180
B. Mohan Reddy et al. / Chinese Chemical Letters 25 (2014) 179–182
O
were separated and the organic layer was collected and it was
washed with distilled water for three times (3 ꢁ 1 L). The collected
organic layer was dried over anhydrous Na2SO4 and filtered,
concentrated and purified by recrystallization using n-hexane
O
10% Silicagel
O
+
Br
Br
R
NBS, Methanol
5-20 min
R
R
Br
minor
Reflux
1
2
major
3
(300 mL). The resulting yield of pure
a-brominated ketone, i.e. 2-
bromo-1-phenylethanone (2a) was 94%. The same experiment was
repeated twice and the yields were 93% and 96%, respectively. The
reproducibility of the protocol was thus confirmed with the
consistent isolated yields of desired product 2-bromo-1-pheny-
lethanone (2a).
R = Acyclic or cyclic alkyl groups, Aryl, Naphthyl
Scheme 1. The
a-bromination of ketones using NBS in presence of silica gel in
methanol.
Column chromatographic grade silica gel (60–120 mesh)
supplied by Merck, India was employed in the present investiga-
tion. The pH value of 10% aqueous suspension of silica gel is ꢀ6.5–
7.5. Silica gel catalyst was used as it is, without any activation or
any further treatment or chemical modifications.
3. Results and discussion
To study the effect of solvents and temperature on the
a-
bromination of ketones, we carried out a reaction with acetophe-
none using N-bromosuccinimide in methanol in presence of silica
gel at room temperature. However a low yield (56%, Table 1 entry
1) of the product 2-bromo-1-phenylethanone (2a) was obtained
after 4 h. When the same reaction was carried out under reflux
conditions (Table 1, entry 1), the yield was 95% within 18 min.
Other solvents such as Et2O, THF, CH3CN, CH2Cl2 and CHCl3 were
also studied, but lower yields of the desired products were
obtained (10–35%) as shown in Table 1. With Et2O, THF, 1,4-
dioxane and acetonitrile, lower yields of the product 2a was
2.1. Typical experimental procedure
The
a-bromination reaction was carried out using acetophe-
none (1200 mg, 10 mmol), N-bromosuccinimide (2136 mg,
12 mmol), 10% (w/w) silica gel (120 mg) in 10 mL of methanol
at reflux conditions until the disappearance of the substrate. (Note:
2136 mg of N-bromosuccinimide was added portion wise i.e.
356 mg for each time in six portions). The progress of the reaction
was monitored by TLC. The reaction mass was filtered after the
completion of the reaction as per TLC and the catalyst was collected
for reuse. The filtrate was concentrated under vacuum. Double
distilled water was added to the reaction mixture and quenched
with aqueous sodium thiosulfate and the product extracted with
dichloromethane (Caution: Severe burning sensation of eyes was
observed during the work-up process). The layers were separated
and the organic layer was collected and washed thrice with
distilled water (3 ꢁ 50 mL). The collected organic layer was dried
over anhydrous Na2SO4, filtered and concentrated. The obtained
crude product was purified by column chromatography over silica
gel (60–120 mesh) using n-hexane–EtOAc (99:1 ratio).
formed, along with very low amounts of the
a,
a0-dibrominated
Table 1
Effect of solvent and temperature on the formation of
a
-brominated product (2a).a
O
O
O
O
Br
Br
+
10% Silicagel
+
NBS, Methanol
Reflux
Br
Br
4a
1a
2a
3a
Entry
Solvent
Time
Major
Yield
(%)b
Yield
(%)c
Selectivity
(min)
product
(2a:3a:4a)
1
2
3
4
5
6
7
8d
MeOH
Et2O
18
15
2a
4a
4a
4a
2a
2a
2a
–
95
24
18
16
35
12
14
0
56
95:03:00
24:04:50
18:03:45
16:05:42
35:14:28
12:01:00
14:04:00
0
With the aim of studying the recycling of the catalyst, the
isolated catalyst was washed with ethyl acetate (5 mL) after its
filtration from the reaction medium, collected and dried in vacuum
18
15
14
22
8
THF
18
1,4-Dioxane
CH3CN
CH2Cl2
CHCl3
28
180
1500
1500
1500
at 70 8C to a constant weight. Subsequently it was reused for the a-
bromination of acetophenone and achieved 95%, 86% and 83%
yields of product (2a) for first, second and third reuse of catalyst
respectively. All products gave spectroscopic data in agreement
with the literature [15,21,27–30].
The method is also very practical for scale up in process
development. We attempted large scale (100 gram scale) synthesis
of 2-bromo-1-phenylethanone 2a and obtained fruitful results
with isolated yields ranging from 93% to 96%.
7
MeOH
0
a
Reactions were conducted with acetophenone (10 mmol); NBS (12 mmol), 10%
(w/w) silica gel, solvent (10 mL) under reflux conditions.
b
Isolated yields under reflux condition.
c
Isolated yields at room temperature.
d
Reaction carried out without catalyst.
Table 2
Role of catalyst load on the formation of
a
-brominated product (2a).a
2.2. General experimental procedure for large scale (100 g scale)
preparation
The
a-bromination reaction was carried out using acetophe-
none (100 g, 0.832 mol), N-bromosuccinimide (213.6 g, 1.2 mol),
10% (w/w) silica gel (10 g) in 1 L of methanol under reflux
conditions until the disappearance of the substrate (Note: 213.6 g
of N-bromosuccinimide was added portion wise i.e. 35.6 g for each
time in six portions). Excess N-bromosuccinimide (+0.1 mol) was
added to complete the reaction as per TLC. The reaction mass was
filtered, after the completion of the reaction as per TLC and the
catalyst was collected for reuse. The solvent was removed and
double distilled water was added to the reaction mixture and was
quenched with aqueous sodium thiosulfate. The product was
extracted with dichloromethane. (Caution: Severe burning sensa-
tion of eyes was observed during the work-up process). The layers
Entry
Catalyst
(w/w %)
Time
Major
Yield
(%)b
Selectivity (%)
(min)
Product
(2a:3a)
1
2
3
4
5
6
1
5
90
60
18
20
15
11
2a
2a
2a
2a
2a
2a
41
65
95
82
74
67
41:03
65:02
95:03
82:14
74:18
67:21
10
15
20
30
a
Reactions were conducted with acetophenone (10 mmol); NBS (12 mmol), 10%
(w/w) silica gel, methanol (10 mL) under reflux conditions.
b
Isolated yields.