we present our first results on cyclization reactions of
alkoxy-substituted amidyl radicals (eq 1).9 Since the O-N
bond can be readily cleaved by various methods, a new
entry into 1,3- and 1,4-amino alcohols should be opened
(via 5-exo and 6-exo cyclizations, respectively). To the best
of our knowledge, N-alkoxyamidyl radical cyclizations
have not been reported to date.
Stereoselective Cyclization Reactions of
IBX-Generated Alkoxyamidyl Radicals
Birgit Janza and Armido Studer*
Organisch-Chemisches Institut,
Westfa¨lische-Wilhelms-Universita¨t, Corrensstrasse 40,
48149 Mu¨nster, Germany
Received May 11, 2005
As a model compound, acetylated alkoxyamine 1 was
readily prepared from 1-phenyl-but-3-en-1-ol via Mit-
sunobu reaction using N-hydroxyphthalimide according
to known procedures (Scheme 1).10,11 All the compounds
SCHEME 1. Preparation of the Acetylated
Alkoxyamine 1
In this paper, a method for the generation of alkoxyamidyl
radicals is presented. These N-centered radicals can ef-
ficiently be formed starting from the corresponding acylated
alkoxyamines using IBX as an oxidant. Stereoselective 5-exo
and 6-exo reactions with these N-heteroatom-centered radi-
cals leading to isoxazolidines and [1,2]oxazinanes are dis-
cussed. The N-O bond in the heterocycles can readily be
cleaved with SmI2 to provide N-acylated 1,3-amino alcohols.
There are many reports in the literature on the
application of N-centered radicals in organic synthesis.1
In general, these heteroatom-centered radicals undergo
H-abstraction or addition reactions. In particular, cy-
clizations leading to biologically important N-heterocyclic
compounds are interesting. Newcomb showed that the
rate of the 5-exo cyclization of an aminyl radical can be
increased upon protonation or complexation of the aminyl
radical.2 Electronic effects are the reason for the ac-
celeration. On the basis of these results, it is obvious that
the more electrophilic amidyl radicals cyclize faster than
aminyl radicals.3 Amidyl radical cyclizations have been
studied using N-chloroamides,4 N-phenylthioamides,5
N-hydroxypyridine-2(1H)thione derivatives,6 N-nitroso-
amides,7 and other systems8 as radical precursors. Herein
described herein were prepared as racemates. Transfor-
mation of 1 into a suitable radical precursor was difficult
to achieve. We tested several methods for the preparation
of N-bromo amide 2a. However, all attempts failed,
probably due to instability of the bromide. Furthermore,
under certain conditions, Br+-induced electrophilic cy-
clizations were obtained.11 We faced the same problems
on the way to chloride 2b and iodide 2c. The N-
phenylthioamide 2d could not be prepared using estab-
lished procedures for the preparation of N-phenylthio-
amides.
We therefore decided to generate the desired alkoxy-
amidyl radical directly from 1 under oxidative condi-
tions.9,12 Recently, Nicolaou and co-workers nicely dem-
onstrated the potential of o-iodoxybenzoic acid (IBX) for
the generation of N-centered radicals.13,14 Pleasingly, we
(1) Reviews: (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22,
337. (b) Zard, S. Z. Synlett 1996, 1148. (c) Stella, L. In Radicals in
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(2) Ha, C.; Musa, O. M.; Martinez, F. N.; Newcomb, M. J. Org. Chem.
1997, 62, 2704. Horner, J. H.; Martinez, F. N.; Musa, O. M.; Newcomb,
M.; Shahin, H. E. J. Am. Chem. Soc. 1995, 117, 11124.
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(4) Mackiewicz, P.; Furstoss, R.; Waegell, B.; Cote, R.; Lessard, J.
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Furstoss, R.; Waegell, B. J. Org. Chem. 1978, 43, 3750. Go¨ttlich, R.
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Chem. 2002, 1848. Schulte-Wu¨lwer, I. A.; Helaja, J.; Go¨ttlich, R.
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(5) Amidyl radicals generated from sulfenamides: Esker, J. L.;
Newcomb, M. Tetrahedron Lett. 1993, 34, 6877.
(6) Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32, 1035.
Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1992, 33, 5913. Esker, J.
L.; Newcomb, M. J. Org. Chem. 1993, 58, 4933. Esker, J. L.; Newcomb,
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(7) Chow, Y. L.; Perry, R. A. Can. J. Chem. 1985, 63, 2203.
(8) Hoang-Cong, X.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett.
1999, 40, 2125. Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron Lett.
2000, 41, 2333. Gagosz, F.; Moutrille, C.; Zard, S. Z. Org. Lett. 2002,
4, 2707. Moutrille, C.; Zard, S. Z. Chem. Commun. 2004, 1848.
(9) Cooley, J. H.; Mosher, M. W.; Khan, M. A. J. Am. Chem. Soc.
1968, 90, 1867. Chen, Q.; Shen, M.; Tang, Y.; Li, C. Org. Lett. 2005, 7,
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(10) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972,
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Am. Chem. Soc. 2001, 123, 7734.
(11) Janza, B.; Studer, A. Synthesis 2002, 2117.
(12) Crawford, R. J.; Raap, R. J. Org. Chem. 1963, 28, 2419.
(13) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L.; Sugita,
K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202. Nicolaou, K. C.;
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10.1021/jo0509399 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/22/2005
J. Org. Chem. 2005, 70, 6991-6994
6991