Journal of Chemistry

Journal of Chemistry / 2013 / Article

Research Article | Open Access

Volume 2013 |Article ID 294107 |

Izabella Jastrzebska, "Preparation of α-Bromoketones Involving the Reaction of Enol Triethyl Borates with N-Bromosuccinimide", Journal of Chemistry, vol. 2013, Article ID 294107, 4 pages, 2013.

Preparation of α-Bromoketones Involving the Reaction of Enol Triethyl Borates with N-Bromosuccinimide

Academic Editor: Stojan Stavber
Received04 Dec 2012
Accepted31 Dec 2012
Published04 Mar 2013


The ketones (5α- and 5β-cholestan-3-one and (1S,7aS)-1-tert-butoxy-hexahydro-7a-methyl-1H-inden-5-one) were efficiently α-monobrominated by treatment of the corresponding enol triethyl borates with N-bromosuccinimide (NBS).

1. Introduction

Bromination of ketones is an important reaction in synthetic organic chemistry [1] because bromoketones obtained this way are common intermediates in the synthesis of biologically active compounds. The bromination reaction constitutes the first step of introducing a heteroatom to generate stabilized carbanions [2] and support conjugation of the carbonyl group.

In the classic procedures for α-bromination of ketones, hazardous molecular bromine is utilized [57]. N-bromosuccinimide (NBS) is a safer brominating reagent which can be used in milder reaction conditions. It has been reported that NBS brominates ketones in α position using radical initiators, such as azobisisobutyronitrile (AIBN) [8] or dibenzoyl peroxide [9]. Recently, methods of α-bromination using NBS in the presence of SiO2-NaHSO4 [10], trimethylsilyl trifluoromethanesulfonate (TMS-OTf) [11], ammonium acetate [12], and solvent-free reaction conditions have been developed [1315]. Photochemical α-bromination (λ = 200–600 nm) has also been described [16].

2. Results and Discussion

Here, I report a new procedure for the preparation of α-bromoketones involving the reaction of enol triethyl borate with NBS (Scheme 1). The potassium enolate was prepared by treatment of the ketone with potassium hexamethyldisilazide (KHMDS). Potassium enoxytriethylborate was easily obtained by reaction of the corresponding potassium enolate with triethylborane. The generation of potassium enoxytriethylborate required a low temperature (−78°C), while the reaction of potassium enoxytriethylborate with NBS occurred at room temperature. Anhydrous reaction conditions (argon atmosphere, anhydrous solvent, and reagents) are necessary.


As a model for examination of the α-bromination process, 5α- and 5β-cholestan-3-one and the indenone system [1, (1S,7aS)-1-tert-butoxy-hexahydro-7a-methyl-1H-inden-5(6H)-one], and some others were chosen.

The α-bromination method described in Scheme 1 showed high regioselectivity (Table 1). In addition, the yields of α-brominated compounds were superior (87% and 90%, respectively, for 5α- (2) and 5β-cholestan-3-one (3)). Furthermore, the tert-butoxy protecting group tolerated the described reaction conditions. Some examples (cyclopentanone and 2-methylcyclohexanone) gave a mixture of products. A likely mechanism of compound 1 reaction is outlined in Scheme 2. A separate experiment of cholestanone (3) with KHMDS and NBS yielded a mixture of various products.

EntryStarting materialProductYielddr %

4294107.fig.004a294107.fig.004b90%d90 : 10
5294107.fig.005a294107.fig.005b85%e50 : 50
6294107.fig.006a294107.fig.006b90%f75 : 25
8294107.fig.008Mixture of products

aThe selected spectral data of (1S,6R,7aS)-tert-butoxyheksahydro-6-bromo-7a-methyl-1H-inden-5-one (1A): mp (CH2Cl2/hexane) 88–91°C; IR (CHCl3) ν max(cm−1) 1725, 1193; 1H NMR (400 MHz, CDCl3): δ H 4.81 (1H, dd, ,  Hz, CH–Br), 3.52 (1H, dd, ,  Hz, CH–OBut), 1.15 (9H, s, OC(CH 3)3), 1.06 (3H, s, CH 3); 13C NMR (ppm): 201.3 (C), 78.6 (CH), 72.8 (C), 54.1 (C), 48.5 (CH2), 45.1 (CH), 45.0 (C), 41.7 (CH2), 32.1 (CH2), 28.6 (CH3 × 3), 25.4 (CH2), 10.9 (CH3); HRMS: calculated 325.0779, found 325.0779 for C14H23O2BrNa.
bData of 2α-bromocholestan-3-one (2A) have been found to be identical with those reported [3].
cThe selected spectral data of 4β-bromocoprostan-3-one (3A): mp (CH2Cl2/hexane) 93–95°C; IR (CHCl3) ν max (cm−1) 1726, 1468, 555; 1H NMR (400 MHz, CDCl3): δ H 4.98 (1H, d,  Hz, CH–Br), 2.95 (1H, m), 2.50 (1H, d,  Hz, CH 3), 1.08 (3H, s, CH 3), 0.90 (3H, d,  Hz, CH 3), 0.87 (3H, d,  Hz, CH 3), 0.69 (3H, s, CH 3); 13C NMR (ppm): 202.5 (C), 60.05 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 42.7 (C), 41.9 (CH), 39.9 (CH2), 39.5 (CH2), 38.3 (C), 36.7 (CH2), 36.5 (CH2), 36.1 (CH2), 35.7 (CH), 35.6 (CH), 28.2 (CH2), 27.9 (CH), 25.6 (CH2), 25.1 (CH2), 24.1 (CH2), 23.8 (CH2), 23.2 (CH3), 22.8 (CH3), 22.5 (CH3), 21.2 (CH2), 18.6 (CH3), 12.0 (CH3); HRMS: calculated 487.2551, found 487.2545 for C27H45OBrNa.
dThe selected spectral data of 4β-bromosmilagenin (4A): mp (CH2Cl2/hexane) 135-136°C; IR (CHCl3) ν max (cm−1) 1727, 1179; 1H NMR (400 MHz, CDCl3): 4.96 (1H, d,  Hz, CH–Br), 4.41 (1H, m, H16), 3.48 (1H, m, H26), 3.37 (1H, m, H26), 1.10 (1H, s, CH 3), 0.97 (1H, d,  Hz, CH 3), 0.80 (1H, s, CH 3), 0.79 (1H, d,  Hz, CH 3); 13C NMR (ppm): 202.2 (C), 109.2 (C), 80.7 (CH), 66.9 (CH2), 62.2 (CH), 59.8 (CH), 56.2 (CH), 54.1 (CH), 42.0 (CH), 42.0 (CH), 40,7 (C), 40.0 (CH2), 38.3 (C), 36.7 (CH2), 36.5 (CH2), 35.3 (CH), 31.7 (CH2), 31.4 (CH2), 30.2 (CH), 28.8 (CH2), 25.5 (CH2), 25.3 (CH2), 23.2 (CH3), 21.1 (CH2), 17.1 (CH3), 16.4 (CH3), 14.4 (CH3); HRMS: calculated 515.2137, found 515.2135 for C27H41O3BrNa.
eSpectral data identical with those from [4].
fSpectral data identical with those from Spectra Database for Organic Compounds (SDBS), number 4818. Mixture of bromides 6A in ratio 25 : 75, respectively, α-bromo : β-bromo; HRMS: calculated 253.0204, found 253.0201 for C10H15OBrNa.

The typical experimental procedure was as follows: to KHMDS (1.1 equivalent of 0.5 M solution in toluene) under argon at room temperature a solution of ketone (1 equivalent) in dry THF was added. The reaction mixture became turbid. After 0.5 hour, the reaction mixture was cooled to −78°C, and BEt3 (1.1 equivalent of 1.0 M solution in THF) was added. The reaction mixture then turned transparent. After 15 minutes, NBS (2 equivalents) in dry THF was added. The reaction mixture was allowed to reach room temperature, and stirring under argon was continued overnight. The organic solvent was evaporated. The residue was washed by 3N HCl solution and then extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried over MgSO4, and evaporated.

3. Conclusions

In conclusion, I have developed a mild and efficient method for the α-monobromination of ketones by treatment of their enol triethylborates with NBS. The simple procedure, high yields, and regioselectivity of the products are the advantages of the described method.


The author would like to thank Prof. D. Covey from the Washington University School of Medicine in S. Louis, MO, USA, for lending one of the testing compound [(1S,7aS)-1-tert-butoxy-hexahydro-7a-methyl-1H-inden-5-one], Prof. J.W. Morzycki from the University of Białystok, Poland, for scientific support. The author also thanks Dr. L. Siergiejczyk for help in NMR spectra interpretation. Financial support from the University of Białystok within the project BST-124 is gratefully acknowledged.


  1. J. March and M. B. Smith, March’s Advanced Organic Chemistry, John Wiley & Sons, New York, NY, USA, 5th edition, 2001.
  2. D. P. Curran, E. Bosch, J. Kaplan, and M. Newcomb, “Rate constants for halogen atom transfer from representative α-halocarbonyl compounds to primary alkyl radicals,” Journal of Organic Chemistry, vol. 54, no. 8, pp. 1826–1831, 1989. View at: Publisher Site | Google Scholar
  3. H. Chodunska, M. Budesinsky, R. Sidova, M. Sisa, A. Kasal, and L. Kohout, “Simple NMR determination of 5α/5β configuration of 3-oxosteroids,” Collection of Czechoslovak Chemical Communications, vol. 66, no. 10, pp. 1529–1544, 2001. View at: Publisher Site | Google Scholar
  4. D. H. Fitzgerald, K. M. Muirhead, and N. P. Botting, “A comparative study on the inhibition of human and bacterial kynureninase by novel bicyclic kynurenine analogues,” Bioorganic & Medicinal Chemistry, vol. 9, no. 4, pp. 983–989, 2001. View at: Google Scholar
  5. E. W. Garbisch Jr., “Cycloalk-2-enones and α,β,α′,β′-cycloalkadienones. A. Synthesis. B. On the direction of bromination of 2-substituted cycloalkanones and their ketals,” Journal of Organic Chemistry, vol. 30, no. 7, pp. 2109–2120, 1965. View at: Google Scholar
  6. A. McKillop and D. Bromlet, “Thallium in organic synthesis. XXV. Electrophilic aromatic bromination using bromine and thallium(III) acetate,” Journal of Organic Chemistry, vol. 37, no. 1, pp. 88–92, 1972. View at: Publisher Site | Google Scholar
  7. D. Y. Chi and H. Y. Choi, “Nonselective bromination-selective debromination strategy:  selective bromination of unsymmetrical ketones on singly activated carbon against doubly activated carbon,” Organic Letters, vol. 5, no. 4, pp. 411–414, 2003. View at: Publisher Site | Google Scholar
  8. A. C. Cope, E. P. Burrows, M. E. Derieg, S. Moon, and W. D. Wirth, “Rimocidin. I. Carbon skeleton, partial structure, and absolute configuration at C-27,” Journal of the American Chemical Society, vol. 87, no. 23, pp. 5452–5460, 1965. View at: Google Scholar
  9. H. Schmid and P. Karrer, “Verbesserung und Erweiterung der Bromierungsmethode mit Brom-succinimid,” Helvetica Chimica Acta, vol. 29, no. 3, pp. 573–581, 1946. View at: Publisher Site | Google Scholar
  10. B. Das, K. Venkateswarlu, G. Mahender, and I. Mahender, “A simple and efficient method for α-bromination of carbonyl compounds using N-bromosuccinimide in the presence of silica-supported sodium hydrogen sulfate as a heterogeneous catalyst,” Tetrahedron Letters, vol. 46, no. 17, pp. 3041–3044, 2005. View at: Publisher Site | Google Scholar
  11. S. K. Guha, B. Wu, B. S. Kim, W. Baik, and S. Koo, “TMS·OTf-Catalyzed α-bromination of carbonyl compounds by N-bromosuccinimide,” Tetrahedron Letters, vol. 47, no. 3, pp. 291–293, 2006. View at: Publisher Site | Google Scholar
  12. K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, and T. Horaguchi, “A mild and efficient procedure for α-bromination of ketones using N-bromosuccinimide catalysed by ammonium acetate,” Chemical Communications, vol. 10, no. 4, pp. 470–471, 2004. View at: Google Scholar
  13. I. Pravst, M. Zupan, and S. Stavber, “Halogenation of ketones with N-halosuccinimides under solvent-free reaction conditions,” Tetrahedron, vol. 64, no. 22, pp. 5191–5199, 2008. View at: Publisher Site | Google Scholar
  14. A. Podgoršek, S. Stavber, M. Zupan, and J. Iskra, “Environmentally benign electrophilic and radical bromination “on water”: H2O2-HBr system versus N-bromosuccinimide,” Tetrahedron, vol. 65, no. 22, pp. 4429–4439, 2009. View at: Publisher Site | Google Scholar
  15. I. Pravst, M. Zupan, and S. Stavber, “Directed regioselectivity of bromination of ketones with NBS: solvent-free conditions versus water,” Tetrahedron Letters, vol. 47, no. 27, pp. 4707–4710, 2006. View at: Publisher Site | Google Scholar
  16. S. S. Arbuj, S. B. Waghmode, and A. V. Ramaswamy, “Photochemical α-bromination of ketones using N-bromosuccinimide: a simple, mild and efficient method,” Tetrahedron Letters, vol. 48, no. 8, pp. 1411–1415, 2007. View at: Publisher Site | Google Scholar

Copyright © 2013 Izabella Jastrzebska. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Related articles

No related content is available yet for this article.
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

No related content is available yet for this article.

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.