Probes for narcotic receptor-mediated phenomena. 33.1 Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine. Synthesis of the penultimate oxide-bridged phenylmorphans

Article abstract of DOI:10.1021/jo040159k

The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9Β-ol ((±)-10), an intermediate containing an a

Full text of DOI:10.1021/jo040159k

P r obes for Na r cotic Recep tor -Med ia ted P h en om en a . 33.1
Con str u ction of a Str a in ed tr a n s-5,6-Rin g System by Disp la cem en t
of a Nitr o-Activa ted Ar om a tic F lu or in e. Syn th esis of th e
P en u ltim a te Oxid e-Br id ged P h en ylm or p h a n s
Akihiro Hashimoto,†,‡ Anna K. Przybyl,†,§ J oannes T. M. Linders,†,| Shinichi Kodato,†,
Xinrong Tian,†,# J effrey R. Deschamps,3 Clifford George,3 J udith L. Flippen-Anderson,3,)
Arthur E. J acobson, and Kenner C. Rice*,†
Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases,
National Institutes of Health, Building 8, Room B1-23, Department of Health and Human Services,
Bethesda, Maryland, 20892-0815, and Laboratory for the Structure of Matter, Naval Research
Laboratory, Washington, D.C. 20375
kr21f@nih.gov
Received March 24, 2004
The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of
rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-
azabicyclo[3.3.1]nonan-9â-ol ((()-10), an intermediate containing an aromatic nitro-activated
fluorine atom. The fluorine atom was used as the leaving group for the formation of the strained
tetracyclic trans-fused 5,6-ring system in rac-(1R,4aR,9aR)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-
2H-1,4a-propanobenzofuro[2,3-c]pyridine ((()-11), although preference for cis ring fusion during
the formation of tricyclic tetra- and hexahydrodibenzofurans has been well-documented. Single-
crystal X-ray crystallographic study of the desired para-e isomer ((()-2), as well as of two
intermediates in its synthesis, provided assurance of the correct structures. The e-isomers are among
the last of the 12 oxide-bridged 5-phenylmorphans to be synthesized. We envisioned the syntheses
of these rigid, tetracyclic compounds in order to determine the three-dimensional pattern of a ligand
that would enable interaction with opioid receptors as agonists or antagonists.
In tr od u ction
1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]py-
ridin-8-ol (1) and (1R,4aR,9aS)-2-methyl-1,3,4,9a-tet-
rahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol (2),
the e-isomers in this rigid series of phenylmorphans
(Figure 1). These o- and p-e oxide-bridged phenylmor-
phans contain a trans-fused 5,6-membered ring that is
sterically strained and has proved difficult to synthesize.
Although we have prepared the c-isomers that also have
that ring-strained trans-fused 5,6-structure, the proce-
dure used for their synthesis did not succeed with the
e-isomers2 possibly because the 5,6-structure in the
c-isomers involves the piperidine ring, and that ring may
have more flexibility. Thus, we anticipated that the major
challenges for the synthesis of the rigid trans tetracyclic
system would lie in deciding when to close the central
furan ring, and how it could be achieved, since it has been
well demonstrated that there is preference for cis ring
fusion during the formation of tricyclic tetra- and hexahy-
drodibenzofurans. A number of synthetic approaches
involving furan ring closure between the two six-
membered rings to give tricyclic structures have afforded
exclusively cis isomers.7-11 Further, the same trend was
also followed when the tetrahydrodibenzofuran was
Methods that were previously used1-6 to prepare oxide-
bridged 5-phenylmorphans were unsuccessful when used
to synthesize the racemic (1R,4aR,9aS)-2-methyl-
† National Institute of Diabetes, Digestive and Kidney Diseases.
‡ Present Address: Achillion Pharmaceuticals Inc, New Haven, CT
06511.
§ Present Address: Faculty of Chemistry, Adam Mickiewicz Uni-
versity, 60-780 Poznan, Poland.
| Present Address: Department of Medicinal Chemistry, J ohnson &
J ohnson Pharmaceutical Research and Development, Turnhoutseweg
30, B-2340 Beerse, Belgium.
Present Address: Quality Affairs Division, Tanabe Seiyaku Co.,
Ltd., Yodogawa-Ku, Osaka, 532-8505, J apan.
#
Present Address: Procter & Gamble Pharmaceuticals, HCRC,
Mason, OH 45040.
3 Naval Research Laboratory.
) Present Address: PDB, Rutgers, the State University of New
J ersey, Piscataway, NJ 08854.
(1) Kodato, S.; Linders, J . T. M.; Gu, X.-H.; Yamada, K.; Flippen-
Anderson, J . L.; Deschamps, J . R.; J acobson, A. E.; Rice, K. C. Org.
Biomolec. Chem. 2004, 2, 330-336.
(2) Tadic, D.; Linders, J . T. M.; Flippen-Anderson, J . L.; J acobson,
A. E.; Rice, K. C. Tetrahedron 2003, 59, 4603-4614.
(3) Linders, J . T. M.; Mirsadeghi, S.; Flippen-Anderson, J . L.;
George, C.; J acobson, A. E.; Rice, K. C. Helv. Chim. Acta 2003, 86,
484-493.
(4) Yamada, K.; Flippen-Anderson, J . L.; J acobson, A. E.; Rice, K.
C. Synthesis 2002, 2359-2364.
(7) Parsons, P. J .; Charles, M. D.; Harvey, D. M.; Sumoreeah, L. R.;
Shell, A.; Spoors, G.; Gill, A. L.; Smith, S. Tetrahedron Lett. 2001, 42,
2209-2211.
(8) Trost, B. M.; Toste, F. D. J . Am. Chem. Soc. 2000, 122, 11262-
11263.
(5) Burke, T. R., J r.; J acobson, A. E.; Rice, K. C.; Silverton, J . V. J .
Org. Chem. 1984, 49, 2508-2510.
(6) Burke, T. R., J r.; J acobson, A. E.; Rice, K. C.; Silverton, J . V. J .
Org. Chem. 1984, 49, 1051-1056.
10.1021/jo040159k This article not subject to U.S. Copyright. Published 2004 American Chemical Society
Published on Web 07/02/2004
5322 J . Org. Chem. 2004, 69, 5322-5327

Probes for Narcotic Receptor-Mediated Phenomena
The successful path to the e-isomers was found through
an intermediate containing an aromatic nitro-activated
fluorine atom as a leaving group. The envisioned proce-
dure then necessitated subsequent formation of the
correct phenolic moiety.
Each of the a-f oxide-bridged phenylmorphan isomers
holds the phenolic ring at a fixed, distinct angle to the
piperidine ring that is determinable through single-
crystal X-ray diffraction studies. We hypothesized that
a three-dimensional pattern existed that was needed for
ligands to efficiently interact with opioid receptors as
agonists or antagonists and that this steric pattern could
be discerned by the synthesis of the a-f isomers. We
conceptualized that the initial synthesis of 12 racemic
oxide-bridged 5-phenylmorphan isomers, the o- and p-
hydroxy derivatives of a series of six compounds, a-f
(Figure 1), and their subsequent pharmacological evalu-
ation, would provide the data needed for determination
of which of these isomers should be resolved. It is well-
known that enantiomers can have distinctly different
pharmacological properties than the racemic mixture.
The 5-phenylmorphans,19 the basis for the molecules in
this series, have been found to be remarkably interesting
and have been examined over the past 50 years. They
have been found to be a class of opioids in which a
considerable number of the members of the group display
at least morphine-like potency as antinociceptive agents
and have high affinity to opioid receptors. The N-methyl
analogue, for example, is as potent as morphine as an
antinociceptive,20 and its (1R,5S)-(-)-enantiomer was
about four times more potent than morphine in mice.21
The (1S,5R)-(+)-enantiomer with the N-methyl moiety
was found to have mixed agonist-antagonist activity. Its
potency as an antagonist was similar to nalorphine.21,22
It was later noted that steric hindrance to the free
rotation of the aromatic ring, and concurrent conversion
to an N-phenylethyl analogue, resulted in the formation
of a pure, potent, opioid antagonist.23 However, we have
found that the steric hindrance appeared only to increase
potency; a nonsterically hindered N-phenylethyl enanti-
omer also showed pure opioid antagonist activity.24 Thus,
the angular relationship of the aromatic ring and pip-
eridine ring embodied in the sterically hindered com-
pound23 might, or might not, show the optimal three-
dimensional pattern.25 Also, the phenolic ring in that
compound23 was not fixed at a specific angle, but rather
held to a limited, but still relatively large area in which
the phenolic ring could freely rotate. To determine a more
precise three-dimensional pattern a rigid skeleton was
required, such as could be obtained in the a-f oxide-
F IGURE 1. Oxide-bridged phenylmorphans.
subjected to a variety of reduction reagents.12 The only
unique route that led to the benzodihydrofuran skeleton
possessing the trans stereochemical relationship was the
photolysis of a vinyl aryl ether13-15 in aprotic solvents
(benzene, toluene, hexane, etc.), although these condi-
tions normally furnished a mixture of products. However,
exclusive formation of trans-dihydrofurans was observed
with certain fused-ring aryloxyenones.15,16 Further, ir-
radiation of the same type of substrates in protic solvents
produced exclusively the less strained cis isomer in
excellent yields.15,17,18 This heteroatom-directed photo-
arylation protocol was unsuccessfully attempted for the
synthesis of the cis tetracyclic b-isomer of the oxide-
bridged 5-phenylmorphan in our laboratory.5,6 In addition
to the photochemical approach, the only other reported
synthetic pathway12 to the simple trans tricyclic hexahy-
drodibenzofurans involved constructing the furan ring
prior to six-membered ring formation so as to establish
the desired trans geometry at the 5,6-ring junction.
However, extension of this route to the synthesis of our
target molecules would require incorporation of suitable
functionality at C4a and C1 to build the piperidine ring,
which might prove extremely challenging in terms of both
stereochemical control and compatibility of functionality.
(9) Chiba, K.; Fukuda, M.; Kim, S.; Kitano, Y.; Tada, M. J . Org.
Chem. 1999, 64, 7654-7656.
(10) Graham, S. R.; Murphy, J . A.; Coates, D. Tetrahedron Lett.
1999, 40, 2415-2416.
(19) May, E. L.; Murphy, J . G. J . Org. Chem. 1954, 19, 618-622.
(20) May, E. L.; Murphy, J . G. J . Org. Chem. 1955, 20, 1197-1201.
(21) Ong, H.; Oh-ishi, T.; May, E. L. J . Med. Chem. 1974, 17, 133-
134.
(22) May, E. L.; Takeda, M. J . Med. Chem. 1970, 13, 805-807.
(23) Thomas, J . B.; Zheng, X. L.; Mascarella, S. W.; Rothman, R.
B.; Dersch, C. M.; Partilla, J . S.; Flippen-Anderson, J . L.; George, C.
F.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. J . Med. Chem.
1998, 41, 4143-4149.
(11) Labidalle, S.; Min, Z. Y.; Reynet, A.; Moskowitz, H.; Vierfond,
J . M.; Miocque, M.; Bucourt, R.; Thal, C. Tetrahedron 1988, 44, 1171-
1186.
(12) Rupprecht, K. M.; Boger, J .; Hoogsteen, K.; Nachbar, R. B.;
Springer, J . P. J . Org. Chem. 1991, 56, 6180-6188.
(13) Dittami, J . P.; Nie, X. Y.; Nie, H.; Ramanathan, H.; Breining,
S. J . Org. Chem. 1991, 56, 5572-5578.
(14) Wolff, T. J . Org. Chem. 1981, 46, 978-983.
(15) Schultz, A. G.; Lucci, R. D.; Fu, W. Y.; Berger, M. H.; Erhardt,
J .; Hagmann, W. K. J . Am. Chem. Soc. 1978, 100, 2150-2162.
(16) Schultz, A. G.; Lucci, R. D.; Napier, J . J .; Kinoshita, H.;
Ravichandran, R.; Shannon, P.; Yee, Y. K. J . Org. Chem. 1985, 50,
217-231.
(24) Hashimoto, A.; Coop, A.; Rothman, R. B.; Dersch, C.; Xu, H.;
Horel, R.; George, C.; J acobson, A. E.; Rice, K. C. In Problems of Drug
Dependence, 1999; Harris, L. S., Ed.; National Institute on Drug Abuse
Research Monograph 180; NIH: Washington, DC, 2000; NIH Publica-
tion No. 00-4737; p 250.
(25) Hashimoto, A.; J acobson, A. E.; Rothman, R. B.; Dersch, C. M.;
George, C.; Flippen-Anderson, J . L.; Rice, K. C. Bioorg. Med. Chem.
2002, 10, 3319-3329.
(17) Yee, Y. K.; Schultz, A. G. J . Org. Chem. 1979, 44, 719-724.
(18) Schultz, A. G.; Fu, W. Y. J . Org. Chem. 1976, 41, 1483-1484.
J . Org. Chem, Vol. 69, No. 16, 2004 5323

Hashimoto et al.
SCHEME 1
bridged 5-phenylmorphans. We have succeeded, thus far,
in synthesizing the racemic o-a oxide-bridged phenyl-
morphan isomer ((4R,6aR,11bR)-3-methyl-2,3,4,5,6,6a-
hexahydro-1H-4,11b-methanobenzofuro[3,2-d]azocin-8-
ol)4,5,26 and its p-a analogue ((4R,6aR,11bR)-3-methyl-
2,3,4,5,6,6a-hexahydro-1H-4,11b-methanobenzofuro[3,2-
d]azocin-10-ol),4 the o- and p-c isomers ((3R,6aS,11aS)-
2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-
benzofuro[2,3-c]azocin-10-ol and (3R,6aS,11aS)-2-meth-
yl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]-
azocin-8-ol)2, the o- and p-d compounds (3R,6aS,11aR)-
2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanoben-
zofuro[2,3-c]azocin-10-ol and (3R,6aS,11aR)-2-methyl-
1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-
c]azocin-8-ol),3,27 the o- and p-f isomers (1R,4aR,9aR)-2-
methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-
c]pyridin-8-ol and (1R,4aR,9aR)-2-methyl-1,3,4,9a-tetra-
hydro-2H-4,4a-propanobenzofuro[2.3-c]pyridin-6-ol,1,5,26 and
have now obtained the penultimate isomers in this series,
the racemic o- and p-e compounds (Figure 1).
mediate (()-8 (5-(2-fluorophenyl)-2-methyl-2-azabicyclo-
[3.3.1]nonan-9-one). The hydroxy compound with the
required configuration, compound (()-9 (Scheme 1, 5-(2-
fluorophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9â-ol) was
obtained by selective reduction of (()-8 with Super
Hydride. The structure of (()-9 was confirmed by X-ray
crystal structure analysis of the hydrobromide salt (Sup-
porting Information, Figure 2).
To activate the aromatic fluorine atom that would
allow ring closure to the oxygenated 5,6-trans ring
system, we introduced the p-nitro functional group using
nitronium tetrafluoroborate. A single racemic isomer was
obtained, 5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo-
[3.3.1]nonan-9â-ol ((()-10). X-ray structure analysis of
the hydrobromide salt of (()-10 confirmed its molecular
structure (Supporting Information, Figure 3). Refluxing
the free base of (()-10 with sodium hydride in tetrahy-
drofuran gave the desired 5,6-trans ring compound
(()-11.
Reduction to the amino compound (()-12 with am-
monium formate and Pd/C, and conversion to the phenol,
provided the p-e isomer (()-2. The structure of (()-2 was
unambiguously determined by X-ray crystallographic
analysis (Supporting Information, Figure 4). This X-ray
crystallographic study also enabled the determination of
the angular relationship between the least-squares plane
of the aromatic ring and the four coplanar atoms in the
piperidine ring (C1, C3, C4, and C9a). The angle between
the planes in the e-isomer was found to be 63.4°. The
angular data will be used in future structure-activity
studies that correlate the three-dimensional structure of
these opioid-like oxide-bridged phenylmorphans with
their binding affinities to opioid receptors and their
actions as opioid agonists or antagonists.
Resu lts a n d Discu ssion
The coupling of 2-fluorophenylacetonitrile (3) and
2-(dimethylamino)ethyl chloride gave the racemic 4-(dim-
ethylamino)-2-(2-fluorophenyl)butyronitrile ((()-4), and
it was reacted with 5-bromovaleronitrile in a Thorpe-
Ziegler reaction to give 2-amino-3-(2-dimethylamino-
ethyl)-3-(2-fluorophenyl)cyclohex-1-enecarbonitrile ((()-
5) as shown in Scheme 1. Acid hydrolysis of (()-5 gave
2-(2-dimethylaminoethyl)-2-(2-fluorophenyl)cyclohex-
anone ((()-6). Bromination and heating in xylene, fol-
lowed by heating in diphenyl ether, gave the key inter-
(26) Burke, T. R., J r.; J acobson, A. E.; Rice, K. C.; Weissman, B. A.;
Silverton, J . V. In Problems of Drug Dependence 1983; Harris, L. S.,
Ed.; National Institute on Drug Abuse Research Monograph 49; DHHS
((ADM) 84-1316): Washington, DC, 1984; Vol. 49, pp 109-113.
(27) Burke, T. R., J r.; J acobson, A. E.; Rice, K. C.; Weissman, B. A.;
Huang, H. C.; Silverton, J . V. J . Med. Chem. 1986, 29, 748-751.
The amino compound (()-12 also served to provide an
entry to the ortho-series, through conversion to the bromo
derivative (()-13 and nitration of (()-13 to (()-14
(Scheme 2). Reduction of the nitro moiety with concomi-
5324 J . Org. Chem., Vol. 69, No. 16, 2004

Probes for Narcotic Receptor-Mediated Phenomena
r a c-2-(2-Dim et h yla m in oet h yl)-2-(2-flu or op h en yl)cy-
cloh exa n on e ((()-6). The mixture of (()-5‚HBr (22.8 g, 62.0
mmol), H3PO4 (80 mL), AcOH (4 mL), and water (4 mL) was
refluxed for 24 h. It was then cooled, neutralized with aqueous
K2CO3, and extracted with CHCl3 (3×). The extracts were dried
over Na2SO4, filtered, and concentrated to give the keto
SCHEME 2
1
compound (()-6 (16.2 g, 99%). Mp: 53-54 °C. H NMR (300
MHz, CDCl3): δ 7.23-7.35 (2H, m), 7.18 (1H, m), 7.04 (1H,
m), 2.70-2.79 (1H, m), 2.42-2.55 (1H, m), 2.31-2.38 (1H, m),
1.92-2.18 (10H, m), 1.60-1.82 (5H, m). CIMS (NH3): m/z 264
[M + H]+. Anal. Calcd for C16H22FNO: C, 72.97; H, 8.42; N,
5.32. Found: C, 73.25; H, 8.49; N, 5.39.
r a c-6-Br om o-2-(2-d im eth yla m in oeth yl)-2-(2-flu or op h e-
n yl)cycloh exa n on e ((()-7). Bromine (3.4 mL, 67 mmol) was
added to a solution of (()-6 (16.0 g, 61.0 mmol) in CHCl3 (30
mL), and the mixture was stirred for 1 h at room temperature.
The solvent was evaporated, and a few drops of HBr were
added. The resulting solid was stirred with 2-propanol (10 mL),
filtered, and dried to give crystalline (()-7‚HBr (15.1 g, 59%).
Mp: 199-200 °C. 1H NMR: δ 7.19-7.36 (3H, m), 7.09 (1H,
m), 4.69-4.78 (1H, m), 2.80-2.89 (1H, m), 2.46-2.56 (1H, m),
2.05-2.28 (9H, m), 1.90-2.04 (2H, m), 1.64-1.86 (3H, m).
CIMS (NH3): m/z 342 [M + H]+. Anal. Calcd for C16H22Br2-
FNO: C, 45.41; H, 5.24; N, 3.31. Found: C, 45.41; H, 5.00; N,
3.00.
tant hydrogenolysis of the bromine substituent gave the
o-amino analogue (()-15, and that was converted via the
diazonium salt to the desired o-e isomer, the phenolic
compound (()-1.
Exp er im en ta l Section
r a c-5-(2-F lu or op h en yl)-2-m et h yl-2-a za b icyclo[3.3.1]-
n on a n -9-on e ((()-8). (()-7‚HBr (1.0 g, 2.4 mmol) was con-
verted to its free base with aqueous NaHCO3 and extracted
with CHCl3. The extract was dried, concentrated, and further
dried under high vacuum. The free base was then dissolved
in xylene (25 mL), and the mixture was refluxed with stirring
for 15 h. After cooling, crystals formed and were collected by
filtration. The crystals were then dissolved in diphenyl ether
(5 mL), and the solution was heated at 200 °C for 5 h. It was
cooled and acidified with aqueous HCl to pH ∼1, and the mix-
ture was extracted with diethyl ether to remove the diphenyl
ether. The aqueous layer was basified by adding K2CO3 and
extracted with CHCl3. The extracts were combined, dried over
Na2SO4, and concentrated. The residue was chromatographed
(silica gel, EtOAc) to afford (()-8 (412 mg, 71%), which was
converted to its hydrobromide salt and recrystallized from
absolute ethanol. Mp: 216-217 °C. 1H NMR (300 MHz,
CDCl3): δ 7.18-7.31 (2H, m), 7.04-7.15 (2H, m), 3.02-3.20
(1H, m), 2.72-2.82 (1H, m), 2.30-2.56 (6H, m), 2.06-2.54 (3H,
m), 1.64-1.82 (2H, m). CIMS (NH3): m/z 248 [M + H]+. Anal.
Calcd for C15H19BrFNO: C, 54.89; H, 5.83; N, 4.27. Found: C,
55.06; H, 5.96; N, 4.31.
r a c-4-Dim e t h yla m in o-2-(2-flu or op h e n yl)b u t yr on i-
tr ile ((()-4). Under argon, sodium hydride (10.2 g, 430 mmol)
was added to a solution of 2-fluorophenylacetonitrile (3, 53.0
g, 390 mmol) in THF (350 mL) in portions and the reaction
mixture was refluxed with stirring for 30 min. A solution of
the free base of 2-(dimethylamino)ethyl chloride in benzene
(the free base solution in benzene was obtained from the
hydrochloride salt (59.3 g, 420 mmol) by treatment with KOH/
H2O and extraction with benzene; the solution was dried over
Na2SO4) was then added, and the reaction was refluxed for
an additional 2 h. The reaction mixture was cooled and
concentrated to remove THF. The remaining solution was
acidified to pH ∼1 with an aqueous solution of citric acid and
washed with diethyl ether. The aqueous solution was neutral-
ized with K2CO3 powder and extracted with CHCl3 (3×). The
extracts were dried over Na2SO4 and filtered, the solvent was
removed, and the product was purified by column chromatog-
raphy (silica gel, hexane/ethyl acetate, 1:1) to give an oil, (()-4
(73.0 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.47 (1H, m),
7.29-7.36 (1H, m), 7.18 (1H, m), 7.09 (1H, m), 4.33 (1H, t, J
) 7.4 Hz), 2.55 (1H, m), 2.34 (1H, m), 2.24 (6H, s), 2.03 (2H,
dt, J ) 7.4, 6.3 Hz). FAB-MS: m/z 207 [M + H]+. Anal. Calcd
for C12H15FN2: C, 69.88; H, 7.33; N, 13.58. Found: C, 70.04;
H, 7.40; N, 13.65.
r a c-2-Am in o-3-(2-d im eth yla m in oeth yl)-3-(2-flu or op h e-
n yl)cycloh ex-1-en eca r bon itr ile ((()-5). To a solution of the
nitrile (()-4 (20.0 g, 97.0 mmol) in THF (150 mL) was added
NaNH2 (12.6 g, 323 mmol) under argon, and the reaction
mixture was stirred for 30 min at a carefully maintained
temperature of 50-52 °C. A solution of 5-bromovaleronitrile
(17.3 g, 108 mmol) in THF (20 mL) was then added, while the
temperature was maintained at 50-53 °C. The mixture was
stirred for 2 h at 53 °C. The reaction mixture was cooled, and
the solvent was removed. The residue was acidified to pH ∼1
with aqueous citric acid solution (0.5 M) and washed with
ether. The aqueous layer was neutralized by adding K2CO3
powder and extracted with CHCl3 (3×). The combined extracts
were dried over Na2SO4 and concentrated. The residue was
dissolved in 2-propanol (200 mL), and excess HBr was added
to give the hydrobromide salt of (()-5, which was collected and
dried (26.5 g, 74%). A second crop was obtained by evaporation
of the mother liquor and recrystallization from 2-propanol (6.4
g, 17%). Mp: 221 °C. 1H NMR (300 MHz, CDCl3): δ 7.21-
7.27 (2H, m), 7.10 (1H, m), 7.00 (1H, m), 6.20 (2H, s), 2.15-
2.30 (6H, m), 2.12 (2H, m), 2.04 (6H, s), 1.46-1.72 (2H, m).
FAB-MS: m/z 288 [M + H]+. Anal. Calcd for C17H23BrFN3:
C, 55.44; H, 6.29; N, 11.41. Found: C, 55.46; H, 6.34; N, 11.25.
r a c-5-(2-F lu or op h en yl)-2-m et h yl-2-a za b icyclo[3.3.1]-
n on a n -9â-ol ((()-9). To a solution of (()-8 (free base, 125 mg,
0.50 mmol) in THF was added dropwise a 1 M solution of
Super Hydride in THF (1.5 mL, 1.5 mmol) at -78 °C. After
being stirred for 1 h, the reaction mixture was allowed to warm
to room temperature and stirred for an additional 2 h. Water
(0.75 mL) and concentrated HCl (0.25 mL) were added, and
the reaction mixture was refluxed with stirring for 30 min.
The solvent was removed, and the residue was basified with
saturated aqueous NaHCO3. The mixture was extracted with
CHCl3, and the extract was dried over Na2SO4 and concen-
trated to give the 9â-ol (()-9 as the free base. Crude 9 was
then converted to its HBr salt, which was recrystallized from
EtOH to give pure (()-9‚HBr (124 mg, 74%). Mp: 237-238
1
°C. H NMR (300 MHz, CDCl3): δ 7.47-7.54 (1H, m), 7.07-
7.21 (2H, m), 6.94-7.02 (1H, m), 4.23 (1H, d, J ) 3.8 Hz),
2.90-3.08 (2H, m), 2.70-2.79 (1H, m), 2.43 (3H, s), 2.26-2.38
(3H, m), 2.34-2.25 (1H, m), 1.44-1.92 (5H, m). CIMS (NH3):
m/z 249 [M - H]+. Anal. Calcd for C15H21BrFNO: C, 54.56;
H, 6.41; N, 4.24. Found: C, 54.67; H, 6.32; N, 4.18.
r a c-5-(2-F lu or o-5-n itr op h en yl)-2-m eth yl-2-a za bicyclo-
[3.3.1]n on a n -9â-ol ((()-10). (()-9‚HBr (2.0 g, 6.1 mmol) was
converted to its free base ((()-9, 1.5 g) using aqueous NaHCO3.
To a solution of (()-9 in sulfolane (20 mL) was added 0.5 M
nitronium tetrafluoroborate solution in sulfolane (14.5 mL,
7.30 mmol) at room temperature. The mixture was stirred for
J . Org. Chem, Vol. 69, No. 16, 2004 5325

Hashimoto et al.
2 h, additional nitronium tetrafluoroborate solution in sul-
folane (14.5 mL, 7.30 mmol) was added, and stirring was
continued for another 2 h. Aqueous NaHCO3 was added, and
the reaction mixture was extracted with EtOAc. The extract
was dried over Na2SO4, filtered, and concentrated. The residue
was subjected to column chromatography (silica gel, CHCl3/
MeOH/NH4OH, 100:10:1) to give compound (()-10 as free base
(1.6 g, 91%), which was then converted to its hydrobromide
salt. Mp: 292-293 °C. 1H NMR (300 MHz, CDCl3): δ 8.45
(1H, dd, J ) 6.9, 2.8 Hz), 8.10 (1H, m), 7.13 (1H, dd, J ) 11.7,
10.4 Hz), 4.28 (1H, d, J ) 3.6 Hz), 2.90-3.08 (2H, m), 2.78-
2.88 (1H, m), 2.70-2.79 (1H, m), 2.47 (3H, s), 2.25-2.35 (3H,
m), 2.12-2.20 (1H, m), 1.50-1.90 (5H, m). CIMS (NH3): m/z
295 [M + H]+. Anal. Calcd for C15H20BrFN2O3: C, 48.01; H,
5.37; N, 7.47. Found: C, 48.14; H, 5.27; N, 7.38.
added to a solution of (()-12 (100 mg, 0.40 mmol) in a mixture
of concentrated hydrobromic acid (0.34 mL) and water (1 mL)
at 0 °C. The mixture was stirred at 0 °C for 1 h, and urea was
added until KI-starch paper did not show a purple color. CuBr
(68 mg, 0.5 mmol), concentrated HBr (0.13 mL), and water
(0.3 mL) were then added consecutively, and the reaction
mixture was vigorously stirred for 1 h at room temperature.
It was basified with NH4OH and extracted with EtOAc (3×).
The combined extracts were dried over Na2SO4, filtered, and
concentrated. The residue was chromatographed (silica gel,
CHCl3/MeOH/NH4OH, 100:10:1) to give (()-13 (107 mg, 85%),
which was converted to its hydrobromide salt and recrystal-
1
lized from absolute ethanol. Mp: 122-123 °C. H NMR (300
MHz, CDCl3): δ 7.22 (1H, dd, J ) 8.3, 2.0 Hz), 7.17 (1H, d, J
) 2.0 Hz), 6.78 (1H, d, J ) 8.3 Hz), 4.07 (1H, d, J ) 3.0 Hz),
3.43 (1H, m), 2.67-2.90 (2H, m), 2.52 (3H, s), 2.20-2.40 (2H,
m), 1.85-1.90 (2H, m), 1.70-1.85 (3H, m), 1.40-1.50 (1H, m).
HRMS (FAB): calcd for C15H19BrNO (M + H)+ 308.0644 [M
+ H]+, requires 308.0650.
r a c-(1r,4a r,9a r)-1,3,4,9a -Tetr a h yd r o-2-m eth yl-6-n itr o-
2H-1,4a -p r op a n oben zofu r o[2,3-c]p yr id in e ((()-11). To a
solution of the free base of (()-10 (1.3 g, 4.5 mmol) in THF
(50 mL) was added sodium hydride (0.22 g, 8.7 mmol), and
the reaction mixture was refluxed with stirring for 24 h. After
additional sodium hydride (0.11 g, 4.4 mmol) was added,
refluxing was continued for another 24 h. The reaction was
cooled, quenched with saturated aqueous NH4Cl solution, and
extracted with EtOAc (3×). The extract was dried over
Na2SO4, filtered, and concentrated. The residue was subjected
to column chromatography (silica gel, CHCl3/MeOH/NH4OH,
100:10:1) to give (()-11 as the free base (1.2 g, 97%), which
was converted to its hydrobromide salt and recrystallized from
r a c-(1r,4ar,9ar)-1,3,4,9a-Tetr ah ydr o-2-m eth yl-6-br om o-
8-n it r o-2H -1,4a -p r op a n ob en zofu r o[2,3-c]p yr id in e ((()-
14). As in the preparation of (()-10, 0.5 M nitronium tetraflu-
oroborate solution in sulfolane (2.57 mL, 1.30 mmol) was added
to a solution of (()-13 (330 mg, 1.10 mmol) in sulfolane (5 mL)
at room temperature, and the reaction mixture was stirred
for 2 h. Additional nitronium tetrafluoroborate in sulfolane
(1.29 mL, 0.60 mmol) was added, and the stirring was
continued for an additional 2 h. The reaction was quenched
with saturated aqueous NaHCO3 solution and extracted with
EtOAc (3×). The combined extracts were dried over Na2SO4,
filtered, and concentrated. The residue was subjected to
column chromatography (silica gel, CHCl3/MeOH/NH4OH, 100:
10:1) to afford (()-14 (203 mg, 54%), which was converted to
its hydrobromide salt. 1H NMR (300 MHz, CDCl3): δ 8.06 (1H,
d, J ) 2.0 Hz), 7.4 (1H, d, J ) 2.0 Hz), 4.30 (1H, d, J ) 3.0
Hz), 3.58 (1H, m), 2.67-2.90 (2H, m), 2.52 (3H, s), 2.30-2.45
(2H, m), 1.85-1.90 (2H, m), 1.70-1.85 (3H, m), 1.40-1.50 (1H,
m). HRMS (FAB): calcd for (M + H)+ C15H18BrN2O3 353.0501,
found 353.0517.
r a c-(1r,4ar,9ar)-1,3,4,9a-Tetr ah ydr o-2-m eth yl-8-am in o-
2H-1,4a -p r op a n oben zofu r o[2,3-c]p yr id in e ((()-15). A mix-
ture of (()-14 (200 mg, 0.60 mmol), K2CO3 (157 mg, 1.10
mmol), and 10% Pd/C (50 mg) in MeOH (20 mL) was stirred
under H2 (40 psi) for 1 h at 40 °C. The reaction mixture was
filtered, and the filtrate was concentrated in vacuo to give a
residue which was chromatographed (silica gel, CHCl3/MeOH/
NH4OH, 100:10:1) to give of (()-15 (86 mg, 62%), which was
converted to its hydrobromide salt and recrystallized from
absolute ethanol. 1H NMR (300 MHz, CDCl3): δ 6.72 (1H, dd,
J ) 8.5, 7.2 Hz), 6.53-6.60 (2H, m), 4.06 (1H, d, J ) 2.7 Hz),
3.65 (2H, m), 3.46 (1H, m), 2.67-2.90 (2H, m), 2.53 (3H, s),
2.30-2.45 (2H, m), 1.70-1.90 (5H, m), 1.40-1.50 (1H, m).
HRMS (FAB): calcd for (M + H)+ C15H21N2O 245.1654, found
245.1654.
r a c-(1r,4a r,9a r)-1,3,4,9a -Tetr a h yd r o-2-m eth yl-2H-1,4a -
p r op a n oben zofu r o[2,3-c]p yr id in -8-ol ((()-1, o-e Isom er ).
This material was prepared using the procedure described for
(()-2. A solution of NaNO2 (29 mg, 0.4 mmol) in water (0.3
mL) was added to a solution of (()-15 (80 mg, 0.3 mmol) in
35% H2SO4 (0.33 mL) at 0 °C. The mixture was stirred 5 min,
and urea was then added until KI-starch indicator paper did
not show a purple color. A solution of Cu(NO3)2‚3H2O (1.24 g,
5.10 mmol) in H2O (11.5 mL) was added, followed by Cu2O
(44 mg, 0.3 mmol), and the mixture was vigorously stirred for
30 min at room temperature. The color of the reaction mixture
changed from blue to greenish/black. The mixture was basified
with NH4OH and extracted with EtOAc (3×). The combined
extracts were dried over Na2SO4 and concentrated. The residue
was purified by column chromatography (silica gel, CHCl3/
MeOH/NH4OH, 100:10:1) to give (()-1 (37 mg, 46%), which
was converted to its hydrobromide salt and recrystallized from
absolute ethanol. Mp: 287-288 °C. 1H NMR (300 MHz,
1
absolute ethanol. Mp: 240-242 °C dec. H NMR: δ 8.13 (1H,
dd, J ) 2.5, 8.6 Hz), 7.98 (1H, d, J ) 2.5 Hz), 6.95 (1H, d, J )
8.6 Hz), 4.22 (1H, d, J ) 3.0 Hz), 3.49 (1H, m), 2.80-2.90 (1H,
m), 2.70-2.78 (1H, m), 2.54 (3H, s), 2.35-2.45 (2H, m), 1.70-
2.00 (5H, m), 1.20-1.27 (1H, m). CIMS (NH3): m/z 275 [M +
H]+. Anal. Calcd for C15H19BrN2O3: C, 50.79; H, 5.39; N, 7.89.
Found: C, 50.48; H, 5.42; N, 7.75.
r a c-(1r,4ar,9ar)-1,3,4,9a-Tetr ah ydr o-2-m eth yl-6-am in o-
2H-1,4a -p r op a n oben zofu r o[2,3-c]p yr id in e ((()-12). Am-
monium formate (230 mg, 3.60 mmol) and a catalytic amount
of 5% Pd/C were added to a solution of (()-11‚HBr (200 mg,
0.70 mmol) in MeOH (10 mL), and the mixture was refluxed
with stirring for 1 h. The catalyst was removed by filtration
and washed with 10 mL of hot MeOH, and the combined
filtrates were concentrated in vacuo. The residue was basified
with aqueous NaHCO3 and extracted with EtOAc (3×). The
extracts were combined, dried over Na2SO4, and concentrated
to give (()-12 (149 mg, 90%), which was used for the next
reaction without purification.
r a c-(1r,4a r,9a r)-1,3,4,9a -Tetr a h yd r o-2-m eth yl-2H-1,4a -
p r op a n oben zofu r o[2,3-c]p yr id in -6-ol ((()-2). To a solution
of (()-12 (145 mg, 0.60 mmol) in 35% H2SO4 (0.6 mL) was
added a solution of NaNO2 (53 mg, 0.8 mmol) in water (0.5
mL) at 0 °C. The mixture was stirred for 5 min, and urea was
added until KI-starch paper did not show a purple color. A
solution of Cu(NO3)2‚3H2O (2.25 g, 9.30 mmol) in water (21
mL) was then added, followed by Cu2O (79 mg, 0.6 mmol). The
resulting mixture was vigorously stirred for 30 min at room
temperature. The color of the reaction mixture changed
from blue to greenish/black. The mixture was basified with
NH4OH and extracted with EtOAc (3×). The extracts were
combined, dried over Na2SO4, and concentrated. The residue
was subjected to column chromatography (silica gel, CHCl3/
MeOH/NH4OH, 100:10:1) to give (()-2 (100 mg, 69%) as a free
base, which was converted to the hydrobromide salt and
recrystallized from absolute ethanol. Mp: 288-289 °C. 1H
NMR: δ 6.74 (1H, d, J ) 8.2 Hz), 6.55 (1H, dd, J ) 8.2, 2.7
Hz), 6.61 (1H, d, J ) 2.7 Hz), 5.20 (1H, s), 4.03 (1H, d, J ) 2.4
Hz), 3.41 (1H, m), 2.67-2.90 (2H, m), 2.52 (3H, s), 2.20-1.40
(2H, m), 1.70-1.90 (5H, m), 1.40-1.50 (1H, m). HRMS
(FAB): calcd for (M + H)+ C15H19NO2 246.1494, found 246.1486.
r a c-(1r,4ar,9ar)-1,3,4,9a-Tetr ah ydr o-2-m eth yl-6-br om o-
2H-1,4a -p r op a n oben zofu r o[2,3-c]p yr id in e ((()-13). A so-
lution of NaNO2 (28 mg, 0.4 mmol) in water (0.5 mL) was
5326 J . Org. Chem., Vol. 69, No. 16, 2004

Probes for Narcotic Receptor-Mediated Phenomena
CDCl3): δ 6.75-6.82 (2H, m), 6.67 (1H, dd, J ) 6.0, 2.5 Hz),
4.10 (1H, d, J ) 3.0 Hz), 3.65 (2H, m), 3.46 (1H, m), 2.67-
2.90 (2H, m), 2.53 (3H, s), 2.30-2.45 (2H, m), 1.70-1.90 (5H,
m), 1.40-1.50 (1H, m). HRMS (FAB): calcd for (M + H)+
) 0.0405 for 2322 observed (I > 2σI) reflections and 0.0412
for the full set of 2427 reflections.
Com p ou n d (()-10: C15H20BrFN2O3, FW ) 375.24 (0.24 ×
0.18 × 0.12 mm3), monoclinic space group P21/c, a ) 16.931-
(2) , b ) 7.0518(7) , c ) 12.845(1) Å, â ) 96.494(2)°, V ) 1523.8-
(3) Å3, Z ) 4, Fcalc ) 1.636 mg mm-3, λ(Mo KR) ) 0.710 73 Å,
µ ) 2.723 mm-1, F(000) ) 768, T ) 93(1) K, R1 ) 0.0521 for
3031 observed (I > 2σI) reflections and 0.0686 for the full set
of 3737 reflections.
Com p ou n d (()-2: C15H19BrNO2; FW ) 325.22 (0.44 × 0.21
× 0.14 mm3), monoclinic space group P21/n, a ) 6.3039(5) Å,
b )24.092(2) Å, c ) 9.7132(8) Å, â ) 107.731(1)°, V ) 1405.1-
(2) Å3, Z ) 4, Fcalc ) 1.537 mg mm-3, λ(Mo KR) ) 0.71073 Å, µ
) 2.923 mm-1, F(000) ) 778, T ) 93(1) K, R1 ) 0.0336 for
2671 observed (I > 2σI) reflections and 0.0453 for the full set
of 3380 reflections.
C
15H20NO2 246.1494, found 246.1504.
Sin gle-Cr ysta l X-r a y Diffr a ction An a lysis of Com -
p ou n d s (()-9, (()-10, a n d (()-2. Single-crystal X-ray dif-
fraction data for compounds (()-10 and (()-2 were collected
at -170 °C using Mo KR radiation on a four-circle diffracto-
meter (Bruker) equipped with a SMART 1000 CCD area
detector (Bruker) and incident beam monochromator. For
compound (()-9 diffraction data were collected at -75 °C using
Cu KR radiation on a three circle diffractometer (Bruker)
equipped with a SMART 6000 CCD area detector (Bruker) and
Go¨bel optics. All of the crystals remained stable during data
collection. Corrections were applied for Lorentz, polarization,
and absorption effects. The structure was solved by direct
methods and refined by full-matrix least-squares on F2 values
using programs found in the SHELXTL system of programs.28
Parameters refined included atomic coordinates and anisotro-
pic thermal parameters for all non-H atoms. H atoms on
carbons were included using a riding model [coordinate shifts
of C applied to H atoms] with C-H distance set at 0.96 Å.
Coordinates only were refined for the hydroxyl hydrogen.
Atomic coordinates have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
nos. 232384, 232385, and 232386, for compounds (()-9, (()-
10, and (()-2, respectively. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(O)-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk.
Ack n ow led gm en t. The authors (at LMC, NIDDK,
DHHS) thank the National Institute on Drug Abuse,
NIH, DHHS, for partial financial support of our re-
search program, and thank Noel Whittaker and Victor
Livingood (NIDDK, DHHS) for the mass spectral data.
The X-ray crystallographic work was supported in part
by the National Institute on Drug Abuse, NIH, DHHS,
and the Office of Naval Research.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
ture data for compounds (()-9, (()-10, and (()-2, and General
Experimental Section. This material is available free of charge
via the Internet at http://pubs.acs.org. The crystal structure
for (()-9, (()-10, and (()-2 have been deposited at the
Cambridge Crystallographic Data Center (CCDC 232384,
232385, and 232386, respectively). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
Com p ou n d (()-9: C15H21BrFNO, FW ) 330.24 (0.37 × 0.16
× 0.08 mm3), monoclinic space group P21/c, a ) 15.8054(2) Å,
b ) 7.1618(1) Å, c ) 12.9254(1) Å, â ) 91.108(1)°, V )
1462.82(3) Å3, Z ) 4, Fcalc ) 1.499 mg mm-3, λ(Cu KR) )
1.541 78 Å, µ ) 3.866 mm-1, F(000) ) 680, T ) 198(1) K, R1
(28) Bruker. SHELXTL v 6.1; Bruker AXS, Inc.: Madison, WI, 2000.
J O040159K
J . Org. Chem, Vol. 69, No. 16, 2004 5327