A simple and efficient method for α-bromination of carbonyl compounds using N-bromosuccinimide in the presence of silica-supported sodium hydrogen sulfate as a heterogeneous catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.03.020

α-Bromination of carbonyl compounds (cyclic and acyclic ketones, amides and β-ketoesters) has been achieved efficiently by treatment with N-bromosuccinimide (NBS) and catalyzed by silica-supported sodium hydrogen sulfate (NaHSO₄?SiO₂

Full text of DOI:10.1016/j.tetlet.2005.03.020

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3041–3044
A simple and efficient method for a-bromination of carbonyl
compounds using N-bromosuccinimide in the presence of silica-
supported sodium hydrogen sulfate as a heterogeneous catalystI
Biswanath Das,* Katta Venkateswarlu, Gurram Mahender and Ibram Mahender
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 January 2005; revised 23 February 2005; accepted 3 March 2005
Available online 18 March 2005
Abstract—a-Bromination of carbonyl compounds (cyclic and acyclic ketones, amides and b-ketoesters) has been achieved efficiently
by treatment with N-bromosuccinimide (NBS) and catalyzed by silica-supported sodium hydrogen sulfate (NaHSO4ÆSiO2). The
products were formed in high yields under mild reaction conditions and in short reaction times.
Ó 2005 Elsevier Ltd. All rights reserved.
Br
NBS
NaHSO4 SiO2
a-Bromination of carbonyl compounds is an important
transformation in organic synthesis as the a-brominated
products are useful synthetic intermediates.1 Bromine in
the presence of protic and Lewis acids is generally
used to achieve this transformation.2 N-Bromosuccini-
mide (NBS), which is a superior brominating agent in
terms of availability and in terms of ease of handling
is now being used increasingly for a-bromination of
carbonyl compounds.3 However, the catalysts and any
accompanying reagent used with NBS should also be
easily available, mild and make the procedure simple
and efficient. Previously, NBS has been utilized for a-
bromination of carbonyl compounds using a radical
initiator [such as, azobisisobutyronitrile (AIBN) or di-
benzoyl peroxide (BPO)]4, or in strongly basic media3a–d
.
R2
R2
R1
R1
Ether or CCl4
O
1
O
2
Scheme 1.
Several ketones (cyclic and acyclic) were treated with
NBS in the presence of NaHSO4ÆSiO2 in ether or CCl4
to obtain the corresponding a-monobrominated prod-
ucts (Table 1). Cyclic ketones were converted at room
temperature while acyclic ketones at 80 °C. The prod-
ucts were obtained in high yields. For an a-monosubsti-
tuted cyclic ketone (entry c), monobromination
occurred at both the a-positions, though mainly at the
substituted position. An unsymmetrical acyclic ketone
also afforded two products derived from monobromina-
tion at the two a-positions (entry g).
or in the presence of Mg(ClO4)2 or NH4OAc.3f a-
3e
Hydroxylation of carbonyls has recently been carried
out using iodine under basic conditions.5 In continua-
tion of our work6 on the applications of heterogeneous
catalysts in organic synthesis we have found that sil-
ica-supported sodium hydrogen sulfate is an efficient
catalyst for a-bromination of carbonyl compounds
using NBS (Scheme 1).
The present method was also found to be applicable for
a-bromination of lactams. Earlier studies on such con-
version using NBS are limited.3 Mg(ClO4)2 combined
with NBS was previously used for a-bromination of
amides.3e Our procedure afforded a-monobromolactams
in good to excellent yields.
Keywords: Carbonyl compounds; a-Bromination; NBS; NaHSO4ÆSiO2;
Heterogeneous catalyst.
q Part 59 in the series, ꢀStudies on Novel Synthetic Methodologiesꢁ.
IICT Communication No. 050305.
The preparation of a-monobromo products of a-unsub-
stituted b-ketoesters is difficult as such bromo com-
pounds are unstable and undergo disproportionation
to dibrominated and debrominated products. In the
*
Corresponding author. Tel./fax: +91 40 7160512; e-mail:
biswanathdas@yahoo.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.020

3042
B. Das et al. / Tetrahedron Letters 46 (2005) 3041–3044
Table 1. a-Bromination of carbonyl compoundsa
Entry
a
Substrate
Product
Time (h)
1.5
Isolated yield (%)
91
O
O
Br
Br
2a
O
O
O
b
0.5
93
2b
O
O
Br
+
c
1.5
91 and 4,
respectively
Br
Br
2c2
2c1
O
O
d
0.5
90
t
Bu
2d
t
Bu
O
O
Br
e
1.0
1.0
1.5
97
2e
Br
f
80
O
O
2f
O
O
O
+
g
61 and 19,
respectively
Br
Br
2g2
2g1
O
O
h
2.5
87
Br
2h

B. Das et al. / Tetrahedron Letters 46 (2005) 3041–3044
3043
Table 1 (continued)
Entry
Substrate
Product
Time (h)
3.0
Isolated yield (%)
95
Br
i
O
N
O
N
Me
Me
2i
Br
O
j
3.0
84
O
N
N
Cyclohexyl
Cyclohexyl
2j
Br
k
3.0
62
O
N
N
O
O
Me
Me
2k
O
O
O
O
OEt
l
2.0
68
OEt
Br
2l
O
O
O
O
m
1.0
72
O
O
Br
2m
O
O
O
O
n
2.5
95
OEt
OEt
OEt
CH2Ph
Br
O
CH2Ph
O
2n
O
o
2.0
95
OEt
Et
Br
Et
2o
a The structures of the products were determined from their spectroscopic (IR, 1H and 13C NMR and MS) and elemental analyses data.
present study, treatment of a-unsubstituted b-ketoesters
with NBS in the presence of NaHSO4ÆSiO2 at room tem-
perature produced the corresponding a-monobromo
products in good yields (entries l, m). a,a-Dibromo com-
pounds were formed as minor products only. However,
a-monosubstituted b-ketoesters afforded the a-bromi-
nated products in excellent yields (entries n, o).
The catalyst, NaHSO4ÆSiO2 can be easily prepared7
from the readily available reagents, NaHSO4 and silica

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B. Das et al. / Tetrahedron Letters 46 (2005) 3041–3044
8. Typical experimental procedure: To a mixture of a carbonyl
compound (1 mmol) and NBS (1.2 mmol) in Et2O or CCl4
(5 mL), NaHSO4ÆSiO2 (100 mg) was added. The mixture
was stirred at room temperature (for a cyclic ketone or a b-
ketoester) or heated at 80 °C (for an acyclic ketone or a
lactam). After completion of the reaction (as indicated by
TLC) the mixture was filtered, the filtrate was concentrated
and the residue was purified by column chromatography
over silica gel using hexane–EtOAc (10:1) as eluent to
obtain the pure a-brominated carbonyl compound. The
spectral data of some representative compounds are given
below.
gel (finer than 200 mesh). It works under heterogeneous
conditions and can easily be handled and removed from
the reaction mixture. The experimental procedure is sim-
ple and structures of all the products were determined
from their spectroscopic (IR, 1H and 13C NMR and
MS) and elemental analyses data.8
In conclusion, we have developed a mild and efficient
method for a-monobromination of carbonyl com-
pounds (cyclic and acyclic ketones, amides and b-keto-
esters) by treatment with NBS and catalyzed by
NaHSO4ÆSiO2. The simple experimental procedure, high
yields of the monobrominated products, application of a
heterogeneous catalyst and short reaction times are
advantages of the present procedure.
1
Compound 2b: IR (neat): 1717, 1450, 1339, 1176 cmÀ1; H
NMR (200 MHz, CDCl3): d 4.34 (1H, dd, J = 8.0, 2.0 Hz),
2.96 (1H, m), 2.33–2.19 (3H, m), 2.08–1.95 (2H, m), 1.83–
1.65 (2H, m); 13C NMR (50 MHz, CDCl3): d 203.2, 53.5,
d
38.2, 37.1, 26.6, 22.4; EIMS: m/z 178, 176 (M+ ). Anal.
Calcd for C6H9BrO: C, 40.68; H, 5.08%. Found: C, 40.72;
H, 5.02%.
1
Compound 2e: IR (neat): 1685, 1583, 1462, 1374 cmÀ1; H
Acknowledgements
NMR (200 MHz, CDCl3): d 8.22 (1H, dd, J = 8.0, 2.0 Hz),
7.62–7.54 (3H, m), 4.06 (1H, t, J = 6.0 Hz), 2.36–2.34 (1H,
m), 2.31–2.29 (1H, m), 2.28–2.24 (2H, m); 13C NMR
The authors thank CSIR and IICT for financial
assistance.
(50 MHz, CDCl3): d 195.2, 136.0, 135.7, 130.2, 129.8, 128.2,
d
128.1, 50.2, 34.1, 28.4; EIMS: m/z 226, 224 (M+ ). Anal.
Calcd for C10H9BrO: C, 53.33; H, 4.00%. Found: C, 53.42;
H, 4.04%.
References and notes
1. Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; VCH: New York, 1999, pp 715–719.
Compound 2g1: IR (neat): 1710, 1462, 1376, 1183 cmÀ1; 1H
NMR (200 MHz, CDCl3): d 3.76 (2H, s), 2.54 (2H, d,
J = 7.0 Hz), 1.79 (1H, m), 0.94 (6H, d, J = 7.0 Hz); 13C
2. (a) Bigelow, L. A.; Hanslick, R. S. In Organic Syntheses
Collections; Wiley: New York, 1943; Vol. 2, p 244; (b)
Garbisch, E. W., Jr. J. Org. Chem. 1965, 30, 2109–2120; (c)
Dowd, P.; Kaufman, C.; Kaufman, P. J. Org. Chem. 1985,
50, 882–885; (d) Hakam, K.; Thielmann, M.; Thielmann,
T.; Winterfeldt, E. Tetrahedron 1987, 43, 2035–2044.
3. (a) Curran, D. P.; Bosch, E.; Kaplan, J.; Newcomb, M. J.
Org. Chem. 1989, 54, 1826–1831; (b) Curran, D. P.; Chang,
C. T. J. Org. Chem. 1989, 54, 3140–3157; (c) Karimi, S.;
Grohmann, K. G.; Todaro, L. J. Org. Chem. 1995, 60, 554–
559; (d) Boyd, R. E.; Rasmussen, C. R.; Press, J. B. Synth.
Commun. 1995, 25, 1045–1051; (e) Yang, D.; Yan, Y.-L.;
Lui, B. J. Org. Chem. 2002, 67, 7429–7431; (f) Tanemura,
K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Hora-
guchi, T. Chem. Commun. 2004, 470–471.
4. Schmid, H.; Karrer, P. Helv. Chim. Acta 1946, 29, 573–581.
5. Zacuto, M. J.; Cai, D. Tetrahedron Lett. 2005, 46, 447–450.
6. (a) Das, B.; Banerjee, J.; Ravindranath, N. Tetrahedron
2004, 60, 8357–8361; (b) Srinivas, K. V. N. S.; Das, B.
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NMR (50 MHz, CDCl3): d 201.5, 54.1, 36.4, 24.1, 21.4;
d
EIMS: m/z 180, 178 (M+ ). Anal. Calcd for C6H11BrO: C,
40.22; H, 6.15%. Found: C, 40.17; H, 6.18%.
Compound 2g2: IR (neat): 1712, 1460, 1385, 1205 cmÀ1; 1H
NMR (200 MHz, CDCl3): d 3.97 (1H, d, J = 7.0 Hz), 2.37
(3H, s), 1.61 (1H, m), 0.91 (6H, d, J = 7.0 Hz); 13C NMR
(50 MHz, CDCl3): d 201.7, 58.7, 28.7, 28.4, 21.2, 19.0;
d
EIMS: m/z 180, 178 (M+ ). Anal. Calcd for C6H11BrO: C,
40.22, H, 6.15%. Found: C, 40.26, H, 6.12%.
1
Compound 2l: IR (neat): 1718, 1462, 1227 cmÀ1; H NMR
(200 MHz, CDCl3): d 4.67 (1H, s), 4.28 (2H, q, J = 7.0 Hz),
2.43 (3H, s), 1.32 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz,
CDCl3): d 197.6, 167.3, 61.8, 54.6, 27.1, 14.2; EIMS: m/z
d
210, 208 (M+ ). Anal. Calcd for C6H9BrO3: C, 34.45; H,
4.31%. Found: C, 34.50; H, 4.27%.
1
Compound 2n: IR: 1726, 1460, 1360, 1244 cmÀ1; H NMR
(200 MHz, CDCl3): d 7.29–7.18 (5H, m), 4.27 (2H, q,
J = 7.0 Hz), 3.62 (1H, d, J = 12.0 Hz), 3.48 (1H, d,
J = 12.0 Hz), 2.32 (3H, s), 1.22 (3H, t, J = 7.0 Hz); 13C
NMR (50 MHz, CDCl3): d 197.8, 168.2, 136.1, 130.2, 128.2,
d
127.5, 62.0, 54.8, 42.2, 27.1, 14.2; EIMS: m/z 300, 298 (M+ );
Anal. Calcd for C13H15BrO3: C, 52.17; H, 5.02%. Found:
C, 52.24; H, 5.11%.
7. Breton, G. W. J. Org. Chem. 1997, 62, 8952–8954.