Role of Benzylic Deprotonation in Nickel-Catalyzed Benzylic Dehydrogenation

Abstract

Alkylarenes are readily functionalized via the corresponding benzylic anions. Benzylic anions have been used for a range of catalytic reactions, including Ni-catalyzed dehydrogenation. Interestingly, the employment of Zn(TMP)₂ for slow and incomplete deprotonation of the benzylic position was observed. This manuscript describes a preliminary investigation into the deprotonation of heteroarenes and its relationship to Ni-catalyzed benzylic dehydrogenation.

Key words

Ni catalysis - dehydrogenation - benzylic anion - heteroarene - deuteration

Publication History

Received: 13 May 2021

Accepted: 09 June 2021

Article published online:
15 July 2021

• References and Notes

• 1a Tasker SZ, Standley EA, Jamison TF. Nature 2014; 509: 299
• 1b Ananikov VP. ACS Catal. 2015; 5: 1964
• 1c Zweig JE, Kim DE, Newhouse TR. Chem. Rev. 2017; 117: 11680
• 2 Zhang P, Huang D, Newhouse TR. J. Am. Chem. Soc. 2020; 142: 1757
• 3a Pines H, Wunderlich D. J. Am. Chem. Soc. 1958; 80: 6001
• 3b Pines H. Acc. Chem. Res. 1974; 7: 155
• 3c Yamashita Y, Suzuki H, Sato I, Hirata T, Kobayashi S. Angew. Chem. Int. Ed. 2018; 57: 6896
• 4a Armstrong DR, García-Álvarez J, Graham DV, Honeyman GW, Hevia E, Kennedy AR, Mulvey RE. Chem. Eur. J. 2009; 15: 3800
• 4b Zhai D, Zhang X, Liu Y, Zheng L, Guan B. Angew. Chem. Int. Ed. 2018; 57: 1650
• 4c Liu G, Walsh P, Mao J. Org. Lett. 2019; 21: 8514
• 5 For a review, see: Yazaki R, Ohshima T. Tetrahedron Lett. 2019; 60: 151225
• 6a Trost BM, Thaisrivongs DA. J. Am. Chem. Soc. 2008; 130: 14092
• 6b Trost BM, Thaisrivongs DA. J. Am. Chem. Soc. 2009; 131: 12056
• 6c Trost BM, Thaisrivongs DA, Hartwig JF. J. Am. Chem. Soc. 2011; 133: 12439
• 7a Zhang J, Stanciu C, Wang B, Hussain M, Da C.-S, Carroll PJ, Dreher SD, Walsh PJ. J. Am. Chem. Soc. 2011; 133: 20552
• 7b Sha S.-C, Zhang J, Carroll PJ, Walsh PJ. J. Am. Chem. Soc. 2013; 135: 17602
• 7c Sha S.-C, Jiang H, Mao J, Bellomo A, Jeong SA, Walsh PJ. Angew. Chem. Int. Ed. 2016; 55: 1070
• 7d Mao J, Zhang J, Jiang H, Bellomo A, Zhang M, Gao Z, Dreher SD, Walsh PJ. Angew. Chem. Int. Ed. 2016; 55: 2526
• 7e Cao X, Sha S.-C, Kim B.-S, Morgan C, Huang R, Yang X, Walsh PJ. Chem. Sci. 2016; 7: 611
• 8 Niwa T, Yorimitsu H, Oshima K. Org. Lett. 2007; 9: 2373
• 9 Hlavinka ML, Hagadorn JR. Organometallics 2007; 26: 4105
• 10 Duez S, Steib AK, Manolikakes SM, Knochel P. Angew. Chem. Int. Ed. 2011; 50: 7686

More examples:
• 11a Moo PJ, Wei Z, Lundgren RJ. J. Am. Chem. Soc. 2018; 140: 17418
• 11b Murakami R, Sano K, Iwai T, Taniguchi T, Monde K, Sawamura M. Angew. Chem. Int. Ed. 2018; 57: 9465
• 12a Liu X.-J, You S.-L. Angew. Chem. Int. Ed. 2017; 56: 4002
• 12b Liu X.-J, Zhang W.-Y, Liu Q.-Q, Zheng C, You S.-L. Angew. Chem. Int. Ed. 2020; 59: 2039
• 13 General Procedure for Deprotonation A flame-dried microwave vial equipped with a magnetic stir bar was evacuated and backfilled with N₂ (this process was repeated three times). To the reaction vessel was added a solution of starting material (0.05 mmol, 1 equiv) in anhydrous 1,4-dioxane (0.1 M, 1 mL), followed by the solution of commercially available or fresh-made base (0.075mmol, 1.5 equiv). The reaction was stirred at room temperature for 30 min and then moved to an 85 °C oil bath for 4 h. Immediately after removal from heat, the reaction was quenched with D₂O (0.5 mL) and stirred for 5 min to cool down to room temperature. A solution of internal standard, 1,3,5-trimethoxybenzene in EtOAc, was added before extraction with EtOAc (4 × 1.5 mL), and the combined organic extracts were dried with Na₂SO₄, filtered through a short silica plug, washed with EtOAc (5 mL), and concentrated under reduced pressure by rotary evaporation. Then 0.2 mL of CDCl₃ was added, and the excess solvent was removed under vacuum. Finally, the deuteration and degradation percentage was determined by crude ¹H NMR spectroscopy based on the internal standard.
• 14 General Procedure for Ni-Catalyzed Benzylic Dehydrogenation To a flame-dried microwave vial equipped with a magnetic stir bar was added starting material 2 (0.20 mmol, 1.0 equiv). The reaction vessel was sealed, evacuated, and backfilled with N₂ (this process was repeated three times). To the reaction vessel was added anhydrous 1,4-dioxane (1.5 mL) and commercial Zn(TMP)₂ (0.48 mL, 0.5 M in toluene, 0.3 mmol, 1.5 equiv) at room temperature. Then to this mixture was added 0.5 mL of a stock solution containing NiBr₂(dme) (6.2 mg, 0.02 mmol, 10 mol%), PMe₃ (0.06 mL, 0.06 mmol, 30 mol%), and 2-bromo-5-methylthiophene (27.4 μL, 0.24 mmol, 1.2 equiv) in 1,4-dioxane. The reaction vessel was placed into a pre-heated oil bath. The reaction was monitored by TLC, after completion the reaction mixture was cooled to ambient temperature and quenched by the addition of sat. aq. NH₄Cl (5 mL). The reaction mixture was diluted with EtOAc (5 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 × 5 mL), and the combined organic extracts were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure by rotary evaporation. Yield was determined by crude ¹H NMR spectroscopy based on the internal standard. Compound 2b: ¹H NMR (400 MHz, CDCl₃): δ = 8.61 (d, J = 3.9 Hz, 1 H), 7.68–7.58 (m, 4 H), 7.40–7.36 (m, 3 H), 7.32–7.28 (m, 1 H), 7.20–7.13 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 155.8, 149.8, 136.8, 136.7, 132.9, 128.9, 128.5, 128.1, 127.2, 122.2, 122.2. IR: 3055, 1597, 1583, 1467, 1449, 1427, 1148, 967, 774, 734, 689, 550, 531 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₃H₁₂N⁺: 182.0964; found: 182.0970.
• 15a Bregestovski PD, Chailachjan LM, Dunin-Barkovski VL, Potapova TW, Veprintsev BN. Nature 1972; 236: 453

For a review about zinc-TMP amides, see:
• 15b Nishimura RH. V, Vaz AL. L, Bozzini LA, Murie VE, Clososki GC. Tetrahedron 2019; 75: 464
• 16a McDonald SL, Hendrick CE, Wang Q. Angew. Chem. Int. Ed. 2014; 53: 4667
• 16b McDonald SL, Hendrick CE, Bitting KJ. Wang Q. Org. Synth. 2015; 92: 356
• 17 Mierde HV, Van Der Voort P, De Vos D, Verpoort FA. Eur. J. Org. Chem. 2008; 1625
• 18 Fürstner A, Leitner A, Méndez M, Krause H. J. Am. Chem. Soc. 2002; 124: 13856