Mild r-Ha logen a tion Rea ction s of 1,3-Dica r bon yl Com p ou n d s
Ca ta lyzed by Lew is Acid s
Dan Yang,* Yi-Long Yan, and Bob Lui
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
Received J une 7, 2002
4 2 3
Lewis acid Mg(ClO ) , combined with NBS, in CH CN or EtOAc provided mild and fast bromination
of 1,3-dicarbonyl compounds. In particular, this protocol could be applied to the R-monobromination
of R-unsubstituted â-keto esters. Similar Lewis acid catalysis was also extended to the R-chlorination
and iodination of 1,3-dicarbonyl compounds with NCS and NIS, respectively.
7
In tr od u ction
R-carbon. Recently, Togni et al used Ti-TADDOLate to
catalyze enantioselective R-halogenation of R-substituted
R-Bromination of 1,3-dicarbonyl compounds is an
8
â-keto esters. We thus investigated the use of Lewis
acids in R-bromination of â-keto esters. Here we report
4 2
that NBS combined with the Lewis acid Mg(ClO ) can
afford mild and fast R-bromination of a wide range of
functionalized 1,3-dicarbonyl compounds. In addition,
1
important transformation, as the resulting R-brominated
products are highly versatile intermediates in organic
2
synthesis. The most commonly used reagents for this
3
transformation include bromine, N-bromosuccinimide
4
5
(
NBS), and cupric bromide. The reaction conditions of
this method can be applied to the R-chlorination and
these methods are in general highly acidic or basic. In
terms of availability and ease of handling, N-bromosuc-
cinimide is a superior brominating reagent. However, in
R-iodination of 1,3-dicarbonyl compounds,9
,10
thereby
1
1,12
providing useful building blocks for organic synthesis.
our investigation of Lewis acid-catalyzed atom-transfer
radical cyclization reactions,6 we found some olefinic
Resu lts a n d Discu ssion
R-bromo â-keto esters, especially R-monobromo â-keto
esters from R-unsubstituted substrates, could not be
conveniently prepared by bromination of â-keto esters
I. Lew is Acid -Ca ta lyzed r-Br om in a tion of r-Su b-
stitu ted â-Keto Ester s. R-Bromination reactions of
R-monosubstituted â-keto esters 1a -1f were conducted
4
with NBS following literature procedures. This led us
to search for a new R-bromination method. It is known
that the chelation of Lewis acids to the two carbonyl
groups of a â-keto ester substrate promotes the enol
formation and thus changes the electronic property of the
(
7) For examples of Lewis acid-catalyzed transformations of â-keto
esters, see: (a) Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.; Cheung, K.-
K. J . Am. Chem. Soc. 2000, 122, 1658-1663. (b) Yang, D.; Ye, X.-Y.;
Gu, S.; Xu, M. J . Am. Chem. Soc. 1999, 121, 5579-5580. (c) Tateiwa,
J .-I.; Hosomi, A. Eur. J . Org. Chem. 2001, 1445-1448. (d) Keller, E.;
Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879-1882. (e) Colombo,
M. I.; Signorella, S.; Mischne, M. P. Tetrahedron 1990, 46, 4149-4154.
(f) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J . Am.
Chem. Soc. 1995, 117, 6194-6198. (g) Sasai, H.; Emori, E.; Arai, T.;
Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561-5564.
(8) (a) Hintermann, L.; Togni, A. Helv. Chim. Acta 2000, 83, 2425-
2435. (b) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39,
4359-4362. (c) Piana, S.; Devillers, I.; Togni, A.; Rothlisberger, U.
Angew. Chem., Int. Ed. 2002, 41, 979-982.
(9) Chlorination with NCS: (a) Davies, D. T.; Kapur, N.; Parsons,
A. F. Tetrahedron 2000, 56, 3941-3949. (b) Tanaka, K.; Chen, X.;
Yoneda, F. Tetrahedron 1988, 44, 3241-3249.
(10) Iodination with NIS: (a) Cossy, J .; Thellend, A. Tetrahedron
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,
6607-6617.
(11) For examples of R-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, 8402-8405. (b) Guerin, D.; Carlier,
R.; Lorcy, D. J . Org. Chem. 2000, 65, 6069-6072. (c) Vasudevan, A.;
Mavandadi, F.; Chen, L.; Gangjee, A. J . Org. Chem. 1999, 64, 634-
638. (d) Hayes, T.; Villani, R.; Weinreb, S. M. J . Am. Chem. Soc. 1988,
110, 5533-5543. (e) Blount, J . F.; Coffen, D. L.; Katonak, D. A. J . Org.
Chem. 1978, 43, 3821-3824.
(12) For examples of R-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, 153-154. (b) Curran, D. P.;
Chen, M. S.; Spletzer, E.; Seong, C. M.; Chang, C. T. J . Am. Chem.
Soc. 1989, 111, 8872-8878. (c) Reference 4c.
(
1) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
VCH Publishers Inc.: New York, 1999; pp 715-719.
2) For examples of R-bromo 1,3-dicarbonyl compounds in organic
(
transformations, see: (a) Misra, A. P.; Raj, K.; Bhaduri; A. P. Synth.
Commun. 1999, 29, 3227-3236. (b) Coats, S. J .; Wasserman, H. H.
Tetrahedron Lett. 1995, 36, 7735-7738. (c) Endo, M.; Droghini, R. Can.
J . Chem. 1988, 66, 1400-1404. (d) Hlavka, J .; Bitha, P.; Lin, Y.;
Strohmeyer, T. J . Heterocycl. Chem. 1985, 22, 1317-1322. (e) Yoshida,
J .; Yano, S.; Ozawa, T.; Kawabata, N. Tetrahedron Lett. 1984, 25,
2
817-2820. (f) Kaye, P. T.; Meakins, G. D.; Smith, A. K.; Tirel, M. D.
J . Chem. Soc., Perkin Trans. 1 1983, 1677-1680.
3) (a) Bigelow, L. A.; Hanslick, R. S. Organic Syntheses; Wiley: New
(
York, 1943; Collect. Vol. 2, p 244. (b) Hakam, K.; Thielmann, M.;
Thielmann, T.; Winterfeldt, E. Tetrahedron 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.
(
4) (a) NBS or Br
2
/NaH: Boyd, R. E.; Rasmussen, C. R.; Press: J .
: Karimi, S.;
B. Synth. Commun. 1995, 25, 1045-1051. (b) NBS/NEt
3
Grohmann, K. G. J . Org. Chem. 1995, 60, 554-559. (c) NBS/NaH:
Curran, D. P.; Bosch, E.; Kaplan, J .; Newcomb, M. J . Org. Chem. 1989,
5
1
4, 1826-1831. (d) NBS/KH: Curran, D. P.; Chang, C. T. J . Org. Chem.
989, 54, 3140-3157.
(
5) (a) Coats, S. J .; Wasserman, H. H. Tetrahedron Lett. 1995, 36,
7
735-7738. (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.
(6) Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K. J . Am.
Chem. Soc. 2001, 123, 8612-8613.
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0.1021/jo026025t CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/26/2002
J . Org. Chem. 2002, 67, 7429-7431
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