A green approach for efficient α-halogenation of β-dicarbonyl compounds and cyclic ketones using N-halosuccinimides in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2005.11.141

Room temperature ionic liquids (ILs) are used as a green recyclable reaction media for the α-monohalogenation of 1,3-diketones, β-keto-esters and cyclic ketones with N-halosuccinimides in excellent yields in the absence of a catalyst. The recovered ionic liquid was reused five to six times with consistent activity.

Full text of DOI:10.1016/j.tetlet.2005.11.141

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 991–995
A green approach for efficient a-halogenation of
b-dicarbonyl compounds and cyclic ketones using
N-halosuccinimides in ionic liquids
H. M. Meshram,* P. N. Reddy, P. Vishnu, K. Sadashiv and J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 19 September 2005; revised 15 November 2005; accepted 25 November 2005
Available online 20 December 2005
Abstract—Room temperature ionic liquids (ILs) are used as a green recyclable reaction media for the a-monohalogenation of 1,3-
diketones, b-keto-esters and cyclic ketones with N-halosuccinimides in excellent yields in the absence of a catalyst. The recovered
ionic liquid was reused five to six times with consistent activity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
a-Halogenation of 1,3-dicarbonyl compounds is an
important transformation as the a-halogenated prod-
ucts are versatile intermediates in organic synthesis1
since their high reactivity makes them prone to react
with a large number of nucleophiles to provide a variety
of useful compounds. a-Monobromination of 1,3-dicar-
bonyl compounds without a-substituents has been a
challenging problem since the monosubstituted product
is always accompanied by a small amount of disubsti-
tuted product. A number of methods have been
described previously for the halogenation of 1,3-dicar-
bonyl compounds.2 Conventional methods for the
bromination of b-keto-esters involve the use of various
reagents include bromine,3 copper(II) bromide4 and N-
bromosuccinimide.5 In terms of accessibility and ease
of handling, N-bromosuccinimide is a superior and inex-
pensive brominating reagent. Previously, NBS has been
utilized for bromination of carbonyl compounds using a
radical initiator such as, azobisisobutyronitrile (AIBN)
or dibenzoyl peroxide (BPO),6 or in the presence of
Mg(ClO4)2,7 NH4OAc8 and NaHSO4ÆSiO2.9 Several
methods have been developed for the 2-chlorination10
and 2-iodination11 of 1,3-dicarbonyl compounds using
NCS or NIS, respectively. Most of these methods
involve strongly acidic or basic conditions and the
undesirable formation of a,a-dihalogenated products
in significant amounts. Other problems associated with
these methods are the use of hazardous chemicals,
tedious work-up procedures and long reaction times.
Furthermore, the use of polar solvents like DMF, DMSO
and CH3CN causes serious environmental pollution.
Very recently, we have reported the use of Amberlyst-
15 for efficient 2-halogenation of 1,3-keto-esters and
cyclic ketones using N-halosuccinimides.12 However, to
the best of our knowledge, a-halogenation of 1,3-dicar-
bonyl compounds and cyclic ketones using ionic liquids
has not been previously reported.
Room temperature ionic liquids (RTLs) are recognized
as green recyclable alternatives to the traditional volatile
organic solvents because of their unique chemical and
physical properties.13 In particular, 1,3-dialkylimidazo-
lium-based ionic liquids have emerged as alternative
reaction media for the immobilization of transition metal
based catalysts, Lewis acids and enzymes.14 They are
referred to as ꢀdesigner solventsꢁ as their properties such
as hydrophilicity, hydrophobicity, Lewis acidity, visco-
sity and density can be altered by changing the cations
and/or the counteranions. Their high polarity and abil-
ity to solubilize both organic and inorganic compounds
can result in enhanced reaction rates and can provide
higher selectivities compared to conventional solvents.
As a result of their green credentials and potential to
enhance rates and selectivities, ionic liquids are finding
increasing applications in organic synthesis.15 Recent
reports have shown that they can also promote and
Keywords: Ionic liquids; Halogenation; N-Halosuccinimides; b-Dicar-
bonyl compounds; Cyclic ketones.
*
Corresponding author. Fax: +91 40 716 0512; e-mail: hmmeshram@
yahoo.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.141

992
H. M. Meshram et al. / Tetrahedron Letters 47 (2006) 991–995
O
O
O
O
O
[Bmim]PF6
N
X
+
R1
R2
r.t.
R2
R1
X
O
X=Br, Cl, I
3
1
2
Scheme 1.
catalyze many transformations of commercial impor-
tance under mild conditions without the need for any
additional acid catalyst.16,17 We report here the use of
an ionic liquid for the halogenation of a wide range
of functionalized ketones using N-halosuccinimides
without the requirement for catalyst, and under mild
conditions.
or NIS under the same conditions and the 2-chloro-
and 2-iodo-1,3-keto-esters were obtained in 93% and
89% yields, respectively. A variety of 2-unsubstituted
and 2-substituted 1,3-keto-esters and 1,3-diketones
reacted well under these conditions to give the corre-
sponding a-halogenated products in high yields. The
results are summarized in Table 1.
The reaction was initially carried out by treating ethyl
benzoylacetate 1a (R1 = Ph, R2 = Et) with 1.05 equiv
of NBS in 2 mL of ionic liquid, [Bmim]PF6 at ambient
temperature affording the a-brominated product in
95% yield (Scheme 1). Next we tested the possibility of
chlorination and iodination of compound 1 with NCS
Both a-bromination and a-chlorination were accom-
plished equally well along with somewhat reduced yields
in the case of a-iodination. In some cases a,a-dihalo
products were formed but as minor products only.
Longer reaction times were necessary for aliphatic
acyclic keto-esters.
Table 1. 2-Halogenation of various 1,3-keto-esters with N-halosuccinimides
Entry
1,3-Keto-esters
1
Producta
X = 3 Br, 30 = Cl, 300 = I
X
Time (min)
Yield (%)b
O
O
O
O
Br
Cl
I
20
20
25
95
93
89
a
Ph
OEt
O
Ph
OEt
O
X
O
O
O
O
O
O
O
b
c
Br
Cl
I
30
35
30
92
88
86
OCH2Ph
OCH2Ph
X
O
O
Br
Cl
I
50
45
50
89
85
86
OEt
OEt
X
N
O
O
O
d
e
f
Br
Cl
I
15
20
35
90
87
78
OEt
OEt
X
N
O
O
O
O
Br
Cl
I
10
10
20
90
92
87
Ph
Ph
Ph
Ph
X
O
O
O
O
X
Br
Cl
I
20
30
30
94
89
82
OEt
OEt

H. M. Meshram et al. / Tetrahedron Letters 47 (2006) 991–995
993
Table 1 (continued)
Entry
1,3-Keto-esters
1
Producta
X = 3 Br, 30 = Cl, 300 = I
X
Time (min)
Yield (%)b
O
O
O
O
Br
Cl
I
55
60
60
92
92
90
g
OEt
OEt
O
X
O
O
O
X
h
Br
Cl
I
20
20
40
90
88
85
OMe
OMe
O
O
O
O
i
Br
Cl
I
45
60
75
82
80
76
OEt
OEt
X
CH2Ph
CH2Ph
O
O
O
O
j
Br
Cl
I
60
75
75
88
85
87
OCH2Ph
OCH2Ph
X
a All products were characterized by 1H NMR, IR and mass spectroscopy.
b Isolated and unoptimized yield.
The method was applied to cyclic ketones, under the
same reaction conditions giving exclusively a-mono
halo products with high yields in short reaction times
(Scheme 2). In the case of 2-methylcyclohexanone
(Table 2, entry c) halogenation occurred predominantly
at the more substituted position. The reaction was found
to applicable to cyclic 1,3-diketones also, dimedone
(Table 2, entry d) furnished the corresponding a-halo
product in good yield. Attempts to perform the a-halo-
genation of lactams under these reaction conditions
failed. The scope and generality of this process is illus-
trated with respect to various cyclic ketones, and the
results are presented in Table 2.18
reacted with enol form of carbonyl compound to give
the a-halogenated products. Since the products were
weakly soluble in the hydrophobic ionic liquid
[Bmim]PF6, they could be easily separated by simple
extraction with ether, then the ionic liquid was thor-
oughly washed with water to remove the water-soluble
succinimide. The recovered ionic liquid was activated
at 80 ꢁC under reduced pressure and reused without
any significant loss of activity. For example, reaction
of tetralone (Table 2, entry e) with N-bromosuccinimide
gave 2-bromotetralone in 92%, 90%, 85% and 80%
yields over four cycles. The reaction was also studied
in the hydrophilic ionic liquid [bmim]BF4 and similar re-
sults were found. However, removal of succinimide is
simple from [Bmim]PF6 in comparison to [Bmim]BF4
due to its hydrophobic nature.
N-Halosuccinimides show enhanced reactivity in the
presence of ionic liquids thereby reducing the reaction
times, and improving the yields. The rate enhancement
in an ionic liquid is probably due to increased polariza-
tion of the N–X bond in the polar ionic medium and
also to stabilization of the charged ionic intermediates.
In an ionic liquid polarization of carbonyl compound
is increased significantly compared to organic solvents.
The halo cation generated from N-halosuccinimide
In summary, an ionic liquid was shown to be an effective
and useful polar alternative reaction medium for the 2-
halogenation of 1,3-keto-esters, 1,3-diketones and for
a-halogenation of cyclic ketones with N-halosuccini-
mides by playing the dual role of solvent as well as pro-
moter. This procedure offers several unique features,
O
O
O
X
[Bmim]PF6
N
X
+
r.t.
()n
()n
O
n=1, 2
X=Br, Cl, I
5
4
2
Scheme 2.

994
H. M. Meshram et al. / Tetrahedron Letters 47 (2006) 991–995
Table 2. a-Halogenation of various cyclic ketones using N-halosuccinimides
Entry
Cyclic ketones
Producta
X = 5 Br, 50 = Cl, 500 = I
X
Time (min)
Yield (%)b
O
O
Br
Cl
I
15
25
40
94
90
87
X
a
O
O
O
X
b
c
Br
Cl
I
20
30
40
93
91
82
O
O
X
Br
Cl
I
20
30
40
89
79
74
X
O
O
X
d
e
Br
Cl
I
30
30
45
81
86
79
O
O
O
O
X
Br
Cl
I
20
30
30
92
84
86
f
Br
Cl
I
30
30
40
88
79
86
X
O
O
a All products were characterized by 1H NMR, IR and mass spectroscopy.
b Isolated and unoptimized yield.
4. (a) Coats, S. J.; Wasserman, H. H. Tetrahedron Lett. 1995,
36, 7735–7738; (b) Rao, A. V. R.; Singh, A. K.; Reddy, K.
M.; Ravikumar, K. J. Chem. Soc., Perkin Trans. 1 1993,
3171–3175; (c) Shi, X.; Dai, L. J. Org. Chem. 1993, 58,
4596–4598.
providing enhanced yields, shorter reaction times,
operational simplicity, mild reaction conditions, ease
of isolation of products and a greener aspect by avoiding
the need for a catalyst.
5. NBS or Br2/NaH: (a) Boyd, R. E.; Rasmussen, C. R.;
Press, J. B. Synth. Commun. 1995, 25, 1045–1051; NBS/
NEt3: (b) Karimi, S.; Grohmann, K. G. J. Org. Chem.
1995, 60, 554–559; NBS/NaH: (c) Curran, D. P.; Bosch,
E.; Kaplan, J.; Newcomb, M. J. Org. Chem. 1989, 54,
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Org. Chem. 1989, 54, 3140–3157.
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Tanaka, K.; Chen, X.; Yoneda, F. Tetrahedron 1988, 44,
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References and notes
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H. Org. Process Res. Dev. 2002, 6, 384–393.
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1999, 29, 3227–3236; (b) Coats, S. J.; Wasserman, H. H.
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hedron Lett. 1990, 31, 1427–1428; (b) Curran, D. P.;
Morgan, T. M.; Schwartz, C. E.; Snider, B. B.; Dombro-
ski, M. A. J. Am. Chem. Soc. 1991, 113, 6607–6617.
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the appropriate time (see Tables 1 and 2). After completion
of the reaction, as indicated by TLC, the reaction mixture
was extracted with diethyl ether (3 · 10 mL). The combined
organic extracts were concentrated under vacuum and the
resulting product was directly charged on a silica gel
(Merck, 60–120 mesh) column and eluted with a mixture of
ethyl acetate/n-hexane (1:9) to afford the corresponding
pure product. The residual ionic liquid was washed with
water to remove the succinimide. The ionic liquid was
reactivated at 80 ꢁC under reduced pressure and recycled in
subsequent runs without any loss of activity. Compound
3b: IR (KBr): m 2963, 1759, 1678, 1461, 1273, 1017, 758,
1
698, 592 cmꢀ1. H NMR (300 Hz, CDCl3): d 5.23 (s, 2H),
5.45 (s, 1H), 6.54 (d, 1H, J = 2.2 Hz), 7.23–7.34 (m, 6H),
7.51 (s, 1H). EIMS Mass: m/z: 325 (M81Br+1, 11), 323
(M79Br+1, 10), 308 (9), 283 (12), 245 (59), 181 (15), 135
(23), 91 (100). Compound 30g: IR (KBr): m 2979, 1761,
1728, 1466, 1299, 1179, 1023 cmꢀ1 1H NMR (300 Hz,
.
CDCl3): d 1.18 (t, 6H, J = 7.5 Hz), 1.33 (t, 3H, J = 7.5 Hz),
3.10 (h, 1H, J = 7.5 Hz), 4.28 (q, 2H, J = 7.5 Hz), 4.83
(s, 1H). EIMS Mass: m/z: 195 (M37Cl+1, 12), 193
(M35Cl+1, 10), 144 (9), 139 (11), 118 (17), 102 (100).
18. General procedure: A mixture of 1,3-keto-ester or cyclic
ketone (1 mmol), N-halosuccinimide (1.05 mmol) in
[bmim]PF6 (2 mL) was stirred at room temperature for