Aq HBr–NaNO2–KI/air: a new catalytic system for α-monobromination of ketones

Article abstract of DOI:10.1016/j.tetlet.2016.09.073

An efficient approach for α-bromination of aryl alkyl ketones, utilizing a system consisting of aqueous hydrobromic acid as bromine source, sodium nitrite–KI as catalyst, and air as terminal oxidant, has been developed. The method offers advantages of selective monobromination, mild reaction conditions, broad substrate scope, and good yield. The use of air as the terminal oxidant makes the reaction very attractive from both economical and environmental viewpoints.

Full text of DOI:10.1016/j.tetlet.2016.09.073

Accepted Manuscript
Aq HBr- NaNO -KI/air: a new catalytic system for α-monobromination of ke-
2
tones
Archana K. Ghorpade, Sameerana N. Huddar, Krishnacharya G. Akamanchi
PII:
S0040-4039(16)31254-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.073
TETL 48143
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 August 2016
19 September 2016
21 September 2016
Please cite this article as: Ghorpade, A.K., Huddar, S.N., Akamanchi, K.G., Aq HBr- NaNO -KI/air: a new catalytic
2
system for α-monobromination of ketones, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
016.09.073
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Tetrahedron Letters
Aq HBr- NaNO -KI/air: a new catalytic system for α-monobromination of ketones
2
*
Archana K. Ghorpade, Sameerana N. Huddar, Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai, 400019, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient approach for α-bromination of aryl alkyl ketones, utilizing a system consisting of
aqueous hydrobromic acid as bromine source, sodium nitrite-KI as catalyst and air as terminal
oxidant, has been developed. The method offers advantages of selective monobromination, mild
reaction conditions, broad substrate scope, and good yield. The use of air as the terminal oxidant
makes the reaction very attractive from both economical and environmental viewpoints.
Available online
Keywords:
Ketones
2016 Elsevier Ltd. All rights reserved.
Bromination
Bromoketones
HBr
NaNO / KI
2
Oxygen as oxidant
Introduction
α-Bromoketones are among the most versatile intermediates in
admirable; however oxidants are required to be used in
stoichiometric amount leading very poor atom economy with
formation of waste. For this reason oxygen as an oxidant is a
very attractive substitute.
organic synthesis as they offer two electrophillic sites and acidic
1
protons due to the presence of two electron withdrawing groups .
2
They find wide applications in heterocyclic synthesis .
Conventional methods for α-bromination of aryl alkyl ketones
19
Iodine monochloride is an iodinating agent , where as iodine
require hazardous and toxic elemental bromine in the presence of
20
3
monobromide(IBr) acts as brominating agent . IBr is mild
protic or Lewis acids . To overcome the difficulty of handling of
brominating agent for electron rich aromatic ring bromination,
liquid bromine, solid bromine reagents such as dioxane-
4
5
dibromide , tetra-butyl ammonium tribromide , MgBr
2
-
for example phenol and salicylic acids have been brominated in
6
7
21
(
hydroxy(tosyloxy)iodo)benzene-MW , BDMS ,
methylpyrrolidin-2-one hydrotribromide (MPHT) , (CH
N-
SiBr–
nitrobenzene
as
solvent .
The
diastereoselective
8
3
)
3
monobromination of steroidal aldehydes using IBr has been also
9
22
KNO
3
have been developed. N-Bromosuccinimide (NBS) is an
reported .
alternative brominating reagent. It has been reported that ketones
1
0
11
are α-brominated using NBS–NH
4
OAc , NBS-photochemical ,
It is an elementary reaction between iodine and bromine to form
IBr. Both iodine and bromine can be generated by reacting with
1
2
13
NBS– PTSA , NBS–silica supported sodium hydrogen sulfate ,
1
4
15
16
NBS–Amberlyst , NBS–Lewis acids and NBS–ionic liquids .
The handling of liquid bromine, due to its hazardous nature, is
troublesome and special equipment and care is needed for the
transfer of these materials in large scale, moreover only one
bromine atom is utilized. Use of NBS is a better alternative for
molecular bromine, but drawback is it is expensive and generates
organic waste. Though all the literature methods provide good
yields, most of them suffer from one or more disadvantages such
as long reaction times, harsh reaction conditions, use of
hazardous chemicals, formation of α, α-dibromination and ring
bromination products. Hence development of an efficient, eco-
friendly procedure for the α-monobromination of ketones
remains a major challenge for organic chemists.
NaNO
2
with the corresponding acid or salt in acidic aqueous
23
medium and in the process generating NO . It is also known that
24
NO can be readily oxidized to NO
Combining these facts we designed a new system for α-
monobromination of various ketones using aqHBr-NaNO -KI/air.
2
simply by mixing with air .
2
In order to optimize the reaction conditions, acetophenone was
chosen as model substrate. The results of optimization reactions
performed under different conditions are summarized in Table1.
Phenacyl bromide was obtained in 88% isolated yield upon
treatment with aqHBr (33%, 1eq), NaNO
2
(1.2eq) and KI (10 mol
%) at room temperature for 12h (Table 1, entry 1).
Generally, oxybromination is carried out with a combination of a
bromide source and variety of oxidizing reagents, such as HBr-
17
18
2 2 4
H O , and NH Br-Oxone . Although these systems are

2
Tetrahedron
a
c
6
12
10
78
84
Table 1: Optimization of reaction conditions
b
Entry
Aq HBr
Eq
1
NaNO
eq
1.2
1.2
1.2
1
0.5
0.25
0.5
0.5
0.5
2
KI
mol%
10
10
10
10
10
10
5
Yield
%
88
1
2
3
4
5
6
7
8
c
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
90
7
90
90
90
56
90
60
trace
8
10
85
0.25
0
9
a
carried out with 10 mmol of acetophenone at room temperature using aq HBr
b
of 33% concentration. isolated yield
c
9
1
10
10
85
84
Several experiments were conducted to arrive at an optimum
ratio of HBr, NaNO
was obtained with 1.2 eq aqHBr, 0.5 eq NaNO
Table 1, entry 5). Lowering the KI amount to 5 mol% led to
2
and KI. As shown in Table 1, 90% yield
2
and 10 mol% KI
c
c
0
1
(
similar results. However with further reduction in amount of KI
to 0.25 mol% yield decreased substantially to 60% (Table 1,
entries 7 and 8). In absence of KI practically no α-bromination
product was formed indicating involvement of IBr rather than
any species generated by reaction between NaNO and HBr. The
2
observed selectivity could be attributed to stereoelectronic factors
1
10
10
83
with respect to both α-bromo compounds and IBr. Finally 1.2 eq
c
1
2
86
aqHBr, 0.5 eq NaNO
2
and 5 mol% KI were considered as
optimum conditions and used to establish general applicability of
2
5
the method . To show generality of this new system, it was
applied to a series of electronically diversified ketones and results
are presented in Table 2. We were delighted to find that the
protocol tolerates a wide range of functionalities. There was no
significant difference in the reaction of substrates having electron
a
b
ketone 10 mmol, aq HBr 12 mmol, NaNO
2
5 mmol , KI 5 mol % , isolated
c
yield, To solubalise the substrates ACN was used as co-solvent in the ratio
2
of H O:ACN , 8:2.
One control experiment was performed to observe effect of air.
Acetopheone 10 mmol was treated with 12 mmol of aqHBr,
5
only 48% yield of phenacyl bromide was obtained due to the
presence of limited amount of oxidizing agent. This proves that
air is indeed acting as terminal oxidant.
3 3
donating (CH , OCH , and OH), halogens (F, Cl, Br) and electron
2
mmol of NaNO and KI 5mol% in the absence of air for 12 h;
withdrawing NO
2
groups and all the substrates afforded moderate
to good yields of corresponding α-bromoketones.
Plausible reaction mechanism is outlined in Figure 1. In the first
instant IBr is generated by the reaction of NaNO
while NO ⁻ is reduced to NO. The NO formed gets reoxidized
back to NO by air. IBr reacts with ketone to form α-
bromoketone and iodide ion is liberated back into the cycle.
Formation of IBr and reoxidation of NO to NO and continuation
2
, HBr and KI;
2
b
Time
Yield
(%)
Entry
1
Substrate
Product
2
(h)
2
of cycle can be understood in the following elementary balanced
equations.
8
92
90
89
2
2
2
NaNO2 + 4HBr + KI → 2NaBr + KBr + IBr + 2NO + 2H
NO + O → 2NO2
NO2 + H O → HNO
+ 2HBr + HI → HNO
+ HBr + HI → IBr + NO + H
2
O
2
10
10
2
2
2
+ HNO3
2
+ IBr + H O
c
3
HNO
HNO
3
2
2
2
O
4
5
10
8
85
84

2
3. Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M.
Advanced inorganic chemistry, Wiley international publication,
John Wiley and Sons, INC, 1999.
2
2
4. Holleman, A. F.; Wiberg, E. (2001) Inorganic Chemistry.
Academic Press: San Diego. ISBN 0-12-352651-5.
5. Experimental procedure: bromination of acetophenone
In a RBF cooled in ice bath at 0ºC, aqHBr 33% (0.97g, 12 mmol,
Fig.1 Catalytic cycle and plausible mechanism of α-bromination
in 2 ml of water) was taken. To this a solution of NaNO
mmol, in 5 ml of water) was added drop wise. The reaction was
stirred for 15 min maintaining the temperature at 0 ºC, and then KI
5 mol %) was added. After 10 min acetophenone (1.2g, 10 mmol)
was added at once. After 15 min reaction temperature was brought
to room temperature slowly. Reaction was monitored by TLC
2
(0.345g,
5
In summary we have developed a new system for α-
monobromination of aryl alkyl ketones. The key features of this
system include broad tolerance of functional groups, good yields
of targeted products, use of oxygen from the air as terminal
oxidant. The use of air as the terminal oxidant makes the system
very attractive from both economical and environmental
perspective. Furthermore environmentally benign water or in
some cases small quantities of organic solvent acetonitrile to
solublize the substrates in aq HBr were employed.
(
(
ethyl acetate: pet ether, 1:9). After completion of reaction 50 ml
of CHCl3 was added and organic layer was separated. Aqueous
layer extracted twice with 25 ml of CHCl and combined organic
layer was washed with 10% NaHSO solution (2 x 20 ml) and
0% NaHCO solution (2 x 20 ml). The organic layer was dried
3
3
1
3
over sodium sulphate and concentrated under reduced pressure
and residue was chromatographed (silica gel, #60-120, eluent
ethyl acetate: pet ether, 10:90) to get pure phenacyl bromide as
1
Acknowledgments
The authors thank the CSIR-UGC, New Delhi, India, for
financial support.
white solid; Yield 90%; mp 48–50 ℃; H NMR (400 MHz,
3
CDCl ): δ (ppm) 7.97 (m, 2H), 7.61 (m, 1H), 7.48 (m, 2H), 4.48
(s, 2H).
Supplementary data:
1
13
The H and C NMR spectra of synthesized compounds are
provided in supporting information.
References and notes:
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2
Tetrahedron
Graphical Abstract
Aq HBr- NaNO
2
-KI/air: a new catalytic
Leave this area blank for abstract info.
system for α-monobromination of ketones
*
Archana K. Ghorpade, Sameerana N. Huddar, Krishnacharya G. Akamanchi

3
Highlights





α-Bromoketones are the most versatile intermediates in organic synthesis.
Method offers new catalytic method for α-monobromination of aryl alkyl ketones.
Mild reaction conditions, broad substrate scope and good yield.
Air as a terminal oxidant makes the method attractive from environmental concern.
This catalytic bromination method holds promise for new application developments.