Metal-free protocol for the synthesis of α-bromo ketones from olefins using TsNBr2

Article abstract of DOI:10.1016/j.tetlet.2014.11.096

TsNBr₂ reacts readily with olefins to produce α-bromo ketones at room temperature. The synthesis was carried out by treating an olefin with TsNBr₂ in acetone-water mixture in 30:1 ratio. Excellent yield of corresponding α-bromo ketone could be achieved within a short time.

Full text of DOI:10.1016/j.tetlet.2014.11.096

Accepted Manuscript
Metal-free protocol for the synthesis of α-bromo ketones from olefins using
TsNBr2
Kamal Krishna Rajbongshi, Debojit Hazarika, Prodeep Phukan
PII:
S0040-4039(14)02000-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.096
TETL 45480
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 June 2014
14 November 2014
21 November 2014
Please cite this article as: Rajbongshi, K.K., Hazarika, D., Phukan, P., Metal-free protocol for the synthesis of α-
bromo ketones from olefins using TsNBr2, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.11.096
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Graphical Abstract
.
Metal-free protocol for the synthesis of α-bromo
ketones from olefins using TsNBr2
Leave this area blank for abstract info.
Kamal Krishna Rajbongshi, Debojit Hazarika and Prodeep Phukan
O
TsNBr2 (2.2 equiv)
R'
R
R'
R
Acetone-water (30:1), rt
Br

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Metal-free protocol for the synthesis of α-bromo ketones from olefins using
TsNBr2
Kamal Krishna Rajbongshi, Debojit Hazarika and Prodeep Phukan*
Department of Chemistry, Gauhati University, Guwahati -781014, Assam, India; E-mail: pphukan@yahoo.com
ARTICLE INFO
ABSTRACT
Article history:
Received
TsNBr2 reacts readily with olefins to produce α-bromo ketones at room temperature. The
synthesis was carried out by treating an olefin with TsNBr2 in acetone-water mixture in 30:1
ratio. Excellent yield of corresponding α-bromo ketone could be achieved within a short time.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
TsNBr2
Olefin
α-Bromo ketone
Bromination
α-Bromo ketones belong to an important class of compounds
which are widely used in synthetic organic chemistry as well as
in medicinal chemistry.1-3 A range of pharmaceutically important
heterocycles such as thiazoles, imidizoles, indoles etc. were
olefins is highly desirable. We have recently found that N,N-
dibromo-p-toluenesulfonamide (TsNBr2) is a very efficient and
powerful reagent for various organic transformations.15 Huang et
al. used TsNBr2 in allenoates system for the synthesis of
(1E,2E)-3-bromo-4-oxo-N-tosyl-2-alkenoxylimidic acid ethyl
esters.16 During our initial investigations on TsNBr2, we found
that this reagent is very efficient for the synthesis of bromohydrin
from olefin.15a We also reported that alcohols can be oxidized to
corresponding carbonyl compound using TsNBr2.15c Based on
these observations, we desired to develop a direct one-pot
procedure for the synthesis of α-bromo ketones from olefin
(Scheme 1).
synthesized using α-bromo ketones as starting materials.2-3
A
common strategy for the synthesis of α-bromo ketones is the
bromination of the corresponding carbonyl compound using
molecular bromine in the presence of a protic or Lewis acid.4
Due to the hazardous nature of liquid bromine, various solid
brominating agents were developed for α-bromination of ketones,
which
include
important
examples
such
as
phenyltrimethylammonium perbromide,3 NBS,5 CuBr2 and
bromide/bromate couple.7 However direct synthesis of α-bromo
ketones from olefins is more preferable from a synthetic point of
view. Literature study reveals that a limited number of methods
are available for the direct synthesis of α-bromo ketones from
olefins. Recently, Guo reported a protocol for the synthesis of
phenacyl bromide from styrene using KBr in presence of K2S2O8
at 60 °C.8 Akamanchi et al. synthesized α-bromo ketone from
6
O
TsNBr2 (2.2 equiv)
R'
R
R'
R
Acetone-water (30:1), rt
Br
Scheme 1. Synthesis of α- bromo ketone from olefin using TsNBr2
olefin
using
O-iodoxybenzoic
acid
along
with
tetraethylammonium bromide in anhydrous dichloromethane.9
Moorthy developed a strategy for the synthesis of α-bromo
ketones and α-iodo ketones from olefins using NBS and NIS in
presence of IBX as oxidising agent.10 Other reagents used for this
particular transformation are: bromide/ bromate,11 HBr–H2O2 -
KBr in the presence of vanadium catalyst,12 HBr-H2O under
photo oxidation13 and sodium bromite in acetic acid.14 Although a
few convenient methods have been reported recently, many
processes have limitations such as long reaction time, use of
additional oxidizing agent, stringent dry reaction conditions, use
of metal catalyst, low yields. Hence, the development of an
improved procedure for direct synthesis of α-bromo ketones from
To begin with, a study was carried out for evaluation of the
efficacy of the reagent TsNBr2, for oxidative bromination of
styrene (Table 1). In a typical reaction, TsNBr2 (2 mmol) was
added to the solution of styrene (1 mmol) in a mixture CH3CN
and H2O (4:1, 5mL) at room temperature. The progress of
reaction was monitored by TLC. The reaction produced
corresponding phenacyl bromide in 58 % yield after 5h of
reaction. The reaction was then studied by using 3mL of
acetonitrile and 0.1 mL of water keeping all other conditions
identical to previous experiment. In this case, better yield (70 %)

2
Tetrahedron Letters
was observed after 3h of reaction. Further study after increasing
O
Br
7
the amount of TSNB2 from 2 equivalents to 2.2 equivalents could
led to an improvement in yield to 77 %. Next, a change of
solvent system to a mixture of acetone and water (30:1),
interestingly produced much better result in terms of both yield
(87 %) and reaction time (1h). Use of some other solvent systems
like DMF-water, DMSO-water was not found fruitful. After
chromatographic purification, p-toluenesulfonamide (TsNH2)
was isolated as a byproduct in the reaction. It has already been
reported that TsNH2 can also be converted to TsNBr2 by the
action of bromine on TsNH2 in presence of a base.17
2
2
82
82
2g
O
Br
8
9
2h
O
1
2
91
81
2i
Br
O
10
11
Table 1. Synthesis of α- bromo ketone from styrene using
TsNBr2a
Entry
Br
2j
Solvent (mL)
TsNBr2 Time Yieldb
(equiv)
(h)
(%)
O
O
O
2
80
1
2
3
4
5
5
CH3CN-H2O (4:1), 5 mL
CH3CN (30:1), 3mL
2
5
3
3
1
5
5
58
70
CH3
CH3
2
Br
2k
CH3CN (30:1), 3mL
2.2
2.2
2.2
2.2
77
O
CH3COCH3 (30:1), 3mL
DMF-H2O (30:1), 3mL
DMSO-H2O (30:1), 3 mL
87
Br
12
13
2
2
2
73
75
trace
Nil
2l
aReaction condition: Styrene (1 mmol), rt. b Isolated yields
O
Br
After establishing the optimum reaction conditions, the
reaction was extended for variety of olefins.16 Results are
summarized in Table 2. From the table, it can be seen that
different kinds of olefins such as substituted styrenes, chalcone
and 1-octene could be transformed into corresponding α-bromo
ketones in excellent yields within a short time. The reaction
works extremely well in case of aromatic olefins. However,
aliphatic olefins such as 1-octene produced slightly lower yield
of the corresponding product (Table 2, entry 12).
2m
O
Br
78
14
2n
a Reaction Conditions. Olefin (1 mmol), Acetone-H2O (30:1;
3 mL), TsNBr2 (2.2 mmol), rt. b Isolated yield
After successfully carrying out the reaction with various
olefins, we have investigated the reaction with a diene system.
Interestingly, when diene 3a was treated with TsNBr2, δ-bromo-
β,γ-unsaturated amine (3b) was isolated in 62% yield under
similar conditions (Scheme 2). However, in this case, we also
observed addition of bromine to aromatic ring.15j The diene 3a
was synthesized following a literature procedure.18
Table 2. Synthesis of α- bromo ketone from various olefinsa
Entry
Substrate
(a)
Product
(b)
Time Yieldb
(h)
(%)
O
Br
1
1
87
2a
NHTs
MeO
O
MeO
MeO
Br
TsNBr2 (2.2 equiv)
2
3
4
5
Br
Br
1.2
83
MeO
Br
Acetone, water (30:1), rt
Br
OMe
OMe
2b
Br
Cl
3b (62%)
3a
O
Scheme 2. Reaction of TsNBr2 with diene
Cl
1.5
2
80
81
87
2c
A probable mechanistic pathway to explain the regioselectivity of
the bromoketone formation is depicted in Scheme 3.
O
Br
F
2d
OH
F
Br
O
TsNBr2
Br
Br
_
OH
4
1.5
1a
3
H3C
2e
H3C
TsNBr2
OBr
O
O
Br
_
6
2
82
HBr
Br
Br
2a
5
2f
CH3
CH3
Scheme 3. A plausible reaction mechanism

3
A three-membered cyclic bromonium ion intermediate 3 is
formed at the initial stage of the reaction due to electrophilic
addition of the Br+ ion (generated from TsNBr2) onto the
olefin.15a, 19 The intermediate 3 undergoes ring opening by water
9
Deshmukh, S. S.; Chaudhari, K. H.; Akamanchi, K. G.
Synlett 2011, 81-83.
10 Moorthy, J. N.; Senapati, K.; Singhal, N. Tetrahedron
Lett. 2009, 50, 2493-2496.
2
via the SN pathway to produce bromohydrin 4. The
11 Patil, R. D.; Joshi, G.; Adimurthy, S.; Ranu, B. C.
Tetrahedron Lett. 2009, 50, 2529-2532.
12 Moriuchi, T.; Yamaguchi, M.; Kikushima, K.; Hirao, T.
Tetrahedron Lett. 2007, 48, 2667-2670.
regioselectivity can be explained by considering the fact that the
β-position is more positive than the α-position. Nucleophilic
opening of the cyclic bromonium intermediate is most likely
from the more positive β -position. The resulting bromohydrin 4
undergoes further oxidation via intermediate 5 to produce the
final product α-bromo ketone readily.20
13 Nobuta, T.; Hirashima, S.-i.; Tada, N.; Miura, T.; Itoh, A.
Synlett 2010, 2335-2339.
14 Kageyama, T.; Tobito, Y.; Katoh, A.; Ueno, Y.; Okawara,
M. Chem. Lett. 1983, 12, 1481-1482.
15 (a) Phukan, P.; Chakraborty, P.; Kataki, D. J. Org. Chem.
2006, 71, 7533-7537; (b) Saikia, I.; Phukan, P.
Tetrahedron Lett. 2009, 50, 5083-5087; (c) Saikia, I.;
Chakraborty, P.; Phukan, P. ARKIVOC, 2009 (xiii), 281
(d) Saikia, I.; Kashyap, B.; Phukan, P. Synth. Commun.
2010, 40, 2647-2652; (e) Saikia, I.; Kashyap, B.; Phukan,
P. Chem. Commun. 2011, 47, 2967-2969; (f) Borah, A.
J.; Phukan, P. Chem. Commun. 2012, 48, 5491-5493; (g)
Saikia, I.; Rajbongshi, K. K.; Phukan, P. Tetrahedron
Lett. 2012, 53, 758-761; (h) Borah, A. J.; Phukan, P.
Tetrahedron Lett. 2012, 53, 3035-3037; (i) Rajbongshi,
K. K.; Phukan, P. Tetrahedron Lett. 2014, 55, 1877-1878;
(j) Saikia, I.; Chakraborty, P.; Sarma, M. J.; Goswami,
M.; Phukan, P. Synth. Commun. 2014, DOI:
10.1080/00397911.2014.956367.
In summary, an efficient process has been developed for
direct synthesis of α- bromo ketones from olefins. Different kinds
of olefins could be transformed into corresponding α-bromo
ketones under mild reaction conditions with excellent yield.
Acknowledgments
Financial Support from DST (Grant No. SR/S1/OC-
43/2011) is gratefully acknowledged.
References and notes
1 (a) Takami, K.; Usugi, S.-i.; Yorimitsu, H.; Oshima, K.
Synthesis 2005, 824-839; (b) Li, L.; Cai, P.; Xu, D.;
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E.; Axiotis, G.; Bertounesque, E. Tetrahedron Lett.
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1969, 47, 694-697; (b) Venkatasubramanian, N.;
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21 Experimental Procedure: To a solution of olefin
(1mmol) in acetone (3 mL) and water (0.1 mL), TsNBr2
(2.2 mmol) was added at room temperature. After
completion of reaction, sodium thiosulfate (200 mg
approx.) was added and the reaction mixture was stirred
for another 10 min. The reaction mixture was extracted
with ethyl actetate, dried (Na2SO4) and concentrated.
Purification of the crude product by flash chromatography
on silica gel (230-400 mesh) with petroleum ether –
EtOAc as eluent gave the pure product.
2 (a) Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules
2003, 8, 793–865; (b) Donohoe, T. J.; Kabeshov, M.
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Marek, A.; Kulhanek, J.; Ludwig, M.; Bures, F.
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8
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Tetrahedron Letters
Highlight
Title of the manuscript:
Metal free protocol for the synthesis of α-bromo ketones from olefins using
TsNBr2
Authors: Kamal Krishna Rajbongshi, Debojit Hazarika and Prodeep Phukan
•
•
•
•
•
A fast method for synthesis of α-bromo ketones from olefins
Use of TsNBr2 as brominating as well as oxidizing agent.
No additional oxidizing agent needed.
The product yields are excellent.
Different kind of olefins could be transformed.