Synthesis of cyclic sulfonamides via intramolecular copper-catalyzed reaction of unsaturated iminoiodinanes

Article abstract of DOI:10.1021/ol000130c

(equation presented) Olefinic primary sulfonamides were treated with iodebenzene diacetate and potassium hydroxide in methanol to give intermediate iminoiodinanes. Catalytic copper(I) or (II) triflate then provided intramolecular nitrene delivery leading to aziridene formation except in one case where a rare copper-catalyzed C-H insertion was observed. The aziridines could be opened by various nucleophiles (methanol, thiophenol, allylmagnesium bromide, benzylamine) to give the corresponding substituted cyclic sulfonamides.

Full text of DOI:10.1021/ol000130c

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2327-2329
Synthesis of Cyclic Sulfonamides via
Intramolecular Copper-Catalyzed
Reaction of Unsaturated Iminoiodinanes
,†
Philippe Dauban* and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, C. N. R. S.,
F-91198 Gif-sur-YVette, France
robert.dodd@icsn.cnrs-gif.fr
Received May 22, 2000
ABSTRACT
Olefinic primary sulfonamides were treated with iodobenzene diacetate and potassium hydroxide in methanol to give intermediate iminoiodinanes.
Catalytic copper(I) or (II) triflate then provided intramolecular nitrene delivery leading to aziridine formation except in one case where a rare
copper-catalyzed C−H insertion was observed. The aziridines could be opened by various nucleophiles (methanol, thiophenol, allylmagnesium
bromide, benzylamine) to give the corresponding substituted cyclic sulfonamides.
Since the initial discovery of the antibacterial activity of the
dye Prontosil 1 and its clinical use in 1933 against a case of
staphylococcal septicemia,1 the sulfonamide function has
been incorporated in a still growing number of biologically
active compounds,2 one of the most famous examples today
being the well-known Sildenafil (Viagra) 2. In addition to
being a carboxyl isostere, the introduction of the SO2-N
moiety induces an increase of stability, for example, toward
protease-catalyzed degradation in the case of sulfonamide-
containing peptidomimetics.3 High interest has also been
directed to their cyclic counterparts, the sultams, which
display a vast array of biological activities. Oxicams (e.g.,
Ampiroxicam 3)4 are a large family of nonsteroidal anti-
inflammatory agents. N-Alkylated saccharin derivatives act
as agonists of 5-HT1A receptors and have therefore found
applications as neuroprotectants5a or anxiolytics (e.g., Ipsa-
spirone 4).5b They also selectively inhibit serine proteases
(tryptase6a or elastase6b). Development of cyclic sulfonamides
as selective inhibitors of the zinc enzyme carbonic anhydrase
has led to the discovery of antiepileptic agents (e.g.,
Sulthiame 5)7 and recently to the approval of Brinzolamide
6 for the topical treatment of glaucoma in the United States.8
Diuretic,9a anticonvulsant,9b cardiotonic,9c â-blocking,9d or
herbicidal9e activities have also been claimed in patents.
(5) (a) Drugs Future 1997, 22, 341. (b) Drugs Future 1986, 11, 565.
(6) (a) Combrink, K. D.; Gulgeze, H. B.; Meanwell, N. A.; Pearce, B.
C.; Zulan, P.; Bisacchi, G. S.; Roberts, D. G.; Stanley, P.; Seiler, S. M. J.
Med. Chem. 1998, 41, 4854. (b) Hlasta, D. J.; Subramanyam, C.; Bell, M.
R.; Carabateas, P. M.; Court, J. J.; Desai, R. C.; Drozd, M. L.; Eickhoff,
W. M.; Ferguson, E. W.; Gordon, R. J.; Johnson, J. A.; Kumar, V.; Maycock,
A. L.; Mueller, K. R.; Pagani, E. D.; Robinson, D. T.; Saindane, M. T.;
Silver, P. J.; Subramanian, S. J. Med. Chem. 1995, 38, 739.
(7) Tanimukai, H.; Inoui, M.; Hariguchi, S.; Kaneko, Z. Biochem.
Pharmacol. 1965, 14, 961.
* Fax: Int. Code + (1) 69077247.
† philippe.dauban@icsn.cnrs-gif.fr.
(1) Domagk, G. Dtsch. Med. Wochenschr. 1935, 61, 250.
(2) For a review, see: (a) Hansch, C.; Sammes, P. G.; Taylor, J. B.
ComprehensiVe Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol.
2, Chapter 7.1. For a compilatory list of recent biological applications, see
(b) Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M. Tetrahedron
Lett. 1999, 40, 4761.
(3) de Bont, D. B. A.; Sliedregt-Bol, K. M.; Hofmeyer, L. J. F.; Liskamp,
R. M. J. Bioorg. Med. Chem. 1999, 7, 1043.
(4) Drugs Future 1992, 17, 451.
(8) (a) Drugs Future 1998, 23, 365. (b) Silver, L. H. Am. J. Ophthalmol.
1998, 126, 400.
(9) (a) Becking, J. B.; Sprague, J. M. U.S. Patent 3,113,075, 1963; Chem.
Abstr. 1964, 60, 5514g. (b) Sianesi, E.; Da Re, P.; Setnikar, I.; Massarani,
E. U.S. Patent 3,770,733, 1973; Chem. Abstr. 1974, 80, 48016p. (c) Tamada,
S.; Fujioka, T.; Ogawa, H.; Teramoto, S.; Kondo, K. Chem. Abstr. 1990,
112, 35887e. (d) Chem. Abstr. 1985, 102, 78901p. (e) Pasteris, R. J. U.S.
Patent 4,842,639, 1989; Chem. Abstr. 1990, 112, 179032t.
10.1021/ol000130c CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

Finally, from a chemical point of view, sultams have served
as efficient chiral auxiliaries10 or reagents.11
The starting ω-alkene-1-sulfonamides 9a-d were prepared
by aminolysis in acetonitrile of ω-alkene-1-sulfonyl chlo-
rides, themselves easily obtained from the corresponding
bromides 8a-d using previously published protocols.17 The
ortho-substituted benzenesulfonamides 11-13 were synthe-
sized in a two-step procedure involving an ortho-metalation
of N-tert-butylbenzenesulfonamide 1018 followed by acidic
cleavage of the tert-butyl group (Scheme 2). In the case of
Scheme 2
In this communication, we wish to report a new strategy
for the preparation of cyclic sulfonamides based on intramo-
lecular copper-catalyzed nitrene delivery. Recent publications
bear witness to a renewed interest in synthetic approaches
to sultams. While most previously described methods rely
on nucleophilic or electrophilic substitutions, as well as on
thermal or photochemical decomposition of azides,12 new
preparations involve ring-closing metathesis2b or radical
processes.13 Further to our work on the [N-(alkylsulfonyl)-
imino]phenyliodinane (PhIdNSes) 714 and in connection with
biological studies, we aimed to study the possibility of
intramolecular copper-catalyzed aziridinations,15 never re-
ported before, as a route to substituted cyclic sulfonamides
(Scheme 1). The success of such a cyclization would strongly
2-vinylbenzenesulfonamide 11, the Schlosser procedure19
prevented any cyclization to 1,2-benzisothiazole 1,1-dioxide.
On the other hand, acidic cleavage of the protected 2-meth-
allylbenzenesulfonamide isolated after the ortho-metalation
step afforded compound 13 in minor quantity, the major
product being the six-membered ring-cyclized product.
Following our previously reported procedure,14 reaction
of the unsaturated sulfonamides with iodobenzene diacetate
and potassium hydroxide in methanol afforded the intermedi-
ate iminoiodinanes, which were isolated simply by extraction
with dichloromethane followed by cold aqueous wash. The
resulting amorphous yellow solids were immediately treated
with a catalytic amount of copper triflate in acetonitrile.20,21
Results are summarized in Table 1.
Scheme 1
Not surprisingly, allylsulfonamide 9a did not lead to the
highly strained bicyclic [2.1.0] structure 14. In contrast, the
(13) (a) Bonfand, E.; Motherwell, W. B.; Pennell, A. M. K.; Uddin, M.
K.; Ujjainwalla, F. Heterocycles 1997, 46, 523. (b) Paquette, L. A.; Leit,
S. M. J. Am. Chem. Soc. 1999, 121, 8126. (c) Leit, S. M.; Paquette, L. A.
J. Org. Chem. 1999, 64, 9225. (d) Katohgi, M.; Togo, H.; Yamaguchi, K.;
Yokoyama, M. Tetrahedron 1999, 55, 14885. (e) Togo, H.; Harada, Y.;
Yokohama, M. J. Org. Chem. 2000, 65, 926.
(14) Dauban, P.; Dodd, R. H. J. Org. Chem. 1999, 64, 5304.
(15) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742.
(16) Boucher, M.; Macikenas, D.; Ren, T.; Protasiewicz, J. D. J. Am.
Chem. Soc. 1997, 119, 9366.
(17) (a) King, J. F.; Harding, D. R. K. J. Am. Chem. Soc. 1976, 98,
3312. (b) Culshaw, P. N.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2,
1991, 1201.
depend first on the stability of the intermediate imino-
iodinanes, particularly their compatibility with a double bond.
Second, their aggregate structures16 could inhibit any in-
tramolecular process and only lead to polymeric materials.
(18) Lombardino, J. G. J. Org. Chem. 1971, 36, 1843.
(19) Wang, Q.; Wei, H.-X.; Schlosser, M. Eur. J. Org. Chem. 1999, 3263
(20) The formation and the purity (>90%) of the iodinanes were verified
by their 1H NMR spectra in which aromatic protons of the iodobenzene
moiety were observed together with the disappearance of those of the
sulfonamide function and the upfield shift of the alkane protons. For
example, for the iminoiodinane derived from sulfonamide 9c: δ 1.26 (m,
2H), 1.76 (m, 2H), 2.00 (m, 2H), 4.95 (m, 2H), 5.64 (m, 1H), 7.39 (m,
2H), 7.54 (m, 1H), 7.96 (d, 1H).
(10) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241.
(11) (a) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919. (b)
Differding, E.; Lang, R. HelV. Chim. Acta 1989, 72, 1248.
(12) (a) The Chemistry of Sulphonic Acids, Esters and DeriVatiVes; Patai,
S., Rappoport, Z., Eds.; Wiley Interscience: New York, 1991; Chapter 19.
(b) Katritzky, A. R.; Wu, J.; Rachwal, B.; Macomber, D. W.; Smith, T. P.
Org. Prep. Proc. Int. 1992, 24, 463.
2328
Org. Lett., Vol. 2, No. 15, 2000

substrates 12 and 13 could be efficiently transformed into
the aziridines 19 and 20, respectively, no reaction occurred
with the iminoiodinane derived from vinylic compound 11.
This is probably related to the nature of this intermediate,
which proved to be highly unstable. However, application
of the bromine-catalyzed aziridination procedure23 to 11 led
to formation of aziridine 18 in good yield.
Table 1. Intramolecular Copper-Catalyzed Reactions
We next turned our attention to the synthetic opportunities
provided by these new bicyclic sultams. Preliminary experi-
ments with different types of nucleophiles (methanol,
thiophenol, allylmagnesium bromide, benzylamine) afforded
aziridine ring-opened products in good yields with concomi-
tant C-O, C-S, C-C, or C-N bond formation (Scheme
3). In the case of compounds 15 and 16, exclusive opening
Scheme 3
of the aziridine at the more substituted site was observed,
leading to six- and seven-membered ring products 21, 22,
and 23. It should be pointed out that no reaction took place
in the absence of boron trifluoride etherate. In contrast,
aziridines 18 and 19 preferentially reacted at their less
substituted carbon atom, forming benzo[d]isothiazole 24 and
benzo[e]thiazine 25, respectively, as the major products.
In conclusion, the intramolecular copper-catalyzed reaction
of an iminoiodinane bearing an olefinic bond represents a
new synthetic route to cyclic sulfonamides. Moreover, in
contrast to most previously described procedures, the present
methodology allows introduction of additional functionality
on the sultam via nucleophilic opening of the intermediate
aziridine. The full scope and limitations of this novel
methodology are currently under investigation.
a Isolated yield after flash chromatography based on starting sulfon-
amides. b Average of three runs. c Bromine-catalyzed aziridination (PTAB,
phenyltrimethylammonium tribromide).
higher homologues 9b,c gave the expected bicyclic aziridines
15 and 16, respectively. In both cases, best results were
obtained using moderately dilute reaction mixtures (i.e., c
) 0.1 M), while acetonitrile was found to be the solvent of
choice. Moreover, both Cu(I)OTf and Cu(II)(OTf)2 catalyzed
the intramolecular process, although the latter appeared to
be less efficient. However, when applied to sulfonamide 9d,
these conditions gave rise exclusively to the allylic insertion
product 17. Although not unprecedented,22 such a copper-
catalyzed C-H insertion has only been rarely observed in
analogous intermolecular aziridination reactions. Another
unexpected result came from the benzenesulfonamides. While
Acknowledgment. This paper is dedicated to Prof. P.
Potier, recipient of this year’s Ernest Guenther Award.
(21) The iodinanes were used as soon as they were isolated in order to
optimize the yield of the aziridination. However, they could be stored at 4
°C under argon for several days. Their stability is therefore comparable to
that of PhINTs or PhINSes.
(22) To the best of our knowledge, there is only one example of the
preparative use of such a Cu-catalyzed C-H insertion: Overman, L. E.;
Tomasi, A. L. J. Am. Chem. Soc. 1998, 120, 4039. In other cases, such
compounds were isolated as minor byproducts. For example, see: (a) ref
15. (b) Albone, D. P.; Aujla, P. S.; Taylor, P. C.; Challenger, S., Derrick,
A. M. J. Org. Chem. 1998, 63, 9569.
Supporting Information Available: Experimental details
and characterization for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL000130C
(23) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844.
Org. Lett., Vol. 2, No. 15, 2000
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