Rearrangement of a mesylate tropane intermediate in nucleophilic substitution reactions. Synthesis of aza-bicyclo[3.2.1]octane and aza-bicyclo[3.2.2]nonane ethers, imides, and amines.

Article abstract of DOI:10.1021/jo010973x

Nucleophilic substitution of 2beta-mesyloxymethyl-N-methyl-3beta-p-tolyl-tropane intermediate with alkoxides, metal imides, or amines was found to lead not only to the expected bicyclo[3.2.1]octane (tropane) ether, imide, and amine derivatives but also to unexpected bicyclo[3.2.2]nonane derivatives. When alkoxides were used as nucleophile, only the rearranged bicyclo[3.2.2]nonane structure was obtained, whereas the use of amines or imides as nucleophile afforded a mixture of the two structures. The bicyclo[3.2.2]nonane structure was assigned by NMR analysis.

Full text of DOI:10.1021/jo010973x

J . Org. Chem. 2002, 67, 3637-3642
3637
Rea r r a n gem en t of a Mesyla te Tr op a n e In ter m ed ia te in
Nu cleop h ilic Su bstitu tion Rea ction s. Syn th esis of
Aza -Bicyclo[3.2.1]octa n e a n d Aza -Bicyclo[3.2.2]n on a n e Eth er s,†
Im id es, a n d Am in es
Lionel Ogier,‡ Fre´de´ric Turpin,§ Ronald M. Baldwin,‡ Franc¸oise Riche´,| Ho Law,
Robert B. Innis,‡ and Gilles Tamagnan*,‡
Department of Psychiatry, Yale University and VA CT HCS, West Haven, Connecticut,
CIS Bio International, filiale de SCHERING S.A. 91192 Gif-sur-Yvette, France, Laboratoire d’Etudes
Dynamiques et Structurales et de la Se´lectivite´, Grenoble I, France, and ERAS Labo,
38330 St Nazaire les Eymes, France
gilles.tamagnan@yale.edu
Received October 4, 2001 (Revised Manuscript Received March 1, 2002)
Nucleophilic substitution of 2â-mesyloxymethyl-N-methyl-3â-p-tolyl-tropane intermediate with
alkoxides, metal imides, or amines was found to lead not only to the expected bicyclo[3.2.1]octane
(tropane) ether, imide, and amine derivatives but also to unexpected bicyclo[3.2.2]nonane derivatives.
When alkoxides were used as nucleophile, only the rearranged bicyclo[3.2.2]nonane structure was
obtained, whereas the use of amines or imides as nucleophile afforded a mixture of the two
structures. The bicyclo[3.2.2]nonane structure was assigned by NMR analysis.
In tr od u ction
tomography) or with γ emitters (123I, 99mTc)9-11 used for
SPECT (single photon emission computed tomography).
A number of potent cocaine analogues have been syn-
thesized to better understand the pharmacological prop-
erties of this drug12 and to find new dopamine transporter
(DAT) ligands.6-10,11
In tropane derivatives such as cocaine, the presence
of 2â-substituents is important for the binding affinity.13-15
However, since the axial 2â-ester group in cocaine tends
to epimerize under basic conditions,16,17 other functional
groups (e.g., ketone,18 alkyl,19,20 ether21,22) have been
substituted and found to retain high potency for DAT.
The tropane moiety, 8-azabicyclo[3.2.1]octane, is found
in the natural substance cocaine 1. Cocaine is known to
have multiple effects on the central nervous system,
mainly by binding to transporter proteins for the monoam-
ine neurotransmitters dopamine (DA), serotonin (5-HT),
and norepinephrine (NE). Alterations of the density and
function of these transporters have been implicated in
neurological disorders such as Parkinson’s disease,1,2
depression,3,4 and schizophrenia.5 Two major uses of
imaging the density of such transporters with radiola-
beled tracers would be to diagnose patients at early
stages of the disorder and to monitor the progression of
the disease. Therefore, many efforts have been expended
to synthesize specific probes labeled either with â+
emitters (18F, 11C)6-8 used for PET (positron emission
(9) Meegalla, S. K.; Plossl, K.; Kung, M. P.; Chumpradit, S.;
Stevenson, D. A.; Kushner, S. A.; McElgin, W. T.; Mozley, P. D.; Kung,
H. F. J . Med. Chem. 1997, 40, 9-17.
(10) Neumeyer, J . L.; Wang, S.; Milius, R. A.; Baldwin, R. M.; Zea-
Ponce, Y.; Hoffer, P. B.; Sybirska, E. H.; Al-Tikriti, M. S.; Laruelle,
M.; Innis, R. B. J . Med. Chem. 1991, 34, 3144-3146.
(11) Kung, M.-P.; Stevenson, D. A.; Plossl, K.; Meegalla, S. K.;
Beckwith, A.; Essman, W. D.; Mu, M.; Lucki, I.; Kung, H. F. Eur. J .
Nucl. Med. 1997, 24, 372-380.
(12) Carroll, F. I.; Howell, L. L.; Kuhar, M. J . J . Med. Chem. 1999,
42, 2721-2736.
(13) Lewin, A. H.; Gao, Y.; Abraham, P.; Boja, J . W.; Kuhar, M. J .;
Carroll, F. I. J . Med. Chem. 1992, 35, 135-140.
(14) Davies, H. M. L.; Saikali, E.; Sexton, T.; Childers, S. R. Eur. J .
Pharmacol., Mol. Pharmacol. Sec. 1993, 244, 93-97.
(15) Kozikowski, A. P.; Roberti, M.; Xiang, L., Bergmann, J . S.;
Callahan, P. M.; Cunningham, K. A.; J ohnson, K. M. J . Med. Chem.
1992, 35, 4764-4766.
(16) Findlay, S. P. J . Am. Chem. Soc. 1954, 76, 2855.
(17) Carroll, F. I.; Gray J . L.; Abraham, P.; Kuzemko, M. A.; Lewin,
A. H.; Boja, J . W.; Kuhar, M. J . J . Med. Chem. 1993, 36, 2886-2890.
(18) Davies, H. M. L.; Saikali, E.; Huby, N. J . S.; Gilliat, V. J .;
Matasi, J . J .; Sexton, T.; Childers, S. R. J . Med. Chem. 1994, 37, 1262-
1268.
† Work presented in part at the 221st American Chemical Society
National Meeting, San Diego, CA, April 2001.
‡ Yale University and VA CT HCS.
§ CIS Bio International.
| Laboratoire d’Etudes Dynamiques et Structurales et de la Se´lec-
tivite´.
ERAS Labo.
(1) Morgan, G. F.; Nowotnik, D. P. Drug News Perspect. 1999, 12,
137.
(2) Agoston, G. E.; Wu, J . H.; Izenwasser, S.; George, C.; Katz, J .
L.; Klein, R.; Newman, A. H. J . Med. Chem. 1997, 40, 4329-4339.
(3) Briner, K.; Dodel, R. C. Curr. Pharm. Des. 1998, 4, 291-302.
(4) Pinder, R. M.; Wieringa, J . H. Med. Res. Rev. 1993, 13, 259-
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Pharmacol. 1986, 35, 1123-1129.
(6) Chaly, T.; Dhawan, V.; Kazumata, K.; Antonini, A.; Dahl, J . R.;
Matacchieri, R.; Margouleff, C.; Belakhlef, A.; Wang, S.; Tamagnan,
G.; Neumeyer, J . L.; Eidelberg, D. Nucl. Med. Biol. 1996, 33, 999-
1004.
(7) Goodman, M. M.; Keil, R.; Shoup, T. M.; Eshima, D.; Eshima,
L.; Kilts, C.; Votaw, J .; Camp, V. M.; Votaw, D.; Smith, E.; Kung, M.
P.; Malveaux, E.; Watts, R.; Huerkamp, M.; Wu, D.; Garcia, E.;
Hoffman, J . M. J . Nucl. Med. 1997, 38, 119-126.
(8) Fowler, J . S.; Volkow, N. D.; Wolf, A. P.; Dewey, S.; Christman,
D.; MacGregor, R.; Logan, J .; Schlyer, D.; Bendriem, B. J . Nucl. Med.
1989, 30, 761.
(19) Kozikowski, A. P.; Saiah, M. K. E.; J ohnson, K. M.; Bergmann,
J . S. J . Med. Chem. 1995, 38, 3086-3093.
(20) Kelkar, S. V.; Izenwasser, S.; Katz, J . L.; Klein, C. L.; Zhu, N.;
Trudell, M. L. J . Med. Chem. 1994, 37, 3875-3877.
(21) Keverline-Frantz, K. I.; Boja, J . W.; Kuhar, M. J .; Abraham,
P.; Burgess, J . P.; Lewin, A. H.; Carroll, F. I. J . Med. Chem. 1998, 41,
247-257.
(22) Neumeyer, J . L.; Baldessarini, R. J .; Kula, N. S.; Tamagnan
G. Progress in Alzheimer’s and Parkinson’s Diseases; Plenum Press:
New York, 1998; pp 739-745.
10.1021/jo010973x CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/08/2002

3638 J . Org. Chem., Vol. 67, No. 11, 2002
Ogier et al.
Ta ble 1. 1H a n d 13C NMR Ch em ica l Sh ifts of Rea r r a n ged
(6-12) a n d Non r ea r r a n ged (13, 14, 16-19) Eth er s a n d
Am in es
δ (ppm)
C1
C3
C5
C9
H1
H3
H5
H9a
H9b
4
68
84
36
34
62
55
63
51
3.4
4.3
3.0
3.4
3.2
3.0
4.6
3.0
3.3
2.4
2a
Ethers Structure II
6
7
8
86
85
84
34
35
35
56
56
56
51
51
51
3.4
3.3
4.4
3.2
3.4
3.4
2.9
2.8
3.0
3.1
3.1
3.0
2.1
2.1
2.4
Amines, Imides Structure II
10
11
12
56
56
63
35
33
34
57
55
56
53
52
52
4.8
3.1
2.8
4.2
3.2
3.8
3.0
2.9
2.9
2.9
2.9
3.0
2.9
2.4
2.3
Ethers Structure I
13
14
16
63
63
64
34
35
35
62
62
62
70
69
68
3.4
3.5
3.4
3.0
3.0
3.0
3.3
3.1
3.1
3.6
4.0
4.1
2.8
3.1
3.3
F igu r e 1.
Amines, Imides Structure I
17
18
19
64
63
66
35
34
35
63
61
62
38
40
49
3.0
3.3
3.2
3.2
3.0
3.0
3.4
3.2
3.2
4.0
2.7
2.7
3.4
2.3
2.4
One of our goals was to synthesize tropane intermediates
that could be used either in basic or acidic conditions
without fear of epimerization, starting with ethers and
amines, i.e., 2â-alkoxymethyl ether or 2â-aminomethyl
groups. Our interest in the ethers was piqued by results
from Carroll’s group showing apparently anomalously low
binding affinity of the ether derivative 2, a rigid analogue
of paroxetine,21 compared to that of a tropane iodopropyl
ether described by Neumeyer et al.22 (Figure 1). The
reported synthesis of 2 proceeded through alkylation of
a tropane mesylate intermediate with the sodium salt of
3,4-methylenedioxyphenol (sesamol). Another method to
get tropane ethers consists of using the alkoxide of the
tropane alcohol 4 as nucleophile; however, this method
has been reported22 to give unreliable yields. Concerning
the 2â-aminomethyl derivatives, only a few compounds
have been reported9 such as TRODAT (3). Those were
synthesized from acyl chloride derivatives and reduction
of the amide intermediate.
We therefore investigated the synthesis of 2â-alkylated
tropane derivatives (ethers and amines) in greater detail,
using the mesylate 5 (Scheme 1) from 2â-hydroxymethyl-
3â-(4-methylphenyltropane) 4,21,23 readily available from
cocaine. Here we report that rearrangement occurred
when 2â-methanesulfonyloxymethyl-N-methyltropane in-
termediate 5 was used in nucleophilic substitution reac-
tions with alcohols, imides, or amines, to lead to aza-
bicyclo[3.2.2]nonane derivatives 6-12. Depending on the
nature of the nucleophile, a mixture of rearranged and
nonrearranged derivatives could be obtained from 5. The
nonrearranged aza-bicyclo[3.2.1]octane compounds 13-
21 could be synthesized exclusively by alternate routes
using either the tropane alcohol 4 as nucleophile, the acyl
chloride derivative 22, or the N-tosyl triflate intermediate
28 as electrophile (Scheme 1).
a
The chemical shifts for 2 were taken from the literature21 and
assigned according to the present study.
its electrophilic carbon C9, displacing the mesyloxy group
(Scheme 2). Such a cyclization reaction has been de-
scribed with aziridine,24 aminoiodohydrin,25 and 2â-
chloromethyl tropane derivatives.26
In the reaction with alkoxides, amide and imide salts,
or amines, we observed a competition between C1 and
C9 as reactive site for the substitution reaction (no trace
of C5 substitution). Therefore, the structure of the result-
ing products could be a 1-C-substituted-aza-bicyclo[3.2.2]-
nonane (structure II) or a 2-C-substituted-aza-bicyclo-
[3.2.1]octane (structure I, Scheme 3).
Syn th esis of Aza -Bicyclo Alk yl Eth er s. By reacting
5a with freshly prepared sodium salts of methanol, allyl
alcohol, or sesamol, we obtained exclusively the rear-
ranged derivatives 6, 7, and 8, respectively (Scheme 2,
Table 1). N-Demethylation of derivative 8 with 1-chloro-
ethyl chloroformate followed by methanol gave the corre-
sponding sesamol ether derivative 9 (45%) with second-
ary amine (Scheme 2, R2 ) H).
The unrearranged derivative 13 was synthesized (41%)
using sodium bis(trimethylsilyl)amide as a base to form
the alkoxide of alcohol 4 and reacting this alkoxide with
methyl trifluoromethanesulfonate (Scheme 4). Likewise,
the allyl ether derivative 14 was obtained (84%) by
reacting the alkoxide with ethyl allyl carbonate in the
presence of 1,4-bis(diphenylphosphino)butane and tris-
(dibenzylideneacetone) dipalladium(0).27 The synthesis of
aryl ether 16 could not use this route. In fact, reaction
of the alkoxide with mesylate reagent 23 led to transes-
terification28 to generate the tropane mesylate 5 and the
alkoxide of sesamol, which reacted with rearrangement
to give derivative 8, formerly obtained by another route
Resu lts a n d Discu ssion
Unstable mesylate intermediate 5 was synthesized by
esterification of alcohol 421,23 with methanesulfonic an-
hydride21 or methanesulfonyl chloride. In our study, we
observed (TLC, NMR) that mesylate 5 rapidly generated
its azetidinium salt form 5a , resulting from the attack
of the lone pair of electrons of the tertiary amine of 5 on
(24) Morie, T.; Kato, S.; Harada, H.; Fujiwara, I. Watanabe, K.;
Matsumoto, J .-I. J . Chem. Soc., Perkin Trans. 1 1994, 2565-2569.
(25) Concello´n, J . M.; Bernad, P. L.; Pe´rez-Andre´s, J . A. Tetrahedron
Lett. 2000, 41, 1231-1234.
(26) Fodor, G.; Mandava, N.; Weisz, I. Tetrahedron 1968, 24, 2357-
2366.
(27) Lakhmiri, R.; Lhoste, P.; Sinou, D. Synth. Commun. 1966,
20(10), 1551-1554.
(28) Pregel, M. J .; Buncel, E. J . Chem. Soc., Perkin Trans. 2 1991,
307-311.
(23) Kozikowski, A. P.; Araldi, G. L.; Prakash, K. R. C.; Zhang, M.;
J ohnson, K. M. J . Med. Chem. 1998, 41, 4973-4982.

Unexpected Bicyclo[3.2.2]nonane Derivatives
J . Org. Chem., Vol. 67, No. 11, 2002 3639
Sch em e 1
Sch em e 2
Sch em e 3
(75%). Tosylation of 25 with p-toluenesulfonyl chloride
in the presence of triethylamine gave 26 (84%), which
was reduced with lithium aluminum hydride in THF to
give alcohol intermediate 27 (85%). The resulting sul-
fonamide bond, conjugated with the lone pair of electrons
of the nitrogen, was intended to prevent the intra-
molecular rearrangement observed with 5. The alcohol
group was activated as the triflate intermediate 28 (96%)
using trifluoromethanesulfonic anhydride and was used
without purification for the next step. Nucleophilic
substitution of 28 with the freshly prepared sodium salt
of sesamol gave a 3:1 mixture (69%) of the expected
alkylated derivative 29 mixed with alkene 30, product
of elimination. Deprotection of the nitrogen by refluxing
29 with sodium-mercury amalgam and sodium hydrogen
phosphate in methanol gave the nortropane intermediate
15 (86%). Methylation with formaldehyde in refluxing
methanol followed by reduction with NaBH4 gave 16
(82%).
(Scheme 1). Spectrometric data (NMR and IR) of the two
products matched each other and corresponded to the
structure of 8.
Neither Mitsunobu reaction between alcohol 4 and
sesamol nor catalyzed (Pd, Ni) coupling reactions of 4
with 4-bromo-1,2-(methylenedioxy)benzene yielded 16.29-32
However, N-demethylation of the 2â-carbomethoxy de-
rivative 2433 with 1-chloroethyl chloroformate and metha-
nol (Scheme 5) gave the nortropane intermediate 25
(29) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J . F. J . Am.
Chem. Soc. 1999, 121, 3224-3225.
(30) Mann, G.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 13109-
13110.
(31) Mitsunobu, O. Synthesis 1981, 1-28.
(32) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 3395-3396.
(33) Clarke, R. L.; Daum, S. J .; Gambino, A. J .; Aceto, M. D.; Pearl,
J .; Levitt, M.; Cumiskey, W. R.; Bogado, E. F. J . Med. Chem. 1973,
16, 1260-1267.

3640 J . Org. Chem., Vol. 67, No. 11, 2002
Ogier et al.
Sch em e 4a
a
Reagents: (a) NaN(Me3)2, MeOTf; (b) Pd2(dba)3, dppb, allyl ethyl carbonate, reflux; (c) NaOH, DMSO or NaN(Me3)2, THF.
Sch em e 5a
a
Reagents: (a) ACE-Cl, dichloroethane, reflux; (b) MeOH, reflux; (c) TsCl, Et3N; (d) LiAlH4, THF, rt; (e) Tf2O, collidine, CH2Cl2; (f)
sesamol, Na, THF; (g) Na/Hg, Na2HPO4, MeOH, reflux; (h) formaldehyde (37% in water), MeOH, reflux; (i) NaBH4/MeOH.
Syn th esis of Aza -Bicyclo Alk yla m in es a n d Im i-
d es. Mesylate 5a was reacted with potassium phthalim-
ide (KPht) in toluene with phase transfer catalyst to lead
to an 85:15 mixture (96%) of the rearranged phthalimido
derivative 10 and the tropane derivative 17, respectively
(Scheme 6). Hydrazinolysis of 17 and 10 yielded the
aminomethyl tropane derivative 18 and the rearranged
amino derivative 11, respectively, in quantitative yield.
Similarly, when benzylamine was used as nucleophile, a
35:65 mixture (59%) of the rearranged benzylamino
derivative 12 and the tropane derivative 19 was obtained
(Scheme 6).
Derivatives 17-19 were characterized by comparing
their NMR spectra with those of derivatives obtained
exclusively from the acyl chloride tropane intermediate
22 (Scheme 7). The aminomethyl tropane 18 was syn-
thesized by two other synthetic routes. In the first one,
acyl chloride 2234,35 was treated with ammonia at 0 °C
to give amide 20 (70%), followed by borane reduction of
the amide group (42%). In the second route, 22 was
treated with benzylamine to give N-benzylamide inter-
mediate 21 (90%) and then reduced with borane to 19
(60%), which was quantitatively reduced to amine 18 by
catalytic hydrogenation. Reaction with phthalic anhy-
dride gave the N-phthalimidotropane 17 (72%).
NMR Stu d y of Bicyclo[3.2.1]octa n es a n d Bicyclo-
[3.2.2]n on a n e. In the tricyclic structure of mesylate 5a ,
three electrophilic carbons could be the site of a nucleo-
philic substitution reaction, and depending on the attack
of the nucleophile on these carbons we could obtain the
three different azabicyclo structures I, II, or III (Scheme
3). For all derivatives, C3 was determined considering the
fact that it was the only tertiary carbon in the range 33-
36 ppm and because the chemical shift value of C3 should
not vary from the nonrearranged to the rearranged
structure. In this range of values, C3 was also the only
(34) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray J . L.; Kuzemko,
M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J . W.; Kuhar,
M. J . J . Med. Chem. 1995, 38, 379-388.
(35) Kotian, P.; Wayne Mascarella, S.; Abraham, P.; Lewin, A. H.;
Boja, J . W.; Kuhar, M. J .; Carroll, F. I. J . Med. Chem. 1996, 39, 2753-
2763.

Unexpected Bicyclo[3.2.2]nonane Derivatives
J . Org. Chem., Vol. 67, No. 11, 2002 3641
Sch em e 6a
a
Reagents: (a) KPht, PhMe, reflux; (b) BnCH2, PhMe, reflux; (c) NH2NH2, EtOH, reflux.
Sch em e 7a
a
Reagents: (a) NH4OH, 0 °C; (b) BH3, THF; (c) PhCH2NH2, CH3Cl2, Et3N; (d) BH3, THF; (e) H2, Pd/C, MeOH; (f) phthalic anhydride,
CHCl3; (g) NH2NH2, EtOH, reflux.
1
tertiary carbon whose proton was coupled with three
protons (H2, H4a, and H4b). In the rearranged structure,
amine and imide derivatives 17-19, as expected. In H
NMR, the chemical shifts of H1 and H5 were identical to
those in alcohol 4 and the two protons H9a and H9b
showed a shielding effect, which varied according to the
nature (ether, amine, imide) of the resulting functional
group and to the substitution (alkyl, aryl) of the nucleo-
phile itself.
1
proton H2 showed H-1H correlations with four protons,
the correlation with H3 being part of them. Two other
correlations were observed with methylenic protons (H2/
H9a and H2/H9b), which were coupled with a characteristic
carbon of vicinal nitrogen (chemical shift in the range
51-53 ppm). The last correlation was observed with a
highly deshielded proton (H2/H1), which was coupled with
an extremely deshielded tertiary carbon, in the case of
ether derivatives. The only rearranged structure that
could corroborate these results was structure II. Struc-
ture II was established unambiguously by NMR analysis
In the 13C NMR spectra of ether derivatives 6-8 and
according to the data above, we expected a deshielding
effect for C9 and chemical shifts of C1 and C5 in the range
61-68 ppm if structure I, but in each case we obtained
C1 close to 85 ppm (15 ppm of deshielding caused by the
vicinal oxygen in structure II), C5 close to 55 ppm (less
strained in structure II because of ring expansion), and
C9 close to 51 ppm (shielding by the vicinal nitrogen). In
the case of nitrogen compounds 10-12 the three positions
1, 5, and 9 showed a shielding effect (5-12 ppm) in 13C
NMR, which could be explained with both the vicinity of
1
(1H, 13C, COSY H-H, and GHMQC J C-H) of rearranged
derivatives 6-12 compared to the tropane structure of
derivatives 13-19 (structure I). Each proton and carbon
in tropane alcohol 4 was formally assigned and taken as
reference for structure I.
1
Derivatives 13, 14, and 16-19 were obtained by
unambiguous route from natural (-)-cocaine, and their
NMR data were in agreement with the configuration
(1R,2S,3S,5S) of the tropane structure I.23-36 Comparison
between the established tropane structure of alcohol 4
and derivatives 13, 14, and 16-19 showed close chemical
shift values in both carbon and proton NMR. In every
case the chemical shifts of C1 and C5 were in the range
61-68 ppm, which is characteristic of bridgehead carbons
in structure I. Compared to its chemical shift in alcohol
4, C9 was slightly deshielded (5-9 ppm) in ether deriva-
tives 13, 14, and 16, whereas shielded (14-25 ppm) in
nitrogen atoms and by the ring expansion. In H NMR,
only four protons (H1, H3, H5, and H9a) were present
beyond 2.7 ppm instead of the five expected for structure
I (H1, H3, H5, H9a, and H9b); however, this could be
explained by the interaction of the shielding cone of the
aromatic ring on C3 with one of the protons on C9. In the
case of derivatives 2, 8, and 10, we observed significant
deshielding for H1; this can be explained by the influence
of aromatic rings (sesamol, phthalimide) close to this
position in structure II. For imide derivative 10, this
deshielding extended to H2 and H3. The same deshielding
effect was observed for H9a in structure I, with derivatives

3642 J . Org. Chem., Vol. 67, No. 11, 2002
Ogier et al.
Ta ble 2. 1H a n d 13C NMR Ch em ica ls Sh ifts for N-Me
a n d N-H Bicyclic Com p ou n d s 16 a n d 15 (Str u ctu r e I)
Com p a r ed to Rea r r a n ged Bicyclic Com p ou n d s 8 a n d 9
(Str u ctu r e II)
δ (ppm)
C1
C5
C9
H1
H5
H9a
H9b
16 (NMe)
15 (NH)
8 (NMe)
9 (NH)
64
57
84
84
62
55
56
48
68
68
51
41
3.4
3.6
4.4
4.3
3.1
3.6
3.0
3.3
4.1
3.9
3.0
3.2
3.3
3.3
2.4
2.8
16 and 17. 13C and H NMR data of ether derivative 2,
formerly described as a tropane derivative, matched those
found in the rearranged structure II of ether derivative
8 (δC1 ) 84, δC9 ) 51, and δH9b ) 2.4 ppm). Therefore,
we conclude that 2 is an aza-bicyclo[3.2.2]nonane deriva-
tive and not the reported21 tropane derivative.
1
F igu r e 2.
Ta ble 3. Selectivity of th e Nu cleop h ilic Su bstitu tion
w ith In ter m ed ia te 5a
nucleophile
total yield (%)
% structure I
% structure II
It is known37 that when the nitrogen of tropane
derivatives (structure I) is demethylated, both H1 and
H5 shift to lower field. Such a difference (+0.3 to +0.5
ppm) in the chemical shifts of H1 and H5 was observed
between derivative 16 and its nor-tropane analogue 15
(Table 2). On the other hand, when 8 was N-demeth-
ylated to give the free base 9, protons H5, H9a, and H9b
shifted to lower field and the chemical shift of H1
remained unchanged. Therefore, we conclude that C1 is
not a carbon vicinal to nitrogen and is no longer a bridge-
head carbon in the aza-bicyclo mainframe of structure
II. Conversely, we conclude that the bonds between the
nitrogen and the carbons C9 and C5 occur as in structure
II.
MeO-
66
70
73
65
59
0
0
0
15
64
100
100
100
85
AllO-
SesO-
PhtN-
PhCH2NH2
36
benzylamine (soft) showed a preferential affinity for C9
and led to bicyclo[3.2.1]octane (I) (Table 3).
Con clu sion
To summarize the present work, it was shown that the
use of mesylate intermediate 5 in nucleophilic substitu-
tion reactions led to unexpected bicyclo[3.2.2]nonane
derivatives. This rearranged structure II was obtained
exclusively with ether derivatives or mixed with the
expected bicyclo[3.2.1]octane structure I (tropane) in the
case of amine and imide derivatives. The new structure
was established by NMR analysis, and the structure
I/structure II selectivity was found to be dependent on
the affinity of the nucleophile used with the softer
character of C9 compared to C1. The present results have
an important implication in the understanding of the
biological activity of earlier reported ether derivatives,21
and the compounds synthesized in this work will be
tested for their affinity with the DAT.
The rearranged derivatives were prepared from alcohol
intermediate 4, whose configuration (1R,2S,3S,5S) is also
known.23 The proposed mechanism of the rearrangement
(Scheme 2) predicts the absolute configuration of struc-
ture II to be (1S,2R,3S,5S), after inversion of configura-
tion for C1 and a change in naming group priorities for
C2. The S configuration of C1 (resulting from SN2-type
reaction) was unambiguously established in derivative
7 by the detection of nuclear Overhauser effect between
H1 and H9b, an effect that would not be possible with an
R configuration.
C1/C9 Selectivity Accor d in g to th e Na tu r e of th e
Nu cleop h ile. Mesylate intermediate 5a can lead to
structures I, II, and III (Scheme 3). However, structure
III implies a four-membered ring, which is not favored
compared to the five- or six-membered rings found in
structures I and II; in fact, structure III has never been
observed in our study. According to the nature (hard or
soft) of the nucleophile used in the substitution reaction,
we observed a different C1/C9 selectivity. Nucleophiles
such as alkoxides or phthalimide (hard) led exclusively
or preferentially to bicyclo[3.2.2]nonane (II), whereas
Ack n ow led gm en t. We gratefully acknowledge help-
ful discussions with Dr. F. I. Carroll. This work was
supported in part by funding from the U.S. Department
of Veterans Affairs (VA Schizophrenia Center and Merit
Review Award), the U.S. Department of Energy
(DEFG02-98ER82653), from EUREKA “DOPIMAG”
program, Project EU 1836, and from CIS Bio Inter-
national, Schering S.A.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data of ether, amine, and imide tropane
and rearranged derivatives, geometry, and population analysis
of mesylate intermediate 5a . This material is available free
of charge via the Internet at http://pubs.acs.org.
(36) Carroll, F. I.; Coleman, M. L.; Lewin, A. H. J . Org. Chem. 1982,
47, 13-19.
(37) Davies, H. M. L.; Kuhn, L. A.; Thornley, C.; Matasi, J . J .;
Sexton, T.; Childers, S. R. J . Med. Chem. 1996, 39, 2554-2558.
J O010973X