Intramolecular 1,3-dipolar cycloadditions of norbornadiene-tethered nitrones

Article abstract of DOI:10.1021/jo015610b

Efficient routes to the synthesis of norbornadiene-tethered nitrones have been developed, and their intramolecular 1,3-dipolar cycloadditions were studied. The cycloadditions occurred in moderate to good yields for a variety of substrates and were found to be highly regio- and stereoselective, giving single regio- and stereoisomers in most cases.

Full text of DOI:10.1021/jo015610b

J . Org. Chem. 2001, 66, 5113-5123
5113
In tr a m olecu la r 1,3-Dip ola r Cycloa d d ition s of
Nor bor n a d ien e-Teth er ed Nitr on es†
Geoffrey K. Tranmer and William Tam*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry
and Biochemistry, University of Guelph, Guelph, Ontario, Canada N1G 2W1
wtam@uoguelph.ca
Received March 2, 2001
Efficient routes to the synthesis of norbornadiene-tethered nitrones have been developed, and their
intramolecular 1,3-dipolar cycloadditions were studied. The cycloadditions occurred in moderate
to good yields for a variety of substrates and were found to be highly regio- and stereoselective,
giving single regio- and stereoisomers in most cases.
Sch em e 1. In tr a m olecu la r 1,3-Dip ola r
In tr od u ction
Cycloa d d ition s of Nor bor n a d ien e-Teth er ed Nitr ile
Oxid es
Intramolecular cycloadditions with high regio- and
stereocontrol are important tools for the efficient as-
sembly of complex molecular structures. We have re-
cently initiated a program on the study of various types
of intramolecular cycloadditions of substituted norbor-
nadienes.1,2 For example, norbornadiene-tethered nitrile
oxides 2 undergo highly regio- and stereoselective in-
tramolecular cycloadditions to provide single regio- and
stereoisomers 3 in good yields (Scheme 1).1 Our long-term
goal is to develop an efficient route for the construction
of angular fused tricyclic frameworks and spirocyclic
frameworks with high regio- and stereocontrol (Scheme
2). Unlike nitrile oxides that belong to the linear prop-
argyl-type 1,3-dipole, nitrones belong to the bent allyl-
type 1,3-dipole. The 1,3-dipolar cycloaddition of a nitrone
is usually more complicated than that of a nitrile oxide
as an additional stereocenter is generated in the nitrone
cycloaddition. 1,3-Dipolar cycloadditions of nitrones are
well-documented and provide efficient entries to the
synthesis of isoxazolidines, which are valuable interme-
diates in organic synthesis.3,4 In this paper, we report
our results on the intramolecular 1,3-dipolar cycloaddi-
tions of norbornadiene-tethered nitrones (Scheme 3).2
Sch em e 2. Gen er a l Ou tlin e for Con str u ction of
Tr icyclic a n d Sp ir ocyclic F r a m ew or k s via
In tr a m olecu la r Cycloa d d ition s of Nor bor n a d ien es
a n d Su bsequ en t Clea va ge of th e Cycloa d d u cts
* To whom all correspondence should be sent. Phone: (519) 824-
4120 (ext 2268). Fax: (519) 766-1499.
† Dedicated to Professor Gord Lange on the occasion of his retire-
ment.
(1) (a) Yip, C.; Handerson, S.; J ordon, R.; Tam, W. Org. Lett. 1999,
1, 791. (b) Yip, C.; Handerson, S.; Tranmer, G. K.; Tam, W. J . Org.
Chem. 2001, 66, 276.
(2) Preliminary results of this work have been published as a
communication: Tranmer, G. K.; Keech, P.; Tam, W. Chem. Commun.
2000, 863.
Four different types of regioisomers could be formed
from the intramolecular 1,3-dipolar cycloaddition of the
norbornadiene-tethered nitrone 13 (Scheme 4). Cycload-
dition on the C2-C3 double bond could occur with the
oxygen of the nitrone attached to C3 and the sp2 carbon
of the nitrone attached to C2 to give cycloadducts 14-
17. Cycloaddition on the C2-C3 double bond could also
occur with the oxygen of the nitrone attached to C2 and
the sp2 carbon of the nitrone attached to C3 to give
cycloadduct 18. Cycloaddition on C5-C6 double bond
would give 19 or 20, and a [3 + 2 + 2] cycloaddition with
both of the double bonds would give cycloadduct 21. Other
than regiochemistry problems, different stereoisomers
are also possible. For example, cycloaddition on the C2-
C3 double bond from the exo face with the oxygen of the
nitrone attached to C3 and the sp2 carbon of the nitrone
(3) (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; J ohn
Wiley & Sons: New York, 1984; Vols. 1 and 2. (b) Gothelf, K. V.;
J orgensen, K. A. Chem. Rev. 1998, 98, 863 and references therein. (c)
Padwa, A.; Schoffstall, A. M. Intramolecular 1,3-Dipolar Cycloaddition
Chemistry. In Advances in Cycloaddition; Curran, D. P., Ed.; J AI
Press: Greenwich, 1990; pp 1-89. (d) Grigg, R. Chem. Soc. Rev. 1987,
16, 89.
(4) (a) Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis;
Torssell, K. B. G., Ed.; VCH: New York, 1988. (b) DeShong, P.; Lander,
S. W., J r.; Leginus, J . M.; Dicken, C. M. In Advances in Cycloaddition;
Curran, D. P., Ed.; J AI Press: Greenwich, 1988; Vol. 1, pp 87-128.
(c) Wade, P. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming I., Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp
1113-1124. (d) Frederickson M. Tetrahedron 1997, 53, 403. (e)
Westling, M.; Smith, R.; Livinghouse, T. J . Org. Chem. 1986, 51, 1159.
(f) Grigg, R.; J ordan, M.; Tangthongkum, A.; Einstein, F. W. B.; J ones,
T. J . Chem. Soc., Perkin Trans. 1 1984, 47. (g) Tsuge, O.; Ueno, K.;
Kanemasa, S. Chem. Lett. 1984, 285.
10.1021/jo015610b CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/30/2001

5114 J . Org. Chem., Vol. 66, No. 15, 2001
Tranmer and Tam
Sch em e 3. In tr a m olecu la r 1,3-Dip ola r
Cycloa d d ition s of Nor bor n a d ien e-Teth er ed
Nitr on es
Sch em e 5. Syn th esis of Nor bor n a d ien e-Teth er ed
Ald eh yd es w ith All-Ca r bon Teth er (27 a n d 28)
Sch em e 6. Syn th esis of Nor bor n a d ien e-Teth er ed
Ald eh yd es w ith a n Oxygen Atom w ith in th e
Teth er (38-40 a n d 44)
Sch em e 4. P ossible Cycloa d d u cts
attached to C2 would lead to the formation of two
different exo cycloadducts 14 or 15 while cycloaddition
from the endo face would give another two different endo
cycloadducts 16 or 17. Thus, many possible cycloadducts
could be formed in the cycloaddition of norbornadiene-
tethered nitrone 13.
Resu lts a n d Discu ssion
Efficient routes to the synthesis of norbornadiene-
tethered aldehydes 27, 28, 38-40, 44, and 48 were
developed (Schemes 5-7), and these aldehydes served as
precursors of the required nitrones for the cycloadditions.
Deprotonation of norbornadiene 22 with Schlosser’s base
(tBuOK/nBuLi)5 in THF at -78 °C followed by addition
of the resulting norbornadienyl anion to an excess of 1,4-
dibromobutane or 1,5-dibromopentane provided the nor-
bornadiene-tethered bromide 23 and 24 (Scheme 5).1
Conversion of these bromides to the corresponding alco-
hols 25 and 26 followed by Swern oxidation provided the
required aldehydes 27 and 28 with all-carbon tethers.
Norbornadiene-tethered aldehydes with an oxygen atom
within the tether were prepared using a similar protocol
(Scheme 6). Trapping the norbornadienyl anion with
paraformaldehyde, ethylene oxide, and 3-bromopropanol
provided norbornadiene-tethered alcohols 29-31. A two-
carbon homologation to the alcohols 35-37 was achieved
by a two-step sequence,6 and Swern oxidation provided
the required aldehydes 38-40. Similarly, a three-carbon
homologation of alcohol 29 to alcohol 43 was achieved in
two steps, and Swern oxidation provided aldehyde 44.
An ester functionality within the tether was prepared
from alcohol 29 (Scheme 7). Reaction of 29 with bro-
moacetyl bromide gave the R-bromo ester 45, which was
converted to the nitrate ester 47 in two steps.7,8 Treat-
ment of the nitrate ester 47 with sodium acetate in
DMSO provided the required aldehyde 48.7,8
(5) For deprotonation of bicyclic alkenes, see: (a) Stable, M.;
Lehmann, R.; Kramar, J .; Schlosser, M. Chimia 1985, 39, 229. (b)
Brandsma, L.; Verkuruijsse, H. D. Recl. Trav. Chim. Pays-Bas 1986,
105, 66. (c) Tranmer, G. K.; Yip, C.; Handerson, S.; J ordan, R. W.; Tam,
W. Can. J . Chem. 2000, 78, 527.
(6) Heinze, I.; Knoll, K.; Moller, R.; Eberbach, W. Chem. Ber. 1989,
122, 2147.

Cycloadditions of Norbornadiene-Tethered Nitrones
J . Org. Chem., Vol. 66, No. 15, 2001 5115
Ta ble 1. In tr a m olecu la r 1,3-Dip ola r Cycloa d d ition s of
Nor bor n a d ien e-Teth er ed Nitr on es
Sch em e 7. Syn th esis of Nor bor n a d ien e-Teth er ed
Ald eh yd es w ith a n Ester F u n ction a lity w ith in th e
Teth er (48)
The results of the intramolecular 1,3-dipolar cycload-
ditions of norbornadiene-tethered nitrones generated
from the aldehydes 27, 28, 38-40, 44, and 48 are shown
in Table 1. Addition of N-methylhydroxylamine to a
solution containing aldehyde 27, pyridine, and 4 Å
molecular sieves in toluene at room temperature led to
the formation of the corresponding norbornadiene-
tethered nitrone, which underwent spontaneous intramo-
lecular 1,3-dipolar cycloaddition at 80 °C to provide a
single cycloadduct 49 in 51% isolated yield (Table 1, entry
1). Very little reaction was observed at a lower temper-
ature, and prolonged heating led to decomposition of the
cycloadduct. Although many possible cycloadducts could
be formed in the reaction (Scheme 4), only cycloadduct
49 was isolated. With one more carbon in the tether
(Table 1, entry 2), the only cycloadduct isolated was 50
but the yield was only 19%. For aldehydes with an oxygen
atom within the tether (Table 1, entries 3-5), the yields
of the cycloadditions were generally much better than
the all-carbon tethered substrates. Aldehyde 38 provided
the five-membered-ring cycloadduct 51 in 71% yield,
while aldehydes 39 and 44 gave the corresponding six-
membered-ring cycloadducts 52 and 53 in 60% and 47%
yield. In all these reactions, cycloadducts 51-53 were the
only cycloadducts isolated. Cycloaddition of the nitrone
generated from aldehyde 40 led to the formation of an
inseparable mixture of three isomers in 52% overall yield
(Table 1, entry 6). Unlike all other cases in which the
cycloadditions occur in such a way that the oxygen of the
nitrone attached to C3 and the sp2 carbon of the nitrone
attached to C2, in this case with the nitrone generated
from aldehyde 40, the two major isomers formed were
found to have the opposite regiochemistry, that is, with
the oxygen of the nitrone attached to C2 and the sp2
carbon of the nitrone attached to C3, vide infra. The
switch of regiochemistry with increasing of the tether
length is not uncommon, and it has been observed in
some other intramolecular nitrone cycloadditions.9 Cy-
cloaddition of the substrate with an ester functionality
(48) within the tether (Table 1, entry 7) gave a single
cycloadduct 55 in 43% yield. As we noticed that most of
a
Reaction conditions: MeNHOH‚HCl (1.2-2 equiv), pyridine
(3-5 equiv), 4 Å molecular sieves, toluene, rt, 12-24 h then 60-
b
90 °C 12-48 h. Except in entry 6, the cycloadducts shown were
the only regio- and stereoisomers isolated in the cycloadditions.
c An inseparable mixture of three isomers was obtained. Isolated
d
yields after column chromatography.
the cycloadducts were thermally unstable and they
decomposed on prolonged heating, we attempted the
reactions at a lower temperature with the use of Lewis
acid catalysts (e.g., TiCl4, ZrCl4, BF3). Unfortunately, the
isolated yields were even lower than the thermal reac-
tions. We have also attempted to generate a six-
membered ring cycloadduct containing an ester function-
ality; unfortunately, only decomposition was observed.
The regio- and stereochemistry of the cycloadducts
were proven by NMR techniques. The presence of two
olefinic protons in the H NMR spectrum eliminated the
1
possibilities of cycloadducts 19 to 21 (Scheme 4). 13C
(APT-attached proton test) NMR spectra were useful to
distinguish the regioisomers with the oxygen of the
nitrone attached to C3 and the sp2 carbon of the nitrone
attached to C2 or the oxygen of the nitrone attached to
C2 and the sp2 carbon of the nitrone attached to C3.
Except for cycloadduct 54 in which the oxygen of the
nitrone attached to C2 and the sp2 carbon of the nitrone
attached to C3, all other cycloadducts were formed with
(7) Melnick, M. J .; Weinreb, S. M. J . Org. Chem. 1988, 53, 850.
(8) Annunziata, R.; Cinquini, M.; Cozzi F.; Raimondi, L. J . Org.
Chem. 1990, 55, 1901.
(9) Oppolzer, W.; Siles, S.; Snowden, R. L.; Bakker, B. H.; Petrzilka,
M. Tetrahedron 1985, 41, 3497.

5116 J . Org. Chem., Vol. 66, No. 15, 2001
Tranmer and Tam
Sch em e 8. Syn th esis of Nor bor n a d ien e-Teth er ed
Ald eh yd es w ith a C3 Su bstitu en t on th e
Nor bor n a d ien e (76-80)
F igu r e 1. Determination of regiochemistry. Note: Chemical
shift (δ) in ppm. CH ) methine carbon and q-C ) quaternary
carbon: determined by 13C (APT) NMR.
F igu r e 2. Determination of stereochemistry.
the oxygen of the nitrone attached to C3 and the sp2
carbon of the nitrone attached to C2 (Figure 1). If the
oxygen of the nitrone is attached to C3, a methine (CH)
carbon peak should be observed with chemical shift (δ)
between 80 and 95 ppm. On the other hand, if the oxygen
of the nitrone is attached to C2, a quaternary carbon (q-
C) signal should be observed with chemical shift (δ)
between 80 and 95 ppm. Except for cycloadduct 54, in
all other cycloadducts the carbons attached to the oxygen
with chemical shift ∼88-95 ppm are methine (CH)
carbons. For cycloadduct 54, a mixture of three isomers
was obtained. The two major isomers were found to have
signals at δ 91.6 and 92.8 ppm (carbons attached to the
oxygen), and these are quaternary carbons (q-C).
As Hc of the cycloadducts showed +ve NOE effect with
Hd, the structure of 49 was confirmed. These assignments
were also supported by X-ray crystallography.12
To investigate the effect of a C3 substituent on the
norbornadiene in the cycloaddition, aldehydes 76-80
were prepared (Scheme 8). Monolithium-halide ex-
change of 2,3-dibromonorbornadiene 565c with tBuLi,
followed by trapping the resulting organolithiums with
methyl iodide or TsCl, provided bromides 57-58 in good
yields.5c Lithium-halide exchange of bromides 56-58
followed by trapping with paraformaldehyde afforded
norbornadiene-tethered alcohols 62 (R ) Me), 64 (R )
Cl), and 65 (R ) Br). Alcohol 63 (R ) Ph) was synthesized
by a two-step sequence. Diels-Alder reaction of cyclo-
pentadiene 59 with acetylene 6013 at 160 °C in a sealed
tube provided norbornadiene 61. DIBAL reduction of 61
afforded the required alcohol 63. A two-carbon homolo-
gation to the alcohols 62-65 was achieved by a two-step
sequence6 to provide norbornadiene-tethered alcohols
71-74. Norbornadiene-tethered alcohols with an ester
on C3 (75, R ) COOEt) was synthesized from bromide
69 in two steps. Lithium-halide exchange of bromide 69
followed by trapping with ethyl chloroformate provided
The exo and endo stereochemistry of the cycloadduct
can easily be distinguished by the coupling constant of
1
Ha and Hb (Figure 2) in the H NMR.10 As the dihedral
angles between Ha and Hb in the exo cycloadducts 49 and
49b are close to 90°, the coupling constant between Ha
and Hb would be very small (J ≈ 0-2 Hz). In the endo
cycloadducts 49c and 49d , the dihedral angle between
Ha and Hb is approximately 42° and would give a doublet
with J ≈ 5 Hz.11 In all cases, Ha of all the cycloadducts
(except cycloadduct 54) are singlets in the 1H NMR
spectra, and therefore, all the cycloadducts must have
exo stereochemistry (49 or 49b). To distinguish the two
exo cycloadducts, NOESY NMR experiments were used.
(10) A similar method has been used for the assignment of exo and
endo stereochemistry of bicyclic alkanes; see: (a) Flautt, T. J .; Erman,
W. F. J . Am. Chem. Soc. 1963, 85, 3212. (b) Mazzocchi, P. H.; Stahly,
B.; Dodd, J .; Rondan, N. G.; Domelsmith, L. N.; Rozeboom, M. D.;
Caramella, P.; Houk, K. N. J . Am. Chem. Soc. 1980, 102, 6482.
(11) The exo and endo cycloadducts 49 and 49d were modeled for
energy minimization at PM3 level (CS Chem 3D Pro Version 3.5.1)
using MOPAC for the assessment of the dihedral angles between Ha
and Hb. These dihedral angles were then compared to the Karplus
curve for the determination of the theoretical coupling constants.
(12) Recrystallization of cycloadduct 55 in 20% EtOAc/hexanes
provided suitable crystals for X-ray analysis. For details of the X-ray
analysis, see: Tam, W.; Tranmer, G. K.; Lough, A. J . Acta Crystallogr.
2001, E57, o269.
(13) J ordan, R. W.; Tam, W. Org. Lett. 2000, 2, 3031.

Cycloadditions of Norbornadiene-Tethered Nitrones
J . Org. Chem., Vol. 66, No. 15, 2001 5117
Ta ble 2. In tr a m olecu la r 1,3-Dip ola r Cycloa d d ition s of
C3-Su bstitu ted Nor bor n a d ien e-Teth er ed Nitr on es
of the reasons for the formation of single cycloadducts in
the cycloadditions. Either the E/Z selectivity of the
formation of nitrones was very high and the cycloaddi-
tions were highly regio- and stereoselective or other
cycloadducts were formed but were too unstable and
decomposed under the reaction conditions. The cycload-
ditions can also be reversible, thus giving rise to the most
stable cycloadducts.16 But nevertheless, although up to
eight possible cycloadducts could be formed in the cy-
cloadditions, we were able to generate and to isolate
single regio- and stereoisomers in the cycloadditions in
most cases.
entry
R
aldehyde
cycloadducta,b
yieldd (%)
1
2
3
4
5
6
H
Me
Ph
Cl
Br
COOEt
38
76
77
78
79
80
51
81
82
83
84c
85
71
53
41
46
15
57
Con clu sion
a
Reaction conditions: MeNHOH‚HCl (1.2-2 equiv), pyridine
(3-5 equiv), 4 Å molecular sieves, toluene, rt, 12-24 h, then 90
We have demonstrated the first examples of the
intramolecular 1,3-dipolar cycloadditions of norborna-
diene-tethered nitrones. Although eight possible cycload-
ducts could be formed in the cycloadditions, in most cases,
single regio- and stereoisomers were formed. Thus, these
cycloadditions were found to be highly regio- and stereo-
selective, giving the exo cycloadducts in moderate to good
yields. Further investigations on subsequent cleavage
reactions of the cycloadducts (Scheme 3) for the construc-
tion of angular-fused tricyclic and spirocyclic frameworks
are ongoing in our laboratory.
b
°C, 12-48 h. Except in entry 5, the cycloadducts shown were the
only regio- and stereoisomers isolated in the cycloadditions. c An
d
inseparable mixture of two isomers (60:40) was obtained. Isolated
yields after column chromatography.
ester 70. Removal of the THP group by PPTS in EtOH
afforded norbornadiene-tethered alcohol 75. Swern oxi-
dation of these alcohols 71-75 provided aldehydes 76-
80, and these aldehydes served as precursors of the
required nitrones for the cycloadditions.
The results of the intramolecular 1,3-dipolar cycload-
ditions of norbornadiene-tethered nitrones with a C3
substituent are shown in Table 2. In all cases, the yields
of the cycloadditions with norbornadiene-tethered ni-
trones with a C3 substituent are lower than the unsub-
stituted case (Table 2, entry 1, R ) H). This may due to
the fact that the C3 substituents retard the cycloadditions
because of steric hindrance. Except with R ) Br (Table
2, entry 5), in all other cases, single regio- and stereoi-
somers were obtained. With an alkyl group (R ) Me) or
aryl group (R ) Ph) at C3 (Table 2, entries 2 and 3),
cycloadducts 81 and 82 were generated in moderate
yields (53% and 41%). With halides at C3 (Table 2, entries
4 and 5), R ) Cl gave a single regio- and stereoisomer
83 in 46% yield, and R ) Br gave cycloadduct 84 as a
60:40 mixture of two stereoisomers in only 15% yield.
Cycloadducts 83 and 84 were rather unstable and
decomposed gradually upon standing even at room tem-
perature. With an ester functionality (R ) COOEt) at
C3, a single regio- and stereoisomer 85 was obtained in
57% yield. The regio- and stereochemistry of these
cycloadducts were confirmed by using NMR techniques
(HCOSY, HSQC, HMBC, and NOESY or GOESY experi-
ments).14,15
Exp er im en ta l Section
Gen er a l In for m a tion . All reactions were carried out in
an atmosphere of dry nitrogen at ambient temperature unless
otherwise stated. Standard column chromatography was per-
formed on 230-400 mesh silica gel (obtained from Silicycle)
by use of flash column chromatography techniques.17 Analyti-
cal thin-layer chromatography (TLC) was conducted on Merck
precoated silica gel 60 F254 plates. All glassware was flame
dried under an inert atmosphere of dry nitrogen. Chemical
shifts for 1H NMR spectra are reported in parts per million
(ppm) from tetramethylsilane with the solvent resonance as
the internal standard (chloroform: δ 7.26). Chemical shifts for
13C NMR spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent as the internal standard
(deuteriochloroform: δ 77.0).
Ma ter ia ls. Unless stated otherwise, commercial reagents
were used without purification. Solvents were purified by
distillation under dry nitrogen: from CaH2 (CH2Cl2, 1,2-
dichloroethane, chloroform, DMF, Et3N, pyridine); from 4 Å
molecular sieves (DMSO, acetonitrile, nitromethane); from
sodium (toluene); from potassium/benzophenone (THF); and
from sodium/benzophenone (Et2O). Norbornadiene (22), 1,4-
dibromobutane, 1,5-dibromopentane, and 2-chloroethanol were
purified by distillation from 4 Å molecular sieves under dry
nitrogen. Substituted norbornadienes (23-25, 27, 29, 30, 32,
33, 35, 36),1b 31,18 56-58,5c and acetylene 6013 were prepared
according to literature procedures.
Several factors could control the regio- and stereose-
lectivity of the cycloadditions. Those factors include the
following: the E/Z ratio of the nitrones generated from
the corresponding aldehydes, the distance and the flex-
ibility of the tether to reach the double bonds, the exo/
endo selectivity of the double bond (C2-C3) in the
norbornadiene in the cycloadditions, and the strain and
the stability of the cycloadducts formed. We are not sure
5-(2-Bicyclo[2.2.1]h ep ta -2,5-d ien -2-yl)p en ta n -1-ol (26).
Dimethyl sulfoxide (DMSO, 100 mL), water (25 mL) and
sodium bicarbonate (5.0 g, 59.5 mmol) were added to a flask
containing bromide 241b (4.6 g, 19.1 mmol). The reaction
mixture was allowed to stir at 95 °C for 22 h. After the reaction
mixture was quenched with water (200 mL), the aqueous layer
(14) HCOSY: 1H-1H correlated spectroscopy. HSQC: heteronuclear
single quantum coherence. HMBC: heteronuclear multiple bond
correlation. NOESY: nuclear Overhauser enhancement spectroscopy.
See: Crews, P.; Rodriguez, J .; J aspars, M. Organic Structure Analysis;
Oxford University Press: Oxford, 1998.
(15) GOESY: gradient enhanced nuclear Overhauser enhancement
spectroscopy. See: (a) Stonehouse, J .; Adell, P.; Keeler, J .; Shaka, A.
J . J . Am. Chem. Soc. 1994, 116, 6037. (b) Stott, K.; Stonehouse, J .;
Keeler, J .; Hwang, T.-L.; Shaka, A. J . J . Am. Chem. Soc. 1995, 117,
4199. (c) Dixon, A. M.; Widmalm, G.; Bull, T. E. J . Magn. Reson. 2000,
147, 266.
(16) As suggested by one of the referees, we have performed
semiempirical molecular mechanics calculations (using AM1, PC
Spartan Pro, Wavefunction, Inc., 1999) of the relative energies of the
isomers of cycloadducts 49, 49b, 49c, and 49d (Figure 2). We found
that cycloadduct 49, which we obtained as the only regio- and
stereoisomer in the cycloaddition, is the most stable isomer. Isomer
49 is approximately 27 kcal/mol more stable than 49b, 29 kcal/mol
more stable than 49c, and 2 kcal/mol more stable than 49d .
(17) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(18) Lautens M.; Tam, W.; Lautens, J . C. Edwards, L. G.; Crudden,
C. M.; Smith, A. C. J . Am. Chem. Soc. 1995, 117, 6863.

5118 J . Org. Chem., Vol. 66, No. 15, 2001
Tranmer and Tam
was extracted with diethyl ether (5 × 100 mL), and the
combined organic layers were washed sequentially with water
(100 mL) and brine (100 mL) and dried over magnesium
sulfate. The solvent was removed by rotary evaporation, and
the crude product was purified by vacuum distillation (0.2
mmHg at 85 °C) to give 26 (2.9168 g, 16.36 mmol, 86%) as a
colorless oil: Rf 0.33 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3326 (br s), 3117 (w), 3064 (m), 2967 (s), 2932 (s), 2863 (s),
evaporation to give ester 45 (1.41 g, 5.80 mmol, 96%) as a
colorless oil that was used in the next step without further
purification: Rf 0.67 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3066 (w), 2982 (m), 2936 (m), 2868 (w), 1740 (s), 1285 (s), 1162
(m), 1108 (m), 965 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.79
(dd, 1H, J ) 5.1, 3.0 Hz), 6.74 (dd, 1H, J ) 5.0, 2.8 Hz), 6.58
(d, 1H, J ) 1.5 Hz), 4.82 (dABd, 1H, J ) 13.1, 1.4 Hz), 4.78
(dABd, 1H, J ) 13.1, 1.5 Hz), 3.83 (s, 2H), 3.56 (br s, 1H), 3.44
(br s, 1H), 2.02 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 166.9,
151.6, 143.2, 142.4, 140.7, 73.8, 64.6, 51.3, 50.2, 25.7.
1
1622 (w), 1555 (m), 1300 (s), 1055 (s) cm-1; H NMR (CDCl3,
400 MHz) δ 6.74 (m, 2H), 6.11 (m, 1H), 3.60 (t, 2H, J ) 6.8
Hz), 3.48 (br s, 1H), 3.26 (br s, 1H), 2.18 (m, 2H), 1.96 (d, 1H,
J ) 5.7 Hz), 1.93 (d, 1H, J ) 5.7 Hz), 1.55 (m, 2H), 1.43 (m,
2H), 1.31 (m, 2H), 1.76 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 158.6, 143.7, 142.3, 133.3, 73.4, 62.8, 53.4, 49.9, 32.5, 31.3,
26.9, 25.3. Anal. Calcd for C12H18O: C, 80.85; H, 10.18.
Found: C, 81.08; H, 9.89.
Iod obicyclo[2.2.1]h ep ta -2,5-d ien -2-yla cetic Acid , Meth -
yl Ester (46). Sodium iodide (1.6982 g, 11.3 mmol) was added
to a flame-dried flask containing reagent-grade acetone (9 mL)
and bromoester 45 (1.1812 g, 4.86 mmol) at room temperature.
The reaction mixture was stirred at room temperature for 5
h. After the reaction mixture was filtered and the precipitate
washed with dichloromethane, the organic layer was washed
with a 10% NaHSO3 solution (30 mL). The aqueous layer was
extracted with dichloromethane (2 × 15 mL), and the combined
organic layers were washed sequentially with water (30 mL)
and brine (30 mL) and dried over sodium sulfate. The solvent
was removed by rotary evaporation to give iodoester 46 (1.1683
g, 4.03 mmol, 83%) as a colorless oil that was used in the next
step without further purification: Rf 0.74 (EtOAc/hexanes )
1:4); IR (neat, NaCl) 3059 (s), 2967 (s), 2886 (s), 1730 (s), 1631
2-[2-(Bicyclo[2.2.1]h epta-2,5-dien -2-ylm eth oxy)pr opoxy]-
tetr a h yd r o-2H-p yr a n (42). To a flame-dried flask containing
alcohol 291b (2.503 g, 20.49 mmol), THP-protected 3-iodopro-
pan-1-ol (6.5362 g, 24.20 mmol), and tetrabutylammonium
bromide (1.36 g, 4.09 mmol) was added 50% NaOH (6.3 g in
6.3 mL water, 158 mmol) at 0 °C. The reddish-brown reaction
mixture was stirred at 70 °C for 51 h. After the reaction was
quenched with saturated sodium chloride (20 mL) and water
(50 mL), the aqueous layer was extracted with diethyl ether
(3 × 50 mL), and the combined organic layers were washed
sequentially with water (50 mL) and brine (50 mL) and dried
over magnesium sulfate. The solvent was removed by rotary
evaporation, and the crude product was purified by column
chromatography (EtOAc/hexanes ) 5:95) to give 42 (3.8331 g,
14.5 mmol, 71%, a 1:1 mixture of diastereomers) as a colorless
oil: Rf 0.48 (EtOAc/hexanes ) 1:9); IR (neat, NaCl) 3065 (w),
2939 (s), 2867 (s), 1555 (w), 1441 (m), 1200 (m), 1125 (s), 1021
(s), 733 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.78 (dd, 1H, J
) 5.0, 3.0 Hz), 6.72 (dd, 1H, J ) 5.0, 3.0 Hz), 6.42 (m, 1H),
4.55 (m, 1H), 4.08 (m, 2H), 3.82 (m, 2H), 3.53 (s, 1H), 3.37-
3.50 (m, 5H), 2.01 (dm, 1H, J ) 6.0 Hz), 1.96 (dm, 1H, J ) 6.0
Hz), 1.74-1.88 (m, 3H), 1.68 (m, 1H), 1.48-1.58 (m, 4H); 13C
NMR (CDCl3, 100 MHz) δ 155.2, 143.3, 142.5, 138.0, 98.8, 98.7,
73.58, 73.56, 69.3, 67.0, 66.9, 64.4, 62.19, 62.17, 51.24, 51.19,
50.1, 30.6, 30.0, 25.4, 19.5. Anal. Calcd for C16H24O3: C, 72.69;
H, 9.15. Found: C, 72.44; H, 9.13.
3-(2-Bicyclo[2.2.1]h ep ta -2,5-d ien -2-ylm eth oxy)p r op a n -
1-ol (43). To a flame-dried flask containing 42 (3.05 g, 11.5
mmol) in MeOH (100 mL) was added pyridinium p-toluene-
sulfonate, PPTS (328.4 mg, 1.82 mmol) at room temperature.
The reaction mixture was stirred at 55 °C for 50 min. After
the reaction was quenched with water (200 mL), the aqueous
layer was extracted with diethyl ether (3 × 50 mL), and the
combined organic layers were washed sequentially with water
(50 mL) and brine (50 mL) and dried over magnesium sulfate.
The solvent was removed by rotary evaporation, and the crude
product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 43 (1.4926 g, 8.28 mmol, 72%) as a
pale yellow oil: Rf 0.12 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3392 (br s), 3064 (w), 2934 (s), 2866 (s), 1635 (w), 1351 (m),
1087 (s), 1069 (s), 699 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ
6.77 (dd, 1H, J ) 5.1, 3.1 Hz), 6.71 (dd, 1H, J ) 5.1, 3.0 Hz),
6.43 (s, 1H), 4.11 (dAB, 1H, J ) 12.8 Hz), 4.06 (dABd, 1H, J )
12.8, 1.3 Hz), 3.72 (t, 2H, J ) 5.6 Hz), 3.46-3.55 (m, 3H), 3.41
(br s, 1H), 2.74 (br s, 1H), 2.01 (d, 1H, J ) 6.0 Hz), 1.96 (d,
1H, J ) 6.0 Hz), 1.79 (p, 2H, J ) 5.7 Hz); 13C NMR (CDCl3,
100 MHz) δ 154.6, 143.3, 142.4, 138.5, 73.7, 69.6, 69.1, 61.8,
51.2, 50.1, 31.9.
(w), 1555 (w), 1413 (m), 1023 (m), 805 (m) cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 6.81 (dd, 1H, J ) 5.0, 4.0 Hz), 6.74 (dd,
1H, J ) 5.0, 3.1 Hz), 6.59 (d, 1H, J ) 1.4 Hz), 4.80 (dABd, 1H,
J ) 13.1, 1.1 Hz), 4.74 (dABd, 1H, J ) 13.1, 1.4 Hz), 3.69 (s,
2H), 3.57 (br s, 1H), 3.46 (br s, 1H), 2.05 (dm, 1H, J ) 6.0 Hz),
1.99 (dm, 1H, J ) 6.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 168.5,
151.8, 143.2, 142.5, 140.6, 73.8, 64.4, 51.3, 50.2, -5.5.
(Nitr ooxy)bicyclo[2.2.1]h ep ta -2,5-d ien -2-yla cetic Acid ,
Meth yl Ester (47). Sodium nitrate (0.8795 g, 5.18 mmol) was
added to a flame-dried flask covered in aluminum foil contain-
ing dry acetonitrile (12 mL) and iodoester 46 (1.0381 g, 3.58
mmol) at room temperature. The reaction mixture was stirred
at room temperature for 15.5 h. The reaction mixture was
filtered, the remaining precipitate was washed with diethyl
ether, and the organic layer was then washed with water (2
× 15 mL) and dried over magnesium sulfate. The solvent was
removed by rotary evaporation to give nitrate 47 (0.7864 g,
3.49 mmol, 97%) as a colorless oil that was used in the next
step without further purification: Rf 0.59 (EtOAc/hexanes )
1:4); IR (neat, NaCl) 3067 (w), 2974 (s), 2939 (s), 2870 (m),
1728 (s), 1632 (s), 1412 (s), 1387 (s), 846 (s) cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 6.79 (dd, 1H, J ) 4.5, 3.1 Hz), 6.75 (dd,
1H, J ) 4.5, 3.1 Hz), 6.60 (d, 1H, J ) 1.5 Hz), 4.91 (s, 2H),
4.85 (dd, 2H, J ) 6.1, 1.4 Hz), 3.59 (s, 1H), 3.42 (s, 1H), 2.05
(dt, 1H, J ) 6.0, 1.5 Hz), 2.01 (dt, 1H, J ) 6.0, 1.5 Hz); 13C
NMR (CDCl3, 100 MHz) δ 165.6, 151.2, 143.3, 142.4, 141.5,
74.0, 67.1, 64.5, 51.4, 50.3; HRMS calcd for C10H11NO5 m/z
225.0637, found m/z 225.0636.
Oxobicyclo[2.2.1]h ep ta -2,5-d ien -2-yla cetic Acid , Meth -
yl Ester (48). Anhydrous sodium acetate (219.5 mg, 2.67
mmol) was added to a flame-dried flask containing dry
dimethyl sulfoxide (15 mL) and nitrate 47 (590.3 mg, 2.62
mmol) at room temperature. The reaction mixture was stirred
at room temperature for 20 min and changed from a cloudy
pale yellow solution to a clear dark yellow solution. After the
reaction mixture was quenched by pouring into ice-cold brine
(50 mL), the aqueous layer was extracted with diethyl ether
(3 × 20 mL), and the combined organic layers were washed
sequentially with saturated sodium bicarbonate (20 mL) and
water (30 mL) and dried over magnesium sulfate The solvent
was removed by rotary evaporation, and the crude product was
purified by column chromatography (EtOAc/hexanes ) 1:3) to
give 48 (237 mg, 1.21 mmol, 46%) as an opaque oil. 48 was
isolated as a 3:1 mixture of its glyoxylate form (hydrated
aldehyde) and its aldehyde form: Rf 0.23 (EtOAc/hexanes )
3:7); IR (neat, NaCl) 3442 (br s), 3067 (m), 2974 (s), 2938 (s),
Br om obicyclo[2.2.1]h epta-2,5-dien -2-ylacetic Acid,Meth -
yl Ester (45). Bromoacetyl bromide (0.59 mL, 6.77 mmol) was
added to a flame-dried flask containing alcohol 291b (742 mg,
6.07 mmol), dichloromethane (20 mL), and pyridine (0.73 mL,
9.11 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 30 min. After the reaction mixture was quenched with
water (20 mL), the aqueous layer was extracted with diethyl
ether (3 × 30 mL), and the combined organic layers were
washed sequentially with saturated copper(II) sulfate (30 mL),
water (2 × 30 mL), and brine (30 mL) and dried over
magnesium sulfate. The solvent was removed by rotary
1
2870 (s), 1744 (s), 1556 (m), 1451 (s) cm-1; H NMR (CDCl3,
400 MHz) δ 9.41 (s, 0.25H), 6.67-6.80 (m, 2H), 6.60 (dm,
0.25H, J ) 1.3 Hz), 6.58 (m, 0.75H), 5.36 (m, 0.4H), 4.82-
4.99 (m, 2H), 3.92 (m, 0.4H), 3.61 (m, 0.25H), 3.58 (m, 0.75H),

Cycloadditions of Norbornadiene-Tethered Nitrones
J . Org. Chem., Vol. 66, No. 15, 2001 5119
1
3.49 (m, 0.25H), 3.44 (m, 0.75H), 1.98-2.08 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 183.7, 168.7, 151.3, 150.8, 143.3, 142.5,
142.4, 142.3, 141.2, 141.0, 88.3, 74.0, 73.8, 65.0, 64.8, 51.4, 51.3,
50.4, 50.3.
1309 (m), 1291 (m), 993 (s) cm-1; H NMR (CDCl3, 400 MHz)
δ 6.81 (dd, 1H, J ) 5.2, 2.8 Hz), 6.76 (dd, 1H, J ) 5.2, 3.0 Hz),
4.23 (d, 1H, J ) 12.2 Hz), 4.12 (d, 1H, J ) 12.2 Hz), 3.53 (s,
1H), 3.27 (s, 1H), 1.95 (dt, 1H, J ) 5.6, 1.6 Hz), 1.89 (dt, 1H,
J ) 5.6, 1.6 Hz), 1.78 (s, 3H), 1.17 (br s, 1H); 13C NMR (CDCl3,
100 MHz) δ 148.9, 144.7, 143.3, 141.8, 71.3, 58.9, 55.7, 51.8,
14.3; HRMS calcd for C9H12O m/z 136.0888, found m/z 136.0882.
3-Ch lor obicyclo[2.2.1]h ep ta -2,5-d ien e-2-m eth a n ol (64).
Following the above general procedure using bromide 585c
(1.5757 g, 7.67 mmol), the crude product was purified by
column chromatography (EtOAc/hexanes ) 5:95) to give 64
(0.7234 g, 4.62 mmol, 60%) as a colorless oil: Rf 0.33 (EtOAc/
hexanes ) 1:4); IR (neat, NaCl) 3365 (br s), 3069 (m), 2980
(s), 2940 (s), 2871 (s), 1637, (m), 1451 (m), 1298 (s), 1048 (s)
cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.86 (m, 2H), 4.31 (d, 1H,
J ) 12.8 Hz), 4.18 (d, 1H, J ) 12.8 Hz), 3.66 (m, 1H), 3.43 (m,
1H), 2.22 (dt, 1H, J ) 6.0, 1.6 Hz), 2.07 (dt, 1H, J ) 6.0, 1.6
Hz), 1.51 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 145.5, 143.8,
142.8, 141.5, 71.5, 58.3, 56.8, 51.6; HRMS calcd for C8H9OCl
m/z 156.0342, found m/z 156.0348.
3-Br om obicyclo[2.2.1]h ep ta -2,5-d ien e-2-m eth a n ol (65).
Following the above general procedure using dibromide 565c
(1.2380 g, 4.95 mmol), the crude product was purified by
column chromatography (EtOAc/hexanes ) 5:95) to give 65
(0.8498 g, 4.23 mmol, 85%) as a colorless oil: Rf 0.33 (EtOAc/
hexanes ) 1:4); IR (neat, NaCl) 3330 (br s), 3068 (m), 2977
(s), 2939 (s), 2869 (s), 1630 (m), 1558 (m), 1449 (m), 1297 (s),
1039 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.84 (dd, 1H, J )
4.8, 2.8 Hz), 6.80 (dd, 1H, J ) 4.8, 2.8 Hz), 4.25 (d, 1H, J )
12.8 Hz), 4.09 (d, 1H, J ) 12.8 Hz), 3.66 (m, 1H), 3.50 (m, 1H),
2.38 (br s, 1H), 2.21 (dt, 1H, J ) 6.2, 1.6 Hz), 2.05 (dt, 1H, J
) 6.2, 1.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 149.4, 142.4,
141.5, 132.3, 71.8, 59.4, 58.3, 51.9; HRMS calcd for C8H9OBr
m/z 199.9837, found m/z 199.9842.
3-P h en ylbicyclo[2.2.1]h epta-2,5-dien e-2-car boxylic Acid,
Eth yl Ester (61). Phenylacetylene ester 6013 (3.4914 g, 20.04
mmol) and freshly distilled cyclopentadiene 59 (1.88 g, 28.4
mmol) were added to a Pyrex pressure tube under an atmo-
sphere of nitrogen. The tube was sealed tightly and heated to
160 °C for 84 h. The crude product was purified by vacuum
distillation (0.5 Torr at 110 °C-120 °C) to give 61 (2.3756 g,
9.89 mmol, 49%) as a clear colorless oil: Rf 0.39 (EtOAc/
hexanes ) 5:95); IR (neat, NaCl) 3054 (m), 2977 (s), 2869 (s),
1712 (s), 1558 (m), 1491 (m), 1444 (s), 1242 (s), 1100 (m) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.54 (m, 2H), 7.36 (m, 3H), 7.00
(dd, 1H, J ) 5.0, 3.0 Hz), 6.93 (dd, 1H, J ) 5.0, 3.1 Hz), 4.15
(q, 2H, J ) 7.1 Hz), 4.08 (m, 1H), 3.87 (m, 1H), 2.27 (dt, 1H,
J ) 5.2, 1.4 Hz), 2.07 (dt, 1H, J ) 6.6, 1.4 Hz), 1.23 (t, 3H, J
) 7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 166.3, 165.5, 143.7,
140.8, 139.3, 135.6, 128.4, 127.8, 127.6, 70.5, 60.0, 58.4, 53.0,
14.1; HRMS calcd for C16H16O2 m/z 240.1150, found m/z
240.1145.
3-P h en ylbicyclo[2.2.1]h ep ta -2,5-d ien e-2-m eth a n ol (63).
Diisobutylaluminum hydride, DIBAL (1 M in hexane, 8.3 mL,
8.3 mmol), was added to a flame-dried flask containing
norbornadiene ester 61 (1.0449 g, 4.345 mmol) and THF (20
mL) at -78 °C (acetone/dry ice bath). The reaction was stirred
for 2 h at -78 °C, quenched at that temperature with water
(10 mL) and saturated ammonium chloride (40 mL), and
allowed to warm to room temperature. The aqueous layer was
extracted with diethyl ether (3 × 20 mL), and the combined
organic layers were washed sequentially with water (40 mL)
and brine (40 mL) and dried over magnesium sulfate. The
solvent was removed by rotary evaporation, and the crude
product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 63 (647.4 mg, 3.265 mmol, 75%) as a
colorless viscous oil: Rf 0.35 (EtOAc/hexanes ) 1:4); IR (neat,
NaCl) 3353 (br s), 3058 (m), 2968 (s), 2936 (s), 2866 (s), 1598
(m), 1493 (s), 1296 (s), 1029 (s), 986 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.35 (m, 2H), 7.24 (m, 3H), 6.95 (dd, 1H, J ) 5.0,
3.0 Hz), 6.89 (dd, 1H, J ) 5.0, 3.0 Hz), 4.45 (d, 1H, J ) 12.0
Hz), 4.40 (d, 1H J ) 12.0 Hz), 3.80 (m, 1H), 3.77 (m, 1H), 2.17
(dt, 1H, J ) 6.4, 1.6 Hz), 2.03 (dt, 1H, J ) 6.0, 1.6 Hz), 1.45
(br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 151.3, 148.2, 142.9,
142.2, 136.5, 128.3, 126.8, 126.3, 71.0, 59.7, 55.4, 53.2; HRMS
calcd for C14H14O m/z 198.1045, found m/z 198.1040.
Gen er a l P r oced u r e for th e Syn th esis of Alcoh ols 62,
64, a n d 65.
Gen er a l P r oced u r e for th e Syn th esis of THP -P r otect-
ed Alcoh ols: 34, 66, 67, 68, a n d 69.
2-[2-(Bicyclo[2.2.1]h ep ta -2,5-d ien -2-ylp r op oxy)eth oxy]-
tetr a h yd r o-2H-p yr a n (34). To a flame-dried flask containing
alcohol 3118 (2.2558 g, 15.02 mmol), THP-protected 2-chloro-
ethanol (4.9537 g, 30.09 mmol), and tetrabutylammonium
bromide (1.004 g, 3.010 mmol) was added 50% NaOH (4.6 g
in 4.6 mL water, 115 mmol) at 0 °C. The reddish-brown
reaction mixture was stirred at 66 °C for 63 h. After the
reaction was quenched with saturated sodium chloride (10 mL)
and water (20 mL), the aqueous layer was extracted with
diethyl ether (4 × 20 mL), and the combined organic layers
were washed sequentially with water (20 mL) and brine (20
mL) and dried over magnesium sulfate. The solvent was
removed by rotary evaporation, and the crude product was
purified by column chromatography (EtOAc/hexanes ) 3:97)
to give 34 as an inseparable mixture of two diastereomers
(4.0362 g, 14.49 mmol, 96%) as a colorless oil: Rf 0.63 (EtOAc/
hexanes ) 1:4); IR (neat, NaCl) 3063 (w), 2938 (s), 2866 (s),
1441 (m), 1201 (m), 1125 (s), 1036 (s), 989 (m) cm-1; 1H NMR
(CDCl3, 400 MHz) δ 6.72 (m, 2H), 6.11 (d, 1H, J ) 1.5 Hz),
4.62 (t, 1H, J ) 3.5 Hz), 3.82 (m, 2H), 3.54-3.60 (m, 3H), 3.46-
3.51 (m, 2H), 3.42 (t, 2H, J ) 6.7 Hz), 3.25 (s, 1H), 2.23 (m,
2H), 1.94 (dABt, 1H, J ) 5.7, 1.5 Hz), 1.91 (dABt, 1H, J ) 5.7,
1.5 Hz), 1.82 (m, 1H), 1.67-1.73 (m, 3H), 1.47-1.62 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 158.1, 143.7, 142.2, 133.5, 98.8,
73.4. 70.8, 69.9, 66.5, 62.1, 53.4, 49.9, 30.5, 27.9, 27.1, 25.4,
19.4.
3-Meth ylbicyclo[2.2.1]h ep ta -2,5-d ien e-2-m eth a n ol (62).
2-Bromo-3-methylnorbornadiene 575c (1.9971 g, 10.79 mmol)
was added to a flame-dried flask and cooled to -78 °C (acetone/
dry ice bath) following the addition of THF (50 mL). tert-
Butyllithium (12.7 mL, 1.7 M, 21.6 mmol) was added via
syringe to the solution, maintaining the temperature below
-65 °C. The reaction mixture was stirred at -78 °C for 15
min. Paraformaldyde (4.6971 g, ∼52.1 mmol) was then added
to the flask and stirred at -78 °C for 1 h, and the solution
was then allowed to warm to room temperature and stirred
for 1 h. After the reaction mixture was quenched with water
(20 mL), the aqueous layer was extracted with diethyl ether
(2 × 30 mL). The aqueous layer was then acidified to a pH of
6 and extracted with diethyl ether (2 × 15 mL), and the
combined organic layers were washed sequentially with water
(40 mL) and brine (40 mL) and dried over magnesium sulfate.
The solvent was removed by rotary evaporation, and the crude
product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 62 (1.1769 g, 8.64 mmol, 80%) as a
colorless oil: Rf 0.30 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3362 (br s), 3064 (m), 2966 (s), 2934 (s), 2866 (s), 1440, (m),
2-(3-Met h ylb icyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy-
eth oxy)tetr a h yd r o-2H-p yr a n (66). Following the above
general procedure using alcohol 62 (1.0049 g, 7.38 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 66 as an inseparable mixture of two
diastereomers (1.6486 g, 6.24 mmol, 85%) as a colorless oil:
Rf 0.55 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 3064 (w), 2938
(s), 2866 (s), 1441 (m), 1353 (m), 1201, (m), 1125 (s), 1075 (s),
1036(s), 732 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.78 (dd,

5120 J . Org. Chem., Vol. 66, No. 15, 2001
Tranmer and Tam
1H, J ) 8.0, 4.8 Hz), 6.72 (dd, 1H, J ) 8.0, 4.8 Hz), 4.63 (t,
1H, J ) 3.6 Hz), 4.16 (dd, 1H, J ) 12.4, 2.0 Hz), 4.00 (d, 1H,
J ) 12.4 Hz), 3.83 (m, 2H), 3.58-3.36 (m, 4H), 3.49 (s, 1H),
3.26 (s, 1H), 1.94 (m, 1H), 1.86 (dm, 1H, J ) 5.6 Hz), 1.77 (s,
3H), 1.82-1.47 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 149.6,
143.22, 143.17, 142.75, 142.72, 141.37, 98.79, 98.73, 71.05,
70.99, 68.2, 66.65, 66.61, 66.48, 66.45, 62.1, 55.7, 52.0, 51.9,
30.5, 25.4, 19.4, 14.4.
1:4); IR (neat, NaCl) 2941 (s), 2871 (s), 1739 (vs), 1699 (s), 1369
(m), 1294 (s), 1125 (s), 1021 (s) cm-1 1H NMR (CDCl3, 400
;
MHz) δ 6.87 (dd, 1H, J ) 4.8, 3.2 Hz), 6.77 (m, 1H), 4.71 (d,
1H, J ) 14.8 Hz), 4.65 (t, 1H, J ) 3.6 Hz), 4.48 (d, 1H, J )
14.8 Hz), 4.17 (m, 2H), 3.93 (m, 1H), 3.88 (m, 1H), 3.85 (m,
2H), 3.55 (m, 4H), 2.08 (m, 1H), 2.00 (dt, 1H, J ) 6.4, 1.6 Hz),
1.84 (m, 1H), 1.73 (m,1H), 1.65-1.51 (m, 4H), 1.30 (t, 3H, J )
6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 168.98, 168.95, 165.3,
143.40, 143.35, 141.55, 141.49, 98.86, 98.82, 71.66, 71.63, 69.7,
67.5, 66.46, 66.43, 62.1, 60.1, 53.5, 51.4, 30.5, 25.4, 19.4, 14.3.
Gen er a l P r oced u r e for th e Syn th esis of Alcoh ols: 37,
71, 72, 73, 74, a n d 75).
2-(3-P h en ylbicyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy-
eth oxy)tetr a h yd r o-2H-p yr a n (67). Following the above
general procedure using alcohol 63 (0.6450 g, 3.25 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 67 as an inseparable mixture of two
diastereomers (0.6372 g, 1.95 mmol, 60%) as a colorless oil:
Rf 0.51 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 3060 (w), 2942
(s), 2869 (s), 1727 (w), 1442 (m), 1201, (m), 1125 (s), 1075 (s),
1035 (s), 909 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.34 (m,
2H), 7.23 (m, 3H), 6.92 (dd, 1H, J ) 5.2, 2.8 Hz), 6.89 (m, 1H),
4.63 (m, 1H), 4.41 (d, 1H, J ) 12.6 Hz), 4.24 (d, 1H, J ) 12.6
Hz), 3.83 (m, 4H), 3.57-3.48 (m, 4H), 2.17 (m, 1H), 2.01 (d,
2-[2-(Bicyclo[2.2.1]h ep t a -2,5-d ien -2-ylp r op oxy)et h a -
n ol (37). To a flame-dried flask containing THP-protected
alcohol 34 (1.2724 g, 4.57 mmol) in MeOH (40 mL) was added
pyridinium p-toluenesulfonate, PPTS (126.5 mg, 0.503 mmol)
at room temperature. The reaction mixture was stirred at 55
°C for 45 min. After the reaction was quenched with water
(200 mL), the aqueous layer was extracted with diethyl ether
(3 × 50 mL), and the combined organic layers were washed
sequentially with water (50 mL) and brine (50 mL) and dried
over magnesium sulfate. The solvent was removed by rotary
evaporation, and the crude product was purified by column
chromatography (EtOAc/hexanes ) 1:4) to give 37 (772.8 mg,
3.98 mmol, 87%) as a colorless oil: Rf 0.18 (EtOAc/hexanes )
1:4); IR (neat, NaCl) 3412 (br s), 3063 (m), 2964 (s), 2864 (s),
1H, J ) 6.0 Hz), 1.83 (m, 1H), 1.72 (m, 1H), 1.57 (m, 4H); 13
C
NMR (CDCl3, 100 MHz) δ 151.87, 151.81, 146.94, 146.90,
142.95, 142.88, 141.77, 141.74, 136.7, 128.2, 126.7, 126.4,
98.77, 98.71, 70.88, 70.84, 69.02, 68.98, 67.4, 66.6, 66.5, 62.05,
62.02, 55.4, 53.45, 53.40, 30.5, 25.4, 19.4.
2-(3-Ch lor ob icyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy-
eth oxy)tetr a h yd r o-2H-p yr a n (68). Following the above
general procedure using alcohol 64 (0.6004 g, 3.83 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 68 as an inseparable mixture of two
diastereomers (0.7917, 2.78 mmol, 73%) as a colorless oil: Rf
0.68 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 2942 (s), 2870
(s), 1636 (w), 1453 (w), 1441 (w), 1124 (s), 1075 (s), 1035 (s),
909 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.82 (m, 2H), 4.63
(t, 1H, J ) 3.6 Hz), 4.21 (d, 1H, J ) 12.8 Hz), 4.04 (dd, 1H, J
) 12.8, 0.8 Hz), 3.84 (m, 2H), 3.64 (m, 1H), 3.57-3.41 (m, 5H),
2.22 (m, 1H), 2.05 (dt, 1H, J ) 6.0, 1.6 Hz), 1.83 (m, 1H), 1.72
(m, 1H), 1.65-1.49 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ
145.2, 143.83, 143.81, 142.8, 142.7, 141.08, 141.03, 98.76,
98.71, 71.38, 71.33, 68.8, 66.47, 66.43, 65.47, 62.05, 56.8, 51.70,
51.67, 30.5, 25.4, 19.4. Anal. Calcd for C15H21O3Cl: C, 63.26;
H, 7.43. Found: C, 62.91; H, 7.54.
1
1692 (m), 1448 (s), 1358 (s), 1120 (s), 1059 (s) cm-1; H NMR
(CDCl3, 400 MHz) δ 6.75 (m, 2H), 6.14 (d, 1H, J ) 1.5 Hz),
3.71 (m, 2H), 3.50-3.53 (m, 3H), 3.44 (t, 2H, J ) 6.6 Hz), 3.28
(s, 1H), 2.26 (m, 2H), 2.06 (t, 1H, J ) 5.8 Hz), 1.97 (dABm, 1H,
J ) 5.8 Hz), 1.94 (dABm, 1H, J ) 5.8 Hz), 1.72 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 158.1, 143.8, 142.3, 133.7, 73.5, 71.7,
70.8, 61.8, 53.4, 50.0, 27.9, 27.2. Anal. Calcd for C12H18O2: C,
74.19; H, 9.34. Found: C, 74.41; H, 9.30.
(3-Met h ylb icyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy)-
eth a n ol (71). Following the above general procedure using
THP-protected alcohol 66 (1.4315 g, 5.42 mmol), the crude
product was purified by column chromatography (EtOAc/
hexanes ) 15:85) to give 71 (595.4 mg, 3.30 mmol, 61%) as a
colorless oil: Rf 0.15 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3399 (br s), 3061 (m), 2936 (s), 2867 (s), 1718 (s), 1454, (m),
2-(3-Br om ob icyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy-
eth oxy)tetr a h yd r o-2H-p yr a n (69). Following the above
general procedure using alcohol 65 (0.8519 g, 4.24 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 69 as an inseparable mixture of two
diastereomers (1.0558, 3.21 mmol, 76%) as a colorless oil: Rf
0.53 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 3068 (w), 2940
(s), 2868 (w), 1629 (m), 1557 (m), 1441 (m), 1297 (m), 1113 (s),
1036 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.82 (m, 2H), 4.63
(t, 1H, J ) 3.6 Hz), 4.21 (d, 1H, J ) 12.8 Hz), 4.02 (d, 1H, J )
12.8 Hz), 3.84 (m, 2H), 3.66 (s, 1H), 3.58-3.42 (m, 5H), 2.23
1
1353 (m), 1269 (m) cm-1; H NMR (CDCl3, 400 MHz) δ 6.79
(dd, 1H, J ) 4.8, 2.8 Hz), 6.74 (dd, 1H, J ) 4.8, 2.8 Hz), 4.14
(d, 1H, J ) 12.0 Hz), 4.00 (d, 1H, J ) 12.0 Hz), 3.69 (t, 2H, J
) 4.6 Hz), 3.48 (s, 1H), 3.42 (dt, 1H, J ) 10.2, 4.6 Hz), 3.35
(dt, 1H, J ) 10.2, 4.6 Hz), 3.27 (s, 1H), 2.25 (br s, 1H), 1.95
(dt, 1H, J ) 6.0, 1.6 Hz), 1.88 (d, 1H, J ) 6.0 Hz), 1.78 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 150.0, 143.1, 142.4, 141.5, 71.2,
70.4, 66.5, 61.8, 55.7, 52.0, 14.4; HRMS calcd for C11H16O2 m/z
180.1150, found m/z 180.1140.
(m, 1H), 2.06 (dt, 1H, J ) 6.4, 1.6 Hz), 1.84-1.49 (m, 6H); 13
C
NMR (CDCl3, 100 MHz) δ 147.84, 147.82, 142.4, 141.2, 134.1,
98.76, 98.72, 71.78, 71.73, 68.8, 66.9 66.5, 62.12, 62.06, 58.52,
58.46, 52.23, 52.13, 30.5, 25.4, 19.4. Anal. Calcd for C15H21O3-
Br: C, 54.72; H, 6.43. Found: C, 54.39; H, 6.66.
(3-P h en ylb icyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy)-
eth a n ol (72). Following the above general procedure using
THP-protected alcohol 67 (0.4915 g, 1.51 mmol), the crude
product was purified by column chromatography (EtOAc/
hexanes ) 15:85) to give 72 (193.4 mg, 0.798 mmol, 53%) as a
colorless oil: Rf 0.18 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3419 (br s), 3060 (m), 2975 (s), 2936 (s), 2866 (s), 1725 (w),
1598 (m), 1352 (m), 1296 (m) cm-1; 1H NMR (CDCl3, 400 MHz)
δ 7.35 (m, 2H), 7.24 (m, 3H), 6.94 (dd, 1H, J ) 5.0, 3.0 Hz),
6.89 (dd, 1H, J ) 5.0, 3.4 Hz), 4.37 (d, 1H, J ) 12.2 Hz), 4.23
(d, 1H, J ) 12.2 Hz), 3.79 (m, 1H), 3.74 (m, 1H), 3.67 (t, 2H,
J ) 4.6 Hz), 3.40 (m, 2H), 2.55 (br s, 1H), 2.18 (dt, 1H, J )
6.0, 1.6 Hz), 2.03 (dt, 1H, J ) 6.4, 1.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 152.2, 146.3, 142.7, 141.8, 136.4, 128.2, 126.7,
126.2, 71.0, 70.9, 67.3, 61.6, 55.4, 53.4; HRMS calcd for
2-(3-Eth oxyca r bon ylbicyclo[2.2.1]h ep ta -2,5-d ien -2-yl-
m eth oxyeth oxy)tetr a h yd r o-2H-p yr a n (70). To a flame-
dried flask containing alcohol 69 (1.3430 g, 4.08 mmol) and
THF (20 mL) that had been cooled to -78 °C in an acetone
dry ice bath was added tert-butyllithium (4.8 mL, 1.7 M, 8.16
mmol) and the mixture stirred for 15 min. Using a cannula,
ethyl chloroformate (1.56 mL, 16.3 mmol) in THF (10 mL) that
had also been cooled to -78 °C was added, and the mixture
was allowed to stir for 1 h. The reaction mixture was allowed
to warm to room temperature and quenched with water (20
mL). The aqueous layer was extracted with diethyl ether (3 ×
20 mL), and the combined organic layers were washed
sequentially with water (25 mL) and brine (25 mL) and dried
over magnesium sulfate. The solvent was removed by rotary
evaporation, and the crude product was purified by column
chromatography (EtOAc/hexanes ) 5:95) to give 70 (0.8417 g,
2.61 mmol, 64%) as a colorless oil: Rf 0.44 (EtOAc/hexanes )
C
16H18O2 m/z 242.1307, found m/z 242.1304.
(3-Ch lor ob icyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy)-
eth a n ol (73). Following the above general procedure using
THP-protected alcohol 68 (0.3247 g, 1.14 mmol), the crude
product was purified by column chromatography (EtOAc/
hexanes ) 15:85) to give 73 (185.3 mg, 0.923 mmol, 81%) as a

Cycloadditions of Norbornadiene-Tethered Nitrones
J . Org. Chem., Vol. 66, No. 15, 2001 5121
colorless oil: Rf 0.24 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3424 (br s), 2940 (s), 2870 (s), 1635 (w), 1454 (w), 1299 (m),
1107 (s), 1062 (s), 912 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ
6.84 (m, 2H), 4.21 (d, 1H, J ) 12.8 Hz), 4.05 (d, 1H, J ) 12.8
Hz), 3.70 (t, 2H, J ) 4.8 Hz), 3.62 (m, 1H), 3.44 (m, 1H), 3.42
(dt, 2H, J ) 9.2, 4.8 Hz), 2.23 (dt, 1H, J ) 6.2, 1.6 Hz), 2.08
(dt, 1H, J ) 6.2, 1.6 Hz), 2.05 (br s, 1H); 13C NMR (CDCl3, 100
MHz) δ 145.6, 143.4, 142.7, 141.2, 71.6, 70.8, 65.5, 61.8, 56.9,
51.8. Anal. Calcd for C10H13O2Cl: C, 59.86; H, 6.53. Found:
C, 60.17; H, 6.40.
to give 38 (1.3868 g, 8.45 mmol, 87%) as a colorless viscous
oil: Rf 0.50 (EtOAc/hexanes ) 3:7); IR (neat, NaCl) 3065 (s),
2979 (s), 2935 (s), 2867 (s), 1736 (s), 1628 (m), 1555 (m) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 9.69 (s, 1H), 6.78 (dd, 1H, J )
5.2, 3.0 Hz), 6.73 (dd, 1H, J ) 5.2, 3.0 Hz), 6.53 (m, 1H), 4.25
(dAB, 1H, J ) 12.8 Hz), 4.17 (dAB, 1H, J ) 12.8 Hz), 3.95 (s,
2H), 3.56 (br s, 1H), 3.48 (br s, 1H), 2.02 (dAB, 1H, J ) 6.0 Hz),
1.99 (dAB, 1H, J ) 6.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 200.8,
153.5, 143.3, 142.5, 140.6, 74.7, 73.8, 69.9, 51.2, 50.2; HRMS
calcd for C10H12O2 m/z 164.0837, found m/z 164.0850.
(3-Br om obicyclo[2.2.1]h ep ta -2,5-d ien -2-ylm eth oxy)eth -
a n ol (74). Following the above general procedure using THP-
protected alcohol 69 (0.9562 g, 2.90 mmol), the crude product
was purified by column chromatography (EtOAc/hexanes ) 15:
85) to give 74 (602.6 mg, 2.46 mmol, 85%) as a colorless oil:
Rf 0.15 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 3419 (br s),
3068 (w), 2973 (s), 2939 (s), 2868 (s), 1629 (m), 1558 (m), 1449
(m), 1351 (s), 1298 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.82
(m, 2H), 4.19 (d, 1H, J ) 12.6 Hz), 4.02 (dd, 1H, J ) 12.6, 1.2
Hz), 3.70 (t, 2H, J ) 4.1 Hz), 3.63 (s, 1H), 3.54 (s, 1H), 3.45
(dt, 1H, J ) 10.4, 4.8 Hz), 3.37 (dt, 1H, J ) 10.4, 4.8 Hz), 2.23
(d, 1H, J ) 6.2 Hz), 2.16 (br s, 1H), 2.07 (d, 1H J ) 6.2 Hz);
13C NMR (CDCl3, 100 MHz) δ 147.4, 142.3, 141.3, 134.5, 71.9,
70.9, 66.9, 61.7, 58.5, 52.3; HRMS calcd for C10H13O2Br m/z
244.0099, found m/z 243.9950.
(3-E t h oxyca r b on ylb icyclo[2.2.1]h ep t a -2,5-d ien -2-yl-
m eth oxy)eth a n ol (75). Following the above general proce-
dure using THP-protected alcohol 70 (0.5669 g, 1.76 mmol)
and using EtOH instead of MeOH, the crude product was
purified by column chromatography (EtOAc/hexanes ) 15:85)
to give 75 (288.7 mg, 1.21 mmol, 69%) as a colorless oil: Rf
0.17 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 3458 (br s), 3070
(w), 2979 (s), 2939 (s), 2872 (s), 1699 (vs), 1627 (s), 1449 (m),
1239 (s), 1101 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.88 (dd,
1H, J ) 4.8, 3.2 Hz), 6.77 (dd, 1H, J ) 4.8, 3.2 Hz), 4.68 (d,
1H, J ) 14.4 Hz), 4.48 (d, 1H, J ) 14.4 Hz), 4.17 (m, 2H), 3.93
(m, 1H), 3.82 (m, 1H), 3.74 (m, 2H), 3.52 (dt, 1H, J ) 10.4, 4.4
Hz), 3.46 (dt, 1H, J ) 10.4, 4.6 Hz), 2.11 (br s, 1H), 2.09 (dt,
1H, J ) 6.6, 1.6 Hz), 2.01 (dt, 1H J ) 6.6, 1.6 Hz), 1.29 (t, 3H,
J ) 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 168.1, 165.2, 143.4,
141.9, 141.4, 71.8, 71.5, 67.3, 61.8, 60.1, 53.6, 51.4, 14.3.
Gen er a l P r oced u r e for Sw er n Oxid a tion s (Syn th esis
of Ald eh yd es 28, 38-40, 44, a n d 76-80).
5-(2-Bicyclo[2.2.1]h ep ta -2,5-d ien -2-yl)p en ta n -1-a l (28).
Dimethyl sulfoxide (DMSO, 1.4 mL, 19.7 mmol) was added to
a flame-dried flask containing oxalyl chloride (0.9 mL, 10.3
mmol) and dichloromethane (15 mL) at -78 °C (dry ice/acetone
bath). Five minutes after the addition, alcohol 26 (1.546 g,
8.672 mmol) in dichloromethane (8 mL) was added slowly to
the reaction mixture via a cannula. The reaction mixture was
stirred at -78 °C for 30 min. Freshly distilled triethylamine
(5.6 mL, 40.2 mmol) was added to the reaction mixture at -78
°C. The reaction was stirred at -78 °C for 15 min and at room
temperature for 1.5 h. After the reaction mixture was quenched
with saturated NH4Cl (20 mL), the aqueous layer was ex-
tracted with diethyl ether (3 × 30 mL), and the combined
organic layers were washed sequentially with water (100 mL)
and brine (100 mL) and dried over magnesium sulfate. The
solvent was removed by rotary evaporation, and the crude
product was purified by bulb-to-bulb distillation (0.5 mmHg,
110 °C) to give 28 (1.0782 mg, 6.12 mmol, 71%) as a colorless
viscous oil: Rf 0.69 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3064 (m), 2967 (s), 2932 (s), 2863 (s), 2830 (m), 2718 (m), 1725
(s), 1555 (m), 1622 (w), 1300 (s), 695 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 9.73 (t, 1H, J ) 1.8 Hz), 6.73 (m, 2H), 6.11 (d, 1H,
J ) 1.6 Hz), 3.47 (br s, 1H), 3.25 (br s, 1H), 2.40 (td, 2H, J )
7.3, 1.8 Hz), 2.19 (m, 2H), 1.95 (dt, 1H, J ) 5.7, 1.5 Hz), 1.92
(dt, 1H, J ) 5.7, 1.6 Hz), 1.59 (p, 2H, J ) 7.3 Hz), 1.44 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ 202.6, 158.0, 143.7, 142.2,
133.7, 73.4, 53.3, 49.9, 43.6, 31.0, 26.5, 21.6. Anal. Calcd for
2-Bicyclo[2.2.1]h e p t a -2,5-d ie n -2-yle t h oxya ce t a ld e -
h yd e (39). Following the above general procedure using
alcohol 361b (753.6 mg, 4.18 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 5:95)
to give 39 (316.6 mg, 1.78 mmol, 43%) as a colorless viscous
oil: Rf 0.62 (EtOAc/hexanes ) 2:3); IR (neat, NaCl) 3117 (m),
3063 (s), 2967 (s), 2866 (s), 1731 (s), 1694 (s), 1555 (m), 1306
1
(s) cm-1; H NMR (CDCl3, 400 MHz) δ 9.72 (s, 1H), 6.75 (m,
2H), 6.25 (d, 1H, J ) 1.5 Hz), 4.06 (s, 2H), 3.62 (t, 2H, J ) 6.9
Hz), 3.51 (m, 1H), 3.34 (m, 1H), 2.52 (m, 2H), 1.99 (dt, 1H, J
) 5.8, 1.5 Hz), 1.95 (dt, 1H, J ) 5.8, 1.4 Hz); 13C NMR (CDCl3,
100 MHz) δ 201.0, 154.7, 143.9, 142.3, 135.6, 76.2, 73.7, 70.3,
53.5, 50.2, 31.6; HRMS calcd for C11H14O2 m/z 178.0994, found
m/z 178.0988.
2-Bicyclo[2.2.1]h ep t a -2,5-d ien -2-ylp r op oxya cet a ld e-
h yd e (40). Following the above general procedure using
alcohol 37 (550.3 mg, 2.83 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 1:4) to
give 40 (301.2 mg, 1.57 mmol, 56%) as a colorless viscous oil:
Rf 0.39 (EtOAc/hexanes ) 1:4); IR (neat, NaCl) 3062 (m), 2969
(s), 2866 (s), 1724 (s), 1642 (w), 1622 (w), 1447 (m), 1325 (m),
1
912 (s) cm-1; H NMR (CDCl3, 400 MHz) δ 9.72 (s, 1H), 6.75
(m, 2H), 6.15 (d, 1H, J ) 1.1 Hz), 4.05 (s, 2H), 3.53 (br s, 1H),
3.49 (t, 2H, J ) 6.6 Hz), 3.28 (br s, 1H), 2.28 (m, 2H), 1.98
(dm, 1H, J ) 5.7 Hz), 1.95 (dm, 1H, J ) 5.7 Hz), 1.77 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 201.1, 143.8, 142.3, 134.4, 133.9,
76.3, 73.5, 71.6, 53.5, 50.1, 27.8, 27.1; HRMS calcd for C12H16O2
m/z 192.1150, found m/z 192.1166.
3-(2-Bicyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxy)p r op a -
n a l (44). Following the above general procedure using alcohol
43 (510.3 mg, 2.83 mmol), the crude product was purified by
column chromatography (EtOAc/hexanes ) 1:9) to give 44 (385
mg, 2.16 mmol, 76%) as a colorless viscous oil: Rf 0.44 (EtOAc/
hexanes ) 1:4); IR (neat, NaCl) 3064 (w), 2961 (s), 2933 (s),
2870 (s), 1725 (s), 1641 (m), 1354 (m), 913 (m), 731 (m) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 9.77 (t, 1H, J ) 1.9 Hz), 6.78
(dd, 1H, J ) 4.8, 3.1 Hz), 6.73 (dd, 1H, J ) 4.8, 3.1 Hz), 6.46
(d, 1H, J ) 1.4 Hz), 4.14 (dABd, 1H, J ) 12.9, 1.2 Hz), 4.08
(dABd, 1H, J ) 12.9, 1.5 Hz), 3.67 (m, 2H), 3.55 (br s, 1H), 3.43
(br s, 1H), 2.64 (td, 2H, J ) 6.0, 1.9 Hz), 2.02 (dt, 1H, J ) 6.0,
1.4 Hz), 1.98 (dm, 1H, J ) 6.0 Hz); 13C NMR (CDCl3, 100 MHz)
δ 201.3, 154.5, 143.3, 142.5, 138.9, 73.7, 69.6, 63.4, 51.2, 50.2,
43.8; HRMS calcd for C11H14O2 m/z 178.0994, found m/z
178.0989.
(3-Meth ylbicyclo[2.2.1]h ep ta -2,5-d ien -2-ylm eth oxy)a c-
eta ld eh yd e (76). Following the above general procedure using
alcohol 71 (205.3 mg, 1.14 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 5:95)
to give 76 (122.4 mg, 0.687 mmol, 60%) as a colorless viscous
oil, Rf 0.32 (EtOAc/hexanes ) 1:4). Spectral data indicated a
mixture of the aldehyde with its glycolate (hydrated aldehyde),
which was used in the next step without further purification
and characterization.
(3-P h en ylbicyclo[2.2.1]h ep ta -2,5-d ien -2-ylm eth oxy)a c-
eta ld eh yd e (77). Following the above general procedure using
alcohol 72 (96.3 mg, 0.397 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 5:95)
to give 77 (58.1 mg, 0.242 mmol, 61%) as a colorless viscous
oil, Rf 0.34 (EtOAc/hexanes ) 1:4). Spectral data indicated a
mixture of the aldehyde with its glycolate (hydrated aldehyde),
which was used in the next step without further purification
and characterization.
C
12H16O: C, 81.77; H, 9.15. Found: C, 81.56; H, 9.43.
2-Bicyclo[2.2.1]h ep t a -2,5-d ien -2-ylm et h oxya cet a ld e-
h yd e (38). Following the above general procedure using
alcohol 351b (1.6164 g, 9.72 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 5:95)
(3-Ch lor obicyclo[2.2.1]h ep ta -2,5-d ien -2-ylm eth oxy)a c-
eta ld eh yd e (78). Following the above general procedure using
alcohol 73 (96.5 mg, 0.481 mmol), the crude product was

5122 J . Org. Chem., Vol. 66, No. 15, 2001
Tranmer and Tam
purified by column chromatography (EtOAc/hexanes ) 5:95)
to give 78 (73.0 mg, 0.367 mmol, 76%) as a colorless viscous
oil, Rf 0.32 (EtOAc/hexanes ) 1:4). Spectral data indicated a
mixture of the aldehyde with its glycolate (hydrated aldehyde),
which was used in the next step without further purification
and characterization.
(3-Br om obicyclo[2.2.1]h ep ta -2,5-d ien -2-ylm eth oxy)a c-
eta ld eh yd e (79). Following the above general procedure using
alcohol 74 (169.5 mg, 0.692 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 5:95)
to give 79 (92.4 mg, 0.380 mmol, 55%) as a colorless viscous
oil, Rf 0.38 (EtOAc/hexanes ) 1:4). Spectral data indicated a
mixture of the aldehyde with its glycolate (hydrated aldehyde),
which was used in the next step without further purification
and characterization.
(3-E t h oxyca r b on ylb icyclo[2.2.1]h ep t a -2,5-d ien -2-yl-
m eth oxy)a ceta ld eh yd e (80). Following the above general
procedure using alcohol 75 (130.1 mg, 0.546 mmol). The crude
product was purified by column chromatography (EtOAc/
hexanes ) 5:95) to give 80 (93.0 mg, 0.394 mmol, 72%) as a
colorless viscous oil, Rf 0.20 (EtOAc/hexanes ) 1:4). Spectral
data indicated a mixture of the aldehyde with its glycolate
(hydrated aldehyde), which was used in the next step without
further purification and characterization.
Gen er a l P r oced u r e for in Situ F or m a tion of Nitr on es
fr om th e Cor r esp on d in g Ald eh yd es a n d Su bsequ en t
In tr a m olecu la r 1,3-Dip ola r Cycloa d d ition s (Syn th esis of
Cycloa d d u cts 49, 50, 51, 52, 53, 54, 55, 81, 82, 83, 84, a n d
85).
2.9 Hz), 6.11 (dd, 1H, J ) 5.7, 3.3 Hz), 4.01 (s, 1H), 3.83 (d,
1H, J ) 10.0 Hz), 3.81 (d, 1H, J ) 9.4 Hz), 3.62 (dd, 1H, J )
10.0, 3.4 Hz), 3.35 (d, 1H, J ) 9.4 Hz), 2.88 (s, 1H), 2.80 (s,
1H), 2.71 (s, 3H), 2.68 (s, 1H), 2.08 (d, 1H, J ) 9.0 Hz), 1.67
(dd, 1H, J ) 9.0, 1.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 137.9,
135.9, 91.1, 78.4, 76.7, 71.3, 70.7, 46.53, 46.50, 46.35, 44.0.
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82. Found: C, 68.52;
H, 7.83.
(4a S*,6a R*,7R*,10S*,10a R*)-1,2,4a ,5,6a ,7-Hexa h yd r o-5-
m eth yl-7,10-m eth an o-4H,10H-pyr an o[3,4-c][1,2]ben z-isox-
a zole (Cycloa d d u ct 52). Following the above general proce-
dure using aldehyde 39 (97.4 mg, 0.545 mmol), the crude
product was purified by column chromatography (EtOAc/
hexanes ) 1:3) to give cycloadduct 52 (68.1 mg, 0.329 mmol,
60%) as a colorless viscous oil: Rf 0.17 (EtOAc/hexanes ) 2:3);
IR (neat, NaCl) 3091 (m), 2955 (s), 2848 (s), 2772 (m), 1434
(s), 1338 (s), 1136 (s), 1064 (s), 1040 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 6.28 (dd, 1H, J ) 5.7, 3.0 Hz), 6.05 (dd, 1H, J )
5.7, 3.3 Hz), 3.86 (dt, 1H, J ) 10.9, 4.6 Hz), 3.77 (dABd, 1H, J
) 13.0, 1.9 Hz), 3.67 (dABd, 1H, J ) 13.0, 4.0 Hz), 3.61 (s, 1H),
3.42 (td, 1H, J ) 11.2, 3.0 Hz), 2.76 (s, 1H), 2.67 (s, 3H), 2.68
(s, 1H), 2.23 (s, 1H), 2.12 (d, 1H, J ) 9.2 Hz), 1.96 (m, 1H),
1.70 (dd, 1H, J ) 9.2, 1.4 Hz), 1.46 (dt, 1H, J ) 14.5, 3.1 Hz);
13C NMR (CDCl3, 100 MHz) δ 139.2, 133.9, 89.5, 70.7, 64.1,
63.6, 57.0, 45.7, 45.4, 45.1, 43.5, 31.6; HRMS calcd for C12H17-
NO2 m/z 207.1259, found m/z 207.1260.
(4a R*,6a R*,7R*,10S*,10a R*)-3,4,4a ,5,6a ,7-H exa h yd r o-
5-m e t h y l-7,10-m e t h a n o -1H ,10H -p y r a n o [4,3-c ][1,2]-
ben zisoxa zole (Cycloa d d u ct 53). Following the above gen-
eral procedure using aldehyde 44 (71.4 mg, 0.401 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 2:3) to give cycloadduct 53 (39.0 mg, 0.188 mmol,
47%) as a colorless viscous oil: Rf 0.32 (EtOAc); IR (neat, NaCl)
3063 (w), 2961 (s), 2861 (s), 2774 (w), 1459 (m), 1430 (m), 1110
(s), 954 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.36 (dd, 1H, J
) 5.7, 3.0 Hz), 6.04 (dd, 1H, J ) 5.7, 3.3 Hz), 3.73 (ddd, 1H, J
) 11.0, 5.9, 2.7 Hz), 3.59 (dAB, 1H, J ) 12.1 Hz), 3.54 (dAB, 1H,
J ) 12.1 Hz), 3.52 (dd, 1H, J ) 11.3, 3.5 Hz), 3.48 (s, 1H),
2.76 (br s, 1H), 2.72 (br s, 1H), 2.68 (s, 3H), 2.47 (m, 1H), 2.17
(d, 1H, J ) 9.2 Hz), 1.71 (d, 1H, J ) 9.2 Hz), 1.97 (m, 1H),
1.61 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 139.6, 134.1, 86.8,
70.8, 68.0, 62.9, 58.9, 45.7, 45.4, 44.5, 43.3, 24.5. Anal. Calcd
for C12H17NO2: C, 69.54; H, 8.27. Found: C, 69.82; H, 8.31.
Cycloa d d u ct 54. Following the above general procedure
using aldehyde 40 (75.9 mg, 0.395 mmol), the crude product
was purified by column chromatography (EtOAc/hexanes )
2:3) to give cycloadducts 54 (45.6 mg, 0.206 mmol, 52%, as a
mixture of two major and one minor isomers) as a colorless
viscous oil: Rf 0.09 (EtOAc/hexanes ) 2:3); IR (neat, NaCl)
3059 (w), 2951 (s), 2845 (s), 2774 (w), 1434 (m), 1331 (m), 1296
(3a R*,5a R*,6R*,9S*,9a R*)-2,3,3a ,4,5a ,6-H exa h yd r o-4-
m et h yl-6,9-m et h a n o-1H ,9H -b en zo[d ]cyclop en t [c]isox-
a zole (Cycloa d d u ct 49). Aldehyde 271b (101 mg, 0.624 mmol)
in toluene (10 mL) was added to a flame-dried flask containing
4 Å molecular sieves (15 mg). Pyridine (0.2 mL, 2.50 mmol)
followed by N-methylhydroxylamine (103 mg, 1.25 mmol) was
added to the reaction mixture at room temperature. The
reaction mixture was stirred at room temperature for 15 h,
and TLC indicated the disappearance of the aldehyde 27. The
reaction mixture was stirred at 90 °C for 69 h. The solvent
was removed by rotary evaporation, and the crude product was
purified by column chromatography (EtOAc/hexanes ) 1:4) to
give cycloadduct 49 (60.8 mg, 0.318 mmol, 51%) as a colorless
viscous oil: Rf 0.43 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3063 (w), 2954 (s), 2857 (s), 1440 (m), 1328 (s), 1136 (w), 1046
1
(s) cm-1; H NMR (CDCl3, 400 MHz) δ 6.24 (dd, 1H, J ) 5.7,
3.0 Hz), 6.00 (dd, 1H, J ) 5.7, 3.2 Hz), 3.72 (s, 1H), 2.76 (br s,
1H), 2.61 (s, 3H), 2.55 (d, 1H, J ) 4.6 Hz), 2.45 (br s, 1H), 1.99
(d, 1H, J ) 8.8 Hz), 1.82 (m, 1H), 1.44-1.60 (m, 5H), 1.27 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ 139.3, 134.3, 91.1, 78.8,
69.4, 48.7, 46.5, 46.3, 43.8, 36.5, 30.6, 25.0; HRMS calcd for
C
12H17NO m/z 191.1310, found m/z 191.1309.
(m), 1262 (m), 1242 (m), 1122 (m), 886 (m) cm-1 1H NMR
;
(1S*,4R*,4aR*,6aR*,10aR*)-4,4a,6,6a,7,8,9,10-octah ydr o-
(CDCl3, 400 MHz) δ 6.25 (dd, 1H, J ) 5.6, 2.8 Hz), 6.21 (dd,
1H, J ) 5.6, 2.8 Hz), 6.08 (dd, 1H, J ) 5.4, 3.0 Hz), 5.97 (dd,
1H, J ) 5.4, 3.1 Hz), 3.98 (m, 2H), 3.86 (m, 2H), 3.60 (m, 2H),
3.30 (m, 2H), 2.95 (s, 1H), 2.88 (s, 1H), 2.83 (s, 3H), 2.80 (s,
3H), 2.76 (s, 2H), 2.71 (s, 2H), 2.13 (m, 2H), 2.00 (m, 2H), 1.80-
1.94 (m, 3H), 1.53-1.63 (m, 3H), 1.46 (m, 2H), 1.27 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 141.3, 140.6, 133.3, 133.2, 66.7,
66.4, 65.4, 52.4, 48.5, 48.4, 48.0, 47.8, 46.3, 46.1, 45.6, 45.2,
41.5, 40.3, 35.5, 25.4, 24.6; HRMS calcd for C13H19NO2 m/z
221.1416, found m/z 221.1420.
6-m eth yl-1,4-m eth a n o-1H-d iben z[c,d ]isoxa zole (Cycloa d -
d u ct 50). Following the above general procedure using alde-
hyde 28 (217.8 mg, 1.21 mmol), the crude product was purified
by column chromatography (EtOAc/hexanes ) 5:95) to give
cycloadduct 50 (46.2 mg, 0.225 mmol, 19%) as a colorless
viscous oil: Rf 0.32 (EtOAc/hexanes ) 1:4); IR (neat, NaCl)
3061 (m), 2938 (s), 2863 (s), 2771 (m), 1456 (s), 1432 (s), 1326
1
(s), 1034 (s), 716 (s) cm-1; H NMR (CDCl3, 400 MHz) δ 6.28
(dd, 1H, J ) 5.6, 3.0 Hz), 6.02 (dd, 1H, J ) 5.6, 3.2 Hz), 3.56
(s, 1H), 2.75 (s, 1H), 2.67 (s, 3H), 2.50 (s, 1H), 2.32 (t, 1H, J )
5.4 Hz), 2.13 (d, 1H, J ) 9.1 Hz), 1.65-1.33 (m, 9H); 13C NMR
(CDCl3, 100 MHz) δ 139.9, 133.2, 88.9, 71.4, 59.4, 46.3, 45.7,
45.3, 43.5, 29.3, 23.7, 19.9, 18.5. Anal. Calcd for C13H19NO:
C, 76.06; H, 9.33. Found: C, 75.71; H, 9.37.
(3a R*,5a S*,6S*,9R*,9a S*)-3a ,4,5a ,6-Tetr a h yd r o-4-m eth -
yl-6,9-m eth a n o-1H,3H,9H-fu r o[3,4-c][1,2]ben zisoxa zol-3-
on e (Cycloa d d u ct 55). Following the above general procedure
using aldehyde 48 (93.5 mg, 0.477 mmol), the crude product
was purified by column chromatography (EtOAc/hexanes ) 15:
85) to give cycloadduct 55 (42.0 mg, 0.203 mmol, 43%) as white
solids. Recrystallization from 20% EtOAc/hexanes provided
crystals suitable for X-ray analysis:12 Rf 0.49 (EtOAc/hexanes
) 2:3); IR (neat, NaCl) 3077 (w), 2971 (m), 2913 (m), 2877 (w),
(3aS*,5aR*,6R*,9S*,9aR*)-3a ,4,5a ,6-Tetr a h yd r o-4-m eth -
yl-6,9-m et h a n o-1H ,3H ,9H -fu r o[3,4-c][1,2]b en zisoxa zole
(Cycloa d d u ct 51). Following the above general procedure
using aldehyde 38 (132.3 mg, 0.806 mmol), the crude product
was purified by column chromatography (EtOAc/hexanes )
1:1) to give cycloadduct 51 (110.8 mg, 0.573 mmol, 71%) as a
colorless viscous oil: Rf 0.24 (EtOAc ) 100%); IR (neat, NaCl)
3068 (m), 2968 (s), 2851 (s), 2781 (m), 1471 (m), 1460 (m), 1329
2852 (w), 1774 (s), 1382 (w), 1328 (w), 1205 (w), 1179 (w) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 6.35 (dd, 1H, J ) 5.6, 2.9 Hz),
6.21 (dd, 1H, J ) 5.6, 3.3 Hz), 4.37 (d, 1H, J ) 9.8 Hz), 4.10
(s, 1H), 3.99 (d, 1H, J ) 9.8 Hz), 3.03 (s, 1H), 2.89 (s, 2H),
2.85 (s, 3H), 2.10 (m, 1H), 1.80 (m, 1H); 13C NMR (CDCl3, 100
1
(s) cm-1; H NMR (CDCl3, 400 MHz) δ 6.26 (dd, 1H, J ) 5.7,

Cycloadditions of Norbornadiene-Tethered Nitrones
J . Org. Chem., Vol. 66, No. 15, 2001 5123
MHz) δ 172.3, 137.11, 137.08, 92.4, 74.7, 45.9, 45.8, 44.4. Anal.
Calcd for C11H13NO3: C, 63.76; H, 6.32. Found: C, 63.82; H,
6.30.
hexanes ) 1:3) to give cycloadduct 84 (11.5 mg, 0.0423 mmol,
15%) as a clear, light brown oil that was found to be a mixture
of two isomers in a ratio of 60:40: Rf 0.23 (EtOAc/hexanes )
2:3); IR (neat, NaCl) 3073 (m), 2986 (s), 2961 (s), 2876 (s), 2853
(3aS*,5aR*,6R*,9S*,9aR*)-3a,4,6-Tr ih ydr o-4,5a-dim eth yl-
6,9-m eth a n o-1H,3H,9H-fu r o[3,4-c][1,2]ben zisoxa zole (Cy-
cloa d d u ct 81). Following the above general procedure using
aldehyde 76 (60.2 mg, 0.338 mmol), the crude product was
purified by column chromatography (EtOAc/hexanes ) 1:3) to
give cycloadduct 81 (37.3 mg, 0.180 mmol, 53%) as a clear,
light brown oil: Rf 0.28 (EtOAc/hexanes ) 2:3); IR (neat, NaCl)
3062 (w), 2965 (s), 2865 (s), 2776 (w), 1454 (s), 1364, (m), 1325
(s), 2784, (w), 1467 (m), 1325 (m), 1061 (s) cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 6.24 (m, 2H), 4.28 (d, 0.6H, J ) 10.0 Hz),
4.22 (d, 0.4H, J ) 10.0 Hz), 4.01 (d, 0.6H, J ) 10.4 Hz), 3.98
(d, 0.4H, J ) 10.4 Hz), 3.64 (dt, 1H, J ) 10.4, 3.4 Hz), 3.44 (d,
0.6H, J ) 10.0 Hz), 3.41 (m, 0.6H), 3.37 (d, 0.4H, J ) 10.0
Hz), 3.26 (m, 0.4H), 3.12 (d, 0.6H, J ) 3.4 Hz), 3.09 (d, 0.4H,
J ) 3.4 Hz), 2.83 (s, 1.8H), 2.82 (s, 1.2H), 2.78 (m, 1H), 2.08
(d, 1H, J ) 9.6 Hz), 1.78 (d, 1H, J ) 9.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 137.8, 137.1, 136.2, 136.0, 79.8, 79.5, 77.2, 74.9,
71.0, 55.2, 53.7, 47.7, 47.1, 46.4, 46.3, 44.2, 44.1; HRMS calcd
for C11H14NBrO2 m/z 271.0208, found m/z 271.0200.
1
(m), 1160 (m), 1081 (m) cm-1; H NMR (CDCl3, 400 MHz) δ
6.17 (m, 2H), 3.84 (d, 1H, J ) 10.0 Hz), 3.69 (d, 1H, J ) 10.0
Hz), 3.56 (dd, 1H, J ) 10.0, 3.4 Hz), 3.21 (d, 1H, J ) 10.0 Hz),
2.89 (d, 1H, J ) 3.4 Hz), 2.71 (s, 1H), 2.69 (s, 1H), 2.68 (s,
3H), 2.20 (d, 1H, J ) 8.8 Hz), 1.57 (dm, 1H, J ) 8.8 Hz), 1.28
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 137.3, 136.0, 93.2, 79.5,
73.2, 72.2, 71.1, 51.2, 48.8, 46.4, 44.0, 19.9. Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27. Found: C, 69.53; H, 8.06.
(3a S*,5a R*,6R*,9S*,9a R*)-3a ,4,6-Tr ih yd r o-4-m et h yl-
5a -p h e n y l-6,9-m e t h a n o -1H ,3H ,9H -fu r o [3,4-c ][1,2]-
ben zisoxa zole (Cycloa d d u ct 82). Following the above gen-
eral procedure using aldehyde 77 (45.6 mg, 0.190 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 1:3) to give cycloadduct 82 (20.8 mg, 0.0772 mmol,
41%) as a clear, light brown oil: Rf 0.58 (EtOAc/hexanes )
2:3); IR (neat, NaCl) 3059 (w), 2959 (s), 2869 (s), 2847 (s), 2778
(3a S*,5a R*,6R*,9S*,9a R*)-3a ,4,6-Tr ih yd r o-5a -et h oxy-
ca r b on yl-4-m et h yl-6,9-m et h a n o-1H ,3H ,9H -fu r o[3,4-c]-
[1,2]ben zisoxa zole (Cycloa d d u ct 85). Following the above
general procedure using aldehyde 80 (93.0 mg, 0.394 mmol),
the crude product was purified by column chromatography
(EtOAc/hexanes ) 1:3) to give cycloadduct 85 (61.1 mg, 0.230
mmol, 57%) as a clear, light brown oil: Rf 0.15 (EtOAc/hexanes
) 2:3); IR (neat, NaCl) 3068 (w), 2981 (s), 2872 (s), 2872 (s),
2848 (s), 2779, (w), 1719 (vs), 1454 (m), 1264 (s), 1098 (s), 1058
1
(s), 915 (m) cm-1; H NMR (CDCl3, 400 MHz) δ 6.20 (dd, 1H,
J ) 5.6, 2.8 Hz), 6.18 (dd, 1H, J ) 5.6, 2.8 Hz), 4.18 (m, 2H),
4.11 (d, 1H J ) 10.0 Hz), 3.84 (d, 1H, J ) 10.0 Hz), 3.58 (dd,
1H, J ) 10.0, 4.0 Hz), 3.21 (d, 1H, J ) 10.0 Hz), 2.96 (s, 1H),
2.93 (d, 1H, J ) 4.0 Hz), 2.77 (s, 1H), 2.73 (s, 3H), 2.16 (d, 1H,
J ) 9.2 Hz), 1.63 (d, 1H, J ) 9.2 Hz), 1.24 (t, 3H, J ) 7.2 Hz);
13C NMR (CDCl3, 100 MHz) δ 171.0, 137.0, 135.6, 94.7, 79.3,
77.1, 72.9, 70.7, 61.0, 50.0, 48.7, 46.5, 44.2, 14.1. Anal. Calcd
for C14H19NO4: C, 63.38; H, 7.22. Found: C, 63.58; H, 7.29.
(w), 1498 (m), 1446 (m), 1241 (m), 912 (m) cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 7.67 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1H),
6.34 (dd, 1H, J ) 5.6, 3.2 Hz), 6.24 (dd, 1H, J ) 5.6, 3.2 Hz),
3.95 (d, 1H, J ) 10.0 Hz), 3.72 (dd, 1H, J ) 9.6, 4.0 Hz), 3.70
(d, 1H, J ) 10.0 Hz), 3.28 (d, 1H, J ) 9.6 Hz), 3.25 (m, 1H),
3.08 (d, 1H, J ) 4.0 Hz), 2.88 (m, 1H), 2.76 (s, 3H), 2.41 (dm,
1H, J ) 8.8 Hz), 1.76 (dt, 1H, J ) 8.8, 1.6 Hz); 13C NMR
(CDCl3, 100 MHz) δ 141.3, 138.1, 135.9, 128.0, 127.9, 127.1,
97.1, 80.2, 75.7, 73.6, 71.0, 50.8, 49.3, 46.9, 44.1. Anal. Calcd
for C17H19NO2: C, 75.81; H, 7.11. Found: C, 76.02; H, 7.01.
(3a S*,5a R*,6R*,9S*,9a R*)-3a ,4,6-Tr ih yd r o-5a -ch lor o-
4 -m e t h y l -6 ,9 -m e t h a n o -1H ,3 H ,9 H -fu r o [3 ,4 -c ][1 ,2 ]-
ben zisoxa zole (Cycloa d d u ct 83). Following the above gen-
eral procedure using aldehyde 78 (73.0 mg, 0.367 mmol), the
crude product was purified by column chromatography (EtOAc/
hexanes ) 1:3) to give cycloadduct 83 (38.7 mg, 0.170 mmol,
46%) as a clear, light brown oil: Rf 0.24 (EtOAc/hexanes )
2:3); IR (neat, NaCl) 3073 (w), 2988 (s), 2962 (s), 2878 (s), 2850
(s), 2782, (w), 1467 (m), 1325 (m), 1141 (m), 1098 (m), 1061
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council (NSERC) of Canada
and the University of Guelph for the generous financial
support of our program. W.T. thanks Boehringer Ingel-
heim (Canada) Ltd. for a Young Investigator Award, and
G.K.T. thanks the Ontario government and NSERC
(Canada) for postgraduate scholarships (OGS and
NSERC PGS B). Mr. Peter Keech is thanked for
preliminary experiments. Mr. Peter Khoury and Profes-
sor J ohn D. Goddard are thanked for semiempirical
molecular mechanics calculations. Professor George
Ferguson and Dr. Alan J . Lough are thanked for X-ray
structure determination, and Ms. Valerie Robertson is
thanked for NMR experiments and discussion of NMR
data.
1
(s), 912 (m) cm-1; H NMR (CDCl3, 400 MHz) δ 6.27 (dd, 1H,
J ) 6.0, 3.2 Hz), 6.22 (dd, 1H, J ) 6.0, 3.2 Hz), 4.12 (d, 1H, J
) 10.0 Hz), 3.96 (d, 1H, J ) 10.0 Hz), 3.63 (dd, 1H, J ) 10.0,
3.2 Hz), 3.35 (d, 1H, J ) 10.0 Hz), 3.25 (m, 1H), 3.08 (d, 1H,
J ) 3.2 Hz), 2.82 (m, 1H), 2.80 (s, 3H), 2.07 (dm, 1H, J ) 9.2
Hz), 1.77 (dt, 1H, J ) 9.2, 1.6 Hz); 13C NMR (CDCl3, 100 MHz)
δ 137.0, 136.1, 117.8, 79.5, 76.2, 74.9, 70.9, 53.7, 47.6, 46.3,
44.1; HRMS calcd for C11H14NClO2 m/z 227.0713, found m/z
227.0710.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C (APT)
NMR spectra for compounds 34, 38, 39, 43-49, 52, 54, 61-
1
66, 70-72, 74, 75, 83, and 84; X-ray structure of 55; H, 13C
(3a S*,5a R*,6R*,9S*,9a R*)-3a ,4,6-Tr ih yd r o-5a -b r om o-
4 -m e t h y l -6 ,9 -m e t h a n o -1H ,3 H ,9 H -fu r o [3 ,4 -c ][1 ,2 ]-
ben zisoxa zole (Cycloa d d u ct 84). Following the above gen-
eral procedure using aldehyde 79 (68.8 mg, 0.283 mmol), the
crude product was purified by column chromatography (EtOAc/
(APT) NMR, HCOSY, HSQC, and GOESY spectra for cycload-
duct 81. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O015610B