An efficacious method for the halogenation of β-dicarbonyl compounds under mildly acidic conditions

Article abstract of DOI:10.1016/j.tetlet.2005.05.055

A variety of 1,3-diketones, β-ketoesters and malonates can be chlorinated in high yields using sodium hypochlorite in a 5:2 mixture of acetone/acetic acid at 0°C for 1 h. Similarly, bromination of these dicarbonyl substrates can be accomplished under the same conditions using sodium hypobromite.

Full text of DOI:10.1016/j.tetlet.2005.05.055

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4749–4751
An efficacious method for the halogenation of
b-dicarbonyl compounds under mildly acidic conditions
Matthew L. Meketa, Yogesh R. Mahajan and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 19 April 2005; revised 11 May 2005; accepted 11 May 2005
Available online 31 May 2005
Abstract—A variety of 1,3-diketones, b-ketoesters and malonates can be chlorinated in high yields using sodium hypochlorite in a
5:2 mixture of acetone/acetic acid at 0 °C for 1 h. Similarly, bromination of these dicarbonyl substrates can be accomplished under
the same conditions using sodium hypobromite.
Ó 2005 Elsevier Ltd. All rights reserved.
O
O
X
A number of methods have previously been described in
the literature for the halogenation of 1,3-dicarbonyl
compounds.1 Reagents which have been used inter alia
for chlorination include sulfuryl chloride,2 NaH/cupric
chloride,3 TEA/triflic chloride,4 NaH/NCS5 and (dichlo-
roiodo)toluene.6 In addition, a few scattered reports
exist of chlorinations of simple malonate derivatives,
which are unsubstituted at the a-position using hypo-
chlorite in the presence of bases such as Na2CO3 or
KOH.7 Brominations of b-dicarbonyl compounds have
often been effected with NBS,2,5 NaH/cupric bromide3
and NaH/Br2.8 We recently revealed that vinyl chlorides
can be efficiently converted to a-chloro or a-bromoke-
tones using sodium hypochlorite or sodium hypobro-
mite, respectively, in a mixture of acetone/acetic acid.9
Herein, we report that this same combination of
reagents is also effective for the halogenation of a variety
of b-dicarbonyl compounds.
O
O
O
O
Y
Y
Y
Y
Y
Y
Y
Y
HOAc
X
Me2CO
1
2
0
oC
NaOX
O
O
R
X = Cl, Br
X
R
3
4
Scheme 1.
reaction conditions affords monochlorinated products
4. Table 1 shows some representative examples of the
transformations, which we have conducted.
It was observed using ethyl 2-oxocyclopentanecarboxyl-
ate as the substrate that omission of the acetic acid leads
to a complex reaction mixture containing a significant
amount of starting material. In addition, although
diethyl malonate (entry f) and diethyl 2-bromomalonate
(entry h) cleanly undergo chlorination, other 2-substi-
tuted malonates are less reactive. For example, diethyl
2-(p-tolyl)malonate is unchanged when exposed to the
standard experimental conditions,10 but can be chlori-
nated in good yield upon stirring at room temperature
overnight (entry g). On the other hand, diethyl 2-meth-
ylmalonate and diethyl 2-ethylmalonate are totally unre-
active even at room temperature. An attempt was made
to monochlorinate diethyl malonate using 1.5 equiv of
sodium hypochlorite, but in this case a mixture of
mono- and dichlorinated products, along with starting
Thus, it was found that a b-dicarbonyl compound 1
which is unsubstituted at the a-position undergoes
dichlorination to afford high yields of 2 upon treat-
ment with 3.0 equiv of commercially available 10–13%
sodium hypochlorite solution in a 5:2 mixture of ace-
tone/glacial acetic acid at 0 °C for 1 h (Scheme 1).
Similarly, exposure of an a-monosubstituted system 3
to 1.5 equivs of sodium hypochlorite under the same
Keywords: Chlorination; Bromination; Vinyl chlorides; 1,3-Diketones;
Malonates; b-Ketoesters.
*
Corresponding author. Tel.: +1 814 863 0189; fax: +1 814 865
3292; e-mail: smw@chem.psu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.055

4750
M. L. Meketa et al. / Tetrahedron Letters 46 (2005) 4749–4751
Table 1. Halogenation of representative 1,3-dicarbonyl compounds
material, was isolated. It is also possible to brominate
these b-dicarbonyl substrates if one replaces the sodium
hypochlorite with a freshly prepared solution of sodium
hypobromite.10 The data in Table 1 indicate that
these bromination reactions generally proceed in good
yields.
Entry 1,3-Dicarbonyl
substrate
Chlorinated
product
Brominated
product
O
O
CO Et
2
a
—
CO Et
2
Cl
88 %
In order to probe some selectivity issues with regard to
this chemistry, vinyl chloride malonate 5 was exposed
to 3.0 equiv of sodium hypochlorite under the standard
conditions10 leading to chemoselective a,a-dichlorina-
tion, with compound 6 formed as the major product
(Scheme 2). In addition, small amounts of trichloro
acetate 7 and a-chloroketone 8 were produced. On the
other hand, with the 2-substituted malonate vinyl
chloride substrate 9, halogenation is completely chemo-
selective for the vinyl chloride functionality, producing
a-chloroketone 10 as the major product. In addition,
acetate 11 is also produced (an inseparable mixture of
diastereomers) along with a small amount of starting
material. This result is not surprising based on our
observation that 2-substituted malonates are resistant
to chlorination under these conditions (vide supra).
Interestingly, in the case of the b-ketoester vinyl chloride
12, chlorination again proved to be highly selective for
the vinyl chloride moiety, leading to a-chloroketone 13
as the major product. In addition, a very small amount
of the a-chloroketone product 14 resulting from haloge-
nation of the b-ketoester moiety of 12 was formed in this
system.
O
O
O
CO Et
2
CO Et
2
CO Et
Cl
Br
2
b
c
94 %
95 %
CO Et
2
Br
Br
O
CO Et
O
2
Cl
O
CO Et
2
Cl
98 %
96%
Cl Cl
Br Br
O
O
O
O
O
O
d
e
67 %
81 %
O
O
Br
Cl
O
O
O
O
Ph
Ph
Ph
96 %
98 %
CO Et
2
CO Et
2
Cl
CO Et
2
Br
CO Et
2
EtO C
2
CO Et
2
f
Cl
Br
90 %
88 %
CO Et
CO Et
2
Finally, we have briefly investigated the chlorination of
oxindole (15) with this reagent.11,12 Treatment of 15
with 4.5 equiv of sodium hypochlorite under the usual
conditions10 (2.5 h reaction time) led to the formation
of a mixture of trichlorinated compound 16 along with
tetrachlorooxindole 17 as the primary product (Scheme
3). However, with 6.0 equiv of sodium hypochlorite,
only tetrachloro product 17 was formed in high yield.
The structure of compound 17 was confirmed by
X-ray crystallography.13
CO Et
2
2
g
h
—
—
Cl
a
CO Et
2
87 %
CO Et
2
CO Et
EtO C
2
Br
CO Et
2
2
Cl
Br
99 %
aAfter sodium hypochlorite addition at 0 °C, reaction mixture was
warmed to rt and stirred for 17 h.
O
O
O
O
HOAc
CO2Et
Me2CO
CO2Et
Cl
CO2Et
CO2Et
O
O
O
O
Cl
+
+
Cl
Cl
Cl
Cl
O
Cl
Cl
0 o
C
NaOCl
(3.0 equiv)
AcO Cl
Cl
Cl
6 (64%)
7 (5%)
8 (7%)
5
O
O
O
HOAc
Me2CO
Me
Me
CO2Et
Me
CO2Et
CO2Et
O
O
O
+
+ SM (9%)
0
oC
Cl
Cl
AcO Cl
NaOCl
(1.5 equiv)
Cl
O
9
10 (53%)
11 (13%)
O
O
O
HOAc
Me2CO
Me
CO2Et
Me
CO2Et
CO2Et
+ SM (8%)
+
Me Cl
0
oC
Cl
13 (64%)
Cl
O
NaOCl
(1.5 equiv)
Cl
O
12
14 (3%)
Scheme 2.

M. L. Meketa et al. / Tetrahedron Letters 46 (2005) 4749–4751
4751
10–13% v/v, Aldrich). The mixture was stirred for 1 h at
0 °C, then poured into saturated Na2CO3 solution and
extracted with CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel
(hexanes/ethyl acetate, 10:1) to afford the monochlori-
nated product. Dichlorination was effected using the same
procedure with 3.60 mmol of sodium hypochlorite.
Cl
Cl
HOAc
Me2CO
Cl
Cl
Cl
Cl
+
O
O
O
N
N
N
H
0 o
C
H
Cl
16
18 %
17
70 %
15
4.5 equiv NaOCl
6.0 equiv NaOCl
0%
98 %
Brominations were conducted as described above using
freshly prepared sodium hypobromite solution. A solution
of sodium hypobromite was prepared by slowly adding
bromine (0.85 mL, 16.6 mmol) to a solution of sodium
hydroxide (2.0 g, 50.0 mmol) in water (25 mL) at 0 °C. The
mixture was stirred for 15 min and used immediately.
Spectral data for new compounds—6: 1H NMR (300
MHz, CDCl3) d 1.28 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.1
Hz, 2H), 4.78 (s, 2H), 5.42 (d, J = 2.0 Hz, 1H), 5.50 (d,
J = 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 162.8,
162.5, 134.2, 117.0, 69.4, 65.3, 65.1, 14.1. 7: 1H NMR
(400 MHz, CDCl3) d 1.29 (t, J = 7.1 Hz, 3H), 2.08 (s, 3H),
3.90 (d, J = 12.1 Hz, 1H), 4.34 (m, 3H), 4.74 (d, J = 2.1 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 169.2, 164.3, 163.6,
96.4, 79.2, 69.5, 67.0, 47.5, 23.5, 15.7. 8: 1H NMR
(300 MHz, CDCl3) d 1.31 (t, J = 7.1 Hz, 3H), 4.12 (s,
2H), 4.34 (q, J = 7.1 Hz, 2H), 5.05 (s, 2H); 13C NMR
(100 MHz, CDCl3) d 194.7, 162.8, 162.7, 69.3, 65.5, 45.9,
30.1, 14.1. 10: 1H NMR (300 MHz, CDCl3) d 1.23 (t,
J = 7.1 Hz, 3H), 1.40 (d, J = 7.3 Hz, 3H), 3.51 (q,
J = 7.3 Hz, 1H), 4.15 (m, 4H), 4.95 (s, 2H); 13C NMR
(75 MHz, CDCl3) d 194.9, 168.5, 168.4, 66.0, 60.8, 44.8,
44.7, 13.0, 12.6. 11: 1H NMR (300 MHz, CDCl3) d 1.21 (t,
J = 7.1 Hz, 3H), 1.39 (d, J = 7.3 Hz, 3H), 2.08 (s, 3H), 3.44
(q, J = 7.3 Hz, 1H), 3.91 (d, J = 2.0 Hz, 1H), 4.16 (q,
J = 7.1 Hz, 2H), 4.39 (d, J = 2.0 Hz, 1H), 4.57 (m, 2H);
13C NMR (100 MHz, CDCl3) d 169.8, 169.1, 167.7, 95.5,
65.8, 62.1, 46.4, 46.0, 21.9, 14.5, 13.9; ESI (+/À): [M+Na]+
calcd for C11H16O6Cl2Na, 337.0; found 337.0. 13: 1H
NMR (300 MHz, CDCl3) d 1.23 (t, J = 7.1 Hz, 3H), 1.42
(d, J = 7.2 Hz, 3H), 2.90 (m, 4H), 3.57 (q, J = 7.2 Hz, 1H),
4.17 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 204.5, 201.5, 170.5, 61.7, 52.9, 48.4, 35.4, 33.5,
14.3, 13.0. 14: 1H NMR (400 MHz, CDCl3) d 1.23 (t,
J = 7.2 Hz, 3H), 1.79 (s, 3H), 2.82 (m, 2H), 2.97 (m, 1H),
3.18 (m, 1H), 4.09 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H); ESI
(+/À): [M+Na]+ calcd for C10H14O4Cl2Na, 291.0; found
291.0. 16: 1H NMR (360 MHz, CDCl3) d 6.89 (d,
J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 2.1 Hz, 1H), 7.54 (d,
J = 2.1 Hz, 1H), 9.12 (s, 1H); 13C NMR (90 MHz, CDCl3)
d 171.2, 136.7, 132.5, 131.4, 130.2, 125.9, 112.9, 74.2; ESI
(+/À): [M+H]+ calcd for C8H3NOCl3, 233.928; found
233.928. 17: 1H NMR (360 MHz, CDCl3) d 6.98 (d,
J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d,
J = 2.0 Hz, 1H); 13C NMR (90 MHz, CDCl3) d 163.9,
137.9, 132.7, 131.5, 130.3, 125.6, 111.8, 72.3; ESI (+/À):
[M+H]+ calcd for C8H4NOCl4, 267.890; found 267.890.
11. A few N-substituted oxindoles have previously been
chlorinated at C-3 with calcium hypochlorite: Stolle, R.;
Bergdoll, R.; Luther, M.; Auerheim, A.; Wacker, W. J.
Prakt. Chem. 1930, 128, 1.
Scheme 3.
In conclusion, we have described a mild, convenient
and inexpensive method for the bromination and chlo-
rination of a variety of 1,3-dicarbonyl compounds.
These reactions occur rapidly at 0 °C and provide the
halogenated products in high yields. Although a pleth-
ora of reagents and reaction conditions have been
reported for halogenation of dicarbonyl compounds,
many involve the use of a base to initially deprotonate
the substrate.1 The procedure outlined here allows one
to effect this transformation under mild acidic condi-
tions, and should provide a good alternative to existing
methodology.
Acknowledgements
We are grateful to the National Institutes of Health
(GM-32299) for financial support of this research.
References and notes
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6. Ibrahim, H.; Kleinbeck, F.; Togni, A. Helv. Chim. Acta
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12. For bromination of oxindoles, see: Sumpter, W. C.;
Miller, M.; Hendrick, L. N. J. Am. Chem. Soc. 1945, 67,
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Commun. 1995, 25, 1045.
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Chem. 2003, 68, 3323.
10. General procedure for halogenation of 1,3-dicarbonyl
compounds: To a solution of the 1,3-dicarbonyl com-
pound (1.20 mmol) in acetone (5 mL) and glacial acetic
acid (2 mL) cooled to 0 °C was added dropwise sodium
hypochlorite solution (0.83 mL, 1.80 mmol, 1.21 g/mL,
13. We are grateful to Dr. Hemant Yennawar for this X-ray
analysis. CCDC 271465 contains the supplementary crys-
tallographic data, which can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.