Direct synthesis of previously inaccessible bridgehead azabicyclics by intramolecular cyclization of α-sulfonamido and α-sulfonimido radicals

Article abstract of DOI:10.1021/jo010216z

Syntheses of the first bridgehead sultams and the only known bridgehead disulfonimide are described. Both approaches capitalize on the electrophilicity of α-sulfonyl radicals and their propensity to undergo intramolecular ring closure. Where double bonds are concerned, 5-exo and 6-exo pathways operate preferentially as long as structural strain is not excessive. When the reaction center is a carbon - carbon triple bond, the first cyclization gives rise to vinyl radicals that hold sufficient reactivity to capture solvent benzene. In the case of 45, this sequential reaction leads importantly to the introduction of a styrene functionality sufficiently activated to allow a second ring closure to be kinetically feasible. The solid-state structural features of 12 and 17 have been elucidated by X-ray crystallographic methods. Despite key differences from the norm in the alignment of the nitrogen lone pair relative to the adjacent sulfonyl groups, these compounds exhibit good hydrolytic stability. For 13, generation of the α-sulfonamide carbanion is possible and regiospecific oxidation with chromyl acetate has been achieved.

Full text of DOI:10.1021/jo010216z

3564
J . Org. Chem. 2001, 66, 3564-3573
Dir ect Syn th esis of P r eviou sly In a ccessible Br id geh ea d
Aza bicyclics by In tr a m olecu la r Cycliza tion of r-Su lfon a m id o a n d
r-Su lfon im id o Ra d ica ls
Leo A. Paquette,* Choon Sup Ra,† J effrey D. Schloss, Silvana M. Leit,‡ and J udith C. Gallucci
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Paquette.l@osu.edu
Received February 28, 2001
Syntheses of the first bridgehead sultams and the only known bridgehead disulfonimide are
described. Both approaches capitalize on the electrophilicity of R-sulfonyl radicals and their
propensity to undergo intramolecular ring closure. Where double bonds are concerned, 5-exo and
6-exo pathways operate preferentially as long as structural strain is not excessive. When the reaction
center is a carbon-carbon triple bond, the first cyclization gives rise to vinyl radicals that hold
sufficient reactivity to capture solvent benzene. In the case of 45, this sequential reaction leads
importantly to the introduction of a styrene functionality sufficiently activated to allow a second
ring closure to be kinetically feasible. The solid-state structural features of 12 and 17 have been
elucidated by X-ray crystallographic methods. Despite key differences from the norm in the
alignment of the nitrogen lone pair relative to the adjacent sulfonyl groups, these compounds exhibit
good hydrolytic stability. For 13, generation of the R-sulfonamide carbanion is possible and
regiospecific oxidation with chromyl acetate has been achieved.
Conformationally unconstrained sulfonamides 1 have
ferred terminal olefin formation (eq 2).11 Both processes
are notable for the expeditious manner in which they
bring about deamination.
held importance for many years in the analysis of
amines,1 as protected amino derivatives,2,3 and most
notably as antibacterial agents.4,5 The structurally re-
lated disulfonimides 26 have elicited interest because of
the ease with which they undergo SN2 displacement7 and
thermal or base-promoted elimination.8 The nucleofugal
capability of amino groups is so appreciably enhanced
by activation in the manner defined by 2 that substitu-
tion occurs as readily as with tosylates in the alcohol
series (eq 1).9,10 Furthermore, the significant steric bulk
of the disulfonimide functionality introduces nonbonded
interactions that are conducive to overwhelmingly pre-
Cyclic variants of 1, called sultams, have served as
more geometrically defined scaffolds onto which a rich
* To whom correspondence should be addressed.
(7) (a) Andersen, N. H.; Uh, H.-S. Synth. Commun. 1972, 2, 297.
(b) Hutchins, R. O.; Cistone, F.; Goldsmith, B.; Heuman, P. J . Org.
Chem. 1975, 40, 2018. (c) Curtis, V. A.; Raheja, A.; Rejowski, J . E.;
Majewski, R. W.; Baumgarten, R. J . Tetrahedron Lett. 1975, 3107. (d)
DeChristopher, P. J .; Adamek, J . P.; Klein, S. A.; Lyon, G. D.;
Baumgarten, R. J . J . Org. Chem. 1975, 40, 3288. (e) Hutchins, R. L.;
Kandasamy, D.; Dux, F., III.; Maryanoff, C. A.; Rotstein, D.; Goldsmith,
B.; Burgoyne, W.; Cistone, F.; Dalessandro, J .; Puglis, J . J . Org. Chem.
1978, 43, 2259. (f) Glass, R. S.; Swedo, R. J . J . Org. Chem. 1978, 43,
2291. (g) Mu¨ller, P.; Thi, M. P. N. Helv. Chim. Acta 1979, 62, 1485.
(h) Townsend, C. A.; Theis, A. B. J . Org. Chem. 1980, 45, 1697. (i)
DeChristopher, P. J .; Adamek, J . P.; Lyon, G. D.; Galante, J . J .;
Haffner, H. E.; Boggio, R. J .; Baumgarten, R. J . J . Am. Chem. Soc.
1969, 91, 2384.
† On leave from the Department of Chemistry, Yeungnam
University, Kyongsan 712-749, Korea.
‡ Present address: MethylGene Inc., 7220 Frederick-Banting,
Montreal, Quebec, Canada H4S 2A1.
(1) Shriner, R. L.; Hermann, C. K. F.; Morrill, T. C.; Curtin, D. Y.;
Fuson, R. C. The Systematic Identification of Organic Compounds, 7th
ed.; J ohn Wiley and Sons: New York, 1998.
(2) Kocienski, P. J . Protecting Groups; Georg Thieme Verlag: Stut-
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ca. 35 and PhSO2NHPh has a pKa of 9.65 [Dauphin, G.; Kergomard,
A. Bull. Soc. Chim. Fr. 1961, 3, 486.], (PhSO2)2NH (pKa ) 1.45) is
approximtely as strong an acid as phosphoric acid and N,N-(p-
nitrobenzene)sulfonimide is stronger yet (pKa ) 0.30).
10.1021/jo010216z CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/17/2001

Synthesis of Bridgehead Azabicyclics
J . Org. Chem., Vol. 66, No. 10, 2001 3565
variety of pharmacophores have been attached.12,13 Many
variants have been examined, including the strained
four-membered â-sultams.14 Numerous reagents possess-
ing these structural elements have presently become part
of common synthetic practice. Included in this group are
the sulfonyloxaziridines,15 10,2-camphorsultams,16 and
saccharin-based electrophilic fluorinating agents.17 In
contrast, cyclic disulfonimides are relatively rare entities,
the most well-known examples being 1,2-benzenedi-
sulfonimide (3)18 and [2.2]paracyclophane-4,15-disulfon-
imides of type 4.19
lographic data for more than 200 sulfonamides of diverse
type, with the geometry at N varying from distinctively
pyramidal to near-planar, has revealed a decided prefer-
ence for the lone pair to reside in the bisector of the
O-S-O internuclear angle as in 7.25 R-Sulfonyl carban-
ions seemingly adopt a comparable staggered conforma-
tion. As seen in 8, the lone pair orbital is likewise gauche
to the two oxygens, both of which are ion-paired to the
lithium ion.26-28
As it concerns disulfonimides, we are aware of a single
study designed to evaluate the difference in structural
features between the parent structure and an ionized
form thereof.29 Crystallographic analysis of dibenzene-
sulfonimide (9) and its sodium salt 10 demonstrated a
major qualitative difference between them in the rota-
tional orientation of the groups bound to the tetrahedral
sulfur atoms. While the phenyl rings lie on opposite sides
of the S-N-S plane in 9, they populate the same side of
this plane in 10. The anti configuration is likely adopted
to minimize global steric interactions within the neutral
molecule. In the anion, the cis arrangement allows close
approach of the electronegative nitrogen and oxygen
atoms to the sodium ion.30 The rotational orientation
observed for 11 is unmistakingly structurally enforced.
The further constraining of compounds of general
formula 1 and 2 by positioning the nitrogen atom at a
bridgehead site in a small bicyclic framework has not
previously been accorded attention.20 The appreciably
heightened hydrolytic reactivity of lactams such as 5 and
621 has been well documented.22 This uncharacteristic
behavior has been properly attributed to the effects of
angle strain and enforced torsional distortion, the com-
bined consequences of which are to orient the nonbonded
nitrogen lone pair orthogonally to the CdO π bond and
inhibit resonance interaction. Since amide resonance
energy usually amounts to 16-22 kcal/mol23 and N-C(d
O)-overlap is subject to a cos θ relationship,24 energy costs
can be expected to rise steeply as resonance interaction
is incrementally curtailed, and they do.
The corresponding scenario in substituted sulfon-
amides and disulfonimides is much less well defined,
although it is recognized that stabilization is derived
quite differently in these systems. Scrutiny of the crystal-
(11) Bartsch, R. A.; Allaway, J . R.; Ingram, D. D.; Lee, J .-G. J . Am.
Chem. Soc. 1975, 97, 6873.
(12) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive
Heterocyclic Chemistry II ; Elsevier: Oxford, 1996; Vols. 3 and 4.
(13) Buglass, A. J .; Tillett, J . G. Chemistry of Sulfonic Acids, Esters,
and their Derivatives; J ohn Wiley and Sons: Chichester, 1991; pp 789-
878.
(14) Chanet-Ray, J .; Vessie`re, R. Org. Prep. Proced. Int. 1986, 18,
157.
(15) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
(16) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241; 1988, 60, 39.
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(b) Differding, E.; Ru¨egg, G. M.; Lang, R. W. Tetrahedron Lett. 1991,
32, 1779.
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burg, D. Cammenga, H. K.; Epple, M.; Steppuhn, I. Z. Anorg. Allg.
Chem. 1993, 619, 912.
(19) van Lindert, H. C. A.; van Doorn, J . A.; Bakker, B. H.;
Cerfontain, H. Recl. Trav. Chim. Pays-Bas 1996, 115, 167.
(20) For a previous communication from this laboratory that outlines
a portion of this investigation, consult Paquette, L. A.; Leit, S. M. J .
Am. Chem. Soc. 1999, 121, 8126.
(21) (a) Yakhontov, L. N.; Rubtsov, M. V. J . Gen. Chem. USSR (Engl.
Trans.) 1957, 27, 83. (b) Hall, H. K., J r.; Shaw, R. G., J r.; Deutschmann,
A. J . Org. Chem. 1980, 45, 3722. (c) Steliou, K.; Poupart, M.-A. J . Am.
Chem. Soc. 1983, 105, 7130. (d) Brehm, R.; Ohnha¨user, D.; Gerlach,
H. Helv. Chim. Acta 1987, 70, 1981.
For the above reasons, it is not clear whether pre-
scribed changes in the orientation of the nitrogen lone
pair relative to the O-S-O internuclear angle will
translate into altered reactivity. One way to address this
(22) (a) Blackburn, G. M.; Skaife, C. J .; Kay, I. T. J . Chem. Res.,
Synop. 1980, 9, 294. (b) Somayaji, V.; Brown, R. S. J . Org. Chem. 1986,
51, 2676. (c) Wang, Q.-P.; Bennet, A. J .; Brown, R. S.; Santarsiero, B.
D. J . Am. Chem. Soc. 1991, 113, 5757.
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Wiley: New York, 1961; pp 11-20.
(25) For a comparable search conducted some time ago, consult
Beddoes, R. L.; Dalton, L.; J oule, J . A.; Mills, O. S.; Street, J . D.; Watt,
C. I. F. J . Chem. Soc., Perkin Trans. 2 1986, 787.
(26) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277 and
relevant references therein.
(27) Raabe, G.; Gais, H.-J .; Fleischhauer, J . J . Am. Chem. Soc. 1996,
118, 4622 and earlier reports by the Gais group.
(28) Terrier, F.; Kizilian, E.; Goumont, R.; Faucher, N.; Wakselman,
C. J . Am. Chem. Soc. 1998, 120, 9496.

3566 J . Org. Chem., Vol. 66, No. 10, 2001
Paquette et al.
Ta ble 1. P r od u cts of F r ee Ra d ica l Cycliza tion of
Sch em e 1
Ha lom eth ylsu lfon a m id es
question is to prepare small bridgehead sultams and
disulfonimides having rigid topography and incremen-
tally modified geometric relationships.
Weak basicity will certainly continue to be mani-
fested.31 In addition, a chemical robustness appreciably
greater than that of the carbonyl analogues 5 and 6 can
be anticipated. Described herein are protocols based on
R-sulfonyl radical chemistry32,33 that provide for direct
entry to 12-17 and preliminary studies on the chemical
reactivity of 13.
molecular cyclization.37 Notwithstanding, the heating of
19a with tri-n-butyltin hydride and AIBN in benzene
with syringe pump delivery resulted very predominantly
in reductive dehalogenation to give 22 (Table 1). An
increase in the ring size by one methylene group as in
19c led to the first fruitful results. Although the reduced
sulfonamide 24 was the major product (47%), the [3.2.1]
bicyclic 12 and its [2.2.2] isomer 15 were formed in a ratio
approximating 2:1. A further increase in ring size dem-
onstrated that this process could be considered to be
preparatively useful for the elaboration of the target
molecules.
Br id geh ea d Su lfon a m id e Syn th esis. A reliable
protocol for the production of the bromo- and chloro-
substituted sulfonamides 18 and 20 has been detailed
elsewhere.32a Individual heating of these intermediates
with the Grubbs catalyst34 resulted in ring-closing meta-
thesis35 to deliver 19 and 21 efficiently (Scheme 1). Yields
in excess of 95% were realized in all of these examples
with the exception of 18e. Formation of the unsaturated
eight-membered ring was met with the generation of a
6.5:1 Z/ E mixture (65% conversion).
Attention is called to the prominent workability of the
5-exo and 6-exo cyclization pathways as depicted in 28
and 29.
The present strategy was to elucidate the propensity
of 19 and 21 in their ability to experience radical-induced
cyclization. R-Sulfonyl radicals are recognized not to be
stabilized36 and consequently to be prone to rapid inter-
(29) Cotton, F. A.; Stokely, P. F. J . Am. Chem. Soc. 1970, 92, 294.
(30) For X-ray crystallographic analyses of other disulfonimide salts,
see: (a) Xue, L.; Des Marteau, D. D.; Pennington, W. T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1331. (b) J ones, P. G.; Moers, O.; Blaschette,
A. Acta Crystallogr. 1997, C53, 1809. (c) J ones, P. G.; Moers, O.;
Blaschette, A. Acta Crystallogr. 1997, C53, 1811.
(31) (a) Laughlin, R. G. J . Am. Chem. Soc. 1967, 89, 4268. (b) Olavi,
P.; Virtanen, I.; Maikkula, M. Tetrahedron Lett. 1968, 4855.
(32) (a) Leit, S. M.; Paquette, L. A. J . Org. Chem. 1999, 64, 9225,
(b) Schloss, J . D.; Leit, S. M.; Paquette, L. A. J . Org. Chem. 2000, 65,
7119 and relevant references cited in these papers.
Rou te to th e Br id geh ea d Disu lfon im id e 17. Con-
sistent with our goal of generating members of this
(37) (a) Oku, M.; Philips, J . C. J . Am. Chem. Soc. 1973, 95, 6495.
(b) Ueno, Y.; Khare, R. K.; Okawara, M. J . Chem. Soc., Perkin Trans.
1 1983, 2637. (c) Clive, D. L. J .; Boivin, T. L. B.; Angoh, A. G. J . Org.
Chem. 1987, 52, 4943. (d) Vacher, B.; Samat, A.; Allouche, A.; Laknifli,
A.; Baldy, A.; Chanon, M. Tetrahedron 1988, 44, 2925. (e) Clive, D. L.
J .; Boivin, T. L. B. J . Org. Chem. 1989, 54, 1997. (f) Reutrakul, V.;
Poolsanong, C.; Pohmakotr, M. Tetrahedron Lett. 1989, 30, 6913. (g)
Renaud, P.; Schubert, S. Angew. Chem., Int. Ed. Engl. 1990, 29, 433.
(h) Singleton, D. A.; Church, K. M. J . Org. Chem. 1990, 55, 4780. (i)
Renaud, P. Tetrahedron Lett. 1990, 31, 4601. (j) Tsai, Y.-M.; Ke, B.-
W.; Lin, C.-H. Tetrahedron Lett. 1990, 31, 6047. (k) Tsai, Y.-M.; Ke,
B.-W.; Yang, C.-T.; Lin, C.-H. Tetrahedron Lett. 1992, 33, 7895. (l)
Mahadevan, A.; Fuchs, P. L. J . Am. Chem. Soc. 1995, 117, 3272. (m)
Ke, B.-W.; Lin, C.-H.; Tsai, Y.-M. Tetrahedron 1997, 53, 7805. (n)
Imboden, C.; Bourquard, T.; Corminboeuf, O.; Renaud, P.; Schenk, K.;
Zahouily, M. Tetrahedron Lett. 1999, 40, 495.
(33) Review: Paquette, L. A. Synlett 2001.
(34) (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995,
28, 446. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(35) (a) Cerezo, S.; Corte´s, J .; Moreno-Man˜as, M.; Pleixats, R.;
Roglans, A. Tetrahedron 1998, 54, 14869. (b) Hanson, P. R.; Probst,
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Long, D. D.; Termin, A. P. Tetrahedron Lett. 2000, 41, 6743.
(36) Block, E. Reactions of Organosulfur Compounds; Academic
Press: New York, 1978.

Synthesis of Bridgehead Azabicyclics
J . Org. Chem., Vol. 66, No. 10, 2001 3567
Sch em e 2
Sch em e 3
sequential reactions46 can be understood on the basis of
the minimization of nonbonded steric interactions during
the attack on solvent benzene.
previously unknown structural class as economically and
simply as possible, we proceeded to activate bromo-
methanesulfonamide38 as its Boc derivative 30 (Scheme
2). Mitsunobu alkylation39 of 30 with three homologous
alkynols gave rise to 31a -c in yields exceeding 90%.
After the generation of 32 by conventional deprotection
methodology, all attempts to introduce a second bromo-
methylsulfonyl residue were met with mediocre yields or
no observable reaction. To remedy this situation, we
turned to the less labile chloromethanesulfonyl chloride.40
Its admixture with 32 in the presence of Hu¨nig’s base
and DMAP did indeed furnish 33 in yields varying from
48% to 89% depending upon the number of methylene
groups.
The time had come to evaluate the importance of chain
length and polar effects on the desired 2-fold bicyclic ring
closure. When the trimethylene example 33c was heated
with tris(trimethylsilyl)hydride41 and AIBN in benzene,
exclusive conversion to 34 (56% isolated) was seen to be
operational. At the other end of the spectrum, analogous
treatment of the smallest member of the series gave rise
to four products (Scheme 3). While the major component
of this mixture was again the monoreduction product,
e.g., 35, the remaining three were recognized on the basis
of their NMR spectra to be products of monocyclization
in which a molecule of solvent had also been assimilated.
Quite unlike the cyclizations involving 19 and 21 where
relatively unreactive cycloalkyl radicals42,43 intervene, the
more electrophilic44 cycloalkenyl radicals 42 and 43 are
energetic enough to attack benzene. The combined
amounts of 36 and 38/40 produced (24% versus 20%/14%)
are indicative that 5-exo ring closure is more kinetically
favorable than the 6-endo pathway45 The somewhat
higher levels of 38 produced relative to 40 in these
Since all three cyclic disulfonimides were amenable to
chromatographic separation, it was possible to react each
entity individually with a tin or silyl hydride in an effort
to realize further ring closure. However, all attempts to
induce bicyclization in this manner resulted exclusively
in reduction to give 37, 39, and 41, respectively. The
resistance to intramolecular addition across the styrene-
like double bond presumably reflects the kinetic deter-
rence to generation of [2.2.2]- and [2.2.1]bicyclic disulfon-
imide frameworks. The distinction between 38 and 40,
preliminarily assigned on the basis of their NMR spectral
characteristics, was confirmed by an X-ray crystallo-
graphic analysis of 41 (Figure 1).
In light of the above findings and our awareness of the
remarkable facility with which R-sulfonyl radicals engage
in 7-endo cyclization to olefinic acceptors,32 33b became
increasingly regarded as the premier test substrate. Were
the anticipated transition state to be kinetically domi-
nant, conversion to vinyl radical 44 would be operative.
Should this pathway operate in tandem with solvent
capture, the formation of 45 would be observed. Indeed,
33b proved to be subject to this sequential reaction and
gave rise to 45 in 59% yield. The nonphenylated hetero-
cycle 46 was also formed (Scheme 4).
When 45 was subsequently heated with tri-n-butyltin
hydride and AIBN in refluxing benzene, smooth conver-
sion to 17 materialized. This cyclization expectedly led
to a single diastereomer as a direct consequence of the
symmetry inherent in the benzylic radical precursor 47.
The quasi-equatorial projection of the phenyl substituent
in 17 was ultimately confirmed by crystallographic
methods.
(38) Goralski, C. T.; Klinger, T. C. J . Chem. Eng. Data 1976, 21,
237.
(39) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
React. 1992, 42, 335.
(40) Paquette, L. A.; Wittenbrook, L. S. Org. Synth. 1969, 49, 18.
(41) (a) Giese, B.; Kopping, B.; Chatgilialoglu, C. Tetrahedron Lett.
1989, 30, 681. (b) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller,
D.; Giese, B.; Kopping, B. J . Org. Chem. 1991, 56, 678. (c) Chatgilia-
loglu, C. Acc. Chem. Res. 1992, 25, 188.
(42) (a) Citterio, A.; Minisci, F.; Porta, O.; Sesana, G. J . Am. Chem.
Soc. 1977, 99, 7960. (b) Mu¨nger, K.; Fischer, H. Int. J . Chem. Kinetics
1985, 17, 809.
Str u ctu r a l F ea tu r es a s Defin ed by Cr ysta llo-
gr a p h ic Meth od s. The molecular structure of 41, a
(43) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: Oxford, 1986; Chapter 5.
(44) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Chapter 4.1.
(45) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; Verlag Chemie: Weinheim, 1996.
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Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301.

3568 J . Org. Chem., Vol. 66, No. 10, 2001
Paquette et al.
monocyclic disulfonimide, constitutes a useful reference
compound. Three informative views of this molecule are
provided in Figure 1. The near planarity of the nitrogen
atom, best appreciated in views B and C, is evident by
summing the associated angles. For 41, the total is 358.2°
(full planarity is present at 360°), indicating its near-
planar status. When inspected down the S1-N1 bond
(view B), the lone pair on N1 is seen to be positioned on
the bisector of the O1-S1-O2 angle. Thus, the uncon-
strained sulfonyl group external to the ring orients itself
in a manner often adopted by sulfonamides (see 7). In
contrast, the confines of the five-membered ring force the
lone pair on N1 to eclipse the S2-O4 bond (view C).
The relevant structural parameters of bridgehead
sultam 12 are displayed in Figure 2. This substance
crystallizes with two molecules per asymmetric unit and
as usual slightly different geometries are featured. The
F igu r e 2. Molecular structure of 12 in the solid state.
Sch em e 4
sums about the nitrogen atoms in these structures are
326.3° and 324.7°, reflecting the significant bending at
the bridgehead position such that planarity cannot be
approached. It is of some interest to determine the
“position” of the lone pair of electrons on nitrogen in this
example. To this end, the nitrogen atom was assumed to
be sp3-hybridized and a hydrogen was added to it at a
calculated position. The hydrogen position was then
assumed to be the position of the lone pair of electrons
and the torsion angles compiled in Table 2 were calcu-
lated. In this instance, it is recognized that the non-
bonded electron pair on nitrogen is projected at a right
angle to the endo sulfonyl oxygen and in an approximate
gauche relationship to the exo counterpart. Thus, the
geometry inherent in 12 results in a significant distortion
away from the equilibrium state represented by 7 and
41.
The two molecules in the asymmetric unit of 17 (Figure
3) have sums of 345.6° and 346.0° about the N atoms and
are therefore also not planar. The lesser strain imposed
on this system is reflected in the adoption of less well-
defined dihedral angle relationships across the disulfon-
imide functionality.
F igu r e 1. Three views of the molecular structure of 41 in
the solid-state drawn with 50% probability displacement
ellipsoids for the non-H atoms. A, From above the plane of
the five-membered ring; B, down the S1-N1 bond; C, down
the S2-N1 bond.
The >N-SO2- and -SO2-N-SO2 motifs present in
12 and 17 are direct isosteres of the amide and imide

Synthesis of Bridgehead Azabicyclics
J . Org. Chem., Vol. 66, No. 10, 2001 3569
Ta ble 2. Tor sion An gles Ca lcu la ted for 12 a n d 17
Sch em e 5
compd
atoms involveda
angle (degrees)
12
O1A-S1A-N1A-lone pair
O2A-S1A-N1A-lone pair
O1B-S1B-N1B-lone pair
O2B-S1B-N1B-lone pair
O1-S1-N1-lone pair
O2-S1-N1-lone pair
O3-S2-N1-lone pair
O4-S2-N1-lone pair
O5-S3-N2-lone pair
O6-S3-N2-lone pair
O7-S4-N2-lone pair
O8-S4-N2-lone pair
-90
40
-90
39
-61
67
43
-86
76
17
-55
-82
46
a
The two structures in the asymmetric unit are distinguished
as A and B.
Discu ssion of Resu lts. In keeping with previous
trends involving radical intermediates free of sulfur, the
bromomethyl sulfonamides 19c-e experience ready 5-exo
cyclization once they are transformed into the corre-
sponding R-sulfonyl radicals. The 6-exo cyclization mode
adopted by 21 is particularly efficient. The lone exception
is 19a , and we attribute its low-yield conversion into 23
to the elevated strain energy resident in this bridgehead
sultam.
Although radical cyclizations onto carbon-carbon triple
bonds, e.g., 5-hexynyl cyclizations, occur at rates some-
what slower than 5-hexenyl cyclizations,48 many ex-
amples are known and synthesis has been well served
by such transformations. Although R-sulfonyl radicals are
inherently electrophilic and highly reactive, it remained
to assess ring size effects during the intramolecular
capture of these functional groups. As noted elsewhere,46
the rates of 7-ring and 8-ring cyclizations onto double
bonds are sufficiently slow to constitute the lower limit
of synthetic utility in many cases. In addition, 7-octenyl
radicals often exhibit reverse regioselectivity and cyclize
via the 8-endo mode. We have demonstrated herein that
the radical derived from 33a prefers the 5-exo pathway
leading to 43 over 6-endo closure resulting in the
transient formation of 42. The efficiency with which 33b
is converted into 45 and 46 suggests that the rate of
7-endo cyclization is especially high and therefore pre-
paratively useful. Since we detected no cyclization with
33c, eight-membered ring formation must be kinetically
unfavorable.
The ability exhibited by alkenyl radicals 42-44 to
effect homolytic aromatic substitution holds considerable
importance in the context of the present study. The
phenomenon has been oft-encountered in earlier work by
others and attempts continue to be made to fully com-
prehend substituent effects and associated steric, stereo-
electronic, and polar factors.49 In particular, the route
followed predominantly by 44 is to attack solvent benzene
and deliver 45. The styrene moiety thereby generated
greatly facilitates the second-stage ring closure to deliver
the target disulfonimide 17 with total control of regio-
selectivity. In essence, the solvent involved in the initial
ring closure of 33b provides the central topological control
F igu r e 3. Molecular structure of 17 in the solid state.
functional groups and display significantly different
physical characteristics. Despite wide-ranging differences
in the geometry at nitrogen, the sulfur-containing sys-
tems constitute hydrolytically stable analogues of the
hydrolysis transition states of their carbonyl equivalents.
P r elim in a r y Rea ctivity Stu d ies. All five homolo-
gous sultams 12-16 and disulfonamide 17 are white,
hydrolytically stable crystalline solids. No sign of hyper-
activity is evident in any given example. When initial
attempts to deprotonate 13 with a variety of bases failed,
recourse was made to tert-butyllithium. Under these
circumstances, regio- and stereoselective allylation and
benzylation to give 48 and 49, respectively, proceeded
uneventfully (Scheme 5). Less reactive electrophiles were
reluctant to engage in covalent bonding.
A particularly interesting reaction involves the action
of chromyl acetate47 on 13. A rapid, exothermic reaction
ensued to give the acetate 50 and the structurally novel
keto sultam 51. Although the combined yield of these two
products (70%) allows for the possible formation of other
positional isomers, none were found. Accordingly, the
methylene group R to nitrogen in the largest bridge is
inherently the most reactive toward this particular
oxidant.
(48) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
(49) Montevecchi, P. C.; Navacchia, M. L. J . Org. Chem. 1998, 63,
537 and relevant references therein.
(47) Freeman, F. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; J ohn Wiley and Sons: Chichester, 1995; p 1282.

3570 J . Org. Chem., Vol. 66, No. 10, 2001
Paquette et al.
3.56 (t, J ) 5.7 Hz, 2 H), 2.29-2.22 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 125.4, 123.0, 45.2, 43.3, 40.1, 25.5; EI MS m/z
element that guides the manner in which the bicyclic end-
product is ultimately assembled.
(M+) calcd 238.9616, obsd 238.9637. Anal. Calcd for C6H10
-
The crystal structures of 12 and 17, arrived at by X-ray
diffraction analysis, provide the first in-depth glimpse of
the spatial arrangements of the heteroatoms in the first
known bridgehead sultams and disulfonimide. The exo
and endo orientations of the sulfonyl oxygens are well
defined. More significantly, although the N lone pair
electrons cannot be precisely located, proper approxima-
tions have been made to show key differences relative to
the neighboring O-S-O bonds.
Despite the significant distortions from the normal
sulfonamide equilibrium state that are exhibited by the
bridgehead systems obtained in the present study, the
stability of these molecules is not compromised. The
efficiency with which 13 is converted into 50 and 51 in
the presence of the powerful oxidant known as chromyl
acetate is noteworthy. This reagent is recognized to be
capable of oxidizing unactivated C-H bonds in bicycloal-
kanes and polycycloalkanes to give alcohols, acetates, and
ketones.50,51 Typically, attack occurs at tertiary C-H
bonds more rapidly than at methylene groups,52 with
methyl groups being unreactive. For 13, the only tertiary
hydrogen is positioned at the bridgehead site and is inert.
The sultam functionality is also unaffected, the bridge-
head nitrogen serving only to activate the neighboring
CH2 group of the tetramethylene bridge.
BrNO2S: C, 30.01; H, 4.20. Found: C, 30.47; H, 4.24.
For 19d : white solid, mp 125-126 °C (98%); IR (CHCl3,
1
cm-1) 1450, 1433, 1372; H NMR (300 MHz, CDCl3) δ 5.92-
5.81 (m, 1 H), 5.76-5.68 (m, 1 H), 4.39 (s, 2 H), 4.02-4.00 (m,
2 H), 3.63 (t, J ) 6.0 Hz, 2 H), 2.42-2.32 (m, 2 H), 1.94-1.86
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 133.4, 127.3, 50.6, 47.1,
41.0, 27.3, 26.9; EI MS m/z (M+) calcd 252.9772, obsd 252.9800.
Anal. Calcd for C7H12BrNO2S: C, 33.08; H, 4.76. Found: C,
33.21; H, 4.82.
For (Z)-19e: white solid, mp 79-81 °C (from ether) (65%,
1
Z/ E ) 6.5:1); H NMR (300 MHz, CDCl3) δ 5.92-5.83 (m, 1
H), 5.61-5.55 (m, 1 H), 4.41 (s, 2 H), 4.05 (d, J ) 5.8 Hz, 2 H),
3.51 (br dd, J ) 5.3, 5.1 Hz, 2 H), 2.44-2.37 (m, 2 H), 1.86-
1.78 (m, 2 H), 1.67-1.57 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 132.5, 125.1, 48.4, 46.5, 40.4, 26.5, 26.2, 24.4; EI MS m/z
(M+) calcd 266.9929, obsd 266.9903. Anal. Calcd for C8H14
-
BrNO2S: C, 35.83; H, 5.26. Found: C, 35.95; H, 5.32.
For 21: white solid, mp 126 °C (98%); IR (CHCl3, cm-1
)
1
1448, 1424, 1366; H NMR (300 MHz, CDCl3) δ 5.82 (t, J )
3.2 Hz, 2 H), 4.41 (s, 2 H), 3.51-3.47 (m, 4 H), 2.41-2.37 (m,
4 H); 13C NMR (75 MHz, CDCl3) δ 130.0 (2 C), 49.3 (2 C), 40.5,
30.9 (2 C); EI MS m/z (M+) calcd 252.9772, obsd 252.9799.
Anal. Calcd for C7H12BrNO2S: C, 33.08; H, 4.76. Found: C,
33.29; H, 4.81.
P r ototyp ica l F r ee Ra d ica l Cycliza tion P r oced u r e. A
solution of tri-n-butylstanne (1.1-1.5 equiv) and AIBN (0.07-
0.30 equiv) in deoxygenated benzene (1-10 mL) was added
over 2-16 h (manual or syringe pump) to a refluxing (0.091-
0.001 M) solution of 19 or 21 (1 equiv) in deoxygenated benzene
(3-260 mL). The reaction mixture was heated for another 3
h, cooled, treated with ether and 8% potassium fluoride
solution, and stirred for 2 h. The separated organic layer was
washed with water and brine, dried, and evaporated under
reduced pressure. The residue was purified by flash chroma-
tography on silica gel (elution with ethyl acetate in hexanes).
Sulfonamide 19a was simply reduced to 22: 1H NMR (300
MHz, CDCl3) δ 5.78 (s, 2 H), 4.16 (s, 4 H), 2.81 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 125.6 (2 C), 54.9 (2 C), 34.5; EI MS
m/z (M+) calcd 147.0354, obsd 147.0348.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Melting points are uncorrected.
The column chromatographic separations were performed with
Woelm silica gel (230-400 mesh). Solvents were reagent grade
and in most cases dried prior to use. The purity of all
compounds was shown to be >95% by TLC and high-field 1H
NMR. The high-resolution electron impact mass spectra were
recorded at The Ohio State University Campus Instrumenta-
tion Center. Elemental analyses were performed at Atlantic
Microlab, Inc., Norcross, GA.
Sulfonamide 19c afforded 47% of 24, 16% of 12 and 7% of
15. For 24: 1H NMR (300 MHz, CDCl3) δ 5.88-5.83 (m, 1 H),
5.72-5.67 (m, 1 H), 3.78-3.74 (m, 2 H), 3.36 (t, J ) 5.7 Hz, 2
H), 2.80 (s, 3 H), 2.28-2.22 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 125.4, 123.0, 44.6, 42.3, 35.4, 25.1; EI MS m/z (M+) calcd
161.0511, obsd 161.0502.
Gen er a l Rin g Closin g Meta th esis P r oced u r e. A homo-
geneous orange-red solution of RuCl2(dCHPh)(PCy3)2 (0.15-
0.30 equiv) in anhydrous CH2Cl2 (5 mL) was added to a
solution of 18 or 20 (1.0 equiv, 0.040-0.005 M) in the same
medium under N2. The mixture was stirred overnight at 45-
50 °C, cooled, and evaporated to leave a residue that was
chromatographed on silica gel (elution with 2:1-10:1 hexanes/
ethyl acetate).
For 12: white solid, mp 214-215 °C (from CH2Cl2/hexanes).
IR (CHCl3, cm-1) 1454, 1424, 1334; 1H NMR (300 MHz, CDCl3)
δ 3.62-3.51 (m, 2 H), 3.37 (dd, J ) 13.1, 7.1 Hz, 1 H), 3.20
(dd, J ) 13.0, 2.2 Hz, 1 H), 3.07 (dt, J ) 13.1, 4.9 Hz, 1 H),
2.98 (br dd, J ) 13.1, 2.3 Hz, 1 H), 2.89-2.84 (m, 1 H), 2.29-
2.14 (m, 1 H), 1.98-1.77 (m, 2 H), 1.60-1.52 (m, 1 H); 13C NMR
(75 MHz, CDCl3) δ 56.1, 55.2, 51.0, 36.9, 29.6, 18.1; EI MS
m/z (M+) calcd 161.0511, obsd 161.0502.
For 19a : white solid, mp 82-83 °C (from ether) (98%); IR
1
(CH2Cl2, cm-1) 1467, 1387, 1352; H NMR (300 MHz, CDCl3)
δ 5.80 (s, 2 H), 4.58 (s, 2 H), 4.32 (s, 4 H); 13C NMR (75 MHz,
CDCl3) δ 125.3 (2C), 55.8 (2C), 54.0; EI MS m/z (M+) calcd
182.9934, obsd 182.9911. Anal. Calcd for C5H8ClNO2S: C,
33.06; H, 4.44. Found: C, 33.28; H, 4.47.
1
For 15: IR (CHCl3, cm-1) 1454, 1424, 1334; H NMR (300
MHz, CDCl3) δ 3.92-3.82 (m, 2 H), 3.31-3.25 (m, 4 H), 2.50-
2.45 (m, 1 H), 1.88-1.77 (m, 2 H), 1.64-1.50 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 57.9 (2C), 45.7, 28.6, 22.2; EI MS m/z (M+)
calcd 161.0511, obsd 161.0502.
The structural assignment to 12 was confirmed by X-ray
crystallographic analysis.
For 19b: white solid, mp 125 °C (from ether) (95%); IR (CH2-
Cl2, cm-1) 1466, 1376, 1351; 1H NMR (300 MHz, CDCl3) δ 5.79
(s, 2 H), 4.47 (s, 2 H), 4.30 (s, 4 H); 13C NMR (75 MHz, CDCl3)
δ 125.3 (2C), 55.9 (2C), 39.5; EI MS m/z (M+) calcd 224.9459,
obsd 224.9459. Anal. Calcd for C5H8BrNO2S: C, 26.56; H, 3.57.
Found: C, 27.05; H, 3.63.
Sulfonamide 19d furnished 12% of 25 and 69% of 13. For
1
25: white solid; IR (CHCl3, cm-1) 1472, 1453, 1418; H NMR
For 19c: white solid, mp 62-63 °C (96%); IR (CH2Cl2, cm-1
)
1456, 1430, 1372; 1H NMR (300 MHz, CDCl3) δ 5.91-5.84 (m,
1 H), 5.72-5.65 (m, 1 H), 4.40 (s, 2 H), 3.96-3.93 (m, 2 H),
(300 MHz, CDCl3) δ 5.90-5.72 (m, 2 H), 3.93 (br d, J ) 4.9
Hz, 2 H), 3.55 (br dd, J ) 6.1, 5.9 Hz, 2 H), 2.84 (s, 3 H), 2.35-
2.32 (m, 2 H), 1.90-1.85 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 133.4, 127.3, 49.8, 45.7, 38.6, 27.3, 26.8; EI MS m/z (M+)
calcd 175.0667, obsd 175.0673.
For 13: white solid, mp 111-112 °C (from CH2Cl2/hexanes);
IR (CHCl3, cm-1) 1473, 1451, 1419; 1H NMR (500 MHz, CDCl3)
δ 3.60 (ddd, J ) 14.8, 12.1, 5.6 Hz, 1 H), 3.41 (ddd, J ) 13.8,
4.7, 1.9 Hz, 1 H), 3.32 (dd, J ) 13.6, 8.5 Hz, 1 H), 3.19 (dd, J
(50) Stewart, R. Oxidation Mechanisms; W. A. Benjamin, Inc.: New
York, 1964; pp 50-55.
(51) Wiberg, K. B. In Oxidation in Organic Chemistry; Wiberg, K.
B., Ed.; Academic Press: New York, 1965; Chapter 2.
(52) Paquette, L. A.; Meehan, G. V.; Marshall, S. J . J . Am. Chem.
Soc. 1969, 91, 6779.

Synthesis of Bridgehead Azabicyclics
J . Org. Chem., Vol. 66, No. 10, 2001 3571
) 13.8, 1.5 Hz, 1 H), 3.13 (br dd, J ) 14.8, 5.9 Hz, 1 H), 2.90
(m, 1 H), 2.65 (br d, J ) 15.0 Hz, 1 H), 1.86-1.80 (m, 1 H),
1.75-1.39 (series of m, 5 H); 13C NMR (75 MHz, CDCl3) δ 53.7,
49.2, 47.3, 39.3, 34.2, 27.6, 21.5; EI MS m/z (M+) calcd
175.0667, obsd 175.0671.
For 31c: colorless oil (92%); IR (film, cm-1) 1727, 1456, 1362;
1H NMR (300 MHz, CDCl3) δ 4.85 (s, 2 H), 3.79 (t, J ) 7.5 Hz,
2 H), 2.24 (dt, J ) 7.5, 2.4 Hz, 2 H), 1.98-1.87 (series of m, 3
H), 1.54 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 150.9, 85.5, 82.8,
69.1, 47.4, 41.9, 28.8, 27.8, 15.8; ES MS m/z (M+) or (M + Na)+
too fleeting for accurate mass measurement. Anal. Calcd for
C11H18BrNO4S: C, 38.83 H, 5.33. Found: C, 38.58; H, 5.34.
Sulfonamide 19e gave rise to 49% of 26 and 37% of 14. For
1
26: white solid; IR (CHCl3, cm-1) 1455, 1325, 1224; H NMR
(300 MHz, CDCl3) δ 5.91-5.74 (m, 1 H), 5.56-5.49 (m, 1 H),
3.89 (d, J ) 5.7 Hz, 2 H), 3.37 (br dd, J ) 5.4, 5.1 Hz, 2 H),
2.79 (s, 3 H), 2.44-2.37 (m, 2 H), 1.89-1.78 (m, 2 H), 1.76-
1.58 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 132.6, 124.7, 47.5,
45.3, 37.1, 27.8, 26.7, 25.9; EI MS m/z (M+) calcd 189.0824,
obsd 189.0828.
Dep r otection of 31a -c. A solution of 31a (630 mg, 2.02
mmol) and trifluoroacetic acid (296 mg, 2.60 mmol) in CH2Cl2
(15 mL) was refluxed for 10 h, cooled, and quenched with 1 N
NaHCO3 solution (1 mL). The product was taken up in CH2-
Cl2 (3 × 30 mL) and the organic phase was washed with brine
(20 mL) prior to drying and solvent evaporation. The residue
was purified chromatographically (silica gel, elution with 30%
ethyl acetate in hexanes) to furnish oily 32a (389 mg, 91%);
For 14: white solid; IR (CHCl3, cm-1) 1455, 1418, 1389; 1H
NMR (300 MHz, CDCl3) δ 3.70-3.61 (m, 1 H), 3.49 (ddd, J )
13.9, 4.7, 1.7 Hz, 1 H), 3.39 (dd, J ) 13.6, 8.4 Hz, 1 H), 3.25
(br d, J ) 13.5 Hz, 1 H), 3.19 (dd, J ) 14.8, 5.7 Hz, 1 H), 3.02-
2.99 (m, 1 H), 2.73 (br d, J ) 13.6 Hz, 1 H), 2.03-1.48 (series
of m, 8 H); 13C NMR (75 MHz, CDCl3) δ 53.7, 49.2, 47.3, 39.3,
34.3, 27.6, 25.5, 21.5; EI MS m/z (M+) calcd 189.0824, obsd
189.0823.
Sulfonamide 21 furnished 27 (10%) and 16 (79%). For 27:
white solid; IR (CHCl3, cm-1) 1403, 1330; 1H NMR (300 MHz,
CDCl3) δ 5.81-5.79 (m, 2 H), 3.38-3.35 (m, 4 H), 2.81 (s, 3
H), 2.39-2.35 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 130.1 (2
C), 48.0 (2 C), 37.5, 30.4 (2 C); EI MS m/z (M+) calcd 175.0667,
obsd 175.0670.
For 16: white solid, mp 228-229 °C (from CH2Cl2/hexanes);
IR (CHCl3, cm-1) 1458, 1321, 1237; 1H NMR (300 MHz, CDCl3)
δ 3.96 (ddd, J ) 10.0, 4.2, 0.9 Hz, 1 H), 3.93-3.83 (m, 1 H),
3.41-3.30 (m, 3 H), 3.10-3.01 (m, 1 H), 2.63-2.58 (m, 1 H),
1.97-1.75 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 59.2, 52.1
46.3, 31.3, 31.2, 24.4, 23.9; EI MS m/z (M+) calcd 175.0667,
obsd 175.0660.
N-(ter t-Bu toxyca r bon yl)-br om om eth a n esu lfon a m id e
(30). A solution of di-tert-butyl dicarbonate (4.39 g, 20.1 mmol)
in dry CH2Cl2 (30 mL) was added to a solution of bromo-
methanesulfonamide (3.50 g, 20.1 mmol), DMAP (246 mg, 2.01
mmol), and triethylamine (3.05 g, 30.2 mmol) in dry CH2Cl2
(50 mL) at 0 °C. The reaction mixture was allowed to warm to
room temperature, stirred for 15 h, carefully washed with 10%
HCl and brine, and then dried. Solvent evaporation and
purification over silica gel (elution with 25% ethyl acetate in
hexanes) gave 30 as a white solid (4.80 g, 87%), mp 99-100
°C; IR (CHCl3, cm-1) 1748; 1H NMR (300 MHz, CDCl3) δ 4.08
(s, 2 H), 0.82 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 149.3, 85.2,
40.7, 27.7 (3 C); EI MS m/z (M+H)+ calcd 273.9748, obsd
273.9713. Anal. Calcd for C6H12BrNO4S: C, 26.29; H, 4.41.
Found: C, 26.77; H, 4.32.
1
IR (film, cm-1) 3287, 1429, 1335; H NMR (300 MHz, CDCl3)
δ 5.13 (br s, 1 H), 4.55 (s, 2 H), 4.03 (dd, J ) 6.3, 2.4 Hz, 2 H),
2.42 (t, J ) 2.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 78.0,
73.7, 42.2, 33.0; ES MS m/z (M + Na)+ calcd 233.9200, obsd
233.9202. Anal. Calcd for C4H6BrNO2S: C, 22.65 H, 2.85.
Found: C, 22.95; H, 2.82.
For 32b: white solid, mp 59 °C (90%); IR (CHCl3, cm-1
)
1
3285, 1328, 1142; H NMR (300 MHz, CDCl3) δ 5.02 (br s, 1
H), 4.46 (s, 2 H), 3.37 (dd, J ) 11.7, 6.3 Hz, 2 H), 2.51 (dt, J )
6.3, 2.6 Hz, 2 H), 2.10 (t, J ) 2.6 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 80.1, 71.2, 42.5, 41.9, 20.5; EI MS m/z (M - C3H3)+
calcd 185.9927, obsd 185.9927. Anal. Calcd for C5H8BrNO2S:
C, 26.56; H, 3.57. Found: C, 26.70; H, 3.57.
For 32c: white solid, mp 59 °C (95%); IR (film, cm-1) 3291,
1430, 1331; 1H NMR (300 MHz, CDCl3) δ 5.10 (br s, 1 H), 4.44
(s, 2 H), 3.31 (t, J ) 6.3 Hz, 2 H), 2.32 (m, 2 H), 2.02 (t, J )
2.6 Hz, 1 H), 1.81 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 99.7,
69.8, 42.8, 41.3, 28.5, 15.6; ES MS m/z (M + Na)+ calcd
261.9513, obsd 261.9497.Anal. Calcd for C6H10BrNO2S: C,
30.01; H, 4.20. Found: C, 30.03; H, 4.39.
Ch or om eth ylsu lfon yla tion of 32a -c. A cold (0 °C) solu-
tion of 32a (940 mg, 4.43 mmol) in CH2Cl2 (10 mL) containing
Hunig’s base (1.26 g, 9.75 mmol) and DMAP (108 mg, 0.89
mmol) was treated dropwise with chloromethanesulfonyl
chloride (1.32 g, 8.86 mmol) dissolved in CH2Cl2 (10 mL).
Stirring was maintained for an additional 1.5 h at this
temperature, saturated NaHSO4 solution (20 mL) was added,
and the product was extracted into CH2Cl2 (3 × 50 mL). The
combined organic phases were washed with 1 N HCl (2 × 30
mL), water (20 mL), and brine (2 × 30 mL) prior to drying.
The concentrate was subjected to flash chromatography (silica
gel, elution with 10% ethyl acetate in hexanes) to furnish 33a
1
as a colorless oil (1.28 g, 89%); IR (film, cm-1) 1369, 1164; H
NMR (300 MHz, CDCl3) δ 4.96 (s, 2 H), 4.89 (s, 2 H), 4.66 (d,
J ) 2.4 Hz, 2 H), 2.58 (t, J ) 2.4 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 77.0, 75.4, 58.7, 44.0, 40.5; ES MS m/z (M + Na)+
calcd 345.8586, obsd 345.8587. Anal. Calcd for C5H7BrClNO4-
Si: C, 18.50; H, 2.17. Found: C, 18.82; H, 2.26.
For 33b: colorless oil (33%; 88% based on recovered 32b);
IR (film, cm-1) 1367, 1161; 1H NMR (300 MHz, CDCl3) δ 4.99
(s, 2 H), 4.91 (s, 2 H), 4.11 (t, J ) 7.0 Hz, 2 H), 2.71 (dt, J )
7.0, 2.6 Hz, 2 H), 2.15 (t, J ) 2.6 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 79.2, 72.0, 58.5, 50.1, 43.8, 20.8; ES MS m/z (M +
Na)+ calcd 359.8743, obsd 359.8739.
P r ototyp ica l Mitsu n obu Alk yla tion of 30. To a cold (0
°C) solution of 30 (1.88 g, 6.86 mmol), triphenylphosphine (2.16
g, 8.23 mmol), and propargyl alcohol (442 mg, 7.88 mmol) in
anhydrous THF (15 mL) was added dropwise over 10 min
diisopropyl azodicarboxylate (1.66 g, 8.23 mmol) dissolved in
dry benzene (10 mL). The magnetically stirred reaction
mixture was allowed to warm slowly to room temperature
during 15 h, at which point water (50 mL) was introduced and
the product was taken up in ether (3 × 100 mL). The combined
organic phases were washed with brine (2 × 30 mL), dried,
and concentrated. Flash chromatography of the residue on
silica gel (elution with 10% ethyl acetate in hexanes) gave 31a
as a colorless oil (2.06 g, 96%); IR (film, cm-1) 1737, 1371, 1144;
1H NMR (300 MHz, CDCl3) δ 4.82 (s, 2 H), 4.44 (d, J ) 2.4
Hz, 2 H), 2.32 t, J ) 2.4 Hz, 1 H), 1.54 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ 150.1, 86.2, 78.1, 72.5, 41.9, 36.8, 27.8; ES MS
m/z (M+Na)+ calcd 333.9725, obsd 333.9732. Anal. Calcd for
C9H14BrNO4S: C, 34.53; H, 4.51. Found: C, 34.93; H, 4.51.
For 33c: colorless oil (25%; 72% based on recovered 32c);
1
IR (film, cm-1) 1394, 1365, 1160; H NMR (300 MHz, CDCl3)
δ 4.94 (s, 2 H), 4.03 (t, J ) 7.6 Hz, 2 H), 2.28 (dt, J ) 7.0, 2.3
Hz, 2 H), 2.09-2.00 (series of m, 3 H); 13C NMR (75 MHz,
CDCl3) δ 82.0, 69.7, 58.2, 51.3, 43.6, 29.4, 15.6; ES MS m/z
(M+) or (M + Na)+ too fleeting for accurate mass measurement.
Ra d ica l Beh a vior of 33c. A magnetically stirred solution
of 33c (130 mg, 0.37 mmol) in degassed refluxing benzene (10
mL) was gradually treated during 2 h via a syringe pump with
a solution of tris(trimethylsilyl)silane (202 mg, 0.81 mmol) and
AIBN (12 mg, 0.11 mmol) in benzene (10 mL). After three
additional hours of heating, the concentrated solution was
chromatographed on silica gel (elution with 20% ethyl acetate
in hexanes) to give 34 as a colorless oil: IR (film, cm-1) 1371,
For 31b: white solid, mp 51 °C (92%); IR (CHCl3, cm-1
)
1
1728, 1368, 1140; H NMR (300 MHz, CDCl3) δ 4.87 (s, 2 H),
3.87 (t, J ) 7.3 Hz, 2 H), 2.60 (dt, J ) 7.3, 2.7 Hz, 2 H), 2.03
(t, J ) 2.7 Hz, 1 H), 1.56 (s, 9 H); 13C NMR (75 MHz, CDCl3)
δ 150.6, 85.8, 80.0, 70.7, 46.0, 42.0, 27.8, 19.8; ES MS m/z (M+)
or (M + Na)+ too fleeting for accurate mass measurement.
Anal. Calcd for C10H16BrNO4S: C, 36.82; H, 4.94. Found: C,
36.94; H, 5.01.
1
1161; H NMR (300 MHz, CDCl3) δ 4.91 (s, 2 H), 3.93 (m, 2

3572 J . Org. Chem., Vol. 66, No. 10, 2001
Paquette et al.
H), 3.32 (s, 3 H), 2.26 (m, 2 H), 2.03-1.96 (series of m, 3 H);
13C NMR (75 MHz, CDCl3) δ 82.1, 69.6, 58.2, 49.7, 43.9, 29.1,
15.6; ES MS m/z (M + Na)+ calcd 295.9794, obsd 295.9789.
Ra d ica l Beh a vior of 33a . Comparable reaction of 33a (138
mg, 0.43 mmol) with tris(trimethylsilyl)silane (316 mg, 1.28
mmol) and AIBN (12 mg, 0.12 mmol) in benzene (total volume
40 mL) afforded following chromatography 35% of 35, 24% of
36, 20% of 38, and 14% of 40.For 36: white solid, mp 92-93
°C; IR (film, cm-1) 1385, 1350, 1150; 1H NMR (300 MHz,
CDCl3) δ 7.36 (m, 5 H), 5.90 (m, 1 H), 4.98 (m, 4 H), 4.15 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 136.8, 136.3, 128.9, 128.8,
126.0, 115.7, 58.6, 51.7, 49.5; ES MS m/z (M + Na)+ calcd
343.9794, obsd 343.9811. Anal. Calcd for C11H12ClNO4S2: C,
41.06; H, 3.76. Found: C, 41.47; H, 3.95.
2 H), 4.27 (d, J ) 6.1 Hz, 2 H), 4.09 (m, 2 H), 2.58 (m, 2 H);
13C NMR (75 MHz, CDCl3) δ 135.6, 118.4, 58.9, 55.8, 50.4, 30.7;
ES MS m/z (M + Na)+ calcd 281.9637, obsd 281.9650.
Cycliza tion of 45. A solution of 45 (50 mg, 0.15 mmol) in
deoxygenated refluxing benzene (5 mL) was treated during 6
h via a syringe pump with a solution of tri-n-butytin hydride
(65 mg, 0.22 mmol) and AIBN (5 mg, 0.03 mmol) in benzene
(5 mL). After an additional 2 h of heating, the complete
consumption of starting material was noted (TLC analysis).
The concentrated residue was chromatographed on silica gel
(elution with 25% ethyl acetate in hexanes) to furnish 17 (30
mg, 67%) as a white solid, mp 203-204 °C; IR (CHCl3, cm-1
)
1387, 1170, 1156; 1H NMR (300 MHz, CDCl3) δ 7.39-7.27
(series of m, 3 H), 7.18 (d, J ) 1.6 Hz, 2 H), 4.27 (m, 1 H), 3.88
(m, 2 H), 3.74 (dt, J ) 14.2, 1.6 Hz, 1 H), 3.67 (dd, J ) 4.5, 2.5
Hz, 1 H), 3.51 (m, 2 H), 3.08 (m, 1 H), 2.46 (m, 1 H), 1.05 (m,
1 H); 13C NMR (75 MHz, CDCl3) δ 144.2, 128.4, 127.7, 125.9,
55.8, 54.7, 47.9, 43.2, 37.9, 30.4; ES MS m/z (M + Na)+ calcd
324.0340, obsd 324.0346. Anal. Calcd for C12H15NO4S2: C,
47.82; H, 5.02. Found: C, 47.82; H, 5.01. The structural
assignment to 17 was confirmed by X-ray crystallographaphy.
For 38: white solid, mp 78-79 °C; IR (film, cm-1) 1352,
1
1173; H NMR (300 MHz, CDCl3) δ 7.37 (m, 3 H), 7.20 (m, 2
H), 6.83 (m, 1 H), 4.95 (s, 2 H), 4.79 (d, J ) 1.4 Hz, 2 H), 4.36
(d, J ) 1.6 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 134.1, 131.5,
128.9, 128.8, 128.4, 119.3, 57.1, 55.5, 53.8; ES MS m/z (M +
Na)+ calcd 343.9794, obsd 343.9484. Anal. Calcd for C11H12
-
ClNO4S2: C, 41.06; H, 3.76. Found: C, 40.99; H, 3.78.
For 40: white solid, mp 155-156 °C; IR (CHCl3, cm-1) 1382,
Allyla tion of 13. A cold (-78 °C), magnetically stirred
solution of 13 (51 mg, 0.29 mmol) in dry THF (3 mL) was
treated dropwise with tert-butylithium in pentane (0.18 mL,
0.31 mmol). The reaction mixture was stirred at this temper-
ature for 15 min prior to the introduction of allyl bromide (0.04
mL, 0.44 mmol). After 2 h, the mixture was warmed to room
temperature, diluted with ether, and quenched with saturated
NH4Cl solution. The separated organic phase was washed with
water and brine, then dried and concentrated in advance of
chromatography on silica gel. Elution with 15% ethyl acetate
in hexanes gave 48 (49 mg, 78%) as a colorless oil; IR (film,
1
1360, 1220; H NMR (300 MHz, CDCl3) δ 7.39 (m, 3 H), 7.19
(m, 2 H), 6.79 (t, J ) 1.7 Hz, 1 H), 4.96 (s, 2 H), 4.92 (d, J )
1.8 Hz, 2 H), 4.28 (d, J ) 1.7 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 133.7, 132.4, 129.0, 128.6, 119.3, 57.2, 57.1, 53.5 (1
C not observed); ES MS m/z (M + Na)+ calcd 343.9794, obsd
343.9802. Anal. Calcd for C11H12ClNO4S2: C, 41.06; H, 3.76.
Found: C, 41.44; H, 3.87.
Red u ction of 36. To a solution of 36 (14 mg, 0.04 mmol)
in degassed refluxing benzene (5 mL) was added a mixture of
tri-n-butyltin hydride (25 mg, 0.09 mmol) and AIBN (1 mg,
0.01 mmol) dissolved in benzene (5 mL) during 10 h via a
syringe pump. After an additional 3 h of stirring, the concen-
trated material was purified by flash chromatography (silica
gel, elution with 15% ethyl acetate in hexanes) and gave 37
1
cm-1) 1371, 1329, 1259; H NMR (500 MHz, CDCl3) δ 5.85-
5.77 (m, 1 H), 5.18-5.10 (m, 2 H), 3.62 (ddd, J ) 14.8, 11.8,
5.2 Hz, 1 H), 3.39 (ddd, J ) 13.9, 4.8, 1.6 Hz, 1 H), 3.16 (dd, J
) 14.7, 5.0 Hz, 1 H), 3.11 (d, J ) 13.9 Hz, 1 H), 2.78 (m, 1 H),
2.71 (m, 1 H), 2.52 (br d, J ) 1.6 Hz, 1 H), 2.35 (m, 1 H), 1.89-
1.84 (m, 1 H), 1.82-1.77 (m, 1 H), 1.68-1.43 (m, 4 H); 13C NMR
(75 MHz, CDCl3) δ 134.2, 118.1, 63.2, 47.2, 47.1, 45.4, 34.2,
34.1, 27.3, 22.2; EI MS m/z (M+) calcd 215.0980, obsd 215.0985.
Anal. Calcd for C10H17NO2S: C, 55.78; H, 7.96. Found: C,
55.86; H, 8.02.
as a white solid (8.0 mg, 64%), mp 140-141 °C; IR (film, cm-1
)
1
1342, 1157; H NMR (300 MHz, CDCl3) δ 7.36 (m, 5 H), 5.87
(m, 1 H), 4.95 (dd, J ) 3.5, 1.7 Hz, 2 H), 4.13 (m, 2 H), 3.45 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 137.2, 136.1, 128.81, 128.78,
126.1, 116.1, 50.6, 48.6, 44.7; ES MS m/z (M + Na)+ calcd
310.0184, obsd 310.0183.
Red u ction of 38. Analogous processing of 38 (20 mg)
Ben zyla tion of 13. A 48.3 mg (0.28 mmol) sample of 13
was deprotonated with tert-butyllithium (0.18 mL, 0.30 mmol)
in the predescribed manner and alkylated with benzyl bromide
(0.05 mL, 0.4 mmol) to provide 48.2 mg (66%) of 49 as a
afforded 14 mg (79%) of 39 as a colorless oil; IR (film, cm-1
)
1355, 1172, 1147; 1H NMR (300 MHz, CDCl3) δ 7.41-7.36
(series of m, 3 H), 7.19 (m, 2 H), 6.83 (d, J ) 1.6 Hz, 1 H), 4.62
(d, J ) 1.5 Hz, 2 H), 4.30 (d, J ) 1.6 Hz, 2 H), 3.03 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 134.2, 131.2, 128.9, 128.8, 128.4,
120.0, 53.6, 52.7, 40.8; ES MS m/z (M + Na)+ calcd 310.0184,
obsd 310.0196.
1
colorless oil; IR (film, cm-1) 1454, 1315, 1140; H NMR (300
MHz, CDCl3) δ 7.34-7.20 (m, 5 H), 3.66 (ddd, J ) 14.8, 11.5,
5.2 Hz, 1 H), 3.49 (dd, J ) 14.0, 4.8 Hz, 1 H), 3.39 (dd, J )
14.2, 5.1 Hz, 1 H), 3.21-3.15 (m, 2 H), 3.06 (ddt, J ) 10.3,
5.2, 1.5 Hz, 1 H), 2.83 (dd, J ) 14.2, 10.3 Hz, 1 H), 2.55 (br d,
J ) 3.3 Hz, 1 H), 1.92-1.82 (m, 1 H), 1.80-170 (m, 1 H), 1.66-
1.33 (series of m, 4 H); 13C NMR (75 MHz, CDCl3) δ 137.7,
128.7 (4 C), 126.8, 64.7, 47.3, 47.1, 45.2, 35.7, 34.3, 27.2, 22.1;
EI MS m/z (M+) calcd 265.1137, obsd 265.1136. Anal. Calcd
for C14H19NO2S: C, 63.37; H, 7.22. Found: C, 63.59; H, 7.16.
Red u ction of 40. Comparable treatment of 40 (12.5 mg)
furnished 8.0 mg (72%) of 41 as a white solid, mp 173-174
°C, and returned 4 mg of starting material.
For 41: IR (film, cm-1) 1363, 1331, 1266; 1H NMR (300 MHz,
CDCl3) δ 7.44-7.33 (series of m, 3 H), 7.16 (m, 2 H), 6.76 (m,
1 H), 4.72 (s, 2 H), 4.23 (s, 2 H), 3.27 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 131.9, 129.0, 128.8, 128.5, 119.7, 56.6, 50.6,
40.8 (one C not observed); ES MS m/z (M + Na)+ calcd
310.0184, obsd 310.0173. The structural assignment to 41 was
confirmed by X-ray crystallographic analysis.
Ra d ica l Beh a vior of 33b. Reaction of 33b (95 mg, 0.28
mmol) in the predescribed manner with tris(trimethylsilyl)-
silane (174 mg, 0.70 mmol) and AIBN (7 mg, 0.03 mmol) in
hot benzene (10 mL total) afforded 56 mg (59%) of 45 and 10
mg (14%) of 46.
For 45: colorless wax; IR (film, cm-1) 1377, 1162; 1H NMR
(300 MHz, CDCl3) δ 7.35 (m, 5 H), 5.96 (t, J ) 7.0 Hz, 1. H),
4.96 (s, 2 H), 4.41 (d, J ) 7.0 Hz, 2 H), 4.23 (m, 2 H), 3.03 (t,
J ) 5.0 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 148.9, 142.4,
128.7, 128.3, 126.2, 115.8, 59.0, 56.1, 50.8, 34.5; ES MS m/z
(M + Na)+ calcd 357.9950, obsd 357.9942. Anal. Calcd for
Ch r om yl Aceta te Oxid a tion of 13. Chromium trioxide
(581 mg, 5.81 mmol) was added to a mixture of acetic acid (2.9
mL) and acetic anhydride (2.9 mL) and the resulting dark red
solution was stirred for 30 min prior to the introduction of 13
(509 mg, 2.90 mmol) in one portion. The exothermic reaction
was cooled in a water bath as necessary. After 18 h of stirring,
the dark green solution was diluted with CH2Cl2, washed with
water, dried, and evaporated. Chromatography of the residue
on silica gel (elution with 50% ethyl acetate in hexanes)
afforded 282 mg (42%) of 50 and 155 mg (28%) of 51.
1
For 50: colorless oil; IR (film, cm-1) 1741, 1668, 1323; H
NMR (300 MHz, CDCl3) δ 6.25 (dd, J ) 10.4, 5.6 Hz, 1 H),
3.55 (d, J ) 14.2 Hz, 1 H), 3.46-3.35 (m, 2 H), 2.97 (br d, J )
3.0 Hz, 1 H), 2.81 (d, J ) 13.7 Hz, 1 H), 2.26-2.20 (m, 1 H),
2.04 (s, 3 H), 1.81-1.72 (m, 3 H), 1.63-1.26 (series of m, 2 H);
13C NMR (75 MHz, CDCl3) δ 169.2, 81.9, 53.9, 46.8, 38.4, 34.2,
31.8, 21.1, 18.4; EI MS m/z (M+) calcd 233.0722, obsd 233.0698.
C
12H14ClNO4S2: C, 42.92; H, 4.20. Found: C, 42.93; H, 4.20.
For 46: white solid, mp 90-91 °C; IR (film, cm-1) 1372; 1H
NMR (300 MHz, CDCl3) δ 6.21 (m, 1 H), 5.75 (m, 1 H), 4.94 (s,

Synthesis of Bridgehead Azabicyclics
J . Org. Chem., Vol. 66, No. 10, 2001 3573
Anal. Calcd for C9H15NO4S: C, 46.34; H, 6.48. Found: C, 46.11;
Ack n ow led gm en t. S.M.L. thanks the Universidad
de Buenos Aires, Argentina for the award of a Rene´
Thalmann postdoctoral fellowship.
H, 6.37.
1
For 51: colorless oil; IR (CHCl3, cm-1) 1734; H NMR (300
MHz, CDCl3) δ 3.90 (dd, J ) 14.7, 1.2 Hz, 1 H), 3.70 (ddd, J )
14.8, 5.2, 1.7 Hz, 1 H), 3.55 (dd J ) 13.6, 8.6 Hz, 1 H), 3.12-
3.07 (m, 1 H), 3.03 (dt, J ) 13.5, 1.8 Hz, 1 H), 2.90 (ddd, J )
15.0, 13.0, 1.9 Hz, 1 H), 2.60-2.53 (m, 1 H), 2.02-1.87 (m, 3
H), 1.84-1.67 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 174.9,
54.2, 50.2, 36.9, 36.7, 32.9, 19.3; EI MS m/z (M+) calcd
189.0460, obsd 189.0428. Anal. Calcd for C7H11NO3S: C, 44.43;
H, 5.86. Found: C, 44.02; H, 5.85.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
experimental details for 41, 12, and 17 including tables of bond
lengths, bond angles, atomic coordinates, and isotropic/aniso-
tropic displacement parameters. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O010216Z