TMS·OTf-Catalyzed α-bromination of carbonyl compounds by N-bromosuccinimide

Article abstract of DOI:10.1016/j.tetlet.2005.11.023

Various carbonyl compounds undergo α-bromination reaction under a mild and practical condition utilizing N-bromosuccinimide (NBS), catalyzed by trimethylsilyl trifluoromethanesulfonate (TMS·OTf). This method is also effective for the side-chain bromination of heteroaromatic carbonyl compounds without the ring brominations.

Full text of DOI:10.1016/j.tetlet.2005.11.023

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 291–293
TMSÆOTf-Catalyzed a-bromination of carbonyl compounds by
N-bromosuccinimide
Samar Kumar Guha, Bo Wu, Beom Soo Kim, Woonphil Baik and Sangho Koo*
Department of Chemistry, Myong Ji University, Yongin, Kyunggi-Do 449-728, Republic of Korea
Received 29 September 2005; revised 1 November 2005; accepted 4 November 2005
Available online 21 November 2005
Abstract—Various carbonyl compounds undergo a-bromination reaction under a mild and practical condition utilizing N-bromo-
succinimide (NBS), catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSÆOTf). This method is also effective for the side-chain
bromination of heteroaromatic carbonyl compounds without the ring brominations.
Ó 2005 Elsevier Ltd. All rights reserved.
The a-bromination of carbonyl compounds1 is the first
step of introducing a heteroatom,2 generating a stabi-
lized carbon radical or carbanion,3 and providing conju-
gation to the carbonyl groups.4 Various a-bromination
protocols of carbonyl compounds5 have been developed
including the basic method using Br2.6 The unfriendly
and dangerous nature of bromine, however, urged on
to invent milder conditions making use of manageable
reagents such as N-bromosuccinimide (NBS).7 The two-
step sequence utilizing NBS through the formation of
silyl enol ethers8 is an efficient and valuable a-bromina-
tion method of carbonyl compounds under a mild and
neutral condition considering the fact that enolization
is the rate determining step in the electrophilic halogena-
tion reactions.
Scheme 1. The catalytic cycle of TMSÆOTf in the bromination of
carbonyl compounds by N-bromosuccinimide.
We envisioned that this reaction would be very useful if
ing those containing a heteroaromatic ring, in which the
the reaction proceeded by a catalytic use of the silicon
ring bromination was usually the major problem.9
Details of our study on the a-bromination of carbonyl
reagent, which would make it a single-step process.
The catalytic cycle may be completed by the utilization
of trimethylsilyl trifluoromethanesulfonate (TMSÆOTf)
compounds are disclosed in this letter.
as delineated in Scheme 1. TMSÆOTf is reactive enough
that the silyl enol ether A from the carbonyl compound
1 can be readily formed without adding a base. Electro-
philic addition of bromonium ion to A produces the
The optimization of the reaction condition for the
TMSÆOTf-catalyzed a-bromination of carbonyl com-
pounds by NBS has been studied for acetophenone
(1a) as a model case (Scheme 2 and Table 1). The desired
intermediary oxocarbenium species B, which then reacts
with the triflate ion that was liberated in the formation
of A to regenerate TMSÆOTf as well as to give rise to
the a-bromination product 2. This scenario has proven
to be successful for various carbonyl compounds includ-
*
Scheme 2. The TMSÆOTf-catalyzed bromination of acetophenone (1a)
by NBS.
Corresponding author. Tel.: +82 31 330 6185; fax: +82 31 335
7248; e-mail: sangkoo@mju.ac.kr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.023

292
S. K. Guha et al. / Tetrahedron Letters 47 (2006) 291–293
Table 1. The TMSÆOTf-catalyzed bromination of acetophenone by
Table 2. The TMSÆOTf-catalyzed bromination of various acetyl
NBS
compounds by NBS
Entry
TMSÆOTf
(mol %)
Solvent
Time
(h)
Ratio
(2a:3a:1a)
Yield
2a (%)
Entry
1
R
TMSÆOTf Time Ratio
Yield
2 (%)a
(mol %)
(h)
(2:3:1)
1
2
3
4
5
6
7
5
5
5
5
5
Et2O
3.5
3.5
3.5
3.5
3.5
24
58:1:41
4:0:96
58:7:35
38:0:62
76:3:21
92:3:5
64a
6a
59a
39a
82a
85b
85b
1
2
3
4
5
6
7
8
b
c
d
4-MeO–Ph
4-Cl–Ph
4-F–Ph
5
5
5
30
5
30
5
30
5
5
24
24
89:7:4
90:4:6
47:1:52
88:4:8
32:2:66
84:3:13
62:1:37
88:4:8
88:12:0
94:6:0
87
89
47
84
32
82
57
86
73
79
DMF
CH2Cl2
THF
MeCN
MeCN
MeCN
24
24b
24
e
f
4-NO2–Ph
2-Naphthyl
t-Butyl
5
30
24b
24
3.5c
90:6:4
24b
24
a Calculated yield of 2a based on the ratio by 1H NMR ( 3%) from the
crude product.
9
g
h
10
11
12
13
14
15
5
b Calculated yield of 2a based on the ratio by 1H NMR ( 3%) after
SiO2 column chromatography.
2-Furanyl
5
24b
24b
24b
24b
24b
70:14:16 68
30
30c
5
75:21:4
89:5:6
63:2:19
86:6:8
66
c A solution of NBS in MeCN was slowly added via dropper.
84
i
3-Thiophenyl
59d
80
30
mono-bromination product 2a was accompanied by the
di-bromination product 3a along with the unreacted
starting material 1a, which were inseparable by the
SiO2 column chromatography. It was reasonable to
obtain the di-bromination product considering the above
reaction mechanism especially for the acetyl compounds
that were not sterically congested. We calculated the
ratio of 2a:3a:1a by the comparison of the calibrated
area of the peaks corresponding to the a-protons of
a Calculated yield of 2 based on the ratio by 1H NMR ( 3%) after SiO2
column chromatography.
b A solution of NBS in MeCN was slowly added via a dropper for 2 h.
c Triisopropylsilyl trifluoromethanesulfonate (TIPSÆOTf) was used.
d Bromination products on the thiophene ring were also obtained, and
the total yield of the ring brominations was calculated to be 15%.
to the level of the model case (entries 4 and 6). The a-
bromination of 2-acetylnaphthalene (1f) was also slow
such that 30 mol % TMSÆOTf was utilized (entries 7
and 8), whilst an appreciable amount of the di-bromin-
ation product 3g was obtained for pinacolone (1g) even
under the condition of using 5 mol % TMSÆOTf in 24 h
(entry 9). The yield of the mono-bromination product 2g
was increased by reducing the reaction time to 5 h (entry
10).
1
the carbonyl groups in the H NMR spectra. It seemed
that a polar medium was required to facilitate the
formation of the silyl enol ether from 1a by TMSÆOTf.
However, most of 1a was recovered unreacted in
DMF presumably because TMSÆOTf reacted preferen-
tially with the solvent (entry 2). Even though 30 mol %
TMSÆOTf accelerated the reaction to be completed
within 3.5 h, 5 mol % TMSÆOTf was sufficed to give
the comparable yield in 24 h (entries 6 and 7). The best
result was obtained using 5 mol % TMSÆOTf in MeCN
at rt for 24 h, in which the yield of 2a was calculated
to be 85% from a 92:3:5 mixture of 2a:3a:1a (entry 6).10
The a-bromination of the acetyl compounds containing
a heteroaromatic ring without the ring brominations is
a challenging task. The TMSÆOTf-catalyzed a-bromina-
tion of the acetyl group by NBS has been studied for
2-acetylfuran (1h) and 3-acetylthiophene (1i). The ring
bromination product was not observed in any cases
for 1h. A significant amount of the di-bromination
product 3h was obtained even with 5 mol % of the cat-
alyst (entry 11). The amounts of 3h as well as the
mono-bromination product 2h were increased a little
with 30 mol % of the catalyst (entry 12). The best result
was obtained with 30 mol % triisopropylsilyl trifluoro-
methanesulfonate (TIPSÆOTf), in which the bulky
catalyst minimized the formation of the di-bromination
product 3h (entry 13). The ring brominations (15% cal-
culated yield) have been observed for 3-acetylthiophene
(1i) when 5 mol % TMSÆOTf was used (entry 14). The
ring bromination products were, however, eliminated
as the rate of the a-bromination was increased with
30 mol % TMSÆOTf, thereby producing 2i in 80% cal-
culated yield from an 86:6:8 mixture of 2i:3i:1i (entry
15). Whenever 30 mol % of the catalyst or the acetyl
compound containing a heteroaromatic ring was used,
a solution of NBS in MeCN was added slowly for
2 h to minimize the side reactions such as the di-
bromination or the bromination on the heteroaromatic
ring.
The generality of the TMSÆOTf-catalyzed a-bromination
utilizing NBS has been tested for diverse acetyl com-
pounds under the above optimized condition (Scheme
3 and Table 2). The p-substituted acetophenone deriva-
tives 1b–e have been studied to check the electronic
effects of the substituents on the a-bromination of the
acetyl group. Comparable yields and ratios of the a-
bromination products to those of the model case were
obtained for 4-MeO- and 4-Cl-substituted aceto-
phenones 1b and 1c under the above condition (entries
1 and 2). However, the a-bromination reaction, presum-
ably the formation of the silyl enol ethers, was sluggish
for acetophenones with electron withdrawing p-substitu-
ents such as F and NO2 (entries 3 and 5), in which
30 mol % TMSÆOTf was required to improve the yields
Scheme 3. The TMSÆOTf-catalyzed bromination of various acetyl
compounds by NBS.

S. K. Guha et al. / Tetrahedron Letters 47 (2006) 291–293
293
Table 3. The TMSÆOTf (5 mol %)-catalyzed bromination of carbonyl
compounds 1 by NBS
MeCN. Our method is especially valuable for the a-bro-
mination of carbonyl compounds containing a hetero-
aromatic ring without the ring brominations.
Entry
1
Time (h)
2
Yield (%)
93a
1
j
4
Acknowledgements
2
3
4
5
6
7
k
l
3.5
82a
This work was supported by the Korea Research Foun-
dation Grants KRF-2003-015-C00342 and 320038. The
latter grant was funded for Mr. Bo Wu in the form of
the Foreign Graduate Student fellowship.
24
87a
m
n
o
p
10 min
91a
References and notes
1. (a) Larock, R. C. In Comprehensive Organic Transforma-
tions, 2nd ed.; VCH: New York, 1999; pp 709–727; (b) De
4
2
1
66b,c
63b,d
72b,e
´
Kimpe, N.; Verhe, R. In The Chemistry of a-Haloketones,
a-Haloaldehydes and a-Haloimines; Patai, S., Rappoport,
Z., Eds.; Wiley: Chichester, 1988.
2. Harwood, H. J. Chem. Rev. 1962, 62, 99–154.
3. (a) Curran, D. P.; Bosch, E.; Kaplan, J.; Newcomb, M. J.
Org. Chem. 1989, 54, 1826–1831; (b) Spencer, T. A.;
Britton, R. W.; Watt, D. S. J. Am. Chem. Soc. 1967, 89,
5727–5729; (c) Vaughan, W. R.; Knoess, H. P. J. Org.
Chem. 1970, 35, 2394–2398.
4. Garbisch, E. W., Jr. J. Org. Chem. 1965, 30, 2109–2120.
5. (a) Avramoff, M.; Weiss, J.; Scha¨chter, O. J. Org. Chem.
1963, 28, 3256–3258; (b) King, L. C.; Ostrum, G. K. J.
Org. Chem. 1964, 29, 3459–3461; (c) Paul, S.; Gupta, V.;
Gupta, R.; Loupy, A. Tetrahedron Lett. 2003, 44, 439–442;
(d) Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y. H.; Lee, S.
J. Tetrahedron Lett. 2004, 45, 191–193; (e) Bekaert, A.;
Provot, O.; Rasolojaona, O.; Alami, M.; Brion, J.-D.
Tetrahedron Lett. 2005, 46, 4187–4191.
a Purified yields after SiO2 column chromatography.
b Calculated yield of 2 based on the ratio by 1H NMR ( 3%) after SiO2
column chromatography.
c 2,6-Dibromocyclohexanone was also obtained, and the yield was
calculated to be 14%.
d 2,6-Dibromo-2-methylcyclohexane was also obtained, and the yield
was calculated to be 13% yield.
e 2,7-Dibromocycloheptanone was also obtained, and the yield was
calculated to be 12%.
6. (a) Langley, W. D. Org. Synth. 1932, I, 127–128; (b)
Bigelow, L. A.; Hanslick, R. S. Org. Synth. 1943, II, 244–
245.
7. (a) Lee, J. C.; Bae, Y. H.; Chang, S.-K. Bull. Korean
Chem. Soc. 2003, 24, 407–408; (b) Das, B.; Venkateswarlu,
K.; Mahender, G.; Mahender, I. Tetrahedron Lett. 2005,
46, 3041–3044; (c) Yang, D.; Yan, Y.-L.; Lui, B. J. Org.
Chem. 2002, 67, 7429–7431; (d) Tanemura, K.; Suzuki, T.;
Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem.
Commun. 2004, 470–471.
8. (a) Reuss, R. H.; Hassner, A. J. Org. Chem. 1974, 39,
1785–1787; (b) Blanco, L.; Amice, P.; Conia, J. M.
Synthesis 1976, 194–196; (c) Hambly, G. F.; Chan, T. H.
Tetrahedron Lett. 1986, 27, 2563–2566.
9. (a) Kim, E.-H.; Koo, B.-S.; Song, C.-E.; Lee, K.-J. Synth.
Commun. 2001, 31, 3627–3632; (b) Mansour, T. S. Synth.
Commun. 1988, 18, 727–733.
10. The representative experimental procedure for 2a: To a
stirred solution of 1a (120 mg, 1.0 mmol) and NBS
(196 mg, 1.1 mmol) in MeCN (6 mL) was added TMSÆOTf
(12 mg, 0.05 mmol). The mixture was stirred at rt for 24 h,
diluted with ether, washed with H2O, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The
crude product was purified by SiO2 flash column chroma-
tography to give a 92:3:5 mixture of 2a:3a:1a (184 mg
total). The yield of 2a was calculated to be 85%.
We then applied the TMSÆOTf-catalyzed a-bromination
reaction using NBS to various carbonyl compounds,
and the reaction time and the yield were summarized
in Table 3. The above standard condition of 5 mol %
TMSÆOTf with 1.1 equiv of NBS in MeCN at rt was uti-
lized in these reactions. Mono-bromination products
were selectively obtained in high yields for 2-cyclopen-
ten-1-one (1j), ethyl acetoacetate (1k), and a-tetralone
(1l). The reaction of b-tetralone (1m) was very fast to
give rise to the aromatic 2-naphthol (2m) within
10 min in 91% yield after dehydrobromination and eno-
lization. The reactions of cycloalkanones 1n–p consis-
tently produced an appreciable amount of the
inseparable a,a0-di-bromination products (12–14%
yields) along with the desired mono-bromination prod-
ucts in 63–72% yields. The major a-bromination at
the more-substituted carbon of 2-methylcyclohexanone
(1o), indicated that the thermodynamically more stable
silyl enol ether was formed.
In conclusion, we have developed an efficient and prac-
tical a-bromination method of various carbonyl com-
pounds by the catalytic use of TMSÆOTf with NBS in