A mild and environmentally acceptable synthetic protocol for chemoselective α-bromination of β-keto esters and 1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2006.02.075

A wide variety of unsubstituted β-keto esters can be brominated chemoselectively to the corresponding α-monobromo-β-keto esters by using a combination of vanadium pentoxide, hydrogen peroxide and ammonium bromide in a biphasic system, dichloromethane-wate

Full text of DOI:10.1016/j.tetlet.2006.02.075

Tetrahedron Letters 47 (2006) 2751–2754
A mild and environmentally acceptable synthetic protocol for
chemoselective a-bromination of b-keto esters and 1,3-diketonesI
Abu T. Khan,* Papori Goswami and Lokman H. Choudhury
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
Received 17 January 2006; revised 7 February 2006; accepted 14 February 2006
Available online 3 March 2006
This letter is dedicated to my mentor Professor K. C. Majumdar, Department of Chemistry, Kalyani University on the occasion of his 60th birthday
Abstract—A wide variety of unsubstituted b-keto esters can be brominated chemoselectively to the corresponding a-monobromo-b-
keto esters by using a combination of vanadium pentoxide, hydrogen peroxide and ammonium bromide in a biphasic system, dichlo-
romethane–water at 0–5 ꢀC. In addition, a-mono substituted b-keto esters, cyclic b-keto-esters and 1,3-diketones can also be bro-
minated selectively using the same protocol.
ꢁ 2006 Elsevier Ltd. All rights reserved.
The chemoselective a-bromination of b-keto esters is an
important organic transformation1 because the resulting
a-brominated products are valuable building blocks in
organic synthesis.2 The transformation is usually
achieved by using either molecular bromine,3 or Br2/
NaH,4 or NBS/Et3N,5 or NBS/NaH,6 or CuBr2 with
[hydroxy(tosyloxy)iodo]benzene7 or NBS/Mg(ClO4)2.8
Recently, other methods have also been reported
employing NBS in combination with silica-supported
NaHSO4,9 Amberlyst-1510 or in ionic liquids.11 Though
all these methods provide good yields, most suffer from
one or more disadvantages. From the green chemistry
point of view,12 the use of molecular bromine has several
drawbacks: the reagent itself is harmful and hazardous
and there are difficulties in handling and maintaining
the stoichiometric ratio during the reaction. In addition,
the reaction needs to be carried out under a dry and in-
ert atmosphere and also uses expensive NaH. Moreover,
NBS has also some limitations such as the requirement
for dry7 and harsh reaction conditions,9 and NBS and
the required solvents, such as an ionic liquids,11 are
expensive. Selective monobromination at the a position
of b-keto esters is a challenging problem, since some of
the a-monobrominated b-keto esters are unstable and
readily disproportionate to dibrominated and debromi-
nated products.13,14 Therefore, there is scope to find
an alternative methodology that would be environmen-
tally benign and efficient.
Recently we reported the synthesis of 6,8-dibromoflav-
one, 8-bromoflavone, 5,7-dibromoaurone and 7-bromo-
aurone using V2O5–H2O2 catalyzed oxidation of
ammonium bromide.15 We also demonstrated the use-
fulness of the same combination in various organic
transformations such as cleavage of dithioacetals,16
hydrolysis of 1-thioglycosides17 and deprotection of
oxathioacetals.18 Based on a knowledge of the reactivity
of peroxovandate(V) complexes for the oxidation of
bromide,19 we have now developed an environmentally
acceptable protocol for a-monobromination of b-keto
esters and 1,3-diketones as shown in Scheme 1.
For the present study, ethyl acetoacetate was chosen as a
model substrate to find optimal conditions, as shown in
Table 1. We noted that a (1:1.5:0.5:19) substrate/ammo-
nium bromide/vanadium pentoxide/hydrogen peroxide
ratio, in dichloromethane/water (1:1, 2.5 mL per mmol
of the substrate), provided the best results. For the same
substrate, a combination of V2O5, NH4Br and H2O2
(0.25:1.5:19) gave only a 40% conversion (calculated
Keywords: b-Keto esters; a-Bromination; Vanadium pentoxide; Hydro-
gen peroxide; Ammonium bromide; a-Bromo-b-keto esters.
q Part of this work was presented at the conference ‘Catalysis and
Biocatalysis in Green Chemistry’, Robinson College, Cambridge,
UK, December 11–13, 2005.
1
from the H NMR spectrum) after 3.5 h with only a-
monobrominated product (Table 1, entry 1). The chemi-
cal yield was 92% based on recovery of the starting
material. The percent of conversion and the ratio of
*
Corresponding author. Tel.: +91 361 2582305; fax: +91 361
2690762; e-mail: atk@iitg.ernet.in
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.075

2752
A. T. Khan et al. / Tetrahedron Letters 47 (2006) 2751–2754
O
O
O
O
O
O
V2O5-H2O2-NH4Br
CH2Cl2/H2O, 0 -5 ºC
+
R1
R1
R1
R
R
R
Br
Br
Br
1
3
2
R = Me/Ph
R1 = OMe, OEt, OBn
Scheme 1.
Table 1. Optimization of the reaction conditions for selective a-bromination of ethyl acetoacetate
Entry
V2O5 (mmol)
NH4Br (mmol)
50% H2O2 (mL)
Time (h)
Conversiona (%)
Yieldb of product 2 (%)
Ratio of 2:3c
1
2
3
4
0.25
0.50
0.50
0.75
1.5
1.5
2
1.3
1.3
1.3
2.1
3.5
3.5
2
40
92
86
92
85
84
13
100:0
10:1
9:1
6
9
100
1:9
a Quantities in the table are based on 1 mmol of ethyl acetoacetate, however, all reactions were carried out with 3.8 mmol scale of the substrate 2.
b Isolated yield.
c Conversion and product ratio were determined using 1H NMR.
Table 2. Selective a-bromination of b-keto esters and 1,3-diketones using V2O5/NH4Br/50% H2O2 (0.5:1.5:19)
Entry
Substrate
Reaction time (h)
Producta
Yieldb,c (%)
83c
O
O
O
O
O
O
1
3.0
OMe
OMe
Br
Br
Br
O
O
O
O
O
O
2
3
4
3.5
4.0
4.0
85c
90
OEt
OEt
OCH2Ph
OCH2Ph
O
O
O
O
O
92
Ph
Ph
OEt
Ph
Ph
OEt
Br
O
O
O
5
6
7
4.5
3.0
3.5
91
94
92
OCH2Ph
OCH2Ph
Br
O
O
O
O
O
OEt
OEt
Br
O
O
O
OEt
OEt
Br
Ph
Ph
O
O
O
O
O
8
9
3.5
3.0
87
90
OEt
OEt
Br
O
O
O
Br
OEt
OEt

A. T. Khan et al. / Tetrahedron Letters 47 (2006) 2751–2754
2753
Table 2 (continued)
Entry
Substrate
Reaction time (h)
2.5
Producta
Yieldb,c (%)
92
O
O
O
O
O
O
10
Ph
Ph
Ph
Br
Br
O
O
11
12
13
3.0
2.5
4.0
95
89
90
Ph
Ph
Ph
O
O
O
O
O
O
Br
O
O
Br
Br
a Products were characterized by recording 1H NMR, 13C NMR spectra and elemental analysis.
b Isolated yield.
c Yield was calculated based on starting material recovery.
mono- and dibrominated products were calculated di-
rectly from the integrations of NMR signals obtained
from the crude reaction mixture. For the substrate ethyl
acetoacetate, the methyl signal attached to the carbonyl
group resonated at d 2.27, whereas in the monobromi-
nated product it appeared at d 2.44. Next we varied
the amount of V2O5. Using 0.5 equiv of V2O5 led to
an increase in conversion from 40% to 92% within the
same time interval (Table 1, entry 2). The chemical yield
of monobrominated product was 85% and dibrominated
product was less than 1%. When the amount of ammo-
nium bromide was increased from 1.5 to 2.0 equiv, the
conversion was 86% within 2 h with almost the same
chemical yield (entry 3). It is clear that the reaction
can be completed in shorter time if the amount of vana-
dium pentoxide, ammonium bromide and hydrogen per-
oxide are increased.
Using the typical reaction protocol,20 methyl acetoace-
tate (Table 2, entry 1) also reacted smoothly to
give the a-monobrominated product in 83% yield along
with 7% dibrominated product based on starting
O
V
O
V
O
O
O
+
VO2
+ VO3
R1COCH2COR2
H2O2
H2O2
R1
VO(O2)+
2H+
+
H2O
Br+
VO(O2)2
+
O
O
O
O
V
+
(
Br
Br2
Br3
)
R2
O
A
(VO)2(O2)3
Br
O
R1 = alkyl / phenyl; R2 = OR / alkyl
1
R
R2
Br
Scheme 2. A plausible mechanism for the a-bromination of b-keto esters and 1,3-diketones showing the dual role of vanadium.

2754
A. T. Khan et al. / Tetrahedron Letters 47 (2006) 2751–2754
4. Stotter, P. L.; Hill, K. A. Tetrahedron Lett. 1972, 40,
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material recovery. Other unsubstituted b-keto esters
(entries 3–5) were exclusively a-monobrominated in
good yields.
Various monoalkyl substituted b-keto esters (entries 6–
9) were also brominated chemoselectively at the a-posi-
tion (Table 2). Following identical reaction conditions,
1-benzoylacetone (entry 10) was smoothly converted to
the corresponding a-monobrominated product in good
yield. Likewise, dibenzoylmethane (entry 11) and dime-
done (entry 12) were transformed chemoselectively to
the corresponding a-monobrominated products, respec-
tively, in good yields. It is important to point out that
a,a-dibromodimedone can be obtained exclusively by
increasing the amount of ammonium bromide from
1.5 to 3.0 equiv.
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12. Chemistry of Waste Minimisation; Clark, J. H., Ed.;
Chapman and Hall: London, 1995.
We believe that the promoter (V2O5) is used not only for
the oxidation of ammonium bromide by H2O2 but also
acts as a Lewis acid for chelation with the two carbonyl
groups present in b-keto esters or 1,3-diketones as
shown in Scheme 2. This promotes enol formation for
chemoselective monobromination.
13. Hoffman, R. V.; Weiner, W. S.; Maslouh, N. J. Org.
Chem. 2001, 66, 5790–5795.
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4937–4940.
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Lett. 2001, 1158–1159.
In conclusion, we have developed a general method for
mild a-bromination of b-keto esters and 1,3-diketones
using a combination of V2O5–H2O2–NH4Br, avoiding
the use of the conventional reagent NBS for this trans-
formation. Additionally, all these reagents are environ-
mentally acceptable. We suggest that vanadium
pentoxide plays the dual role in: (i) formation of peroxo
complexes, which oxidize bromide ion to the bromo-
nium ions and (ii) promotion of enol formation by che-
lating with the two carbonyl groups of the b-keto ester
or 1,3-diketone. We also note, that the ester functional-
ity does not undergo hydrolysis under the experimental
conditions. We believe our protocol will find a position
in the arsenal of synthetic organic chemistry because of
its high selectivity, high yields, simplicity and economic
viability.
17. BujarBarua, P. M.; Sahu, P. R.; Mondal, E.; Bose, G.;
Khan, A. T. Synlett 2002, 81–84.
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20. General procedure: To a stirred solution of vanadium
pentoxide (1.9 mmol, 345 mg) in water (5 mL) was added
50% hydrogen peroxide (5 mL, 73.5 mmol) at ice-bath
temperature with stirring. The colour changed from light
orange to deep red after 25–30 min. Then, ammonium
bromide (5.7 mmol, 560 mg) was added and the reaction
mixture was stirred for another 10 min. Subsequently,
ethyl acetoacetate (495 mg, 3.8 mmol) in CH2Cl2 (5 mL)
was added and the reaction mixture was then stirred for a
further 3.0 h at the same temperature. After completion of
the reaction as monitored by TLC, it was extracted with
dichloromethane (25 mL · 2) and the organic layer was
washed with saturated sodium metabisulfite solution to
destroy unreacted molecular bromine. Finally, it was
washed with water and dried over anhydrous sodium
sulfate. Removal of the organic layer provided a crude
residue, which was purified by short path distillation.
Some of the compounds were purified through silica gel
column (60–120 mesh, SRL) chromatography by eluting
with a mixture of (2% ethyl acetate in hexane) to obtain
the pure products.
Acknowledgements
The authors acknowledge financial support from
the Council of Scientific and Industrial Research, New
Delhi [Grant No. 01(1541)/98/EMR-II to A.T.K.].
P.G. and L.H.C. are thankful to the CSIR, New Delhi,
for their research fellowships. The authors are grateful
to the Director, IIT Guwahati for providing general
facilities for this work. We are grateful to the referee
for his valuable comments and suggestions.
Spectroscopic data of the a-monobrominated product of
benzyl acetoacetate: IR (neat): 1747, 1718 cmÀ1; 1H NMR
(400 MHz, CDCl3): d 2.39 (s, 3H, COCH3), 4.79 (s, 1H,
CHBr), 5.23 (s, 2H, OCH2Ph), 7.35 (bs, 5H, ArH). Anal.
Calcd for C11H11BrO3: C, 48.73; H, 4.09. Found: C, 48.52;
H, 4.01. For a-monobrominated product of benzoylace-
References and notes
tone: IR (neat): 1726, 1680 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d 2.45 (s, 3H, COCH3), 5.61 (s, 1H, CHBr), 7.48
(t, 2H, J = 7.6 Hz, ArH), 7.61 (t, 1H, J = 7.6 Hz, ArH),
7.95 (t, 2H, J = 7.2 Hz, ArH). 13C NMR (100 MHz,
CDCl3): d 27.5, 53.3, 127.2, 128.8, 129.2, 130.9, 133.9,
134.6, 190.0, 198.2. Anal. Calcd for C10H9BrO2: C, 49.82;
H, 3.76. Found: C, 49.56; H, 3.70.
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