Directed regioselectivity of bromination of ketones with NBS: solvent-free conditions versus water

Article abstract of DOI:10.1016/j.tetlet.2006.04.119

The reaction conditions employed directed the site of functionalisation of ketones with NBS: under solvent-free conditions α-bromination was the exclusive process, while in water, ring functionalisation occurred in the case of methoxy substituted aromatic ketones.

Full text of DOI:10.1016/j.tetlet.2006.04.119

Tetrahedron Letters 47 (2006) 4707–4710
Directed regioselectivity of bromination of ketones with
NBS: solvent-free conditions versus water
a
a,b
b,
*
Igor Pravst, Marko Zupan and Stojan Stavber
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sˇ ker cˇ eva 5, 1000 Ljubljana, Slovenia
Laboratory for Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute, Jamova 39, 1000 Ljubljana, Slovenia
b
Received 15 February 2006; revised 19 April 2006; accepted 26 April 2006
Available online 22 May 2006
Abstract—The reaction conditions employed directed the site of functionalisation of ketones with NBS: under solvent-free condi-
tions a-bromination was the exclusive process, while in water, ring functionalisation occurred in the case of methoxy substituted
aromatic ketones.
Ó 2006 Elsevier Ltd. All rights reserved.
Demands for sustainable and ecologically friendly or-
ganic syntheses have led to investigations of the condi-
Aryl substituted ketones have been shown to be
very sensitive model compounds in electrophilic func-
tionalisation, and the site of their fluoro and iodo
functionalisation could be selectively modulated by the
solvent.
1
11
12
tions involved in reactions. Among these conditions,
2
3
solvent-free strategies and the use of water as the reac-
tion medium represent important alternatives. Very
4
recently, Sharpless and co-workers reported an
important observation that some organic molecules
can react on the surface of water, and in some cases very
strong enhancement in the reaction rate was noticed in
comparison to reactions without solvent. On the other
In continuation of our interest in organohalogen chemis-
try, we now report an investigation of the reactions of
ketones with NBS under green reaction conditions: in
water and under solvent-free conditions. It is known
that NBS reacts with various aromatic compounds
5
hand, Mayr and co-workers reported an important
1
3
modulation of the reactivity of organic molecules by
water, enabling alkylation of aromatic molecules with
benzyl halides without the use of Friedel–Craft cata-
lysts, while water could also be used as a heat exchanger
under solvent-free conditions; however, an equimolar
mixture of 5-methoxy-indanone (1a) and NBS when
stirred in a mortar at room temperature remained
unchanged after 5 h, while heating at 80 °C for 2 h gave
a complex reaction mixture containing up to 24% of
2-bromo-5-methoxy-indanone (2a). Careful analysis
showed that at this temperature the reaction mixture
remains in the solid state (mp 1a: 108 °C, mp NBS:
175–180 °C). In the next experiment we added 10 mol %
of p-toluenesulfonic acid (PTSA) as catalyst, but unfortu-
nately the reaction mixture remained unchanged after
5 h at room temperature, while a complex mixture con-
taining up to 48% of 2a was observed when the reaction
mixture in the solid state was heated for 5 h at 40 °C. At
60 °C, the reaction mixture started to melt and after
10 min a substantial amount of 2a (89%) was formed,
while an almost quantitative conversion (Table 1) was
achieved after 1 h at 80 °C. A similar high yield side
chain bromination under these reaction conditions
was also achieved in the case of 6-methoxytetralone
(1b).
6
in exothermic reactions. Halogenations have not been
2
a
extensively studied under solvent-free conditions,
7
while recently the important role of solvent vapour in
the efficiency of bromination in comparison to solvent-
free conditions has been reported. It has been demon-
8
strated that the reactivity of NBS (N-bromosuccinimide)
could be modulated with various catalysts, including the
9
BF /H O couple and ammonium acetate. Some new
3
2
catalysts were reported recently for the bromination of
1
0
ketones with NBS in organic solvents, but to our
knowledge these reactions in water or under solvent-free
conditions have not been reported so far.
Keywords: Ketones; Bromination; NBS; Neat; Solvent-free; Water;
Regioselectivity.
*
Corresponding author. Tel.: + 386 1477 3660; fax: 386 1423 5400;
e-mail: stojan.stavber@ijs.si
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.119

4708
I. Pravst et al. / Tetrahedron Letters 47 (2006) 4707–4710
a
Table 1. Effect of reaction conditions on the regioselectivity of bromination
O
O
Br
neat
2
a-b
a-b
O
(
CH2)n
H CO
3
NBS
(
CH2)n
H CO
3
3
H O
2
1
1
a (n=1)
b (n=2)
(CH2)n
H CO
3
Br
b
Substrate
1a (n = 1)
Solvent
Catalyst
Temperature (°C)
Time (min)
Product (%)
Neat
Neat
Neat
Neat
/
20
20
60
80
300
300
10
/
/
PTSA
PTSA
PTSA
2a (89)
2a (97)
60
H
2
H
2
H
2
O
O
O
20
60
60
300
300
300
3a (60)
3a (78)
3a (87)
/
2 4
H SO
1b (n = 2)
Neat
PTSA
SO
60
60
10
2b (97)
3b (81)
H
2
O
H
2
4
300
a
Reaction conditions: ketone (1 mmol), NBS (1 mmol); p-toluenesulfonic acid (PTSA, 0.10 mmol) or H
Conversion determined by H NMR spectroscopy of the crude reaction mixture.
2
SO
4
(2 mmol) were used where noted.
b
1
We further studied the effect of water as solvent on the
bromination of benzocycloalkanones 1 and found that
in the case of 1a the regioselectivity changed completely.
In the reaction of 1a with NBS in water, 4-bromo-5-
methoxy-indanone (3a) was formed after 5 h at room
temperature with 60% conversion. At 60 °C, 78% con-
version was observed, but an even higher conversion
was achieved in the presence of sulfuric acid as catalyst
Table 2. Effect of the reaction conditions on the functionalisation of
acetophenone (4) with NBS to give 2-bromo-1-phenyl-ethanone (5)
a
b
Solvent
mol % of
Catalyst
Temper-
ature (°C)
Time
(min)
Conversion
(%)
Neat
Neat
Neat
Neat
/
20
20
20
20
1440
180
180
180
19
85
93
2% PTSA
5% PTSA
10% PTSA
>95
(
Table 1). A similar regioselectivity was observed in the
H
H
H
H O
2
H
2
2
2
O
O
O
/
60
60
60
60
60
1440
240
240
240
240
15
15
80
70
72
case of bromination of derivative 1b in water.
10% PTSA
2H
50% DOWEX
10% I
2 4
SO
The important role of the reaction conditions observed
on the regioselectivity of this functionalisation of
ketones stimulated us to investigate reactions with liquid
ketones. A solvent-free mixture of acetophenone (4)
and NBS at room temperature after 24 h gave only
2
O
2
a
Reaction conditions: ketone (1 mmol), NBS (1 mmol); catalyst was
used where noted.
Conversion determined by H NMR spectroscopy of the crude
b
1
1
9% of 2-bromo-1-phenyl-ethanone (5), while a catalytic
reaction mixture.
amount of PTSA (2 mol %) sharply increased the degree
of bromination and an 85% conversion of 4 was
achieved after 3 h at room temperature, while in the
presence of 10 mol % of PTSA, an almost quantitative
conversion to 5 (Table 2) was achieved after 3 h.
nitrile an almost quantitative conversion to 5 could be
obtained in the presence of 10 mol % of PTSA.
1
4
The role of the reaction conditions and substrate aggre-
gate state in the reactivity and regioselectivity stimulated
us to study the bromination with two solid (6a, 6d) and
two liquid (6b, 6c) methoxy substituted acetophenones
(Table 3). All the isomeric acetophenones (6a–c) res-
ponded to the reaction conditions similarly, as in the
case of 1, and high yields of side chain bromination
products were obtained under solvent-free conditions,
while ring bromination occurred in water in the presence
of PTSA or sulfuric acid (Table 3). However, the regio-
selectivity changed when an additional methoxy group
was present on the aromatic ring (6d, solid); ring bro-
mination also took place in the absence of a solvent. It
Contrary to the above observed results, water almost
completely stopped the bromination of 4 and even after
2
4 h at 60 °C, only 15% conversion was observed. A sim-
ilar result was achieved after 4 h with 10 mol % of
PTSA, while sulfuric acid proved to be a more conve-
nient catalyst leading to an 80% conversion. Finally,
we examined more ecologically friendly catalysts and
found that the polymer supported analogue (DOWEX)
or iodine gave comparable results (Table 2). Addition-
ally, we studied the effect of other solvents on the
bromination of 4 and found that in methanol or aceto-

I. Pravst et al. / Tetrahedron Letters 47 (2006) 4707–4710
4709
Table 3. Effect of the reaction conditions on the regioselectivity of the
bromination of methoxy substituted acetophenones
derivatives (Table 5). Finally, we studied the possibility
of further bromination under solvent-free conditions
and established that 1-indanone (15a) could be success-
fully converted to 2,2-dibromo-indanone (yield 99%)
after 1 h at 80 °C, when 2 mmol of NBS and 10 mol %
PTSA were used. A similar reaction with an excess of
NBS was performed on 5-methoxyindanone (1a), and
also in this case only the side chain dibromo derivative
was formed in 98% yield.
a
O
O
O
Br
NBS
Br
H CO
H CO
H CO
3
3
3
b
6
Solvent Temperature Time 7 (%)
8 (%)
(
°C)
(min)
Typical procedures: Bromination in water: To a suspen-
sion of ketone 1a (1 mmol) in water (10 mL), N-bromo-
succinimide (NBS, 1 mmol) was added and the reaction
mixture heated to 60 °C while stirring. H SO (40% aq
6
a
Neat
20
60
120
300
73
85
91
(4-Methoxy)
H
2
O
72
94
95
6
b
Neat
H O
2
20
60
120
300
2
4
solution, 2 mmol) was then added and stirring continued
for 5 h. The crude product isolated from the reaction
mixture using tert-butyl methyl ether/water extraction
contained 3a (72%), which was additionally purified by
crystallisation from ethanol to give pure 3a, mp 120 °C
(3-Methoxy)
6
c
Neat
H O
2
20
60
120
300
(2-Methoxy)
6
d
Neat
H O
2
20
60
120
60
93
97
(2,4-Dimethoxy)
(
Found: C, 49.85; H, 3.91. C H BrO requires C,
10 9 2
a
À1
Reaction conditions: ketone (1 mmol), NBS (1 mmol); yield deter-
mined by H NMR spectroscopy with 1,4-di-tert-butyl-benzene as an
49.82; H, 3.76), IR mmax(KBr)/cm 3051, 2934, 1724,
1591, 1327, 1277, 1250, 1111, 1057, 806, 584; H NMR
1
1
internal standard.
(
300 MHz; CDCl ) dH 2.69–2.73 (m, 2H, CH ), 3.02–
3
2
b
Isomers: 8a: 3-bromo; 8b: 6-bromo, 8c and 8d: 5-bromo.
3
.07 (m, 2H, CH ), 4.00 (s, 3H, CH O), 6.94 (d,
2 3
J = 8.4 Hz, 1H, ArH) 7.69 (d, J = 8.4 Hz, 1H, ArH);
1
3
is also interesting to note the effect of water on the reg-
ioselectivity of ring bromination, since only one bromi-
nated isomer was formed; 3-bromo (8b), 5-bromo (8c) or
C NMR (76 MHz; CDCl ) dC 27.1 (CH ), 36.3
3 2
(CH ), 56.8 (CH O), 110.0 (ArC), 11.2 (ArCH), 124.0
(ArCH), 131.8 (ArC), 156.9 (ArC), 160.9 (ArC), 204.8
(CO); MS (EI, 70 eV) m/z 239.97902 (100%, M .
C H BrO requires 239.97859). Neat bromination:
2
3
+
5
-bromo (8d) substituted methoxy acetophenones in the
bromination of the 3-methoxy (6b), 2-methoxy (6c) and
,4-dimethoxy (6d) derivatives, respectively.
1
0
9
2
2
Ketone 1a (1 mmol), N-bromosuccinimide (NBS,
mmol) and p-toluenesulfonic acid (PTSA, 0.1 mmol)
1
Finally, we evaluated the solvent-free bromination
method on various structural types of ketones, 1,3-di-
ketones and b-keto esters. In all cases good to excellent
results were observed (Table 4). Bromination of 1,3-
diketone 9c and b-keto ester 9d occurred at room
temperature in the absence of a catalyst, while the
bromination of solid ketones 9b and 9f initially required
heating to achieve melting (ꢀ80 °C) and then transfor-
mation was completed in 10 min.
were ground in a porcelain mortar and then heated to
60 °C for 10 min. This turned the reaction mixture into
a paste. When the reaction mixture was cooled to room
temperature, isolation using tert-butyl methyl ether/
water extraction gave a crude product containing 2a
(87%), which was additionally purified by crystallisation
from ethanol. Dibromination was achieved using a simi-
lar procedure with 2 mmol of NBS by heating at 80 °C
for 1 h. The crude product contained 2,2-dibromo-5-
methoxyindanone (99%), which was additionally crys-
tallised from ethanol to give the pure compound, mp
109–110 °C (Found: C, 37.23; H, 2.66. C H Br O
Under solvent-free conditions, we also effectively bromi-
nated various cycloalkanones to give their a-bromo
1
0
8
2
2
a
Table 4. Bromination of various ketones, diketones and keto esters under solvent-free conditions
O
O
R2
NBS
neat
R2
R1
R1
Br
9
10
1
2
b
Substrate
R
R
Catalyst
Temperature (°C)
Time (min)
Product (%)
9a
9b
9c
9d
9e
9f
Ph
Ph
Ph
Ph
n-C
Me
Ph
COPh
COOEt
n-C
H
PTSA
PTSA
/
20
80
20
20
20
80
180
10
180
180
180
10
10a (75)
10b (95)
10c (98)
10d (97)
10e (93)
10f (80)
/
4
H
9
3
H
7
PTSA
PTSA
Adamantyl
a
Reaction conditions: ketone (1 mmol), NBS (1 mmol) and PTSA (0.1 mmol) when noted.
Yield determined by H NMR spectroscopy of the crude reaction mixture with internal standard (1,4-di-tert-butyl-benzene for 9a, 9b and 9c,
o-xylene for 9d and naphthalene for 9e and 9f).
b
1

4710
I. Pravst et al. / Tetrahedron Letters 47 (2006) 4707–4710
a
Table 5. Solvent-free bromination of cyclic ketones with NBS
b
Substrate
Product
Yield (%)
1
1a n = 1
b n = 2
c n = 3
12a
b
84
93
84
O
O
Br
c
(CH2)n
(CH )
2 n
tBu
O
tBu
O
13d
14
83
a: cis
1
4a:14b = 1:1
b: trans
Br
O
O
Br
1
5a n = 1
b n = 2
16a
b
87
86
(CH2)n
(CH )
2 n
a
Reaction conditions: ketone (1 mmol), NBS (1 mmol), PTSA (0.1 mmol), 20 °C, 2 h.
Yield after column chromatography.
b
À1
requires C, 37.54; H, 2.52), IR mmax(KBr)/cm 1710,
Lindstr o¨ m, U. M. Chem. Rev. 2002, 102, 2722–2751; (c)
Otto, S.; Engberts, B. F. N. Org. Biomol. Chem. 2003, 1,
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1
595, 1490, 1300, 1260, 1095, 1015;
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2
(
2
809–2820; (d) Li, C. J. Chem. Rev. 2005, 105, 3095–3165;
e) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett
002, 5, 674–686.
(
300 MHz; CDCl ) 3.93 (s, 3H, CH O), 4.25 (s, 2H,
CH ), 6.81–6.83 (m, 1H, ArH), 7.00 (dd, J = 2.2 Hz
and 8.6 Hz, 1H, ArH), 7.86 (d, J = 8.6 Hz, 1H, ArH);
C NMR (76 MHz; CDCl ) dC 52.3, 55.9, 57.4, 109.1
ArCH), 117.0 (ArCH), 121.6 (ArC), 128.4 (ArCH),
50.1 (ArC), 167.0 (ArC), 191.1 (CO); MS (EI, 70 eV)
m/z 317.89025 (50%, M . C H Br O requires
17.88910), 239 and 241 (100%), 160 (85%), 132 (40%),
9 (45%), 69 (55%), 63 (40%).
3 3
2
1
3
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Acknowledgements
2
005, 46, 1901–1903.
This research was supported by the Ministry of Higher
Education, Science and Technology of the Republic of
Slovenia and the Young Researcher program (I.P.) of
the Republic of Slovenia. We are thankful to the staff
of the National NMR Centre at the National Institute
of Chemistry in Ljubljana.
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