Regioselective α-bromination of aralkyl ketones using n-bromosuccinimide in the presence of montmorillonite K-10 clay: A simple and efficient method

Article abstract of DOI:10.1080/00397911.2012.725264

A simple and more convenient method has been developed for regioselective α-bromination of various aralkyl ketones with N-bromosuccinimide (NBS) in the presence of Montmorillonite K-10 catalyst in methanol at 60-65 °C. The present procedure offers advantages of short reaction time, simple workup, good yields of products and reusability of the catalyst for four times without loss of activity. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.725264

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Regioselective α-Bromination of Aralkyl
Ketones Using N-Bromosuccinimide in
the Presence of Montmorillonite K-10
Clay: A Simple and Efficient Method
Reddy Bodireddy Mohan a & N. C. Gangi Reddy a
a Department of Chemistry , School of Physical Sciences, Yogi
Vemana University , Kadapa , Andhra Pradesh , India
Accepted author version posted online: 26 Mar 2013.Published
online: 26 Jun 2013.
To cite this article: Reddy Bodireddy Mohan & N. C. Gangi Reddy (2013): Regioselective α-
Bromination of Aralkyl Ketones Using N-Bromosuccinimide in the Presence of Montmorillonite K-10
Clay: A Simple and Efficient Method, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:19, 2603-2614
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Synthetic Communications1, 43: 2603–2614, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.725264
REGIOSELECTIVE a-BROMINATION OF ARALKYL
KETONES USING N-BROMOSUCCINIMIDE IN THE
PRESENCE OF MONTMORILLONITE K-10 CLAY: A
SIMPLE AND EFFICIENT METHOD
Reddy Bodireddy Mohan and N. C. Gangi Reddy
Department of Chemistry, School of Physical Sciences,
Yogi Vemana University, Kadapa, Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract A simple and more convenient method has been developed for regioselective
a-bromination of various aralkyl ketones with N-bromosuccinimide (NBS) in the presence
of Montmorillonite K-10 catalyst in methanol at 60–65 ꢀC. The present procedure offers
advantages of short reaction time, simple workup, good yields of products and reusability
of the catalyst for four times without loss of activity.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Aralkyl ketones; a-bromination; Montmorillonite K-10 clay; N-
bromosuccinimide; regioselectivity
INTRODUCTION
Development of simple and efficient synthetic routes for widely used organic
compounds from readily available reagents is one of the major challenges in organic
synthesis. Organic bromides are regarded as important precursors for various trans-
formations employed in organic and pharmaceutical synthesis. The bromination of
aralkyl ketones may lead to side-chain a-bromination as well as ring bromination
depending upon the conditions employed. The side-chain bromination has attracted
attention because of the potential of the resulting bromoacetophenones as versatile
building blocks in the synthesis of carbo- and heterocyclic compounds used in the
Received May 10, 2012.
Address correspondence to N. C. Gangi Reddy, Department of Chemistry, School of Physical
Sciences, Yogi Vemana University, Kadapa, Andhra Pradesh, India. E-mail: ncgreddy@yahoo.co.in
2603

2604
R. B. MOHAN AND N. C. G. REDDY
design of novel and highly effective pharmaceuticals with a broad spectrum of bior-
esponses and also as intermediates for a variety of biologically active compounds.[1]
Arabaci et al. reported that a-bromoacetophenone derivatives actively participated
in the inhibition of protein tyrosine phosphatase such as SHP-1 and PTP1B.[2]
Considerable efforts have been focused on the development of efficient bromin-
ation methods instead of conventional methods that require hazardous and toxic
elemental bromine[3,4] in the presence of protic or Lewis acid.[5,6] A number of bromin-
ation protocols of carbonyl compounds have been developed, for example, use of cupric
bromide,[7] dioxane, dibromide[8] and tetra-butyl ammonium tribromide.[9] In terms of
user friendliness and availability, N-bromosuccinimide (NBS) is a superior brominating
agent.[10,11] It has been reported that ketones are a-brominated using NBS catalyzed
by Mg(ClO4)2,[12] NBS=sonochemical bromination,[13] NBS=NH4OAc,[14] NBS=
Amberlyst-15,[15] NBS=silica-supported NaHSO4,[16] NBS=sulfonic acid functionalized
silica,[17] NBS=ionic liquids,[18] NBS=solvent-free reaction conditions,[19] bromodimethyl
sulfoniumbromide,[20] ethylene bis(N-methylimidazolium)ditribromide,[21] H2O2-
HBr,[22] NBS=ht,[23] trihaloisocyanuric acids,[24] pyridinium bromochromate,[25] and
NH4Br-oxone.[26]
However, all these methods suffer from one or more disadvantages such as long
reaction times, preparation of catalyst, use of hazardous chemicals, and intricate
workup procedures. Hence, the development of a simple and efficient method for
a-monobromination of aralkyl ketones remains a major challenge for synthetic
organic chemists. Hence, a study has been undertaken using Montmorillonite
K-10 clay as a catalyst for the conversion of aralkylketones to a-monobrominated
aralkylketones with NBS in methanol. Montmorillonite K-10 clay has been used
as catalyst for number of synthetic organic transformations and offers several advan-
tages over classical acids, for example, strong acidity, noncorrosiveness, low cost,
mild reaction conditions, good yields, selectivity, and ease of workup.[27]
Herein, we report a simple, more convenient, and regioselective method for the
preparation of a-monobrominated aralkyl ketones in good yields by the reaction
of various aralkyl ketones with N-bromosuccinimide (NBS) in the presence of
Montmorillonite K-10 catalyst in methanol at 60–65 ꢀC (Scheme 1).
In the present study, our initial objective was to identify an appropriate cata-
lyst or solvent for regioselective a-bromination of various aralkyl ketones with NBS.
For this purpose, we choose to assess regioselective a-bromination of acetophenone
(1a), and all the reaction parameters were optimized with respect to it. Acetophenone
can undergo electrophilic ring bromination at the m-position as well as electrophilic
a-bromination in the side chain. Electrophilic ring bromination using NBS in the
Scheme 1. Synthesis of a-brominated aralkyl ketones from aralkyl ketones using NBS in the presence of
10% Montmorillonite K-10 catalyst.

a-BROMINATION OF ARALKYL KETONES
2605
Scheme 2. a-Bromination of acetophenone using NBS in presence of 10% of Montmorillonite K-10 clay
catalyst.
Scheme 3. Plausible mechanism for the preparation of 2-bromo-1-phenylethanone (major) from
acetophenone.
presence of p-TsOH has been achieved.[4] In the present study, we have achieved the
electrophilic a-bromination in the side chain using NBS in the presence of Montmor-
illonite K-10 clay (Scheme 2).
In the presence of an acidic catalyst such as Montmorillonite K-10, NBS may
undergo protonation at the carbonyl oxygen resulting in the generation of the bro-
mocation. The bromocation may directly attack at the aromatic ring or a potential
nucleophilic center like the a-carbon atom of a ketone. Alternatively, the bromoca-
tion may react with a nucleophilic solvent such as methanol to form an electrophilic
species, such as CH3OBr, which can react with the enol form of the ketone to form
a-bromo derivative as shown in Scheme 3.
RESULTS AND DISCUSSION
Different type of solvents, temperature, and mode of NBS addition were exam-
ined for their effect on the transformation of acetophenone (1a) into 2-bromo-1-phe-
nylethanone (2a) by treatment with NBS in the presence of Montmorillonite K-10
catalyst, and the obtained results are discussed. Initially, a-bromination of acetophe-
none (1a) was carried out with NBS in methanol in the absence of the catalyst, and
bromination was not observed even up to 24 h (entry 1, Table 1). In the presence of
Montmorillonite K-10 catalyst, it afforded 68% yield of the desired product (2a) in
4.0 h at 30–35 ꢀC (entry 2, Table 1), and the same reaction was completed within
18 min at 60–65 ꢀC with 94% of isolated yield (entry 3, Table 1).
Later, optimization of the reaction conditions was scrutinized to increase the
yield of the product. A variety of solvents were also examined. The results presented
in Table 2 showed that solvents provided various and yields (entries 1–4, Table 2).

2606
R. B. MOHAN AND N. C. G. REDDY
Table 1. Screening of catalyst for synthesis of 2-bromo-1-phenylethanonea
Entry
Catalyst
Temp. (ꢀC) Time (h) Product(s)b 2a and 2b Selectivity (%) 2a:3a
1
2
3
—
Montmorillonite K-10
Montmorillonite K-10
30–35
30–35
60–65
24
4.0
0.3
—
2a and 3a
2a and 3a
0:0
68:32
94:06
aReaction conditions: Acetophenone (10 mmol), NBS [10 (þ2) mmol: portionwise addition], 10%
Montmorillonite K-10, and methanol (20 ml).
bScheme 2.
Solvents such as Et2O and tetrahydrofuran (THF) gave product 2a in lower yields
(entries 1 and 2, Table 2). When ethanol was used as a solvent, moderate yield of
the product (2a) was obtained (entry 4, Table 2). Solvents such as dimethylsulfoxide
(DMSO), dimethylformamide (DMF), CH2Cl2, and CCl4 were generally employed
for NBS bromination.[28] However, we did not observe conversion in any of these
solvents (entries 5–8, Table 2) at 30–35 ꢀC. In this study, we found that methanol
is the best solvent (entry 3, Table 2) for maximum isolated yield of the desired
product (2a), especially at reflux temperature.
It is interesting to mention the effect of reaction temperature on the course of
bromination in the presence of Montmorillonite K-10 catalyst, since at higher tem-
perature (65 ꢀC) regioselectivity would be changed. In the case of acetophenone sub-
strate, with increasing temperature a-monobromination was increased instead of a-
dibromination (entries 1–5, Table 3). a-Bromination was also predominant in the
case of other substituted acetophenones and substituted acetonaphthones even at
higher temperature (entries 1–14, Table 5). In this study, we found that the optimum
temperature is 60–65 ꢀC to obtain highest yields of the desired products within a
short period of time.
To obtain some further insight into the bromination process, we investigated
the effect of mode of NBS addition. Portionwise addition and one time addition
of NBS had a significant effect on the isolated yield of the desired product (2a).
Table 2. Screening of solvents for synthesis of 2-bromo-1-phenylethanonea
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Et2O
THF
0.5
1.5
4.0
7.0
24
35 (63)c
29 (45)c
68 (94)c
54 (69)c
0 (6)c
CH3OH
CH3CH2OH
DMF
DMSO
CH2Cl2
CCl4
24
24
0 (7)c
0 (10)
0 (5)
24
aReaction conditions: Acetophenone (10 mmol), NBS (11 (þ2) mmol: portionwise
addition), 10% Montmorillonite K-10, methanol (20 ml), and temperature 30–35 ꢀC.
bIsolated yield.
cIsolated yields were shown in parentheses, when the reactions were carried out
under reflux temperature.

a-BROMINATION OF ARALKYL KETONES
2607
Figure 1. Solvents obtained yield of 2-bromo-1-phenylethanone. Solvents: A-Et2O, B-THF, C-CH3OH,
D-CH3CH2OH, E-DMF, F-DMSO, G-CH2Cl2, and H-CCl4. (Figure is provided in color online.)
For example, the isolated yield of the product (2a) was increased on addition of NBS
in portion wise (entries 2–4, Table 4) when compared to one-time addition of NBS
(entry 1, Table 4). From this study, we concluded that portionwise addition is the
best option to obtain improved yields.
Table 3. Optimization of temperature for synthesis of 2-bromo-1-phenylethanonea
Entry
Time (h)
Temp. (ꢀC)
Yield (%)b
1
2
3
4
5
6.0
4.0
2.5
1.0
0.3
20–30
30–40
40–50
50–60
60–65
51
68
75
82
94
aReaction conditions: Acetophenone (10 mmol), NBS [10 (þ2) mmol: portionwise
addition], 10% Montmorillonite K-10, and methanol (20 ml).
bIsolated yield.
Table 4. Optimization of mode of N-bromosuccinimide additiona
Entry
Mode of NBS addition
Time (min)
Yield (%)b
1
2
3
4
Once
10
12
14
18
71
78
85
94
2 portions
4 portions
6 portions
aReaction conditions: Acetophenone (10 mmol), NBS [10 (þ2) mmol)], 10%
Montmorillonite K-10, and methanol (20 ml) at 65 ꢀC.
bIsolated yield.

2608
R. B. MOHAN AND N. C. G. REDDY
Figure 2. Temperature-dependent yield of 2-bromo-1-phenylethanone. (Figure is provided in color
online.)
Finally, with intention of further investigation into the bromination process,
we studied the effect of substituents present on the aromatic ring of aralkyl ketones.
The Presence of electron-releasing and electron-withdrawing groups on substrates
had significant effect on isolated yields of the products (entries 1–14, Table 5). In
this study, we found that substrates, without substituents (entry 1, Table 5) or with
electron releasing groups (entries 3–10, Table 5) or with extensive conjugation (entries
13 and 14) gave excellent isolated yields. In contrast to this, the substrates containing
electron withdrawing groups (entries 11 and 12, Table 5) gave lower yields of the pro-
ducts.
Based on optimized conditions, a series of a-bromoketones were prepared by
the reaction of aralkyl ketone (10 mmol) with N-bromosuccinimide (12 mmol) in
Figure 3. Mode of NBS addition–dependent yield of 2-bromo-1-phenylethanone. (Figure is provided in
color online.)

a-BROMINATION OF ARALKYL KETONES
2609
Table 5. a-Bromination of aralkyl ketones using NBS in the presence of Montmorillonite K-10 in
methanola
Yield (%)
Entry
Substrate
Product
Time (min) NBS in one portion NBS in portions
1
18
12
15
74
44
82
94[29]
65[30]
92[31]
2
3
4
5
6
16
12
16
81
85
76
94[32]
96[29]
88[33]
7
8
13
13
79
75
95[29]
85[34]
(Continued )

2610
R. B. MOHAN AND N. C. G. REDDY
Table 5. Continued
Yield (%)
Time (min) NBS in one portion NBS in portions
Entry
Substrate
Product
9
11
12
79
52
92[34]
10
11
78[35]
20
15
24
44
45[36]
12
65[36]
13
14
11
12
65
72
88[37]
91[38]
aReaction conditions: Substrate (10 mmol), NBS 10 (þ2) mmol added in either one or six portions, 10%
Montmorillonite K-10 catalyst, methanol (20 ml), and temperature 60–65 ꢀC.
20 ml of methanol containing 10% Montmorillonite K-10 catalyst, and the obtained
results are listed in the Table 5. In the absence of catalyst, bromination was not
observed.
In conclusion, we have developed an efficient methodology for a-bromination
of aralkylketones by using a NBS=Montmorillonite K-10=methanol system within
20–30 min. Operational simplicity, good regioselectivity, rapid completion of the
reactions, good yields of the products, and reusability of catalyst are the notable
advantages of this method, which make it an attractive addition to the existing

a-BROMINATION OF ARALKYL KETONES
2611
literature. To broaden this methodology, further investigations on a-bromination of
cyclic and acyclic ketones, amides, and b-ketoesters are under way.
EXPERIMENTAL
A mixture of aralkyl ketone (10 mmol), N-bromosuccinimide (12 mmol), 10%
(w=w) Montmorillonite K-10 clay, and 20 ml of methanol were stirred at 60–65 ꢀC
up to the disappearance of the substrate. N-Bromosuccinimide was added portion-
wise (six portions). The reaction mixture was filtered to collect catalyst, solvent
was removed under reduced pressure, the crude product was added to aqueous
sodium thiosulfate, and the product was extracted with dichloromethane. The
organic layer was dried over Na2SO4, filtered, and concentrated. The obtained crude
was purified over silica gel using eluent of n-hexane and EtOAc (99:1 ratio).
Bulk-scale crude materials were purified using the recrystallization technique
by dissolving in n-hexane EtOAc (9:1 ratio) at 40–45 ꢀC and subsequent cooling to
0–5 ꢀC. Then, the formed solid product was filtered and washed with cold n-hexane.
The obtained pure product was dried in vacuum oven.
SUPPLEMENTARY INFORMATION
Supplementary information (experimental procedures, IR, 1H NMR, and mass
spectral data of compounds) associated with this article can be found in the online
version.
ACKNOWLEDGMENTS
We are thankful to the Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for financial support for this work under a major research project
(No. 01 (2391)=10=EMR-II).
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