Synthesis of functionalized sulfonamides via 1,3-dipolar cycloaddition of pentafluorophenyl vinylsulfonate

Article abstract of DOI:10.1021/ol0347388

(Matrix presented) An efficient intermolecular 1,3-dipolar cycloaddition of a variety of nitrones to pentafluorophenyl (PFP) vinylsulfonate is described. The transformation produces stable "reversed" cycloadducts of unprecedented stereo- and regioselectiv

Full text of DOI:10.1021/ol0347388

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2489-2492
Synthesis of Functionalized
Sulfonamides via 1,3-Dipolar
Cycloaddition of Pentafluorophenyl
Vinylsulfonate
Stephen Caddick* and Hannah D. Bush
Centre for Biomolecular Design and Drug DeVelopment, The Chemistry Laboratory,
UniVersity of Sussex, Falmer, Brighton BN1 9QJ, U.K.
s.caddick@sussex.ac.uk
Received May 2, 2003
ABSTRACT
An efficient intermolecular 1,3-dipolar cycloaddition of a variety of nitrones to pentafluorophenyl (PFP) vinylsulfonate is described. The
transformation produces stable “reversed” cycloadducts of unprecedented stereo- and regioselectivity. Subsequent amine displacement of
the PFP moiety furnished functionalized sulfonamide products in good yields.
The sulfonamide structural motif is widely found in mol-
ecules of medicinal interest, particularly antibacterial agents.1a
Their ability to act as carbonic anhydrase inhibitors has
resulted in sulfonamides being used clinically for over 50
years in the treatment of diseases such as glaucoma, epilepsy,
and heart failure.1b More recently, sulfonamides have been
found to be potent cysteine protease inhibitors, which could
possibly extend their therapeutic applications to include
conditions such as Alzheimer’s Disease, arthritis, and cancer.2
The significant potential that still exists for sulfonamides
as potent therapies for disease had led us to investigate novel
routes to their synthesis. We have recently described a new
strategy for sulfonamide formation, using the readily avail-
able and shelf-stable pentafluorophenyl vinylsulfonate 1. In
that work, we described intermolecular radical addition
reactions followed by substitution of the PFP group with a
wide range of amine nucleophiles (Scheme 1).3
Scheme 1. Previously Described Strategy for Sulfonamide
Formation
Encouraged by the impressive selective reactivity dis-
played by 1, we decided to explore the scope of its reactivity
and hence its general applicability for the preparation of
structurally diverse sulfonamides. In this paper, we describe
our preliminary findings concerning the 1,3-dipolar cycload-
(1) (a) Maren, T. H. Annu. ReV. Pharmacol. Toxicol. 1976, 16, 309. (b)
Supuran, C. T.; Briganti, F.; Tilli, S.; Chegwidden, W. R.; Scozzafava, A.
Bioorg. Med. Chem. 2001, 9, 703. Scozzafava, A.; Menabuoni, L.; Mincione,
F.; Briganti, F.; Mincione, G.; Supuran, C. T. J. Med. Chem. 2000, 43,
4542.
(2) Roush, W. R.; Gwaltney, S. L.; Cheng, J.; Scheidt, K. A.; McKerrow,
J. H.; Hansell, E. J. Am. Chem. Soc. 1998, 120, 10994. Roush, W. R.; Cheng,
J.; Knapp-Reed, B.; Alvarez-Hernandez, A.; McKerrow, J. H.; Hansell, E.;
Engel, J. C. Bioorg. Med. Chem. Lett. 2001, 11, 2759.
(3) Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd, D.
B. Org. Lett. 2002, 4 (15), 2549.
10.1021/ol0347388 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/18/2003

dition reactions of 1 with a variety of functionalized nitrones.
Sulfonates are widely applicable dienophiles in both inter-
and intramolecular cycloaddition reactions,4 the latter being
the subject of a review by Metz.5 Their ability as dipolaro-
philes has yet to be investigated as thoroughly, although
Chiacchio and co-workers have employed vinylsulfonamides
in selective intramolecular cycloaddition reactions with a
series of 1,3-dipoles.6
Scheme 2. Isoxazolidine Formation via 1,3-Dipolar
Cycloadditiona
Intermolecular examples of sulfonates as dipolarophiles
are infrequent; however, Chan and co-workers have recently
shown that prop-1-ene-1,3-sulfone will undergo regio- and
stereoselective 1,3-dipolar cycloaddition with both nitrile
oxides and nitrones.7
Hence, we were intrigued to discover if 1, whose vinyl
portion is recognized as being especially electron deficient,
would undergo cycloaddition to 1,3-dipoles. If successful,
this would provide a direct route to heterocyclic PFP-
sulfonates, which could subsequently be employed in the
preparation of functionalized sulfonamides using our previ-
ously described amination methodology.3
a Reaction conditions: (a) MeNHOH. HCl (1.2 equiv), NaHCO3
(3.0 equiv), DCM, 40 °C, 2 h. (b) R′SO2CHCH2 (0.4-1.0 equiv),
PhMe, 110 °C, 2-20 h.
Notably, Chan and co-workers observed reversed regiose-
lectively in the aforementioned nitrone cycloaddition reac-
tions.7
Nitrones were initially of interest, as they are one of the
most widely studied 1,3-dipoles and can be simply prepared
from the corresponding aldehyde.8 Following literature
procedures,9 we synthesized a variety of functionalized
nitrones in excellent yield, which were then subjected to
cycloaddition with 1 (Scheme 2). For the purpose of
comparison, C-phenyl-N-methylnitrone was also used in
reactions with phenyl vinyl sulfone and phenyl vinylsulfonate
(Table 1, entries 1 and 2).
It is generally acknowledged that the cycloaddition of
nitrones to olefins generates 5C-substituted isoxazolidines
(Scheme 2, B). However, experimental observations have
shown that the “reversed” 4C-substituted cycloadduct in-
creasingly predominates when very electron-deficient dipo-
larophiles are involved (Scheme 2, A).10 This “reversal”
in regioselectivity is known to be a characteristic of only a
small number of specific electron-deficient dipolarophiles;
hence, the criterion for the formation of 4C-substituted
isoxazolidines via cycloaddition is particularly selective.8
This atypical behavior has been successfully explained by
Houk and co-workers using frontier orbital theory,11 who
have wholly supported their hypothesis with numerous
examples of 1,3-dipolar cycloadditions utilizing highly
electron-deficient dipolarophiles such as phenyl vinyl
sulfone.10a,b
With this information in hand, it was of great interest for
us to observe the regiochemical outcome in the cycloaddition
of nitrones with 1. From literature precedent and theoretical
considerations, it was reasonable to predict that we would
achieve the trans 4C-substituted regioisomer as the major
product.
It was very pleasing to observe that 1 readily underwent
cycloaddition with a variety of nitrones to give the isoxazo-
lidine cycloadducts (Table 1). The addition was successful
with a variety of C-aryl-N-methyl and C-alkyl-N-methyl
nitrones, including species with electron-withdrawing nitro
and halogen functionalities, and electron-donating methoxy,
allyloxy, and alkyl substituents. The cycloaddition could also
be achieved with poly and heteroaromatic systems such as
naphthyl and furyl rings. Consequently, this methodology
represents a general and versatile route to highly function-
alized heterocycles.
(4) Metz, P.; Fleischer, M.; Fro¨hlich, R. Tetrahedron 1995, 51, 711.
Bovenschulte, E.; Metz, P.; Henkel, G. Angew. Chem., Int. Ed. Engl. 1989,
28, 202. Klein, L. L.; Deeb, T. M. Tetrahedron Lett. 1985, 26, 3935. Distler,
H. Angew. Chem., Int. Ed. Engl. 1965, 4, 300. Jiang, L. S.; Chan, W. H.;
Lee, A. W. M. Tetrahedron 1999, 55, 2245.
(5) Metz, P. J. Prakt. Chem. 1998, 340, 1.
A NOE analysis of entry 12 (Table 1) confirmed that
cycloadducts of this type were indeed trans 4C-substituted
as predicted and represents further evidence to support the
prior rationalization of related cycloadditions.12
An interesting theme that emerged from our study was
the excellent regioselectivity we observed in the cycload-
ducts. Even for the previously reported cycloaddition of
phenyl vinyl sulfone to C-phenyl-N-methyl nitrone10a (Table
1, entry 1), we attained a significantly improved product ratio
of 94:6 A:B simply by performing the cycloaddition at
elevated temperatures. We presume that this result is
(6) Chiacchio, U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.; Grassi, G.;
Piperno, A.; Privitera, T.; Romeo, G. Tetrahedron 2001, 57, 3425.
(7) Zhang, H.; Chan, W. H.; Lee, A. W. M.; Wong, W. Y. Tetrahedron
Lett. 2003, 44, 395.
(8) Gru¨nanger, P.; Vita-Finzi, P. In The Chemistry of Heterocyclic
Compounds; Taylor, E. C., Ed.; J. Wiley & Sons: New York, 1991; Vol.
49, Part 1, Chapter 3.3. Torssell, K. B. G. In Nitrile Oxides, Nitrones and
Nitronates in Organic SynthesissNoVel Strategies in Synthesis; VCH: New
York, 1987; Chapter 1.5. Confalone, P. N.; Huie, E. M. In Organic
Reactions; J. Wiley & Sons: New York, 1988; Vol. 36, Chapter 1. Padwa,
A.; Fisera, L.; Koehler, K. F.; Rodriguez, A.; Wong, G. S. K. J. Org. Chem.
1984, 49, 276. Black, D. St. C.; Crozier, R. F.; Davis, V. C. Synthesis 1975,
205.
(9) For example, see: Chan, K. S.; Yeung, M. L.; Chan, W.; Wang, R.
J.; Mak, T. J. Org. Chem. 1995, 60, 1741. Heaney, F.; Rooney, O.;
Cunningham, D.; McArdle, P. J. Chem. Soc., Perkin Trans. 2 2001, 373.
Baruah, A. K.; Prajapati, D.; Sandhu, J. S. Tetrahedron 1988, 44, 6137.
(10) (a) Sims, J.; Houk, K. N. J. Am. Chem. Soc. 1973, 95, 5798. (b)
Bimanand, A. Z.; Houk, K. N. Tetrahedron Lett. 1983, 24, 435. (c) Seidl,
H.; Huisgen, R.; Knorr, R. Chem. Ber. 1969, 102, 904.
(11) Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Strozier, R. W.; George, J.
K. J. Am. Chem. Soc. 1973, 95, 7287. Houk, K. N.; Sims, J.; Watts, C. R.;
Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301.
(12) For details, see Supporting Information.
2490
Org. Lett., Vol. 5, No. 14, 2003

consistent with a thermodynamically controlled process,
especially considering that isoxazolidines are prone to
undergo cycloreversion at high temperatures.8
Table 1. Cycloaddition of Functionalized Nitrones to 1
Once the PFP-substituted isoxazolidines had been suc-
cessfully produced, our attention was turned to the con-
version into sulfonamides via amine displacement of the PFP
moiety (Scheme 3). On the basis of our prior work,3 we
Scheme 3. Sulfonamide Formation from PFP-Substituted
Isoxazolidinesa
a Reaction conditions: (a) R′NH2 (3.0 equiv), DBU (1.0-1.4
equiv), THF, 65 °C, 1-5 h.
envisaged that treatment of the PFP derivatives with amines
under basic conditions would furnish the desired sulfona-
mides.
As anticipated, aminolysis proceeded smoothly to give the
sulfonamide products in good yield. Structural evidence
provided by X-ray crystallographic analysis of compound 2
(2-methyl-3-(4-nitro-phenyl)-isoxazolidine-4-sulfonic acid
4-methyl-benzylamide), indicated that the transformation was
achieved with clean retention of stereochemistry (Figure 1).3
Figure 1. 2-Methyl-3-(4-nitro-phenyl)-isoxazolidine-4-sulfonic acid
4-methyl-benzylamide.
Comprehensive results from the displacement reactions are
presented in Figure 2, which illustrates that a variety of
sulfonamides can be prepared from the novel cycloadducts
derived from 1.
In conclusion, we have shown that pentafluorophenyl
vinylsulfonate 1 is an active participant in regio- and
a Isolated yields. Regioselectivity of A:B ) 100:0 except where indicated.
b A:B ) 94:6. c A:B ) 99:1. d A:B ) 98:2.
Org. Lett., Vol. 5, No. 14, 2003
2491

outcome of these cycloadditions is consistent with prior
theoretical predictions for electron-deficient alkenes. How-
ever, our findings demonstrate that modification of reaction
conditions can lead to significantly improved levels of
regioselectivity. The PFP-isoxazolidines are shelf-stable and
can be transformed into a variety of sulfonamides using a
simple substitution protocol. The application of 1,3-dipolar
cycloaddition methodology to sulfonates such as 1 offers an
excellent opportunity for the preparation of diverse com-
pound collections of potentially valuable sulfonamide struc-
tures.
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for generous financial support of this work. We
also thank the Association for International Cancer Research,
BBSRC, Novartis, Pfizer, and AstraZeneca for the support
of our program. We also thank the University of Sussex for
providing funds to establish the Centre for Biomolecular
Design and Drug Development. We also gratefully acknowl-
edge the contributions of Dr. A. G. Avent, Dr. A. Abdul-
Sada, Dr. P. B. Hitchcock, and the EPSRC Mass Spectros-
copy Service at Swansea.
Supporting Information Available: Characterization
data for the pentafluorophenyl sulfonate isoxazolidines and
for the functionalized sulfonamides. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 2. Isoxazolidine sulfonamides formed from PFP-substituted
cycloadducts via aminolysis.
stereoselective cycloaddition reactions with a wide range of
functionalized nitrones. The regio- and stereochemical
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Org. Lett., Vol. 5, No. 14, 2003