Synlett 2021; 32(16): 1652-1656
DOI: 10.1055/s-0040-1720446
cluster
Modern Nickel-Catalyzed Reactions

Role of Benzylic Deprotonation in Nickel-Catalyzed Benzylic Dehydrogenation

,
Rachel L. Cantrell
,
Timothy R. Newhouse
We are grateful for financial support from Yale University, Amgen, Genentech, Boehringer-Ingelheim Pharmaceuticals, the Sloan Foundation, the National Science Foundation (NSF), an Anderson Postdoctoral Fellowship (P.Z.) and an National Institutes of Health (NIH) training grant (R.L.C.).


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.

Supporting Information

Primary Data



Publication History

Received: 13 May 2021

Accepted: 09 June 2021

Article published online:
15 July 2021

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  • 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