ORGANIC
LETTERS
2007
Vol. 9, No. 20
4029-4032
Catalytic Activation of the Leaving
Group in the SN2 Reaction§
Hirofumi Yamamoto, Ghanshyam Pandey, Yumiko Asai, Mayo Nakano,
Atsushi Kinoshita, Kosuke Namba, Hiroshi Imagawa, and Mugio Nishizawa*
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
Received July 20, 2007
ABSTRACT
A novel catalytic activation of the leaving group in the SN2 reaction is achieved as an extension of our mercuric triflate-catalyzed reactions.
Derivatives of anilinoethyl 4-pentynoate reacted smoothly with catalytic amounts of Hg(OTf)2 to give indoline derivatives in excellent yield with
efficient catalytic turnovers under very mild conditions. The reaction of optically pure secondary alcohol derivatives resulted in inversion of
stereochemistry, which is a definitive feature of the SN2 reaction. The procedure is applicable for benzoazepine synthesis.
The SN2 reaction is a single-step reaction via a transition
state as formulated by Hughes and Ingold in 1937, and it is
a principal backbone of organic chemistry.1 Mitsunobu
developed the second generation of SN2 reactions of alcohol
using diethylazodicarboxylate, benzoic acid, and triphen-
ylphosphine, the so-called Mitsunobu reaction.2,3 So far, the
SN2 reaction has been recognized as a stoichiometric
bimolecular reaction between a nucleophile and a substrate.
Herein we report a novel catalytic activation of the leaving
group for the SN2 reaction as an extension of our original
mercury(II) trifluoromethanesulfonate [hereafter Hg(OTf)2]-
catalyzed reactions.4,5 Recently, we found that the Hg(OTf)2
complex showed highly efficient catalytic activity based upon
a significant affinity for the alkynyl group as well as an
efficient protodemercuration sequence resulting in regenera-
tion of Hg(OTf)2.6 We found that the Hg(OTf)2‚tetra-
(4) (a) Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y. Tetra-
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K.; Kan, Y.; Uenoyama, K.; Imagawa, H. Synlett 1995, 169-170. (c)
Nishizawa, M. Studies in Natural Product Chemistry.; Vol. 1, Stereoselective
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688. (e) Nishizawa, M.; Imagawa, H. J. Syn. Org. Chem. Jpn. 2006, 64,
744-751.
(5) (a) Nishizawa, M.; Takenaka, H.; Hirotsu, K.; Higuchi, T.; Hayashi,
Y. J. Am. Chem. Soc. 1984, 106, 4290-4291. (b) Nishizawa, M.; Takenaka,
H.; Hayashi, Y. J. Am. Chem. Soc. 1985, 107, 522-523. (c) Nishizawa,
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M.; Morikuni, E.; Takeji, M.; Asoh, K.; Hyodo, I.; Imagawa, H.; Yamada,
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Yamada, H.; Imagawa, H. Synlett 1998, 76-78. (i) Nishizawa, M.; Imagawa,
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§ In memory of the late Professor Yoshihiko Ito.
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759. (b) Hughes, E. D.; Ingold, C. K.; Scott, A. D. J. Chem. Soc. 1937,
1201-1208. (c) Hughes, E. D.; Ingold, C. K.; Martin, L. R. J.; Meigh, D.
F. Nature 1950, 166, 679-680.
(2) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380-2382. (b) Mitsunobu, O. Synthesis 1981, 1-28.
(3) (a) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34,
1639-1642. (b) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett.
1994, 539-542. (c) Tsunoda, T.; Ozaki, F.; Ito, S. Tetrahedron Lett. 1994,
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Tetrahedron Lett. 1995, 36, 2529-2530. (e) Tsunoda, T.; Nagino, C.; Oguri,
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10.1021/ol701737x CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007