Oxidative bromination of ketones using ammonium bromide and oxone

Article abstract of DOI:10.1016/j.tetlet.2011.11.011

A highly efficient, environmentally safe and economic method for selective α-monobromination of aralkyl, cyclic, acyclic, 1,3-diketones and β-keto esters and α,α-dibromination of 1,3-diketones and β-keto esters without catalyst is reported using ammonium bromide as a bromine source and oxone as an oxidant. The reaction proceeds at ambient temperature and yields range from moderate to excellent. Bromination of unsymmetrical ketones takes place at the less substituted α-position predominantly. Aromatisation of tetralones is also carried out with this reagent system.

Full text of DOI:10.1016/j.tetlet.2011.11.011

Tetrahedron Letters 53 (2012) 191–195
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative bromination of ketones using ammonium bromide and oxoneÒ
Arun Kumar Macharla, Rohitha Chozhiyath Nappunni, Mahender Reddy Marri, Swamy Peraka,
⇑
Narender Nama
I&PC Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient, environmentally safe and economic method for selective a-monobromination of aral-
Received 26 September 2011
Revised 31 October 2011
Accepted 3 November 2011
Available online 9 November 2011
kyl, cyclic, acyclic, 1,3-diketones and b-keto esters and
a,a-dibromination of 1,3-diketones and b-keto
esters without catalyst is reported using ammonium bromide as a bromine source and oxoneÒ as an oxi-
dant. The reaction proceeds at ambient temperature and yields range from moderate to excellent. Bro-
mination of unsymmetrical ketones takes place at the less substituted
Aromatisation of tetralones is also carried out with this reagent system.
a-position predominantly.
Keywords:
Ketones
Ó 2011 Elsevier Ltd. All rights reserved.
Bromine
Regioselectivity
Green chemistry
Dehydrogenation
The
a
-bromination of ketones is an important transformation in
several environmental drawbacks. 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.
Though all these 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 and cumber-
some work-up procedures. The use of NBS is a better alternative for
molecular bromine, which does not produce HBr in this reaction;
but it is expensive and generates organic waste. Furthermore, most
of these methods generally employ strongly acidic or basic condi-
synthetic organic chemistry.1
a-Bromoketones are among the most
versatile intermediates in organic synthesis and their high reactiv-
ity makes them prone to react with large number of nucleophiles
to provide a variety of biologically active compounds.2
a-Bromo-
acetophenone derivatives have been investigated for their active
participation in the inhibition of protein tyrosine phosphatase such
as SHP-1 and PTP1B.3 Bromination at the reactive position in a 1,3-
keto compound enhances bioactivity, particularly cytotoxicity
against breast cancer 1A9 cells, with respect to the unsubstituted
compound.4
tions and accompany undesirable formation of
a,a-dibrominated
The most commonly used reagents for
a-bromination of ketones
products in significant amount. Hence, the development of an effi-
include molecular bromine,5 N-bromosuccinimide (NBS)6 and
cupric bromide.7 Recently, various methods have been reported
using NBS–NH4OAc,8 NBS-photochemical,9 NBS–PTSA,10 NBS–silica
supported sodium hydrogen sulfate,11 NBS–Amberlyst-15,12 NBS–
Lewis acids,13 NBS–ionic liquids,14 MgBr2-(hydroxy(tosyloxy)iodo)
benzene-MW,15 N-methylpyrrolidin-2-one hydrotribromide (MPHT),16
(CH3)3SiBr–KNO3,17 BDMS,18 NaBr.19
Reagents used for the bromination of unsymmetrical acyclic
ketones are NBS–NH4OAc,8 NBS-photochemical,9 and NBS–PTSA10
and all these methods provide a mixture of 1-bromo(terminal) and
3-bromo ketones with predominant formation of 3-bromo product.
Gaudry and Marquet reported the selective terminal bromination of
unsymmetrical acyclic ketone using elemental bromine.20 From the
green chemistry point of view the use of elemental bromine has
cient, eco-friendly, atom-economic (100% with respect to bromine)
and selective procedure for the a-monobromination of ketones re-
mains a major challenge for synthetic organic chemists.
OxoneÒ (2KHSO5, KHSO4, K2SO4), a potassium triple salt con-
taining potassium peroxy monosulfate, is an effective oxidant. Ox-
oneÒ is becoming increasingly popular reagent for oxidative
transformations21–25 due to its stability, water solubility, ease of
transport, nontoxic ‘green’ nature, safety profile, cost-effectiveness
and non-polluting byproducts.
In continuation of our work on the application of NH4Br/oxoneÒ
system,26 we wish to explore the applicability of this reagent
system for the bromination of ketones. Herein, we report the
bromination of various ketones such as aralkyl, cyclic, acyclic,
1,3-diketones and b-keto esters at room temperature (or reflux
temperature) without the use of catalyst.27 However, to the best
of our knowledge bromination of ketones using NH4Br/oxoneÒ
system has not been previously reported.
⇑
Corresponding author. Tel.: +91 40 27191703; fax: +91 40 27160387/757.
E-mail address: narendern33@yahoo.co.in (N. Nama).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.011

192
A. K. Macharla et al. / Tetrahedron Letters 53 (2012) 191–195
Table 1 (continued)
Table 1
Bromination of aralkyl ketones using NH4Br and oxoneÒa
Entry
Substrate
Time
Product
Yieldb (%)
Entry
Substrate
Time
Product
Yieldb (%)
O
O
Br
O
O
44 hc
89
97
Br
Br
13
7 hc
81
97
1.3 hd
F
F
1
15 mind
1m
1a
O
O
O
O
O
Br
O
48 hc
3 hd
14 (16)e
46 (14)e
26 hc
92
91
14
2
3
2.5 hd
NO2
NO2
1b
1n
O
O
Br
Br
24 hc
84
96
24 hc
8 (12)e
40 mind
15
16
17
18
19
1.5 hd
21 (34)e
O2N
O2N
1o
1c
O
O
O
O
Br
Br
48 hc
16 hd
38
6 hc
63
94
4
5
6
35 (6)e
2.5 hd
NC
NC
Br
1p
1d
O
O
O
O
Br
4.5 hc
1.5 hd
61 (26)f
48 (28)f
7 hc
54
86
1.5 hd
OH
O
OH
Et
Et
1q
1e
O
O
O
Br
Br
Br
1 hc
93
83
42
56
48 hc 4 hd
5 mind
NH2
O
NH2
Br
O
Br
1s
1f
O
O
26 hc
10
58
48 hc
2 hd
37 (28)e
73
Br
7.5 hd
7
Br
Br
1t
1g
O
O
Br
O
O
O
24 hc
39
87
Br
48 hc
37
98
20
21
1.25 hd
8
9
1.5 hd
Br
Br
1u
1h
O
O
O
Br
24 hc
60
97
Br
Br
48 hc
3 hd
50
73
20 mind
Cl
O
Cl
1v
1i
O
O
O
40 minc
10 mind
97
94
47 hc
2 hd
49
87
22
23
O
O
10
11
12
Br
Cl
Cl
1w
1j
O
O
O
O
O
OH
OH
Br
Br
Br
24 hc
2 hd
81
85
3 hc
98
98
15 mind
F
F
O
1k
O
1x
O
Reaction conditions: Substrate (2 mmol), NH4Br (2.2 mmol), oxoneÒ (2.2 mmol),
a
39 (34)e
83
methanol (10 ml), room or reflux temperature.
24 hc 2 hd
b
The products were characterized by 1H NMR, Mass spectra and quantified by GC.
c
F
F
Room temperature.
Reflux temperature.
a
d
1l
e
-Bromo dimethyl ketal.
f
3-Bromo-2-hydroxyacetophenone (1r).

A. K. Macharla et al. / Tetrahedron Letters 53 (2012) 191–195
193
Table 2
Bromination of various cyclic and acyclic ketones using NH4Br and oxonea
Entry
Substrate
Time
Product (Yieldb (%))
O
O
Br
(65)
2 hc
(80)
1
30 mind
2a
O
O
O
(92)
Br
Br
6 hc
(98)
2
3
20 mind
2b
O
(77)
(77)
28 hc
2 hd
2c
O
O
Br
(79)
(95)
6 hc
4
20 mind
2d
O
Br
O
(90)
(87)
2 hc
5
6
20 mind
OMe
OMe
2e
O
O
Br
O
MeO
MeO
Br
MeO
(17)
(42)
(42)
(18)
2.5 hc
1 hd
2f
2g
O
O
O
Br
(80)
(09)
7
8
9
8 hc
Br
2h
2i
O
O
O
-
(90)
(85)
Br
7 hc
(06)
Br
5 mind
2k
2j
O
O
O
(65)
(10)
(21)
5 hc
Ph
Br
Br
Ph
Ph
(71)
Br
30 mind
2m
2l
O
O
O
C4H9
C4H9
C4H9
(62)
(55)
(37)
(44)
9 hc
1 hd
10
11
Br
2n
2o
O
O
O
C6H13
(71)
(28)
(23)
C6H13
C6H13
Br
7 hc
(76)
20 mind
Br
2p
2q
a
b
c
Substrate (2 mmol), NH4Br (2.2 mmol), oxoneÒ (2.2 mmol), methanol (10 ml).
The products were characterized by 1H NMR, Mass spectra and quantified by GC.
Room temperature.
d
Reflux temperature.
Initially, the effect of different solvents on the
a
-bromination of
Among the solvents used, methanol appeared to be the most
suitable in terms of maximum yield.
acetophenone was studied using NH4Br/oxoneÒ system. In metha-
nol at room temperature, the reaction completed within 7 h to give
With the optimized conditions in hand, a variety of aralkyl
ketones (acetophenone, substituted acetophenones, acetonaph-
thone and substituted acetonaphthones) were subjected to the
bromination reactiontotest thegeneralityofthismethodandthere-
sults are summarized in Table 1. All the reactions were performed
the a-brominated product in an 81% yield together with recovery
of the starting material. The reaction in CH3CN, H2O gave less than
a 15% yield after 7 h and in case of other solvents (DCM, CHCl3,
CCl4, EtOH, hexane, ether and THF) the yields were negligible.

194
A. K. Macharla et al. / Tetrahedron Letters 53 (2012) 191–195
Table 3
using 2 mmol of substrate with 2.2 mmol of NH4Br and 2.2 mmol of
oxoneÒ in 10 ml methanol at room temperature (or reflux
temperature).
Bromination of 1,3-dicarbonyl compounds using NH4Br and oxoneÒ
Entry Substrate
O
Time
Product (Yielda (%))
It is interesting to mention the effect of reaction temperature on
course of bromination, high yields are obtained at reflux tempera-
ture in short reaction time compared to room temperature. In or-
der to determine the influence of the substitution on aromatic
ring on the reaction path with this reagent system, we studied
the reaction with different substitutions on phenyl ring of aceto-
phenone and acetonaphthones. Presence of highly activating
groups (Table 1, entries 17, 18 and 22) on phenyl ring favours nu-
clear bromination, whilst moderately activating and deactivating
O
O
O
O
O
-
(94)
-
40 minb
30 hc
Ph
Ph
Ph
Ph
Ph
Ph
(90)
1
Br
Br Br
3a
3b
O
O
O
Br
(10)
(95)
(80)
-
1 hb
Br
Br
2
40 mind
O
O
O
3c
3d
O
O
O
O
O
O
(75)
-
O
O
(24)
(94)
O
O
3 hb
groups favours the
electron-withdrawing groups (Table 1, entries 14 and 15) present
on phenyl ring gave -brominated product, along with substantial
amount of -bromo dimethyl ketals. Propiophenone gave the
a
-bromination (Table 1, entries 2–13). Strong
O
Br
Br
Br
3
30 mind
a
3e
3f
a
a
-
O
O
(81)
O
O
(18)
(96)
35 minb
30 mind
-
O
O
Ph
O
O
Ph
brominated product with this reagent system, but yield was less
even after longer reaction time (Table 1, entry 19). 2-Hydroxy-
1,4-naphthoquinone showed good reactivity with this reagent sys-
tem and gave 3-bromo-2-hydroxy-1,4-naphthoquinone (1x) in
high yield within short reaction time (Table 1, entry 23).
Further, we studied the bromination of cyclic and acyclic ke-
tones under similar reaction conditions and results are summarized
in Table 2. Cyclic ketones are reacted well under the present reac-
O
Ph
4
5
6
Br
O
Br
Br
3g
3h
O
(90)
-
O
O
(09)
30 minb
3 hc
(94)
Ph
O
O
Ph
O
Ph
O
Br
Br
Br
3i
3j
O
O
O
O
(70)
O
O
O
9 hb
Br
tion condition to furnish corresponding
a-bromo ketone in good
3k
to excellent yields, except 5-methoxy and 7-methoxytetralone. 5-
Methoxytetralone afforded the respective ring brominated product
(2e) selectively and 7-methoxy-1-tetralone at room temperature
O
O
O
O
(87)
(95)
O
Br
7
8
5 hb
Ph
Ph
forms the corresponding
a-brominated (2f) and ring brominated
3l
(2g) products in the ratio of 17:42 in 2.5 h and the same reaction
at reflux temperature afforded a 42:18 ratio within 1 h.
Interesting results were observed when unsymmetrical acyclic
ketones subjected to the bromination with this reagent system.
On contrary to the earlier reports8–10, bromination took place at
O
O
O
O
O
30 minb
Br
3m
a
The products were characterized by 1H NMR, Mass spectra and quantified by
less substituted
Finally, we investigated the bromination of 1,3-dicarbonyl com-
pounds under similar reaction conditions. A variety of -unsubsti-
tuted 1,3-diketones and b-keto esters were -mono brominated
and
-dibrominated using NH4Br and oxoneÒ with excellent
yields (Table 3, entries 1–5). Similarly, -substituted-b-keto esters
underwent -bromination smoothly under similar conditions and
a-position predominantly (Table 2, entries 7–11).
GC.
b
Substrate (2 mmol), NH4Br (2.2 mmol), oxoneÒ (2.2 mmol), methanol (10 ml),
room temperature.
a
c
Substrate (2 mmol), NH4Br (4.4 mmol), oxoneÒ (4.4 mmol), methanol (10 ml),
a
reflux temperature.
a,a
d
Room temperature.
a
a
afforded the corresponding
(Table 3, entries 6–8).
a-brominated product in high yields
OH
OH
O
O
RII
R
RII
R
RII
RII
Br
R
NH4Br,Oxone®
DCM
Different results were observed in case of tetralone depending
on the solvent. The -brominated product (2b) was obtained in
Br
+
+
a
RI
RI
RI
RI
MeOH whilst the corresponding dehydrogenated product, that is
1-naphthol (7), was formed in DCM, 1 equiv of tetralone with
1.1 equiv of NH4Br and 1.1 equiv of oxoneÒ in DCM yielded 65%
of 7, with 2.2 equiv of NH4Br yielded 90% of 7. In case of substituted
tetralones (5 and 6) side products 8 and 9 were also observed
(Scheme 1).
7
8
9
4 R = H, RI = H, RII = H
5 R = H, RI = Me, RII = Me
6 R = Me, RI = H, RII = H
90
31
27
-
8
-
-
17
8
Scheme 1. Aromatization of tetralones.
We propose a plausible reaction mechanism for the a-bromin-
ation of ketones as shown in Scheme 2. It is assumed that oxidation
of bromide ion by peroxymonosulfate ion could give the hypobro-
-
Br-
2-
HO-Br+
+
SO4
HSO5
+
mite ion, which in turn reacts with ketones to afford
ketones.
a-brominated
H
O+
OH
HO
In conclusion, we have developed a novel and efficient approach
for the mild -bromination of various ketones and 1,3-dicarbonyl
compounds and -dibromination of 1,3-dicarbonyl compounds
Br
a
R
HO-Br+
R
a, a
using NH4Br and oxoneÒ without catalyst, avoiding the use of
conventional reagent NBS for this transformation. The noteworthy
feature of the present method is the use of NH4Br/oxoneÒ system
as a mild, non-toxic, inexpensive reagent coupled with simple
operation and formation of cleaner products with high yields. An-
other notable benefit of this system is that, unsymmetrical acyclic
- H2O
O
O
Br
R
R
ketones brominated at less substituted
a
-position predominantly.
Scheme 2. Plausible reaction mechanism.

A. K. Macharla et al. / Tetrahedron Letters 53 (2012) 191–195
195
8. Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. J. Chem.
Soc., Chem. Commun. 2004, 470–471.
Acknowledgments
9. Arbuj, S. S.; Waghmode, S. B.; Ramaswamy, A. V. Tetrahedron Lett. 2007, 48,
1411–1415.
10. Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64, 5191–5199.
11. Das, B.; Venkateswarlu, K.; Mahender, G.; Mahender, I. Tetrahedron Lett. 2005,
46, 3041–3044.
M.A.K. and M.M.R. acknowledge the financial support from the
CSIR, India in the form of fellowships. P.S. acknowledges the finan-
cial support from the UGC, India in the form of fellowship.
12. Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S. Tetrahedron Lett. 2005,
46, 623–626.
13. Yang, D.; Yan, Y. L.; Lui, B. J. Org. Chem 2002, 67, 7429–7431.
14. Meshram, H. M.; Reddy, P. N.; Vishnu, P.; Sadashiv, K.; Yadav, J. S. Tetrahedron
Lett. 2006, 47, 991–995.
15. Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y. H.; Lee, S. J. Tetrahedron Lett. 2004, 45,
191–193.
16. Bekaert, A.; Provot, O.; Rasolojaona, O.; Alami, M.; Brion, J. D. Tetrahedron Lett.
2005, 46, 4187–4191.
Supplementary data
Supplementary data (experimental procedures, 1H NMR and
Mass spectral data of compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.11.011.
17. Prakash, G. K. S.; Ismail, R.; Garcia, J.; Panja, C.; Rasul, G.; Mathew, T.; Olah, G. A.
Tetrahedron Lett. 2011, 52, 1217–1221.
References and notes
18. Khan, A. T.; Ali, M. A.; Goswami, P.; Choudhury, L. H. J. Org. Chem. 2006, 71,
8961–8963.
19. Kim, E.-H.; Koo, B.-S.; Song, C.-E.; Lee, K.-J. Synth. Commun. 2001, 31, 3627–3632.
20. Gaudry, M.; Marquet, A. Tetrahedron 1970, 26, 5611–5615.
21. Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031–
1034.
22. Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814–4818.
23. Gomzalez-Nunez, M. E.; Mello, R.; Olmos, A.; Asensio, G. J. Org. Chem. 2006, 71,
6432–6436.
24. Ashford, S. W.; Grega, K. C. J. Org. Chem. 2001, 66, 1523–1524.
25. Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2011, 76, 623–630.
26. (a) Kumar, M. A.; Rohitha, C. N.; Kulkarni, S. J.; Narender, N. Synthesis 2010, 10,
1629–1632; (b) Narender, N.; Krishna Mohan, K. V. V.; Kulkarni, S. J.; Raghavan,
K. V. J. Chem. Res. 2003, 597–598.
1. (a) Erian, A. M.; Sherif, S. M.; Gaber, H. M. Molecules 2003, 8, 793–865; (b)
Benjamin, W. A.; House, H. O. Modern Synthetic Reactions, 2nd ed., New York,
1972, p. 459.; (c) Comprehensive Organic Transformations; Larock, R. C., Ed., 2nd
ed.; VCH: New York, 1999; p 715.
2. (a) Bolton, R. In Bromine Compounds Chemistry and Applications; Price, D., Iddon,
B., Wakefield, B. J., Eds.; Elsevier: Amsterdam, 1988; p 151; (b) Kimpe, N. D.;
Verhe, R. In The Chemistry of
a-Haloketones, a-Haloaldehydes and a-Haloimines;
Patai, S., Rappoport, Z., Eds.; Wiley, 1988; pp 1–119.
3. (a) Arabaci, G.; Guo, X.-C.; Beebe, K. D.; Coggeshall, K. M.; Pei, D. J. Am. Chem.
Soc. 1999, 121, 5085–5086; (b) Arabaci, G.; Yi, T.; Fu, H.; Porter, M. E.; Beebe, K.
D.; Pei, D. Bioorg. Med. Chem. Lett. 2002, 12, 3047–3050.
4. Ishida, J.; Ohtsu, H.; Tachibana, Y.; Nakanishi, Y.; Bastow, K. F.; Nagai, M.; Wang,
H. K.; Itokawa, H.; Lee, K. H. Bioorg. Med. Chem. 2002, 10, 3481–3487.
5. (a) Bigelow, L. A.; Hanslick, R. S. In Organic Synthesis; Wiley: New York, 1943;
Collect. Vol. 2, p. 244; (b) Hakam, K.; Thielmann, M.; Thielmann, T.;
Winterfeldt, E. Tetrahedron 1987, 43, 2035–2044; (c) Ogilvie, W.; Rank, W.
Can. J. Chem. 1987, 65, 166–169; (d) Dowd, P.; Kaufman, C.; Kaufman, P. J. Org.
Chem. 1985, 50, 882–885.
6. (a) Boyd, R. E.; Rasmussen, C. R.; Press, J. B. Synth. Commun. 1995, 25, 1045–
1051; (b) Karimi, S.; Grohmann, K. G. J. Org. Chem. 1995, 60, 554–559; (c)
Curran, D. P.; Bosch, E.; Kaplan, J.; Comb, M. N. J. Org. Chem. 1989, 54, 1826–
1831; (d) Curran, D. P.; Chang, C. T. J. Org. Chem. 1989, 54, 3140–3157.
7. (a) Coats, S. J.; Wasserman, H. H. Tetrahedron Lett. 1995, 36, 7735–7738; (b) Rao,
A. V. R.; Singh, A. K.; Reddy, K. M.; Kumar, K. R. J. Chem. Soc., Perkin Trans. 1
1993, 3171–3175; (c) Shi, X.; Dai, L. J. Org. Chem. 1993, 58, 4596–4598.
27. General procedure for the bromination of carbonyl compounds: OxoneÒ (1.352 g,
2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and
NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was
allowed to stir at room temperature (or reflux temperature). After completion
of the reaction, as monitored by TLC, the reaction mixture was quenched with
aqueous sodium thiosulfate, and extracted with ethyl acetate (3 Â 25 ml).
Finally, the combined organic layer was washed with water, dried over
anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a
crude residue, which was further purified by column chromatography over
silica gel (finer than 200 mesh) to afford pure products. All the products were
identified on the basis of 1H NMR and mass spectral data.