Direct comparison of the response of bicyclic sultam and lactam dienes to photoexcitation. Concerning the propensity of differing bond types to bridgehead nitrogen for homolytic cleavage

Article abstract of DOI:10.1021/jo061404y

A convergent strategy has allowed access to bridgehead sultam 9 and the related carboxamides 10 and 11. The synthetic routing proceeds via the coupling of a suitably constructed dienamine to either o-iodobenzenesulfonyl choride or o-iodobenzoyl chloride t

Full text of DOI:10.1021/jo061404y

Direct Comparison of the Response of Bicyclic Sultam and Lactam
Dienes to Photoexcitation. Concerning the Propensity of Differing
Bond Types to Bridgehead Nitrogen for Homolytic Cleavage
Leo A. Paquette,* Robert D. Dura, Nathan Fosnaugh, and Marshall Stepanian
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210-1185
paquette.1@osu.edu
ReceiVed July 6, 2006
A convergent strategy has allowed access to bridgehead sultam 9 and the related carboxamides 10 and
11. The synthetic routing proceeds via the coupling of a suitably constructed dienamine to either
o-iodobenzenesulfonyl choride or o-iodobenzoyl chloride to generate the amides. The application in
sequence of ring-closing metathesis and an intramolecular Heck reaction gave rise to advanced tricyclic
intermediates. The final two steps involved bromination in liquid bromine and proper 2-fold dehydro-
bromination. The latter maneuver was best achieved with tetrabutylammonium fluoride in DMSO at
elevated temperature. While the irradiation of 9 led principally via SO2-N bond homolysis and [1,5]
sigmatropic rearrangement to generate 37, 10 proceeded via disrotatory cyclization to the exo cyclobutene
39, and 11 resisted photoisomerization. The inertness of 11 may stem from its distorted structural features
which force its conjugated diene double bonds to be rigidly oriented 32° out-of-plane. The unique ability
of the sulfonamide linkage to excited-state homolysis holds comparative interest.
Introduction
the heterocyclic realm motivated us to investigate the response
of the structurally related bridgehead sultam 4 to photoactiva-
tion.3
In 1972, Jefford and Delay reported on the light-induced
electrocyclic ring closure of bicyclo[4.2.1]nona-2,4-diene (1).1
This study was based on orbital symmetry considerations2 and
viewed as an attempt to provide insight into the underlying cause
of the exo selectivity exhibited by norbornene during electro-
philic capture. Since the atoms defining the bridgehead atoms
(C-1 and C-6) and the diene moiety (C-2 to C-5) reside in the
same plane, the competitive disrotatory processes should be
guided in their stereochemical outcome only by steric factors.
Bond formation between C-2 and C-5 as in 2 and 3 was expected
to be indifferent to those electronic considerations normally
associated with exo and endo partitioning. The salient feature
of the photoisomerization of 1 (hexane, 200 W Hanovia lamp,
25 °C) was the production of a 30:70 mixture of 2 and 3.
Irrespective of the inferences that can be drawn from this
dichotomy, the lack of additional examples particularly from
This particular extension caused us to become aware of the
fact that 4 is subject to heretofore unprecedented light-induced
SO2-N bond cleavage with the ultimate generation of spirocycle
5 (Scheme 1). The structural intricacy of this photoproduct, with
its combination of cyclobutene, thietane dioxide, and pyrrolidine
rings, is quite striking. This excited-state transformation was
best achieved in a 2:1 acetonitrile/acetone solvent system by
irradiation through Pyrex with 350 nm light in a Rayonet reactor.
The behavior of 4 clearly represents a dramatic departure from
the pathway adopted by 1. At the mechanistic level, the first
(1) Jefford, C. W.; Delay, F. J. Am. Chem. Soc. 1972, 94, 4794.
(2) Woodward, R. B.; Hoffman, R. The ConserVation of Orbital
Symmetry; Verlag Chemie: Weinheim, 1970; pp 38-68.
(3) Paquette, L. A.; Barton, W. R. S.; Gallucci, J. C. Org. Lett. 2004, 6,
1313.
10.1021/jo061404y CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/29/2006
8438
J. Org. Chem. 2006, 71, 8438-8445

Response of Bicyclic Sultam and Lactam Dienes to Photoexcitation
SCHEME 1
SCHEME 2
step appears to involve the formation of biradical 6 followed
by rebonding to generate bicyclic isomer 7. Generation of this
intermediate allows for operation of a thermally induced
suprafacial [1,5] sigmatropic hydrogen shift and arrival at 8.
The second leg of the biphotonic sequence now occurs with
absorption by 8 of another quantum of light energy. These
findings raise several issues pertinent to amide chemistry. For
example, can it be inferred from the pathway adopted by 4 that
the customarily robust sulfonamide linkage may be generally
amenable to facile homolysis when reasonably good stereo-
electronic overlap is available? Also, will similar architectural
features have comparable consequences when carboxamides are
involved? We report here our more recent investigation of the
three benzo-fused systems 9-11 in order to determine if a
related pattern of structural change emerges.
to Heck reaction conditions10,11 afforded a chromatographically
separable two-component mixture consisting of 16 (47%) and
17 (40%). When the dibromination of 16 and 17 in various
halogenated solvents was found to proceed slowly, recourse was
made instead to liquid Br2 as the reaction medium. These
conditions led effectively to 18 and 19. The 2-fold dehydromi-
nation of these dibromides was examined with a host of basic
reagents.12 While our inability to transform 18 into 9 was not
unexpected, the sluggishness exhibited by 19 proved surprising.
Ultimately, it was discovered that 1 M solutions of tetra-n-
butylammonium fluoride in THF13 were significantly superior
in bringing about this transformation. The two-step route from
17 to 9 shown in Scheme 2 proceeds in 57% overall yield.
Synthetic Considerations
The strategy applied to the acquisition of 9 began with the
coupling of 2-iodobenzenesulfonyl chloride (12)4 to secondary
amine 135 (Scheme 2). The latter was generated in 40% overall
yield by boric acid catalyzed amidation6 involving 4-pentenoic
acid and allylamine with subsequent lithium aluminum hydride
reduction. Ring-closing metathesis represents a powerful strategy
for the construction of medium-ring products.7 In line with the
tolerance of this process to a wide range of functionality in-
cluding the sulfonamide group,8 the conversion of 14 to 15
proceeded very well (in near-quantitative yield). This level of
efficiency was made possible by effective removal of ruthenium-
containing byproducts with lead tetraacetate.9 Submission of 15
(8) For example: (a) Paquette, L. A.; Leit, S. J. Am. Chem. Soc. 1999,
121, 8126. (b) Paquette, L. A.; Ra, C. S.; Schloss, J. D.; Leit, S. M.; Gallucci,
J. C. J. Org. Chem. 2001, 66, 3564. (c) Wanner, J.; Harned, A. M.; Probst,
D. A.; Poon, K. W. C.; Klein, T. A.; Snelgrove, K. A.; Hanson, P. R.
Tetrahedron Lett. 2002, 43, 917.
(9) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.;
Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259.
(10) (a) Grigg, R.; York, M. Tetrahedron Lett. 2000, 41, 7255. (b) Evans,
P.; McCabe, T.; Morgan, B.; Reau, S. Org. Lett. 2005, 7, 43.
(11) This ring closure lacks generality and could not, for example, be
successfully applied to the conversion of i to ii. Multicomponent mixtures
resulted, and recourse to tris-3-furylphosphine (T2F) as a ligand was not
particularly helpful.
(4) Chau, M. M.; Kice, J. L. J. Org. Chem. 1977, 42, 3265.
(5) (a) Surzur, J. M.; Stella, L. Tetrahedron Lett. 1974, 2191. (b)
Newcomb, M.; Marquardt, D. J.; Deeb, T. M. Tetrahedron 1990, 46, 2329.
(c) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50,
1295. (d) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 707. (e) Li, Y.;
Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757. (f) Evans, P.; Grigg, R.;
Ramzan, M.; Imran, M.; Sridharan, V.; York, M. Tetrahedron Lett. 1991,
40, 3021.
(12) The reagent combinations included, but were not limited to, sodium
hydride in THF at 25 °C, DBU in acetonitrile at reflux in a sealed tube,
LiF and Li2CO3 in HMPA at 90 °C, and potassium tert-butoxide in THF at
the reflux temperature.
(6) Tang, P. Org. Synth. 2004, 81, 262.
(7) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Verlag
GmbH, Weinheim, 2003; Vol. 2.
J. Org. Chem, Vol. 71, No. 22, 2006 8439

Paquette et al.
SCHEME 3
SCHEME 4
The conversion of 2-iodobenzoyl chloride to amide 22 was
readily accomplished via a parallel sequence capped by ring-
closing metathesis (Scheme 3). More advanced cyclization of
this intermediate gave predominantly 23 and 24 alongside 15%
of the [3.3.2] tricyclic isomer 25. The first two lactams were
individually brominated in neat bromine at room temperature
to give 26 and 27. Of these, only 27 proved to be a progenitor
of 10. The recalcitrance of 26 to the loss of HBr may stem
from its conformational characteristics, corroborated by X-ray
crystallographic analysis, that indicate no suitable trans-diaxial
relationships to be readily attainable (see the Supporting
Information).
At this juncture, it seemed advisable to introduce an additional
methylene group so as to enlarge the methano bridge. To reach
this goal, the commercially available nitrile 28 was reduced with
LiAlH4, and the amine so generated was acylated with 4-pen-
tenoyl chloride. The doubly unsaturated amide 29 formed in
this manner smoothly underwent conversion to the homologated
secondary amine 30 upon further reduction. The program for
accessing 11 continued with the action of 20 on 30 and the
cyclization of 31 under Grubbs’ conditions to deliver 32 in a
remarkable 92% yield (Scheme 4). The product distribution
realized from application of the intramolecular Heck reaction
to 32 was closely related to that observed earlier. Thus, the aza-
bicyclo[4.3.1]undecenone 34 having a double bond distal to the
methano bridge is formed to an extent approximately twice that
noted for the more proximal isomer 33. All of the above
assignments are undergirded by extensive NMR spectral data.
Results of Photoactivation
As conditions for effecting the photorearrangement of 9 were
researched, note was taken of the fact that triplet sensitization
invariably resulted in slow polymer formation. Therefore,
attention was profitably directed to the application of direct
irradiation conditions such as those originally applied to
hydrocarbon 1. Under these experimental circumstances, two
rearrangement pathways were operational. The predominant
process gave rise to dihydroazepine 37 (50%), presumably via
1,5-migration of the sulfonyl group with cleavage of the SO2-N
linkage (Scheme 5). The structural assignment to 37 was
corroborated by X-ray crystallographic analysis. The minor
product proved to be cyclobutene 38 (5%), the likely conse-
quence of disrotatory ring closure. The exo orientation of the
four-membered ring in 38 was easily recognized on the basis
of the coupling constants, or absence thereof, exhibited by the
associated protons.14
These data demonstrate that 9 shows the same propensity as
does 4 to undergo photoisomerization to the fused dihydro
azepines 37 and 8, respectively, despite the need to apply
different irradiation conditions in the two examples. Interest-
ingly, the subsequent ring closure of 8 to generate 5 is not
mirrored by 37. This divergence could possibly be a reflection
(14) Marchand, A. P. Stereochemical Applications of NMR Studies in
Rigid Bicyclic Systems; Verlag Chemie International: Deerfield Beach, FL,
1982.
(13) (a) Clark, J. H. Chem. ReV. 1980, 80, 429. (b) Dura, R. D.; Paquette,
L. A. Synthesis 2006, 2837.
8440 J. Org. Chem., Vol. 71, No. 22, 2006

Response of Bicyclic Sultam and Lactam Dienes to Photoexcitation
FIGURE 1. Ground-state geometries of 8 (left column) and 37 (right column) as visualized by the Mercury 1.4.1 program.
FIGURE 2. Ground-state geometries of 10 and 11 as visualized by the Mercury 1.4.1 program.
1
identified as 40 on the basis of its H and 13C NMR spectra,
SCHEME 5
especially at the 2D level. The progenitor of 40 was shown to
be 39 by independent photoactivation of the latter for an
extended 60 min time period. The conclusion that 38 and 39
share in common an exo-oriented cyclobutene ring stems from
the similar features of their 2-D NMR spectra.
In contrast to the responsiveness of 10 to activation by light,
11 proved unreactive to comparable irradiation. More forcing
photochemical conditions involving, for example, 200 and
450 W mercury lamp sources, brought about polymerization.
We recognized that 10 and 11 differ appreciably in their
ultraviolet absorption properties (see the Experimental Section)
and that both compounds are characterized by very rigid
molecular architectures. Once again, insight into the respective
ground-state geometries was gained by computational means.
As before, only one minimum energy conformer was found for
each structure (Figure 2). The results show 10 to adopt a nicely
shaped convex topography. The ethano bridge in 11 is much
less well accommodated, and a significant level of structural
distortion is consequently induced. This feature is most strikingly
reflected in the dihedral angle adopted about the conjugated
diene component, which is appreciably enlarged from 9.8° to
32.4° when progressing from 10 to 11. This dichotomy is
believed to be the root cause of the different chemical behavior
and spectroscopic characteristics of this pair of bridgehead
lactams.
of the near-planarity of the conjugated diene unit in 8, with the
improved orbital overlap facilitating disrotatory cyclization to
generate the cyclobutene ring. Some indication of the existing
level of disparity in overlap was secured by making recourse
to MacroModel version 8.6 calculations performed in conjunc-
tion with the MMFFs force field. As shown in Figure 1, the
lowest minimum energy conformation of 37 features a dihedral
angle (-23.3°) that is considerably wider than that exhibited
by 8 (-12.2°).
Entirely comparable processing of lactam 10 afforded 39 as
the major product (38%). Also formed was a less polar product
J. Org. Chem, Vol. 71, No. 22, 2006 8441

Paquette et al.
8-Thia-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6,12-tetraene 8,8-
Dioxide (16). Sulfonamide 15 (500 mg, 1.38 mmol), triphenylphos-
phine (144.8 mg, 0.55 mmol), K2CO3 (436 mg, 3.45 mmol), Et4NCl‚
H2O (228 mg, 1.38 mmol), and 150 mg of 4 Å MS were added to
15 mL of DMF and deoxygenated with Ar for 45 min. Pd(OAc)2
(61.4 mg, 0.276 mmol) was introduced, and degassing was
continued for 15 min prior to heating at 90 °C for 24 h. The reac-
tion mixture was cooled to rt, ether was added, and the organic
phase was washed with water, saturated NH4Cl solution, and brine
prior to solvent evaporation and purification over silica gel (elu-
tion with 4:1 hexane/ethyl acetate) to furnish 16 as a white solid
(153 mg, 47%): mp 148-149 °C; IR (neat, cm-1) 1476, 1441,
Finally, it is noteworthy that attempts to carry out the
irradiation of diene lactam 10 in the manner originally reported
for 4 (350 nm, acetone, with and without CH3CN as cosolvent)
resulted exclusively in the recovery of unreacted starting
material.
Overview
Three key reactions consisting of ring-closing metathesis, an
intramolecular Heck cyclization, and bromination-dehydro-
bromination enabled a convergent and relatively abbreviated
route to 9-11 to be developed. These platforms provided an
excellent opportunity to compare the response of the related
sulfonamide/carboxamide pair 9 and 10 to photoactivation. A
second subset of probes involved 10 and its higher homologue
11. Only in the bridgehead sulfonamide example was homolysis
of the bond to nitrogen subject to homolytic cleavage with
translocation to a site five atoms away. To our knowledge, an
azepine substituted as in 37 has not been heretofore described.
Also defined experimentally was the divergency in photoreac-
tivity separating 10 from 11. Seemingly, the marked structural
distortion within the diene moiety of 11 is an apt deterrent either
to valence isomerization or to CO-N bond fragmentation.
Further elucidation of similarly dramatic reactivity differences
in related systems is in progress.
1
1322; H NMR (500 MHz, CDCl3) δ 7.77 (d, J ) 8.0 Hz, 1H),
7.44 (dt, J ) 1.0, 7.5 Hz, 1H), 7.38-7.35 (m, 1H), 7.24 (d, J )
7.5 Hz, 1H), 5.79-5.74 (m, 1H), 5.51-5.46 (m, 1H), 4.70 (dd, J
) 4.0, 15.5 Hz, 1H), 4.45 (dd, J ) 6.5, 17.0 Hz, 1H), 3.71 (dd, J
) 2.0, 16.5 Hz, 1H), 3.63 (d, J ) 15.5 Hz, 1H), 3.16 (q, J )
3.5 Hz, 1H), 2.70-2.68 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
138.5, 138.1, 131.7, 129.9, 128.8, 128.7, 127.7, 123.5, 54.4, 49.6,
37.3, 33.6; HRMS ES m/z (M + Na)+ calcd 258.0559, obsd
258.0559.
8-Thia-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6,11-tetraene 8,8-
Dioxide (17). Continued elution furnished 17 as a white solid (141
mg, 40%): mp 141-143 °C; IR (neat, cm-1) 1473, 1440, 1325;
1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J ) 1.0, 7.5 Hz, 1H),
7.45 (dt, J ) 1.0, 6.5 Hz, 1H), 7.38 (dt, J ) 1.0, 7.5 Hz, 1H), 7.21
(d, J ) 8.0 Hz, 1H), 6.24-6.19 (m, 1H), 5.88-5.84 (m, 1H), 4.50
(dd, J ) 4.5, 15.0 Hz, 1H), 4.01 (ddd, J ) 3.5, 4.5, 14.5 Hz, 1H),
3.68 (d, J ) 20.5 Hz, 1H), 3.50 (q, J ) 4.5 Hz, 1H), 3.23-3.17
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 137.3, 136.6, 134.1, 131.9,
130.0, 127.6, 123.7, 50.6, 50.1, 36.8, 27.0; HRMS ES m/z (M +
Na)+ calcd 258.0559, obsd 258.0554.
Experimental Section
N-Allyl-2-iodo-N-pent-4-enylbenzenesulfonamide (14). Amine
13 (1.7 g, 13.6 mmol), triethylamine (2.5 mL, 18.4 mmol), and a
catalytic amount of DMAP were dissolved in a mixture of ether
and dichloromethane (35 mL, 1:1). This mixture was cooled to
0 °C under Ar, a solution of 2-iodobenzenesulfonyl chloride
(3.6 g, 12.2 mmol) in a mixture of ether and dichloromethane (20
mL, 1:1) was introduced via syringe over 2 h, and warming to
rt was allowed to occur overnight. The reaction mixture was
washed with 1 M HCl, saturated NaHCO3 solution, and brine,
dried, and purified over silica gel (elution with 20:1 hexane/ethyl
12,13-Dibromo-8-thia-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6-
triene 8,8-Dioxide (18). Sulfonamide 16 (10 mg, 0.043 mmol) was
dissolved in 1 mL of neat bromine and allowed to stir overnight.
The next day, the residual bromine was removed under a constant
stream of air for 2 h. The residue was partitioned between 5 mL of
dichloromethane and 10 mL of saturated NaHSO3 solution. The
reaction mixture was stirred until it became colorless. The separated
organic layer was washed further with 10% NaHSO3 solution, water,
and brine, dried, and evaporated. Chromatography of the residue
on silica gel (elution with 4:1 hexane/ethyl acetate) afforded 18 as
acetate) to give 14 as a colorless oil (3.0 g, 62%): IR (neat, cm-1
)
1
a tan solid (15 mg, 89%): mp 203-205 °C dec; IR (CHCl3, cm-1
)
1640, 1596, 1446; H NMR (300 MHz, CDCl3) δ 8.14 (dd, J )
2.6, 7.9 Hz, 1H), 8.07 (dd, J ) 1.1, 7.8 Hz, 1H), 7.46 (td, J ) 1.2,
7.7 Hz, 1H), 7.17 (td, J ) 1.7, 6.9 Hz, 1H), 5.79-5.59 (m, 2H),
5.25-5.16 (m, 2H), 4.96-4.88 (m, 2H), 3.94 (d, J ) 6.4 Hz, 2H),
3.26 (t, J ) 7.6 Hz, 2H), 1.95 (quintet, J ) 7.2 Hz, 2H), 1.58
(quintet, J ) 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 142.8,
142.0, 137.2, 133.1, 132.9, 131.7, 128.1, 118.9, 115.1, 92.5, 49.7,
46.1, 30.5, 26.4; HRMS ES m/z (M + Na)+ calcd 413.9995, obsd
413.9971.
1
1463, 1442, 1326; H NMR (500 MHz, CDCl3) δ 7.84 (dd, J )
1.0, 7.5 Hz, 1H), 7.52 (td, J ) 1.0, 7.5 Hz, 1H), 7.45 (m, 1H),
7.38 (d, J ) 8.0 Hz, 1H), 5.01-5.00 (m, 1H), 4.69 (q, J ) 4.0 Hz,
1H), 4.50 (dd, J ) 4.5, 16.5 Hz, 1H), 4.29 (qd, J ) 4.0, 11.5 Hz,
1H), 4.08 (d, J ) 16.5 Hz, 1H), 3.55 (d, J ) 4.0 Hz, 1H), 3.52 (t,
J ) 4.0 Hz, 1H), 2.84-2.78 (m, 1H), 2.11-2.05 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 137.8, 136.2, 132.0, 129.7, 128.8, 124.2, 59.5,
51.7, 45.4, 44.2, 42.4, 29.7; HRMS ES m/z (M + Na)+ calcd
417.8911, obsd 417.8910.
1-(2-Iodobenzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine (15).
Sulfonamide 14 (1.27 g, 3.75 mmol) was dissolved in 100 mL of
dichloromethane and deoxygenated with Ar for 45 min. The reaction
mixture was heated to 50 °C, Grubbs I catalyst (80 mg, 0.01 mmol)
was added in one portion, and the mixture was stirred for 36 h.
After the mixture was cooled to rt, lead tetraacetate (86 mg, 0.19
mmol) was added in one portion and stirring was maintained for
an additional 6 h prior to concentration and purification over silica
gel (elution with 20:1 hexane/ethyl acetate) to yield 15 as a white
solid (1.24 g, 91%), mp 74-75 °C; IR (neat, cm-1) 1567, 1445,
11,12-Dibromo-8-thia-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6-
triene 8,8-Dioxide (19). Sulfonamide 17 (15 mg, 0.0638 mmol)
was dissolved in 2 mL of neat bromine and allowed to stir overnight.
The next morning, excess bromine was removed under a stream of
air for 2 h. The residue was taken up in 10 mL of dichloromethane,
treated with saturated NaHSO3 solution, and stirred until it became
colorless. The organic phase was washed with 10% NaHSO3
solution, water, and brine and then dried. Chromatography of the
residue on silica gel (elution with 4:1 hexane/ethyl acetate) gave
19 as a white solid (25 mg, 99%). The material was isolated as a
5:2 mixture of isomers that could not be separated by further
chromatography or recrystalization: IR (neat, cm-1) 1477, 1442,
1320; 1H NMR (500 MHz, CDCl3) δ 7.84-7.80 (m, 1.4H), 7.53-
7.47 (m, 1.4H), 7.44-7.40 (m, 1.4H), 7.33 (d, J ) 7.5 Hz, 1H),
7.23 (d, J ) 7.5 Hz, 0.4H), 4.93 (dd, J ) 5.0, 16.5 Hz, 1H), 4.77-
4.75 (m, 1H), 4.64-4.61 (m, 1H), 4.57-4.56 (m, 0.4H), 4.54-
4.52 (m, 0.8H), 4.50-4.46 (m, 0.4H), 4.45-4.38 (m, 1H), 4.22-
1
1325; H NMR (300 MHz, CDCl3) δ 8.13 (dd, J ) 1.5, 7.8 Hz,
1H), 8.08 (dd, J ) 1.2, 7.8 Hz, 1H) 7.47 (td, J ) 1.2, 7.6 Hz, 1H),
7.17 (td, J ) 1.6, 7.7 Hz, 1H), 5.91-5.83 (m, 1H), 5.77-5.69 (m,
1H), 3.98 (dd, J ) 1.1, 4.9 Hz, 2H), 3.48 (t, J ) 6.0 Hz, 2H),
2.37-2.31 (m, 2H), 1.91-1.83 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 142.9, 142.0, 133.1, 133.0, 131.6, 128.1, 127.6, 99.8,
92.1, 49.8, 46.5, 27.1, 26.9; HRMS ES m/z (M + Na)+ calcd
385.9682, obsd 385.9665.
8442 J. Org. Chem., Vol. 71, No. 22, 2006

Response of Bicyclic Sultam and Lactam Dienes to Photoexcitation
4.18 (m, 1.4H), 4.05 (dd, J ) 0.5, 15.5 Hz, 0.4H), 3.90 (dd, J )
3.5, 16.5 Hz, 1H), 3.31 (q, J ) 4.0 Hz, 1H), 3.23-3.22 (m, 0.4H),
3.14 (dt, J ) 4.5, 16.0 Hz, 1H), 2.97-2.93 (m, 0.4H), 2.87-2.81
(m, 0.4H), 2.60 (ddd, J ) 4.0, 7.0, 16.0 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 139.4, 138.4, 138.0, 137.9, 132.4, 131.8, 129.5,
129.2, 128.1, 124.1, 123.8, 53.2, 52.9, 52.18, 52.12, 51.6, 50.1,
47.4, 46.6, 44.0, 39.2, 36.2, 35.3.
of DMF and deoxygenated with argon for 30 min. Palladium acetate
(200 mg, 0.88 mmol) was added, and the reaction mixture was
heated to 75-80 °C, stirred for 16 h, cooled, and filtered through
Celite. Ethyl acetate was added, and the organic layer was washed
exhaustively with water and brine prior to drying and concentra-
tion. The residue was chromatographed on silica gel to yield 670
mg (38%) of 24, a pale orange oil: IR (neat, cm-1) 1649, 1601,
1
8-Thia-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6,10,12-pen-
taene 8,8-Dioxide (9). To a solution of dibromide 19 (500 mg,
1.26 mmol) in 7 mL of dry THF was added 1 M TBAF in THF
(6.3 mL, 6.3 mmol). The resulting mixture was allowed to stir
vigorously at rt for 1 h. The organic phase was washed with water
and brine, dried, and concentrated. The residue was chromato-
graphed on silica gel (elution with 20:1 hexane/ethyl acetate) to
give 9 (178 mg, 57%) as a white solid: mp 84.1-84.2 °C; IR (neat,
1483; H NMR (300 MHz, CDCl3) δ 7.95 (dd, J ) 1.8, 7.5 Hz,
1H), 7.44-7.32 (m, 2H), 7.19 (dd, J ) 1.8, 7.5 Hz, 1H), 5.53-
5.51 (m, 2H), 4.61-4.51 (m, 1H), 3.87 (dd, J ) 2.4, 13.5 Hz, 1H),
3.69 (d, J ) 13.5 Hz, 1H), 3.56 (s, 1H), 3.31 (ddd, J ) 2.0, 7.7,
13.5 Hz, 1H), 2.87-2.76 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
168.3, 144.0, 131.7, 131.4, 130.5, 129.1, 127.5, 125.0, 123.7, 47.5,
46.6, 43.3, 25.5; HRMS ES m/z (M)+ calcd 199.0991, obsd
199.1006.
cm-1) 1635, 1598, 1568; H NMR (500 MHz, CDCl3) δ 7.88 (m,
9-Azatricyclo[7.4.1.02,7]tetradeca-2,4,6,12-tetraen-8-one (23):
1
1H), 7.47 (m, 1H), 7.31 (m, 2H), 6.58 (d, J ) 9.0 Hz, 1H), 6.41 (t,
J ) 9.5 Hz, 1H), 6.03 (dd, J ) 7.5, 10.5 Hz, 1H), 5.59 (t, J ) 8.5
Hz, 1H), 4.86 (m, 1H), 4.20 (dd, J ) 5.0, 9.0 Hz, 1H), 3.20 (d, J
) 14.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 137.2, 135.8,
135.2, 132.5, 131.9, 131.0, 127.2, 125.0, 124.3, 114.2, 47.9, 39.8;
HRMS ES m/z (M + Na)+ calcd 256.0408, obsd 256.0406; λ 250
(ꢀ 28 210) and 269 nm (ꢀ 33 190).
isolated as 654 mg (37%) of a pale reddish oil; IR (neat, cm-1
)
1
1657, 1603, 1471; H NMR (300 MHz, CDCl3) δ 7.99 (dd, J )
1.5, 8.8 Hz, 1H), 7.42-7.31 (m, 1H), 7.16 (dd, J ) 1.5, 8.8 Hz,
1H), 5.60-5.53 (m, 2H), 5.16 (dd, J ) 2.4, 17.1 Hz, 1H), 3.69-
3.53 (m, 3H), 3.12-3.06 (m, 1H), 2.79-2.68 (m, 1H), 2.31-2.23
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 167.1, 147.7, 131.5, 129.8,
128.9, 127.4, 127.1, 126.0, 125.3, 50.9, 50.0, 37.8, 32.7; HRMS
ES m/z (M)+ calcd 199.0991, obsd 199.1006.
N-Allyl-2-iodo-N-(pent-4-enyl)benzamide (21). N-Allylpent-
4-en-1-amine (1.7 g, 13.6 mmol), triethylamine (2.5 mL, 18.6
mmol), and DMAP (cat.) were dissolved in 55 mL of ether/
dichloromethane (1:1) and brought to 0 °C under an argon
atmosphere. 2-Iodobenzoyl chloride (3.26 g, 12.24 mmol) dissolved
in dichloromethane (5 mL) was added dropwise over 30 min. The
reaction mixture was allowed to warm to rt overnight. Workup
consisted of washing the organic layer with 100 mL of 1 M HCl,
saturated NaHCO3 solution, and brine and then drying. Purification
of the residue on silica gel (elution with 3:1 hexane/ethyl acetate)
9-Azatricyclo[7.3.2.02,7]tetradeca-2,4,6,13-tetraen-8-one (25):
isolated as 266 mg (15%) of a pale yellow oil; IR (neat, cm-1
)
1
1662, 1630, 1602, 1458; H NMR (300 MHz, CDCl3) δ 8.04-
8.01 (m, 1H), 7.44-7.33 (m, 2H), 7.21-7.19 (m, 1H), 6.94 (dt, J
) 3.2, 12.5 Hz, 1H), 5.49-5.44 (m, 1H), 3.69 (d, J ) 3.8 Hz,
2H), 3.00-2.93 (m, 1H), 2.35-2.19 (m, 4H), 1.60-1.47(m, 1H);
13C NMR (100 MHz, CDCl3) δ 168.2, 147.8, 135.5, 131,7, 129.4,
129.3, 127.2, 125.5, 122.3, 53.7, 37.6, 32.8, 27.0.
12(S*),13(S*)-Dibromo-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6-
trien-8-one (26). A solution of 23 (25 mg, 0.125 mmol) in
dichloromethane (5 mL) was brought to 0 °C. Bromine (40 µL,
0.25 mmol) was introduced, and the reaction mixture was allowed
to warm to rt overnight. A 10% NaHSO3 solution was added until
the color was discharged. The organic layer was separated, washed
with water and brine, and then dried to leave a residue that was
purified on silica gel (elution with 95:5 hexane/ethyl acetate) to
give 40 mg (90%) of a waxy solid that was crystallized from
chloroform as colorless needles: mp 132-136 °C; IR (CHCl3,
cm-1) 1653, 1558, 1540; 1H NMR (500 MHz, CDCl3) δ 7.95 (dd,
J ) 2.0, 6.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.36 (dd, J ) 2.0, 6.0
Hz, 1H), 4.63 (dd, J ) 7.0, 9.5 Hz, 1H), 4.60-4.55 (m 1H), 4.20
(dt, J ) 1.5, 10.0 Hz, 1H), 3.86 (dd, J ) 2.0, 14.5 Hz, 1H), 3.69
(dd, J ) 2.0, 14.5 Hz, 1H), 3.47 (td, J ) 2.0, 7.0 Hz, 1H), 3.04
(ddd, J ) 3.0, 6.5, 13.5 Hz, 1H), 2.94 (dddd, J ) 2.0, 3.0, 7.0,
15.5 Hz, 1H), 2.53-2.45 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
167.6, 140.3, 130.9, 130.3, 130.2, 128.4, 127.9, 60.6, 53.1, 47.8,
44.3, 43.2, 36.9; HRMS ES m/z (M + H) calcd 359.9422, obsd
359.9412.
provided 4.0 g (92%) of 21 as a colorless oil: IR (neat, cm-1
)
1
1637, 1584, 1424; H NMR (500 MHz, CDCl3) δ 7.82-7.79 (m,
1H), 7.39-7.32 (m, 1H), 7.19 (ddd, J ) 1.5, 7.5, 12.0 Hz, 1H),
7.05 (ddd, J ) 1.5, 7.5, 12.0 Hz, 1H), 6.00-5.81 (m, 1H), 5.71-
5.54 (m, 1H), 5.34-4.85 (m, 4H), 4.48-4.46 (m, 0.3H), 3.89-
3.82 (m, 1H), 3.69 (d, J ) 5.0 Hz, 1H), 3.16-3.09 (m, 1.5H), 2.17
(s, 1H), 1.85-1.51 (m, 3.0H); 13C NMR (125 MHz, CDCl3) δ
170.4, 170.3, 142.48, 142.44, 139.1, 139.0, 137.8, 136.9, 132.9,
129.9, 128.0, 127.1, 126.9, 118.0, 117.7, 115.2, 115.0, 92.7, 92.5,
51.3, 47.3, 46.9, 44.1, 31.2, 30.5, 27.1, 26.0; HRMS ES m/z (M +
Na)+ calcd 378.0325, obsd 378.0325.
(Z)-(3,4-Dihydro-2H-azepin-1(7H)-yl)(2-iodophenyl)metha-
none (22). A solution of 21 (500 mg, 1.41 mmol) in 50 mL of
dichloromethane was deoxygenated with argon for 30 min then
heated to reflux. Grubbs generation I catalyst (17.3 mg, 0.021 mmol)
was added, and the reaction mixture was refluxed for 36 h. After
cooling, lead tetraacetate (13.4 mg, 0.029 mmol) was introduced,
and the mixture was stirred for an additional 6 h, concentrated,
and purified on silica gel (elution with 4:1 hexane/ethyl acetate)
producing 300 mg (60%) of 22 as a viscous white semisolid: IR
11,12-Dibromo-9-azatricyclo[7.4.1.02,7]tetradeca-2,4,6-trien-
8-one (27). A solution of 24 (810 mg, 4.07 mmol) in neat bromine
(3 mL) was stirred overnight. The residual bromine was removed
under a stream of air. The residue was taken up into dichlo-
romethane and washed with 10% NaHSO3 solution until the organic
layer was colorless. This solution was dried and evaporated to leave
1.4 g (98%) of 27 as a white foam: IR (neat, cm-1) 1660, 1601,
1
(neat, cm-1) 1635, 1473, 1425; H NMR (500 MHz, CDCl3) δ
7.82-7.81 (m, 1H), 7.38-7.33 (m, 1H), 7.19-7.16 (m, 1H), 7.07-
7.03 (m, 1H), 5.92-5.87 (m, 0.5H), 5.85-5.81 (m, 1H), 5.41-
5.37 (m, 0.5H), 4.44-4.40 (m, 0.5H), 4.25-4.20 (m, 0.5H), 4.07-
4.04 (m, 0.5H), 3.84-3.80 (m, 0.5H), 3.70-3.65 (m, 0.5H), 3.54-
3.49 (m, 0.5H), 3.39-3.35 (m, 1H), 2.35-2.27 (m, 2H), 2.03-
1.96 (m, 1H), 1.81-1.72 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
170.3, 169.8, 142.8, 142.7, 139.2, 139.1, 132.9, 132.0, 129.93,
129.92, 128.1, 128.0, 127.5, 127.1, 127.0, 126.5, 92.7, 92.6, 50.6,
47.8, 46.1, 42.4, 27.0, 26.9, 25.8; HRMS ES m/z (M + Na)+ calcd
350.0012, obsd 350.0026.
1
1475; H NMR (500 MHz, CDCl3) δ 8.04 (dd, J ) 1.0, 7.5 Hz,
1H), 7.47 (td, J ) 1.0, 7.5 Hz, 1H), 7.41 (td, J ) 1.0, 7.5 Hz, 1H),
7.33 (d, J ) 7.5 Hz, 1H), 4.96 (t, J ) 1.5 Hz, 1H), 4.69 (dd, J )
3.5, 6.0 Hz, 1H), 4.52-4.45 (m, 1H), 3.74-3.71 (m, 2H), 3.63 (s,
1H), 3.39 (dd, J ) 7.5, 14.0 Hz, 1H), 3.10-3.03 (m, 1H), 2.17-
2.11 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 168.3, 140.7, 132.1,
131.3, 128.9, 128.4, 127.3, 58.6, 48.5, 47.0, 44.2, 43.7, 28.0; HRMS
ES m/z (M + Na)+ calcd 379.9261, obsd 379.9246.
Heck Cyclization of 22. 9-Azatricyclo[7.4.1.02,7]tetradeca-
2,4,6,11-tetraen-8-one (24). DMF was degassed under high vacuum
for 30 min to remove any traces of dimethylamine. Lactam 22 (3.35
g, 8.85 mmol), triphenylphosphine (464 mg, 1.77 mmol), K2CO3
(2.44 g, 17.7 mmol), and 4 Å MS (500 mg) were added to 150 mL
9-Azatricyclo[7.4.1.02,7]tetradeca-2,4,6,10,12-pentaen-8-one (10).
A solution of 27 (480 mg, 1.28 mmol) in 15 mL of dry DMSO
J. Org. Chem, Vol. 71, No. 22, 2006 8443

Paquette et al.
was treated with 1 M TBAF/THF (5.13 mL, 5.13 mmol) in one
portion, and the mixture was heated at 110 °C for 25 min, cooled,
and diluted with ethyl acetate. The organic layer was washed
exhaustively with water and brine, dried, and evaporated. The
residue was chromatographed on silica gel to yield 190 mg (74%)
syringe, stirred for 16 h, cooled to rt, and treated with lead
tetraacetate (95.4 mg, 0.216 mmol). After an additional 6 h of
stirring, the reaction mixture was concentrated and passed rapidly
through a plug of silica gel (elution with 4:1 hexane/ethyl acetate)
to yield 4.28 g (92%) of 32 as an off-white solid: mp 73-75 °C;
IR (neat, cm-1) 1632, 1476, 1418; 1H NMR (500 MHz, CDCl3) δ
7.82-7.80 (m, 1.3H), 7.38-7.35 (m, 1.3H), 7.24 (dd, J ) 1.5, 7.5
Hz, 0.3H), 7.16 (dd, J ) 1.5, 7.5 Hz, 1H), 7.06-7.02 (m, 1.3H),
5.89-5.80 (m, 1H), 5.72-5.64 (m, 1.3H), 4.01 (s, 0.3H), 3.89 (m,
1H), 3.34 (s, 0.3H), 3.24-3.11, (m, 4H), 2.39 (q, J ) 6.0 Hz, 0.6H),
2.28-2.03 (m, 6H), 1.81-1.74 (m, 1H), 1.29-1.23 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 171.1, 170.8, 143.3, 142.6, 139.1, 139.0,
132.3, 130.1, 129.9, 129.7, 129.4, 128.1, 127.8, 127.7, 127.5, 127.1,
93.1, 92.6, 51.2, 48.4, 48.2, 46.7, 28.2, 27.1, 26.3, 25.7, 24.2, 23.4;
HRMS ES m/z (M + Na)+ calcd 364.0174, obsd 364.0185.
9-Azatricyclo[7.4.2.02,7]pentadeca-2,4,6,12-tetraen-8-one (33).
DMF was degassed under high vacuum for 30 min to remove any
residual dimethylamine. Lactam 33 (4.28 g, 12.5 mmol), triphen-
ylphosphine (655 mg, 2.5 mmol), K2CO3 (3.46 g, 25.1 mmol), and
4 Å MS (500 mg) were added to 200 mL of DMF and deoxygenated
further with Ar for 30 min. Pd(OAc)2 (280 mg, 1.25 mmol) was
introduced, and the mixture was heated to 75-80 °C overnight prior
to cooling, filtration through Celite, dilution with ethyl acetate, and
extensive washing with water and brine. The organic layer was
dried and evaporated, and the residue was purified over silica gel
to give 270 mg (10%) of a reddish oil alongside 670 mg of
recovered 32. For 33: IR (neat, cm-1) 1627, 1521, 1468; 1H NMR
(500 MHz, CDCl3) δ 7.72-7.70 (m, 1H), 7.37-7.31 (m, 2H),
7.16-7.14 (m, 1H), 5.86-5.82 (m, 1H), 5.68-5.61 (m, 1H), 5.29-
5.24 (m, 1H), 3.46 (dd, J ) 5.0, 17.3 Hz, 1H), 3.43-3.38 (m, 1H),
3.30-3.25 (m, 1H), 3.18 (dd, J ) 7.3, 15.0 Hz, 1H), 2.76-2.68
(m, 1H), 2.53-2.47 (m, 1H), 2.46-2.40 (m, 1H), 1.75-1.70 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 172.5, 144.5, 135.5, 131.0,
128.9, 128.3, 127.5, 127.1, 48.9, 47.5, 39.0, 33.8, 32.6; HRMS ES
m/z (M + Na)+ calcd 236.1051, obsd 236.1049.
1
of 10 as a colorless film: IR (neat, cm-1) 1662, 1601, 1457; H
NMR (500 MHz, CDCl3) δ 8.05 (d, J ) 7.5 Hz, 1H), 7.44 (td, J
) 1.0, 7.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.12-7.11 (m, 1H), 6.15-
6.11 (m, 1H), 5.90-5.85 (m, 2H), 4.08 (dt, J ) 2.0, 13.0 Hz, 1H),
3.73-3.72 (m, 1H), 3.33 (dd, J ) 2.5, 13.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 169.4, 146.2, 140.2, 137.1, 132.1, 130.3,
129.2, 127.3, 126.4, 122.7, 121.4, 51.5, 43.9; HRMS ES m/z (M +
Na)+ calcd 220.0816, obsd 220.0801; λ 203 (ꢀ 19 765) and 203
nm (ꢀ 25 975).
N-(But-3-enyl)pent-4-enamide (29). Homoallylamine (16.89 g,
238 mmol) and DMAP (cat.) were dissolved in 800 mL of ether
under an argon atmosphere, the reaction mixture was brought to 0
°C, a solution of 4-pentenoic acid chloride (12.2 g, 108.2 mmol)
in 10 mL of dichloromethane was introduced, and stirring was
maintained for 16 h. Workup consisted of washing the reaction
mixture with 1 M HCl, saturated NaHCO3 solution, and brine prior
to drying and chromatography of the residue on silica gel (elution
with 7:3 hexane/ethyl acetate) to yield 29 as a colorless oil (8.0 g,
1
48%): IR (neat, cm-1) 3079, 2928, 1646; H NMR (500 MHz,
CDCl3) δ 5.91 (s, 1H), 5.82-5.68 (m, 2H), 5.07-4.94 (m, 4H),
3.28 (q, J ) 7.0 Hz, 2H), 2.36-2.32 (m, 2H), 2.28 (t, J ) 7.0 Hz,
4H); 13C NMR (125 MHz, CDCl3) δ 172.2, 136.9, 135.2, 116.9,
115.3, 38.3, 35.7, 33.6, 29.5; HRMS ES m/z (2M + Na)+ calcd
329.2199, obsd 329.2216.
N-(But-3-enyl)pent-4-en-1-amine (30). Amide 29 (8.0 g, 52.2
mmol) was dissolved in 300 mL of ether under argon and brought
to 0 °C. Lithium aluminum hydride (4.0 g, 104.5 mmol) was added
portionwise over 20 min. The reaction mixture was stirred for 16
h, sequentially quenched with 4 mL of water, 4 mL of 2 M NaOH
solution, and 12 mL of water, and stirred for an additional 3 h.
After filtration and drying, the ether was distilled off to leave 7.2
g (99%) of 30 as a colorless oil: IR (neat, cm-1) 3299, 1458, 1127;
1H NMR (300 MHz, CDCl3) δ 5.85-5.69 (m, 2H), 5.09-4.90 (m,
4H), 2.62 (dt, J ) 7.4, 17.0 Hz, 4H), 2.23 (qt, J ) 1.2, 7.0 Hz,
2H), 2.10-2.02 (m, 2H), 1.56 (quintet, J ) 7.5 Hz, 2H), 1.06 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 138.4, 136.4, 116.1, 114.5,
49.2, 48.7, 34.2, 31.5, 29.1; HRMS ES m/z (M)+ calcd 139.1355,
obsd 139.1359.
N-(But-3-enyl)-2-iodo-N-(pent-4-enyl)benzamide (31). Amine
30 (7.2 g, 51.9 mmol), diisopropylethylamine (9.03 mL, 51.9
mmol), and DMAP (cat.) were dissolved in 600 mL of ether and
brought to 0 °C under an argon atmosphere. 2-Iodobenzoyl chloride
(12.5 g, 47.2 mmol) was dissolved in dichloromethane (10 mL)
and introduced to the ethereal solution via syringe over 1 h. The
reaction mixture was allowed to warm to rt overnight and washed
with 1 M HCl, saturated NaHCO3 solution, water, and brine prior
to drying and chromatography on silica gel (elution with 4:1 hexane/
ethyl acetate) to yield 14.37 g (82%) of 31 as a yellowish oil: IR
(neat, cm-1) 1637, 1425, 1301; 1H NMR (400 MHz, CDCl3) δ 7.81
(dd, J ) 1.2, 8.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.19 (dt, J ) 1.6,
7.2 Hz, 1H), 7.06 (dt, J ) 1.6, 7.2 Hz, 1H), 5.95-5.82 (m, 1H),
5.64-5.49 (m, 1H), 5.19-4.87 (m, 4H), 3.81-3.79 (m, 1H), 3.37-
3.04 (m, 3H), 2.56-2.46 (m, 1H), 2.29-2.18 (m, 2H), 1.89-1.81
(m, 2H), 1.66-1.51 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
170.45, 170.44, 142.6, 139.14, 139.11, 137.8, 136.9, 135.4, 134.1,
129.93, 129.90, 128.11, 128.10, 127.4, 127.1, 117.4, 116.7, 115.3,
115.1, 92.78, 92.76, 48.3, 48.1, 44.34, 44.30, 32.9, 31.5, 31.1, 30.6,
27.5, 26.1; HRMS ES m/z (M + Na)+ calcd 392.0481, obsd
392.0488.
9-Azatricyclo[7.4.2.02,7]pentadeca-2,4,6,11-tetraen-8-one (34):
also isolated was 34 as a yellowish oil (543 mg, 20%); IR (neat,
1
cm-1) 1644, 1462, 1450; H NMR (400 MHz, CDCl3) δ 7.65-
7.63 (m, 1H), 7.41-7.32 (m, 2H), 7.16-7.14 (m, 1H), 5.74-5.69
(m, 1H), 5.63-5.55 (m, 1H), 4.43-4.34 (m, 1H), 3.74-3.71 (m,
1H), 3.52-3.43 (m, 1H), 3.29 (dd, J ) 7.2, 15.0 Hz, 1H), 2.25-
2.18 (m, 1H), 1.96 (quintet, J ) 6.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 172.9, 140.4, 136.6, 136.1, 131.1, 128.7, 127.7, 127.6,
122.5, 46.4, 45.4, 44.3, 33.5, 26.8; HRMS ES m/z (M + Na)+ calcd
236.1051, obsd 236.1046.
12,13-Dibromo-9-azatricyclo[7.4.2.02,7]pentadecatrien-8-one
(35). Lactam 33 (30 mg, 0.139 mmol) was dissolved in dichlo-
romethane (2 mL) at 0 °C and placed under an argon atmosphere,
treated with bromine (14 µL, 0.278 mmol) via syringe, and allowed
to warm to rt over 16 h. The next morning, 10% NaHSO3 solution
was added until the reaction mixture turned colorless. The separated
organic layer was washed with water and brine and then dried.
After evaporation, the residue was chromatographed on silica gel
(elution with 4:1 hexane/ethyl acetate) to furnish 23 mg (44%) of
35 as a waxy yellow solid: IR (neat, cm-1) 1638, 1470, 1452; 1H
NMR (500 MHz, CDCl3) δ 7.74-7.72 (m, 0.3H), 7.71-7.69 (m,
1H), 7.42-7.35 (m, 2.6H), 7.17-7.16 (m, 1.6H), 4.46-4.43 (m,
0.3H), 3.50-3.34 (m, 4H), 3.30-3.26 (m, 0.3H), 3.23 (dd, J )
11.0, 14.5 Hz, 1H), 3.13 (dd, J ) 6.7, 15.0 Hz, 1H), 2.73-2.56
(m, 0.9H), 2.47-2.40 (m, 1H), 2.30-2.23 (m, 1H), 1.98-1.92 (m,
0.6), 1.90-1.83 (m, 1.3H); 13C NMR (125 MHz, CDCl3) δ 173.6,
171.5, 142.8, 142.0, 135.2, 134.7, 131.5, 131.2, 129.4, 128.8, 128.5,
128.4, 127.92, 127.90, 74.14, 61.5, 55.2, 55.1, 53.6, 50.4, 48.4,
45.2, 42.5, 40.7, 40.0; HRMS ES m/z (M + Na)+ calcd 395.9398,
obsd 395.9395.
(Z)-(2-Iodophenyl)(3,4,7,8-tetrahydroazocin-1(2H)-yl)metha-
none (32). Amide 31 (5.0 g, 13.5 mmol) was dissolved in 1 L of
dichloromethane and deoxygenated with Ar for 1 h. The reaction
mixture was heated to reflux and treated with Grubbs generation I
catalyst (89 mg, 0.108 mmol) in 2 mL of dichloromethane via
11,12-Dibromo-9-azatricyclo[7.4.2.02,7]pentadeca-2,4,6-trien-
8-one (36). A solution of 34 (543 mg, 2.54 mmol) in dichlo-
romethane (25 mL) was cooled to 0 °C and placed under an argon
atmosphere, treated with bromine (262 µL, 5.09 mmol) via syringe,
8444 J. Org. Chem., Vol. 71, No. 22, 2006

Response of Bicyclic Sultam and Lactam Dienes to Photoexcitation
and allowed to warm to rt overnight. The next morning, 10%
NaHSO3 solution was added until the reaction mixture turned a
light yellow. The separated organic layer was washed exhaustively
with water and brine, dried, and evaporated to leave 36 as a sticky
yellow foam (650 mg, 68%): IR (neat, cm-1) 1653, 1450, 1410;
1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J ) 1.0, 7.5 Hz, 1H),
7.46 (dt, J ) 1.5, 7.5 Hz, 1H), 7.41 (dt, J ) 1.5, 7.0 Hz, 1H),
7.36-7.35 (m, 1H), 4.58-4.53 (m, 1H), 4.36 (dd, J ) 3.0, 8.5 Hz,
1H), 4.19 (dd, J ) 8.0, 12.0 Hz, 1H), 3.39-3.28 (m, 3H), 3.06
(ddd, J ) 5.5, 10.5, 10.5 Hz, 1H), 2.63-2.51 (m, 2H), 2.33-2.24
(m, 1H), 1.90-1.83 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 162.9,
139.9, 131.6, 129.1, 128.6, 128.0, 127.4, 60.6, 44.6, 43.7, 40.7,
35.0, 31.0, 30.9; HRMS ES m/z (M + H)+ calcd 371.9593, obsd
371.9594.
1H), 6.21 (s, 1H), 6.12 (d, J ) 2.0 Hz, 1H), 5.06 (s, 1H), 4.34 (d,
J ) 13 Hz, 1H), 3.84 (dd, J ) 3.5, 13 Hz, 1H), 3.34 (s, 1H), 2.98
(d, J ) 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.9, 139.6,
136.6, 135.9, 132.5, 128.6, 127.5, 126.3, 64.0, 55.9, 52.0, 39.3;
HRMS ES m/z (M + Na)+ calcd 256.0408, obsd 256.0385.
Photoisomerization of 10. A solution of 10 (140 mg, 0.7 mmol)
in 750 mL of hexane was placed in a quartz reaction vessel. The
reaction mixture was deoxygenated with Ar and irradiated at 3000
Å in a Rayonet reactor for 30 min. After concentration and
purification of the residue on 10% deactivated silica gel (elution
with 20:1 dichloromethane/ethyl acetate), 39 was isolated as a
yellowish oil (53 mg, 38%): IR (neat, cm-1) 1702, 1659, 1601,
1
1458; H NMR (500 MHz, CDCl3) δ 7.99 (d, J ) 8.0 Hz, 1H),
7.49 (dt, J ) 1.5, 7.5 Hz, 1H), 7.33 (dt, J ) 1.5, 7.5 Hz, 1H), 7.22
(d, J ) 7.5 Hz, 1H), 6.23 (d, J ) 2.0 Hz, 1H), 6.16 (d, J ) 2.0 Hz,
1H), 4.31 (s, 1H), 3.53 (dd, J ) 3.0, 12.5 Hz, 1H), 3.49 (d, J )
12.5 Hz, 1H), 3.29 (s, 1H), 2.90 (d, J ) 3.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 181.4, 148.1, 139.1, 136.6, 133.8, 130.1,
128.7, 127.5, 126.2, 67.3, 54.6, 54.1, 38.8; HRMS ES m/z (M +
Na)+ calcd 220.0738, obsd 220.0728.
9-Azatricyclo[7.4.2.02,7]pentadeca-2,4,6,10,12-pentaen-8-one
(11). A solution of 36 (250 mg, 0.642 mmol) in DMSO (10 mL)
was treated with 1 M TBAF/THF (2.57 mL) and heated to 110 °C
for 25 min, cooled to rt, added to 20 mL of ethyl acetate, and
washed exhaustively with water and brine. The organic layer was
dried and evaporated to leave a residue that was purified over silica
gel (elution with ethyl acetate) to yield 98 mg (73%) of 11 as an
off-white solid: mp 132-134 °C; IR (neat, cm-1) 1648, 1620, 1593;
1H NMR (500 MHz, CDCl3) δ 8.45 (d, J ) 9.0 Hz, 1H), 7.75 (d,
J ) 8.5 Hz, 1H), 7.65-7.62 (m, 1H), 7.44 (t, J ) 7.5 Hz, 1H),
6.81 (dd, J ) 11.0, 4.0 Hz, 1H), 5.56 (dd, J ) 1.0, 11.0 Hz, 1H),
5.41 (dd, J ) 1.5, 17.5 Hz, 1H), 4.23 (t, J ) 7.0 Hz, 2H), 3.20 (t,
J ) 7.5 Hz, 2H), 2.18 (quintet J ) 7.5 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 160.8, 141.3, 136.9, 131.9, 130.9, 127.5, 125.6,
124.9, 123.0, 118.9, 110.1, 48.3, 31.5, 21.8; HRMS ES m/z (M +
H)+ calcd 212.1075, obsd 212.1063; λ 214 (ꢀ 14 645), 232 (ꢀ
13 335), and 296 nm (ꢀ 7775).
2,4-Divinyl-3,4-dihydro-2H-isoquinolin-1-one (40). A solution
of 39 (20 mg, 0.1 mmol) in 100 mL of hexane was placed in a
quartz reaction vessel. The reaction mixture was deoxygenated with
Ar and irradiated at 3000 Å in a Rayonet reactor for 60 min. After
concentration and purification of the residue on 10% deactivated
silica gel (elution with 20:1 dichloromethane/ethyl acetate), 4 mg
(20%) of 40 was recovered as a yellowish film: IR (neat, cm-1
)
1
3285, 1665, 1473; H NMR (500 MHz, CDCl3) δ 8.15 (dd, J )
1.0, 8.0 Hz, 1H), 7.70 (dd, J ) 9.5, 17.0 Hz, 1H), 7.50 (dt, J )
1.5, 7.5 Hz, 1H), 7.40 (dt, J ) 1.0, 7.5 Hz, 1H), 7.24 (d, J ) 7.5
Hz, 1H), 5.92 (ddd, J ) 7.5, 10.5, 17.5 Hz, 1H), 5.27 (d, J ) 10.0
Hz, 1H), 5.14 (d, J ) 17.5 Hz, 1H), 4.61 (dd, J ) 1.0, 16.5 Hz,
1H), 4.57 (dd, J ) 1.5, 9.2 Hz, 1H), 3.81-3.74 (m, 2H), 3.67 (dd,
J ) 6.5, 11.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 162.2, 139.6,
136.8, 131.46, 132.43, 129.0, 128.4, 127.5, 126.6, 118.6, 93.9, 46.5,
41.4; HRMS ES m/z (M + Na)+ calcd 222.0895, obsd 222.0891.
Photoisomerization of 9. A sample of 9 (40 mg, 0.17 mmol)
was dissolved in 170 mL of hexane (0.001 M) and placed in a
quartz reaction vessel. The sample required 15 min of sonication
to completely dissolve the reactant. The reaction mixture was then
deoxygenated with Ar and irradiated at 3000 Å in a Rayonet reactor
for 30 min. Concentration and purification of the residue on silica
gel (elution with 1:1 hexane/ethyl acetate) yielded 37 as a crystalline
solid (20 mg, 50%): mp 196-198 °C; IR (neat, cm-1) 3372, 1633,
Acknowledgment. We are grateful to the Astellas USA
Foundation for financial support, Dr. Judith Gallucci for the
X-ray crystallographic analyses, Lydia Mateos Buron for early
experiments, and Shuzhi Dong for computational contributions.
1
1582; H NMR (500 MHz, CDCl3) δ 7.83 (d, J ) 7.7 Hz, 1H),
7.62 (td, J ) 1.0, 7.7 Hz, 1H), 7.53-7.50 (m, 2H), 7.01 (dd, J )
2.2, 8.0 Hz, 1H), 6.62 (t, J ) 7.2 Hz, 1H), 5.10 (s, 1H), 4.89 (m,
1H), 4.24 (qd, J ) 2.2, 7.0 Hz, 1H), 3.97 (d, J ) 7.1 Hz, 1H), 3.09
(qd, J ) 2.7, 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 142.0,
139.2, 135.3, 133.1, 130.8, 129.3, 129.2, 125.3, 121.6, 93.1, 50.3,
45.5; HRMS ES m/z (M + Na)+ calcd 256.0405, obsd 256.0417.
Supporting Information Available: ORTEP diagram and tables
of X-ray crystal data, atomic coordinates, bond lengths, and bond
angles for 26 and 37, as well as high-field 1H and 13C NMR spectra
of all new compounds reported herein. This material is available
free of charge via the Internet at http://pubs.acs.org.
Also isolated was 38 as a colorless oil (3 mg, 5%): IR (neat, cm-1
1595, 1568, 1472; H NMR (500 MHz, CDCl3) δ 7.78 (dd, J )
0.5, 7.3 Hz, 1H), 7.45-7.41 (m, 2H), 7.20 (dd, J ) 0.5, 7.5 Hz,
)
1
JO061404Y
J. Org. Chem, Vol. 71, No. 22, 2006 8445