Ring contraction of bridgehead sultams by photoinduced di-π-methane rearrangement

Article abstract of DOI:10.1021/jo0526587

Triplet-sensitized irradiation of 8-thia-9-azatricyclo[7.2.1.0 ^2'7]dodeca-2,4,6,10-tetraene (16) in acetone solution gives rise exclusively to tetracyclic sultam 20. This strong preference for benzo-vinyl bridging distal to the sulfonamide func

Full text of DOI:10.1021/jo0526587

Ring Contraction of Bridgehead Sultams by Photoinduced
Di-π-methane Rearrangement
Robert D. Dura and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
ReceiVed December 27, 2005
Triplet-sensitized irradiation of 8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10-tetraene (16) in acetone
solution gives rise exclusively to tetracyclic sultam 20. This strong preference for benzo-vinyl bridging
distal to the sulfonamide functional group has also been observed in eight derivatives carrying chemically
diverse functional groups at C-10. In none of these examples is regiospecificity eroded. This overall
result suggests that the added substituents act in harmony with the electronic rebonding pathway found
operative in the parent system. From the structural perspective, this transformation constitutes a facile
means for accomplishing the ring contraction of a bridgehead sultam.
Introduction
Thus, the availability of 2 and 5 by intramolecular copper-
catalyzed nitrene insertion within 1 and 42 has resulted in the
demonstration that these sultams are subject to preferential
aziridine C-N bond cleavage by nucleophiles. However, while
3 results from exclusive attack at the more substituted three-
membered ring site, 5 reacts at its less substituted carbon. In
both examples, the sultam linkage is preserved. Along other
lines, the bicyclo[4.2.1]nonadienyl framework resident in 7
experiences rupture of its SO2N bond and conversion to 8 when
irradiated at 350 nm.3
In this report, experiments defining a photochemical means
for effecting the ring contraction of sulfonamides of general
formula 9 are reported. Recourse to the di-π-methane rear-
rangement4 was also intended to allow for variations in the
nature of X on regioselectivity to be explored. Background
information concerning the involvement of heterocyclic systems
in related photochemistry is sparse. More than three decades
ago, the response of 10 to triplet sensitization (acetone) was
Bridgehead sultams, constrained for structural reasons to
deviate significantly from adoption of the normal orientation
of the nitrogen lone pair in the bisector of the O-S-O
internuclear angle,1 hold interest from both the constitutional
and reactivity perspectives. Particularly fascinating is the
dichotomy surrounding whether diminished orbital interaction
or conventional ring strain contributes more to the enhancement
of chemical reactivity as ring size is diminished. To this date,
attempts to shed light on these issues have been limited by the
lack of availability of a sufficient number of probe systems.
Nevertheless, the findings uncovered so far reveal an unusually
divergent sensitivity to ring size.
(1) (a) Beddoes, R. L.; Dalton, L.; Joule, J. A.; Miller, O. S.; Street, J.
D.; Watt, C. I. F. J. Chem. Soc., Perkin Trans. 2 1986, 787. For additional
examples, see: (b) Klug, H. P. Acta Crystallogr. 1968, 24, 792. (c) Oppolzer,
W.; Rodriguez, I.; Starkmann, C.; Walther, E. Tetrahedron Lett. 1990, 31,
5019.
(2) (a) Dauben, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327. (b) Liang,
J.-L.; Yuan, S.-X.; Chang, P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507.
(3) Paquette, L. A.; Barton, W. R. S.; Gallucci, J. C. Org. Lett. 2004, 6,
1313.
(4) Zimmerman, H. E.; Armesto, D. Chem. ReV. 1996, 96, 3065 and
references therein.
10.1021/jo0526587 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/17/2006
2456
J. Org. Chem. 2006, 71, 2456-2459

Ring Contraction of Bridgehead Sultams
disclosed.5 The resulting product distribution indicated that
advancement via the biradical proximal to the amide nitrogen
was favored by a factor of 3:1. In the intervening years, the
influence of pyridine nitrogen as in 11 and 12 in controlling
the course of the “dual-channeled” triplet state rearrangement
was similarly accorded attention.6
leading edge of 16 (as drawn) serves to impede rebonding in
the manner defined by 18.
The exclusive formation of 20 prompted investigation of the
possibilities available for functionalization of one or both of
the available vinyl sites as in 21 and 22. These substrates hold
the capability for revealing whether the X group will work
cooperatively with the existing sulfonamide functionality to
foster unidirectional structural organization or induce a change
in the overall regioselectivity pattern.10,11
The bromination of 16 was expected to occur on the exo face
of the isolated π-bond, with subsequent capture of the second
halogen materializing competitively from either the cis or trans
direction. In practice, treatment of the bridgehead sultam with
bromine in a chlorinated solvent (CCl4, CHCl3, or CH2Cl2)
afforded a mixture of 23 and 24 (Scheme 2). The use of neat
bromine returned 23 exclusively. Proper distinction between
these dibromides was realized on the basis of an X-ray
crystallographic analysis of 23. Subjection of equimolar mixtures
of 23 and 24 or isomerically pure 23 to dehydrobromination
with a variety of basic reagents (see Table 1) resulted in the
production of 25 exclusively. Regrettably, no suggestion of a
second vinyl bromide was seen under any circumstances. The
unidirectional nature of these reactions is noteworthy. Also of
interest is the notable efficiency with which tetra-n-butyl-
ammonium fluoride accomplishes this transformation.
Synthetic Considerations
The acquisition of parent sultam 16 was realized straight-
forwardly by adaptation of earlier work emanating from the
Grigg7 and Evans laboratories.8 As shown in Scheme 1, the
SCHEME 1
Bromo sultam 25 readily undergoes halogen-metal exchange
in the presence of methyl- or tert-butyllithium. The resulting
organometallic is in turn amenable to C-alkylation (f 26 and
27), C-acylation (f 28 and 29), and conversion to silyl (e.g.,
30), stannyl (e.g., 31), and selenyl derivatives (e.g., 32, Scheme
2). Pd(0)-catalyzed Sonagashira coupling to a terminal alkyne
(f 33) also proved possible, albeit inefficiently so.
Photochemical Results
All of the di-π-methane reactants of interest have chromo-
phores absorbing at wavelengths above 270 nm. This feature
allowed acetone to be used as the triplet sensitizer. Operation-
ally, the reaction vessel was a large-size quartz tube which was
irradiated with a bank of low-pressure lamps emitting 3000 Å
transformation of sulfonyl chloride 13 to 14 set the stage for
the implementation of ring-closing metathesis (workup with lead
tetraacetate9) and ensuing intramolecular Heck reaction. Irradia-
tion of dilute solutions of 16 in acetone at 3000 Å in a Rayonet
reactor provided 20 in 48% yield. The proton assignments are
based on a combination of COSY and NOE data. Evidently,
the increased distance separating the reaction centers along the
(10) The triplet-sensitized photoisomerization of benzonorbornadienes
carrying substituents at the bridgehead positions and vinyl segments has
been thoroughly scrutinized: (a) Paquette, L. A.; Ku, A. Y.; Santiago, C.;
Rozeboom, M. D.; Houk, K. N. J. Am. Chem. Soc. 1979, 101, 5972. (b)
Ku, A. Y.; Paquette, L. A.; Rozeboom, M. D.; Houk, K. N. J. Am. Chem.
Soc. 1979, 101, 5981. (c) Paquette, L. A.; Bay, E.; Ku, A. Y.; Rondan, N.
G.; Houk, N. K. J. Org. Chem. 1982, 47, 422. (d) Paquette, L. A.; Bay, E.
J. Org. Chem. 1982, 47, 4597. (e) Paquette, L. A.; Bay, E. J. Am. Chem.
Soc. 1984, 106, 6693. (f) Paquette, L. A.; Varadarajan, A.; Bay, E. J. Am.
Chem. Soc. 1984, 106, 6702.
(5) Paquette, L. A.; Meisinger, R. H. Tetrahedron Lett. 1970, 1469.
(6) (a) Paquette, L. A.; Coghlan, M. J.; Cottrell, C. E.; Irie, T.; Tanida,
H. J. Org. Chem. 1986, 51, 696. (b) Paquette, L. A.; Burke, L. D.; Irie, T.;
Tanida, H. J. Org. Chem. 1987, 52, 3246.
(7) (a) Grigg, R.; Santhakumar, V.; Sridharan, V.; Stevenson, P.;
Teasdale, A.; Thornton-Pett, M.; Worakun, T. Tetrahedron 1991, 49, 9703.
(b) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39, 4139.
(c) Grigg, R.; York, M. Tetrahedron Lett. 2000, 41, 7255.
(11) Full consideration has also been given to the control of benzo-vinyl
bonding options by aryl-bound functionality: (a) Paquette, L. A.; Cottrell,
D. M.; Snow, R. A.; Gifkins, K. B.; Clardy, J. J. Am. Chem. Soc. 1975, 97,
3275. (b) Santiago, C.; Houk, K. N.; Snow, R. A.; Paquette, L. A. J. Am.
Chem. Soc. 1976, 98, 7443. (c) Paquette, L. A.; Cottrell, D. M.; Snow, R.
A. J. Am. Chem. Soc. 1977, 99, 3723. (d) Snow, R. A.; Cottrell, D. M.;
Paquette, L. A. J. Am. Chem. Soc. 1977, 99, 3734. (e) Santiago, C.;
McAlduff, E. J.; Houk, K. N.; Snow, R. A.; Paquette, L. A. J. Am. Chem.
Soc. 1978, 100, 6149. (f) Paquette, L. A.; Burke, L. D. J. Org. Chem. 1987,
52, 2674.
(8) Evans, P.; McCabe, T.; Morgon, B.; Reau, S. Org. Lett. 2005, 7, 43.
(9) Paquette, L. A.; Schloss, J.; Efremov, I.; Fabris, F.; Gallou, F.;
Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259.
(12) Lane, J. W.; Holcomb, R. L. Org. Lett. 2003, 5, 4017.
J. Org. Chem, Vol. 71, No. 6, 2006 2457

Dura and Paquette
SCHEME 2
TABLE 1. Dehydrobromination of 23 and 24
pathway is followed when chemically diverse substituents are
placed at C-10 is construed to be an indication of a cooperative
effect. The reactivity pattern reveals that the bridgehead sultam
group totally controls the pivotal bridging step.
reactanta
reaction conditions
23:24
yield, %
23/24
23/24
23/24
23/24
23
KOt-Bu, THF, reflux, 3 hb
DBU, CH3CN, reflux, 24 h
NaH, THF, reflux, 24 h
100:0
100:0
100:0
100:0
100:0
100:0
77
60
70
98
83
82
1 M TBAF, THF, rt, 24 hc
NaH, THF, 0 °C f rt, 16 h
1 M TBAF, THF, rt, 16 h
23
a 1:1 mixtures of 23 and 24. b See ref 11f. c Clark, J. H. Chem. ReV.
1980, 80, 429.
light. Each experiment was carried out under an argon atmo-
sphere for 1 h in the manner defined earlier for 16.
In each instance, isomerization materialized to generate a
single photoproduct despite the inherent capacity for bifurcate
reactivity in every instance. The uniformity of the reaction
conditions revealed no substantial differences in the individual
rates of starting material disappearance or product formation.
The salient feature of the photoreaction is that the new C-C
bond forms part of a five-membered sultam. Overall, this new
bonding arrangement represents a formal ring contraction
relative to the connectivity present in the reactants. The resulting
distorted structure clearly is more strained, with fused azetidine
and cyclopropane subunits also incorporated therein.
Experimental Section
Photoisomerization of 16. Prototypical Procedure. A solution
of 16 (50 mg, 0.24 mmol) in acetone (75 mL) was carefully
deoxygenated with argon for 10 min after being placed in a quartz
test tube and fitted with an appropriate septum. Irradiation for 1 h
in a Rayonet reactor equipped with a bank of 3000 Å bulbs was
followed by solvent evaporation and chromatography on silica gel.
Elution with 7:3 hexanes/ethyl acetate furnished 24 mg (48%) of
20 as a colorless oil; IR (neat, cm-1) 1479, 1382, 1339, 1176; H
1
NMR (500 MHz, CDCl3) δ 7.83-7.81 (m, 1H), 7.56 (dt, J ) 1.0,
7.5 Hz, 1H), 7.48-7.42 (m, 2H), 4.54 (dd, J ) 3.5, 6.5 Hz, 1H),
4.40 (dd, J ) 3.0, 10.0 Hz, 1H), 3.34 (dd, J ) 2.5, 10.0 Hz, 1H),
Summary
2.33 (dt, J ) 3.5, 6.5 Hz, 1H), 2.16 (dd, J ) 3.5, 6.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 133.2, 132.7, 132.4, 130.2, 128.4, 125.1,
51.1, 48.3, 18.0, 16.4; HRMS ES m/z (M + Na)+ calcd 230.0246,
obsd 230.0256.
Bromination of 6. A. In Neat Bromine. A 2.0-g (9.6 mmol)
sample of 16 was placed in neat bromine (4 mL) and allowed to
stand overnight in a sealed flask. The excess bromine was
evaporated in a stream of air to leave 23 (3.5 g, 99%), which was
isolated as an off-white solid, mp 185-188 °C after dissolution in
CH2Cl2, washing with NaHSO3 solution, and drying; 1H NMR (500
MHz, CDCl3) δ 7.83-7.81 (m, 1H), 7.57-7.54 (m, 2H), 7.37-
We have developed a general route to strained bridgehead
sultams that allows for the regiospecific incorporation of an
additional functional group. The protocol consists of early steps
involving olefin metathesis and an intramolecular Heck reaction
and is capped by a bromination-dehydrobromination sequence
and functional group manipulation in advance of di-π-methane
photorearrangement. The strongly favored electronic rebonding
that operates occurs distal to the sulfonamide component and
eventuates in its direct ring contraction. That the same reaction
2458 J. Org. Chem., Vol. 71, No. 6, 2006

Ring Contraction of Bridgehead Sultams
7.35 (m, 1H), 6.48 (d, J ) 6.5 Hz, 1H), 4.67 (dd, J ) 2.0, 6.5 Hz,
1H), 4.31 (d, J ) 13.0 Hz, 1H), 4.13 (dd, J ) 3.0, 13.0 Hz, 1H),
3.63 (d, J ) 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 135.8,
134.8 133.6, 130.5, 128.6, 126.5, 67.5, 57.8, 52.7, 52.3; HRMS
ES m/z (M + Na)+ calcd 389.8598, obsd 389.8594.
6.20 (s, 1H), 4.48 (d, J ) 11.7 Hz, 1H), 4.13 (dd, J ) 4.0, 10.0
Hz, 1H), 3.21 (t, J ) 3.5 Hz, 1H), 2.10 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 145.4, 141.7, 134.6, 131.5, 129.7, 129.5, 127.7,
125.2, 64.5, 42.8, 16.3; HRMS ES m/z (M + Na)+ calcd 244.0408,
obsd 244.0406.
1-(8,8-Dioxo-8λ6-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10-
tetraen-1-yl)-2,2-dimethylpropan-1-one (28). Prototypical Pro-
cedure for tBuLi. A 100-mg (0.35 mmol) sample of 25 was
dissolved in dry THF (3.5 mL), cooled to -78 °C under an argon
atmosphere, and treated dropwise over 10 min with tert-butyllithium
(0.56 mL of 1.26 M in hexanes, 0.70 mmol). After 30 min, pivalolyl
chloride (0.043 mL, 0.35 mmol) was introduced in one portion,
and the reaction mixture was allowed to warm to room temperature.
After 2 h, the product was taken up in ethyl acetate (25 mL), and
the organic solution was washed with NH4Cl solution, water, and
brine. The organic layer was dried and evaporated to leave a residue
that was chromatographed on silica gel (7:3 hexanes/ethyl acetate)
The structural assignment to 23 was corroborated by X-ray
crystallography (see Supporting Information).
B. In a Chlorinated Solvent. A solution of 16 (25 mg, 0.12
mmol) in CH2Cl2 (20 mL) was cooled to 0 °C and treated dropwise
with bromine until a red color persisted during 1 h. After the
addition of sodium bisulfite solution, the separated organic layer
was dried and evaporated. The residue was purified over silica gel
(elution with 4:1 hexanes/ethyl acetate) to give a 1:1 mixture of
23 and 24 as a white solid (37 mg, 87%). For 24: 13C NMR (125
MHz, CDCl3) δ 136.8, 136.0, 133.7, 129.9, 128.9, 126.1, 65.0, 58.2,
55.8, 50.2.
10-Bromo-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10-tet-
raene 8,8-Dioxide (25). A. Dehydrobromination with Potassium
tert-Butoxide. Potassium metal (61 mg, 1.58 mmol) was added to
tert-butyl alcohol with stirring. After 2 h, a solution of 23 (480
mg, 1.31 mmol) in 2:1 THF/tert-butyl alcohol (15 mL) was
introduced, and the mixture was heated at reflux for 3 h prior to
cooling and solvent evaporation. The residue was partitioned
between ethyl acetate and water, and the separated organic phase
was dried and concentrated. Purification over silica gel (4:1 hexanes/
ethyl acetate) yielded 350 mg (77%) of 25 as a white solid, mp
to furnish 45 mg (44%) of 28 as a colorless oil; IR (film, cm-1
)
1
1682, 1593, 1477; H NMR (500 MHz, CDCl3) δ 7.70 (dd, J )
0.5, 7.5 Hz, 1H), 7.48 (dt, J ) 1.0, 7.5 Hz, 1H), 7.43-7.40 (m,
1H), 7.16 (d, J ) 7.5 Hz, 1H), 7.05 (d, J ) 3.5 Hz, 1H), 4.59 (d,
J ) 12.0 Hz, 1H), 4.27 (dd, J ) 4.1, 12.0 Hz, 1H), 3.45 (t, J ) 4.1
Hz, 1H), 1.29 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 200.7, 145.1,
139.5, 137.7, 131.9, 130.4, 127.4, 125.7, 64.5, 44.0, 42.9, 27.0;
HRMS ES m/z (M + Na)+ calcd 314.0827, obsd 314.0814.
10-Hex-1-ynyl-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10-
tetraene 8,8-Dioxide (33). Sonagashira Protocol. Sultam 25 (100
mg, 0.35 mmol), tetrakistriphenylphosphinepalladium (40 mg, 0.035
mmol), copper(I) iodide (13 mg, 0.07 mmol), and 1-hexyne (0.04
mL, 0.35 mmol) were added to a 0.8:1 mixture of DMF and
triethylamine (1.8 mL). The reaction vessel was flushed with argon
for 20 min, stirred overnight, diluted with ethyl acetate, and filtered
through Celite. The filtrate was washed with saturated NH4Cl
solution, water, and brine prior to drying and solvent evaporation.
Chromatography of the residue on silica gel (4:1 hexanes/ethyl
acetate) afforded 10 mg (10%) of 33 as a yellowish oil; IR (neat,
cm-1) 2232, 1343; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J ) 7.5
Hz, 1H), 7.47 (t, J ) 7.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.10 (d, J
) 8.0 Hz, 1H), 6.60 (d, J ) 4.0 Hz, 1H), 4.56 (d, J ) 12.0 Hz,
1H), 4.15 (dd, J ) 4.0, 12.0 Hz, 1H), 3.32 (t, J ) 3.5 Hz, 1H),
2.39 (t, J ) 7.1 Hz, 1H), 1.58-1.52 (m, 2H), 1.47-1.41 (m, 2H),
0.91 (t, J ) 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 139.7,
136.9, 134.6, 131.7, 129.9, 129.8, 127.4, 125.3, 98.0, 72.9, 63.5,
43.0, 30.1, 21.9, 19.3, 13.5; HRMS ES m/z (M + Na)+ calcd
310.0878, obsd 310.0875.
1
179 °C dec; IR (CHCl3, cm-1) 1592, 1473, 1446, 1352; H NMR
(500 MHz, CDCl3) δ 7.77 (dd, J ) 1.0, 7.5 Hz, 1H), 7.51 (dt, J )
1.5, 7.3 Hz, 1H), 7.43 (dt, J ) 1.5, 7.3 Hz, 1H), 7.14 (dd, J ) 1.0,
7.5 Hz, 1H), 6.67 (d, J ) 3.5 Hz, 1H), 4.60 (d, J ) 0.5, 12.0 Hz,
1H), 4.38 (dd, J ) 4.0, 12.0 Hz, 1H), 3.30 (t, J ) 4.0 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 139.3, 135.9, 134.5, 132.0, 130.1, 127.3,
125.4, 124.9, 65.4, 42.8; HRMS ES m/z (M + Na)+ calcd 307.9357,
obsd 307.9365.
B. Use of Tetrabutylammonium Fluoride. A 1:1 mixture of
23 and 24 (2.0 g, 5.4 mmol) was dissolved in 1 M TBAF in THF
(27.2 mL, 27.2 mmol), stirred overnight, and freed of solvent. The
residue was taken up in CH2Cl2 (100 mL), washed with NaHSO3
solution (2 × 50 mL), dried, evaporated, and chromatographed on
silica gel (4:1 hexanes/ethyl acetate) to give 1.54 g (99%) of 25.
10-Methyl-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10-tet-
raene 8,8-Dioxide (26). Prototypical Procedure for CH3Li.
Bromo sultam 25 (500 mg, 1.75 mmol) was dissolved in dry THF
(17.5 mL), cooled to -78 °C under argon, and treated with
methyllithium (1.86 mL, 2.98 mmol) while being stirred. After 30
min, the reaction mixture was warmed quickly to 0 °C in an ice
bath, treated immediately with dimethyl sulfate (0.215 mL, 2.27
mmol), and maintained at room temperature during 4 h. Ethyl
acetate (50 mL) and water (50 mL) were introduced, and the
aqueous phase was extracted with ethyl acetate (2 × 50 mL). The
combined organic layers were dried and concentrated to leave a
residue that was chromatographed on silica gel. Elution with 4:1
hexanes/ethyl acetate gave 270 mg (70%) of 26 as a white solid,
mp 118-121 °C; IR (neat, cm-1) 1652, 1597, 1471; 1H NMR (500
MHz, CDCl3) δ 7.73 (d, J ) 8.0 Hz, 1H), 7.44 (dt, J ) 1.2, 9.0
Hz, 1H), 7.37 (dt, J ) 1.2, 9.0 Hz, 1H), 7.10 (d, J ) 8.0 Hz, 1H),
Acknowledgment. This work was financially supported by
the Astellas USA Foundation. In addition, we thank Dr. Judith
Gallucci for the X-ray determination.
Supporting Information Available: Details of the X-ray
1
crystallographic analysis of 23 in addition to H and 13C NMR
spectra for all compounds described herein. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0526587
J. Org. Chem, Vol. 71, No. 6, 2006 2459