Rapid and catalyst-free α-halogenation of ketones using N-halosuccinamides in DMSO

Article abstract of DOI:10.1080/00397910701574908

α-Halogenation of various carbonyl compounds such as β-keto-esters, cyclic ketones, and lactams with N-halosuccinamides (NBS, NCS, NIS) in the presence of DMSO proceeded very smoothly to give the corresponding α-monohalogenated products in good to excellent yields with high selectivity under catalyst-free conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701574908

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Rapid and Catalyst‐Free α‐Halogenation of
Ketones using N‐Halosuccinamides in DMSO
B. Sreedhar a , P. Surendra Reddy a & M. Madhavi a
a Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India
Available online: 10 Dec 2007
To cite this article: B. Sreedhar, P. Surendra Reddy & M. Madhavi (2007): Rapid and Catalyst‐Free
α‐Halogenation of Ketones using N‐Halosuccinamides in DMSO, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 37:23, 4149-4156
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Synthetic Communicationsw, 37: 4149–4156, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701574908
Rapid and Catalyst-Free a-Halogenation
of Ketones using N-Halosuccinamides
in DMSO
B. Sreedhar, P. Surendra Reddy, and M. Madhavi
Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India
Abstract: a-Halogenation of various carbonyl compounds such as b-keto-esters,
cyclic ketones, and lactams with N-halosuccinamides (NBS, NCS, NIS) in the
presence of DMSO proceeded very smoothly to give the corresponding a-mono-
halogenated products in good to excellent yields with high selectivity under catalyst-
free conditions.
Keywords: carbonyl compounds, catalyst-free conditions, a-halogenation, NBS
NCS, NIS
The central importance of halogenation reactions, in which organic molecules
are formally oxidized, is a widely accepted fact in synthetic organic
chemistry.[1] Halocarbon products are useful chemical intermediates serving
as branch points in the synthesis of functionalized molecules. Within this
context, a-bromination of 1,3-dicarbonyl compounds is an important trans-
formation because the resulting a-brominated products are highly versatile
intermediates in organic synthesis.[2] The most commonly used reagents for
these transformations include molecular bromine in the presence of protic
or Lewis acids,[3] copper(II) bromide,[4] and N-bromosuccinamide (NBS).[5]
In terms of availability and the ease of handling, NBS is a superior bromi-
nating agent. The major advantage of NBS is that the by-product succinamide
can be easily recovered and reconverted to NBS to be used in subsequent
Received April 30, 2007
Address correspondence to B. Sreedhar, Indian Institute of Chemical Technology,
Inorganic and Physical Chemistry Division, Tarnaka, Hyderabad 500 007, India.
E-mail: sreedharb@iict.res.in
4149

4150
B. Sreedhar, P. S. Reddy, and M. Madhavi
reactions. It has been reported that ketones are a-brominated by reactions with
NBS initiated by azobisisobutyronitrile (AIBN) or dibenzylperoxide (BPO) in
refluxing CCl4,[6] NH4OAc,[7] MgClO4,[8] and amberlyst.[9] In addition,
several methods have been developed for the a-chlorination and a-iodonation
of b-keto-esters using N-chlorosuccinimide (NCS)[10] and N-iodosuccinimide
(NIS),[11] respectively. Most of these methods generally employed strongly
acidic and basic conditions and are accompanied by undesirable formation
of a,a-dihalogenated products.
In the context of green chemistry, noncatalytic processes have attracted
considerable attention. However, to the best of our knowledge, an efficient a-
halogenation of carbonyl compounds without catalyst has not been reported so far.
Recently, Watahiki et al. reported the cyanobenzylatiopn and hydro-
cyanation of aldehydes and silylation of alcohols using dimethyl sulfoxide
(DMSO) as solvent under catalyst-free conditions.[12] Spontaneous aldol
and Michael reaction of enoxytrimethylsilanes have been recently reported
in DMSO.[13] We are interested in the properties of DMSO and envisioned
the generation of halogen ions by activating the N-halosuccinamides.
From the point of view of green chemistry, a noncatalytic process is very
significant and attractive for synthetic organic chemistry. Herein, we report an
efficient and convenient method to selectively produce monohalogenated
carbonyl compounds from various b-keto-esters and cyclic ketones with
N-halosuccinamides under neutral conditions (Schemes 1 and 2).
At room temperature, when NBS is added to a DMSO solution of
carbonyl compounds (b-keto-esters and cyclic ketones), an exothermic
reaction takes place, and the temperature of the reaction mixture rises to
Scheme 1.
Scheme 2.

a-Halogeneration of Ketones
4151
55–658C within a minute. The reaction mixture was stirred for few minutes to
obtain the corresponding a-monobrominated products in good to excellent
yields. Under similar reaction conditions, NCS and NIS were also screened
to obtain the corresponding a-monochlorinated and a-mono-iodinated
products, respectively. Among these reactions, both a-bromination and
a-chlorination reactions were accomplished equally well with somewhat
reduced yields in the case of a-iodonation. However, increasing the
reaction time gave good yields as illustrated in Tables 1 and 2, which may
be attributed to the less electrophilic nature of iodine.
As shown in Table 1, various a-substituted and unsubstituted b-keto-
esters were converted to their halogenated products in good yields (Table 1,
entries 1–11). Among the substrates screened, 2-substituted b-keto-esters
are less reactive than 2-unsubstituted b-keto-esters and require long reaction
times (entries 5 and 6). Cyclic b-keto-esters also reacted smoothly and gave
the corresponding product in good yield (entry 4). It is noteworthy that
no dihalogenated products were observed while using 1.05 equiv. of
N-halosuccinamides.
To extend the scope and general applicability of this reaction, several
cyclic ketones were reacted with NXS (X¼Br, Cl, I) in DMSO, and the
results are tabulated in Table 2. As can be seen from Table 2, 2-methyl-
cyclohexanone (entry 5) underwent halogenation predominantly at the
highly substituted position. In addition, the system was also applied to
1,3-cyclicdiketones (entry 7). Further, the reaction of NBS with lactams
gave the corresponding a-monobromo lactams in moderate yields
(entries 8 and 9).
N-Halosuccinamides show enhanced reactivity in the presence of DMSO,
thereby reducing reaction times and improving the yields. The rate of
enhancement in DMSO, is probably due to increased polarization of the
N-X bond in the polar DMSO solvent.
In summary, we have presented a highly efficient and convenient method
for a-halogenation of various ketones with N-halosuccinamides (NBS, NCS,
and NIS) in DMSO. This is the first example for the synthesis of 2-halogenated
derivatives without using any catalyst. Accordingly, these reactions are very
attractive from the standpoint of green chemistry.
GENERAL PROCEDURE FOR THE a-HALOGENATION OF
KETONES
To the DMSO solution of 1,3-keto ester or cyclic ketone (1.0 mmol), N-halosuc-
cinamide (1.05 mmol) was added, and the resultant mixture was stirred for an
appropriate time at room temperature (see Tables 1 and 2). After completion
of the reaction as indicated by thin-layer chromatography (TLC), the reaction
mixture was washed with NH4Cl solution. The product was extracted with

Table 1. 2-Halogenation of various b-ketoesters using N-halosuccinamides in DMSOa
Productsb la: X ¼ Br, lb:
Time (min)
NCS
Yield (%)c
NCS
Entry
b-keto-ester
X ¼ Cl, lc: X ¼ I
NBS
NIS
50
NBS
92
NIS
86
1
20
20
90
2
3
4
20
25
40
20
25
45
50
60
90
90
86
92
90
80
90
80
75
85
5
6
45
45
45
45
120
120
85
85
80
82
75
70

7
8
9
20
25
25
25
30
30
45
60
60
90
90
85
85
88
80
78
80
80
10
11
25
40
30
40
60
85
95
80
92
75
90
120
aReaction conditions as exemplified in the typical experimental procedure.
bAll products were characterized by 1H NMR, IR, and mass spectroscopy.
cIsolated yields.

4154
B. Sreedhar, P. S. Reddy, and M. Madhavi
Table 2. 2-Halogenation of various cyclic ketones using N-halosuccinamides in
DMSOa
Time (min)
Yield (%)c
Cyclic
ketone
Entry
1
Productb
NBS NCS NIS NBS NCS NIS
10
15
10
10
15
10
30
45
30
95
90
95
92
87
90
85
82
85
2
3
4
5
6
20
85
15
20
82
15
60
76
60
90
85
91
90
82
90
82
76
78
7
8
60
60
60 120 72
60 120 75
67
75
60
60
aReaction conditions as exemplified in the typical experimental procedure.[14]
1
bAll products were characterized by H NMR, IR, and mass spectroscopy.
cIsolated yields.
ethyl acetate, dried over sodium sulphate, and purified by column
chromatography.
2-Chloro-3-oxo-3-pyridin-2-yl-propionic Acid Ethyl Ester (Table 1,
Entry 9)
IR (neat): y 2953, 2621, 1739, 1619, 1436, 751, 621 cm21. 1H NMR (300 MHz,
CDCl3): d 7.99–7.30 (m, 4H), 5.27 (s, 1H), 4.33–4.23 (q, 2H J ¼ 7.30 Hz),
1.37–1.31 (t, J ¼7.3 Hz). MS (EI) m/z: 229, 227 (Mþ), 192, 151, 71.

a-Halogeneration of Ketones
4155
1-Bromo-2-oxo-cyclohexanecarboxylic Acid Ethyl Ester (Table 1,
Entry 4)
IR (neat): y 2946, 2871, 1732, 1451, 1241, 755, 562 cm21. 1H NMR (300 Hz,
CDCl3): d 1.27 (t, 3H, J ¼ 7.4 Hz), 1.66–1.75 (m, 1H), 1.82–1.96 (m, 3H),
2.03–2.11 (m, 1H), 2.30–2.39 (m, 1H), 2.67–2.74 (m, 1H), 2.75–2.83
(m, 1H), 4.23 (q, 2H, J ¼ 7.4 Hz). MS (EI) m/z: 250 (M2þ), 248 (Mþ),
169, 139, 43.
2-Bromo-1-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-propane-
1,3-dione (Table 1, Entry 11)
1
IR (neat): y 3031, 2975, 2361, 1712, 1455, 1180, 751, 697, 637 cm21. H
NMR (300 Hz, CDCl3): 7.99–7.90 (4H, m), 7.46–7.41 (d, 2H, J ¼ 8.60),
6.91–6.87 (d, 2H, J ¼ 8.60), 6.59 (1H, s), 3.84 (3H, s), 1.33 (1H, s). MS
(EI) m/z: 391 (M2þ), 369 (Mþ), 309.
ACKNOWLEDGMENTS
P. S. R. thanks the Council of Scientific and Industrial Research, New Delhi,
for the award of a senior research fellowship. M. M. thanks the director, Indian
Institute of Chemical Technology (IICT), for providing facilities to carrying
out her dissertation work.
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