Tetrahedron Letters 47 (2006) 1097–1099

TetrahedronLetters

Visible light induced ‘on water’ benzylic bromination withN-bromosuccinimide

Ajda Podgorsek,a Stojan Stavber,a Marko Zupanb and Jernej Iskraa,*

a‘Jozef Stefan’ Institute, Jamova 39, 1000 Ljubljana, SloveniabFaculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, Ljubljana, Slovenia

Received 13 October 2005; revised 29 November 2005; accepted 7 December 2005Available online 27 December 2005

Abstract—Benzylic bromination of various 4-substituted toluenes (Me, tert-Bu, COOEt and COMe) was effectively conducted withNBS in pure water and with a 40 W incandescent light-bulb as an initiator of the radical chain process, while electron donatinggroups (OMe and NHAc) directed the reaction to electrophilic aromatic substitution.� 2005 Elsevier Ltd. All rights reserved.

Although water is a unique solvent for biochemical pro-cesses, it is traditionally avoided as a medium for organ-ic reactions.1,2 As demands for ‘greener’ chemistryincrease, attention is being focused on reducing or elim-inating the use of volatile organic compounds (VOCs),especially when they are used as solvents. In this case,the best substitute for VOCs is no solvent at all, but ifa solvent is required then water is preferred (non-toxic,easily available, inexpensive and non-flammable).3 Anobvious problem when dealing with reactions in aque-ous media is the solubility of organic molecules. Never-theless, the group of Sharpless has shown with its ‘onwater’ principle that reactions can be accelerated bywater despite the non-solubility of the reactants.4 Wateris also suitable for radical reactions as it does not inter-fere with the radical chain process due to its strong OHbond.5 The well-knownWohl–Ziegler reaction, free radi-cal benzylic bromination, is traditionally performed withN-bromosuccinimide (NBS) in boiling carbon tetrachlo-ride with the addition of a radical initiator.6 The benzylbromides thus obtained are valuable chemicals and syn-thons. Although CCl4 has optimal characteristics forthis reaction, its ozone-depleting ability and increasingrestrictions impelled us to find a system for free radicalbromination with less of an impact on the environment.

0040-4039/$ - see front matter � 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.tetlet.2005.12.040

Keywords: Water; Halogenation; Benzyl bromination; Radical reac-tions; N-Bromosuccinimide; Aqueous media.* Corresponding author. Tel.: +386 14773631; fax: +386 14773822;e-mail: jernej.iskra@ijs.si

So far, research has focused on providing more benignsolvents (e.g., ionic liquids, ethyl or methyl acetate,and biphasic media)7–9 and different modes of activation(e.g., light, microwaves, zeolites, and grinding).8,10–12

This report shows that benzylic bromination of hydro-phobic substrates can be very effectively conducted byNBS in pure water at ambient temperature and with vis-ible light as an activator, while the solubility of succin-imide in water enables easy isolation of the products.

Initially, we wanted to define the best mode of activationof a radical reaction in water (heat, initiator, and light)and so conducted a series of reactions with 1 mmolof 4-tert-butyltoluene 1 and an equimolar amount ofN-bromosuccinimide which were stirred at 500 rpm in5 mL of water. A blank experiment in the dark afforded25% conversion of 1 to benzyl bromide 2a despite theabsence of radical-chain initiators (Scheme 1, line 1).Thermal activation of the radical process (80 �C) waseffective for radical bromination, but 8% of electrophilicbromination also occurred (Scheme 1, line 2). Next weactivated the radical chain process by adding variousinitiators; these included hydrophobic 2,2 0-azobis(2-methylpropionitrile) (AIBN), dibenzoyl peroxide(DBP), and water soluble 4,4 0-azobis(4-cyanovalericacid) (ACVA) and 2,2 0-azobis(2-methylpropionamidine)dihydrochloride (AMPA).13 Surprisingly, benzyl bro-mination was selectively achieved only with non-solubleAIBN, while DPB and especially both the water solubleinitiators gave a mixture of radical and electrophilicbromination products (lines 3–6). Finally, we tested a

CH3

tBu

NBS

H2O

CH2Br

tBu

CHBr2

tBu

CH3

tBu

Br+

1 2a 2b

25%

76%

77%

73%

43%

38%

78%

86%

83%

8%

5%15%

23%

10%

6%

1%

1%

4%

6%

6%

1) 24 ˚C, 22 h

2) 80 ˚C, 5 h

3) 5% AIBN, 80 ˚C, 1.5 h

4) 5% DBP, 80 ˚C, 2.5 h

5) 5% ACVA, 80 ˚C, 2 h

6) 5% AMPA, 80 ˚C, 2 h

7) ambient light, 24 ˚C, 22 h

8) 40 W bulb, 27 ˚C, 22 h

9) "sunlight", 30 ˚C, 3.5 h

3

+

Scheme 1.

1098 A. Podgorsek et al. / Tetrahedron Letters 47 (2006) 1097–1099

third mode of activation of the radical process—light.Reaction under ambient conditions was selective forthe radical reaction and benzyl bromination was theonly reaction that took place (line 7). When we placedan incandescent 40 W light bulb 15 cm from the flask,the yield of benzyl bromide increased (line 8). Similarresults were obtained with a ‘solar’ lamp (high-pressuremercury lamp, OSRAM HQL 125 W), the reaction rateincreased and bromination occurred in three and a halfhours (line 9, react. temp. = 30 �C).

OCH3

CH2Br

1 2a: 86 (70)b

CH2Br

4

CH2Br

6

CH2R

5a: 89 (70)b

Substrate Time Yield (%)a

22 h

7a (R=H): 71 (66)7b (R=Br): 11 (5)

Br

8 9a: 94 (85)d

OCH3

Br

10 11a: 93 (82)d

22 h

22 h

24 h

3 h

aYields were determined by 1H NMR spectroscopy of the crude mixture aftewith literature data, yields in parentheses refer to yields of compounds isolatebenzyl dibromides in the following isolated yields: 2b (4%), 5b (3%), 15b (3mmol). dAmbient light and 20 mL of water.

5a: 84 (77)c25 h

Scheme 2. Visible light-induced benzylic bromination with NBS in water.

We found that simple visible light (40 W incandescentlight-bulb) induced radical reaction with NBS in waterwas superior in yield to the other modes of activationthat were investigated. Therefore, we used the followingreaction conditions for benzylic bromination of variousmethyl benzene derivatives (2 mmol substrate, 2 mmolNBS and 10 mL water were stirred at 500 rpm and illu-minated with a 40 W incandescent light-bulb, react.temp. = 27 �C). Methyl benzenes have a lower densitythan water and during the reaction form a layer ‘onwater’, but as soon as they are brominated theybecome denser and sink to the bottom of the flask. Asthe residue of NBS is soluble in water and the organicphase is only comprised of product(s), the isolationprocedure is very simple and consists of only phase sepa-ration or filtration. In cases where clear phase separa-tions did not occur, such as in small-scale experiments,liquid–liquid extraction was necessary. Following thisprocedure, toluene 4 was converted selectively to benzylbromide 5a (Scheme 2). Visible light induced bromina-tion of p-xylene 6 afforded mainly a product preferen-tially brominated at only one of the methyl groups(7a/7b = 6.5). This is in contrast to the reaction withbromine in water, where the reactivity was the opposite(7a/7b = 0.2).14 Mesitylene 8, as well as 4-methylanisole10 and 4-methylacetanilide 12 reacted solely at the aro-matic ring, while ethyl 4-methylbenzoate 14 reacted atthe methyl group. Interestingly, 4-methylacetophenone16 was exclusively brominated by a free radical processat the benzyl position leading to benzyl bromide 17a. On

NHAc NHAc

Br12 13a: 100 (93)d23 h

r phase separation and the products were determined by comparison d by column chromatography. bAccompanied by a small amount of %), 17b (6%) and 19b (3%). cExperiment on a larger scale (50

COOEt

COCH3

Substrate Time Yield (%)a

CH2Br

COOEt

15a: 81 (72)b14

CH2Br

COCH3

16 17a: 81 (76)b

23 h

25 h

CH2COCH3 CHBrCOCH3

25 h 19a: 86 (83)b18

O

20

O

Br

21a: 70% (52%)24 h

A. Podgorsek et al. / Tetrahedron Letters 47 (2006) 1097–1099 1099

the contrary, free radical bromination with diffusioncontrolled addition of molecular bromine through a flu-orous bulk membrane yielded only the product of bro-mination at the acetyl group.15 This interestingselectivity of free radical bromination at the benzyl posi-tion over the ketone group stimulated us to investigatephenylacetone 18 and 1-indanone 20, as they both havea benzyl position as well as a reactive carbon a to theketone group. In both cases, the benzyl position wasmore reactive towards bromination than the a-C atomof the carbonyl group.

In conclusion, we have shown that water is a very goodmedium for a ‘greener’ protocol for the Wohl–Zieglerbromination and moreover the initiator and heat aresubstituted by visible light (40 W incandescent lightbulb) activation of the radical chain reaction. A furtheradvantage of this reaction system is the simple isolationprotocol, as the only reaction residue is succinimidewhich is soluble in water, unlike the hydrophobic organicproducts. An interesting feature of this method is theselectivity of benzylic bromination in the presence of aketone functionality. Experiments with aromatics withOMe and NHAc activating groups indicate that theNBS/water system can also be applied for electrophilicbromination on the aromatic ring.

Acknowledgements

This research was supported by the Ministry of HigherEducation, Science and Technology of the Republic ofSlovenia and the Young Researcher Program (A.P.).We are grateful to the staff of the National NMR Centre

at the National Institute of Chemistry in Ljubljana andthe Mass Spectroscopy Centre at the JSI.

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