Photochemical α-bromination of ketones using N-bromosuccinimide: a simple, mild and efficient method

Article abstract of DOI:10.1016/j.tetlet.2006.12.101

Aromatic and aliphatic carbonyl compounds undergo facile bromination with N-bromosuccinimide under UV-vis irradiation to give the corresponding α-brominated ketones in good yields, at low temperatures (30 °C), without any catalyst, catalyst support or radical initiator and within a short time.

Full text of DOI:10.1016/j.tetlet.2006.12.101

Tetrahedron Letters 48 (2007) 1411–1415
Photochemical a-bromination of ketones using
N-bromosuccinimide: a simple, mild and efficient method
Sudhir S. Arbuj, Suresh B. Waghmode* and A. V. Ramaswamy*
Department of Chemistry, University of Pune, Pune 411 007, India
Received 18 August 2006; revised 14 December 2006; accepted 18 December 2006
Available online 20 December 2006
Abstract—Aromatic and aliphatic carbonyl compounds undergo facile bromination with N-bromosuccinimide under UV–vis irra-
diation to give the corresponding a-brominated ketones in good yields, at low temperatures (30 °C), without any catalyst, catalyst
support or radical initiator and within a short time.
Ó 2007 Elsevier Ltd. All rights reserved.
The a-bromination of carbonyl compounds is an impor-
tant transformation in synthetic organic chemistry.1 a-
Bromination of the side chain of aromatic ketones has
attracted attention because the resulting bromoketones
are intermediates for the synthesis of a variety of biolog-
ically active compounds.2 a-Bromination is the first step
of introducing a heteroatom so as to provide additional
conjugation to the carbonyl group, and for generating
stabilized carbon radicals or carbanions. Various a-bro-
minated carbonyl compounds have been synthesized
using bromine in the presence of protic and Lewis
acids,3 cupric bromide,4 dioxane dibromide,5 tetra-butyl-
ammonium tribromide6 and others. The environmen-
tally hazardous bromine has given way to N-bromosuc-
cinimide (NBS) as a user friendly reagent and the
conditions for bromination have become milder with
the advent of suitable catalysts and co-catalysts. The
byproduct, succinimide, can be recycled. It has been re-
ported that a-bromination of carbonyl compounds can
be carried out by NBS, with radical initiators such as
azobisisobutyronitrile7 (AIBN) and dibenzoyl peroxide8
(BPO). Das et al.9 and Tanemura et al.10 reported that
a-bromination using NBS over silica-supported sodium
hydrogen sulfate and ammonium acetate leads to good
yields of the corresponding ketones. However, this
reaction requires high temperatures (ꢀ80 °C) and the
reaction is slower for the formation of monobromo-
acyclic ketones. Adhikari and Samant11 reported sono-
chemical a-bromination of acetophenones catalyzed by
p-toluenesulfonic acid using NBS. Recently, Koo and
co-workers12 reported the a-bromination of carbonyl
compounds catalyzed by trimethylsilyl trifluoro-
methanesulfonate in the presence of NBS. Here, we
report the photochemical a-bromination of a number
of ketones using NBS at room temperature without
the use of any catalyst (Scheme 1). Optimization of the
reaction conditions for the photochemical a-bromina-
tion of carbonyl compounds with NBS was investigated
using cyclohexanone as the model substrate (Scheme 2).
The effect of different solvents on the a-bromination of
cyclohexanone was studied and the results are summa-
rized in Table 1. The reaction was fast without any cat-
alyst with 86% conversion and a selectivity of 91% for
monobromocyclohexanone and 9% for dibromocyclo-
hexanone in diethyl ether (Table 1; entry 1). The conver-
sion of cyclohexanone in different solvents was in
the order: Et2O > CH3CN > CCl4 ꢀ THF > CH2Cl2 ꢀ
DMSO > DMF, whereas the selectivity towards a-
bromocyclohexanone was in the following order:
DMF ꢀ DMSO > CCl4 > CH3CN > Et2O > CH2Cl2 >
THF (Table 1). Among the solvents used, Et2O and
THF appeared to be the most suitable in terms of the
time required for maximum conversion of the cyclohex-
anone. In all other solvents, the reaction proceeded
O
O
R1
R1
NBS, hν, 30 °C
R
R
Et2O, 0.5 to 10 min
*
Corresponding authors. Tel.: +91 9423219557; fax: +91 2025691728
(S.B.W.); e-mail addresses: suresh@chem.unipune.ernet.in; avram@
chem.unipune.ernet.in
Br
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.101

1412
S. S. Arbuj et al. / Tetrahedron Letters 48 (2007) 1411–1415
O
O
O
Br
Br
Br
NBS, hν, 30 °C
solvent, 0.5 to 17 min
2a
2
2b
Scheme 2.
Table 1. Effect of solvent on the bromination of cyclohexanone using
NBS in the presence of UV–vis irradiation
95
90
85
80
75
70
Entry Solvent Timea Conversion
(min) wt %
Selectivity %
Monobromo- Dibromo-
1
2
3
4
5
6
7
Et2O
CH3CN 17.0
CCl4
THF
CH2Cl2 13.5
0.5
86
78
74
73
64
64
61
91
95
97
77
90
98
98
9
5
3
23
10
2
10.7
0.7
DMSO
DMF
7.2
10.5
2
Reaction conditions: cyclohexanone (1 mmol), NBS (1.05 mmol) and
the solvent (5 ml) were stirred under a nitrogen atmosphere and UV–
vis irradiation at 30 2 °C. NBS was added in a single portion.
a Time taken for maximum conversion of cyclohexanone under the
reaction conditions.
65
15
10
5
5
10
15
20
25
30
35
40
Temperature in °C
rather slowly with the time required for maximum con-
version ranging from 7 to 17 min. In general, the selec-
tivity for the monobromo product was higher at lower
conversions of the cyclohexanone.
Figure 1. Influence of temperature on the bromination of cyclohex-
anone and selectivity (%). The reaction between cyclohexanone and
NBS in diethyl ether as a solvent was carried out at 30 2 °C under a
nitrogen atmosphere and UV–vis irradiation. (j) % Conversion; ( ) %
selectivity for a-bromocyclohexanone;
(
)
%
selectivity for
dibromocyclohexanone.
The a-bromination of cyclohexanone with NBS was
studied at different temperatures in diethyl ether and
the results are shown in Figure 1. The reaction was com-
plete within minutes with a-monobrominated ketone 2a
as the major product and dibrominated ketone 2b as the
minor product. Even at 10 °C, a conversion of 67% and
a high selectivity (96%) for 2a was observed. With an
increase in temperature, the conversion increased but the
selectivity for 2a decreased due to bromination of 2a
further to give 2b. At 35 °C, 89% of cyclohexanone was
converted to give 88% of 2a and 12% of 2b, respectively.
100
90
80
70
60
50
40
30
20
10
0
This reaction using different reagent to substrate mole
ratios was studied in Et2O and the results are shown
in Figure 2. From 0.25:1 to 0.75:1 (reagent/substrate)
ratios, the conversion increased appreciably while the
selectivity for 2a was 100%. Thereafter, no significant
increase in conversion was observed (86–92%). How-
ever, the selectivity for 2a decreased considerably from
91% to 59%, accompanied by an increase in the dibromi-
nated product along with other undesired side products.
It was found that for bromination in Et2O, a mole ratio
of 1.05:1 at room temperature (30 2 °C) gave the best
yield of 2a. Under these conditions the reaction was also
carried out by adding the NBS in four portions, but
there was no difference in conversion or selectivity.
0.25:1 0.50:1 0.75:1 1.05:1 1.25:1 1.50:1 1.75:1 2.0:1
Reagent to substrate ratio
--
Figure 2. Reagent to substrate ratio versus conversion and selectivity
(%) for the reaction between cyclohexanone and NBS in diethyl ether
as solvent at 30 2 °C under a nitrogen atmosphere and UV–vis
irradiation. (j) % conversion; ( ) % selectivity for a-bromocyclo-
hexanone; ( ) % selectivity for dibromocyclohexanone; ( ) % selec-
tivity for other by-products.
Photochemical a-bromination with NBS was carried out
with a number of cyclic as well as acyclic ketones. These
substrates were converted at 30 2 °C to the corresponding
a-brominated products in excellent yields within a few
minutes. The results of these studies are summarized in
Table 2. These reactions were carried out with different

S. S. Arbuj et al. / Tetrahedron Letters 48 (2007) 1411–1415
1413
Table 2. a-Bromination of cyclic and acyclic ketones with NBS in the presence of UV–vis irradiation
Entry
Substrate
Product
Time (min)
Conversion,
wt %
Selectivitya
(a)
%
(a)
(a0)
(a0)
73b
O
O
1
0.5
84
62
94b
91
Br
O
O
2
3
0.5
—
90
—
Br
O
O
Br
2
0.5
76
—
99
48b
100
—
97
97b
O
O
Br
4
2
0.5
84
43b
98
—
100
100b
89
—
O
O
Br
5
6
7
4
1.5
71
97
—
100
78
—
35b
100b
O
O
Br
5
1.5
63
23b
100
—
100
100b
93
—
Br
Br
O
O
Br
4
67
98
100
85
H3CO
H3CO
O
O
Br
8
9
10
15
75
—
—
100
100
—
—
OH
OH
O
O
Br
5
HO
Cl
OH
HO
Cl
OH
O
O
Br
10
11
5
5
41
67
—
100
100
—
94
OH
OH
O
O
Br
74
H3CO
H3CO
(continued on next page)

1414
S. S. Arbuj et al. / Tetrahedron Letters 48 (2007) 1411–1415
Table 2 (continued)
Entry
Substrate
Product
Time (min)
Conversion,
wt %
Selectivitya %
(a)
(a0)
(a)
(a0)
O
O
12
13
14
5
2
3
65
93
98
90
92
61
63
Br
O
O
93
76
70
Br
O
O
O
100
—
72
96
84
Br
O
O
O
O
O
15
16
3
3
92
98
—
—
O
O
Br
O
O
—
Br
Reaction conditions: substrate (1 mmol), NBS (a) 1.05 mmol added in four portions and (a0) 1.5 mmol added in six portions, temperature 30 2 °C,
Et2O 5 ml. The reaction mixture was stirred under a nitrogen atmosphere and UV–vis irradiation.
a Selectivity of the corresponding a-bromoketones.
b NBS was added in one portion.
equivalents of NBS (1.05 and 1.5 mmol). It was ob-
served that the conversion of the ketones increased with
additional moles of NBS. However, the stepwise addi-
tion of NBS to the reaction mixture generally led to a
higher conversion of the substrate and a higher selectiv-
ity for the monobrominated product. Usually portion-
wise addition required a longer reaction time than for
a single addition (entries 3–6). This may be due to con-
trolled formation and release of Br free radicals that re-
act with the substrate molecules at a steady rate, thereby
increasing the conversion of the substrate as well as the
selectivity to monobromoketones and eliminating un-
wanted side products. The bromination of cyclopenta-
none gave 62% conversion with 90% selectivity (entry
2). The conversion decreased with the ring size of the
cyclic ketones (entries 1 and 2); however, there was no
change in selectivity. Cyclododecanone (entry 3) showed
76% and 99% conversion with 100% and 97% selectivity
for a-bromocyclododecanone using 1.05 and 1.5 equiv
of NBS, respectively. For tetralone and acetophenone,
the addition of NBS in a single portion (entries 4 and
5) gave conversions of 43% and 35%, respectively, with
100% selectivity for the respective monobromoketones.
However, the conversion of tetralone and acetophenone
increased to 84% and 71% with 100% selectivity for
monobromo products by the addition of NBS in four
portions. Aromatic ketones gave only monobrominated
products (entries 5–11). As compared to para-substi-
tuted acetophenones, ortho-substituted acetophenones
showed lower conversions to the respective a-mono-
bromoketones. Unsymmetric acyclic ketones also affor-
ded two products derived from bromination at the two
a-positions (entries 13 and 15). When 1.5 equiv of
NBS was used, a mixture of the two a-monobromo
products was observed. These reactions were also car-
ried out under irradiation using sunlight. Similar con-
versions and selectivity were recorded, indicating the
general nature of the photoinitiated bromination.
The mechanism is believed to follow a radical path-
way.13 This was verified by the addition of the reaction
mixture to 2,2-diphenyl-1-picrylhydrazyl (DPPH) solu-
tion prepared in ethanol and recording the UV–vis spec-
trum.14 A blue shift in the absorption wavelength, from
kmax at 517 nm for DPPH in ethanol to 385 nm for
DPPH and the reaction mixture in ethanol (Fig. 3) con-
firmed the formation of free radicals in this reaction.
In conclusion, we have demonstrated a simple, photo-
chemical reaction procedure for the effective bromina-
tion of ketones with NBS, which within a short
reaction time gives high conversions of ketones and very
high selectivity for the a-monobrominated products.
General experimental procedure: A mixture of the ketone
(1 mmol) and NBS (1.05–1.5 mmol) was stirred under a
nitrogen atmosphere in 5 ml of diethyl ether in a two-
neck round bottom flask under a Philips HPL-N
(250 W, k = 200–600 nm) lamp fitted with a water circu-
lation arrangement at room temperature (30 2 °C). In
order to achieve the best yield of the product, NBS was
added in four portions, each portion containing
0.25 equiv. The reaction product was filtered, diluted
with diethyl ether and washed with water. The organic

S. S. Arbuj et al. / Tetrahedron Letters 48 (2007) 1411–1415
1415
Synthetic Reactions, 2nd ed.; New York, 1972; p 459; (c)
Larock, R. C. In Comprehensive Organic Transformations,
2nd ed.; VCH: New York, 1999; p 715.
1.0
0.5
0.0
2. Talegaonkar, J.; Mukhija, S.; Boparai, K. S. Talanta 1982,
29, 327.
3. (a) Garbisch, E. W., Jr. J. Org. Chem. 1965, 30, 2109; (b)
Beachdel, C.; Klaubert, D. H. Tetrahedron Lett. 1998, 39,
4987.
4. King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29,
3459.
5. Pasaribu, S. J.; Williams, L. K. Aust. J. Chem. 1973, 26,
1327.
6. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S.
Bull. Chem. Soc. Jpn. 1987, 60, 1159.
7. (a) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumaba-
yashi, K.; Horaguchi, T. Chem. Lett. 2003, 32, 932; (b)
Cope, A. C.; Burrows, E. P.; Derieg, M. E.; Moon, S.;
Wirth, W. D. J. Am. Chem. Soc. 1965, 87, 5452; (c) Lee, J.
C.; Bae, Y. H.; Chang, S. K. Bull. Korean Chem. Soc.
2003, 24, 407.
8. Schmid, H.; Karrer, P. Helv. Chim. Acta 1946, 29, 573.
9. Das, B.; Venkateswarlu, K.; Mahender, G.; Mahender, I.
Tetrahedron. Lett. 2005, 46, 3041.
10. (a) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumaba-
yashi, K.; Horaguchi, T. Chem. Commun. 2004, 470; (b)
Ramesh, C.; Mahender, G.; Ravindranath, N.; Das, B.
Tetrahedron 2003, 59, 1049.
11. Adhikari, M. V.; Samant, S. D. Ultrason. Sonochem. 2002,
9, 107.
400
500
600
700
Wavelength (nm)
Figure 3. UV–vis absorption spectra of ( ) DPPH in ethanol and (—)
reaction mixture in DPPH.
layer was separated and dried over sodium sulfate. The
product was analyzed by GC (HP 5890) using a capillary
column (HP-5). GC mass spectra were taken on a Shi-
madzu GC–MS-QP5050A spectrometer equipped with
a DB-5 column to identify the products.
12. Guha, S. K.; Wu, B.; Kim, B. S.; Baik, W.; Koo, S.
Tetrahedron Lett. 2006, 47, 291.
Acknowledgements
13. (a) Traynham, J.; Lee, Y. J. Am. Chem. Soc. 1974, 96,
3590; (b) Adam, J.; Gosselain, P.; Goldfinger, P. Nature
1953, 171, 704; (c) Braun, A. M.; Maurette, M. T.;
Oliveros, E. Photochemical Technology; John Wiley and
Sons: England, 1991; p 343.
The authors are thankful to the Shimadzu Analytical
Center of the Department of Chemistry for spectral
assistance and to the Department of Atomic Energy
for a Research Fellowship to one of us (S.S.A.).
14. (a) Aligiannis, N.; Mitaku, S.; Tsitsa-tsardis, E.; Harvala,
C.; Tsaknis, I.; Lalas, S.; Haroutounian, S. J. Agric. Food
Chem. 2003, 51, 7308; (b) Lai, L.; Chou, S.; Chao, W. J.
Agric. Food Chem. 2001, 49, 963; (c) Katalinic, V.;
Milos, M.; Kulisic, T.; Jukic, M. Food Chem. 2006, 94,
550.
References and notes
1. (a) Erian, A. M.; Sherif, S. M.; Gaber, H. M. Molecules
2003, 8, 793; (b) Benjamin, W. A.; House, H. O. Modern