A concise approach to 2-azabicyclo[3.3.1]nonane derivatives from an acyclic precursor

Article abstract of DOI:10.1021/jo051471c

Condensation of a readily available 5-amino-2-alkenoate ester with α-unsubstituted aliphatic aldehydes leads to substituted 1,2,3,4-tetrahydropyridines. Subsequent manipulation of the ester and enamine functions gives a quick access to 2-azabicyclo[3.3.1]

Full text of DOI:10.1021/jo051471c

respectively, which are common precursors in the total
syntheses of several uleine and Strychnos alkaloids.1b,c,2
Some of these approaches rely on the use of R-aminoni-
triles 5 to generate iminium ions 6. However, this
presents the drawback of lack of regioselectivity in the
formation of 5 from the corresponding 3,4-disubstituted
piperidine precursors, thus reducing the efficiency of the
overall process.1b,3 We report here an alternative strategy
for the assembly of the 2-azabicyclo[3.3.1]nonane bicyclic
system that takes advantage of (i) a direct one-step
regioselective synthesis of tetrahydropyridines 4 from a
readily available acyclic amine 1 and (ii) the generation
of the morphan skeleton in one step from 4 using
conventional procedures for manipulation of the ester
functionality. The application of this strategy to the
preparation of 7 and analogues thereof, as well as an
expeditious one-pot synthesis of tetracyclic indole 8 from
4a (R ) Et), will be demonstrated.
A Concise Approach to
2-Azabicyclo[3.3.1]nonane Derivatives from
an Acyclic Precursor
Jose´ M. Aurrecoechea,* Jose´ M. Gorgojo, and
Carlos Saornil
Departamento de Quı´mica Orga´nica II, Facultad de Ciencia
y Tecnologı´a, Universidad del Paı´s Vasco, Apartado 644,
48080 Bilbao, Spain
jm.aurrecoechea@ehu.es
Received July 15, 2005
We have already reported the simple preparation of
bicyclic lactone analogues of enamines 4 by condensation
of R-unsubstituted aliphatic aldehydes (RCH2CHO) with
γ,δ-unsaturated secondary amines derived from the
vinylogous Mannich reaction between trimethylsilyloxy-
furan and iminium ions.4 The application of this kind of
reaction to the preparation of enamine 4a required the
condensation of amine 15 and butyraldehyde (9a) (Scheme
2). Thus, heating a mixture of 1 and 9a in EtOH gave,
after chromatographic purification, a good yield (77%) of
tetrahydropyridine 4a, which was fully characterized
spectroscopically. The identity of 4a was further con-
firmed by its conversion into the known piperidines 106
(Scheme 2).
It was initially envisioned that conversion of 4a into
the corresponding methyl ketone 2, followed by acid
treatment, would yield 7-oxomorphan 7 via an intramo-
lecular Mannich reaction.1b Thus, following the reported
protocol for transformation of a related ester into the
corresponding methyl ketone,6 4a was treated with
methylsulfinyl carbanion,7 and this resulted in the direct
formation of morphan derivative 11a (Scheme 3). This
became apparent by the absence of the typical enaminic
proton resonance displayed by 4a at δ ∼5.80 and was
chemically confirmed by reduction of 11a with Zn/AcOH,
which afforded the desulfinylated product 12a, identified
by comparison of its spectroscopic properties with those
reported for the C-9 epimer of 7-oxomorphan 7.1b
It is interesting that presumably related intermediates
of type 6 would yield different relative configurations at
Condensation of a readily available 5-amino-2-alkenoate
ester with R-unsubstituted aliphatic aldehydes leads to
substituted 1,2,3,4-tetrahydropyridines. Subsequent ma-
nipulation of the ester and enamine functions gives a quick
access to 2-azabicyclo[3.3.1]nonane-containing compounds.
The synthesis of the 2-azabicyclo[3.3.1]nonane (mor-
phan) skeleton is a topic of current interest due to its
occurrence in a number of natural products and other
compounds of biological relevance.1 Some approaches to
the morphan framework have utilized cyclic enamines
related to tetrahydropyridines 2-4 either as synthetic
precursors or reaction intermediates.1a-d,g,o For example,
tetrahydropyridines 2 and 3 are key intermediates in the
acid-promoted equilibration of cis- and trans-iminium
ions 6 (Y ) Ac or indol-2-yl, R ) Et), leading to 7 and 8,
(1) Selected representative references: (a) Amat, M.; Sanfeliu, E.;
Bonjoch, J.; Bosch, J. Tetrahedron Lett. 1989, 30, 3841-3844. (b)
Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994,
59, 3939-3951. (c) Saito, M.; Kawamura, M.; Hiroya, K.; Ogasawara,
K. Chem. Commun. 1997, 765-766. (d) Thomas, J. B.; Zheng, X. L.;
Brieaddy, L. E.; Burgess, J. P.; Mascarella, S. W.; Fix, S. E.; Cantrell,
B. E.; Zimmerman, D. M.; Carroll, F. I. Tetrahedron Lett. 1998, 39,
7001-7004. (e) Quirante, J.; Escolano, C.; Merino, A.; Bonjoch, J. J.
Org. Chem. 1998, 63, 968-976. (f) Quirante, J.; Escolano, C.; Diaba,
F.; Bonjoch, J. J. Chem. Soc., Perkin Trans. 1 1999, 1157-1162. (g)
Thomas, J. B.; Gigstad, K. M.; Fix, S. E.; Burgess, J. P.; Cooper, J. B.;
Mascarella, S. W.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I.
Tetrahedron Lett. 1999, 40, 403-406. (h) Sole´, D.; Peidro´, E.; Bonjoch,
J. Org. Lett. 2000, 2, 2225-2228. (i) Sato, T.; Okamoto, K.; Nakano,
Y.; Uenishi, J.; Ikeda, M. Heterocycles 2001, 54, 747-755. (j) Maeng,
J. H.; Funk, R. L. Org. Lett. 2001, 3, 1125-1128. (k) Brummond, K.
M.; Lu, J. L. Org. Lett. 2001, 3, 1347-1349. (l) Wardrop, D. J.; Zhang,
W. M. Org. Lett. 2001, 3, 2353-2356. (m) Suzuki, H.; Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 2001, 42, 3013-3015. (n) Hashimoto,
A.; Jacobson, A. E.; Rothman, R. B.; Dersch, C. M.; George, C.; Flippen-
Anderson, J. l.; Rice, K. C. Bioorg. Med. Chem. 2002, 10, 3319-3329.
(o) Kim, I. J.; Dersch, C. M.; Rothman, R. B.; Jacobson, A. E.; Rice, K.
C. Bioorg. Med. Chem. 2004, 12, 4543-4550. (p) Amat, M.; Pe´rez, M.;
Llor, N.; Escolano, C.; Luque, F. J.; Molins, E.; Bosch, J. J. Org. Chem.
2004, 69, 8681-8693. (q) Carroll, F. I.; Zhang, L.; Mascarella, S. W.;
Navarro, H. A.; Rothman, R. B.; Cantrell, B. E.; Zimmerman, D. M.;
Thomas, J. B. J. Med. Chem. 2004, 47, 281-284. (r) Brummond, K.
M.; Hong, S. J. Org. Chem. 2005, 70, 907-916.
(2) For enantioselective syntheses of these alkaloids, see references
1c, 1p, and references therein.
(3) See also D´ıez, A.; Castells, J.; Forns, P.; Rubiralta, M.; Grierson,
D. S.; Husson, H.-P.; Solans, X.; Font-Bard´ıa, M. Tetrahedron 1994,
50, 6585-6602 for a different approach to related R-cyanopiperidines
that also suffers from regioselectivity problems.
(4) Aurrecoechea, J. M.; Suero, R. Tetrahedron Lett. 2005, 46, 4945-
4947.
(5) (a) Hirai, Y.; Terada, T.; Hagiwara, A.; Yamazaki, T. Chem.
Pharm. Bull. 1988, 36, 1343-1350. (b) Aurrecoechea, J. M.; Ferna´ndez,
A.; Gorgojo, J. M.; Saornil, C. Tetrahedron 1999, 55, 7345-7362.
(6) Bonjoch, J.; Linares, A.; Guardia`, M.; Bosh, J. Heterocycles 1987,
26, 2165-2174. For a recent enantioselective synthesis of 3-ethyl-4-
piperidineacetates, see ref 1p.
(7) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345-
1353.
10.1021/jo051471c CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/11/2005
9640
J. Org. Chem. 2005, 70, 9640-9643

SCHEME 1. Synthetic Approaches to
7-Oxomorphan 7 and Tetracyclic Indole 8
SCHEME 4. Mechanism of Formation of 11 from 4
TABLE 1. Preparation of Tetrahydropyridines 4 and
Morphans 12 from Amine 1 and Aldehydes 9a
R
yield of 4b
yield of 12b
1c
2
Et
77 (4a)
75 (4b)
67 (4c)
43 (12a)
43 (12b)
45 (12c)
CH2Ph
SCHEME 2. Preparation of Piperidine 10 from
Amine 1 and Butyraldehydea
3
i-Pr
a Reagents and conditions: (a) EtOH, 4 Å MS, reflux; (b) DMSO/
NaH, THF, 0 f 25 °C; (c) Zn/AcOH, EtOH, 65 °C. b Yield (%) of
isolated purified product. c Reaction run without 4 Å MS.
TABLE 2. Comparison of 13C NMR Resonances for
Morphans 7, 12a-ca
morphan
C-4
C-6
C-8
7b
12a
12b
12c
32.7
26.4
26.3
26.4
42.4
48.4
48.3
48.5
35.9
40.4
40.4
40.4
a Reagents and conditions: (a) EtOH, reflux; (b) NaBH3CN/
ZnCl2, THF, MeOH, rt.
SCHEME 3. Preparation of Morphan Derivatives
from Tetrahydropyridine 4aa
a Selected chemical shifts (δ). Assignments were made on the
basis of δ values and DEPT data and by comparison with the
extensive data collected in ref 8. b Data taken from ref 8.
tively mildly acidic cyclization and desulfinylation condi-
tions, respectively.
The chemistry described in Schemes 2-4 readily
suggests the possibility of preparing 3-azabicyclo[3.3.1]-
nonan-3-one derivatives using amine 1 and aldehydes 9
other than butyraldehyde. Thus, following the same
protocols, 3-phenylpropanal and isovaleraldehyde also led
with similar ease to 7-oxomorphans 12b,c, as single
diastereoisomers, through the corresponding tetrahydro-
pyridines 4b,c (Table 1).
The relative stereochemistry of 12b,c at C-9 was
initially assigned by analogy with that of the known 12a
and later confirmed by the observation of diagnostic C-4,
C-6, and C-8 13C NMR resonances that had closely similar
values within the series 12a-c but differed substantially
from those of the (C-9)-epimer 7 (Table 2).8
a Reagents and conditions: (a) DMSO/NaH, THF, 0 f 25 °C;
(b) Zn/AcOH, EtOH, 65 °C; (c) 12 N HCl, MeOH, reflux.1b
C-9 in 3-azabicyclo[3.3.1]nonan-7-ones 7 and 12a pre-
pared from R-cyanopiperidine 51b or enamine 4a, respec-
tively. Isomer 7 was calculated to be more stable than
12a, and in fact, the complete conversion of 12a into 7
has been reported under relatively strong acidic condi-
tions, presumably via enamine 2.1b It is apparent that
in our case proton transfer takes place at the level of
putative intermediate 13 to give 14 with a trans-arrange-
ment between the ethyl and ketosulfoxide moieties
(Scheme 4). Subsequent cyclization from the diaxial
conformer 15 then affords the kinetic product 11, and
the implication is that both 11 and its derived reduced
product 12 are configurationally stable under the rela-
On the basis of the above results, the preparation of
tetracyclic indole derivative 8 (Scheme 1) was readily
(8) Casamitjana, N.; Bonjoch, J.; Gra`cia, J.; Bosch, J. Magn. Reson.
Chem. 1992, 30, 183-186.
J. Org. Chem, Vol. 70, No. 23, 2005 9641

aldehyde 9 (0.42 mmol), 4 Å MS (840 mg), and absolute EtOH
(7 mL) was refluxed until consumption of the starting materials
and then filtered through Celite. The crude product after
evaporation was purified by flash chromatography (silica gel
saturated with Et3N, hexanes/Et3N mixtures as eluent) to afford
tetrahydropyridines 4 as yellowish oils in the yields indicated
in Table 1.
SCHEME 5. One-Pot Synthesis of Tetracyclic
Indoles 8 and 16 from Tetrahydropyridine 4aa
Ethyl (1-Benzyl-5-ethyl-1,2,3,4-tetrahydropyridin-4-yl)-
acetate (4a). Prepared from butyraldehyde in 5.5 h without 4
Å MS: 1H NMR δ 0.99 (t, J ) 7.4 Hz, 3H), 1.25 (t, J ) 7.1 Hz,
3H), 1.60-1.71 (m, 1H), 1.83-2.17 (m, 3H, overlapped with dd
at δ 2.07), 2.07 (dd, J ) 17.2, 11.2 Hz, 1H), 2.52-2.82 (m, 4H),
3.90 and 3.93 (AB q, J ) 14.5 Hz, 2H), 4.12 (q, J ) 7.1 Hz, 2H),
5.80 (s, 1H), 7.21-7.37 (m, 5H); 13C NMR δ 13.3, 14.2, 25.5, 27.4,
30.4, 39.7, 43.3, 59.6, 60.1, 112.7, 127.0, 128.1, 128.2, 131.6,
a Reagents and conditions. Conditions A: N-TMS-o-toluidine,
n-BuLi, hexane/THF, -78 f 25 °C. Conditions B: (i) N-TMS-o-
toluidine, n-BuLi, hexane/THF, -78 f 25 °C; (ii) 1 M HCl, THF,
reflux.
138.5, 173.0; IR (neat) υ 1730 (s, CdO), 1660 (m, CdC) cm-1
;
LRMS (EI) m/z 287 (M, 28), 272 (15), 200 (base), 91 (57); HRMS
calcd for C18H25NO2 287.1885, found 287.1885.
Ethyl (1,5-Dibenzyl-1,2,3,4-tetrahydropyridin-4-yl)ace-
tate (4b). Obtained from 3-phenylpropanal in 3 h, with spectral
characteristics identical to those reported in the literature for
the same compound.5b
Ethyl (1-Benzyl-5-isopropyl-1,2,3,4-tetrahydropyridin-
4-yl)acetate (4c). Prepared from isovaleraldehyde in 3 h: 1H
NMR δ 1.02 (d, J ) 6.7 Hz, 3H), 1.03 (d, J ) 6.8 Hz, 3H), 1.24
(t, J ) 7.1 Hz, 3H), 1.61-1.71 (m, 1H), 1.78-1.92 (m, 1H), 2.01
(dd, J ) 15.1, 10.7 Hz, 1H), 2.18 (hept, J ) 6.8 Hz, 1H), 2.49-
2.81 (m, 4H), 3.94 (s, 2H), 4.12 (q, J ) 7.1 Hz, 2H), 5.82 (s, 1H),
7.22-7.36 (m, 5H); 13C NMR δ 14.3, 21.6, 23.7, 27.2, 29.8, 29.9,
40.3, 42.7, 59.8, 60.2, 117.0, 127.0, 128.1, 128.3, 130.6, 138.6,
173.1; IR (neat) υ 1740 (s, CdO), 1660 (m, CdC) cm-1; LRMS
(EI) m/z 301 (M, 25), 286 (63), 214 (84), 172 (7), 162 (6), 91 (base);
HRMS calcd for C19H27NO2 301.2042, found 301.2038.
Ethyl cis- and trans-(1-Benzyl-3-ethylpiperidin-4-yl)-
acetate (10). ZnCl2 (0.5 M in THF, 4.1 mL, 2.05 mmol) was
added to a suspension of NaBH3CN (0.268 g, 4.20 mmol) in
MeOH (2.9 mL) under Ar, and the mixture was stirred at room
temperature for 1 h and then added to 4a (0.581 g, 2.02 mmol)
dissolved in MeOH (4.4 mL). The solution was stirred a further
2 h and poured over 1 M NaOH (50 mL), and the whole was
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (NaSO4), and the residue after evaporation was
purified by flash chromatography (silica gel saturated with Et3N,
99:1 hexanes/Et3N) to yield in order of elution cis-10 (142 mg,
24%) and trans-10 (326 mg, 55%), whose spectral data coincide
with those reported in the literature6 for the same compounds.
Preparation of Morphans 12. In a typical experiment,
under an Ar atmosphere DMSO (2.2 mL) was added to NaH
(60% in mineral oil, 0.138 g, 3.46 mmol) at 0 °C, followed by
THF (2.7 mL), and to this mixture was added dropwise a solution
of a tetrahydropyridine 4 (1.12 mmol) in THF (3 mL). The
resulting mixture was allowed to reach room temperature and
further stirred for 1 h. Water (8 mL) was added followed by 1 M
HCl until pH ) 8. The aqueous phase was extracted with CH2Cl2
(3 × 40 mL), and the combined organic layers were washed with
brine (40 mL) and dried (Na2SO4). Evaporation of the solvents
afforded a yellow powder that, without further purification, was
dissolved in EtOH (7 mL) and AcOH (0.3 mL), and this solution
was added to a suspension of activated Zn (0.329 g) in AcOH
(0.3 mL) and EtOH (1 mL). The stirred mixture was heated at
65 °C for 1 h, cooled, and filtered. Water (10 mL) was added,
and the pH was brought to 8 with solid K2CO3. The aqueous
phase was extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were successively washed with saturated NaHCO3
and brine and dried (Na2SO4). The crude product after evapora-
tion was purified by flash chromatography (silica gel saturated
with Et3N, hexanes/Et3N mixtures as eluent) to yield morphans
12 in the yields indicated in Table 1.
foreseen as arising from the cyclization of a tetrahydro-
pyridine-indole intermediate 3, which could in principle
be directly generated from ester 4a (R ) Et) using a
conventional protocol for indole synthesis. Thus, tetrahy-
dropyridine 4a was treated with the dianion derived from
N-TMS-o-toluidine9 at low temperature. Not unexpect-
edly, tetracyclic indole 16, a C-12 epimer of 8, was
directly formed in moderate yield upon workup, ac-
companied by a smaller amount of 8 (Scheme 5). As in
the preceding discussion with morphans 12, the prefer-
ential formation of isomer 16 is thought to be the result
of a faster irreversible cyclization from the trans-isomer
of an equilibrating mixture of iminium ions 6 (Y ) indol-
2-yl, R ) Et) generated by proton transfer from 3 (Scheme
1).10 It is then surmised that, under the foregoing
nonacidic conditions, indole 16 is stable and does not
revert to 6. However, when the crude 16/8 mixture was
directly heated with aqueous HCl in THF, the C-12
epimer 8 was obtained exclusively in a one-pot process
starting from 4a. In this case, protonation at the indole
3-position renders the cyclization step reversible and the
more stable isomer 8 is obtained.1b,11
In conclusion, this alternative use of readily available
amine 1 and tetrahydropyridine 4a as key intermediates
represents a simple, viable, and direct approach to
compounds containing a 3-azabicyclo[3.3.1]nonane sub-
structure. This strategy obviates any regioselectivity
problem, does not require the separation and handling
of mixtures of isomers, and minimizes the number of
steps and synthetic manipulations. This is illustrated by
the preparation of tetracyclic indole 8 in just two steps
and 34% overall yield from amine 1. The possibility of
performing the tetracycle-forming ring-closure step in the
absence of added acid gives access to either one of the
C-12 epimers depending on the reaction conditions.
Finally, the formation of a series of morphan derivatives
12a-c by the simple expedient of employing different
starting aldehydes 9 highlights the opportunity for easy
structural diversification offered by the use of amine 1
as convenient precursor of tetrahydropyridines 4.
Experimental Section
Preparation of Tetrahydropyridines 4. In a typical
experiment, a mixture of amine 15 (97 mg, 0.42 mmol), an
(1R*,5S*,9S*)-2-Benzyl-9-ethyl-2-azabicyclo[3.3.1]nonan-
7-one (12a). Prepared from 4a: 1H NMR δ 0.89 (t, J ) 7.3 Hz,
3H), 1.34 (dm, J ) 17.0 Hz, 1H), 1.61-2.01 (m, 3H), 2.06 (dd, J
) 17.2, 4.9 Hz, 1H), 2.12-2.20 (m, 2H), 2.30 (td, J ) 13.1, 3.5
Hz, 1H), 2.51 (m, 2H), 2.57 (dd, J ) 12.7, 5.2 Hz, 1H), 2.92 (dm,
J ) 17.0 Hz, 1H), 3.11 (m, 1H), 3.56 (s, 2H), 7.22-7.31 (m, 5H);
(9) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957-2969.
(10) Forns, P.; D´ıez, A.; Rubiralta, M.; Solans, X.; Font-Bard´ıa, M.
Tetrahedron 1996, 52, 3563-3574.
(11) Bonjoch, J.; Casamitjana, N.; Gra`cia, J.; Bosch, J. Tetrahedron
Lett. 1989, 30, 5659-5662.
9642 J. Org. Chem., Vol. 70, No. 23, 2005

13C NMR δ 12.1, 23.1, 26.3, 32.0, 40.3, 42.9, 44.6, 48.3, 55.8, 59.4,
126.9, 128.1, 128.5, 139.2, 212.4; IR (neat) υ 1710 (s, CdO) cm-1
Et2O (5 × 30 mL). The combined organic layers were washed
with brine (15 mL) and dried (Na2SO4). The crude product after
evaporation was purified by flash chromatography (silica gel,
hexanes/EtOAc, 9:1) to yield 16 (49 mg, 40%) as a foam. Further
elution with 50:48:2 hexanes/EtOAc/Et2NH afforded an slightly
impure sample of 8 (12 mg). The spectral data for these materials
matched those reported in the literature1b for the same com-
pounds.
Preparation of (1R*,5R*,12S*)-2-Benzyl-12-ethyl-1,2,3,4,5,6-
hexahydro-1,5-methanoazocino[4,3-b]indole (8). The pro-
cedure described above for the preparation of 16 was followed
starting from 0.123 g (0.43 mmol) of 4a. After the reaction
mixture reached room temperature, the solvent was evaporated,
and the residue was redissolved in THF (4 mL). Then, 1 M HCl
(4 mL) was added, and the mixture was refluxed for 48 h. After
cooling, saturated NaHCO3 was added until pH ) 8, and the
aqueous layer was extracted with Et2O (5 × 15 mL). The
combined organic layers were washed with brine (20 mL) and
dried (Na2SO4). The crude product after evaporation was purified
by flash chromatography (silica gel saturated with Et2NH, 70:
26:4 hexanes/EtOAc/Et2NH) to yield 81b (62 mg, 44%) as an oil.
.
These data coincide with those reported in the literature for the
same compound.1b
(1R*,5S*,9S*)-2,9-Dibenzyl-2-azabicyclo[3.3.1]nonan-7-
one (12b). Prepared from 4b: 1H NMR δ 1.37-1.48 (m, 1H),
2.04 (dd, J ) 17.2, 5.0 Hz, 1H), 2.12-2.40 (m, 4H), 2.43-2.80
(m, 3H), 2.90-2.98 (m, 2H), 3.08-3.15 (m, 1H), 3.22 (dd, J )
13.5, 8.3 Hz, 1H), 3.56 and 3.59 (AB q, J ) 13.5 Hz, 2H), 7.16-
7.40 (m, 10H); 13C NMR δ 26.3, 32.0, 36.8, 40.4, 43.4, 44.3, 48.3,
56.0, 59.5, 125.9, 126.9, 128.3, 128.7, 129.0, 139.0, 141.2, 211.9;
IR (neat) υ 1705 (s, CdO) cm-1; LRMS (EI) m/z 319 (M, 40), 263
(21), 262 (base), 91 (70); HRMS calcd for C22H25NO 319.1936,
found 319.1939.
(1R*,5S*,9S*)-2-Benzyl-9-isopropyl-2-azabicyclo[3.3.1]-
nonan-7-one (12c). Prepared from 4c: 1H NMR δ 0.86 (d, J )
6.5 Hz, 3H), 0.96 (d, J ) 6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.95-
2.11 (m, 2H), 2.05 (dd, J ) 17.1, 5.0 Hz, included in m at 1.95-
2.11), 2.24-2.49 (m, 5H), 2.57 (dd, J ) 13.0, 5.6 Hz, 1H), 2.94
(d, J ) 17.2 Hz, 1H), 3.24-3.30 (m, 1H), 3.53 and 3.59 (AB q, J
) 13.3 Hz, 2H), 7.21-7.31 (m, 5H); 13C NMR δ 20.6, 21.3, 25.6,
26.4, 30.0, 40.4, 44.4, 48.3, 48.5, 54.9, 59.6, 126.9, 128.2, 128.7,
139.2, 212.5; IR (KBr) υ 1690 (m, CdO) cm-1; LRMS (EI) m/z
271 (M, 37), 256 (30), 214 (base), 91 (30); HRMS calcd for C18H25-
NO 271.1936, found 271.1939.
Acknowledgment. Financial support by Ministerio
de Educacio´n y Ciencia (CTQ2004-04901) Universidad
del Pa´ıs Vasco (9/UPV00041.310-14471/2002) and Jan-
ssen-Cilag is gratefully acknowledged.
Preparation of (1R*,5R*,12R*)-2-Benzyl-12-ethyl-1,2,3,4,5,6-
hexahydro-1,5-methanoazocino[4,3-b]indole (16). n-BuLi
(1.5 M in hexane, 0.9 mL, 1.35 mmol) was added to a solution of
N-trimethylsilyltoluidine (85 mg, 0.47 mmol) in hexane (3 mL)
at 0 °C under Ar. The solution was refluxed for 6.5 h and cooled
to -78 °C, and a solution of 4a (106 mg, 0.37 mmol) in THF (3
mL) was added dropwise. The mixture was allowed to reach
room temperature, diluted with Et2O (15 mL), and extracted
with brine (6 mL). The aqueous layer was back-extracted with
1
Supporting Information Available: Copies of H NMR
spectra for compounds 4a, 4c, 12b, and 12c. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO051471C
J. Org. Chem, Vol. 70, No. 23, 2005 9643