Cycloadditions of N-sulfonyl nitrones generated by Lewis acid catalyzed rearrangement of oxaziridines

Article abstract of DOI:10.1021/ja711335d

We have developed cycloaddition reactions of novel, electron-deficient N-nosyl nitrones that arise from the titanium(IV)-catalyzed rearrangement of the corresponding N-nosyl oxaziridines. A diverse range of styrenes and oxaziridines react smoothly in this

Full text of DOI:10.1021/ja711335d

Published on Web 02/15/2008
Cycloadditions of N-Sulfonyl Nitrones Generated by Lewis Acid Catalyzed
Rearrangement of Oxaziridines
Katherine M. Partridge, Mary E. Anzovino, and Tehshik P. Yoon*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received December 21, 2007; E-mail: tyoon@chem.wisc.edu
Scheme 1
The weak N-O bond of 1,2-isoxazolidines can undergo facile
reductive cleavage to furnish 1,3-aminoalcohols. Due to the ease
with which isoxazolidines can be processed into these synthetically
valuable structures, considerable effort has been invested toward
the development of methods for [3 + 2] nitrone cycloadditions.1
This enormous body of work, however, has focused primarily upon
N-alkyl nitrones that produce 1,2-isoxazolidines whose N-substit-
uents cannot be removed without concomitant cleavage of the
sensitive N-O bond;2 cycloadditions of nitrones bearing easily
hydrolyzed electron-withdrawing N-substituents are almost com-
pletely unexplored.3 Recently, 1,2-isoxazolidines have begun to
attract significant attention as nucleoside analogues4 and synthetic
transcriptase activators.5 Exploration of the biological activity of
this class of heterocycles would be facilitated by new methods to
Table 1. Effect of Oxophilic Lewis Acids on the Efficiency and
Diastereoselectivity of 1,2-Isoxazolidine Formationa
access the parent N-unsubstituted isoxazolidines for diversification
into libraries of N-modified analogues. Herein, we report a novel
method for Lewis acid catalyzed formation and cycloaddition of
otherwise inaccessible N-nosyl nitrones, which produce 1,2-
isoxazolidines that can be deprotected under mild conditions without
loading
mol %
time
h
d.r.c
accompanying ring cleavage.
entry
catalyst
yieldb
(syn/anti)
Our group has been developing new synthetic methods based
upon activation of oxaziridines with exogenous catalysts. We
recently reported a new aminohydroxylation procedure in which
N-sulfonyl oxaziridine 1 reacts with styrenes in the presence of
Cu(TFA)2 to provide 1,3-oxazolidines.6 In an unusual example of
divergent, catalyst-controlled reactivity, we have discovered that
the isomeric 1,2-isoxazolidine 3 is produced when styrene reacts
with 1 in the presence of Sc(OTf)3 (Scheme 1). This heterocycle
presumably arises from rearrangement of the oxaziridine to a
transient N-sulfonyl nitrone (2) that undergoes [3 + 2] cycloaddition
with styrene. While the corresponding rearrangement of N-alkyl
oxaziridines to nitrones is precedented,7 we are unaware of any
previous studies describing the Lewis acid catalyzed rearrangement
of N-sulfonyl oxaziridines to nitrones.8
Careful analysis of the Sc(OTf)3-catalyzed reaction revealed that
benzaldehyde oxime, O-sulfonyl oxime 4, and polystyrene are
significant byproducts. We speculated that these compounds could
arise upon heterolytic decomposition of the N-sulfonyl nitrone
(Scheme 1);9 the sulfonyl cation could either recombine with the
oxime anion to produce 4 or initiate the cationic polymerization of
styrene. This mechanistic hypothesis suggests that the efficiency
of the desired cycloaddition would be improved by decreasing the
propensity of the nitrone to undergo ionic fragmentation. Indeed,
optimized reaction conditions for this novel transformation utilized
toluene as a nonpolar solvent, which disfavors formation of ionic
intermediates, as well as oxaziridines bearing N-4-nitrobenzene-
sulfonyl groups that would further destabilize the problematic
sulfonyl cation (Vide infra).
1
2
3
4
5
Sc(OTf)3
BF3‚OEt2
SnCl4
TiCl4
TiCl4
20
20
20
20
10
6
6
6
1
4
23%
58%
80%
93%
95%
1.2:1
>10:1
6:1
>10:1
>10:1
a Ns ) 4-nitrobenzenesulfonyl. b Isolated yields. c Diastereomer ratio
determined by H NMR.
1
on the nature of the Lewis acid, which suggests that the catalyst is
intimately involved in both the isomerization and cycloaddition
steps. Of the catalysts screened, TiCl4 provided the optimal yield
and selectivity, and we found that the catalyst loading could
successfully be reduced to 10 mol %.
A variety of olefins are successful dipolarophiles in this reaction
(Table 2). Styrenes bearing electron-withdrawing substituents are
excellent reaction partners (entries 2-4), although substrates that
react slowly require stoichiometric quantities of TiCl4 to proceed
to completion. Conversely, electron-rich styrenes and olefins
particularly prone to cationic polymerization require slow addition
to achieve good yields (entries 5-9). In all reactions of simple
monosubstituted alkenes investigated, the cycloaddition shows very
high diastereoselectivity, affording the cis isomer with >10:1
selectivity. Both R- and trans-â-methylstyrene are also good
substrates for this process (entries 9 and 10). Finally, while primary
aliphatic olefins react sluggishly, 1,3-dienes and 1,1-disubstituted
aliphatic olefins are suitable dipolarophiles for this transformation
(entries 11 and 12).
The scope of this reaction with respect to the oxaziridine is
somewhat more limited (Table 3). Oxaziridines bearing only
aliphatic C-substituents do not undergo rearrangement to the nitrone,
and aryl oxaziridines bearing strongly electron-donating para
substituents are unstable and cannot be isolated.10 Within these
The effect of various Lewis acids on the cycloadditions of
N-nosyl oxaziridine 5 in toluene is summarized in Table 1. A wide
range of oxophilic Lewis acids afford the desired 1,2-isoxazolidine.
The diastereoselectivity of the cycloaddition shows a dependence
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J. AM. CHEM. SOC. 2008, 130, 2920-2921
10.1021/ja711335d CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Investigation of Olefin Scope in Nitrone Cycloadditions
mixture. In contrast, treatment of 5 using sodium napthalenide
results in selective cleavage of the N-O bond of the isoxazole
without reduction of the nosyl moiety (eq 2). Thus, our new method
for generation and cycloaddition of N-sulfonyl nitrones enables
access to either unprotected 1,2-isoxazolidine heterocycles or
N-protected 1,3-aminoalcohols under orthogonal conditions.
This new method for the synthesis of N-nosyl 1,2-isoxazolidines
involves the first Lewis acid catalyzed cycloaddition of N-sulfonyl
nitrones. Efforts to understand the divergent reactivity of N-sulfonyl
oxaziridines in the presence of titanium and copper catalysts and
to develop enantioselective methods based upon these reactions are
the focus of current investigations in our lab.
Acknowledgment. We thank the University of Wisconsin-
Madison, the NSF (CHE-0645447), and the ACS Petroleum
Research Fund (PRF# 44783-G1) for financial support. NMR
facilities at UW-Madison are funded by the NSF (CHE-9208463,
CHE-9629688) and NIH (RR08389-01). David Michaelis is ac-
knowledged for preliminary studies.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reactions performed using 1 equiv of oxaziridine and 1.5-2 equiv of
olefin in toluene unless otherwise noted. b Isolated yields. c Diastereomer
ratio determined by 1H NMR. d Reaction performed in CH2Cl2. e Alkene
added by syringe pump over 2-3 h. f Used 3-4 equiv of alkene.
References
Table 3. Investigation of Oxaziridine Scope in Nitrone
Cylcoadditions
(1) For recent reviews, see: (a) Merino, P. In Science of Synthesis, Vol. 27;
Padwa, A., Ed.; Thieme: Stuttgart, 2004; pp 511-580. (b) Jones, R. C.
F.; Martin, J. N. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; John Wiley: New York, 2002; pp 1-81.
(2) Vasella’s carbohydrate-derived auxiliaries are an important exception to
this generalization: Vasella, A. HelV. Chim. Acta 1977, 60, 1273-1295.
(3) Two isolated examples of N-acyl and N-carbamoyl nitrone cycloadditions
have been reported. Like N-sulfonyl nitrones, they are not isolable, and
their cycloaddition chemistry was not further investigated: (a) Hussain,
S. A.; Sharma, A. H.; Perkins, M. J.; Griller, D. J. Chem. Soc., Chem.
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a Reactions performed using 1 equiv of oxaziridine and 1.5 equiv of
(7) (a) Emmons, W. D. J. Am. Chem. Soc. 1957, 79, 5739-5754. (b)
Christensen, D.; Jørgensen, K. A.; Hazell, R. G. J. Chem. Soc., Perkin
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1
olefin. b Isolated yields. c Diastereomer ratio determined by H NMR.
(8) N-Sulfonyl nitrone 2 has been postulated to be an intermediate in the
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Chem. Soc., Chem. Commun. 1977, 25-26.
(9) The thermal isomerization of N-benzyl nitrones to O-benzyl oximes has
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4896-4903. (b) Grubbs, E. J.; McCullough, J. D., Jr.; Weber, B. H.;
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(10) Davis has commented upon the instability of N-sulfonyl oxaziridines
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constraints, however, electron-donating and -withdrawing substit-
uents can be accommodated on the nitrone precursor (entries 1-3),
and other oxaziridines bearing electron-stabilizing moieties such
as alkynes undergo facile rearrangement and cycloaddition under
our optimized conditions (entry 4).
Synthetic manipulation of the nitrone cycloadducts can be
accomplished under mild conditions. Treatment of N-nosyl isox-
azolidine 5 with thiophenol and potassium carbonate11 reveals the
N-unsubstituted isoxazolidine 6 in 78% yield (eq 1). Importantly,
no products resulting from ring opening of the 1,2-isoxazolidine
could be observed upon 1H NMR analysis of the unpurified reaction
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