dition reactions of amines with alkenes,4 alkynes,5 and allenes6
have been intensively studied, since they are often associated
with high stereo- and regioselectivities. Furthermore, palladium
can usually be used in catalytic amounts, tolerates a wide variety
of functional groups, and proceeds under mild reaction condi-
tions. Recently, Krishna Gopal Dongol and Boon Ying Tay7
reported the Pd-catalyzed cascade reaction of N-Boc protected
O-homoallylhydroxylamines with aryl iodides to afford the
corresponding isoxazolidines,8 contaminated by substantial
Heck-type side products with modest diastereoselectivity. Of
particular interest to us was that this chemistry could potentially
offer a rapid entry to N-aryl isoxazolidines which can serve as
precursors for â-amino alcohols9 and â-amino acids.10 Herein,
we report on stereocontrolled palladium-catalyzed syntheses of
isoxazolidines via tandem arylation of O-homoallylhydroxyl-
amines.
Palladium-Catalyzed Highly Stereoselective
Synthesis of N-Aryl-3-arylmethylisoxazolidines
via Tandem Arylation of
O-Homoallylhydroxylamines
Jinsong Peng,†,‡ Wenqing Lin,† Shixue Yuan,† and
Yuanwei Chen*,†
Key Laboratory of Asymmetric Synthesis & Chirotechnology of
Sichuan ProVince and Union Laboratory of Asymmetric
Synthesis, Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, China, and Graduate
School of Chinese Academy of Sciences, Beijing 100039, China
ReceiVed December 18, 2006
It was known that both palladium-catalyzed N-arylations of
amines and Pd-catalyzed carboamination reactions are very
sensitive to catalyst structure and ligand.4 Therefore, a judicious
choice of palladium catalyst, ligand, and base is needed to carry
out this domino N-arylation11/carboamination process of O-
homoallylhydroxylamine and suppress the formation of the
undesired N,N-bisarylation4c and Heck-type side product.7 To
(4) (a) Fritz, J. A.; Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2006, 8, 2531.
(b) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128,
2893. (c) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (d)
Yang, Q.; Ney, J. E.; Wolfe, J. P. Org. Lett. 2005, 7, 2575. (e) Ney, J. E.;
Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605. (f) Lira, R.; Wolfe, J.
P. J. Am. Chem. Soc. 2004, 126, 13906.
The palladium-catalyzed tandem arylation of O-homoallyl-
hydroxylamines with 2 equiv of aryl bromides was examined.
With Pd2(dba)3 (1 mol %) as the catalyst, Xantphos
(2 mol %) as the ligand, and NaOt-Bu as the base, the
reactions of O-homoallylhydroxylamines with aryl bromides
via sequential N-arylation/cyclization/C-arylation in toluene
afforded the corresponding N-aryl-3-arylmethylisoxazolidines
in good yields with excellent diastereoselectivity.
(5) For a recent report, see: (a) Rossi, R.; Bellina, F.; Biagetti, M.;
Catanese, A.; Mannina, L. Tetrahedron Lett. 2000, 41, 5281. (b) Mukho-
padhyay, R.; Kundu, N. G. Synlett 2001, 1143. (c) Bouyssi, D.; Balme, G.
Synlett 2001, 1191. (d) Chaplin, J. H.; Flynn, B. L. Chem. Commun. 2001,
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Lett. 2001, 3, 2501. (f) Arcadi, A.; Cacchi, S.; Cassetta, A.; Fabrizi, G.;
Parisi, L. M. Synlett 2001, 1605. (g) Arcadi, A.; Cacchi, S.; Di Giuseppe,
S.; Fabrizi, G.; Marinelli, F. Synlett 2002, 453. (h) Hu, Y.; Zhang, Y.; Yang,
Z.; Fathi, R. J. Org. Chem. 2002, 67, 2365. (i) Cacchi, S.; Fabrizi, G.;
Goggiomani, A. Heterocycles 2002, 56, 613. (j) Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Parisi, L. M. Tetrahedron 2003, 59, 4661.
(6) (a) Ma, S.; Zhang, J. Chem. Commun. 2000, 117. (b) Ohno, H.; Anzai,
M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J.
Org. Chem. 2001, 66, 4904. (c) Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3,
511. (d) Hiroi, K.; Hiratsuka, Y.; Watanabe, K.; Abe, I.; Kato, F.; Hiroi,
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Karstens, W. F. J.; Klomp, D.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron
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Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989. (j) Ma, S.; Xie, H. J. Org. Chem.
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Chem. 2003, 68, 6149.
One-pot catalytic processes incorporating two or more
different transformations hold great promise for the rapid buildup
of molecular complexity and diversity.1 In recent years great
interest has been focused on the development of tandem or
sequential reactions that form several different bonds, stereo-
centers, and rings.2 Transition metal-catalyzed transformations
have played an important role in the development of many of
these processes.3 The palladium-catalyzed intramolecular ad-
† Chengdu Institute of Organic Chemistry.
‡ Graduate School of Chinese Academy of Sciences.
(1) For recent examples, see: (a) Ajamian, A.; Gleason, J. L. Angew.
Chem., Int. Ed. 2004, 43, 3754. (b) Yamamoto, Y.; Nakagai, Y.; Itoh, K.
Chem. Eur. J. 2004, 10, 231. (c) Cossy, J.; Bargiggia, F.; BouzBouz, S.
Org. Lett. 2003, 5, 459. (d) Thadani, A. N.; Rawal, V. H. Org. Lett. 2002,
4, 4317. (e) Son, S. U.; Park, K. H.; Chung, Y. K. J. Am. Chem. Soc. 2002,
124, 6838. (f) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 11312. (g) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc.
2001, 123, 4609.
(2) (a) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
(b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
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(7) Dongol, K. G.; Tay, B. Y. Tetrahedron Lett. 2006, 47, 927.
(8) Isoxazolidines can be prepared via 1,3-dipolar cycloaddition reaction
of nitrones with alkenes. For a recent synthetic example of N-arylisoxazo-
lidine, see: (a) Saito, T.; Yamada, T.; Miyazaki, S.; Otani, T. Tetrahedron
Lett. 2004, 45, 9585. For other methods for the synthesis of isoxazolidines
see: (b) Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225. (c) Dongol, K.
G.; Tay, B. Y.; Xiang, K. Synth. Commun. 2006, 36, 1247. (c) Lombardo,
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(9) (a) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000,
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(10) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am. Chem.
Soc. 2005, 127, 5376.
10.1021/jo0625958 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/17/2007
J. Org. Chem. 2007, 72, 3145-3148
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