Amberlyst-15-promoted efficient 2-halogenation of 1,3-keto-esters and cyclic ketones using N-halosuccinimides

Article abstract of DOI:10.1016/j.tetlet.2004.11.140

A simple and rapid process has been developed for the α- monohalogenation of 1,3-keto-esters with N-halosuccinimides catalyzed by Amberlyst-15 at room temperature to produce the corresponding 2-halo 1,3-keto-esters in high yields. This protocol also extended to α-halogenation of cyclic ketones.

Full text of DOI:10.1016/j.tetlet.2004.11.140

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 623–626
â
Amberlyst-15 -promoted efficient 2-halogenation of
,3-keto-esters and cyclic ketones using N-halosuccinimides
1
*
H. M. Meshram, P. N. Reddy, K. Sadashiv and J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 9 September 2004;revised 15 November 2004;accepted 26 November 2004
Available online 13 December 2004
Abstract—A simple and rapid process has been developed for the a-monohalogenation of 1,3-keto-esters with N-halosuccinimides
catalyzed by Amberlyst-15 at room temperature to produce the corresponding 2-halo 1,3-keto-esters in high yields. This protocol
ꢀ
also extended to a-halogenation of cyclic ketones.
ꢁ
2004 Elsevier Ltd. All rights reserved.
Preparation of 2-bromo 1,3-dicarbonyl compounds has
always received attention due to their versatile uses as
intermediates in organic synthesis. a-Monobromina-
methods were successful for the monohalogenation of
b-keto-esters, a number of these methods are practically
inconvenient to use or employ rather harsh reaction
conditions and sometimes produce dihalogenated
products. Here we report that NBS combined with the
1
tion of b-keto-esters without a-substituents has been a
challenging problem since the monosubstituted product
is always accompanied by a small amount of disubsti-
tuted product. The most commonly used reagents
ꢀ
heterogeneous solid acidic catalyst Amberlyst-15
achieves fast 2-monobromination of a wide range of
1,3-keto-esters. In addition, this method can be applied
to the 2-chlorination and 2-iodination of 1,3-keto-
2
3
include bromine, copper(II) bromide and N-bromo-
4
succinimide. In terms of accessibility and ease of
superior and
1
1,12
handling, N-bromosuccinimide is
a
esters.
inexpensive brominating reagent. The major advantage
of the use of the NBS is that the byproduct succinimide
can be easily recovered and reconverted to NBS to be re-
used in subsequent reactions. Classically, the NBS
a-bromination of ketones proceeds via a radical process
promoted by initiators such as azobisisobutyronitrile
1
2
Firstly, ethyl benzoylacetate 1a (R = Ph, R = Et) was
chosen as a model substrate for bromination in order
to find optimal conditions. Compound 1a was treated
ꢀ
with 1.05 equiv NBS in the presence of Amberlyst-15
at room temperature in ethyl acetate. The reaction was
complete within 15 min to give brominated product 3a
(R = Ph, R = Et) in 94% yield (Scheme 1). When the
reaction solvent was changed to CHCl , CH Cl , or
CH CN the reaction required a much longer time and
(
CCl . Lewis acid Mg(ClO ) is also employed to pro-
AIBN) and dibenzoyl peroxide (BPO) in refluxing
5
1
2
4
4 2
6
mote 2-halogenation of 1,3-dicarbonyl compounds. Re-
cently, a mild and efficient method for the bromination
3
2
2
3
of b-keto-esters using N-bromosuccinimide catalyzed by
unreacted 1a remained, thus ethyl acetate gave the best
results. Next we tested the possibility of using Amber-
lyst-15 to catalyze chlorination and iodination of com-
pound 1a using NCS or NIS. In this study, the 2-chloro-
and 2-iodo-1,3-keto-esters were obtained in excellent
yields. Various other 2-unsubstituted and 2-substituted
1,3-keto-esters were converted to their corresponding
7
NH OAc was described. Togni et al. used Ti(TADDO-
Lato) complex to catalyze enantioselective a-halogena-
4
ꢀ
8
tion of a-substituted b-keto-esters. Subsequently,
several methods have been developed for the 2-chlorina-
9
10
tion and 2-iodination of 1,3-dicarbonyl compounds
using NCS or NIS, respectively. Although some of these
2-halo products in high yields using this procedure
(
Table 1, entries b–f). Cyclic 1,3-keto-esters also reacted
smoothly. In all cases, the reactions proceeded efficiently
within 10–30 min in high yields at ambient temperature.
In some cases dichlorination and diiodination was
observed.
Keywords: Ion exchange resin; N-Halosuccinimides;Halogenation;
b-Keto-esters;Cyclic ketones.
Corresponding author. Fax: +91 40 7160512;e-mail: hmmeshram@
yahoo.com
*
0
040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.140

624
H. M. Meshram et al. / Tetrahedron Letters 46 (2005) 623–626
O
O
O
O
O
Amberlyst-15
R2
+
N
X
R2
R1
O
R1
EtOAc, r.t.
O
O
X
X=Br, Cl, I
1
3
2
Scheme 1.
Table 1. 2-Halogenation of various 1,3-keto-esters with N-halosuccinimides
a
1
11
Product X = 3 Br, 3 = Cl, 3 = l
b
Entry
1,3-Keto-esters 1
X
Time (min)
Yield (%)
O
O
O
O
Br
Cl
I
15
10
20
94
92
90
a
Ph
Ph
OEt
Ph
Ph
OEt
X
X
O
O
Br
Cl
I
10
10
15
95
92
86
O
O
b
c
OBn
O
OBn
O
O
O
O
Br
Cl
I
15
20
30
89
85
86
OEt
OEt
N
N
X
O
O
O
X
d
e
f
Br
Cl
I
10
20
20
90
92
88
OEt
OEt
O
O
O
O
X
OMe
OMe
Br
Cl
I
15
15
20
93
90
86
Cl
Cl
O
O
O
O
X
Br
Cl
I
30
45
30
92
92
90
OMe
OMe
a
1
All products were characterized by H NMR, IR and mass spectroscopy.
Isolated and unoptimized yield.
b
We now examined the a-halogenation of cyclic ketones
under the same reaction conditions and found that the
reactions proceeded rapidly at room temperature with
high yields (Scheme 2). In the case of 2-methylcyclo-
hexanone (Table 2, entry b) halogenation occurred pre-
dominantly at the more substituted position.
Halogenation of acyclic ketones using NXS under these
conditions failed. The scope and generality of this pro-
cess is illustrated with respect to various cyclic ketones
We have shown that N-halosuccinimides show enhanced
reactivity in the presence of Amberlyst-15 thereby
ꢀ
reducing the reaction times dramatically, and substan-
tially improving the yields. Low conversions (35–55%)
were obtained when other solid acid catalysts such as
heteropoly acid H PW O , and H-ZSM were em-
3
12 40
ployed. The Amberlyst catalyst could be easily separated
by simple filtration and the recovered acid resin could be
re-used in subsequent reactions with a gradual decrease
in activity. For example, cyclohexanone with N-bromo-
1
3
and the results are presented in Table 2.

H. M. Meshram et al. / Tetrahedron Letters 46 (2005) 623–626
625
O
O
O
Amberlyst-15
X
N
X
+
EtOAc, r.t.
(
)n
(
)n
O
n=1, 2, 3
X=Br, Cl, I
4
2
5
Scheme 2.
Table 2. a-Halogenation of various cyclic ketones using N-halosuccinimides
a
Product X = 5 Br, 5 = Cl, 5 = l
1
11
b
Entry
Cyclic ketones
X
Time (min)
Yield (%)
O
O
X
a
Br
Cl
I
25
30
40
90
87
84
O
O
O
X
b
c
Br
Cl
I
20
30
60
88
90
82
X
O
O
X
Br
Cl
I
30
25
40
90
84
79
O
O
d
e
Br
Cl
I
30
30
60
86
81
78
X
O
O
X
Br
Cl
I
20
25
30
92
90
86
a
1
All products were characterized by H NMR, IR and mass spectroscopy.
Isolated and unoptimized yield.
b
succinimide given 2-bromocyclohexanone in 90%, 86%,
0%, and 75% yields over four cycles.
Tetrahedron Lett. 1995, 36, 7735–7738;(c) Endo, M.;
Droghini, R. Can. J. Chem. 1988, 66, 1400–1404;(d)
8
Hlavka, J.;Bitha, P.;Lin, Y.;Strohmeyer, T.
J. Hetero-
cycl. Chem. 1985, 22, 1317–1322;(e) Yoshida, J.;Yano, S.;
Ozawa, T.;Kawabata, N. Tetrahedron Lett. 1984, 25,
In conclusion, we have developed a novel and efficient
approach for the mild 2-halogenation of 1,3-keto-esters
and a-halogenation of cyclic ketones with N-halosuccin-
2
817–2820;(f) Kaye, P. T.;Meakins, G. D.;Smith, A. K.;
Tirel, M. D. J. Chem. Soc., Perkin Trans. 1 1983, 1677–
680.
ꢀ
imides using Amberlyst-15 as a heterogeneous solid
1
acid catalyst. Because of its simplicity, high selectivity,
short reaction times, high yields, the use of an inexpen-
sive and recyclable acid resin, this method is simple, con-
venient and economically viable.
2
. (a) Bigelow, L. A.;Hanslick, R. S. Org. Synth. Collect.;
Wiley: New York, 1943;Vol. 2, p 244;(b) Hakam, K.;
Thielmann, M.;Thielmann, T.;Winterfeldt, E. Tetrahe-
dron 1987, 43, 2035–2044;(c) Ogilvie, W.;Rank, W. Can.
J. Chem. 1987, 65, 166–169;(d) Dowd, P.;Kaufman, C.;
Kaufman, P. J. Org. Chem. 1985, 50, 882–885.
3
. (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.
References and notes
1
. (a) Misra, A. P.;Raj, K.;Bhaduri, A. P. Synth. Commun.
999, 29, 3227–3236;(b) Coats, S. J.;Wasserman, H. H.
1

6
26
H. M. Meshram et al. / Tetrahedron Letters 46 (2005) 623–626
/NaH: Boyd, R. E.;Rasmussen, C. R.; Seong, C. M.;Chang, C. T. J. Am. Chem. Soc. 1989, 111,
8872–8878.
4
. (a) NBS or Br
Press, J. B. Synth. Commun. 1995, 25, 1045–1051;(b) NBS/
2
NEt : Karimi, S.;Grohmann, K. G. J. Org. Chem. 1995,
3
13. General procedure: A mixture of 1,3-keto-ester or cyclic
ketone (1 mmol), N-halosuccinimide (1.05 mmol), and
Amberlyst-15 (0.75 g) in ethyl acetate (10 mL) was
6
0, 554–559;(c) NBS/NaH: Curran, D. P.;Bosch, E.;
Kaplan, J.;Newcomb, M. J. Org. Chem. 1989, 54, 1826–
831;(d) NBS/KH: Curran, D. P.;Chang, C. T. J. Org.
ꢀ
1
stirred at room temperature for the appropriate time (see
Tables 1 and 2). After completion of the reaction, as
indicated by TLC, the reaction mixture was filtered and
washed with ethyl acetate (2 · 10 mL). The combined
organic extracts were dried over anhydrous Na SO
Chem. 1989, 54, 3140–3157.
. Schmid, H.;Karrer, P. Helv. Chim. Acta 1946, 29, 573–
5
6
7
8
5
81.
. Yang, D.;Yan, Yi.-L.;Lui, B. J. Org. Chem. 2002, 67,
429–7431.
2
4
7
concentrated in vacuo and the resulting product was
directly charged on a small 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.
Compound 3b: IR (KBr): t2966, 1743, 1682, 1450, 1258,
. Tanemura, K.;Suzuki, T.;Nishida, Y.;Satsumabayashi,
K.;Horaguchi, T. Chem. Commun. 2004, 470–471.
. (a) Hintermann, L.;Togni, A. Helv. Chem. Acta 2000, 83,
2425–2435;(b) Hintermann, L.;Togni, A. Angew. Chem.,
À1
1
Int. Ed. 2000, 39, 4359–4362;(c) Piana, S.;Devillers, I.;
Togni, A.;Rothlisberger, U. Angew. Chem., Int. Ed. 2002,
964, 737, 688, 615 cm . H NMR (300 Hz, CDCl ): d 5.23
3
(s, 2H), 5.60 (s, 1H), 7.24–7.31 (m, 5H), 7.44 (t, 2H,
J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.94 (d, 2H,
41, 979–982.
8
1
+
J = 7.5 Hz). EIMS Mass: m/z: 335 ( Br, M , 17), 333
9
. Chlorination with NCS: (a) Davis, D. T.;Kapur, N.;
Parsons, A. F. Tetrahedron 2000, 56, 3941–3949;(b)
Tanaka, K.;Chen, X.;Yoneda, F. Tetrahedron 1988, 44,
7
( Br, M , 17), 120 (9), 105 (100), 91 (9), 77 (26), 57 (25).
9
+
1
Compound 3 d: IR (KBr): t 2946, 2871, 1732, 1451, 1241,
À1
1
3241–3249.
751, 562 cm . H NMR (300 Hz, CDCl ): d 1.27 (t, 3H,
3
1
0. Iodination with NIS: (a) Cossy, J.;Thellend, A. Tetrahe-
dron Lett. 1990, 31, 1427–1428;(b) Curran, D. P.;
Morgan, T. M.;Schwartz, C. E.;Snider, B. B.;
Dombroski, M. A. J. Am. Chem. Soc. 1991, 113, 6607–
J = 7.4 Hz), 1.66–1.75 (m, 1H), 1.82–1.96 (m, 3H), 2.03–
2.11 (m, 1H), 2.30–2.39 (m, 1H), 2.67–2.74 (m, 1H), 2.75–
2.83 (m, 1H), 4.23 (q, 2H, J = 7.4 Hz). EIMS Mass: m/z:
3
7
+
35
+
206 ( Cl, M , 7), 204 ( Cl, M , 19), 169 (12), 139 (100),
1
6617.
43 (60). Compound 3 f: IR (KBr): t 2954, 2849, 1760,
1693, 1601, 1438, 1252, 738, 582 cm . H NMR (300 Hz,
À1
1
1
1. For examples of 2-chloro 1,3-dicarbonyl compounds in
organic transformations, see: (a) Hayashi, Y.;Orikasa, S.;
Tanaka, K.;Kanoh, K.;Kiso, Y. J. Org. Chem. 2000, 65,
CDCl ): d 2.44–2.55 (m, 1H), 2.92–3.04 (m, 2H), 3.22–3.35
3
(m, 1H), 3.84 (s, 3H), 7.24 (d, 1H, J = 7.5 Hz), 7.34 (t, 1H,
J = 7.5 Hz), 7.51 (t, 1H, J = 7.5 Hz), 8.05 (d, 1H,
8402–8405;(b) Guerin, D.;Carlier, R.;Lorcy, D. J. Org.
3
7
+
J = 7.5 Hz);EIMS Mass: m/z: 240 ( Cl, M , 2), 238
Chem. 2000, 65, 6069–6072;(c) Vasudevan, A.;Mavand-
adi, F.;Chen, L.;Gangjee, A. J. Org. Chem. 1999, 64,
3
( Cl, M , 4), 203 (29), 171 (21), 118 (100), 90 (47), 63 (8).
5
+
6
34–638;(d) Hayes, T.;Villani, R.;Weinreb, S. M. J. Am.
Compound 5c: IR (KBr): t 2925, 1683, 1599, 1454, 1217,
À1
1
Chem. Soc. 1988, 110, 5533–5543;(e) Blount, J. F.;Coffen,
D. L.;Katonak, D. A. J. Org. Chem. 1978, 43, 3821–3824.
2. For examples of 2-iodo 1,3-dicarbonyl compounds in
organic transformations, see: (a) Kang, J.;Lee, J. H.;Noh,
S. B.;Oh, C. S.;Kim, H. Y.;Chung, B. Y. Synlett 1990,
888, 772, 594 cm . H NMR (300 Hz, CDCl ): d 2.41–
3
2.57 (m, 2H), 2.89 (dt, 1H, J = 3.7, 17 Hz), 3.29–3.38 (m,
1H), 4.67 (t, 1H, J = 3.7 Hz), 7.25 (d, 1H, J = 8.1 Hz), 7.33
(t, 1H, J = 7.4 Hz), 7.49 (t, 1H, J = 8.1 Hz), 8.06 (d, 1H,
1
8
1
+
J = 8.1 Hz). EIMS Mass: m/z: 226 ( Br, M , 16), 224
( Br, M , 16), 144 (23), 118 (100), 90 (40), 63 (13).
7
9
+
153–154;(b) Curran, D. P.;Chen, M. S.;Spletzer, E.;