Synlett 2016; 27(05): 789-793
DOI: 10.1055/s-0035-1560549
© Georg Thieme Verlag Stuttgart · New York

Sodium Bromide-Catalyzed Oxidation of Secondary Benzylic Alcohols Using Aqueous Hydrogen Peroxide as Terminal Oxidant

Hiromi Komagawa
Department of Chemistry, Faculty of Science, Kochi University, 2-5-1 Akebonocho, Kochi 780-8520, Japan   Email: [email protected]
Yukako Maejima
Department of Chemistry, Faculty of Science, Kochi University, 2-5-1 Akebonocho, Kochi 780-8520, Japan   Email: [email protected]
Takashi Nagano*
Department of Chemistry, Faculty of Science, Kochi University, 2-5-1 Akebonocho, Kochi 780-8520, Japan   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 18 September 2015

Accepted after revision: 23 October 2015

Publication Date:
09 December 2015 (online)


A halide salt, hydroperoxide and AcOH catalyst system was applied to the oxidation of secondary benzylic alcohols. This simple system can be applied to a variety of secondary benzylic alcohols and scaled up for gram-scale preparation. High secondary benzylic alcohol selectivity of the present method is demonstrated in hydroxyketone synthesis. Based on several experimental results, a catalytic cycle for our oxidation is proposed.

Supporting Information

  • References and Notes

    • 1a Nagano T, Hayashi T. Org. Lett. 2004; 6: 1297
    • 1b Nagano T, Hayashi T. Org. Lett. 2005; 7: 491
    • 1c Nagano T, Kobayashi S. Chem. Lett. 2008; 37: 1042
    • 1d Nagano T, Kobayashi S. J. Am. Chem. Soc. 2009; 131: 4200
  • 2 Anastas PT, Warner JC. Green Chemistry: Theory and Practice . Oxford University Press; Oxford: 1998
  • 3 Nagano T, Jia Z, Li X, Yan M, Lu G, Chan AS. C, Hayashi T. Chem. Lett. 2010; 39: 929
  • 4 Jia Z, Nagano T, Li X, Chan AS. C. Eur. J. Org. Chem. 2013; 858

    • For selected pioneering works, see:
    • 5a Kirihara M, Asai Y, Ogawa S, Noguchi T, Hatano A, Hirai Y. Synthesis 2007; 3286
    • 5b Uyanik M, Okamoto H, Yasui T, Ishihara K. Science 2010; 328: 1376
    • 5c Uyanik M, Suzuki D, Yasui T, Ishihara K. Angew. Chem. Int. Ed. 2011; 50: 5331
    • 5d Chen L, Shi E, Liu Z, Chen S, Wei W, Li H, Xu K, Wan X. Chem. Eur. J. 2011; 17: 4085
    • 5e Froehr T, Sindlinger CP, Kloeckner U, Finkbeiner P, Nachtsheim BJ. Org. Lett. 2011; 13: 3754

      For recent reviews on oxidative coupling using halide salts/ROOH system, see:
    • 6a Uyanik M, Ishihara K. ChemCatChem 2012; 4: 177
    • 6b Finkbeiner P, Nachtsheim BJ. Synthesis 2013; 45: 979
    • 6c Wu X.-F, Gong J.-L, Qi X. Org. Biomol. Chem. 2014; 12: 5807
    • 6d Liu D, Lei A. Chem. Asian J. 2015; 10: 806
  • 7 Needless to say, halogen should not be incorporated into the product.

    • For selected examples, see:
    • 8a Br2/DABCO: Struss JA, Barnhart WD, Velasco MR, Bronley-DeLancey A. Tetrahedron Lett. 2006; 47: 6635
    • 8b Br2/AcONa: Rosenberger M, Andrews D, DiMaria F, Duggan AJ, Saucy G. Helv. Chim. Acta 1972; 55: 249
    • 8c Cl2/pyridine: Wicha J, Zarecki A. Tetrahedron Lett. 1974; 15: 3059
    • 8d I2/K2CO3: Fusaro MB, Chagnault V, Josse S, Postel D. Tetrahedron 2013; 69: 5880

      For recent reviews on catalytic oxidation of alcohols, see:
    • 9a Noyori R, Aoki M, Sato K. Chem. Commun. 2003; 1977
    • 9b Mallat T, Baiker A. Chem. Rev. 2004; 104: 3037
    • 9c Irie R, Katsuki T. Chem. Record 2004; 4: 96
    • 9d Schultz MJ, Sigman MS. Tetrahedron 2006; 62: 8227
    • 9e Matsumoto T, Ueno M, Wang N, Kobayashi S. Chem. Asian J. 2008; 3: 196
    • 9f Dohi T, Kita Y. Chem. Commun. 2009; 2073
    • 9g Mizuno N, Kamata K, Yamaguchi K. Top. Catal. 2010; 53: 876

      For the combination of stoichiometric amounts of alkali bromide salts and oxidants for alcohol oxidation, see:
    • 10a Koo B.-S, Lee CK, Lee K.-J. Synth. Commun. 2002; 32: 2115
    • 10b Tesevic V, Gladysz JA. J. Org. Chem. 2006; 71: 7433
    • 10c Han M, Jeong KS, Lee JC. Bull. Korean Chem. Soc. 2012; 33: 2405
    • 10d Pääkkönen S, Pursiainen J, Lajunen M. Synth. Commun. 2012; 42: 534

      Catalytic amounts of alkali bromide salts were frequently used in TEMPO-based and related catalyst system. However, in these catalyst systems, redox cycle between Br and [Br+] works for re-oxidation of TEMPO to the corresponding oxoammonium salt which is active species, see:
    • 11a Rychnovsky SD, Vaidyanathan R. J. Org. Chem. 1999; 64: 310
    • 11b Bolm C, Magnus AS, Hildebrand JP. Org. Lett. 2000; 2: 1173
    • 11c Tanaka H, Kawakami Y, Goto K, Kuroboshi M. Tetrahedron Lett. 2001; 42: 445
    • 11d Tanaka H, Kubota J, Itogawa S.-I, Ido T, Kuroboshi M, Shimamura K, Uchida T. Synlett 2003; 951
    • 11e De Luca L, Giacomelli G, Masala S, Porcheddu A. J. Org. Chem. 2003; 68: 4999
    • 11f Wu X.-E, Ma L, Ding M.-X, Gao L.-X. Synlett 2005; 607
    • 11g Shibuya M, Tomizawa M, Suzuki I, Iwabuchi Y. J. Am. Chem. Soc. 2006; 128: 8412
    • 11h Demizu Y, Shiigi H, Mori H, Matsumoto K, Onomura O. Tetrahedron: Asymmetry 2008; 19: 2659
    • 11i Kuroboshi M, Goto K, Tanaka H. Synthesis 2009; 903

      For the combination of stoichiometric amounts of oxidant and catalytic amounts of alkali bromide salts for oxidation of alcohols, see:
    • 12a Morimoto T, Hirano M, Ashiya H, Egashira H, Zhuang X. Bull. Chem. Soc. Jpn. 1987; 61: 4143
    • 12b Hirano M, Morimoto T, Itoh K. Bull. Chem. Soc. Jpn. 1988; 61: 3749
    • 12c Hirano M, Morimoto T. Bull. Chem. Soc. Jpn. 1989; 62: 4069
    • 12d Tohma H, Takizawa S, Maegawa T, Kita Y. Angew. Chem. Int. Ed. 2000; 39: 1306
    • 12e Surendra K, Krishnaveni NS, Rao KR. Can. J. Chem. 2004; 82: 1230
    • 12f Kuhakarn C, Kittigowittana K, Pohmakotr M, Reutrakul V. Tetrahedron 2005; 61: 8995
    • 12g Zolfigol MA, Shirini F, Chehardoli G, Kolvari E. J. Mol. Catal. A: Chem. 2007; 265: 272
    • 12h Hirashima S.-I, Itoh A. Green Chem. 2007; 9: 318
  • 13 Recently, Moriyama and Togo reported KBr-catalyzed oxidation of alcohol with H2O2 in the presence of PhSO3H, see: Moriyama K, Takemura M, Togo H. J. Org. Chem. 2014; 79: 6094

    • For the HBr- or Br2-catalyzed oxidation of alcohol, see:
    • 14a Amati A, Dosualdo G, Zhao L, Bravo A, Fontana F, Minisci F, Bjørsvik H.-R. Org. Process Res. Dev. 1998; 2: 261
    • 14b Sharma VB, Jain SL, Sain B. Synlett 2005; 173
    • 14c Joseph JK, Jain SL, Sain B. Eur. J. Org. Chem. 2006; 590
    • 14d Jain SL, Sharma VB, Sain B. Tetrahedron 2006; 62: 6841
    • 14e Uyanik M, Fukatsu R, Ishihara K. Chem. Asian J. 2010; 5: 456
  • 15 In our previous study on α-acetoxylation H2O2 was not effective; see ref. 3. Use of other organic solvents (EtOAc, MeCN, DMF) instead of AcOH resulted in no reaction.
  • 16 In our previous study, stepwise addition of oxidant was found to be effective; see ref 3. Ishihara and co-workers have also reported stepwise or slow addition of oxidant in their iodide salt catalyzed oxidation, see: Uyanik M, Suzuki D, Watanabe M, Tanaka H, Furukawa K, Ishihara K. Chem. Lett. 2015; 44: 387
  • 17 Reaction of 1g with 0.5 equiv of H2O2 in AcOH for 1 h at 60 °C in the absence of NaBr gave 3 and 4 in 59% and 20% yields, respectively.
  • 18 In Togo’s catalyst system (see ref. 13), cyclic substrate like 1-tetralol does not undergo oxidation.
  • 19 We did not perform the reaction in more than 15-mmol scale.
  • 20 We have tried the oxidation of 1-hexadecanol (aliphatic primary alcohol) under optimized condition. However no oxidation took place, resulting in recovery of the starting material. Oxidation of 3-undecanol (aliphatic secondary alcohol) under optimized conditions proceeded sluggishly to afford the corresponding ketone in 38% yield. Furthermore, oxidation of substrates possessing alkenyl moiety such as 1-phenyl-5-hexen-1-ol and cinnamyl alcohol did not proceed well probably due to the rapid consumption of catalytically active [Br+] species by olefin.
  • 21 Hoover JM, Stahl SS. J. Am. Chem. Soc. 2011; 133: 16901
  • 22 For a detail, see the Supporting Information.
  • 23 Yamaguchi K, Mizuno N. Angew. Chem. Int. Ed. 2002; 41: 4538
  • 24 Formation of Br2 from the reaction of Br with H2O2 in the presence of H+ does not occur quantitatively because H2O2 also works as reducing agent toward Br2 according to the following equation: H2O2 + Br2 = O2 + 2 Br + 2 H+. See: Bray WC. Chem. Rev. 1932; 10: 161
  • 25 The amount of [Br+] was determined by titration using cyclohexene in hexane (three independent experiments). After titration, usual aqueous work up was performed, and major product from the reaction with cyclohexene was found to be trans-1,2-dibromocyclohexane, indicating the formation of Br2 instead of other [Br+] species, see the Supporting Information.
  • 26 Because we observed vigorous evolution of gas immediately after mixing NaBr, AcOH, TEMPO, and H2O2, TEMPO might promote the decomposition of H2O2.
  • 27 Farkas L, Perlmutter B, Schächter O. J. Am. Chem. Soc. 1949; 71: 2829
  • 28 NaOAc-assisted dehydrobromination like E2-elimination is an alternative possibility for step C.
  • 29 General Procedure for NaBr-Catalyzed Oxidation: Under a nitrogen atmosphere, to a solution of substrate alcohol (0.5 mmol) in AcOH (1.0 mL) or AcOH–EtOAc (3:7, 2.0 mL) was added a stock solution of aq NaBr solution (1.94 M, 25 μL) and 30% aq H2O2 (50 μL, 0.5 mmol). After stirring the mixture for 1 h at 60 °C, additional 30% aq H2O2 (50 μL, 0.5 mmol) was added, and stirring was continued for another 1 h. After cooling, the mixture was poured into a sat. aq NaHCO3 solution (ca. 30 mL) with the aid of CH2Cl2, and the resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhyd MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (flash column or preparative TLC) to afford the corresponding ketone. Caution: When the reaction is carried out on a large scale, treatment of the combined organic layers with aq Na2S2O3 solution is recommended to avoid unexpected explosion. 1-Phenylnonan-1-one (2a): Compound 2a was obtained according to the general procedure and purified by preparative TLC (hexane–EtOAc, 20:1) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 7.5 Hz, 2 H), 7.54–7.57 (m, 1 H), 7.45–7.48 (m, 2 H), 2.96 (t, J = 7.5 Hz, 2 H), 1.74 (m, 2 H), 1.27–1.44 (m, 10 H), 0.88 (t, J = 6.9 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 200.6, 137.0, 132.8, 128.5, 128.0, 38.6, 31.8, 29.4, 29.3, 29.1, 24.3, 22.6, 14.1. The NMR data are in agreement with those previously reported in literature (see ref. 30).
  • 30 Vautravers NR, Regent DD, Breit B. Chem. Commun. 2011; 47: 6635