A mild and efficient procedure for α-bromination of ketones using N-bromosuccinimide catalysed by ammonium acetate

Article abstract of DOI:10.1039/b315340a

Cyclic ketones reacted with N-bromosuccinimide (NBS) catalysed by NH ₄OAc in Et₂O at 25°C to give the corresponding α-brominated ketones in good yields, while acyclic ketones were efficiently brominated in CCl₄ at 80°C.

Full text of DOI:10.1039/b315340a

A mild and efficient procedure for a-bromination of ketones using
N-bromosuccinimide catalysed by ammonium acetate
Kiyoshi Tanemura,*a Tsuneo Suzuki,a Yoko Nishida,a Koko Satsumabayashia and Takaaki
Horaguchib
a School of Dentistry at Niigata, The Nippon Dental University, Hamaura-cho, Niigata 951-8580, Japan.
E-mail: tanemura@ngt.ndu.ac.jp; Fax: +81 25 267 1134
b Department of Chemistry, Faculty of Science, Niigata University, Ikarashi, Niigata 950-2181, Japan
Received (in Cambridge, UK) 11th November 2003, Accepted 6th January 2004
First published as an Advance Article on the web 28th January 2004
Table 1 The reactions of 1 with NBS catalysed by NH4OAc
Cyclic ketones reacted with N-bromosuccinimide (NBS) cata-
lysed by NH4OAc in Et2O at 25 °C to give the corresponding a-
brominated ketones in good yields, while acyclic ketones were
efficiently brominated in CCl4 at 80 °C.
Entry
Solvent
Time/h
Yield (%)a
1
2
3
4
5
6
7
CCl4
0.5
7
56
0.5
1
71b
68c
53d
92
26e
75f
43g
CHCl3
CH2Cl2
Et2O
THF
CH3CN
CH3OH
As a-bromoketones are highly useful synthetic intermediates, a-
bromination of ketones is an important transformation in synthetic
chemistry.1 The most commonly used reagent for this purpose is
molecular bromine in the presence of protic or Lewis acids.2
However, the monosubstituted product is often accompanied by a
small amount of the disubstituted product in the presence of an
excess of the ketone.2,3
In terms of ease of handling and availability, N-bromosuccini-
mide (NBS) is a superior brominating reagent.4,5 It has been
reported that ketones are a-brominated by reactions with NBS
initiated by azobisisobutyronitrile (AIBN) or dibenzoyl peroxide
(BPO) in refluxing CCl4.6
Recently, Das et al. reported the deprotection of aromatic
acetates using NH4OAc as a neutral catalyst, but the mechanism
was not mentioned.7 We were interested in the properties of
NH4OAc and planned to generate Br2 and HBr by the redox
reactions between NBS and NH3, which was generated by the
dissociation of NH4OAc.
Here we report that various ketones react with NBS in the
presence of the neutral catalyst, NH4OAc, to give the correspond-
ing a-monobrominated ketones in good yields.
First, 4-tert-butylcyclohexanone (1) was chosen as a model for
bromination. Compound 1 was treated with 1.05 equiv. of NBS in
the presence of 10 mol% of NH4OAc at 25 °C in various solvents.
The results are shown in Table 1. In CCl4, the reaction completed
within 0.5 h to give a-brominated product 2 in 71% yield together
with the recovery of 1 (17%) (entry 1). The reactions in CHCl3,
CH2Cl2 and CH3CN required longer reaction times and unreacted 1
remained (entries 2, 3 and 6). In Et2O, bromination completed
within 0.5 h to give 2 in 92% yield (entry 4). The reaction in THF
gave 3 (60%) as well as 2 (26%) (entry 5). In MeOH, 2 (43%) and
acetal 4 (57%) were yielded (entry 7). The most effective solvent
was Et2O for the bromination of 1. Reactions in Et2O require
cooling with water in order to avoid sudden boiling of the
solvent.
7
5
a Isolated yields. b 17% of 1 was recovered. c 19% of 1 was recovered.
d 34% of 1 was recovered. e 3 was obtained in 60% yield. f 21% of 1 was
recovered. g 4 was obtained in 57% yield.
in 78% yield together with 9% of 2,6-dibromocyclohexanone (39).
In the case of 2-methylcyclohexanone (6), the more substituted
position was brominated predominantly (entry 3).2 Bromination of
3,4-dihydro-1(2H)-naphthalenone (9) led to the a-brominated
ketone 15 in 99% yield (entry 6). When 9 was treated with NBS in
the presence of AIBN or BPO in CCl4 at 80 °C for 1 h, bromination
occurred at the benzylic position exclusively to give 4-bromo-
3,4-dihydro-1(2H)-naphthalenone (40) in quantative yield.
In the cases of acyclic ketones, heating at 80 °C in CCl4 was
necessary. The results are shown in Table 3. In all cases, the
reactions proceeded smoothly to give the corresponding a-
brominated ketones. Bromination occurred at the more substituted
positions predominantly (entries 1–3).
Table 4 shows the bromination of b-keto esters. A mild method
for the bromination of b-keto esters using NBS catalysed by
Mg(ClO4)2 was devised recently.8 a-Monobromination of a-
unsubstituted b-keto esters has been a challenging problem, since
some compounds such as 34 and 36 were reported to be unstable
and readily disproportionated to dibrominated and debrominated
Table 2 Bromination of various cyclic ketonesa
Entry
Substrate
Time/h
Products (Yield (%))
1
1
0.5
2 (92)
2
5
0.5
10 (87)
3
4
5
6
6
1.5
0.5
0.5
1.5
11 (93)
13 (81)
14 (92)
15 (99)
12 (2)
7
Next, we examined the bromination of various cyclic ketones
and the results are summarized in Table 2. Cyclic ketones reacted
with 1.05 equiv. of NBS in the presence of 10 mol% of NH4OAc in
Et2O at 25 °C to give the corresponding a-monobrominated
ketones in good yields. In all cases, the yields of dibromo
derivatives were < 1%. Cyclohexanone (5) was transformed to
2-bromocyclohexanone (10) in 87% yield (entry 2). Even when 2.1
equiv. of NBS was employed, monobromoketone 10 was obtained
8
9
a Reagents and conditions: Substrate 10 mmol, NBS 10.5 mmol, NH4OAc
1 mmol, Et2O 10 mL, temp. 25 °C.
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C h e m . C o m m u n . , 2 0 0 4 , 4 7 0 – 4 7 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 3 Bromination of various acyclic ketonesa
Entry Substrate
1
Time/h Products (Yield (%))
16 0.5
21 (74)
23 (65)
22 (16)
24 (15)
2
17 0.5
Scheme 1
3
18
1
25 (70)
26 (10)
Supports for this mechanism may be provided by the following
experiments. (i) Treatment of NBS with aqueous ammonia (25%)
afforded Br2, succinimide and N2. The reaction of Br2 with aqueous
ammonia gave HBr and N2.12 (ii) When NH4OAc was mixed with
1.0 equiv. of NBS in CCl4 at 0 °C, the yellow Br2–succinimide
complex was precipitated with the formation of N2 and CH3COOH.
The complex decomposed at 85–86 °C to give Br2 and succini-
mide.13 The ratio [Br2]/[succinimide] = 0.2, which was determined
by iodometric titration. The complex was soluble in Et2O, CH3CN,
MeOH and H2O to give Br2 and succinimide, but not in CCl4 and
CH2Cl2. This complex can be used as a brominating agent. The
reaction with cyclooctene in Et2O at 25 °C gave 1,2-dibromocy-
clooctane (98%).
4
5
19
0.5
3
27 (81)
PhCOCH3 20
PhCOCH2Br 28 (84)
a Reagents and conditions: Substrate 10 mmol, NBS 10.5 mmol, NH4OAc
1 mmol, CCl4 10 mL, temp. 80 °C.
Table 4 Bromination of various b-keto estersa
Products
Entry Substrate
Solvent T/°C Time/h (Yield (%))
1
2
29
Et2O
Et2O
25
25
1.5
3
34 (82)
35 (92)
In conclusion, the present procedure provides a highly efficient
method for a-monobromination of ketones. In addition, it is
possible to carry out a-bromination of ketones without benzylic
bromination.
30
A typical experimental procedure is as follows: to a mixture of 1
(10 mmol) and NBS (10.5 mmol) in dry Et2O (10 mL) was added
NH4OAc (1 mmol). After stirring at 25 °C for 0.5 h, the mixture
was filtered and the filtrate was washed with water, dried and
evaporated. The residue was chromatographed (hexane–acetone =
10 : 1) on silica gel to give 2 (92%).
3
4
5
31 Et2O
CCl4
25
80
80
3
36 (83)
32
33
0.5
37 (97)
CCl4
1
38 (98)
a Reagents and conditions: Substrate 10 mmol, NBS 10.5 mmol, NH4OAc
1 mmol, solvent 10 mL.
Notes and references
1 H. O. House, Modern Synthetic Reactions, 2nd edn., W. A. Benjamin,
New York, 1972, p. 459.
2 E. W. Garbisch, Jr., J. Org. Chem., 1965, 30, 2109.
products.8,9 a-Unsubstituted b-keto esters were treated with NBS
catalysed by NH4OAc in Et2O at 25 °C to afford the corresponding
a-brominating products in good yields (entries 1–3). a-Substituted
b-keto esters reacted with NBS in the presence of NH4OAc in CCl4
at 80 °C to give the corresponding a-brominated b-keto esters
(entries 4 and 5). Bromination of 33 afforded a-brominated b-keto
ester 38 in 98% yield. Under Wohl–Ziegler bromination conditions
(NBS, AIBN, CCl4, 80 °C, 8 h), the generation of the desired
product 38 (62%) was accompanied by ethyl 2-bromophenylme-
thyl-3-oxobutyrate (41) (18%) which was substituted at the
benzylic position.
Chlorination or iodination of compound 1 using N-chloro-
succinimide (NCS) or N-iodosuccinimide (NIS) at 25 °C in CCl4,
Et2O or CH3CN did not occur. (CAUTION!: When NH4OAc was
added to a mixture of 1 and NIS in CH3CN at 25 °C, an explosion
occurred. It has been reported that explosive NI3 is generated when
I2 is mixed with ammonia although explosive products of the
present reaction are not clear.10)
3 K. E. Teo and E. W. Warnhoff, J. Am. Chem. Soc., 1973, 95, 2728.
4 K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi and T.
Horaguchi, Chem. Lett., 2003, 32, 932.
5 A. C. Cope, E. P. Burrows, M. E. Derieg, S. Moon and W.-D. Wirth, J.
Am. Chem. Soc., 1965, 87, 5452.
6 H. Schmid and P. Karrer, Helv. Chim. Acta, 1946, 29, 573.
7 C. Ramesh, G. Mahender, N. Ravindranath and B. Das, Tetrahedron,
2003, 59, 1049.
8 D. Yang, Y.-L. Yan and B. Lui, J. Org. Chem., 2002, 67, 7429.
9 R. V. Hoffman, W. S. Weiner and N. Maslouh, J. Org. Chem., 2001, 66,
5790; X.-X. Shi and L.-X. Dai, J. Org. Chem., 1993, 58, 4596.
10 J. W. Mellor, Comprehensive Treatise Inorganic and Theoretical
Chemistry, vol. 8, suppl. 2, Longman, London, 1967, p. 416; G. G.
Hawley, The Condensed Chemical Dictionary, 9th edn., Van Nostrand
Reinhold Company, New York, 1977, p. 616.
11 A. W. Davidson and W. H. McAllister, J. Am. Chem. Soc., 1930, 52,
507.
12 M. Grayson, Kirk-Othmer Concise Encyclopedia of Chemicla Technol-
ogy, John Wiley and Sons, New York, 1985 (Japanese translation,Mar-
uzen, Tokyo, 1988, p. 98).
13 Similarly, the colourless Cl2-succinimide complex was isolated from the
reaction of NH4OAc with NCS in CCl4 at 15 °C The complex
decomposed at 98–107 °C to give Cl2 and succinimide. The ratio [Cl2]/
[succinimide] = 0.2. The complex was soluble in MeOH and H2O to
give Cl2 and succinimide, but not in less polar solvents (CCl4, CH2Cl2,
CHCl3, Et2O and CH3CN). The reaction with cyclooctene in MeOH at
25 °C gave 1-chloro-2-methoxycyclooctane (77%). The fact that
chlorination of ketones using NCS and NH4OAc did not proceed might
be attributed to the high stability of the complex.
A possible mechanism for the generation of Br2 and HBr is
shown in Scheme 1. Since NH4OAc is a salt which consists of a
weak acid and a base, the behaviour of NH4OAc in an organic
solvent may be represented by the parallel equations shown in eqn.
(1).11 NH4OAc is dissociated into NH4+ and OAc2. Proton transfer
from NH4+ to OAc2 affords NH3 and HOAc. NBS may be reduced
by NH3 to give Br2, succinimide and N2 (eqn. (2)). Reduction of Br2
by NH3 may lead to HBr and N2 (eqn. (3)).
C h e m . C o m m u n . , 2 0 0 4 , 4 7 0 – 4 7 1
471