Manganese-Catalyzed α-Trideuteromethylation of Sulfones

Abstract

Recent advancements in deuteration techniques have garnered significant attention from both academia and industry. Herein, we report a manganese-catalyzed α-trideuteromethylation of sulfones with CD₃OD as a deuterating reagent via a deuterium autotransfer strategy under mild conditions. Our approach yields target compounds with 60–96% efficiency and deuteration levels up to 99%. This methodology stands out due to its reliance on accessible deuterium sources, an earth-abundant transition-metal catalyst, and mild conditions.

Key words

manganese - homogeneous catalysis - deuterated methanol - α-trideuteromethylation - deuterium autotransfer

• References and Notes

• 1 Kopf S, Bourriquen F, Li W, Neumann H, Junge K, Beller M. Chem. Rev. 2022; 122: 6634
• 2 Gant TG. J. Med. Chem. 2014; 57: 3595
• 3 Schmidt C. Nat. Biotechnol. 2017; 35: 493
• 4 Sun Q, Soule JF. Chem. Soc. Rev. 2021; 50: 10806
• 5 Steverlynck J, Sitdikov R, Rueping M. Chem. Eur. J. 2021; 27: 11751
• 6 Sivakumar G, Kumar R, Yadav V, Gupta V, Balaraman E. ACS Catal. 2023; 13: 15013
• 7 Biswas N, Srimani D. J. Org. Chem. 2021; 86: 10544
• 8 Choi G, Hong SH. Angew. Chem. Int. Ed. 2018; 57: 6166
• 9 Dang TT, Ramalingam B, Seayad AM. ACS Catal. 2015; 5: 4082
• 10 Dang TT, Seayad AM. Adv. Synth. Catal. 2016; 358: 3373
• 11 Kaithal A, Schmitz M, Hölscher M, Leitner W. ChemCatChem 2019; 11: 5287
• 12 Chan LK, Poole DL, Shen D, Healy MP, Donohoe TJ. Angew. Chem. Int. Ed. 2014; 53: 761
• 13 Shee S, Kundu S. J. Org. Chem. 2021; 86: 6943
• 14 Tsukamoto Y, Itoh S, Kobayashi M, Obora Y. Org. Lett. 2019; 21: 3299
• 15 Mamidala R, Biswal P, Subramani MS, Samser S, Venkatasubbaiah K. J. Org. Chem. 2019; 84: 10472
• 16 Wang L, Neumann H, Beller M. Angew. Chem. Int. Ed. 2019; 58: 5417
• 17 Elangovan S, Neumann J, Sortais JB, Junge K, Darcel C, Beller M. Nat. Commun. 2016; 7: 12641
• 18 Ganguli K, Mandal A, Kundu S. ACS Catal. 2022; 12: 12444
• 19 Liu Y, Shao Z, Wang Y, Xu L, Yu Z, Liu Q. ChemSusChem 2019; 12: 3069
• 20 Mondal A, Karattil Suresh A, Sivakumar G, Balaraman E. Org. Lett. 2022; 24: 8990
• 21 Emayavaramban B, Chakraborty P, Dahiya P, Sundararaju B. Org. Lett. 2022; 24: 6219
• 22 Polidano K, Allen BD. W, Williams JM. J, Morrill LC. ACS Catal. 2018; 8: 6440
• 23 Liu Z, Yang Z, Yu X, Zhang H, Yu B, Zhao Y, Liu Z. Adv. Synth. Catal. 2017; 359: 4278
• 24 Das J, Singh K, Vellakkaran M, Banerjee D. Org. Lett. 2018; 20: 5587
• 25 Sklyaruk J, Borghs JC, El-Sepelgy O, Rueping M. Angew. Chem. Int. Ed. 2019; 58: 775
• 26 Song D, Chen L, Li Y, Liu T, Yi X, Liu L, Ling F, Zhong W. Org. Chem. Front. 2021; 8: 120
• 27 Liu P, Chen X, Xu X, Yang L, Zeng G, Ye C, Shi Q, Yang J, Li F. J. Catal. 2022; 410: 333
• 28 Liu D, Xu X, Zhang P, Shi Q, Li F. J. Catal. 2024; 430: 115301
• 29 Yu K, Nie Q, Chen Q, Liu W. Nat. Commun. 2024; 15: 6798
• 30 Lin Q, Sun F, Wang T, Yang J, Tang J, Liu W. Adv. Synth. Catal. 2024; 367: e202401080
• 31 Tang J, He J, Zhao SY, Liu W. Angew. Chem. Int. Ed. 2023; 62: e202215882
• 32 Sun F, Chen X, Wang S, Sun F, Zhao S.-Y, Liu W. J. Am. Chem. Soc. 2023; 145: 25545
• 33 Corma A, Navas J, Sabater MJ. Chem. Rev. 2018; 118: 1410
• 34 Huang F, Liu Z, Yu Z. Angew. Chem. Int. Ed. 2016; 55: 862
• 35 Jankins TC, Fayzullin RR, Khaskin E. Organometallics 2018; 37: 2609
• 36 Manganese-Catalyzed α-Trideuteromethylation of Sulfones; General Procedure: In a nitrogen-filled glove box, an oven-dried Schlenk pressure tube (10 mL) containing a stirring bar was charged with [Mn] (1.0 mol%). Dry and degassed 1,4-dioxane (0.5 mL) and NaOtBu (50 mol%) were added and the mixture was stirred at room temperature for 5.0 min. Compound 1 (0.25 mmol) and CD₃OD (2.5 mmol) were then added in sequence. The tube was brought out of the glovebox and heated at 120 °C for 12 h. Upon reaction completion, the reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified by column chromatography on silica gel (100–200 mesh) using PE/EtOAc as the eluent to afford the final product. ((1-Phenylethyl-1,2,2,2-d ₄)sulfonyl)benzene (3) The procedure was followed using (benzylsulfonyl)benzene (0.25 mmol, 58.1 mg), CD₃OD (2.5 mmol, 102 μL) stirred at 120 °C for 12 h. Purification by column chromatography (PE/EtOAc = 10:1) gave 3 (56.3 mg, 90%) as a white solid. ¹H NMR (600 MHz, CDCl₃): δ = 7.64–7.48 (m, 3 H), 7.42–7.37 (m, 2 H), 7.31–7.27 (m, 1 H), 7.27–7.22 (m, 2 H), 7.15–7.11 (m, 2 H), 4.22 (s, 0.15 H). ¹³C NMR (150 MHz, CDCl₃): δ = 136.8, 133.7, 133.6, 129.4, 129.2, 128.8, 128.7, 128.4, 66.2–65.0, 13.7–12.7 HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₁₄H₁₄D₄O₂NS: 268.1304; found: 268.1301.