Intramolecular carbolithiation reactions for the preparation of azabicyclo [2.2.1] heptanes

Article abstract of DOI:10.1021/jo000088z

Tin-lithium exchange and intramolecular carbolithiation (anionic cyclization) have been used to construct the three nitrogen-positional isomers of the azabicyclo[2.2.1]heptane ring system. The 7- azabicyclo[2.2.1]heptane ring system is accessed from either diastereomer of a 2,5-disubstituted pyrrolidine, via a chiral organolithium intermediate. The 2-azabicyclo[2.2.1]heptane ring system is formed stereoselectively in low yield by a tandem cyclization, together with the product from monocyclization. Better yields of the 2-aza ring system can be obtained using an alternative approach from a 2-tributylstannyl-4-allylpyrrolidine, despite the trans arrangement of the tin (and, hence, lithium) atom and the allyl unit. The 1-azabicyclo[2.2.1]heptane ring system is accessed in just three steps from 4-piperidone.

Full text of DOI:10.1021/jo000088z

3788
J . Org. Chem. 2000, 65, 3788-3795
In tr a m olecu la r Ca r bolith ia tion Rea ction s for th e P r ep a r a tion of
Aza bicyclo[2.2.1]h ep ta n es
Iain Coldham,* J oan-Carles Ferna`ndez, Kathy N. Price, and David J . Snowden
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, U.K.
Received J anuary 22, 2000
Tin-lithium exchange and intramolecular carbolithiation (anionic cyclization) have been used to
construct the three nitrogen-positional isomers of the azabicyclo[2.2.1]heptane ring system. The
7-azabicyclo[2.2.1]heptane ring system is accessed from either diastereomer of a 2,5-disubstituted
pyrrolidine, via a chiral organolithium intermediate. The 2-azabicyclo[2.2.1]heptane ring system
is formed stereoselectively in low yield by a tandem cyclization, together with the product from
monocyclization. Better yields of the 2-aza ring system can be obtained using an alternative approach
from a 2-tributylstannyl-4-allylpyrrolidine, despite the trans arrangement of the tin (and, hence,
lithium) atom and the allyl unit. The 1-azabicyclo[2.2.1]heptane ring system is accessed in just
three steps from 4-piperidone.
Sch em e 1
In tr od u ction
The formation of a carbon-carbon bond by an intra-
molecular carbolithiation (anionic cyclization) reaction to
give a cyclopentane ring system has been gaining in-
creasing use for organic synthesis.1 Anionic cyclization
offers a valuable alternative to the related radical cy-
clization and indeed can be successful where the radical
chemistry fails and can provide enhanced or complemen-
tary stereoselectivity. The extension of this chemistry to
heterocyclic systems has proven possible using aryl- or
vinyllithium species, normally generated by halogen-
lithium exchange,2 or using alkyllithium species gener-
ated by tin-lithium exchange3 or by proton abstraction.4
This chemistry has provided a convenient route to
pyrrolidine, tetrahydrofuran, indoline, pyrrolizidine, and
indolizidine ring systems. As a further development in
this area, we wished to extend the range of products that
can be accessed by such anionic cyclizations by applying
this methodology to the preparation of the three types
of nitrogen-positional isomers of the azabicyclo[2.2.1]-
heptanes. These ring systems are present in a number
of natural products and biologically active compounds.5
The three isomers are shown in Scheme 1, together with
one type of disconnection of a derivative (containing a
methyl group â- to the nitrogen atom) for each substrate.
In all cases, these disconnections allow the use of an
R-amino-organolithium species (formed by tin-lithium
exchange), followed by anionic cyclization onto an alkene.
Resu lts a n d Discu ssion
7-Aza bicyclo[2.2.1]h ep ta n es. Only one type of dis-
connection, as outlined in Scheme 1, is possible for the
preparation of the 7-azabicyclo[2.2.1]heptane ring system
using an anionic cyclization with an R-aminoorgano-
lithium species.6 A pyrrolidine substrate is required, in
which the initial 2-lithio species, generated by tin-
lithium exchange, is attached to a chiral carbon center.
With an allyl group in the 5-position of the pyrrolidine
ring, this gives rise to two diastereomeric organolithium
species, one with the lithium atom cis to the allyl unit
and one trans to it. Anionic cyclization reactions onto
unactivated alkenes are thought to proceed by initial
coordination of the lithium atom to the alkene π-bond,
followed by insertion across the double bond (carbolithia-
tion). Evidence for this comes from calculations,7 NMR
experiments,8 the enhanced stability of organolithium
species containing a suitably positioned π-bond,9,10 and
(1) For an example, see: J amison, T. F.; Shambayati, S.; Crowe,
W. E.; Schreiber, S. L. J . Am. Chem. Soc. 1997, 119, 4353.
(2) (a) Barluenga, J .; Sanz, R.; Granados, A.; Fan˜ana´s, F. J . J . Am.
Chem. Soc. 1998, 120, 4865. (b) Nishiyama, H.; Sakata, N.; Sugimoto,
H.; Motoyama, Y.; Wakita, H.; Nagase, H. Synlett 1998, 930. (c)
Comins, D. L.; Zhang, Y. J . Am. Chem. Soc. 1996, 118, 12248. (d)
Zhang, D.; Liebeskind, L. S. J . Org. Chem. 1996, 61, 2594. (e) Bailey,
W. F.; J iang, X.-L. J . Org. Chem. 1996, 61, 2596.
(3) (a) Coldham, I.; Hufton, R.; Rathmell, R. E. Tetrahedron Lett.
1997, 38, 7617. (b) Coldham, I.; Hufton, R. Tetrahedron 1996, 52,
12541. (c) Lautens, M.; Kumanovic, S. J . Am. Chem. Soc. 1995, 117,
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Wibbeling, B.; Hoppe, D. Synlett 1998, 797. (d) Tomooka, K.; Komine,
N.; Sasaki, T.; Shimizu, H.; Nakai, T. Tetrahedron Lett. 1998, 39, 9715.
(5) Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
(6) Coldham, I.; Ferna`ndez, J .-C.; Snowden, D. J . Tetrahedron Lett.
1999, 40, 1819.
(7) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.;
Rossi, K.; Thiel, Y.; Wiberg, K. B. J . Am. Chem. Soc. 1991, 113, 5720.
(8) Ro¨lle, T.; Hoffmann, R. W. J . Chem. Soc., Perkin Trans. 2 1995,
1953.
10.1021/jo000088z CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/20/2000

Preparation of Azabicyclo[2.2.1]heptanes
J . Org. Chem., Vol. 65, No. 12, 2000 3789
Sch em e 2a
from the known stereoselectivity of the cyclization, which
occurs with retention of configuration at the carbanion
center.10,11 It would seem apparent therefore, that only
the diastereomer in which the lithium atom and allyl
units are cis to one another would be aligned for cycliza-
tion. We therefore wished to test the ability of both the
cis and the trans diastereomers to undergo cyclization.
The 2-allylpyrrolidine 1 was prepared from N-Boc-
pyrrolidine by proton abstraction with 1.2 equiv of sec-
butyllithium (with TMEDA as external ligand) and
trapping with allyl bromide.12 At this stage, we needed
to introduce the tin group on the other side of the
nitrogen atom from the allyl group using similar meth-
odology. Proton abstraction of N-Boc-2-alkylpyrrolidines
with sec-butyllithium in Et2O and TMEDA is a known
process.13 However, under these conditions, N-Boc-2-
allylpyrrolidine 1 gave only a mixture of the recovered
starting material and some of the diene 3. Deprotonation
at C-5 was successful using the ligand (-)-sparteine,
rather than TMEDA. Treatment of the pyrrolidine 1 with
sec-butyllithium and (-)-sparteine in Et2O at -78 °C for
4 h, followed by addition of Bu3SnCl and allowing the
mixture to warm slowly to room temperature, gave an
equal mixture of the two diastereomeric (cis and trans)
racemic pyrrolidines 2 in 25% yield (eq 1). There was no
asymmetric kinetic resolution in this process, and the
recovered starting material 1 (10%) was racemic. Other
products isolated from this reaction included the diene
3 (24%) and the stannane 4 (15%). Despite the poor yield
of the pyrrolidines 2, this represented a very short (two
step) and convenient route to the desired 2,5-disubsti-
tuted pyrrolidine.
a
Key: (i) B-bromocatechol borane, CH2Cl2, then NaOH, Ph-
COCl; (ii) AlH3, Et2O.
(Scheme 2). The amides 5a and 5b were separable by
chromatography over silica gel. Reduction of each amide
using alane15 gave the cis- and trans-pyrrolidines 6a and
6b (79% and 71% yields, respectively). The stereochem-
istry of these amines was confirmed by 1H NMR NOESY
studies. Alternatively, the N-Boc-pyrrolidines 2 (mixture
of cis and trans isomers) could be converted directly to
the mixture of diastereomeric N-benzylpyrrolidines 6
(45%) using B-bromocatecholborane, followed by trapping
with benzyl bromide.
With the separated N-benzylpyrrolidines 6 in hand, we
were ready to test whether the anionic cyclization would
take place from either or both diastereomers. We were
pleased to find that, on treatment of the cis isomer 6a
with n-butyllithium, the 7-azabicyclo[2.2.1]heptane 7 was
formed in good yield and as a single diastereomer (eq 2).
The stereochemistry of the product 7 (exo) was assigned
by NOESY experiments and by analogy with the prefer-
ence for a chairlike conformation in the transition state,
as observed in other examples.7,10 The transmetalation
was most effective using the mixed solvent system
hexanes-Et2O-THF (4:1:1) with warming from -78 °C
to room temperature (essentially no transmetalation
takes place below 0 °C). Somewhat surprisingly, the use
of THF alone did not promote transmetalation, even at
room temperature. Treatment of the corresponding trans-
pyrrolidine 6b with n-butyllithium also gave the desired
exo-2-methyl-7-azabicyclo[2.2.1]heptane 7 (eq 3). As tin-
lithium exchange is expected to occur with retention of
configuration,16 this result suggests that the organo-
lithium species derived from the trans isomer 6b epimer-
izes17 to the cis isomer before cyclization. Alternative
explanations include an anionic cyclization with inversion
of configuration at the organolithium center (although
anionic cyclizations have been shown to proceed with
retention of configuration10) or the formation of an ion
pair, with cyclization from the carbanion.18 The ability
to form the same 7-azabicyclo[2.2.1]heptane ring from
either diastereomer of the starting stannane is particu-
larly noteworthy.
We have reported previously that an anionic cyclization
of an N-Boc derivative was unsuccessful,3b and consistent
with this, treatment of the pyrrolidines 2 with n-butyl-
lithium gave no identifiable cyclized products. Trans-
metalation of 2 does occur, to give tetrabutyltin, but the
only other products were very polar, indicating loss of
the N-Boc group. Conversion of the N-Boc group to an
N-alkyl group was carried out using either a one- or a
two-step procedure. Addition of 2 equiv of B-bromocate-
cholborane,14 followed by trapping the resulting N-
unsubstituted pyrrolidine with benzoyl chloride, gave a
mixture of the diastereomeric amides 5 in 80% yield
(9) Gawley, R. E.; Zhang, Q.; Campagna, S. J . Am. Chem. Soc. 1995,
117, 11817.
(10) Coldham, I.; Hufton, R.; Snowden, D. J . J . Am. Chem. Soc. 1996,
(15) Burchat, A. F.; Chong, J . M.; Nielsen, N. J . Org. Chem. 1996,
61, 7627.
118, 5322.
(16) (a) Still, W. C.; Sreekumar, C. J . Am. Chem. Soc. 1980, 102,
1201. (b) Sawyer, J . S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G.
J . J . Am. Chem. Soc. 1988, 110, 842. (c) Pearson, W. H.; Lindbeck, A.
C. J . Am. Chem. Soc. 1991, 113, 8546. (d) Weisenburger, G. A.; Faibish,
N. C.; Pippel, D. J .; Beak, P. J . Am. Chem. Soc. 1999, 121, 9522.
(17) Amano, S.; Fujiwara, K.; Murai, A. Chem. Lett. 1998, 409.
(18) Hoffmann, R. W.; Koberstein, R.; Harms, K. J . Chem. Soc.,
Perkin Trans. 2 1999, 183.
(11) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron Lett. 1997,
38, 8939.
(12) Beak, P.; Lee W. K. J . Org. Chem. 1993, 58, 1109.
(13) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc. 1994,
116, 3231.
(14) Boeckman, R. K.; Potenza, J . C. Tetrahedron Lett. 1985, 26,
1411.

3790 J . Org. Chem., Vol. 65, No. 12, 2000
Coldham et al.
Sch em e 3a
a
Key: (i) PhCOCl, Et3N, Et2O; (ii) LiAlH4, THF, 0 °C; (iii)
(COCl)2, DMSO, CH2Cl2, -60 °C then Et3N; (iv) Ph3PMeBr,
tBuOK, THF; (v) NaH, ICH2SnBu3, THF, rt, 3 d; (vi) AlH3, Et2O,
-78 °C to rt.
After anionic cyclization, it is possible to add an
electrophile to the resulting organolithium species in
order to prepare a variety of substituted cyclic amine
products.3b,6 The addition of electrophiles was investi-
gated with the 7-azabicyclo[2.2.1]heptanes to give the
2-substituted products 8 (eq 4). The yields of the substi-
tuted products are modest to good, and care must be
taken to purify the electrophile in order to avoid the
formation of the protonated 2-methyl product 7. This
methodology therefore allows a rapid access to 2-substi-
tuted 7-azabicyclo[2.2.1]heptane derivatives with com-
plete stereochemical control in favor of the exo diastere-
omer.
2-Aza bicyclo[2.2.1]h ep ta n es. There are two obvious
disconnections to the 2-azabicyclo[2.2.1]heptane ring
system that allow the use of an R-aminoorganolithium
species (formed by tin-lithium exchange), followed by
anionic cyclization onto an alkene. The first disconnection
(shown in Scheme 1) was chosen in order to investigate
the possibility of carrying out a cascade/tandem cycliza-
tion. Our previous work had demonstrated that it is
possible to prepare 2,4-disubstituted pyrrolidines as
predominantly (g6:1) the cis isomer.3a We expected
therefore that anionic cyclization of a 2-vinyl derivative
would generate a cis-2-vinyl-4-lithiomethylpyrrolidine in
which a second in situ cyclization would be possible. This
procedure would provide a method for the preparation
of a bicyclic product from an acyclic precursor with the
formation of two carbon-carbon bonds in a single opera-
tion. If the organolithium species formed after the second
cyclization could be trapped with carbon-based electro-
philes, then three carbon-carbon bonds could be formed
in one step.
ester 10, which was reduced to the alcohol 11 and
oxidized under Swern conditions20 to give the aldehyde
12. Wittig olefination using Ph3PMeBr and KOtBu in
THF gave the diene 13. This substrate is a carboxylic
amide rather than a secondary amine, so the alkylation
on the nitrogen atom is best performed using sodium
hydride and iodomethyltributyltin21 (rather than the
corresponding mesylate,21b used for the formation of
amines). Reduction of the amide 14 with alane15 gave
access to the desired substrate 15.
Transmetalation of the stannane 15 with n-butyl-
lithium in hexanes-Et2O (9:1) was very sluggish, and
the substrate 15 was recovered in this nonpolar solvent
mixture. Addition of THF allowed efficient transmeta-
lation of the stannane 15 to the organolithium species,
although no cyclization occurred at -78 °C. Warming to
room temperature did, however, effect cyclization (eq 5).
Two major products, the desired bicyclic amine 16 (22%)
and the pyrrolidine 17 (32%), were isolated using these
reaction conditions. The product 17 arises from monocy-
clization of the organolithium species to give the new
organolithium species 18. Protonation of this organo-
lithium species could occur on quenching the reaction;
however, extended reaction times did not enhance the
yield of the bicyclic product 16. Variation of the conditions
(including the use of TMEDA) did not improve this result,
and it appears that, although monocyclization to the
pyrrolidine ring occurs easily, the second cyclization is
slow. The mixture must be warmed to room temperature
to effect the transmetalation-cyclization, and at this
temperature organolithium species are known to abstract
a proton from THF.22 This proton abstraction seems to
compete with the second cyclization, thereby diminishing
the yield of the 2-azabicyclo[2.2.1]heptane product 16.
The product 16 was formed as a single stereoisomer with
endo stereochemistry, as verified by 1NMR NOESY
studies (see Supporting Information) and is consistent
The route to the substrate needed to test the cascade
cyclization is shown in Scheme 3. The known â-amino
ester 9 was prepared in two steps from butadiene,
according to the literature.19 N-Benzoylation gave the
(19) Zablocki, J . A.; Rico, J . G.; Garland, R. B.; Rogers, T. E.;
Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy, P. R.; Tjoeng, F. S.;
Lindmark, R. J .; Toth, M. V.; Zupec, M. E.; McMacins, D. E.; Adams,
S. P.; Markos, M. M. C. S.; Milton, M. N.; Paulson, S.; Herin, M.;
J acqmin, P.; Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N. F.; Page,
J . D.; Szalony, J . A.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion,
J . G.; Faigen, L. P. J . Med. Chem. 1993, 38, 2378.
(20) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(21) (a) Seyferth, D.; Andrews, S. B. J . Organomet. Chem. 1971, 30,
151. (b) Seitz, D. E.; Carroll, J . J .; Cartaya, C. P.; Lee, S.-H.; Zapata,
A. Synth. Commun. 1983, 13, 129. (c) Ahman, J .; Somfai, P. Synth.
Commun. 1994, 24, 1117.
(22) J ung, M. E.; Blum, R. B. Tetrahedron Lett. 1977, 3791.

Preparation of Azabicyclo[2.2.1]heptanes
J . Org. Chem., Vol. 65, No. 12, 2000 3791
Sch em e 4a
with cyclization in a chairlike conformation. On the basis
of previous studies on the anionic cyclization to give 2,4-
disubstituted pyrrolidine products,3a the product 17 was
assigned cis stereochemistry. The organolithium species
18 generated by monocyclization would therefore be of
the required stereochemistry to effect the second cascade/
tandem cyclization to give the 2-azabicyclo[2.2.1]heptane
product 16.
a
Key: (i) NaH, DMF, PhCH2Br; (ii) LDA, THF/HMPA,
CH2dCHCH2Br; (iii) AlH3, Et2O, 0 °C; (iv) nBuLi, hexane-Et2O
(4:1), -78 °C to rt, 16 h, then MeOH.
resulted in lower yields of the stannane 23. Reduction of
23 with alane gave the required pyrrolidine 25 (72%).
Tin-lithium exchange and anionic cyclization are
known to occur with retention of configuration at the
metal-bearing carbon center,10 so it may be anticipated
that the trans substrate 25 would be unsuitable for
cyclization. However, epimerization of organolithium
species is possible, and this would account for the
successful cyclization using the substrate trans-6b. Such
epimerization would generate the cis isomer, thereby
allowing Li-π complexation and subsequent cyclization.
We were pleased to find that treatment of the stannane
25 with n-butyllithium in hexanes-Et2O (4:1) gave the
desired 2-azabicyclo[2.2.1]heptane product 16 in reason-
able yield (60%). Conducting the transmetalation-cy-
clization in the presence of THF gave a mixture of
products predominantly (by NMR spectroscopy) with the
allyl unit intact and only a trace of the desired bicyclic
amine 16. Some of the protodestannylated pyrrolidine 26
(16%) was also isolated. The reaction mixture must be
warmed to room temperature to complete transmetala-
tion-cyclization, and this result suggests that epimer-
ization of the intermediate organolithium species can
take place, thereby generating the isomer with the
lithium and allyl units cis to one another, as required
for cyclization.
The related carbocyclic version of this cyclization has
been reported by Bailey (eq 6).23 Treatment of the iodide
19 with 2.2 equivalents of tert-butyllithium and TMEDA
at 0 °C for 4 min resulted in the formation, after the
addition of one of various electrophiles, of the bicyclo-
[2.2.1]heptanes 20 in high yield. Some monocyclized
product (∼10%) as the trans isomer was formed, but no
cis-1-ethenyl-3-methylcyclopentane was detected. It would
appear, therefore, that a nitrogen atom within our
substrate slows the intramolecular carbolithiation reac-
tion, possibly by coordination of the nitrogen lone pair
with the lithium atom. While monocyclization from an
R-aminoorganolithium species is high yielding, a second
cascade-type cyclization from a γ-aminoorganolithium
species is slow.
After the poor yield achieved in the preparation of the
2-azabicyclo[2.2.1]heptane ring system by the cascade/
tandem cyclization route, we studied an alternative route
using a second obvious disconnection. To carry out this
new synthetic approach, we needed to prepare the
stannane 21 (Scheme 4). This compound has been
reported;24 however, in our hands the final displacement
of the benzotriazole group for the tributyltin group using
Bu3SnH and LDA was very low yielding. We were pleased
to find, however, that the use of Bu3SnLi generated from
Bu6Sn2 and BuLi gave satisfactory yields (up to 75%) of
the stannane 21.
N-Benzylation of the stannane 21 gave the stannane
22 (72%). Enolization of 22 followed by allylation gave
the stannane 23 (51%) exclusively as the trans isomer
(by 1NMR NOESY studies). A small amount of the easily
separable diallylated compound 24 (18%) was also pro-
duced, in which a second allylation had occurred at the
benzylic position. Using LDA in the absence of HMPA
To our surprise, the only isomer isolated from the
anionic cyclization of the substrate 25 was the endo
product 16 and it was not possible to observe (by NMR
spectroscopy) any exo isomer. We had anticipated that
the anionic cyclization from the substrate 25 would
generate the exo isomer, based on a chair-shaped transi-
tion state (Figure 1). Anionic cyclization from the sub-
strates 15 and 19 give the expected endo-bicyclo[2.2.1]-
(23) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K. V. J . Am. Chem.
Soc. 1992, 114, 8053.
(24) Pearson, W. H.; Stevens E. P. J . Org. Chem. 1998, 63, 9812.

3792 J . Org. Chem., Vol. 65, No. 12, 2000
Coldham et al.
Sch em e 5a
a
Key: (i) MsOCH2SnBu3, MeCN, K2CO3, rt, 4 d; (ii) Ph3PMeBr,
nBuLi, THF, rt, 12 h; (iii) 2 equiv, nBuLi, hexane-Et2O (9:1) then
2 equiv of TMEDA, -78 °C to rt, 4 h, then -78 °C MeOH, then
picric acid.
F igu r e 1.
analogue, which cyclizes within 1 h at room temperature,
but within 11 min in the presence of TMEDA.27 It
appears therefore that the nitrogen atom slows the rate
of cyclization, presumably by coordination to the lithium
atom. Successful cyclization to the 1-azabicyclo[2.2.1]-
heptane ring system requires a transition state with boat-
shaped conformation for the six-membered ring.
heptane ring system, based on a chair-shaped transition
state. The product resulting from the anionic cyclization
of the stannane 25 was identical in every respect to that
from the stannane 15. It appears, therefore, that cycliza-
tion from the stannane 25 favors a boat-shaped transition
state (Figure 1). A possible explanation for this lies in
the expected coordination of the lithium atom to the
nitrogen lone pair.25 It is constructive to consider the
difference between the two isomeric organolithium spe-
cies generated from the stannanes 25 and 6a . These two
organolithium species differ only in the position of the
nitrogen atom in the five-membered ring. In both cases,
the observed product is that in which the transition state
has the alkene π-bond aligned on the same side as the
nitrogen atom. This backs up the evidence for lithium-π
complexation7-11 combined with coordination of the lithium
atom with the lone pair of the nitrogen atom.25,26 The
transition state from the stannane 6a would favor the
normal chair shape, as this places the alkene unit closer
to the lithium atom coordinated to the nitrogen lone pair,
whereas the boat-shape transition state is favored from
the stannane 25. Semiempirical molecular orbital calcu-
lations (MOPAC version 6.0, AM1 Hamiltonian) support
this postulate (in the gas phase), as the lowest energy
conformations of the organolithium species generated
from cis-25 and 6a resemble those shown in Figure 1,
with relatively short Li-π (2.42 Å) and Li-N (2.39 or
2.87 Å respectively) distances.
1-Aza bicyclo[2.2.1]h ep ta n es. Of the three types of
azabicyclo[2.2.1]heptanes, the 1-aza ring system proved
easiest to access. Treatment of the commercially available
hydrochloride salt of 4-piperidone monohydrate 27 with
the alkylating agent O-methanesulfonyl tributylstannyl-
methanol (MeSO2OCH2SnBu3)21b in MeCN and K2CO3
gave the ketone 28 (Scheme 5). Wittig olefination gave
the substrate 29. Tin-lithium exchange with n-butyl-
lithium (2 equiv) in hexanes-Et2O (9:1) at -78 °C,
followed by addition of TMEDA (2 equiv) and warming
to room temperature for 4 h, gave after quenching with
methanol and isolation as the picrate salt 4-methyl-1-
azabicyclo[2.2.1]heptane 30 (60%). This represents a
short and efficient route to this bridged bicyclic amine.
Transmetalation was successful in the absence of TME-
DA, but no cyclized products were observed under these
conditions. This is in contrast to the related carbocyclic
Con clu sion
Anionic cyclizations are a convenient method to access
complex cyclic amine products with excellent stereose-
lectivity. All three nitrogen-positional isomers of the
azabicyclo[2.2.1]heptane ring system can be prepared
using this methodology. We are currently extending this
chemistry to prepare other bicyclic amine products, with
cyclizations onto alkene or carbonyl electrophiles28 and
their application to the synthesis of biologically active
targets.
Exp er im en ta l Section
(2RS,5RS)- a n d (2RS,5SR)-1-(ter t-Bu toxyca r bon yl)-2-
p r op -2′-en yl-5-(t r i-n -b u t ylst a n n yl)p yr r olid in e (2). sec-
Butyllithium (1.3 M in cyclohexane, 8.5 mL, 11.1 mmol) was
added to (-)-sparteine (2.6 g, 11.1 mmol) in dry Et2O (40 mL)
under argon at -78 °C. The mixture was allowed to stir for 2
h at -78 °C and was added to the pyrrolidine 112 (2.0 g, 9.3
mmol) in Et2O (80 mL) under argon at -78 °C. After 4 h at
-78 °C, tri-n-butyltin chloride (4.7 mL, 16.9 mmol) was added.
The mixture was allowed to warm to 25 °C for 12 h. Water
was added, and the mixture was extracted with Et2O. The
combined extracts were dried (MgSO4), evaporated, and puri-
fied by column chromatography on silica gel, eluting with light
petroleum-EtOAc (95:5) to give the stannane 2 (1.2 g, 25%)
as an oil: ratio of diastereomers 50:50 [determined by 1H and
13C NMR spectroscopy]; νmax (film)/cm-1 1675, 1640; δH (400
MHz, CDCl3) 5.75 (1H, ddt, J ) 17, 8, 7 Hz), 5.05 (1H, dd, J
) 17, 2 Hz), 5.00 (1H, dd, J ) 8, 2 Hz), 3.82-3.66 (1H, m),
3.37 (0.5H, dd, J ) 8, 6 Hz), 3.25 (0.5H, dd, J ) 9, 7 Hz), 2.53-
2.37 (1H, m), 2.24-1.65 (5H, m), 1.63-1.37 (15H, m), 1.37-
1.21 (6H, m), 1.00-0.68 (15H, m); δC (75 MHz, CDCl3) 9.77
and 10.28, 13.68, 27.47, 27.85, 28.39, 28.54, 31.36, 39.12 and
39.26, 47.31 and 47.48, 57.05 and 57.34, 78.50 and 78.60,
116.57 and 116.77, 135.36 and 135.84, 154.02 (found M+,
501.2640, C24H47NO2120Sn requires M 501.2631) and the diene
3 (up to 24%) as an oil and the stannane 4 (up to 15%) as an
oil (see the Supporting Information for spectroscopic data).
(2RS,5SR)- a n d (2RS,5RS)-1-Ben zoyl-2-p r op -2′-en yl-5-
(tr i-n -bu tylsta n n yl)p yr r olid in e (5). B-Bromocatechol bo-
rane14 (464 mg, 2.32 mmol) in CH2Cl2 (5.8 mL) was added
dropwise to the carbamate 2 (604 mg, 1.16 mmol) in CH2Cl2
(10 mL) at room temperature under argon. After 5 min,
benzoyl chloride (0.27 mL, 2.32 mmol) was added. After 4 h,
(25) Boche, G.; Marsch, M.; Harbach, J .; Harms, K.; Ledig, B.;
Schubert, F.; Lohrenz, J . C. W.; Ahlbrecht, H. Chem. Ber. 1993, 126,
1887.
(26) The 1-azabicyclo[2.2.1]heptane product 30 could not arise from
combined lithium-π and lithium-nN coordination, although this product
is formed only in the presence of TMEDA, which may affect the extent
of such coordination.
(27) Bailey, W. F.; Khanolkar, A. D. Organometallics, 1993, 12, 239.
(28) Coldham, I.; Lang-Anderson, M. M. S.; Rathmell, R. E.;
Snowden, D. J . Tetrahedron Lett. 1997, 38, 7621.

Preparation of Azabicyclo[2.2.1]heptanes
J . Org. Chem., Vol. 65, No. 12, 2000 3793
the mixture was extracted with aqueous NaOH. The organic
phase was dried (MgSO4), evaporated, and purified by column
chromatography on silica gel, eluting with light petroleum-
EtOAc (95:5) to give the amides cis-5a (220 mg, 38%) as an
oil [νmax (film)/cm-1 1640, 1600, 1575; δH (300 MHz, CDCl3)
7.45-7.26 (5H, m), 5.37 (1H, ddt, J ) 17, 10, 7 Hz), 4.90 (1H,
d, J ) 10 Hz), 4.77 (1H, d, J ) 17 Hz), 3.97-3.96 (1H, br m),
3.52 (1H, dd, J ) 10, 7 Hz), 2.24-1.79 (6H, m), 1.68-1.45 (6H,
m), 1.45-1.24 (6H, m), 1.05-0.79 (15H, m); δC (75 MHz,
CDCl3) 10.25, 13.73, 27.04, 27.64, 29.25, 31.37, 39.05, 47.54,
58.78, 117.43, 126.44, 128.31, 128.98, 134.37, 137.98, 168.19
(found M+, 505.2370, C26H43NO120Sn requires M 505.2367)]
and trans-5b (244 mg, 42%) as an oil: νmax (film)/cm-1 1640,
1610, 1575; δH (300 MHz, CDCl3) 7.47-7.29 (5H, m), 5.42 (1H,
ddt, J ) 17, 10, 7 Hz), 4.91 (1H, dd, J ) 10, 1 Hz), 4.79 (1H,
dd, J ) 17, 1 Hz), 4.00-3.89 (1H, br m), 3.61 (1H, dd, J ) 8.5,
4.5 Hz), 2.39-2.21 (1H, m), 2.04-1.79 (5H, m), 1.65-1.45 (6H,
m), 1.45-1.18 (6H, m), 1.05-0.84 (15H, m); δC (75 MHz,
CDCl3) 10.55, 13.71, 26.70, 27.61, 29.22, 31.04, 38.81, 47.17,
58.95, 117.73, 126.65, 128.36, 129.22, 133.87, 137.63, 168.36
(found M+ 505.2370, C26H43NO120Sn requires M 505.2367).
(2RS,5RS)-1-Ben zyl-2-pr op-2′-en yl-5-(tr i-n -bu tylstan n yl)-
p yr r olid in e (6a ). Aluminum chloride (65 mg, 0.49 mmol) and
lithium aluminum hydride (56 mg, 1.47 mmol) in Et2O (5 mL)
were stirred at 0 °C for 15 min, and then amide 5a (243 mg,
0.5 mmol) in Et2O (5 mL) was added dropwise. After 2 h,
MeOH (1 mL) was added, the solvent was evaporated, and the
mixture was purified by column chromatography on silica,
eluting with light petroleum-EtOAc (95:5) to give the amine
6a (190 mg, 80%) as an oil: νmax (film)/cm-1 1635, 1605, 1490;
δH (300 MHz, CDCl3) 7.29-7.05 (5H, m), 5.81 (1H, ddt, J )
17, 10, 7 Hz), 5.03 (1H, dd, J ) 10, 2 Hz), 4.97 (1H, dd, J )
17, 2 Hz), 3.99 (1H, d, J ) 14 Hz), 3.56 (1H, d, J ) 14 Hz),
2.80 (1H, t, J ) 9 Hz), 2.60 (1H, ddt, J ) 8, 5, 3.5 Hz), 2.16-
2.06 (1H, m), 2.03-1.88 (3H, m), 1.88-1.55 (8H, m), 1.55-
1.34 (6H, m), 1.16-0.95 (15H, m); δC (75 MHz, CDCl3) 9.35,
14.02, 28.07, 29.70, 29.90, 32.14, 41.07, 58.34, 60.46, 64.91,
115.98, 127.27, 128.46, 129.36, 136.94, 140.67 (found M+
491.2568, C26H45N120Sn requires M 491.2574).
(1RS,2SR,4SR)-7-Ben zyl-2-deu ter iom eth yl-7-azabicyclo-
[2.2.1]h ep ta n e (8, E ) D). In the same way as the amine 7,
n-butyllithium (2.5 M in hexanes, 0.3 mL, 0.82 mmol) and the
amine 6a (100 mg, 0.20 mmol) gave, after quenching with CD3-
OD (0.1 mL), the amine 8, E ) D (30 mg, 75%), as an oil: νmax
(CHCl3)/cm-1 1495; δH (400 MHz, CDCl3) 7.42-7.22 (5H, m),
3.61 (1H, d, J ) 14 Hz), 3.48 (1H, d, J ) 14 Hz), 3.26-3.23
(1H, m), 2.83-2.80 (1H, m), 1.86-1.83 (2H, m), 1.62-1.59 (1H,
m), 1.47 (1H, dd, J ) 11, 8 Hz), 1.31-1.27 (2H, m), 1.27-1.24
(1H, m), 1.00-0.98 (2H, m); δC (100 MHz, CDCl3) 21.06, 21.25,
21.44, 26.06, 26.48, 37.49, 40.00, 51.60, 60.03, 64.71, 126.43,
128.03, 128.20, 140.99 (found M+ 202.1578, C14H18DN requires
M 202.1580).
(1RS,2SR,4SR)-7-Ben zyl-2-bu t-3′-en yl-7-azabicyclo[2.2.1]-
h ep ta n e (8, E ) Allyl). In the same way as the amine 8, E )
D, n-butyllithium (2.5 M in hexanes, 0.4 mL, 1.05 mmol), the
amine 6a (129 mg, 0.26 mmol), and allyl bromide (0.09 mL,
1.05 mmol, distilled over CaH2) gave the amine 8, E ) allyl
(36 mg, 60%), as an oil: νmax (CHCl3)/cm-1 1495; δH (400 MHz,
CDCl3) 7.41-7.23 (5H, m), 5.82-5.78 (1H, m), 5.01-4.92 (2H,
m), 3.59 (1H, d, J ) 14 Hz), 3.48 (1H, d, J ) 14 Hz), 3.26-
3.22 (1H, m), 2.97-2.94 (1H, m), 2.00-1.89 (2H, m), 1.88-
1.84 (2H, m), 1.61-1.58 (1H, m), 1.47-1.43 (3H, m), 1.33-
1.27 (3H, m); δC (100 MHz, CDCl3) 26.21, 26.62, 31.97, 35.12,
38.26, 42.94, 51.59, 59.64, 63.01, 114.08, 126.48, 128.07,
128.16, 139.26, 141.00 (found M+ 241.1832, C17H23N requires
M 241.1830).
(1RS,2RS,4SR)-7-Ben zyl-7-a za b icyclo[2.2.1]h ep t a n -2-
yla ceta ld eh yd e (8, E ) CHO). In the same way as the amine
8, E ) D, n-butyllithium (2.5 M in hexanes, 0.4 mL, 0.92
mmol), the amine 6a (115 mg, 0.20 mmol), and DMF (0.07 mL,
0.92 mmol, distilled over CaH2) gave the amine 8, E ) CHO
(18 mg, 34%) as an oil: νmax (CHCl3)/cm-1 1720, 1495; δH (400
MHz, CDCl3) 9.71 (1H, s), 7.35-7.22 (5H, m), 3.53 (1H, d, J )
13 Hz), 3.47 (1H, d, J ) 13 Hz), 3.25-3.24 (1H, m), 2.95-2.94
(1H, m), 2.57-2.50 (2H, m), 1.99-1.87 (2H, m), 1.57-1.24 (5H,
m); δC (100 MHz, CDCl3) 26.04, 26.19, 37.52, 37.80, 50.4, 51.53,
59.42, 63.34, 126.70, 128.14, 128.32, 143.94, 202.62 (found M+
229.1466, C15H19NO requires M 229.1466).
(2RS,5SR)-1-Ben zyl-2-pr op-2′-en yl-5-(tr i-n -bu tylstan n yl)-
p yr r olid in e (6b). In the same way as 6a , aluminum chloride
(45 mg, 0.3 mmol), lithium aluminum hydride (38 mg, 1.0
mmol), and the amide 5b (168 mg, 0.3 mmol) gave the amine
6b (105 mg, 71%) as an oil: νmax (film)/cm-1 1640, 1495; δH
(300 MHz, CDCl3) 7.26-7.05 (5H, m), 5.80 (1H, ddt, J ) 16,
11, 7 Hz), 5.08 (1H, dd, J ) 16, 2 Hz), 5.02 (1H, dd, J ) 11, 2
Hz), 4.06 (1H, d, J ) 14 Hz), 3.54 (1H, dd, J ) 9.5, 1.5 Hz),
3.33 (1H, d, J ) 14 Hz), 2.76-2.61 (1H, m), 2.39-2.11 (3H,
m), 2.00-1.89 (2H, m), 1.82-1.68 (1H, m), 1.68-1.53 (6H, m),
1.53-1.34 (6H, m), 1.11-0.95 (15H, m); δC (75 MHz, CDCl3)
11.00, 13.97, 28.10, 28.90, 30.01, 30.60, 37.82, 57.85, 58.01,
62.26, 116.42, 127.06, 128.40, 128.57, 136.50, 140.81 (found
M+ 491.2568, C26H45N120Sn requires M 491.2574).
(1RS,2SR,4SR)-7-Ben zyl-2-m eth yl-7-a za bicyclo[2.2.1]-
h ep ta n e (7). n-Butyllithium (2.5 M in hexanes, 0.18 mL, 0.45
mmol) was added to the amine 6a (42 mg, 0.09 mmol) in dry
hexanes-Et2O-THF (4:1:1) (1 mL) under argon at -78 °C.
The mixture was stirred for 30 min and was allowed to warm
slowly to 25 °C for 9 h. The mixture was quenched with MeOH
(0.2 mL) at -78 °C and was allowed to warm to room
temperature for 30 min. The solvent was evaporated, and the
mixture was purified by column chromatography on alumina,
eluting with light petroleum-EtOAc (50:1 then 9:1) to give
the amine 7 (15 mg, 83%) as an oil: νmax (CHCl3)/cm-1 1605,
1490; δH (400 MHz, CDCl3) 7.44-7.24 (5H, m), 3.63 (1H, d, J
) 14 Hz), 3.49 (1H, d, J ) 14 Hz), 3.28-3.23 (1H, br m), 2.85-
2.82 (1H, br m), 1.90-1.83 (2H, m), 1.64-1.55 (1H, m), 1.49
(1H, dd, J ) 11, 8.5 Hz), 1.35-1.28 (2H, m), 1.28-1.20 (1H,
m), 1.03 (3H, d, J ) 7 Hz); δC (100 MHz, CDCl3) 21.57, 26.07,
26.50, 37.58, 40.05, 51.62, 60.06, 64.75, 126.46, 128.06, 128.23,
140.97 (found M+ 201.1510, C14H19N requires M 201.1517).
In the same way, n-butyllithium (2.5 M in hexanes; 0.42
mL, 0.17 mmol) and the amine 6b (102 mg, 0.21 mmol) in dry
hexanes-Et2O-THF (4:1:1) (3 mL) gave the amine 7 (35 mg,
83%) as an oil, data as above.
(1RS,2SR,4SR)-7-Ben zyl-2-tr im eth ylsilylm eth yl-7-a za -
bicyclo[2.2.1]h ep ta n e (8, E ) TMS). In the same way as
the amine 8, E ) D, n-butyllithium (2.5 M in hexanes, 0.3 mL,
0.82 mmol), the amine 6a (100 mg, 0.20 mmol) and TMSCl
(0.06 mL, 0.82 mmol, distilled over CaH2) gave the amine 8,
E ) TMS (30 mg, 55%) as an oil: νmax (CHCl3)/cm-1 1495; δH
(400 MHz, CDCl3) 7.41-7.23 (5H, m), 3.64 (1H, d, J ) 14 Hz),
3.47 (1H, d, J ) 14 Hz), 3.26-3.23 (1H, m), 2.84-2.81 (1H,
m), 1.85-1.82 (2H, m), 1.60-1.55 (1H, m), 1.51 (1H, dd, J )
11, 8 Hz), 1.30-1.27 (3H, m), 0.80-0.78 (2H, m), -0.30 (9H,
s); δC (100 MHz, CDCl3) -0.72, 24.89, 26.00, 26.58, 39.36,
41.56, 51.69, 60.14, 66.14, 126.45, 128.04, 128.23, 140.88 (found
M+ 273.1913, C17H27NSi requires M 273.1913).
Eth yl 3-(N-Ben zoyla m in o)p en t-4-en oa te (10). Benzoyl
chloride (9.9 g, 70 mmol) was added to a mixture of triethyl-
amine (11.8 g, 117 mmol) and the hydrochloride salt of the
ester 919 (10.5 g, 58 mmol) in Et2O (100 mL) at 0 °C. After 18
h, water (100 mL) was added, and the mixture was extracted
with Et2O. The combined Et2O extracts were washed with
saturated NaHCO3, water, and brine, dried (MgSO4), evapo-
rated, and purified by column chromatography on silica gel
eluting with light petroleum-EtOAc (4:1) to give the ester 10
(10.87 g, 75%) as an oil: νmax (film)/cm-1 3315, 1735, 1640,
1535; δH(400 MHz, CDCl3) 7.79-7.34 (5H, m), 5.89 (1H, ddd,
J ) 17, 10, 5 Hz), 5.23 (1H, dd, J ) 17, 1 Hz), 5.13 (1H, dd, J
) 10, 1 Hz), 5.08-5.00 (1H, m), 4.11 (2H, q, J ) 7 Hz), 2.69
(2H, d, J ) 5 Hz), 1.21 (3H, t, J ) 7 Hz); δC (100 MHz, CDCl3)
14.2, 38.3, 48.0, 60.9, 116.0, 127.0, 128.6, 131.5, 134.3, 136.5,
166.5, 171.8 (found M+ 247.1213, C14H17NO3 requires M
247.1208).
3-(N-Ben zoyla m in o)p en t-4-en -1-ol (11). The ester 10
(3.37 g, 13.6 mmol) in THF (20 mL) was added to a suspension
of lithium aluminum hydride (517 mg, 13.6 mmol) in THF (50
mL) at 0 °C. After 15 min at room temperature, water was
added at 0 °C until the precipitated inorganic salts became
granular. The mixture was filtered through Celite and washed

3794 J . Org. Chem., Vol. 65, No. 12, 2000
Coldham et al.
with THF, evaporated, and purified by column chromatogra-
phy on silica gel, eluting with CH2Cl2-MeOH (95:5) to give
the alcohol 11 as an oil (2.26 g, 81%): νmax (film)/cm-1 3295,
1635, 1525; δH (400 MHz, CDCl3) 7.81-7.43 (5H, m), 6.55-
6.45 (1H, m), 5.94 (1H, ddd, J ) 17, 10, 2 Hz), 5.30 (1H, dd, J
) 17, 2 Hz), 5.23 (1H, dd, J ) 10, 2 Hz), 4.95-4.85 (1H, m),
3.77-3.71 (2H, m), 3.18 (1H, br s), 2.09-2.04 (1H, m), 1.66-
1.60 (1H, m); δC (100 MHz, CDCl3) 37.31, 48.87, 58.85, 115.54,
126.95, 128.67, 131.75, 134.03, 137.79, 167.85 (found M+
205.1100, C12H15NO2 requires M 205.1103).
0.90-0.85 (15H, m); δC (100 MHz, CDCl3) 9.65, 13.65, 27.43,
29.19, 36.43, 37.60, 58.10, 64.82, 115.66, 117.23, 126.57,
128.07, 128.59, 136.61, 136.69, 140.44 (found M+ 491.2588,
C
26H45N120Sn requires M 491.2574).
(1RS,4RS,6SR)-2-Ben zyl-6-m eth yl-2-a za bicyclo[2.2.1]-
h ep ta n e (16). In the same way as the amine 7, n-butyllithium
(2.5 M in hexanes, 0.25 mL, 0.6 mmol) and the stannane 15
(100 mg, 0.2 mmol) in hexanes-Et2O-THF (2.5 mL, 4:1:1)
gave, after purification by column chromatography eluting
with CH2Cl2-EtOH-NH3 (50:1:0.5), the amine 16 (9 mg, 22%)
as an oil [νmax (film)/cm-1 2960, 2865; δH (400 MHz, CDCl3)
7.40-7.19 (5H, m), 3.71 (1H, d, J ) 13 Hz), 3.57 (1H, d, J )
13 Hz), 2.83 (1H, s), 2.65 (1H, d, J ) 9 Hz), 2.30 (2H, m), 1.85
(1H, m), 1.75 (1H, m), 1.63 (1H, dd, J ) 10, 1 Hz), 1.23 (1H, d,
J ) 10 Hz), 1.07 (3H, d, J ) 7 Hz), 0.69 (1H, m); δC (100 MHz,
CDCl3) 16.56, 34.55, 36.24, 37.17, 39.31, 61.55, 61.92, 65.26,
3-(N-Ben zoyla m in o)p en t-4-en a l (12). Dimethyl sulfoxide
(1.07 g, 13.7 mmol) in CH2Cl2 (3.2 mL) was added to oxalyl
chloride (0.87 g, 6.8 mmol) in CH2Cl2 (16 mL) at -50 °C. After
2 min, the alcohol 11 (1.28 g, 6.2 mmol) in CH2Cl2 (3 mL) was
added. After 15 min, Et3N (3.1 g, 31 mmol) was added, and
the mixture was allowed to warm to room temperature. Water
was added, and the aqueous layer was extracted with CH2-
Cl2. The combined CH2Cl2 extracts were washed with aqueous
HCl, saturated NaHCO3, water, and brine, dried (MgSO4),
evaporated, and purified by column chromatography on silica
gel eluting with CH2Cl2-MeOH (95:5) to give the aldehyde
12 (997 mg, 79%) as an oil: νmax (film)/cm-1 3315, 1725, 1635,
1540; δH (400 MHz, CDCl3) 9.85 (1H, s), 7.78-7.41 (5H, m),
6.70-6.60 (1H, m), 5.98 (1H, ddd, J ) 18, 10, 2 Hz), 5.28 (1H,
dd, J ) 18, 2 Hz), 5.22 (1H, dd, J ) 10, 2 Hz), 5.15-5.06 (1H,
m), 2.93-2.90 (2H, m); δC (100 MHz, CDCl3) 47.41, 47.70,
116.41, 126.93, 128.62, 131.70, 134.10, 136.51, 166.73, 200.66
(found M+ 203.0944, C12H13NO2 requires M 203.0946).
3-(N-Ben zoyla m in o)h exa -1,5-d ien e (13). Methyltriphen-
ylphosphonium bromide (0.97 g, 2.73 mmol) was added to
potassium tert-butoxide (0.26 g, 2.37 mmol) in THF (5 mL)
under nitrogen at 0 °C. The yellow suspension was stirred for
30 min at room temperature prior to the addition of the
aldehyde 12 (370 mg, 1.82 mmol) in THF (5 mL). After 18 h,
saturated NH4Cl(aq) was added, and the mixture was extracted
with Et2O. The combined Et2O extracts were dried (MgSO4),
evaporated, and purified by column chromatography on silica
gel eluting with light petroleum-EtOAc (4:1) to give the diene
13 (167 mg, 46%) as needles: mp 49-51 °C; νmax (film)/cm-1
3310, 1635, 1545; δH (400 MHz, CDCl3) 7.78-7.41 (5H, m),
6.20-6.05 (1H, m), 5.95-5.78 (2H, m), 5.27-5.13 (4H, m),
4.85-4.75 (1H, m), 2.52-2.39 (2H, m); δC (100 MHz, CDCl3)
39.06, 50.56, 115.17, 118.48, 126.84, 128.57, 131.44, 133.78,
134.70, 137.64, 166.73 (found M+ 201.1156, C13H15NO requires
M 201.1154). Anal. Calcd for C13H15NO: C, 77.57; H, 7.52; N,
6.96. Found: C, 77.19; H, 7.42; N, 6.79.
126.40, 127.95, 128.41, 141.27 (found M+ 201.1510, C14H19
N
requires M 201.1517)] and the pyrrolidine 17 (13 mg, 32%) as
an oil: νmax (film)/cm-1 2955, 2870; δH (400 MHz, CDCl3) 7.32-
7.21 (5H, m), 5.79 (1H, ddd, J ) 17, 10, 8 Hz), 5.19 (1H, dd, J
) 17, 2 Hz), 5.08 (1H, dd, J ) 10, 2 Hz), 3.99 (1H, d, J ) 13
Hz), 3.12 (1H, d, J ) 13 Hz), 2.92 (1H, m), 2.57 (1H, dd, J )
9, 4 Hz), 2.38 (1H, t, J ) 9 Hz), 2.14 (2H, m), 1.22 (1H, m),
0.95 (3H, d, J ) 6 Hz); δC (100 MHz, CDCl3) 21.57, 30.38, 41.35,
57.80, 60.46, 69.14, 116.09, 126.53, 128.03, 128.67, 140.00,
141.40 (found M+ 201.1524, C14H19N requires M 201.1517).
5-(Tr i-n -bu tylsta n n yl)-2-p yr r olid in on e (21). n-Butyl-
lithium (0.4 mL, 0.94 mmol, 2.5 M in hexanes) was added to
hexa-n-butylditin (0.59 mL, 1.19 mmol) in THF (2 mL) at -20
°C under nitrogen. After 15 min, 5-(benzotriazol-1-yl)-2-
pyrrolidinone (120 mg, 0.59 mmol) in THF (5 mL) was added
at 0 °C. After 2 h, NaOH (2 M) was added, and the organic
layer was washed with NaOH (2 M) and brine and then dried
(Na2SO4) and evaporated. Purification by chromatography
eluting with light petroleum-EtOAc (100:1 to 1:100) gave the
stannane 21 (168 mg, 75%) as an oil, data as reported.24
1-Ben zyl- 5-(tr i-n -bu tylsta n n yl)-2-p yr r olid in on e (22).
The pyrrolidinone 21 (0.33 g, 0.89 mmol) in DMF (5 mL) was
added to sodium hydride (0.11 g, 2.6 mmol, 60% dispersion in
mineral oil) in DMF (5 mL) under nitrogen at room temper-
ature. After 15 min, benzyl bromide (0.21 mL, 1.78 mmol) in
DMF (2.5 mL) was added. After 16 h, water was added, and
the mixture was extracted into EtOAc. The organic extracts
were combined, dried (MgSO4), evaporated, and purified by
column chromatography on silica gel eluting with light petro-
leum-EtOAc (99:1 to 5:1) to give the stannane 22 (300 mg,
72%) as an oil: νmax (film)/cm-1 1685; δH (400 MHz, CDCl3)
7.37-7.24 (3H, m), 7.18 (2H, d, J ) 7 Hz), 5.22 (1H, d, J ) 15
Hz), 4.70 (1H, d, J ) 15 Hz), 3.54 (1H, dd, J ) 9, 5 Hz), 2.49-
2.47 (1H, m), 2.40-2.32 (2H, m) 2.29-2.27 (1H, m), 1.48-1.41
(6H, m), 1.33-1.24 (6H, m), 0.94-0.86 (15H, m); δC (75 MHz,
CDCl3) 9.42, 13.57, 24.07, 27.43, 29.07, 31.97, 46.77, 47.83,
127.38, 127.46, 128.61, 136.67, 174.41 (found M+ 465.2056,
3-[N-Ben zoyl-N-(t r ib u t ylst a n n ylm et h yl)a m in o]h exa -
1,5-d ien e 14. Sodium hydride (0.16 g, 3.9 mmol, 60% disper-
sion in mineral oil) was added to the amide 13 (0.26 g, 1.3
mmol) in THF (5 mL) under nitrogen at room temperature.
After 2 h, iodomethyltributyltin (0.83 g, 1.9 mmol) was added.
After 70 h, water was added, and the mixture was extracted
into CH2Cl2. The organic extracts were combined, dried
(MgSO4), evaporated, and purified by column chromatography
on silica gel eluting with light petroleum-EtOAc (99:1) to give
the stannane 14 (478 mg, 73%) as an oil: νmax (film)/cm-1 1640,
1635, 1545; δH (400 MHz, CDCl3) 7.38-7.31 (5H, m), 5.85-
5.75 (1H, m), 5.60-5.50 (1H, m), 5.26-5.04 (4H, m), 4.38-
4.32 (1H, m), 2.72-2.63 (2H, m), 2.50-2.40 (1H, m), 2.35-
2.25 (1H, m), 1.60-1.45 (6H, m), 1.35-1.29 (6H, m), 0.95-
0.88 (15H, m); δC (100 MHz, CDCl3) 11.04, 13.71, 27.07, 27.50,
29.25, 36.13, 61.34, 116.95, 118.05, 126.68, 128.38, 129.07,
C
23H39NO120Sn requires M 465.2054). Anal. Calcd for C23H39
-
NOSn: C, 59.50; H, 8.47; N, 3.02. Found: C, 59.48; H, 8.51;
N, 2.83.
tr a n s-1-Ben zyl- 3-p r op -2′-en yl-5-(t r i-n -b u t ylst a n n yl)-
2-p yr r olid in on e (23). The pyrrolidinone 22 (210 mg, 0.45
mmol) in THF (1.5 mL) was added to LDA [0.54 mmol,
prepared from n-BuLi (0.22 mL, 0.54 mmol) and diisopropyl-
amine (0.09 mL, 0.63 mmol] in THF (3 mL) and HMPA (0.1
mL) at -78 °C. After 1 h, allyl bromide (0.05 mL, 0.54 mmol)
was added, and the mixture was warmed to -40 °C over 2 h.
Water was added, and the mixture was extracted into EtOAc.
The organic layer was washed with brine, dried (Na2SO4),
evaporated, and purified by column chromatography on silica
gel eluting with light petroleum-EtOAc (99:1 to 4:1) to give
the stannane 23 (118 mg, 51%) as an oil: νmax (film)/cm-1 1685,
1650; δH(400 MHz, CDCl3) 7.34-7.26 (3H, m), 7.16 (2H, d, J
) 7 Hz), 5.83-5.79 (1H, m), 5.24 (1H, d, J ) 15 Hz), 5.13-
5.04 (2H, m), 3.60 (1H, d, J ) 15 Hz), 3.43 (1H, dd, J ) 9, 3
Hz), 2.75-2.67 (1H, m), 2.47-2.40 (1H, m), 2.25-2.19 (2H,
m), 2.01-1.99 (1H, m), 1.46-1.42 (6H, m), 1.32-1.27 (6H, m),
0.92-0.86 (15H, m); δC (75 MHz, CDCl3) 9.56, 13.57, 27.43,
29.08, 30.23, 35.11, 42.20, 45.72, 46.77, 116.65, 127.40, 127.51,
133.77, 136.23, 136.84, 171.46 (found M+ 505.2370, C26H43
-
NO120Sn requires M 505.2367). Anal. Calcd for C26H43NOSn:
C, 61.75; H, 8.58; N, 2.77. Found: C, 61.58; H, 8.56; N, 3.11.
3-[N-Ben zyl-N-(tr ibu tylstan n ylm eth yl)am in o]h exa-1,5-
d ien e (15). In the same way as the amine 6a , lithium
aluminum hydride (72 mg, 1.9 mmol), aluminum chloride (85
mg, 0.64 mmol), and the amide 14 (478 mg, 0.95 mmol) gave,
after purification by column chromatography on alumina, the
stannane 15 (410 mg, 88%) as an oil: νmax (film)/cm-1 1640;
δH (400 MHz, CDCl3) 7.22-7.22 (5H, m), 5.85-5.77 (2H, m),
5.24-4.99 (4H, m), 3.71 (1H, d, J ) 14 Hz), 3.37 (1H, d, J )
14 Hz), 3.02-2.95 (1H, m), 2.65-2.55 (1H, m), 2.46-2.42 (2H,
m), 2.27-2.24 (1H, m), 1.50-1.43 (6H, m), 1.32-1.27 (6H, m),

Preparation of Azabicyclo[2.2.1]heptanes
J . Org. Chem., Vol. 65, No. 12, 2000 3795
128.61, 135.82, 136.71, 174.73 (found M+ 505.2443, C26H43
-
was added dropwise to a suspension of methyltriphenylphos-
phonium bromide (1.5 g, 4.2 mmol) in THF (15 mL) at 25 °C.
After 20 min, the ketone 28 (759 mg, 2.1 mmol) in THF (5
mL) was added. After 12 h, the mixture was quenched with
MeOH, evaporated, and purified by column chromatography
on silica gel, eluting with light petroleum-EtOAc (95:5) to give
the amine 29 (706 mg, 95%) as an oil: νmax (film)/cm-1 1655;
δH (400 MHz, CDCl3) 4.68 (2H, s), 2.55 (2H, s), 2.35 (4H, t, J
) 6 Hz), 2.25 (4H, t, J ) 6 Hz), 1.60-1.42 (6H, m), 1.42-1.24
(6H, m), 1.00-0.78 (15H, m); δC (100 MHz, CDCl3) 10.13, 13.65,
27.38, 29.20, 34.82, 46.70, 58.86, 107.62, 146.08 (found M+
401.2111, C19H39N120Sn requires M 401.2104).
4-Meth yl-1-a za bicyclo[2.2.1]h ep ta n e (30). n-Butyllithi-
um (2.4 M in hexanes, 0.47 mL, 1.13 mmol) was added to the
amine 29 (200 mg, 0.57 mmol) in dry hexanes-Et2O (9:1) (2.5
mL) under argon at -78 °C. The mixture was allowed to stir
for 15 min, and TMEDA (0.17 mL, 1.13 mmol) was added. The
mixture was allowed to warm slowly to room temperature for
4 h and was quenched with MeOH at -78 °C. The mixture
was allowed to warm slowly to room temperature, and picric
acid (0.2 M in EtOH, 2.85 mL, 0.57 mmol) was added. After
15 min, the solvent was evaporated, and the residue was
purified by column chromatography on silica gel, eluting with
light petroleum, then 2% MeOH in CH2Cl2 to give the picrate
salt of the amine 30 (117 mg, 60%) as needles: mp 251-252
°C (picrate salt); νmax (picrate salt, CHCl3)/cm-1 1610, 1570,
1495, 1550, 1365; δH (400 MHz, CDCl3, picrate salt) 8.81 (2H,
s), 3.65 (2H, dddd, J ) 12, 10, 5, 2.5 Hz), 3.32 (2H, ddd, J )
12, 7.5, 5 Hz), 3.05 (2H, s), 1.97 (2H, dddd, J ) 13, 10, 5, 2.5
Hz), 1.85 (2H, ddd, J ) 13, 7.5, 5 Hz), 1.44 (3H, s); δC (100
MHz, CDCl3, picrate salt) 16.42, 34.31, 44.40, 54.07, 63.47,
126.48, 128.13, 141.69, 162.23 (found M+ - picric acid 111.1045,
C7H13N requires M - picric acid, 111.1048).
NO120Sn requires M 505.2445). Anal. Calcd for C26H43NOSn:
C, 61.75; H, 8.58; N, 2.77. Found: C, 61.82; H, 8.69; N, 2.66.the
pyrrolidinone 24 (45 mg, 18%) was also obtained as a mixture
of diastereomers (3:1): νmax (film)/cm-1 1680, 1640; δH (400
MHz, CDCl3) 7.34-7.26 (5H, m), 5.80-5.71 (2H, m), 5.14-
5.01 (4H, m), 4.94 (0.75H, dd, J ) 8, 7 Hz), 4.86 (0.25H, t, J )
7 Hz), 3.47 (0.75H, dd, J ) 9, 2 Hz), 3.27 (0.25H, dd, J ) 9, 2
Hz), 2.94-2.88 (2H, m), 2.63-2.61 (1H, m), 2.46-2.36 (1H,
m), 2.17-2.13 (2H, m), 2.02-1.92 (1H, m), 1.38-1.22 (12H,
m), 0.89-0.61 (15H, m); δC (75 MHz, CDCl3, major isomer)
9.68, 13.55, 27.36, 29.06, 31.85, 34.90, 35.72, 43.15, 44.53,
57.16, 116.37, 117.30, 127.68, 127.87, 128.61, 135.17, 136.01,
140.03, 175.44 (found M + H 546.2751, C29H47NO120Sn re-
quires M + H 546.2758). Anal. Calcd for C29H47NOSn: C,
63.82; H, 8.69; N, 2.57. Found: C, 63.81; H, 8.86; N, 2.43.
tr a n s-1-Ben zyl-4-p r op -2′-en yl-2-(t r i-n -b u t ylst a n n yl)-
p yr r olid in e (25). In the same way as the amine 6a , the
pyrrolidinone 23 (111 mg, 0.22 mmol) and alane [0.22 mmol,
prepared from LiAlH4 (25 mg, 0.66 mmol) and AlCl3 (29 mg,
0.22 mmol) in Et2O (3 mL)] gave, after purification by
chromatography over alumina eluting with light petroleum-
EtOAc (98:2), the stannane 25 (77 mg, 72%) as an oil: νmax
(film)/cm-1 1650; δH (400 MHz, CDCl3) 7.32-7.24 (5H, m),
5.77-5.67 (1H, m), 5.02-4.91 (2H, m), 4.00 (1H, d, J ) 12 Hz),
3.02 (1H, d, J ) 12 Hz), 2.93-2.91 (1H, m), 2.60-2.56 (1H,
m), 2.19-2.07 (4H, m), 1.65-1.49 (7H, m), 1.37-1.30 (7H, m),
0.94-0.75 (15H, m); δC (75 MHz, CDCl3) 9.05, 13.66, 27.51,
29.32, 35.88, 38.19, 39.46, 56.72, 61.22, 115.12, 126.71, 128.13,
128.59, 137.58, 140.06 (found M+ 492.2649, C26H45N120Sn
requires M 492.2652).
(1RS,4RS,6SR)-2-Ben zyl-6-m eth yl-2-a za bicyclo[2.2.1]-
h ep ta n e (16). n-Butyllithium (2.5 M in hexanes, 0.25 mL, 0.6
mmol) was added to the stannane 25 (60 mg, 0.12 mmol) in
hexanes-Et2O (1 mL, 4:1) at room temperature under argon.
After 16 h, the mixture was quenched with MeOH (0.1 mL),
evaporated, and purified by column chromatography on alu-
mina, eluting with light petroleum-EtOAc (98:2) to give the
amine 16 (14 mg, 60%) as an oil, data as above.
1-(Tr i-n -bu tylstan n ylm eth yl)-4-piper idon e (28). O-Meth-
anesulfonyltributylstannylmethanol21b (1.3 g, 3.3 mmol) in
MeCN (5 mL) was added dropwise to 4-piperidone monohy-
drate hydrochloride (500 mg, 3.3 mmol) and K2CO3 (1.8 g, 13.2
mmol) in MeCN (30 mL) at room temperature. After 4 d, the
mixture was filtered, evaporated, and purified by column
chromatography on silica gel, eluting with light petroleum-
EtOAc (95:5) to give the amine 28 (795 mg, 64%) as an oil:
νmax (film)/cm-1 1725; δH (400 MHz, CDCl3) 2.68 (4H, t, J ) 6
Hz), 2.62 (2H, s), 2.40 (4H, t, J ) 6 Hz), 1.63-1.42 (6H, m),
1.42-1.18 (6H, m), 1.00-0.79 (15H, m); δC (100 MHz, CDCl3)
9.86, 13.65, 27.34, 29.16, 41.34, 45.60, 57.18, 209.04 (found
M+ 403.1885, C18H37NO120Sn requires M 403.1897).
Ack n ow led gm en t. We thank the EPSRC for project
studentships (to D.J .S. and K.N.P.), the Spanish Gov-
ernment (Ministerio de Educacio´n y Cultura) for a
postdoctoral fellowship (to J .-C.F.), Pfizer Ltd for an
unrestricted grant, and Zeneca Pharmaceuticals (Stra-
tegic Research Fund). We are grateful to Dr. J ohn P.B.
Sandall for the molecular orbital calculations. We
acknowledge the use of the EPSRC mass spectrometry
service at the University of Wales Swansea.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and data for all novel compounds, including 1H and
13C NMR spectra of compounds 2, 5, 6a ,b, 7, 8, 10-12, 15-
17, 25, and 28-30. NOESY spectra of the amines 6a ,b, 7, and
16. In addition, an unsuccessful route to the 1-azabicyclo[2.2.1]-
heptane ring system using N-lithiomethyl-3-vinylpyrrolidine
is described. This material is available free of charge via the
Internet at http://pubs.acs.org.
1-(Tr i-n -bu t ylst a n n ylm et h yl)-4-m et h ylen ep ip er id in e
(29). n-Butyllithium (2.4 M in hexanes, 1.32 mL, 3.15 mmol)
J O000088Z