Preparation of α-Bromoketones Involving the Reaction of Enol Triethyl Borates with N-Bromosuccinimide
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).
Bromination of ketones is an important reaction in synthetic organic chemistry  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  and support conjugation of the carbonyl group.
In the classic procedures for α-bromination of ketones, hazardous molecular bromine is utilized [5–7]. 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)  or dibenzoyl peroxide . Recently, methods of α-bromination using NBS in the presence of SiO2-NaHSO4 , trimethylsilyl trifluoromethanesulfonate (TMS-OTf) , ammonium acetate , and solvent-free reaction conditions have been developed [13–15]. Photochemical α-bromination (λ = 200–600 nm) has also been described .
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.
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.
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.
J. March and M. B. Smith, March’s Advanced Organic Chemistry, John Wiley & Sons, New York, NY, USA, 5th edition, 2001.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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