then stirred overnight at r.t. The solvent was removed under vacuum, EtOH (28 mL) and concd aq HCl (1.4 mL) were added, and the resultant mixture was refluxed for 1 h. The solvent was removed under a vacuum and the resulting oil was dissolved in H₂O (30 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The organic phase was washed with NaHCO₃ (20 mL), H₂O (3 × 20 mL), and brine (20 mL), then dried (MgSO₄) and concentrated to afford thiazolethione 2a as a yellow powder; yield: 6.08 g (23.8 mmol, 86%). ¹H NMR (400 MHz, CDCl₃): δ = 4.98 (br s, 1 H), 3.42 (br s, 1 H), 2.69 (br s, 2 H), 2.56–2.53 (m, 2 H), 1.83–1.82 (m, 2 H), 1.68–1.64 (m, 4 H), 1.03 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 187.2, 142.8, 124.0, 56.3, 35.6, 31.8, 30.5, 29.4, 27.6, 26.8, 26.4. 3-Neopentyl-5,6,7,8-tetrahydro-4H-cyclohepta[d][1,3]thiazol-3-ium Hexafluorophosphate (3a); Typical Procedure A 60 wt% solution of HPF₆ in H₂O (8.8 mL, 60 mmol) was added to a solution of thiazolin-2-thione 2a (20 mmol) in THF; the mixture was then cooled to –78 °C, and a 70–75 wt% solution of m-CPBA in H₂O (14.8 g, 60 mmol) was added in a portionwise manner. The resulting mixture was stirred for 2 h at r.t., then H₂O (60 mL) and concd aq Na₂SO₃ (40 mL) were added, followed by CH₂Cl₂ (40 mL). The organic phase was separated and washed with H₂O (2 × 50 mL), then transferred to an Erlenmeyer flask. A solution of concd aq NaHCO₃ (60 mL) was added with vigorous stirring until the pH reached 7–8. The organic phase was extracted and washed with brine (30 mL), dried (MgSO₄), and concentrated. The residue was washed with Et₂O and collected by filtration to afford a white powder; yield: 5.12 g (14 mmol, 69%); mp 108 °C. ¹H NMR (500 MHz, CDCl₃): δ = 9.21 (s, 1 H), 4.27 (s, 2 H), 3.00–2.96 (m, 4 H), 1.94–1.91 (m, 2 H), 1.80–1.73 (m, 4 H), 0.99 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 153.2, 149.2, 139.5, 63.7, 33.7, 31.0, 28.1, 27.8, 27.2, 26.4, 25.1. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –72.1 (d, J = 713 Hz). HRMS (ESI): m/z [M – PF₆]⁺ calcd for C₁₃H₂₂NS: 224.1468; found: 224.1463.
• 18 For the observation in an enzymatic environment of the natural thiazolylidene NHC stemming from thiamine, see: Meyer D, Neumann P, Koers E, Tittmann K. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 10867
• 19 Borden WT. Chem. Rev. 1989; 89: 1095
• 20 CCDC 2329189 contains the supplementary crystallographic data for compound 5e. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures