7-Substituted 2-Azabicyclo[2.2.1]heptanes as key intermediates for the synthesis of novel epibatidine analogues; synthesis of syn- and anti-Isoepiboxidine

Article abstract of DOI:10.1021/jo0492564

Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl- 2-azabicyclo[2.2.1]heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles and opens the way to a range of novel 7-substituted 2-azab

Full text of DOI:10.1021/jo0492564

7-Su bstitu ted 2-Aza bicyclo[2.2.1]h ep ta n es a s Key In ter m ed ia tes for
th e Syn th esis of Novel Ep iba tid in e An a logu es; Syn th esis of syn -
a n d a n ti-Isoep iboxid in e
J ohn R. Malpass* and Richard White
Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
jrm@le.ac.uk
Received May 1, 2004
Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]-
heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles
and opens the way to a range of novel 7-substituted 2-azabicyclo[2.2.1]heptanes. Conversion of an
anti-7-ethoxycarbonyl group into a methylisoxazole ring provides anti-isoepiboxidine, a conversion
that is possible even without protection of the secondary bicyclic nitrogen. Successful base-induced
epimerization R to the carbonyl of the anti-7-ethoxycarbonyl derivative gives the syn-stereoisomer
and hence syn-isoepiboxidine.
In tr od u ction
further reinforced by the very recent report of the potent
nAChR agonist homoepiboxidine 2b by the Daly group.4
The emphasis in the search for therapeutically useful
compounds is now on high nAChR subtype selectivity.5
We have recently reported analogues based on the more
highly strained 2-azabicyclo[2.1.1]hexane ring system6a
together with epibatidine isomers 3-6 in which the
heterocycle is attached to the 5- and 6-positions of
2-azanorbornane.6b-d Compounds 3 and 4 have shown
sufficient promise in this and other work6b,e,f to encourage
us to explore routes to the remaining 2-azanorbornane
derivatives syn-7 and anti-7 in which the positions of the
bicyclic nitrogen and the heterocycle of 1a have simply
Interest in the 7-azabicyclo[2.2.1]heptane (7-azanor-
bornane) ring system has increased dramatically since
the discovery of epibatidine 1a , a natural product with
unusually high activity at the nicotinic acetylcholine
receptor (nAChR).1 Intense synthetic interest has led to
a large number of approaches to 1a , together with an
ever-increasing variety of analogues bearing different
heterocycles;2 prominent among these is epiboxidine 2a
in which replacement of the chloropyridyl substituent by
methylisoxazole leads to high nAChR affinity but lower
toxicity compared to 1a .2a Homologous systems showing
high nAChR affinity include homoepibatidine 1b,3 and
interest in the methylisoxazole substituent has been
(3) (a) Malpass, J . R.; Hemmings, D. A.; Wallis, A. L.; Fletcher, S.;
Patel, S. J . Chem. Soc., Perkin Trans. 1 2001, 1044-1050. Malpass,
J . R.; Hemmings, D. A.; Wallis, A. L. Tetrahedron Lett. 1996, 37, 3911-
3914. (b) Xu, R.; Bai, D. L.; Chu, G. H.; Tao, J . N.; Zhu, X. Z. Bioorg.
Med. Chem. Lett. 1996, 6, 279-282. Bai, D. L.; Xu, R.; Chu G. H.; Zhu,
X. Z. J . Org. Chem. 1996, 61, 4600-4606.
* To whom correspondence should be addressed. Ph: + 44 116 252
2126. Fax: +44 116 252 3789.
(1) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J .
C.; Pannell, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475-3478.
For leading references to epibatidine analogue synthesis, see: (b)
Carroll, F. I.; Lee, J . R.; Navarro, H. A.; Ma, W.; Brieaddy, L. E.;
Abraham, P.; Damaj, M. I., Martin, B. R. J . Med. Chem. 2002, 45,
4755-4761. (c) Wei, Z.-L.; George, C.; Kozikowski, A. P. Tetrahedron
Lett. 2003, 44, 3847-3850.
(4) Fitch, R. W.; Pei, X.-F.; Kaneko, Y.; Gupta, T.; Shi, D.; Federova,
I.; Daly, J . W. Bioorg. Med. Chem. 2004, 12, 179-190.
(5) For leading reviews and references to nAChR affinities, see: (a)
Carroll, F. I. Bioorg. Med. Chem. Lett. 2004, 14, 1889-1896. (b)
Bunnelle, W. H.; Dart, M. J .; Schrimpf, M. R. Curr. Top. Med. Chem.
2004, 4, 299-334. (c) Astles, P. C.; Baker, S. R.; Boot, J . R.; Broad, L.
M.; Dell, C. P.; Keenan, M. Curr. Drug Targets: CNS Neurol. Disord.
2002, 1, 337-348. (d) Tønder, J . E.; Olesen, P. H. Curr. Med. Chem.
2001, 8, 651-674. (e) Lloyd, G. K.; Williams, M. J . Pharmacol. Exp.
Ther. 2000, 292, 461-467. (f) Curtis, L.; Chiodini, F.; Spang, J . E.;
Bertrand, S.; Patt, J . T.; Westera, G.; Bertrand, D. Eur. J Pharmacol.
2000, 393, 155-163. (g) Tønder, J . E.; Hansen, J . B.; Begtrup, M.;
Petterson, I.; Rimvall, K.; Christensen, B.; Ehrbar, U.; Olesen, P. H.
J . Med. Chem. 1999, 42, 4970-4980. (h) Holladay, M. W.; Dart M. J .;
Lynch, J . K. J . Med. Chem. 1997, 40, 4169-4194.
(2) Recent examples of alternative heterocycles incorporated into
the epibatidine framework and into analogues include the following.
(a) Methylisoxazole: Badio, B.; Garraffo, H. M.; Plummer, C. V.;
Padgett, W. L.; Daly, J . W. Eur. J . Pharmacol. 1997, 321, 189-194.
(b) Isoxazoles: Silva, N. M.; Tributino, J . L. M.; Miranda, A. L. P.;
Barreiro, E. J .; Fraga, C. A. M. Eur. J . Med. Chem. 2002, 37, 163-
169. (c) Pyridazines: Che, D.; Wegge, T.; Stubbs, M.; Seitz, G.Meier,
H.; Methfessel, C. J . Med. Chem., 2001, 44, 47-57. (d) Substituted
pyridines: Carroll, F. I.; Lee, J . R.; Navarro, H. A.; Ma, W.; Brieaddy,
L. E.; Abraham, P.; Damaj, M. I., Martin, B. R. J . Med. Chem. 2002,
45, 4755-4761. Avalos, M.; Parker, M. J .; Maddox, F. N.; Carroll, F.
I.; Luetje, C. W. J . Pharmacol. Exp. Ther. 2002, 302, 1246-1252.
Carroll, F. I.; Lee, J . R.; Navarro, H. A.; Brieaddy, L. E.; Abraham, P.;
Damaj, M. I.; Martin, B. R. J . Med. Chem. 2001, 44, 4039-4041. (e)
6-Chloropyridazin-3-yl derivatives: Toma, L.; Quadrelli, P.; Bunnelle,
W. H.; Anderson, D. J .; Meyer, M. D.; Cignarelli, G.; Gelain, A.;
Barlocco, D. J . Med. Chem. 2002, 45, 4011-4017. (f) See also: Gohlke,
H.; Schwarz, S.; Gu¨ndisch, D.; Tilotta, M. C.; Weber. A.; Wegge, T.;
Seitz, G. J . Med. Chem. 2003, 46, 2031-2048 for recent work on 3D
QSAR analysis in the design of heterocyclic substituents for high
nAChR subtype selectivity in epibatidine analogues and homologues.
(6) (a) Malpass, J . R.; Patel, A. B.; Davies, J . W.; Fulford, S. Y. J .
Org. Chem. 2003, 68, 9348-9355. (b) Cox, C. D.; Malpass, J . R.; Rosen,
A.; Gordon, J . J . Chem. Soc., Perkin Trans. 1 2001, 2372-2379. (c)
Malpass, J . R.; Cox, C. D. Tetrahedron 1999, 55, 11879-11888. (d)
Malpass, J . R.; Cox, C. D. Tetrahedron Lett. 1999, 40, 1419-1422. (e)
Dart, M. J .; Wasicak, J . T.; Ryther, K. B.; Schrimpf, M. R.; Kim, K.
H.; Anderson, D. J .; Sullivan, J . P.; Meyer, M. D. Pharm. Acta Helv.
2000, 74, 115-123. (f) Hodgson, D. M.; Maxwell, C. R.; Wisedale, R.;
Matthews, I. R.; Carpenter, K. J .; Dickenson, A. H.; Wonnacott, S. J .
Chem. Soc., Perkin Trans. 1 2001, 3150-3158. Hodgson, D. M.;
Maxwell, C. R.; Matthews, I. R. Synlett 1998, 12, 1349-1350.
10.1021/jo0492564 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/03/2004
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J . Org. Chem. 2004, 69, 5328-5334

Synthesis of syn- and anti-Isoepiboxidine
CHART 1
been reversed.7 Although 7-substituted-7-azabicyclo[2.2.1]-
heptyl (7-azanorbornyl) derivatives 8 have been reported
recently,8 we are not aware of any compounds having
heterocycles directly attached to the 7-position of 2-
azanorbornanes.
We chose syn-isoepiboxidine 9 as our first target. We
demonstrate here that this and related 7-substituted-2-
azanorbornanes are available by way of the key anti-7-
substituted intermediates 10. Neighboring group par-
ticipation by the 2-azanorbornyl nitrogen is the key to
displacements from the 7-position, extending its estab-
lished role in the loss of 6-substituents. Epimerization
at the 7-position [e.g., for the ester 10 (R ) CO2Et)]
provides the essential first entry into the 7-syn series and
hence a route to 9.
positive charge during electrophilic addition to double
bonds, leading again to skeletal rearrangement.11,12 Such
involvement of N-acyl and N-alkoxycarbonyl nitrogen in
skeletal rearrangement is well established during elec-
trophilic addition to derivatives of the 2-azanorborn-5-
ene system 11,12 leading for example to dibromo deriva-
tives such as 12a .12b In the case of N-alkyl derivatives,
the pioneering work of Raasch11 has been developed,
leading to isolation of the aziridinium intermediates 13b
during bromination.13a Indeed when R is alkyl, the
equilibrium shown in Scheme 1 is biased completely in
favor of the aziridinium salt 13b with none of the
dibromide 12b.
SCHEME 1
Discu ssion
Neighboring group participation by σ and π bonds is a
key feature of the rearrangement chemistry of bicyclo-
[2.2.1]heptanes (norbornanes), and similar participation
has also been established in the chemistry of azanorbor-
nanes and -enes; σ or π electrons can participate in
displacement of a nucleofuge from nitrogen in the 2-9 or
the 7-position10 of the azanorbornane skeleton. More
usually, nitrogen is seen to participate in the displace-
ment of leaving groups from carbon,9,11 and the nitrogen
lone pair can also overlap with centers of developing
We had hoped that addition of nucleophiles to the
N-ethoxycarbonyl derivative 12a h 13a might allow
interception of a small equilibrium concentration of 13a
(effectively achieving substitution at the 6-position), but
we were unable to demonstrate any replacement of the
6-bromine in 12a ,14a despite the fact that carbamate
(12) (a) For work in the 2-azabicyclo[2.2.1]hept-5-ene-3-one system,
see: Faith, W. C.; Booth, C. A.; Foxman, B. M.; Snider, B. B. J . Org.
Chem. 1985, 50, 1983-1985. Evans, C.; McCague, R.; Roberts, S. M.;
Sutherland, A. G. J . Chem. Soc., Perkin Trans. 1 1991, 656-657.
Palmer, C. F.; McCague, R. M. J . Chem. Soc., Perkin Trans. 1 1998,
2977-2978. (b) Bromination of N-ethoxycarbonyl-2-azanorborn-5-ene
also proceeds smoothly with rearrangement to give 12a (R ) CO2CH2-
Ph): Cox, C. D. PhD thesis, University of Leicester, 2000.
(7) Clearly, the N-N distances and orientation will be important
in determining the binding ability of these ligands. Compounds 3 and
4 show much higher affinities and subtype selectivity than 5 and 6,6b
and it is reasonable to expect syn-7 to be a better ligand than anti-7.
(8) Cheng, J .; Zhang, C.; Stevens, E. D.; Izenwasser, S.; Wade, D.;
Chen, S.; Paul, D.; Trudell, M. L. J . Med. Chem. 2002, 45, 3041-3047.
In addition, 7-substituted 1-azabicyclo[2.2.1]heptanes have been re-
ported: Ullrich, T.; Binder, D.; Pyerin, M. Tetrahedron Lett. 2002, 43,
177-179.
(9) (a) Davies, J . W.; Malpass J . R.; Walker, M. P. J . Chem. Soc.,
Chem. Commun. 1985, 686-687. (b) Durrant, M. L.; Malpass J . R.;
Walker, M. P. J . Chem. Soc., Chem. Commun. 1985, 687-688 and
references to earlier work.
(13) (a) Sosonyuk, S. E.; Bulanov, M. N.; Leshcheva, I. F.; Zyk, N.
V. Russ. Chem. Bull. 2002, 51, 1254-1261. For other azatricyclene
intermediates, see: Portoghese, P. S.; Sepp, D. T. Tetrahedron 1973,
29, 2253-2256 and ref 9. (b) A 6-methoxy derivative was isolated on
treatment of 13 (R ) Me) with sodium methoxide in MeOH (ref 12a).
A very recent paper from the same group has widened the range of
nucleophiles: Bulanov, M. N.; Sosonyuk, S. E.; Zyk, N. V.; Zefirov, N.
S. Russ. J . Org. Chem. 2003, 39, 415-421.
(10) Durrant, M. L.; Malpass J . R. Tetrahedron 1995, 51, 7063-
7076. Davies, J . W.; Durrant, M. L.; Naylor, A.; Malpass, J . R.
Tetrahedron 1995, 51, 8655-8664.
(14) (a) Barth, G. S.; (b) Fulford, S. Y.; (c) Rimmington, S. Unpub-
lished work, University of Leicester.
(11) Raasch, M. S. J . Org. Chem. 1975, 40, 161-172.
J . Org. Chem, Vol. 69, No. 16, 2004 5329

Malpass and White
SCHEME 2
nitrogen participates during additions to N-alkoxycar-
bonyl-2-azanorborn-5-enes and also electrophilic ring
opening of the derived exo-5,6-epoxides.14b However,
interception of 13 using a wider range of nucleophiles is
possible in the N-alkyl series and has been used to make
6-substituted 2-azabicyclo[2.2.1]heptanes following re-
ductive removal of the 7-substituent.13b
We were concerned to do the opposite: to remove the
6-substituent and introduce a range of functional groups
at the 7-position. Treatment of 13b (R ) Bn) with hydride
allows effective removal of the 6-bromine yielding the
7-bromo derivative 14a (Scheme 2). At low temperature
(-78 °C followed by warming to -20 °C over 1 h), LiAlH4
gave 14a in 58% yield after chromatography on silica.15
The use of Red-Al16 is preferable.
Nucleophilic substitution at the 7-position of 14a was
then attempted, despite the fact that direct (SN2) sub-
stitution is difficult to achieve at this position in simple
norbornanes.17 The key substitution reactions occurred
at elevated temperatures (ca. 100 °C). Thus, treatment
of 14a with LiCl in DMF gave the chloro analogue 14b
in 77% yield (Scheme 2),18 and LiOH in DMF provided
14c in 56% yield.16b
seen between H7syn and H3exo and between the CH2 of the
inverting N-benzyl group and both H7syn and H6endo
.
Similar reaction of 14a with KCN in DMF yielded 14d
in 66% yield, and use of the imidazolyl anion followed
the same pathway, producing 14e in 53% yield. Here, the
protons H5exo and H6exo appeared ca. 0.5 ppm upfield of
the corresponding signals in 14b-d , shielded by the ring
current of the anti imidazole ring.
The anti stereochemistry in all of the 7-derivatives
14a -f was confirmed by detailed spectroscopic analysis
and is presumably the result of participation by nitrogen,
as shown by 14a f 15 (Scheme 2). Such involvement of
the 2-nitrogen in displacements from the 7-position is
clearly more energetically demanding than in displace-
ment from the 6-position (12 f 13, Scheme 1) so that
there was no competition during the earlier substitution
at C-6 in the 6,7-dibromo compound 12b.
Participation by the nitrogen lone pair in displacement
of an anti substituent from C-7 is closely analogous to
the involvement of π-electrons in the overall retention
of stereochemistry observed in the classic studies by
Cristol, Winstein, and others on the solvolysis of 7-sub-
stituted norbornenyl tosylates and brosylates21 (e.g.,
Scheme 3). Similar π-participation has been observed in
the loss of chloride ion from a range of N-chloro-7-
azanorbornadienes.10
All of the substitutions based on 14a occurred with
complete retention of configuration at C-7. For example,
the anti stereostructure of 14b was confirmed by COSY
experiments that identified “W” coupling between H7syn
SCHEME 3
19
and H5endo/H6endo
.
In addition, NOE interactions were
(15) Addition of NaBH4 in MeOH to 13 led only to isolation of the
6-methoxy compound (17% yield).13b Treatment of 13 with LiAlH4 at
room temperature led to loss of both bromines and gave N-benzyl-2-
azanorbornane, which was identical to a sample obtained by careful
hydrogenation14c of 11.
(16) (a) Mitch, C. H.; Quimby, S. J . Patent WO 00/75140 A1, 2000;
US 6,559,171 B1, 2003. (b) The reaction conditions described in this
patent were different to ours and were claimed to provide the 7-endo-
hydroxy compound (OH syn to nitrogen). In our hands they gave only
the anti stereoisomer, identical to our sample 14c.
(17) (a) See: J enkins, M. N.; Nash, J . J .; Morrison, H. Tetrahedron
Lett. 2002, 43, 3773-3775 and references therein to earlier work. (b)
The work in ref 17a indicates, for example, that carbonyl groups in
the 2-/3-position(s) of the norbornyl skeleton can exert a significant
effect on substitution at C-7.
(18) Yields in these reactions have not been optimized in all cases.
Typical reactions were performed on a 5-20 mmol scale but smaller-
scale reactions in sealed reaction vials were effective down to a 0.1
mmol scale.
It is not unreasonable, in principle, that SN2 substitu-
tion at the 7-position might proceed (with inversion), and
on the basis of existing work in norbornanes17 a slow
reaction would be expected and a high temperature would
(20) (a) We and others have previously exchanged N-benzyl for
N-Cbz or N-Boc groups, e.g., ref 6a and references therein. (b)
Conversion of N-benzyl into N-Boc was carried out prior to methyl-
isoxazole formation in the recent work by Fitch et al.4
(21) (a) Cristol, S. J .; Nachtigall, G. W. J . Am. Chem. Soc. 1968, 90,
7132-7133; 7133-7134. (b) Tanida, H. Acc. Chem. Res. 1968, 1, 239-
245. (c) Winstein, S. J . Am. Chem. Soc. 1961, 83, 1516-1517 and
earlier references therein.
(19) See: Belkacemi, D.; Malpass, J . R. Tetrahedron 1993, 40, 9105-
9116 for examples of W-coupling in 2-azanorbornanes.
5330 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of syn- and anti-Isoepiboxidine
SCHEME 4
be required. However, our demonstration of anti stere-
ochemistry for all of the derivatives 14a -f strongly
suggests that participation of the 2-nitrogen is general
and provides a lower-energy alternative to SN2 displace-
ment for all of the nucleophilic substitutions studied. We
are currently exploring alternative routes to the syn-7-
hydroxy compound. Calculations make it clear that syn-
7-heterocyclic derivatives will have more appropriate
N-N distances for interaction with nicotinic receptors
than anti stereoisomers, and it was thus important to
achieve inversion of configuration at C-7.
The conversion of 14d into the ester 14f proceeded in
an overall yield of 77% (Scheme 2). Crucially, epimer-
ization of 14f with base led to a mixture containing
approximately 55% of the syn-epimer 16 (Scheme 4).22,23
Base-induced epimerization at the 7-position in norbor-
nanes is precedented24 but is more difficult than at
normal unstrained sp3 carbon. This area is currently
under active investigation, as is the influence of substit-
uents elsewhere in the azanorbornyl ring system on the
ease of bimolecular nucleophilic substitution at the
7-position.17b
converted into the syn-methylisoxazole derivative 17
using standard methods2a,4 in 36% yield. However, at-
tempts to deprotect the N-benzyl compound 17 by hy-
drogenolysis were unsuccessful (Scheme 4); not surpris-
ingly, the methylisoxazole ring did not survive such
treatment.
Our failure to obtain 9 from 17 prompted exchange of
the N-benzyl for an N-alkoxycarbonyl protecting group
in the 7-esters prior to heterocycle formation.20 In the anti
series, hydrogenolysis of 14f gave the secondary amine
18, which was N-Boc-protected to give 19 prior to
heterocycle formation and N-deprotection of 20; anti-
isoepiboxidine 21 was formed in an overall yield of 30%
from 18. However, an unexpected observation avoided
this reprotection/deprotection strategy and compensated
for our earlier inability to enter the N-alkoxycarbonyl
series by direct interception of 13a (R ) CO2Alkyl) with
nucleophiles. Thus, treatment of 18 with the dianion of
acetoxime2a gave the methylisoxazole derivative anti-
isoepiboxidine 21 directly (Scheme 4) in 24% yield. In
similar fashion, debenzylation of 16 gave 22, which was
successfully converted into the target syn-isoepiboxidine
9 directly in 26% yield. The overall yield using the
alternative 3-step procedure (via 23 and 24) was 33%.
Reported yields for the construction of methylisoxazoles
are consistently low,2a,4,6a and mechanistic interest in this
conversion4 deserves to be extended. In the meantime,
we believe that formation of the methylisoxazole ring
without protection of the secondary amino-nitrogen (pre-
viously assumed to be an essential requirement) is a
significant observation that will have wider application.
Further studies of substitution at the 7-position of the
2-azabicyclo[2.2.1]heptane ring system are under way.
The application of coupling reactions to 7-halo compounds
is being explored as a means of extending the range of
available heterocyclic substituents as part of our program
of synthesis of compounds having potential as high-
affinity nAChR ligands.
Chromatographic separation of the stereoisomers 14f
and 16 was straightforward. The syn-ester 16 was
(22) This situation is reminiscent of early syntheses of epibatidine
1a , which gave predominantly the endo-stereoisomer, requiring sub-
sequent epimerization at the 2-position of the 7-azanorbornyl ring
system, for example: Fletcher, S. R.; Baker, R.; Chambers, M. S.;
Herbert, R. H.; Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A.
P.; Ball, R. G. J . Org. Chem. 1994, 59, 1771-1778. For a significant
improvement to the epimerization methodology for epibatidine, see:
Habermann, J .; Ley, S. V.; Scott, J . S. J . Chem. Soc., Perkin Trans. 1
1999, 1253-1256.
(23) The methylene protons of the syn-ester ethyl group in 16
appeared as a complex pattern, interpreted as an overlapping pair of
doublets of quartets. These complex signals collapsed to an AB pattern
on double irradiation of the ester methyl triplet, confirming the
diastereotopic relationship (in keeping with the position over the
unsymmetrical C-N bond). The syn-ester 22 showed similar complexity
for the methylene “quartet”. The ester CH2 protons in the anti isomers
14f and 18 sit over a near-symmetrical C-C linkage and do not show
diastereotopicity. In the case of 16, the CH2 protons of the N-benzyl
group appear as a singlet; benzyl protons in these compounds often
show accidental equivalence, and in this case this may be a conse-
quence of the shift in the inversion equilibrium19 towards the endo-
N-benzyl invertomer as a result of steric interactions between the exo-
invertomer and the syn-7 substituent.
Exp er im en ta l Section
NMR spectra were recorded in CDCl3 using tetramethylsi-
lane as internal standard. Routine mass spectra were mea-
sured using electrospray and accurate mass measurements
(24) Buske, G. R.; Ford, W. T. J . Org. Chem. 1976, 41, 1998-2006.
J . Org. Chem, Vol. 69, No. 16, 2004 5331

Malpass and White
using FAB or EI. IR spectra were measured as films. All
reactions were performed in oven-dried glassware under dry
nitrogen unless stated otherwise. Commercially available
solvents were purified and dried, when necessary, prior to use.
“Ether” refers to diethyl ether and “petrol” to petroleum ether,
bp 40-60 °C.
Flash chromatography was carried out using silica gel (60).
Thin-layer chromatography was conducted on silica 60-254
plates. Chromatography solvents were routinely saturated
with ammonia gas for amine (and N-protected amine) separa-
tions.
LiOH (173 mg, 4.1 mmol) in dry DMF (8 mL) were stirred at
100 °C for 24 h. The reaction mixture was cooled, added to
water (30 mL), and extracted with ether (4 × 25 mL). The
combined extracts were washed with water (3 × 35 mL), dried
over MgSO4, and then filtered. Removal of solvents in vacuo
gave a yellow oil that was chromatographed (9:1, EtOAc/
MeOH, NH3), yielding 14c as a pale yellow oil (47 mg, 56%).
Rf 0.53. δH (300 MHz, CDCl3) 1.34-1.43 (m, 1H), 1.70-1.78
(m, 1H), 1.88-2.00 (m, 2H), 2.11 (brs, 1H), 2.19 (d, J ) 9.3
Hz, 1H), 2.40 (brs, OH), 3.03 (brs, 1H), 3.05 (ddd, J ≈ 9.3, 3.6,
3.0 Hz, 1H), 3.65, 3.70 (AB, J ) 13.4 Hz, 2H), 4.29 (brs,1H),
7.21-7.35 (m, 5H). δC (75.5 MHz, CDCl3) 22.7, 26.5, 41.6, 57.7,
58.0, 62.9, 76.3, 126.8, 128.2, 128.5, 139.2. νmax 3053m, 2970m,
2303w, 1421w, 1265s cm-1. m/z 204.13886 (MH+); C13H18NO
requires 204.13884.
Using the procedure described in ref 16a, 14a (3.06 g, 11.5
mmol) and 1-methyl-2-pyrrolidinone (containing 15% v/v H2O;
56 mL) were stirred at 100 °C for 67 h. The reaction mixture
was diluted with water (150 mL), basified with aqueous NaOH,
and extracted with ether (4 × 100 mL). The combined organic
extracts were washed with water (4 × 100 mL), dried over
anhydrous MgSO4, filtered, and evaporated to yield 14c as a
yellow oil (1.54 g, 66%) showing NMR spectra identical to those
of the sample obtained above.
a n ti-7-Cya n o-2-ben zyl-2-a za bicycl[2.2.1]h ep ta n e (14d ).
KCN (2.36 g, 35.70 mmol) and 18-crown-6 (∼1 mg) were added
to 14a (0.765 g, 2.88 mmol) in anhydrous DMF (10 mL), and
the mixture was stirred vigorously at 110 °C for 24 h. After
filtration, the solid residue was washed with ether, and the
combined organic extracts were dried prior to removal of
solvent in vacuo to give a yellow oil that was chromatographed
(3:7 petrol/ether, NH3), yielding 14d as a yellow oil (0.405 g,
66%), Rf 0.32. δH (250 MHz, CDCl3) 1.49 (m, 1H), 1.94 (m, 3H),
2.45 (d, J ) 9.4 Hz, 1H), 2.73 (m, 3H), 3.47 (brs, 1H), 3.59,
3.67 (AB, J ) 13.4 Hz, 2H), 7.29 (m, 5H). δC (62.9 MHz, CDCl3)
26.2, 26.6, 35.3, 42.6, 58.6, 58.7, 64.3, 119.5, 127.0, 128.2, 128.3,
138.7. νmax 2973s, 2874s, 2234s, 1494s, 1453s cm-1 m/z
213.13914; C14H17N2 (MH+) requires m/z 213.13917.
3-Br om o-1-b en zyl-1-a zon ia t r icyclo[2.2.1.02,6]h ep t a n e
Br om id e (13). Using the procedure described by Sosonyuk
et al.,13a 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene (11)25 (12.03 g,
64.9 mmol) was dissolved in dry CH2Cl2 (120 mL). Bromine
(6.0 mL, 129.5 mmol) was added dropwise at -78 °C. The
mixture was stirred as the temperature rose to 20 °C.
Evaporation in vacuo gave an orange oil, which was dissolved
in dry CH3CN (100 mL), cooled to 0 °C, and stirred vigorously
while more 11 (12.06 g, 65.0 mmol) in dry CH3CN (60 mL)
was added dropwise. After warming to 20 °C, the solvents were
evaporated in vacuo, yielding 13 as pale yellow crystals (22.3
g, 100%), mp 128-130 °C. [The NMR spectra are broadly
similar to those described for the corresponding N-Me com-
pound and the N-benzyl derivative having a Br3- counterion13a].
δH (250 MHz, CDCl3) 2.42 (brs, 2H), 2.83 (brs, 1H), 3.41 (d, J
) 8.9 Hz, 1H), 3.94 (d, J ) 8.9 Hz, 1H), 4.42 (m, 2H), 4.86
(brs, 1H), 5.34 (s, 2H), 7.42-7.73 (m, 5H). δC (62.9 MHz, CDCl3)
30.9, 37.6, 44.5, 44.8, 46.2, 55.1, 55.3, 129.4, 129.5, 130.3, 131.1.
ν
max 3049s, 3003w, 2318w, 1426m, 1278m, 898m cm-1. m/z 264/
266 (1:1) (M+). C13H15NBr [M+] requires m/z 264.03879;
observed 264.03884.
a n ti-7-Br om o-2-ben zyl-2-azabicyclo[2.2.1]h eptan e (14a).
LiAlH4 (0.53 g, 13.97 mmol) and 13 (3.056 g, 8.85 mmol) were
cooled to -78 °C in a dry flask. Dry THF (100 mL) was added
with stirring, and the mixture allowed to warm to -20 °C over
a period of 1 h followed by addition of water-saturated ether
until effervescence stopped. The mixture was filtered, the
residue was washed with CH2Cl2, and after drying with MgSO4
the solvents were removed in vacuo to give crude 14a , which
was chromatographed (petrol/ether 7:3; NH3) to give a pale
yellow oil (1.359 g, 58%), Rf (7:3, petrol/ether). δH (250 MHz,
CDCl3) 1.42, 1.77-2.13 (m, 4H), 2.43 (brs, 1H), 2.47 (d, J )
9.2 Hz, 1H), 2.82 (ddd, J ≈ 9.2, 3.3, 3.3 Hz, 1H), 3.23 (brs,
1H), 3.67, 3.69 (AB, J ) 13.4 Hz, 2H), 4.24 (d, J ) 1.7 Hz,
1H), 7.18 (m, 5H). δC (62.9 MHz, CDCl3) 25.2, 26.7, 44.0, 53.4,
58.0, 59.0, 64.9, 126.9, 128.1, 128.2, 139.2. νmax 3064s, 2982m,
2276w, 1504m, 1463m, 1430m, 1380w, 1279s, 1150w, 907m
cm-1. m/z 266/268 (1:1) (MH+). C13H16NBr [EI, M+] requires
m/z 265.04661; observed 265.04659.
a n ti-7-(Im id a zole-1-yl)-2-b en zyl-2-a za b icyclo[2.2.1]-
h ep ta n e (14e). Butyllithium (0.31 mL, 1.6 M in hexanes, 0.49
mmol) was added dropwise to imidazole (34 mg, 0.50 mmol)
in anhydrous DMF (1.5 mL), and the mixture was stirred at
20 °C for 0.25 h. A solution of 14a (103 mg, 0.39 mmol) in
anhydrous DMF (4 mL) was added, and after stirring at 100
°C for 96 h the mixture was filtered, the residue was washed
with diethyl ether, the combined organic extracts were washed
with water (4 × 2 mL), and the solvents were removed in
vacuo. After chromatography (ether, NH3), 14e was isolated
as a yellow oil (52 mg, 53%), Rf 0.20. δH (250 MHz, CDCl3)
1.42 (m, 1H), 1.47 (m, 1H), 1.68 (m, 1H), 2.00 (m, 1H), 2.45 (d,
J ) 9.4 Hz, 1H), 2.81 (brs, 1H), 3.15 (ddd, J ≈ 9.4, 3.2, 3.2 Hz,
1H), 3.63 (brs, 1H), 3.69 (brs, 2H), 4.36 (brs, 1H), 6.87 (brs,
1H), 7.06 (brs, 1H), 7.14 (m, 5H), 7.46 (brs, 1H). δC (62.9 MHz,
CDCl3) 23.9, 26.6, 41.1, 57.9, 58.2, 61.6, 62.9, 118.5, 127.0,
128.2, 128.3, 129.0, 136.6, 139.0. νmax 3052m, 2972m, 2305w,
1501w, 1452w, 1374w, 1265s, 1082w, 910w cm-1. m/z 254.16572;
Alternatively, reduction using Red-Al16 (65+ wt % solution
in toluene, 7.65 mL, 26.0 mmol) and 13 (8.96 g, 26.0 mmol) in
dry THF (225 mL) at -10 °C for 2 h gave 14a as a pale yellow
oil (6.42 g, 24.1 mmol, 93%).
a n ti-7-Ch lor o-2-ben zyl-2-azabicyclo[2.2.1]h eptan e (14b).
To a solution of 14a (63.7 mg, 0.24 mmol) in anhydrous DMF
(1.0 mL) in a reaction vial was added LiCl (217.5 mg, 5.13
mmol). The mixture was heated to 100 °C for 24 h, cooled, and
poured into water (2 mL), followed by extraction with ether
(3 × 2 mL). The combined organic extracts were dried over
MgSO4 and filtered, and the solvents were evaporated in vacuo,
yielding 14b as a pale yellow oil (41 mg, 77%). Rf 0.79 (EtOAc/
MeOH, 9:1). δH (250 MHz, CDCl3) 1.41 (m, 1H), 1.80-2.08 (m,
3H), 2.34 (brs, 1H), 2.38 (d, J ) 9.2 Hz, 1H), 2.85 (ddd, J ≈
9.2, 3.2, 3.2 Hz, 1H), 3.16 (brs, 1H), 3.66 (brs, 2H), 4.20 (brs,
1H), 7.27 (m, 5H). δC (62.9 MHz, CDCl3) 24.2, 26.2, 43.5, 58.0,
58.5, 62.0, 64.5, 126.8, 128.1, 128.3, 139.1. νmax 3064m, 2991m,
2318w, 1683s, 1500w, 1453w, 1289w, 1256s, 843w cm-1. m/z
222.10500 (MH+); C13H17NCl requires 222.10495.
C
16H20N3 [MH+] requires 254.16564.
a n ti-2-Ben zyl-2-a za bicyclo[2.2.1]h ep t a n e-7-ca r b oxyl-
ic Acid Eth yl Ester (14f). Aqueous HCl (4 mL, 8 M) was
added to 14d (0.309 g, 1.46 mmol) and stirred at 90 °C for 65
h. The mixture was evaporated to dryness; thionyl chloride (4
mL) was added, and the mixture was stirred at 40 °C for 6 h.
Excess thionyl chloride was removed in vacuo, dry ethanol (5
mL) was added, and the mixture stirred at 20 °C for 0.5 h.
After removal of the solvents in vacuo, the resulting yellow
oil was dissolved in HCl (4 mL, 1 M) and washed with CH2Cl2
(3 × 4 mL). The aqueous layer was basified with ammonium
hydroxide solution (8 mL, 35% ammonia) and extracted with
CH2Cl2 (3 × 4 mL). The organic layers were combined and
dried over anhydrous MgSO4. Removal of solvents in vacuo
gave 14f as a yellow oil (0.290 g, 77%; the sample was
sufficiently pure for the epimerization to give 16). Rf 0.41 (3:2
a n ti-7-H yd r oxy-2-b en zyl-2-a za b icyclo[2.2.1]h ep t a n e
(14c). The 7-bromo compound 14a (110 mg, 0.41 mmol) and
(25) Larsen, P. A.; Grieco, P. A. Org. Synth. 1990, 68, 206-209.
5332 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of syn- and anti-Isoepiboxidine
ether/petrol). δH (250 MHz, CDCl3) 1.24 (t, J ) 7.1 Hz, 3H),
1.40, 1.60-1.95 (m, 4H), 2.40 (d, J ) 9.4 Hz, 1H), 2.61 (brs,
1H), 2.86 (ddd, J ≈ 9.4, 3.4, 3.4 Hz, 1H), 2.93 (brs, 1H), 3.44
(brs, 1H), 3.66, 3.74 (AB, J ) 13.5 Hz, 2H), 4.13 (q, J ) 7.1
Hz, 2H), 7.33 (m, 5H). δC (62.9 MHz, CDCl3) 14.0, 25.5, 26.9,
40.1, 51.2, 58.4, 59.9, 60.0, 62.2, 126.8, 128.2, 128.2, 128.4,
138.9, 171.7. νmax 3053s, 2982s, 2305w, 1725s, 1452m, 1370m,
1265s, 1214m, 1180m, 1043m, 896w cm-1. m/z 260.16510;
were stirred in THF (2 mL) and water (6 mL) at room
temperature for 20 h. The reaction mixture was extracted with
ether (4 × 4 mL), the organic extracts were combined, dried
over anhydrous MgSO4, and filtered, and the solvents were
removed in vacuo. The resulting colorless oil was chromato-
graphed (7:3 ether/petrol, NH3) yielding 19 (105 mg, 64%), Rf
0.54. δH [300 MHz, CDCl3; where there is signal duplication
(slow N-CO rotation, ratio ∼52:48) the minor rotamer signal
is shown in italics] 1.27 (bt, J ) 7.0 Hz, 3H), 1.45, 1.46 (2 × s,
9H), 1.57-1.88 (m, 4H), 2.76 (m, 2H), 3.01, 3.07 (2 × d, J )
9.7 Hz, 1H), 3.32, 3.35 (2 × brs, 1H), 4.15 (bq, J ) 7.0 Hz,
2H), 4.31, 4.45 (2 × brs, 1H). δC (75.5 MHz, CDCl3) 14.1, 25.8
& 26.0, 28.5, 29.1 & 29.3, 39.1 & 39.6, 52.6 & 53.0, 53.1 &
53.7, 57.3 & 58.1, 60.5, 79.2 & 79.3, 153.7 & 154.1, 170.5. νmax
2977s, 1736s, 1697s, 1408s, 1173s, 1101s, 1048s cm-1. m/z
270.17050; C14H24NO4 (MH+) requires 270.17053.
a n ti-2-Boc-7-(3-m eth yl-isoxazol-5-yl)-2-azabicyclo[2.2.1]-
h ep ta n e (20). Using the procedure described by Fitch et al.,4
a solution of butyllithium (0.58 mL, 1.6 M in hexanes, 0.93
mmol) was added dropwise over 10 min to a solution of
acetoxime (34 mg, 0.47 mmol) in dry THF (1 mL) under argon
at 0 °C. After stirring for 2 h at 0 °C, a solution of the anti-
ethyl ester 19 (58 mg, 0.22 mmol) in dry THF (1 mL) was
added over 10 min. The reaction mixture was stirred under
argon at 0 °C for 20 h and then transferred to vigorously
stirred 1 M HCl (8 mL) over 40 min. This mixture was
neutralized (NaHCO3) and extracted with CH2Cl2 (5 × 15 mL),
the combined organic extracts were dried over anhydrous
MgSO4 and filtered, and the solvents were removed in vacuo.
The resulting yellow oil was chromatographed (7:3 ether/
petrol), yielding 20 (19 mg, 48% based on recovered 19), Rf
0.21 and 19 (19 mg). NMR signals were broadened; where
there is signal duplication (slow N-CO rotation, ratio ∼2:3)
the minor rotamer signal is shown in italics. δH (300 MHz,
CDCl3) 1.47 (s, 9H), 1.60-1.86 (m, 4H), 2.28 (s, 3H), 2.85 (brs,
1H), 3.14 (brs, 1H), 3.45 (bddd, J ≈ 9.6, 2.7, 2.7 Hz, 1H), 4.43,
4.51 (2 × brs, 1H), 5.88 (brs, 1H). δC (100.6 MHz, CDCl3) 11.4,
25.9, 28.5, 28.9 & 29.2, 40.1 & 40.7, 46.0 & 46.3, 53.2 & 53.7,
58.3 & 59.3, 79.6, 102.6, 154.2, 159.7, 170.0. νmax 2976m, 1694s,
1406s, 1173m, 1112m cm-1. m/z 279.17085; C15H23N2O3 (MH+)
requires 279.17087.
a n t i-7-(3-Me t h yl-isoxa zol-5-yl)-2-a za b icyclo[2.2.1]-
h ep ta n e (21) fr om 20. The ester 20 (8.3 mg, 0.030 mmol)
was stirred in a mixture of EtOH (0.435 mL), ethyl acetate
(1.205 mL), and acetyl chloride (0.359 mL) at 0 °C for 1 h.
The reaction mixture was evaporated to dryness to give the
hydrochloride salt of 21 (6.4 mg, 99%). Data for the free amine
21: δH (300 MHz, CDCl3) 1.40-1.75 (m, 4H), 1.9 (brs, NH),
2.27 (s, 3H), 2.71 (brs, 1H), 2.77 (d, J ) 9.6 Hz, 1H), 3.09 (brs,
1H), 3.13 (m,1H), 3.71 (brs, 1H), 5.85 (s, 1H). δC (75.5 MHz,
CDCl3) 11.4, 26.8, 31.0, 40.4, 47.2, 52.3, 58.7, 102.3, 159.6,
171.4. νmax 3392b, 2968s, 2876m, 1725w, 1602s, 1534m, 1415s
cm-1. m/z 179.11839; C10H15N2O [MH+] requires m/z 179.11844.
Dir ect F or m a tion of 21 fr om 18. The procedure described
for 17 was followed using acetoxime (76 mg, 1.04 mmol) in
dry THF (3 mL), butyllithium (1.43 mL, 1.6 M, 2.29 mmol),
and the ester 18 (65 mg, 0.38 mmol) in dry THF (2 mL). HCl
(8 mL, 10.2 M) was used in the second step, and after workup
21 was isolated as an orange oil (28 mg). Quantitative 1H NMR
analysis gave a yield of 16.2 mg, 24%.
C
16H22NO2 [MH+] requires m/z 260.16505.
syn -2-Ben zyl-2-a za b icyclo[2.2.1]h ep t a n e-7-ca r b oxyl-
ic Acid Eth yl Ester (16). To the ester 14f (3.387 g, 13.10
mmol) was added NaOEt in EtOH (0.63 M, 42 mL) and dry
HMPA (0.1 mL), and the mixture was stirred at 65 °C for 24
h. After addition of the mixture to water (50 mL) and
extraction with CH2Cl2 (5 × 60 mL), the organic extracts were
combined, dried over anhydrous MgSO4, and filtered. Capillary
GC analysis [25 m HP-FFAP column] indicated the presence
of both 14f and 16 (anti/syn ) 45:55). Chromatography (3:2
ether/petrol, NH3) yielded 14f (1.399 g; 41%), Rf 0.41, and 16
(1.56 g, 6.02 mmol, 46%), Rf 0.59. δH (300 MHz, CDCl3) 1.28
(t, J ) 7.1 Hz, 3H), 1.32-1.54, 1.54-1.69, 1.84 (3 × m, 2H,
1H, 1H), 1.93 (d, J ) 8.4 Hz, 1H), 2.48 (brs, 1H), 2.55 (brs,
1H), 3.28 (ddd, J ≈ 8.4, 3.5, 3.5 Hz, 1H), 3.48 (brs, 1H), 3.68
(brs, 2H), 4.18, 4.20 (complex, 2 overlapping dq,23 J ) 7.1 Hz,
2H), 7.25-7.28 (m, 5H). δC (75.5 MHz, CDCl3) 14.3, 23.7, 29.7,
39.4, 53.7, 55.5, 56.5, 60.0, 62.7, 126.5, 128.0, 140.0, 172.2. νmax
2976s, 2870s, 1733s, 1453s, 1186s cm-1. m/z 260.16509 (MH+);
C
16H22NO2 [MH+] requires m/z 260.16505.
syn -2-Ben zyl-7-(3-m et h yl-isoxa zol-5-yl)-2-a za b icyclo-
[2.2.1]h ep ta n e (17). Using the procedure described by Badio
et al.,2a acetoxime (129 mg, 1.77 mmol) was dissolved in dry
THF (4 mL) and held at 0 °C. Butyllithium (2.21 mL, 1.6 M,
3.53 mmol) was added, and the mixture was stirred at 20 °C
for 0.8 h. The ester 16 (174 mg, 0.67 mmol) dissolved in dry
THF (2 mL) was added. After stirring at 60 °C for 1 h the
solvent was evaporated using nitrogen. HCl (8 mL, 10.2 M)
was added, and the mixture was stirred at 80 °C for 4.5 h and
then 12 h at room temperature. The reaction mixture was
basified with saturated NaHCO3 solution (∼15 mL) and
extracted with CH2Cl2 (4 × 40 mL). The organic layers were
combined, and removal of the solvents in vacuo gave an orange
oil that was dissolved in HCl (1 M, 3 mL) and washed with
ether (4 × 2 mL). The aqueous layer was basified (NH4OH
solution) and extracted with CH2Cl2 (4 × 2 mL). The CH2Cl2
extracts were dried over MgSO4 and filtered. Flash chroma-
tography (9:1, ether/MeOH, NH3) gave 17 as a colorless oil (65
mg, 36%), Rf 0.56. δH (300 MHz, CDCl3) 1.45-1.62 (m, 2H),
1.74-1.87 (m, 1H), 2.00-2.13 (m, 1H), 2.02 (d, J ) 9.1 Hz,
1H), 2.30 (s, 3H), 2.52 (brs, 1H), 2.88 (brs, 1H), 3.09 (ddd, J ≈
9.1, 3.5, 3.5 Hz, 1H), 3.46 (brs, 1H), 3.68, 3.74 (AB, J ) 13.8
Hz, 2H), 6.16 (s, 1H), 7.17-7.33 (m, 5H). δC (75.5 MHz, CDCl3)
11.5, 24.1, 29.9, 41.8, 46.6, 55.8, 56.2, 63.0, 102.3, 126.6, 128.1,
138.8, 159.6, 172.3. νmax 2961s, 1601s, 1494m, 1418s, 1370m,
1184m, 1010m. m/z 269.16537; C17H21N2O [MH+] requires m/z
269.16539.
a n ti-2-Azabicyclo[2.2.1]h eptan e-7-car boxylic Acid Eth -
yl Ester (18). A solution of 14f (1.399 g, 5.40 mmol) in dry
MeOH (40 mL) was hydrogenolyzed over Pd/C (10%, 0.25 g)
with stirring for 24 h. The reaction mixture was filtered
through Celite, and the solvent was removed in vacuo to leave
a yellow oil that was chromatographed (17:3, ether/MeOH,
NH3) to provide 18 (0.612 g, 67%), Rf 0.29. δH (300 MHz, CDCl3)
1.25 (t, J ) 7.1 Hz, 3H), 1.48-1.57, 1.77-1.98 (2 × m, 2H,
2H), 2.62 (brs, 1H), 2.69 (d, J ) 9.5 Hz, 1H), 2.73 (brs, 1H),
3.01 (ddd, J ≈ 9.5, 3.0, 3.0 Hz, 1H), 3.61 (brs, 1H), 4.12 (q, J
) 7.1 Hz, 2H). δC (75.5 MHz, CDCl3) 13.9, 26.8, 30.9, 39.2,
51.9, 53.6, 57.4, 60.0, 171.5. νmax 3407b, 2979s, 1730s, 1541m,
1372m, 1226s, 1051m cm-1. m/z 170.11811; C9H16NO2 [MH+]
requires 170.11810.
syn -2-Aza bicyclo[2.2.1]h ep ta n e-7-ca r boxylic Acid Eth -
yl Ester (22). The ester 16 (1.56 g, 6.02 mmol) in dry MeOH
(40 mL) was hydrogenolyzed as described for 14f to yield 22
as a yellow oil (0.625 g, 61%), Rf 0.30. δH (300 MHz, CDCl3)
1.27 (t, J ) 7.1 Hz, 3H), 1.40-1.77 (m, 4H), 2.0 (brs NH),
2.59 (brs, 1H), 2.61 (d, J ) 9.8 Hz, 1H), 2.51 (brs, 1H), 3.13
(ddd, J ≈ 9.8, 3.1, 3.1 Hz, 1H), 3.61 (bd, ≈ 2.6 Hz, 1H), 4.14
(complex “q”,23 J ) 7.1 Hz, 2H). δC (75.5 MHz, CDCl3) 13.9,
28.8, 30.8, 40.0, 49.8, 52.2 & 52.4, 58.27 & 58.31, 60.0, 172.3
& 172.7. νmax 3406b, 2977s, 1728s, 1542m, 1409s, 1303m,
1192m, 1037m cm-1. m/z 170.11812; C9H16NO2 [MH+] requires
m/z 170.11810.
a n ti-2-Boc-2-azabicyclo[2.2.1]h eptan e-7-car boxylic Acid
Eth yl Ester (19). The anti-ethyl ester 18 (103 mg, 0.61 mmol),
Boc2O (202 mg, 0.93 mmol), and NaHCO3 (187 mg, 2.23 mmol)
J . Org. Chem, Vol. 69, No. 16, 2004 5333

Malpass and White
syn -2-Boc-2-azabicyclo[2.2.1]h eptan e-7-car boxylic Acid
Eth yl Ester (23). Treatment of the ester 22 (128 mg, 0.76
mmol) with Boc2O (262 mg, 1.20 mmol) and NaHCO3 (200 mg,
2.38 mmol) in THF (2 mL) and water (6 mL) using the method
described for 19 gave 23 (130 mg, 64%), Rf (7:3, ether/petrol,
NH3) 0.39. δH [300 MHz, CDCl3; where there is signal duplica-
tion due to slow N-CO rotation (ratio ∼45:55) the minor
rotamer signal is shown in italics.] 1.24 (t, J ) 7.1 Hz, 3H),
1.44 & 1.46 (2 × s, 9H), 1.64-1.80 (m, 4H), 2.53 (brs, 1H),
2.72 & 2.75 (2 × brs, 1H), 2.94 & 3.00 (2 × d, J ) 9.8 Hz, 1H),
3.51 (m, 1H), 4.13 (m, 2H), 4.39 & 4.51 (2 x brs, 1H). δC (75.5
MHz, CDCl3) 14.2, 27.4, 28.5, 30.7, 39.4, 40.0, 50.6, 51.2, 52.2,
53.0, 58.2, 58.9, 60.4, 60.5, 79.0, 79.1, 154.2, 154.5, 170.6, 170.9.
νmax 2974m, 1735s, 1696s, 1406s, 1163s, 1104s cm-1. m/z
270.17057; C14H24NO4 [MH+] requires m/z 270.17053.
58.6 & 59.7, 79.4 & 79.6, 102.1 & 102.3, 154.5, 159.8, 170.2 &
170.4. νmax 2976s, 2359s, 1694s, 1406s, 1150s, 1112s cm-1. m/z
279.17088; C13H23N2O3 [MH+] requires m/z 279.17087.
syn -7-(3-Me t h y l-is o x a zo l-5-y l)-2-a za b ic y c lo [2.2.1]-
h ep ta n e (syn -isoep iboxid in e) (9). The N-Boc compound 24
(12.5 mg, 0.0450 mmol) was deprotected as described for
compound 20, yielding the hydrochloride salt of compound
9 (9.6 mg, 99%). Data for the free amine 9: δH (300 MHz,
CDCl3) 1.49-1.68 (m, 2H), 1.72-1.91 (m, 2H), 2.27 (bs, 3H &
NH), 2.66 (brs, 1H), 2.67 (d, J ) 9.9 Hz, 1H), 2.91 (brs, 1H),
2.99 (ddd, J ≈ 9.9, 3.2, 3.2 Hz, 1H), 3.66 (bd, J ) 2.5 Hz,
1H), 5.96 (s, 1H). δC (75.5 MHz, CDCl3) 11.3, 29.0, 31.9, 40.8,
46.5, 49.9, 59.2, 102.4, 159.7, 171.6). νmax 3400b, 2966s, 2877s,
1602s, 1418s cm-1. m/z 179.11842; C9H16NO2 [MH+] requires
179.11844.
syn -2-Boc-7-(3-m eth yl-isoxa zol-5-yl)-2-a za bicyclo[2.2.1]-
h ep ta n e (24). Acetoxime (74 mg, 1.01 mmol), butyllithium
in hexanes (1.27 mL, 1.6 M, 2.03 mmol), and the ester 23 (133
mg, 0.49 mmol) were reacted using the procedure described
for 20 to give 24 (61 mg, 52% based on recovered 23), Rf (7:3,
ether/petrol, NH3) 0.35, and recovered 23 (19 mg). δH [300
MHz, CDCl3; where there is signal duplication because of slow
N-CO rotation (ratio ∼45:55), the minor rotamer signal is
shown in italics.] 1.43 & 1.47 (2 × s, 9H), 1.57-1.95 (m, 4H),
2.24 & 2.25 (2 × s, 3H), 2.74 & 2.80 (2 × brs, 1H), 2.94 & 2.95
(2 × brs, 1H), 2.96 & 3.03 (2 × d, J ) 10.1 Hz, 1H), 3.15 &
3.27 (2 × ddd, J ≈ 9.9, 2.7, 2.7 Hz, 1H), 4.35 & 4.51 (2 × brs,
1H), 5.84 & 5.91 (2 × brs, 1H). δC (100.6 MHz, CDCl3) 11.4,
28.5 & 28.6, 30.6 & 30.9, 40.8 & 41.4, 45.6 & 46.1, 50.1 & 50.8,
Dir ect F or m a tion of 9 fr om 22 Acetoxime (72 mg, 0.99
mmol) in dry THF (3 mL) was treated with butyllithium (1.30
mL, 1.6 M, 2.08 mmol) and the ester 22 (54 mg, 0.32 mmol) in
dry THF (2 mL) following the procedure described for 17.
Following workup using HCl (8 mL, 10.2 M), 9 was isolated
1
as an orange oil (30 mg). Quantitative H NMR analysis using
an internal standard gave a yield of 14.6 mg, 26%.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0492564
5334 J . Org. Chem., Vol. 69, No. 16, 2004