Brønsted Acid Mediated Direct α-Hydroxylation of Cyclic α-Branched Ketones

Abstract

We report a Brønsted acid mediated direct α-hydroxylation of cyclic α-branched ketones via a tandem aminoxylation/N–O bond-cleavage process. Nitrosobenzene is used as the oxidant and subsequently promotes the liberation of the free alcohol. The desired products could be isolated in moderate to good yields at a maximum tested scale of 10 mmol. Derivatizations of the obtained products are presented.

Key words

α-branched ketones - α-hydroxylation - aminoxylation - α-functionalization of ketones - enolization - Brønsted acid mediated

• References and Notes

• 1a Edwards MG. Kenworthy MN. Kitson RR. A. Scott MS. Taylor RJ. K. Angew. Chem. Int. Ed. 2008; 47: 1935
• 1b Palomo C. Oiarbide M. Garcia JM. Chem. Soc. Rev. 2012; 41: 4150
• 1c Taj RA. Green JR. J. Org. Chem. 2010; 75: 8258
• 2 Smith AM. R. Hii KK. Chem. Rev. 2011; 111: 1637

For commonly applied methods, see:
• 3a Davis FA. Chen BC. Chem. Rev. 1992; 92: 919
• 3b Rubottom GM. Vazquez MA. Pelegrina DR. Tetrahedron Lett. 1974; 15: 4319

For selected publications regarding the direct α-hydroxylation of α-branched ketones, see:
• 4a Schulz M. Kluge R. Sivilai L. Kamm B. Tetrahedron 1990; 46: 2371
• 4b Ishikawa T. Hino K. Yoneda T. Murota M. Yamaguchi K. Watanabe T. J. Org. Chem. 1999; 64: 5691
• 4c Chuang GJ. Wang W. Lee E. Ritter T. J. Am. Chem. Soc. 2011; 133: 1760
• 4d Liang Y.-F. Jiao N. Angew. Chem. Int. Ed. 2014; 53: 548
• 4e Liang Y.-F. Wu K. Song S. Li X. Huang X. Jiao N. Org. Lett. 2015; 17: 876
• 4f Chen T. Peng R. Hu W. Zhang F.-M. Org. Biomol. Chem. 2016; 14: 9859
• 4g Tsang AS. K. Kapat A. Schoenebeck F. J. Am. Chem. Soc. 2016; 138: 518
• 4h Sim S.-BD. Wang M. Zhao Y. ACS Catal. 2015; 5: 3609

For selected reviews on organocatalytic aminoxylations, see:
• 5a Merino P. Tejero T. Delso I. Matute R. Synthesis 2016; 48: 653
• 5b Vilaivan T. Bhanthumnavin W. Molecules 2010; 15: 917
• 5c Janey JM. Angew. Chem. Int. Ed. 2005; 44: 4292
• 6a Ramachary DB. Barbas CF. Org. Lett. 2005; 7: 1577
• 6b Lu M. Zhu D. Lu Y. Zeng X. Tan B. Xu Z. Zhong G. J. Am. Chem. Soc. 2009; 131: 4562

For publications regarding enol catalysis by our group, see:
• 7a Felker I. Pupo G. Kraft P. List B. Angew. Chem. Int. Ed. 2015; 54: 1960
• 7b Shevchenko GA. Pupo G. List B. Synlett 2015; 26: 1413
• 7c Pupo G. Properzi R. List B. Angew. Chem. Int. Ed. 2016; 55: 6099
• 7d Shevchenko GA. Oppelaar B. List B. Angew. Chem. Int Ed. 2018; 57: 10756

For independent contributions from other groups, see:
• 7e Pousse G. Le Cavalier F. Humphreys L. Rouden J. Blanchet J. Org. Lett. 2010; 12: 3582
• 7f Burns AR. Madec AG. E. Low DW. Roy ID. Lam HW. Chem. Sci. 2015; 6: 3550
• 7g Yang X. Toste FD. J. Am. Chem. Soc. 2015; 137: 3205
• 7h Yang X. Toste FD. Chem. Sci. 2016; 7: 2653
• 7i Spanka M. Schneider C. Org. Lett. 2018; 20: 4769

For an account on heterodimeric activation in organocatalysis, see:
• 7j Monaco MR. Pupo G. List B. Synlett 2016; 27: 1027
• 8 Bestmann HJ. Angew. Chem., Int. Ed. Engl. 1977; 16: 349
• 9a Rocca JR. Tumlinson JH. Glancey BM. Lofgren CS. Tetrahedron Lett. 1983; 24: 1889
• 9b Rubottom GM. Juve HD. J. Org. Chem. 1983; 48: 422
• 9c Yao S. Johannsen M. Hazell RG. Jørgensen KA. J. Org. Chem. 1998; 63: 118
• 9d Eidman KF. MacDougall BS. J. Org. Chem. 2006; 71: 9513
• 10 Exemplary Procedure In a GC vial 2-phenylcyclohexanone (1a, 43.6 mg, 0.25 mmol, 1.0 equiv) was dissolved in a solution of trichloroacetic acid (0.75 mmol, 3.0 equiv) in dry PhMe (2.5 mL) and nitrosobenzene (0.625 mmol, 2.5 equiv) was added. The vial was closed with a screw cap, and the resulting mixture was stirred at r.t. for 16 h. The crude reaction mixture was directly purified by flash column chromatography (SiO₂, hexanes/EtOAc = 100:0 then 10:1) to give 2-hydroxy-2-phenylcyclohexan-1-one (2a) as an orange oil (28.7 mg, 60%). ¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.27 (m, 2 H), 7.35–7.29 (m, 3 H), 5.04 (s_br, 1 H), 3.06–2.99 (m, 1 H), 2.59–2.51 (m, 1 H), 2.48–2.39 (m, 1 H), 2.11–2.02 (m, 1 H), 1.91–1.83 (m, 2 H), 1.82–1.68 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 212.9, 139.8, 129.3, 128.6, 126.5, 80.3, 39.0, 38.9, 28.5, 23.2. HRMS (ESI+): m/z calcd for C₁₂H₁₄O₂Na [M + Na]⁺: 213.0886; found: 213.0885.