PAPER

www.rsc.org/greenchem | Green Chemistry

Bromination of ketones with H2O2HBr on water{

Ajda Podgorsek,a Stojan Stavber,a Marko Zupanab and Jernej Iskra*a
Received 10th May 2007, Accepted 11th July 2007 First published as an Advance Article on the web 7th August 2007 DOI: 10.1039/b707065a Various 1,3-diketones, b-ketoesters, cyclic ketones, aryl alkyl and dialkyl ketones were effectively brominated with an aqueous H2O2HBr system on water at room temperature without the need for a catalyst or organic solvent. The resultant brominated ketones were isolated in yields of 6997% with high selectivity for monobromination vs. dibromination. Reactivity was manipulated by using more diluted aqueous solutions of H2O2 and HBr and the use of an excess of HBr where necessary. Dilution also increases selectivity of ring bromination vs. a-bromination of aryl ketones with an activated phenyl ring. Finally, an aqueous H2O2HBr system was used for a tandem oxidationbromination process and alcohols were transformed into a-bromoketones. This simple but effective on water bromination of ketones with an aqueous H2O2HBr system is characterised by the use of inexpensive reagents, a lower impact on the environment and the absence of organic waste that make it a good alternative to existing bromination methods.

Introduction
a-Bromination of carbonyl compounds is an important reaction in organic synthesis as the resulting a-bromo-ketones are used in the synthesis of variety of molecules, including biologically active compounds.1 A number of various bromination protocols of carbonyl compounds have been developed, including the use of molecular bromine or its complexes in the presence of protic or Lewis acid.2 The use of molecular bromine has several drawbacks arising out of its hazardous nature, difficult handling, low atom efficiency, low selectivity and the formation of HBr as a by-product. Alternative brominating agents, such as tetralkylammonium tribromides3 and N-bromosuccinimide,4 have been increasingly used for a-bromination of carbonyl compounds resulting in easier handling and increased selectivity of the reaction. Nevertheless, these brominating reagents have some limitations including their low atom efficiency, the need for reagent residue removal and that molecular bromine is required for their preparation. To fulfil increasing demands for green chemistry and to achieve higher efficiency and selectivity of the reactions, researchers are focusing on the development of sustainable and ecologically more acceptable bromination protocols based on the oxidation of the bromide salt with a suitable oxidant.5,6 Rothenberg and Clark have made an important study on the best choice of bromine atom (Br2 vs. HBr vs. MBracid) in oxybromination reactions, including large-scale bromination.5b Amongst oxidants, hydrogen peroxide is a valuable oxidant since water is the only effluent of the process (Scheme 1). Moreover, the molar mass and cost of H2O2 are much lower than those of bromine and other brominating
a Jozef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia. E-mail: jernej.iskra@ijs.si; Fax: +386 1 4773 811; Tel: +386 1 4773 631 b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000, Ljubljana, Slovenia { Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/b707065a

agents. Also, bromination in the presence of H2O2 allows complete utilization of bromine atoms and therefore the atom economy is much higher. While oxidative bromination with hydrogen peroxide has been known since 1924,7 it still attracts considerable attention for electrophilic bromination8,9,10 as well as for free-radical processes.11 However, there are only separate examples of oxidative bromination of ketones.8c,10c,10d Recently, b-dicarbonyl compounds were oxybrominated with NH4Br catalyzed by V2O512 and with KBr and concentrated HCl in toluene.13 In contrast, acetophenones could only be converted to a,a-dibromoacetophenones with HBrH2O2 in boiling dioxane.14 While the aforementioned methods use organic solvents, such as dichloromethane, dioxane and toluene, which have serious environmental impacts, and involves a laborious workup procedure, we report how an aqueous H2O2HBr system without added catalyst is an efficient and greener method for a-bromination of 1,3-diketones, b-ketoesters and ketones under mild, organic solvent-free and organic waste-free conditions (Scheme 1). The utilization of this brominating system in aqueous phase resembles the action of haloperoxidases, where bromination takes place at an active site providing that local concentration of reactants is sufficiently high.

Scheme 1

Results
Oxidative bromination is based on the in situ oxidation of HBr into bromine (eqn (1)), which then acts as the brominating agent (eqn (2)). However, bromine also catalyzes the decomposition of H2O2 (eqn (3)), and consequently a higher amount of H2O2 is needed to compensate for this. In our study, to
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minimize this decomposition, we evaluated various modes of reagent addition for the bromination of two model substrates: acetophenone 1a and b-ketoester 2a. H2O2 + 2HBr A Br2 + 2H2O SH + Br2 A SBr + HBr 2 H2 O2 DCCA 2 H2 OzO2
or HBr Br2

(1) (2) (3)

Reactions were performed at room temperature by adding an appropriate amount of 30% aqueous solution of H2O2 and 48% aqueous solution of HBr to a stirred suspension of 1 mmol of ketone 1a or 2a in 0.5 mL of water (Table 1). Results show that the stepwise addition of H2O2 (Method B) produced higher yields of brominated products 1b and 2b than when H2O2 was added in a single addition (Method A). This effect is more pronounced in the case of the less reactive ketone 1a. Improved reaction conditions comprise the stepwise addition of HBr and H2O2 (Method C, Table 1). Therefore, reaction of ketones 1a and 2a with 2 equiv. of H2O2 and 1.5 equiv. of HBr using Method C gave a-brominated products 1b and 2b in 85% and 95% isolated yields, respectively, while the further excess of H2O2 up to 2.5 equiv. did not significantly influence the conversion; even with an excess of HBr no formation of the dibromo ketone was observed. We confirmed the importance of the gradual addition of H2O2 by following its decomposition upon mixing with HBr (Fig. 1). For the system, where the initial concentration of H2O2 and HBr were 8% and 9%, respectively (conditions used for bromination of ketones in our experiments) it was shown that 50% of the maximum quantity of bromine is formed within minutes. However, H2O2 constantly decomposes so that after three hours only 23% of the initial quantity of H2O2 remained. Therefore, the stepwise addition of H2O2 into the
Table 1 The effect of the mode of addition of H2O2 and HBr on bromination of ketones 1a and 2a

Fig. 1 Time dependence of concentration of bromine and hydrogen peroxide in 8% H2O2 and 9% HBr aqueous solution.

Product 1bc

H2O2 : HBr 2:1 2:1 2:1 2.5 : 1 2 : 1.5 2.5 : 1.5 2:1 2:1 2:1 2.5 : 1 2 : 1.5

Methoda A B C C C C A B C C C

Conv.b (%) 60 70 80 80 89 (85) 87 85 88 93 95 100 (95)

2bd

a Method A: H2O2 and HBr were added in one portion. Method B: H2O2 was added gradually (0.5 equiv. per 3 h). Method C: H2O2 and HBr were added gradually (0.5 equiv. per 3 h). b Determined by 1 H NMR spectroscopy; yields in parentheses refer to isolated yields. c Reaction time 24 h. d Reaction time 9 h.

reaction mixture during the reaction would allow good conversion of the ketone using a smaller amount of H2O2. First, we brominated the ketones with either activated methylene or the methyne group with an aqueous H2O2HBr system. The reaction of various 1,3-diketones was achieved by stepwise addition of 1 equiv. of 48% aqueous HBr and 2 equiv. of 30% aqueous H2O2 (Method C, the initial addition of reagents yielded an aqueous reaction mixture of 3% H2O2 and 6% HBr) into a stirred mixture of 1 mmol of ketone in 0.5 mL of water at room temperature (Table 2). Under these conditions bromination of 2-methylcyclohexane-1,3-dione 3a, 5,5-dimethylcyclohexane-1,3-dione 4a and 1,3-diphenylpropane-1,3-dione 5a took place selectively and only monobrominated products were isolated in good yields. Only the reaction with 1-phenylbutane-1,3-dione 6a produced a small amount of the dibrominated product 6c. b-Ketoester 7a was brominated under identical reaction conditions, while for 8a a longer reaction time and 2 equivalents of HBr were necessary. We found the method using an aqueous H2O2HBr system as a brominating agent to be applicable also to the cyclic ketone 9a. The reaction was performed with a 10% excess of HBr without the addition of 0.5 mL of water (addition of first portion of reagents yielded an aqueous reaction mixture of 12% H2O2 and 29% HBr) and the corresponding brominated product 9b was formed in good yield after 24 h. We also tested the method on several less reactive substrates including aryl alkyl and dialkyl ketones to determine its limitations. 4-Methylacetophenone 10a showed good reactivity, with 10% excess of HBr resulting in an 80% conversion. Higher amounts of HBr (1.5 equiv.) lowered the selectivity of the reaction, and also the a,a-dibrominated product 10c was formed in small amounts. The acetophenones 11a and 12a were effectively brominated using 1.5 equiv. of HBr and water as a solvent. Functionalization of the less reactive derivatives 13a and 14a was effective when the amount of HBr was increased to 2 equivalents and without additional water. Finally, we found that dialkylketones 15a17a could also be effectively brominated. Unsymmetrical acyclic ketone heptyl(methyl)ketone 16a preferentially reacted at a more substituted carbon atom yielding 3-bromononan-2-one 16b and 1-bromononan-2-one 16d in a yield of 49% and 21%, respectively.
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Table 2 system

a-Bromination of various ketones in aqueous H2O2HBr

Product

H2O2 : HBr

Time

Yield (%)a

3b R1LCH3, R2LR3LH 4b R1LH, R2LR3LCH3

2:1 2:1

8h 8h

95 (90) 90 (87)

5b R1LPh 6b R1LCH3

2:1 2:1

9h 9h

85 (82) 81 (79)b

7b

2:1

8h

90 (85)

We further upgraded our green approach to bromination by adopting an environmentally friendly work-up procedure. The absence of organic waste and an organic solvent in the reaction enabled simple isolation comprised of filtration for solid products, or the addition of a minimum quantity of nonchlorinated organic solvent, drying agent and filtration of insoluble material for liquid products. On a larger scale experiment, the work-up procedure was simple and required only the separation of the denser bromo ketone layer from the aqueous phase without the need for an organic solvent (see Table 4, 23a). Next, we investigated the effect of water on the regioselectivity of the bromofunctionalization of phenylalkanones 18a 20a (Table 3) and benzocycloalkanones 21a24a (Table 4) with H2O2HBr. Bromination of 18a occurred at the side chain regardless of the addition of water (Table 3). Introduction of a methoxy group on the para position of the phenyl ring altered the regioselectivity of the reaction; 19a preferentially reacted on the aromatic ring (19b : 19d = 1 : 4.6) while an higher amount of water in the reaction mixture promoted only ring bromination and 19d was obtained, when isolated, in yield of 95% . Functionalization of 4-aryl-2-butanone 20a, with the less activated a-position, was selectively performed on the aromatic ring even without added water.
Table 3 The effect of water on the regioselectivity of bromination of phenylalkanones in aqueous H2O2HBr system

8b

2:2

24 h

100 (95)

9b

2 : 1.1c

24 h

73 (69)

Substrate 10b 2 : 1.1 24 h 80 (78) 18a RLH, n = 1 19a RLOCH3, n = 1 11b 12b 13b 14b R1LPh R1LCH2Ph R1LCH3 R1Lcy-Butyl 2 2 2 2 : : : : 1.5 1.5 2c 2c 24 24 24 24 h h h h 94 94 80 80 (88) (86) (78) (76) 20a RLOCH3, n = 2

Mol. equiv. H2O2 : HBr 2:2 2:2 2:1 2:1 2:1 2:1

Added water No Yes No Yes No Yes

Distribution a:b:d

7 : 93(88) : 13 : 87 : : 18 : 82 3 : : 97(95) : : 100 : : 100(96)

a Determined by 1H NMR spectroscopy; yields in parentheses refer to isolated yields after column chromatography.

15b R1LR2LPropyl 16b R1LHeptyl,R2LCH3

2:2 2:1

24 h 24 h

82 (80) 49d

17b
a

2:2

24 h

81 (77)

Method C; yields are based on starting compound; yields in parentheses refer to isolated yields. b 9% (5%) of 2,2-dibromo-1phenyl-butane-1,3-dione 6c was formed. c Without addition of water. d 21% of 1-bromononan-2-one 16d was formed.

Similarly, indanone 21a and tetralone 23a were brominated only on the side chain (Table 4), while their methoxy derivatives 22a and 24a were brominated preferentially on the aromatic ring. Again, the addition of water completely retarded a-bromination and only the ring-brominated products 22d and 24d were formed. NBS showed a similar activation of aromatic bromination in water vs. neat.4c Activation of ring bromination is even stronger in the system HBrH2O2 since dibromination is observed. This bromination protocol could enable tandem oxidation bromination of alcohols to synthesize a-bromo ketones directly from sec-alcohols. HBr alone catalyzes oxidation of
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alcohols with 30% aq. H2O2 but it is difficult to selectively oxidize the alcohol into the ketone without its concomitant bromination (Table 5, entries 14), although it is claimed otherwise.15 Alternatively, using higher amount of reagents (H2O2 and HBr were used in ratio 4 : 1.7) resulted in yields of a-bromoacetophenone 1b of 83% and 93% in 24 and 48 h, respectively (Table 5, entries 5 and 6). Tandem oxidation bromination worked well for the other tested sec-alcohols, 26 and 27 (Table 5, entries 79).
Table 4 The effect of water on the regioselectivity of bromination of benzocycloalkanones in aqueous H2O2HBr system

Substrate 21a RLH, n = 1 22a RLOCH3, n = 1 23a RLH, n = 2 24a RLOCH3, n = 2

Mol. equiv. H2O2 : HBr 2 2 2 2 2 2 2 2 : : : : : : : : 1.1 1.1 1 1 1.1 1.1d 1 1

Added water No Yes No Yes No Yes No Yes

Distributiona a:b:d 3 : 90(87)b : 6 : 88b : 27 : 17 : 49c 24 : : 61c 7 : 93(90) : 5 : 95(88) : 13 : 28 : 49e 20 : : 64e

evaluate the influence of water on the bromination of b-dicarbonyl compounds and ketones in an aqueous H2O2 HBr system. While this process proceeds through an enol, we predicted that water activates the reaction by promoting the formation of the enol form. This was confirmed by 1H NMR studies in the case of the reactive substrate, such as b-ketoester 8a. A 1H NMR experiment in CDCl3 solution indicated that only 5% of 8a is present in the enol form (Fig. 2, spectrum A). However, in an aqueous solution (D2O : DMSO, 3 : 2) the entire amount of the enol form increased to 44% (Fig. 2, spectrum B), while the addition of 0.5 equiv. of HBr did not have a significant influence (Fig. 2, spectrum C). In the case of the less reactive ketone 1a, the concentration of the enol form is too low to be observed by 1H NMR. To evaluate the influence of water on this reaction, bromination of acetophenone 1a was performed in CHCl3 and the results compared to the reaction in the aqueous phase. Oxidative bromination of 1a in chloroform proceeded with only 10% conversion, compared to 89% in water (Scheme 2). Both the aforementioned findings indicate that water plays an important role in the activation of the a-bromination process.

a Determined by 1H NMR spectroscopy; yields in parentheses refer to isolated yields. b 7% (4%) and 6% of a,a-dibromoindanone 21c was formed, respectively. c 7% and 15% of 4,6-dibromo-5-methoxyindanone was formed (dH 7.94 ppm (s, 1H, ArH)), respectively. d Large scale experiment and organic solvent-free isolation. e 10% and 16% of 5,7-dibromo-6-methoxy-tetralone (dH 8.22 ppm (s, 1H, ArH)) was formed, respectively.

Table 5 Oxidation and a-bromination in aqueous H2O2HBr system

Entry 1 2 3 4 5 6 7 8

sec-Alcohol 1-phenyl-ethanol 25

H2O2 : HBr 2 2 2 2 4 4 4 4 : : : : : : : : 0.1b 0.1 0.2 0.2 1.7 1.7 1.5 1.5

Time 0.75 h 30 h 16 h 24 h 24 h 48 h 10 h 10 h

Distributiona sec-alcohol : a : b 17 46 13 : : : : : : : : 73 : 10 54 : 85 : 2 87 : 13 17 : 83 7 : 93 (90) 7 : 93 (88) : 97 (92)

cycloheptanol 26 3-pentanol 27

a Distribution determined by 1H NMR spectroscopy. Isolated yield in parenthesis. b 80 uC.

Discussion
Recent reports have shown that some reactions are accelerated in the presence of water in comparison to those in organic solvent or without solvent.16,17 In this study, we wanted to
This journal is The Royal Society of Chemistry 2007
Fig. 2 1H NMR spectra of ethyl 2-benzyl-3-oxobutanoate 8a in CDCl3 (spectrum A), D2O : DMSO 3 : 2 (spectrum B) and in D2O : DMSO 3 : 2 with addition of 0.5 equiv. of HBr (spectrum C).

Green Chem., 2007, 9, 12121218 | 1215

(0.204 ml, 2.0 mol equiv.) was added gradually (0.051 mL, 0.5 mol equiv.) over a period of 23 h. The mixture was then stirred at room temperature and the progress of the reaction monitored by TLC. At the end of the reaction the work-up procedure follows that of Method A.
Scheme 2

Conclusion
1,3-Diketones, b-ketoesters and ketones were successfully brominated at room temperature in an aqueous H2O2HBr system without a catalyst with high selectivity for monobromination vs. dibromination. Reactivity could be manipulated by addition of water, i.e. using a more diluted aqueous solution of HBr and H2O2. This approach also increases selectivity of ring bromination vs. a-bromination, when the phenyl ring is activated with an electron donating group like a methoxy group. The green features of this protocol include the use of inexpensive reagents and a lower impact on the environment, since bromine is generated in situ from H2O2 and HBr. The use of H2O2 as a green oxidant produces water as the only by-product of the reaction. All these advantageous features make the procedure organic waste-free and organic solvent-free and therefore a good alternative to existing bromination methods. The results presented here also demonstrate that water is not just a good reaction media for a-bromination of carbonyl compounds but also plays an important role in the activation of the ketone group for a-bromination. Furthermore, the H2O2HBr system could be used for tandem oxidationbromination and to synthesize a-bromoketones directly from alcohols.

Method C. Ketone 1a or 2a (1.0 mmol) was suspended in water (0.5 mL) and the flask was covered with aluminium foil. A 48% aqueous solution of HBr (0.057 mL, 0.5 mol equiv.) was added. After stirring the mixture at room temperature for 5 min, 30% aqueous solution of H2O2 (0.051 mL, 0.5 mol equiv.) was added. This procedure (0.5 mol equiv. HBr, stirring for 5 min, 0.5 mol equiv. H2O2) was then repeated every 23 h until an appropriate amount of bromide and oxidant were added. The progress of the reaction was monitored by TLC. After completion of the reaction the workup procedure follows that of Method A. Typical reaction procedure for bromination of ketones in aqueous H2O2HBr system The substrate (1.0 mmol) was suspended in 0.5 mL of water (in case of performing reaction with additional water) and the flask was covered with aluminium foil to shield the reaction mixture from light. A 48% aqueous solution of HBr (0.057 mL, 0.5 mol equiv.) was added. After stirring the mixture at room temperature for 5 min, 30% aqueous solution of H2O2 (0.051 mL, 0.5 mol equiv.) was added. This procedure (0.5 mol equiv. HBr, stirring for 5 min, 0.5 mol equiv H2O2) was then repeated every 23 h until an appropriate amount of bromide and oxidant were added (Tables 1, 2, 3, and 4). The progress of the reaction was monitored by TLC. At the end of the reaction (8 to 24 h), the work-up procedure depended on the aggregate state of the products. Work-up procedure for liquid products The reaction mixture was dissolved in 5 mL of an appropriate mixture of hexane and ethylacetate (20 : 1 or 10 : 1), solid NaHSO3 was added to reduce unreacted Br2 and H2O2 and the solution dried over anhydrous Na2SO4. The insoluble material was filtered off and then the organic solvent was evaporated under reduced pressure. The crude reaction mixture was then analyzed by 1H NMR spectroscopy. Finally, the product was isolated by column chromatography (SiO2, hexaneEtOAc) and its structure determined by comparison with the literature data. Ethyl 2-bromo-3-oxo-3-phenyl-propanoate (2b, Table 1)4d 2a (192 mg, 1.0 mmol) was transformed using reaction conditions: 0.204 mL (2.0 mmol) H2O2, 0.171 mL (1.5 mmol) HBr, 0.5 mL H2O, stirring for 9 h at room temperature. Column chromatography gave 2b (257 mg, 95%) as a pure oily product; dH(300 MHz; CDCl3; Me4Si) 1.25 (3H, t, J 7.1 Hz, CH3), 4.29 (2H, q, J 7.1 Hz, CH2), 5.67 (1H, s, CHBr), 7.477.54 (2H, m, ArH), 7.607.66 (1H, m, ArH), 7.988.01 (2H, m, ArH); dC(76 MHz; CDCl3; Me4Si) 13.6 (CH3), 46.3 (CH2), 63.3 (CHBr), 128.9 (ArC), 129.2 (ArC), 133.3 (ArC), 134.2 (ArC), 165.1 (CO), 188.1 (CO);
This journal is The Royal Society of Chemistry 2007

Experimental
Reaction procedure for bromination of ketones 1a and 2a in aqueous H2O2HBr system Method A. Ketone 1a or 2a (1.0 mmol) was suspended in water (0.5 mL) and the flask was covered with aluminium foil. A 48% aqueous solution of HBr (0.114 mL, 1.0 mol equiv.) and 30% aqueous solution of H2O2 (0.204 mL, 2.0 mol equiv.) were added in one portion and the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After 24 h in the case of 1a and 9 h in the case of 2a, the reaction mixture was dissolved in 5 mL of a mixture of hexane and ethylacetate (20 : 1 or 10 : 1), then solid NaHSO3 was added to reduce unreacted Br2 and H2O2 and the solution was dried over anhydrous Na2SO4. The insoluble material was filtered off and the organic solvent evaporated under reduced pressure. The crude reaction mixture was then analyzed by 1H NMR spectroscopy. Finally, products were isolated by column chromatography and the structure determined by comparison with the literature data. Method B. Ketone 1a or 2a (1.0 mmol) was suspended in water (0.5 mL) and the flask was covered with aluminium foil. Then 48% aqueous solution of HBr (0.114 mL, 1.0 mol equiv.) was added in one portion, while 30% aqueous solution of H2O2
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m/z (EI, 70 eV) 272 (2%, M++2), 270 (2%, M+), 105 (100%), 77 (57%). Work-up procedure for solid products The reaction mixture was filtered off and rinsed with water (10 mL). The crude reaction mixture was then analyzed by 1H NMR spectroscopy. Finally, the products were isolated by column chromatography (SiO2, hexaneEtOAc) or purified by crystallization and their structures determined by comparison with the literature data. 2-bromo-5,5-dimethylcyclohexane-1,3-dione (4b, Table 2)2g 4a (140 mg, 1.0 mmol) was transformed using reaction conditions: 0.204 mL (2.0 mmol) H2O2, 0.114 mL (1.0 mmol) HBr, 0.5 mL H2O, stirring for 8 h at room temperature. Crystallization from EtOH gave 4b (190 mg, 87%) as pure solid product; mp 176177 uC (mp2g 174176 uC); dH(300 MHz; CDCl3; Me4Si) 1.12 (6H, s, CH3), 2.48 (4H, s, CH2); dC(76 MHz; CDCl3; Me4Si) 28.0 (CH3), 32.0 (CH2), 100.6 (CHBr); m/z (EI, 70 eV) 220 (53%, M++2), 218 (53%, M+), 205 (10%), 203 (10%), 164 (100%), 162 (100%), 149 (17%), 147 (17%), 139 (27%), 111 (32%), 83 (73%), 69 (14%), 55 (54%). Large scale bromination Water (5 mL) was placed in a conical flask and 48% aqueous solution of HBr (0.57 mL, 5.0 mmol, 0.5 mol equiv.) was added, followed by the addition of a-tetralone 23a (1.462 g, 10.0 mmol). The flask was covered with aluminium foil, the mixture was stirred at room temperature for 5 min before adding 30% aqueous solution of H2O2 (0.5 mL, 5.0 mmol, 0.5 mol equiv.). This procedure (5.0 mmol of HBr, stirring for 5 min, 5.0 mmol of H2O2) was then repeated every three hours until an appropriate amount of HBr (11.0 mmol, 1.1 mol equiv.) and H2O2 (20.0 mmol, 2.0 mol equiv.) were added. After 24 h, the organic and aqueous phases were separated and organic phase transferred directly to the column. Column chromatography (SiO2, n-hexane : EtOAc 20 : 1) gave 23b (1.981 g, 88%) as pure oily product; 2-bromo-1-tetralone (23b, Table 4);2g dH(300 MHz; CDCl3; Me4Si) 2.412.60 (2H, m, CH2), 2.90 (1H, dt, J 17.2 and 4.5 Hz, CH2), 3.263.37 (1H, m, CH2), 4.73 (1H, t, J 4.5 Hz, CHBr), 7.25 (1H, d, J 7.9 Hz, ArH), 7.34 (1H, t, J 7.9 Hz, ArH), 7.51 (1H, td, J 7.9 and J 1.5 Hz, ArH), 8.09 (1H, dd, J 7.9 and 1.4 Hz, ArH); dC(76 MHz; CDCl3; Me4Si) 26.1 (CH2), 31.9 (CH2), 50.4 (CHBr), 127.1 (ArC), 128.6 (ArC), 128.7 (ArC), 129.9 (Ar C), 134.1 (ArC), 142.9 (ArC), 190.5 (CO); m/z (EI, 70 eV) 226 (18%, M++2), 224 (18%, M+), 144 (33%), 118 (100%), 115 (32%), 90 (42%). Tandem oxidation and bromination of sec-alcohol 1-Phenyl-ethanol 25 (122 mg, 1.0 mmol) was suspended in water (0.5 mL) and the flask was covered with aluminium foil. Then, a 48% aqueous solution of HBr (0.057 mL, 0.5 mol equiv.) was added. After stirring the mixture at room temperature for 5 min, 30% aqueous solution of H2O2 (0.051 mL, 0.5 mol equiv.) was added. This procedure (0.5 mol equiv. of HBr, stirring for 5 min, 0.5 mol equiv. of
This journal is The Royal Society of Chemistry 2007

H2O2) was then repeated every four hours until an appropriate amount of HBr (1.7 mol equiv.) and H2O2 (4.0 mol equiv.) had been added. After 48 h, the crude reaction mixture was isolated following the work-up procedure for liquid products. Column chromatography (SiO2, hexaneEtOAc) gave pure solid product abromoacetophenone 1b (178 mg, 90%); mp 48.8 49.3 uC (mp2g 4951 uC); dH(300 MHz; CDCl3; Me4Si) 4.46 (2H, s, CH2Br), 7.49 (2H, t, J 7.4 Hz, ArH), 7.61 (1H, tt, J 7.4 and 1.5 Hz, ArH), 7.98 (2H, dd, J 7.4 and 1.5 Hz, ArH); dC(76 MHz; CDCl3; Me4Si) 30.9 (CH2Br), 128.8 (ArC), 128.9 (ArC), 133.89 (ArC), 133.92 (ArC), 191.2 (CO); m/z (EI, 70 eV) 200 (7%, M++2), 198 (7%, M+), 105 (100%), 77 (22%), 69 (12%), 57 (19%).

Acknowledgements
This research was financially supported by the Ministry of Higher Education, Science and Technology of the Republic of Slovenia and the Young Researcher program (A.P.) of the Republic of Slovenia. We are grateful to the National NMR Centre at the National Institute of Chemistry in Ljubljana and to the Mass Spectroscopy Centre at the Jozef Stefan Institute of Ljubljana.

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