Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine

Article abstract of DOI:10.1021/jm0704696

Epibatidine analogues 3-5, possessing the pyridine ring fused to the 2,3 position of the 7-azabicyclo[2.2.1]heptane ring, and analogue 8a, possessing a benzene ring fused to the 5,6 position, were synthesized by procedures involving key steps of trapping

Full text of DOI:10.1021/jm0704696

J. Med. Chem. 2007, 50, 6383–6391
6383
Synthesis and Nicotinic Acetylcholine Receptor Binding Properties of Bridged and Fused Ring
Analogues of Epibatidine
,
†
†
†
†
†
‡
F. Ivy Carroll,* T. Philip Robinson, Lawrence E. Brieaddy, Robert N. Atkinson, S. Wayne Mascarella, M. Imad Damaj,
‡
†
Billy R. Martin, and Hernán A. Navarro
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and Department of
Pharmacology and Toxicology, Virginia Commonwealth UniVersity, Richmond, Virginia 23298
ReceiVed April 20, 2007
Epibatidine analogues 3–5, possessing the pyridine ring fused to the 2,3 position of the 7-azabicyclo[2.2.1]heptane
ring, and analogue 8a, possessing a benzene ring fused to the 5,6 position, were synthesized by procedures
involving key steps of trapping 2,3-pyridyne, 3,4-pyridyne, and benzyne with tert-butyl 1H-pyrrole-1-
carboxylate. Two epibatidine analogues, 6 and 7, which have the 2′-chloropyridine ring bridged to the
7
-azabicyclo[2.2.1]heptane ring via a methylene group, were synthesized, where the key step was an
intramolecular reductive palladium-catalyzed Heck-type coupling. Even though the conformationally restricted
epibatidine analogues, 3–7, and the benzo analogue 8a possess nAChR pharmacophore features thought to
4 2
be needed for R ꢀ binding, they all showed low affinity for nAChRs relative to epibatidine. These studies
provide new information concerning the pharmacophore for nAChRs and suggest that nitrogen lone-pair
directionality and steric factors may be important. Interestingly, N-methylepibatidine, prepared as a standard
compound for the study of bridged analogues 6 and 7, was a potent nAChR mixed agonist antagonist.
a
Introduction
Scheme 1
In 1992, Daly and co-workers reported the isolation and
structure determination of a compound showing potent anti-
nociceptive activity from the skin of the Ecuadorean poison frog,
1
Epipedobates tricolor, which they named epibatidine. Subse-
quent studies showed that the analgesic activity of epibatidine
resulted from the interaction with nicotinic acetylcholine recep-
a2–4
tors (nAChRs).
Epibatidine, similar to nicotine (2), possesses
a pyridine ring connected to a second pyrrolidine ring. However,
unlike nicotine, the pyrrolidine ring is less flexible because of
the 2-carbon bridge between the 1 and 4 positions. In addition,
the pyridine ring of epibatidine has a 2′-chloro substituent not
present in nicotine. The unique structure and biological activity
of epibatidine generated considerable interest and precipitated
the synthesis and biological evaluation of a number of analogues
as a means of learning more about the nAChR pharmacophore.
However, the exact conformation for receptor affinity and
modulation is currently still in doubt.
a
Reagents: (a) CsF, CH3CN, 25 °C; (b) H2, 10% Pd/C, EtOAc; (c)
CH3OH, HCl, 0 °C.
5–7
of 11 using 10% palladium on carbon in ethyl acetate yielded
2. Treatment of 11 and 12 with hydrogen chloride in methanol
provided the desired 3,4-pyridine fused ring epibatidine ana-
logues 3 and 4, respectively. A totally different synthesis of 4,
which involved 16 steps and a very low overall yield, has been
1
To gain additional information on the nAChR pharmacophore,
we synthesized and evaluated the nAChR binding affinity of
the conformationally restricted epibatidine analogues 3–7. In
addition, because the 5,6-benzo analogue 8a was reported to
have high affinity for nAChR, we synthesized and evaluated
1
1
reported.
The 2,3-pyridine-ring-based analogue 5 was synthesized by
a procedure similar to that for 4 (Scheme 2). 2-Pyridyne,
generated by treating 3-trimethylsilylpyridin-2-yl trifluo-
romethanesulfonate (13) with cesium fluoride in acetonitrile,
was added to tert-butyl 1H-pyrrole-1-carboxylate (10) to give
8
the nAChR binding properties of this compound. Preliminary
1
2
9
results on the synthesis of 6 and 7 have been reported.
1
4. Catalytic reduction of 14 in ethyl acetate using 10%
Chemistry
palladium on a carbon catalyst yielded 15. Removal of the tert-
butyloxycarbonyl protecting group using trifluoroacetic acid in
methylene chloride provided 5.
The bridged epibatidine analogue 6 was synthesized as shown
in Scheme 3, starting with 2-amino-4-methylpyridine (16).
Iodination of 16 using iodine in a periodic, sulfuric, and acetic
acid mixture afforded a 71% yield of 2-amino-5-iodo-4-
methylpyridine (17). The structure of 17 was established by
The fused ring epibatidine analogues 3 and 4 were synthesized
as outlined in Scheme 1. 3-Pyridyne, generated by treating
1
0
4
-triethylsilylpyridin-3-yl trifluoromethanesulfonate (9) with
cesium fluoride in acetonitrile, was added to tert-butyl 1H-
pyrrole-1-carboxylate (10) to give 11. Catalytic hydrogenation
*
To whom correspondence should be addressed. Telephone: 919-541-
6
679. Fax: 919-541-8868. E-mail: fic@rti.org.
1
†
analysis of the H nuclear magnetic resonance (NMR) spectrum,
which showed singlets at δ 2.23, 6.46, and 8.27 ppm for the
C4-methyl, H-3, and H-6 protons, respectively. The reaction
Research Triangle Institute.
Virginia Commonwealth University.
‡
a
3
Abbreviations: nAChR, nicotinic acetylcholine receptor; [ H], tritium.
1
0.1021/jm0704696 CCC: $37.00

2007 American Chemical Society
Published on Web 11/10/2007

6
384 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Carroll et al.
a
Scheme 2
The 5,6-benzofused ring epibatidine analogues 8a and 8b
were synthesized as outlined in Scheme 5. Benzyne, generated
2
1–23
by treating 2-trimethylsilyl trifluoromethanesulfonate (37)
with cesium fluoride in acetonitrile, was added to tert-butyl 1H-
pyrrole-1-carboxylate (10) to give 38. Subjection of 38 to
reductive Heck conditions using 2-amino-5-iodopyridine gave
3
9. Diazotization of 39 using sodium nitrite in concentrated
hydrochloride acid yielded the desired 8a. Bromination of 39
provided 40. The palladium-acetate-catalyzed reaction of 40 with
phenylboronic acid in dimethoxyethane in the presence of tri-
(2-tolyl)phosphine and sodium carbonate gave the tert-butoxy-
carbonyl-protected 2-amino-3-phenyl analogue 41. Diazotization
of 41 using sodium nitrite in pyridine containing 70% hydrogen
fluoride yielded the desired 2-fluoro-3-phenyl analogue 8b.
a
Reagents: (a) CsF, CH3CN, 25 °C; (b) H2, 10% Pd/C, EtOAc; (c) TFA,
CH2Cl2.
of 17 with meta-chloroperbenzoic acid in acetone gave the
N-oxide 18, which was isolated as the hydrochloride salt in 85%
yield. Treatment of the hydrochloride salt of 18 with acetic
anhydride in dioxane was expecting to give the 4-acetoxymethyl
or 4-hydroxymethyl compounds 19a and 19b, respectively.
Surprisingly, 2-acetamido-4-chloromethyl-5-iodopyridine (19c)
was isolated in 56% yield. Apparently, chloride ion displaced
the acetoxy or hydroxy group from the expected 4-acetoxy-
methyl or 4-hydroxymethyl intermediate to give 19c. Alkylation
1
3
of 7-azabicyclo[2.2.1]hept-2-ene (20a), generated from tert-
butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (20b) using tri-
methylsilyl iodide in chloroform, with 19c provided the
N-alkylated product 21 in 43% yield. Two possible approaches
1
4–16
for the conversion of 21 to 22 were the Heck cyclization
and a radical initiated cyclization.
1
7,18
We found that intramo-
lecular cyclization of 21 using reductive Heck conditions similar
1
9
to that used for intermolecular coupling (palladium diacetate,
potassium formate, and tetrabutyl ammonium chloride in
dimethylformamide at 90 °C) provided the hexahydro-7,10-
methanopyrrolo-2-[1,2-b]-2,6-naphthyridine 22 in 45% yield.
Hydrolysis of 22 using refluxing 3 N hydrochloric acid gave a
90% yield of the 3-amino analogue 23. Diazotization of 23 using
sodium nitrite in concentrated hydrochloric acid yielded the
desired epibatidine analogue 6 in 28% yield.
Bridged epibatidine analogue 7 was synthesized from 2-amino-
6
-methylpyridine (24) by a set of reactions exactly analogous
Biology
to those used to prepare analogue 6 that proceeded through
intermediate 24-30 (see Figure 1). The yield in each step was
similar to the analogous step in the synthesis of 6.
3
The inhibition of [ H]epibatidine binding at R4ꢀ2 nAChRs
125
and [ I]iodo-MLA at R7 nAChRs, respectively, were conducted
as previously reported. The epibatidine analogues were tested
for their effects on body temperature and two pain models after
acute administration as previously described. For the antagonist
experiments, mice were pretreated s.c. with either saline or
epibatidine analogues 10 min before nicotine. Nicotine was
administered at a dose of 2.5 mg/kg, s.c. (an ED84 dose), and
mice were tested 5 min later. ED50 and AD50 values with 95%
confidence limits were determined.
24
4
′-Methylepibatidine (32), 6′-methylepibatidine (34), and
24
N-methylepibatidine (35) were synthesized as reference com-
pounds for a comparison to the nAChR binding affinities of
the bridged analogues 6 and 7. The synthesis of compounds 32
and 34 is shown in Scheme 4. Subjection of 20b to reductive
19
Heck conditions using 2-amino-5-iodo-4-methylpyridine (36a)
or 2-amino-5-iodo-6-methylpyridine (36b) provided the inter-
mediates 31 and 33. Diazotization of 31 and 33 using sodium
nitrite and concentrated hydrochloric acid yielded the desired
Results and Discussion
4
′-methyl- and 6′-methylepibatidine analogues 32 and 34,
The key steps in the synthesis of the pyridine ring fused
epibatidine analogues 3–5 and 8a–8b were the trapping of 2,3-
pyridyne, 2,4-pyridyne, and benzyne with tert-butyl 1-pyrrole-
respectively. N-Methylepibatidine (35) was prepared as previ-
ously reported.
2
0

Bridged and Fused Ring Analogues of Epibatidine
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6385
a
Scheme 3
a
Reagents: (a) H5IO6, I2, H2SO4, HOAc, H2O, 80 °C; (b) MCPBA; (c) ethereal HCl; (d) Ac2O, dioxane; (e) (CH3)3SiI, CHCl3; (f) NaOMe, MeOH; (g)
+
-
HCO2K, Pd(OAc)2, (C4H9)4N Cl , DMF, 90 °C; (h) 3 N HCl, reflux; (i) NaNO2, concentrated HCl.
a
Scheme 5
Figure 1. Structures of starting material and intermediates used to
synthesize 7.
a
Scheme 4
a
Reagents: (a) 2-amino-5-iodo-4-methylpyridine (36a), HCO2K, Pd(OAc)2,
+
-
(
C4H9)4N Cl , DMF, 120 °C; (b) NaNO2, concentrated HCl; (c) 2-amino-5-
iodo-6-methylpyridine (36b), HCO2K, Pd(OAc)2, (C4H9)4N Cl , DMF,
+
-
a
- +
Reagents: (a) CsF, CH3CN; (b) 2-amino-5-iodopyridine, HCO2 K ,
+
-
100 °C.
(C4H9)4N Cl , Pd(Cl2)2, DMF, 60 °C; c) Na2NO2, concentrated HCl; (d)
Br2, (C2H5)3N, HOAc; (e) C6H5B(OH)2, Pd(OAc)2, P(o-tolyl)3, DME, H2O,
9
0 °C; (f) pyridine, HF, NaNO2.
1
-carboxalate to give intermediate compounds 11, 14, and 38
that could be modified using standard chemical techniques to
provide the desired target compounds. The key steps in the
synthesis of the bridged epibatidine analogues 6 and 7 were
intramolecular reductive Heck cyclization of 21-22 and 28-29.
The inhibition of radioligand binding for the 2,3- and 3,4-
pyridine fused ring epibatidine analogues 3–5 and the 5,6-
benzene fused analogues 8a–8b is given in Table 1. The
pyridine-fused analogues 3–5 displace less than 15% of the
radioligand at 31.6 µM for R4ꢀ2 nAChRs and have no affinity
for R7 nAChRs (Table 1). Geometrically, the fused analogues
found in the conformations of epibatidine (4.58-5.66 Å). The
torsional angle (as measured between the azabicylo ring
bridgehead atoms and the pyridinyl ring) is also different: for
the fused analogues, this torsional angle is ∼0°, whereas the
corresponding angle is either 70° or 256° for the two minimum-
energy conformations of epibatidine. One could speculate that
this is due to the fact that analogues 3–5 do not possess a chloro
substituent comparable to the 2′-chloro group in epibatidine.
However, this seems unlikely because deschloroepibatidine (42)
25
3
and 4 are quite different from epibatidine. The fixed
has a Ki ) 0.02 nM for the R4ꢀ2 nAChR. It seems much more
likely that these conformationally rigid analogues do not possess
features required for the R4ꢀ2 or R7 nAChR pharmacophores.
nitrogen-nitrogen distance in the rigid analogues 3 and 4 (4.56
Å) is near the low end of the range of corresponding distances

6
386 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Carroll et al.
Table 1. Radioligand Binding Data for Benzene- and Pyridine-Fused
Epibatidine Analogues
system, the compounds were evaluated for their in vivo nicotinic
pharmacological properties in mice (Table 3). Consistent with
the lack of affinity for the R4ꢀ2 receptor, the compounds
possessed no antinociceptive activity in the tail-flick or hot-
plate tests or significantly changed body temperature.
One could speculate that the reason for the low binding
affinity of the bridged analogues 6 and 7 is that they have an
extra 4′- and 6′-methylene substituents not present in epibatidine.
Alternatively, compounds 6 and 7 could be viewed as N-
substituted analogues of epibatidine. To gain information on
this possible explanation, we synthesized and evaluated the R4ꢀ2
nAChR binding affinity of the 4′-methyl-, 6′-methyl-, and
N-methylepibatidine analogues 32, 34, and 35, respectively. The
3
125
R4ꢀ2 [ H]epibatidine (Ki, nM) R7 [ I]iodoMLA
compound
X
Y
or percent inhibition
percent inhibition
nicotine (2)
epibatidine (1)
1.50 ( 0.30
0.026 ( 0.002
<15% at 31.6 µM
<15% at 31.6 µM
<15% at 31.6 µM
65.2 ( 7.2
3
4
5
0% at 50 nM
0% at 50 nM
0% at 50 nM
0% at 50 nM
0% at 50 nM
8
a
8
b
128 ( 22
Table 2. Radioligand Binding Data for Bridged Ring Epibatidine
Analogues
4
′-methyl and 6-methyl analogues have Ki values of 17.2 and
2
56 nM, respectively (Table 2). Thus, it seems unlikely that
the extra methylene substituents in 6 and 7 play a major part in
their low R4ꢀ2 nAChR affinity. Because N-methylepibatidine
has a Ki ) 0.038 nM at the R4ꢀ2 nAChR, apparently N
substitution does not contribute to the low affinity of the bridged
analogues 6 and 7. Compounds 32, 34, and 35 were also
evaluated for their in vivo nicotinic pharmacological properties
3
R4ꢀ2 [ H]epibatidine
compound
structure
X
Y
Z
R
(Ki, nM)
(
+)-epibatidine
C
B
A
B
A
C
C
C
Cl
Cl
Cl
NH2
NH2
Cl
Cl
Cl
H
H
H
0.026 ( 0.002
3330 ( 310
1260 ( 400
12400 ( 900
7370 ( 1240
17.2 ( 2.2
6
7
2
3
3
3
3
(
Table 3). Compound 35 has an ED50 ) 0.004 mg/kg in the
tail-flick test, which is consistent with the previously reported
3
0
2
4
5
3
5
value of 0.009 mg/kg. It also had an ED50 of 0.003 mg/kg in
both the hot-plate and hypothermia tests. Surprisingly, N-
methylepibatidine also blocked nicotine-induced antinociception
in the tail-flick test with a very high potency (AD50 ) 0.048
µg/kg), which is 90 times greater than its agonist activity.
Compounds 32 and 34 blocked the analgesic effects of nicotine
in the tail-flick test with a potency that correlates with their
CH3
H
H
H
CH3
H
H
H
CH3
256 ( 74
0.038 ( 0.003
a
a
Ref 20 reports a Ki ) 0.027 nM.
Even so, the information from the study of these compounds
does help further define nAChR pharmacophores.
3
affinity in the [ H]epibatidine binding assay. Only compound
The 5,6-benzo fused epibatidine analogue 8a has a Ki ) 65.2
nM at the R4ꢀ2 nAChR and has no affinity for the R7 nAChR.
The most likely explanation for the low binding affinity of 8a
compared to epibatidine is that the nAChRs cannot accom-
modate the extra steric bulk added to the 5,6 position. In earlier
studies, we showed that 2′-fluoro-3′-phenyldeschloroepibatidine
3
2 blocked nicotinic effects in the hot-plate test.
In summary, methods were developed for the synthesis of
three epibatidine analogues (3–5), which have the pyridine ring
annotated to the 3,4 position of the 7-azabicyclo[2.2.1]heptane
ring, and two analogues (6 and 7), which have a 2′-chloropy-
ridine ring bridged to the 7 position of the 7-azabicyclo[2.2.1]-
heptane ring via a methylene group. Similar to previously
(
43) had a Ki ) 0.24 nM at the R4ꢀ2 nAChR. The 5,6-benzo
26
36,37
analogue 8b has a Ki ) 128 nM, again showing that steric
bulk is not allowed in the 5,6 position.
reported conformationally restricted epibatidine analogues,
compounds 3–7 possessed low affinity for the nAChR relative
to that for epibatidine and did not show any activity in the
nicotinic pharmacological test in mice. Nevertheless, results
from this study provide valuable information concerning the
pharmacophore for nAChRs. In addition, we developed a new
synthesis of an epibatidine analogue (8a) possessing a benzene
ring fused to the 5,6 position on the 7-azabicyclo[2.2.1]heptane
ring. We found that 8a possessed low affinity for nAChRs,
The bridged epibatidine analogues 6 and 7 have Ki values of
3
330 and 1260 nM, respectively, for the R4ꢀ2 nAChR (Table
2
). Compounds 6 and 7 can be viewed as conformationally
locked analogues of epibatidine and are comparable to the two
principal low-energy conformations of the freely rotating
2
7–30
pyridine ring in epibatidine.
It has been suggested that the
pharmacologically significant conformation of epibatidine is the
3
1–33
8
global energy minimum conformation.
formation of epibatidine, the N-C1-C2-N dihedral angle is
42°, while in compound 7, the corresponding dihedral angle
In the “syn” con-
which is in contrast to a reported value. Results from this study
show that these structures do not encompass the ideal conforma-
tion for high affinity to the nAChRs. The fact that the
nitrogen-nitrogen distance in the analogues are within the range
generally required for receptor recognition suggests that direc-
tionality of the nitrogen lone pair of epibatidine’s 7-amino group
or steric hindrance may explain their lack of nAChR binding
affinity. Surprisingly, N-methyepibatidine is a potent mixed
agonist/antagonist.
∼
3
4
is ∼43°. In the “anti” conformation of epibatidine, the
N-C1-C2-N dihedral angle is ∼133°, while in compound 6,
the corresponding dihedral angle is ∼138°. The nitrogen-nitrogen
distances are somewhat shorter in the bridged analogues than
in the corresponding epibatidine conformations (3.8 versus 4.6
Å for compound 7/“syn” epibatidine pair and 5.1 versus 5.6 Å
for compound 6/“anti” epibatidine pair). However, the nitrogen-
nitrogen distance for compound 6 in particular is within the
Experimental Section
4
.5-5.5 Å range that has been proposed by several authors for
27–30
Melting points were determined on a Mel-temp (Laboratory
Devices, Inc.) capillary tube apparatus. NMR spectra were recorded
on a Bruker Avance 300 or AMSX 500 spectrometer using
tetramethylsilane as an internal standard. Thin-layer chromatography
was carried out on Whatman silica gel 60 plates. Visualization was
accomplished under UV or in an iodine chamber. Microanalysis
was carried out by Atlantic Microlab, Inc. Flash chromatography
the nicotinic pharmacophore.
Thus, even though the analogues 6 and/or 7 possess several
of the structural features in proposed pharmacophores for the
R4ꢀ2 nAChR, they did not show high affinity for this receptor
site. To determine if the bridged ring epibatidine analogues 6,
7
, 23, or 30 might be allosteric modulators of the nAChR

Bridged and Fused Ring Analogues of Epibatidine
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6387
AD50 (µg/kg)
Table 3. Pharmacological Data for Epibatidine Analogues
ED50 mg/kg
tail flick
ED50 mg/kg
hot plate
ED50 mg/kg
hypothermia
compound
tail flick
hot plate
body temperature
1
6
7
2
3
3
3
3
0.006
2% at 10
3% at 10
2% at 10
4% at 10
4% at 10
1% at 10
0.0044 (0.002–0.006)
0.004
18% at 10
17% at 10
16% at 10
10% at 10
20% at 10
14% at 10
0.003 (0.001–0.004)
0.004
0% at 10
0% at 10
0% at 10
0% at 10
0% at 10
0% at 10
0.003 (0.002–0.006)
3
0
2
4
5
400 (300–600)
9000 (8600–9600)
0.048 (0.01–0.17)
1200 (1000–1800)
10% at 15 000
23% at 0.5
0% at 5000
0% at 15 000
0% at 0.5
1
3
was carried out using silica gel 60 (230–400 mesh). CMA80 is
0% CHCl -18% CH OH-2% NH OH.
The [ H]epibatidine was purchased from Perkin-Elmer Inc.
0.95 (m, 15H). NMR (CDCl
3
) δ: 152.6, 148.3, 141.5, 140.7,
8
3
3
4
131.3, 119.0 (d, J ) 320 Hz), 7.8, 3.3.
3
tert-Butyl 5,8-Dihydro-5,8-epiminoisoquinoline-9-carboxylate
(11). Anhydrous cesium fluoride (20.9 g, 0.138 mol) was added to
a stirred solution of 4-triethylsilylpyridin-3-yl trifluoromethane-
sulfonate (9, 23.5 g, 0.07 mol) and t-butyl 1-pyrrole-1-carboxylate
(10, 57.5 g, 0.344 mol) in 69 mL of anhydrous acetonitrile. The
solution was allowed to stir overnight at room temperature. Water
was added, and the mixture was extracted with ether. The combined
ether extracts were washed with brine, dried with magnesium
sulfate, filtered, and evaporated. Flash chromatography over silica
gel with 50% hexanes in ethyl acetate afforded 6.3 g of an orange
1
25
(
Boston, MA). The [ I]iodo-MLA was synthesized as previously
38
reported.
4
-(Triethylsilyl)pyridin-3-yl Trifluoromethanesulfonate (9).
The title compound was synthesized by a modification of the
10
reported method. Diethylcarbamoyl chloride (74.9 mL, 552 mmol)
was added to a stirred, cold (0 °C) solution of 3-hydroxypyridine
(
50.0 g, 0.526 mol) in 263 mL of pyridine. The solution warmed
to room temperature overnight. Water was added, and the mixture
was extracted with ether. The combine ether extracts were washed
with 10% aqueous sodium carbonate solution and brine, dried with
oi1. Distillation of the oil at 95–100 °C (0.067 torr) provided 4.72 g
(28%) of 11 as a white solid. H NMR (CDCl
8.29 (d, J ) 4.5 Hz, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 6.95 (s, 1H),
3
5.58 (s, 1H), 5.52 (s, 1H) 1.38 (s, 9H). C NMR (CDCl ) δ: 158.1,
154.7, 147.5, 143.8, 142.9, 142.0, 140.4, 116.7, 81.2, 65.9, 64.6,
28.1.
5,8-Dihydro-5,8-iminoisoquinoline (3). Ice-cold concentrated
hydrochloric acid (10 mL) was added to a stirred solution of 11
(400 mg, l.64 mmol) in 2.0 mL of methanol cooled to 0 °C. The
reaction mixture was stirred at 0 °C for 3 h. Concentrated
ammonium hydroxide (15 mL) was added dropwise, and the product
was extracted with chloroform. The chloroform extracts were
combined, dried with sodium sulfate, and evaporated. Flash
chromatography over silica gel with 5% methanol in ethyl acetate
1
magnesium sulfate, filtered, and evaporated to yield 92.3 g (90%)
3
) δ: 8.46 (s, 1H),
1
of pyridin-3-yl diethylcarbamate as a yellow oil. H NMR (CDCl
3
)
13
δ: 8.44 (dd, J ) 1.5, 4.8 Hz, 2H), 7.53 (m, 1H), 7.30 (m, 1H),
3
.46 (q, J ) 7.2 Hz, 2H), 3.40 (q, J ) 7.2 Hz, 2H), 1.27 (t, J ) 7.2
1
3
Hz, 3H), 1.22 (t, J ) 7.2 Hz, 3H). C NMR (CDCl
48.2, 146.2, 143.6, 129.3, 123.6, 42.4, 42.0, 14.2, 13.3.
Lithium diisopropylamide [85.0 mL, 170 mmol, 2 M solution
3
) δ: 153.5,
1
in tetrahydrofuran (THF)] was added dropwise over 15 min to a
cold (-78 °C) solution of 30.0 g (0.154 mol) of the compound
above in 309 mL of THF. The reaction mixture was stirred for 25
min, at which time chlorotriethylsilane (170 mL, 170 mmol, 1 M
solution in THF) was added dropwise over 15 min. The solution
was allowed to warm to room temperature overnight. Water was
added, and the mixture was extracted with ether. The combined
ether extracts were washed with brine, dried with magnesium
sulfate, filtered, and evaporated. Flash chromatography over silica
gel with 50% ethyl acetate in hexanes provided 42.7 g (90%) of
1
provided 165 mg (70%) of 3 as a clear, colorless oil. H NMR
(CDCl
3
) δ: 8.42 (s, 1H), 8.23 (d, J ) 4.5 Hz, 1H), 7.22 (d, J ) 4.5
Hz, 1H), 7.05 (5, 1H), 6.98 (5, 1H), 5.08 (s, 1H), 5.01 (s, 1H),
1
3
3.11 (br s, 1H). C NMR (CDCl
3
) δ: 147.0, 145.3, 143.7, 140.3,
): C, H, N.
4
-(triethylsilyl)pyridin-3-yl diethylcarbamate as a clear crystal-
116.6, 66.0, 64.4 ppm. Anal. Calcd (C H N
9 8 2
1
line solid. H NMR (CDCl
3
) δ: 8.39 (d, J ) 4.5 Hz, 1H), 8.33
tert-Butyl 5,6,7,8-Tetrahydro-5,8-epiminoisoquinoline-9-car-
boxylate (12). Compound 11 (500 mg, 2.05 mmol) was weighed
in a Parr vessel and diluted with 35 mL of ethyl acetate. Palladium
(10%) on carbon (100 mg) was added, and the solution was
hydrogenated at 30 psi for 14 h. The catalyst was removed by
filtration over celite, and the ethyl acetate was evaporated to yield
410 mg (81%) of 12 as a white solid. H NMR (CDCl
(
s, 1H), 7.33 (d, J ) 4.8 Hz, 1H), 3.49 (q, J ) 7.2 Hz, 2H),
3
7
1
7
.40 (q, J ) 7.2 Hz, 2H), 1.27 (t, J ) 7.2 Hz, 3H), 1.20 (t, J )
13
3
.2 Hz, 3H), 0.95 (m, 9H), 0.85 (m, 6H). C NMR (CDCl ) δ:
54.0, 153.1, 145.3, 144.3, 138.8, 129.7, 42.2, 41.8, 14.3, 13.3,
.4, 3.2.
1
Methanol (50 mL) was added to a solution of 40.1 g (0.130 mol)
3
) δ: 8.45 (s,
of the above compound in 300 mL of 25% sodium methoxide in
methanol. The solution was stirred at room temperature overnight.
Hydrochloric acid (10%) was added dropwise, and the mixture was
extracted with ether. The combined ether extracts were washed with
brine, dried with magnesium sulfate, filtered, and evaporated. Flash
chromatography over silica gel with 50% ethyl acetate in hexanes
1H), 8.38 (d, J ) 4.5 Hz, 1H), 7.22 (d, J ) 4.5 Hz, 1H), 5.20 (s,
13
1H), 5.14 (s, 1H), 2.18 (m, 2H), 1.39 (s, 9H), 1.27 (m, 2H).
NMR (CDCl
C
3
) δ: 155.4, 153.8, 148.8, 140.9, 140.6, 115.5, 81.0,
61.0, 59.6, 28.5, 26.8, 26.2.
5,6,7,8-Tetrahydro-5,8-iminoisoquinoline (4). Ice-cold con-
centrated hydrochloric acid (3 mL) was added to a stirred, 0 °C
solution of 12 (190 mg, 0.771 mmol) in 2.0 mL of methanol. The
reaction mixture was stirred at 0 °C for 1 h. Concentrated
ammonium hydroxide (5 mL) was added dropwise, and the product
was extracted with chloroform. The chloroform extracts were
combined, dried with sodium sulfate, filtered, and evaporated. Flash
provided 21.6 g (80%) of 4-triethylsilyl)pyridin-3-ol as a white solid.
1
H NMR (CDCl ) δ: 11.8 (s, 1H), 8.26 (s, 1H), 8.02 (d, J ) 3 Hz,
3
13
1
1
3
H), 7.30 (d, J ) 3 Hz, 1H), 0.96 (m, 15H). C NMR (CDCl ) δ:
60.5, 138.6, 135.5, 135.4, 131.2, 7.8, 3.3.
Trifluoromethanesu1fonic anhydride (18.8 mL, 112 mmol) was
added dropwise over 10 min to a cooled (0 °C), stirred solution of
1.3 g (0.102 mol) of the above compound in 102 mL of pyridine.
chromatography over silica gel with 50% methanol in ethyl acetate
provided 60.0 mg (53%) of a clear, colorless oil. H NMR (CDCl
1
2
3
)
The reaction mixture was allowed to warm to room temperature
overnight. Water was added, and the mixture was extracted with
ether. The combined ether extracts were washed with brine, dried
with magnesium sulfate, filtered, and evaporated. Flash chroma-
δ: 8.44 (s, 1H), 8.36 (d, J ) 3 Hz, 1H), 7.18 (d, J ) 4.5 Hz, 1H),
4.64 (d, J ) 4.5 Hz, 1H), 4.58 (d, J ) 3 Hz, 1H), 2.60 (br s, 1H),
1
3
3
2.08 (m, 2H), 1.27 (m, 2H). C NMR (CDCl ) δ: 157.4, 148.2,
144.1, 140.4, 115.3, 61.0, 59.3, 26.5, 26.0. To a stirred, 0 °C solution
of the free amine (60.0 mg, 0.410 mmol) in methylene chloride
was added hydrochloric acid in ether (1.0 mL, 1.01 mmol, 1 M).
The solution was stirred for 2 h while warming to room tempera-
tography over silica gel with 10% ethyl acetate in hexanes provided
1
2
8
3.5 g (68%) of 9 as a clear, colorless oil. H NMR (CDCl
3
) δ:
.61 (s, 1H), 8.56 (d, J ) 4.5 Hz, 1H), 7.42 (d, J ) 4.8 Hz, 1H),

6
388 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Carroll et al.
1
ture. The solution was evaporated, and the resulting solid was dried
on the vacuum pump. Recrystallization from methanol-ether
provided 62 mg (73%) of 4·HCl as small, white needles. Anal.
clear, colorless oil. H NMR (CDCl
3
) δ: 8.20 (dd, J ) 1.5, 5.1 Hz,
1H), 7.44 (d, J ) 7.5 Hz, 1H), 6.97 (dd, J ) 5.1, 7.2 Hz, 1H), 4.60
(d, J ) 2.7 Hz, 1H), 4.52 (d, J ) 3.9, 1H), 2.4 (br s, 1H), 2.12 (m,
13
Calcd (C
-Trimethylsilyl-2-pyridyl Trifluoromethanesulfonate (13). The
title compound was prepared by modification of the reported
9
H12C1
2
N
2
): C, H, N.
3
2H), 1.35 (m, 2H). C NMR (CDCl ) δ: 169.6, 146.4, 141.6, 126.8,
3
121.2, 62.1, 60.4, 26.9, 25.2. To a stirred, 0 °C solution of the free
amine (21.5 mg, 0.147 mmol) in methylene chloride was added
hydrochloric acid in ether (1.5 mL, 1.47 mmol, 1 M). The solution
was evaporated, and the resulting solid was dried on the vacuum
pump. Recrystallization from methanol-ether provided 31.4 mg
(98%) of the dihydrochloride salt. mp 175.5 °C (decomp). Anal.
1
2
method. Lithium diisopropylamide (2 M, 231 mL, 463 mmol)
was added dropwise over 15 min to a stirred, 0 °C solution of 20.0 g
(
0.210 mol) of 2-hydroxypyridine in 500 mL of THF under nitrogen.
The solution was stirred for 5 min at 0 °C and for 1 h while warming
to room temperature. The solution was again placed in an ice bath,
and chlorotrimethylsilane (29.3 mL, 231 mmol) was added over
9 2 2
Calcd (C H12Cl N ): C, H, N.
2-Amino-5-iodo-4-methylpyridine (17). Compound 16 (27.0 g,
1
0 min to the solution. After stirring 5 min longer at 0 °C, the
0.25 mol) was mixed with periodic acid (11.4 g, 0.050 mol), HOAc
solution was allowed to stir overnight at room temperature. The
THF was evaporated, and ethyl acetate was added. The ethyl acetate
was filtered and evaporated. Flash chromatography over silica gel
with ethyl acetate yielded 23.4 g (67%) of 3-trimethylsilyl-2-
hydroxypyridine as an off-white solid. H NMR (CDCl
(150 mL), H
mol) was added, and the reaction mixture was stirred at 80 °C for
4 h. The mixture was cooled and poured into H O containing 40 g
of Na . The reaction mixture was decanted from a reddish oil,
2 4 2
SO (4.5 mL), and H O (30 mL). Iodine (25.4 g, 0.10
2
2 2 3
S O
1
3
) δ: 12.4
and the filtrate was basified with 50% NaOH. The resulting solids
(
br s, 1H), 7.54 (d, J ) 6 Hz, 1H), 7.34 (d, J ) 6 Hz, 1H), 6.23 (t,
were extracted with diethyl ether (2 × 300 mL). The ether layer
1
3
J ) 6 Hz, 1H), 0.28 (s, 9H). C NMR (CDCl
35.5, 132.1, 106.7, -1.6.
To a stirred, ice-cold solution of 3-trimethylsilyl-2-hydroxypy-
3
) δ: 167.7, 147.5,
2 4
was separated, dried (Na SO ), and concentrated. The solids were
1
recrystallized from EtOH-H
2
O to afford 17 (41.8 g, 71%) as a
) δ: 2.23 (s, 3H), 4.35 (br s, 2H), 6.46
1
tan solid. H NMR (CDCl
(s, 1H), 8.27 (s, 1H).
3
ridine (5.56 g, 0.033 mol) in 33 mL of pyridine under nitrogen
was added dropwise trifluoromethanesulfonic anhydride (6.15 mL,
2-Amino-5-iodo-4-methylpyridine-N-oxide (18) Hydrochlo-
ride. To compound 17 (29.6 g, 0.13 mol) in acetone (200 mL) was
added meta-chloroperbenzoic acid (50–55%, 48.3 g) in acetone (100
mL). The reaction was stirred at room temperature for 90 min and
3
6.6 mmol). The solution was allowed to stir at room temperature
overnight. The solvent was evaporated, and ether and water were
added. The ether extracts were washed with brine, dried with
magnesium sulfate, filtered, and evaporated. Flash chromatography
then concentrated in vacuo. The residue was dissolved in CHCl
3
over silica gel with 5% ethyl acetate in hexanes provided 9.50 g
and stirred while adding 2 M ethereal HCl (100 mL). The mixture
1
(
(
96%) of 13 as a clear, colorless oi1. H NMR (CDCl
3
) δ: 8.32
was filtered, and the salt was recrystallized from EtOH-diethyl
dd, J ) 1.8, 4.8 Hz, 1H), 7.92 (dd, J ) 1.8, 7.2 Hz, 1H), 7.31 (dd,
ether to yield 18 hydrochloride (30.8 g, 85%) as a tan solid. mp
1
3
1
J ) 4.8, 7.2 Hz, 1H), 0.37 (s, 9H). C NMR (CDCl
49.0, 147.1, 125.4, 123.4, 120.8, 118.7 (d, Jcf ) 317 Hz), -1.4.
tert-Butyl 5,8-Dihydro-5,8-epiminoquinoline-9-carboxylate
14). Cesium fluoride (30.0 g, 0.198 mol) was added to a stirred
3
) δ: 161.1,
198–200 °C. H NMR (DMSO-d
6
) δ: 2.34 (s, 3H), 7.08 (s, 1H),
1
8.39 (br s, 3H), 8.74 (s, H).
2-Acetamido-4-chloromethyl-5-iodopyridine (19c). Acetic an-
hydride (2.4 g, 0.023 mol) was added to a heterogeneous mixture
of 18·HCl (3.0 g, 0.0105 mol) in dioxane (50 mL). The reaction
mixture was stirred at reflux for 17 h. The resulting dark brown
mixture was concentrated in vacuo, and the residue was partitioned
(
solution of 13 (29.6 g, 0.099 mol) and tert-butyl 1-pyrrolecarboxy-
late (82.6 g, 0.494 mol) in 100 mL of acetonitrile at room
temperature. The reaction was allowed to stir overnight. Water was
added, and the reaction mixture was extracted with ethyl acetate.
The ethyl acetate fractions were combined, washed with brine, dried
with magnesium sulfate, filtered, and evaporated. Flash chroma-
tography over silica gel with 20% ethyl acetate in hexanes provided
between 5% NaHCO
separated, washed with brine, dried (Na
3
solution and CH
2
Cl
2
. The organic layer was
), and concentrated.
2
SO
4
The residue was dissolved in EtOAc and passed through a plug of
silica gel. The filtrate was concentrated to give 2.9 g of a tan solid.
The resulting product was purified by flash chromatography on silica
6
.6 g of a bright yellow solid. Distillation at 90 °C (0.054 torr)
1
provided 3.4 g (14%) of 14 a white solid. H NMR (CDCl
3
) δ:
.02 (d, J ) 5.4 Hz, 1H), 7.42 (d, J ) 7.2 Hz, 1H), 7.04 (br s, 2H),
.84 (dd, J ) 5.4, 7.2, 1H), 5.56 (s, 1H), 5.43 (s, 1H), 1.40 (s,
H). C NMR (CDCl
1.2, 67.6, 65.4, 28.1.
This product was used in the next step without further puri-
fication.
tert-Butyl 5,6,7,8-Tetrahydro-5,8-epiminoquinoline-9-carbox-
gel using 75% hexane-acetone, as the eluent, to yield 19c (1.82
1
8
6
9
8
g, 56%) as a beige solid. mp 173–174 °C. H NMR (CDCl
3
) δ:
2.22 (s, 3H), 4.57 (s, 2H), 7.98 (br s, 1H), 8.37 (s, 1H), 8.50 (s,
1H).
13
3
) δ: 171.5, 154.9, 143.6, 141.6, 126.9, 119.3,
7-Azabicyclo[2.2.1]hept-2-ene (20a). Iodotrimethylsilane (4.84
g, 0.024 mol) was added to a solution of 7-(tert-butoxy)carbonyl-
1
7-azabicyclo[2.2.1]hept-2-ene (20b, 3.9 g, 0.02 mol) in 150 mL
3
of CHCl . The reaction mixture was stirred at room temperature
for 1 h, quenched with MeOH (3.1 g, 0.097 mol), and concentrated.
ylate (15). Compound 14 (476 mg, 1.95 mmol) was weighed in a
Parr vessel and diluted with 35 mL of ethyl acetate. Palladium
The residue was triturated with ether to give 20a (3.26 g, 73%) as
1
(
10%) on carbon (100 mg) was added, and the solution was
a tan solid. mp 184–185 °C. H NMR (CDCl
3
) δ: 1.45 (dd, J )
hydrogenated at 30 psi for 15 h. The catalyst was removed by
3.6, 8.7 Hz, 2H), 2.42 (m, 2H), 4.90 (s, 2H), 6.40 (s, 2H), 7.95 (br
s, 1H).
filtration over celite, and the ethyl acetate was evaporated to yield
1
4
(
5
2
34 mg (91%) of 14 as a white solid. H NMR (CDCl
3
) δ: 8.27
N-[4-(7-Azabicyclo[2.2.1]hept-2-en-7-yl)methyl-5-iodo-2-py-
ridin-2-yl] Acetamide (21). To NaOMe (0.26 g, 0.0045 mol) in
MeOH (50 mL) was added 20a (1.0 g, 0.0045 mol) followed by
19c (1.29 g, 0.0044 mol). The reaction mixture was stirred at reflux
for 18 h then concentrated in vacuo. The solid residue was triturated
dd, J ) 1.5, 5.1 Hz, 1H), 7.44 (d, J ) 7.5 Hz, 1H), 7.04 (dd, J )
.1, 7.2 Hz, 1H), 5.18 (d, J ) 2.7 Hz, 1H), 5.13 (d, J ) 3.9, 1H),
.18 (m, 2H), 1.41 (s, 9H), 1.27 (m, 2H).
This product was used in the next step without further purification.
2
,7
3
,11-Diazatricyclo[6.2.1.0 ]undeca-2(7),3,5-triene (5) Dihy-
drochloride. Trifluoroacetic acid (2 mL) was added to a stirred, –9
C solution of 15 (450 mg, 1.83 mmol) in 2.0 mL of methylene
chloride. The reaction mixture was stirred at 0 °C for 30 min and
h while warming to room temperature. Concentrated ammonium
3
with CHCl , filtered, and concentrated. The solids were purified
by silica gel column chromatography using EtOAc-hexane (1:1)
°
as the eluent to give 21 (0.50 g, 43%) as a beige solid. mp 130–132
1
°C. H NMR (CDCl
3
) δ: 1.03 (m, 2H), 1.93 (d, J ) 7.8 Hz, 2H),
2
2.20 (s, 3H), 3.34 (s, 2H), 3.88 (s, 2H), 6.05 (s, 2H), 8.00 (s, 1H),
8.34 (s, 1H), 8.44 (s, 1H).
hydroxide (3 mL) was added dropwise, and the product was
extracted with methylene chloride. The methylene chloride extracts
were combined, washed with brine, dried with sodium sulfate,
filtered, and evaporated. Flash chromatography over silica gel with
This product was used in the next step without further purification.
N-(5,7,8,9,9a,10-Hexahydro-7,10-methanopyrrolo[1,2-
b][2,6]naphthyridin-3-yl)acetamide (22). To N,N-dimethylforma-
mide (DMF, 10 mL) in a closed reaction vessel was added
5
0% methanol in ethyl acetate provided 160 mg (60%) of 5 as a

Bridged and Fused Ring Analogues of Epibatidine
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6389
compound 21 (1.60 g, 0.0043 mol), HCO
tetrabutylammonium chloride (0.31 g, 0.0043 mol), and palladium
II) acetate (0.047 g, 0.000 21 mol). The reaction mixture was stirred
at 90 °C for 19 h and cooled, and brine (100 mL) and EtOAc (100
mL) were added followed by NH OH (50 mL). The mixture was
filtered, and the organic layer was separated, washed with brine,
dried (Na SO ), and concentrated to give solids. The solids were
2
K (0.36 g, 0.0043 mol),
3.53 (t, J ) 4.3 Hz, 1H), 3.89 (d, J ) 19 Hz, 1H), 4.28 (d, J ) 19
Hz, 1H), 7.24 (d, J ) 8 Hz, 1H), 7.87 (d, J ) 8 Hz, 1H), 8.61 (br
s, 1H).
5,5a,6,7,8,10-Hexahydro-5,8-methanopyrrolo[2,1-
g][1,7]napthyridin-2-amine (30). Using a procedure analogous to
(
4
that described for 23 afforded a 61% yield of 30 as a white solid.
1
2
4
mp (HCl salt) 201–206 °C. H NMR (base, CDCl
3
) δ: 1.29–1.86
purified by silica gel column chromatography using CMA80-
(m, 6H), 2.73 (d, J ) 6 Hz, 1H), 3.16 (d, J ) 5 Hz, 1H), 3.49 (t,
J ) 5 Hz, 1H), 3.85 (d, J ) 19 Hz, 1H), 4.26 (d, J ) 19 Hz, 1H),
4.29 (br s, 2H), 6.21 (d, J ) 8 Hz, 1H), 7.01 (d, J ) 8 Hz, 1H).
2-Chloro-5,5a,6,7,8,10-hexahydro-5,8-methanopyrrolo[2,1-
g][1,7]naphthyridine (7). Using a procedure analogous to that
hexane-EtOAc (2:1:1) as the eluent to afford 22 (0.45 g, 45%) as
1
a beige solid. mp 204–205 °C. H NMR (CDCl
3
) δ: 1.34 (m, 1H),
1
3
4
1
.48 (m, 2H), 1.88 (m, 3H), 2.18 (s, 3H), 2.87 (d, J ) 6.5 Hz, 1H),
.09 (d, 1H), 3.48 (t, J ) 4.3 Hz, 1H), 3.95 (d, J ) 19 Hz, 1H),
.38 (d, J ) 19 Hz, 1H), 7.92 (s, 11H), 7.99 (s, 1H), 8.45 (br s,
described for 6 gave a 32% yield of 7 as a white solid. mp 127–129
1
H).
°C. H NMR (CDCl
1
1
(
3
) δ: 1.33–1.89 (m, 6H), 2.88 (d, J ) 6 Hz,
H), 3.17 (d, J ) 5 Hz, 1H), 3.54 (t, J ) 5 Hz, 1H), 3.98 (d, J )
9 Hz, 1H), 4.41 (d, J ) 19 Hz, 1H), 7.04 (d, J ) 8 Hz, 1H), 7.21
·0.25H O): C, H, N.
5
,7,8,9,9a,10-Hexahydro-7,10-methanopyrrolo[1,2-
b][2,6]naphthyridin-3-amine (23). Compound 22 (1.10 g, 0.0045
mol) was stirred at reflux in 3 N HCl (400 mL) for 7 h. The reaction
d, J ) 8 Hz, 1H). Anal. Calcd (C12
H13ClN
2
2
tert-Butyl 2-(6-Amino-4-methylpyridin-3-yl)-7-azabicyclo-
2.2.1]heptane-7-carboxylate (31). To DMF (10 mL) in a closed
was cooled, basified with solid NaOH, and extracted with CHCl
2 × 200 mL). The combined CHCl extracts were washed with
brine, separated, and dried (Na SO ). Evaporation of the solvent
3
[
(
3
reaction vessel was added 2-amino-5-iodo-4-methylpyridine (36a,
.60 g, 0.015 mol), compound 20b (1.5 g, 0.0077 mol), HCO
1.30 g, 0.015 mol), tetrabutylammonium chloride (0.53 g, 0.0019
2
4
3
2
K
gave 23 (0.82 g, 90%) as a cream-colored solid. mp 149–152 °C.
The hydrochloride salt obtained by adding an ethereal HCl solution
(
mol), and palladium (II) acetate (0.094 g, 0.000 42 mol). The
to a solution of the free base in CH
2
Cl
2
had an mp of 283–286 °C.
1
reaction was stirred at 120 °C for 17 h and cooled, and EtOAc
H NMR (base, CDCl
3
) δ: 1.46–1.88 (m, 6H), 2.81 (d, J ) 6.0
(
200 mL) was added followed by NH
4
OH (200 mL). The organic
SO ), and
Hz, 1H), 3.07 (d, J ) 5.0 Hz, 1H), 3.44 (t, J ) 4.5 Hz, 1H), 3.84
d, J ) 19 Hz, 1H), 4.23 (d, J ) 19 Hz, 1H), 4.29 (br s, 2H), 6.24
s, 1H), 7.68 (s, 1H). Anal. Calcd (di-HCl salt) (C12 ·H O):
layer was separated, washed with brine, dried (Na
2
4
(
concentrated to give 31 as a solid. The solid was purified by silica
(
H17Cl N
2 3
2
gel column chromatography using 80% EtOAc-MeOH as the
C, H, N.
-Chloro-5,7,8,9,9a,10-hexahydro-7,10-methanopyrrolo[1,2-
b][2,6]naphthyridine (6). NaNO (3.1 g, 0.045 mol) was added to
1
eluent to yield 0.25 g (11%) of 31 as a tan solid. H NMR (CDCl
3
)
3
δ: 1.44 (s, 9H), 1.56 (t, J ) 9.0 Hz, 2H), 1.65–1.95 (m, 5H), 2.16
s, 3H), 2.86 (m, 1H), 4.23 (bd, 2H), 4.35 (bs, 1H), 6.33 (s, H),
.04 (s, 1H).
-(6-Chloro-4-methylpyridin-3-yl)-7-azabicyclo[2.2.1]heptane
32). NaNO (5.3 g, 0.077 mol) was added to compound 31 (1.30
2
(
8
compound 23 (0.65 g, 0.0032 mol) in 12 N HCl (20 mL) at ice
bath temperatures, and the mixture was stirred for 30 min and then
2
at room temperature for 2 h. The mixture was added to NH
4
OH
(2 × 100 mL), separated, dried
4
), and concentrated. The residue was purified by silica gel
(
2
(40 mL), extracted with CHCl
Na SO
3
g, 0.0043 mol) in 12 N HCl (14 mL) at ice bath temperatures. The
reaction mixture was stirred at ice bath temperatures for 30 min
and then at room temperature for 2 h. The mixture was added to
(
2
column chromatography using CMA80-hexane-EtOAc (2:1:1) as
the eluent to afford 6 (0.20 g, 28%) as a beige solid. mp 138–139
NH
CHCl
4
OH (75 mL) and extracted with CHCl
3
(2 × 100 mL). The
1
°
1
1
C. H NMR (CDCl
3
) δ: 1.34–1.95 (m, 6H), 2.92 (d, J ) 6 Hz,
3
layer was separated, dried (Na SO ), and concentrated. The
2
4
H), 3.08 (d, J ) 5 Hz, 1H), 3.49 (t, J ) 5 Hz, 1H), 3.98 (d, J )
9 Hz, 1H), 4.31 (d, J ) 19 Hz, 1H), 7.04 (s, 1H), 8.00 (s, 1H).
): C, H, N.
-Amino-5-iodo-6-methylpyridine (25). Compound 25 was
residue was purified by silica gel column chromatography using
CMA80-hexane-EtOAc (2:1:1) as the eluent to afford 0.35 g
Anal. Calcd (C12H13ClN
2
(
40%) of 32 as an orange oil. The HCl salt was prepared by
2
dissolving the free base in ether and adding ethereal HCl to give
prepared from 2-amino-6-methylpyridine 23 by a procedure similar
to that used for 17 to afford 49% of 25 as a beige solid. mp 100–102
solids that were crystallized from MeOH-EtOAc mixtures to yield
1
the hydrochloride as a white solid. mp 120–122 °C. H NMR
1
°
)
C. H NMR (CDCl
3
) δ: 2.54 (s, 3H), 4.54 (br s, 2H), 6.17 (d, J
(
1
CDCl
H), 3.70 (m, 1H), 3.81 (m, 1H), 7.02 (s, 1H), 8.39 (s, 1H). Anal.
Calcd (C12 ·1.25H O): C, H, N.
3
, free base) δ: 1.51–1.69 (m, 6H), 1.92 (m, 1H), 2.87 (m,
8 Hz, 1H), 7.66 (d, J ) 8 Hz, 1H).
This product was used in the next step without further purification.
-Amino-5-iodo-6-methylpyridine-N-oxide (26) Hydrochlo-
ride. The title compound was prepared from 25 following the same
procedure used for 18 to yield 26, as a copper-colored solid. H
NMR (CD OH) δ: 2.54 (s, 3H), 4.95 (bs, 3H), 6.22 (d, J ) 7.7
Hz, 1H), 7.68 (d, J ) 7.8 Hz, 1H).
-Acetamido-6-chloromethyl-5-iodopyridine (27). Using a
H16Cl
2
N
2
2
tert-Butyl 2-(6-Amino-2-methylpyridin-3-yl)-7-azabicyclo-
2.2.1]heptane-7-carboxylate (33). 2-Amino-5-iodo-6-methylpy-
2
[
1
ridine (36b, 4.79 g, 0.021 mol), HCO K (1.72 g, 0.021 mol), and
2
+ -
Bu
added to a reaction tube containing 20b (2.00 g, 10.2 mmol) in
DMF (10 mL). Pd(OAc) (114 mg, 0.51 mmol) was added to the
reaction mixture. The mixture was placed under a N atmosphere,
4
N Cl (709 mg, 2.55 mmol), fol1owed by DMF (10 mL), was
3
2
2
2
procedure analogous to that described for 19c, an overall 82% yield
1
sealed, and heated at 100 °C in an oil bath for 24 h. The reaction
mixture was cooled to room temperature and diluted with EtOAc
of 27 from 26 was obtained as a tan solid. mp 146–149 °C. H
NMR (CDCl
3
) δ: 2.21 (s, 3H), 4.71 (s, 2H), 7.91 (br s, H), 7.94 (s,
(
4
100 mL). NH OH (15%, 100 mL) was added to the reaction
1
H), 8.04 (d, J ) 8 Hz, 1H).
mixture, and the organic layer was separated. The aqueous layer
N-[6-(7-Azabicyclo[2.2.1]hept-2-en-7-yl)methyl-5-iodopyridin-
-yl] Acetamide (28). Using a procedure analogous to that
was extracted with EtOAc (3 × 50 mL). The organic layer was
2
2 4
collected and dried (Na SO ), and the solvent was removed under
described for 21 gave an 81% yield of 28 as a beige solid. mp
reduced pressure to give a solid that was purified by column
chromatography using CMA80-EtOAc-hexanes (2:1:1) as the
eluent to afford 1.48 g (47%) of 33 as a yellow oil.
1
1
28–130 °C. H NMR (CDCl
J ) 8 Hz, 2H), 2.10 (s, 3H), 3.55 (s, 2H), 3.91 (s, 2H), 6.04 (s,
H), 7.82 (d, J ) 8.4 Hz, 1H), 7.98 (d, J ) 8.6 Hz, 1H), 8.84 (br
s, 1H).
N-(5,5a,6,7,8,10-hexahydro-5,8-methanopyrrolo[2,1-
3
) δ: 0.96 (d, J ) 7 Hz, 2H), 1.82 (d,
2
6′-Methylepibatidine (34) Hydrochloride. Concentrated HCl (20
mL, 37%), cooled to 0 °C, was added to 33 (900 mg, 2.97 mmol) at
0 °C and stirred for 45 min. At 0 °C, NaNO (4.10 mg, 5.94 mmol)
2
g][1,7]naphthyridin-2-yl)acetamine (29). Using a procedure analo-
was added in small portions and the reaction mixture was stirred at 0
°C for an additional 30 min. The reaction mixture was warmed to
room temperature and stirred for 1 h. The mixture was poured into
4 3
ice (75 g) containing NH OH (30%, 75 mL) and extracted with CHCl
gous to that described for 22 gave a 43% yield of 29 as a tan solid.
1
mp 129–132 °C. H NMR (CDCl
1
3
) δ: 1.33 (m, 1H), 1.51 (m, 2H),
.88 (m, 3H), 2.16 (s, 3H), 2.86 (d, J ) 6.5 Hz, 1H), 3.18 (d, 1H),

6
390 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Carroll et al.
(
8 × 50 mL). The organic layer was collected and dried (Na
2
SO
4
),
amine was dissolved in 3 mL of ether at 0 °C. Hydrochloric acid
in ether (0.13 mL, 0.136 mmol, 1 M) was added. The solution was
stirred for 1 h, and the ether was evaporated to yield 45 mg (100%)
and the solvent was removed under reduced pressure. The resulting
solidwaspurifiedbycolumnchromatographyusingCMA80-EtOAc-hexanes
(
2:1:1) as the solvent mixture to afford 0.207 g (31%) of 34 as a
of a white solid (hydrochloride salt). mp 186 °C (decomp). Anal.
1
2
clear, colorless oil. H NMR (CDCl
3
) δ: 7.78 (d, J ) 8.2 Hz, 1H),
.09 (d, J ) 8.3 Hz, 1H), 3.78 (t, J ) 4.0 Hz, 1H), 3.62 (m, 1H),
.86 (dd, J ) 5.1, 8.9 Hz, 1H), 2.49 (s, 3H), 1.92 (dd, J ) 12.0,
Calcd (C15
H14Cl
2
N
2
· /
3
H
2
O): C, H, N.
7
2
9
1
tert-Butyl 2-(6-Amino-5-bromopyridin-3-yl)-1,2,3,4-tetrahy-
dro-1,4-epiminonaphthalene-9-carboxylate (40). Bromine (0.24
mL, 4.67 mmol) and triethylamine (0.24 mL) were added, under
nitrogen, dropwise to a stirred, 0 °C solution of 39 (1.05 g, 0.003
mol) in 7.0 mL of acetic acid and 7.8 mL of methylene chloride.
After stirring at 0 °C for 4 h, the solution was neutralized with
1
3
.0 Hz, 1H), 1.62 (m, 6H). C NMR (CDCl
39.1, 136.7, 121.8, 61.7, 56.9, 42.9, 39.6, 31.7, 30.7, 22.7. LRMS
ES) m/z: 223.2 (M + H) . A sample was converted to the
3
) δ: 157.2, 147.4,
+
(
hydrochloride salt. Anal. Calcd (C12 O): C, H, N.
H16Cl
2
N
2
·0.75H
2
N-Methylepibatidine (35) Hydrochloride. Epibatidine (0.70 g,
5
0% ammonium hydroxide in water and extracted with chloroform.
0
.00335 mol), paraformaldehyde (3.5 g, 0.167 mol), and formic
The combined chloroform extracts were dried with magnesium
sulfate, filtered, and evaporated. Flash chromatography of the
acid (20 mL) were placed in a sealed vessel and stirred at 110 °C
for 5 h. The flask was cooled, diluted with water (200 mL), basified
with 50% NaOH, and extracted with CH
layer was separated, dried (Na SO ), and concentrated in vacuo to
afford 0.30 g of a beige solid. The base was dissolved in ether (75
mL), filtered, and acidified with ethereal HCl. The mixture was
concentrated by a stream of nitrogen gas and then dried in a vacuum
oven to afford 0.23 g (24%) of 35 as a white solid. mp 180–184
°
residue over silica gel with 20% ethyl acetate in hexane afforded
Cl
2 2
(200 mL). The organic
1
8
1
5
10 mg (62%) of 40 as a white solid. H NMR (CDCl
3
) δ: 7.94 (s,
2
4
H), 7.78 (s, 1H), 7.30 (m, 2H), 7.15 (m, 2H), 5.24 (br s, 1H),
.00 (br s, 2H), 4.95 (s, 1H), 2.72 (dd, J ) 4.5, 8.7, 1H), 2.07 (dt,
J ) 4.5, 11.7, 1H), 1.90 (dd, J ) 8.7, 12 Hz, 1H), 1.34 (s, 9H).
13
3
C NMR (CDCl ) δ: 155.8, 154.7, 146.4, 146.1, 139.5, 131.8,
1
27.1, 126.9, 120.4, 120.1, 105.1, 80.8, 67.8, 61.6, 42.9, 38.0, 28.6.
This product was used in the next step without further purification.
tert-Butyl 2-(6-Amino-5-phenylpyridin-3-yl)-1,2,3,4-tetrahy-
1
C. H NMR (CDCl
3
) δ: 1.68–1.95 (m, 6H), 2.26 (s, 3H), 2.57–2.62
(
1
dd, J ) 5, 9 Hz, 1H), 3.17 (br s, 1H), 3.34 (br s, 1H), 8.22 (s,
H), 8.48 (s, 1H), 8.65 (s, 1H). Anal. Calcd (C12
2
H16Cl N
2 2
3 2
·1 / H O):
dro-1,4-epiminonaphthalene-9-carboxylate (41). A solution of 40
500 mg, 0.0012 mol), sodium carbonate (255 mg, 2.40 mmol),
C, H, N.
(
tert-Butyl 1,4-Dihydro-1,4-epiminonaphthalene-9-carboxylate
38). 2-Trimethylsilylphenyl trifluoromethanesulfonate (37, 2.98 g,
phenylboronic acid (234 mg, 1.92 mmol), tri(o-tolyl)phosphine (7.3
mg, 0.024 mmol), palladium (II) acetate (2.7 mg, 0.012 mmol),
and 0.9 mL degassed water in 4.8 mL of dimethyl ethylene glycol
was placed in a sealed tube, stirred, and heated at 90 °C for 22 h.
Saturated sodium bicarbonate solution was added, and the solution
was extracted with ethyl acetate. The combined ethyl acetate extracts
were washed with brine, dried with magnesium sulfate, filtered,
and evaporated. Flash chromatography over silica gel with 50%
(
0
.010 mol) was stirred overnight at room temperature with t-butyl
-pyrrolecarboxylate (10, 1.67 g, 0.010 mol) and anhydrous cesium
1
fluoride (1.67 g, 0.011 mol) in 10 mL of anhydrous acetonitrile.
The solid was filtered, and the solvent was evaporated. Ether was
added, and a solid formed that was separated. The ether was
evaporated to yield a yellow oil. Flash chromatography over silica
gel with 20% ethyl acetate in hexane afforded 1.21 g (50%) of 38
as a white solid. H NMR (CDCl
5
1
1
ethyl acetate in hexane afforded 468 mg (94%) of 41 as a white
3
) δ: 7.25 (s, 2H), 6.96 (m, 4H),
1
13
solid. H NMR (CDCl ) δ: 8.00 (d, J ) 2.4 Hz, 1H), 7.49 (d, J )
.48 (s, 2H), 1.37 (s, 9H). C NMR (CDCl
42.8, 125.3, 121.4, 121.1, 80.9, 67.2, 66.6, 28.5.
3
) δ: 155.5, 148.7, 143.9,
3
2
.4 Hz, 1H), 7.38 (m, 7H), 7.16 (dd, J ) 3, 5.4 Hz, 2H), 5.24 (br
s, 1H), 5.01 (s, 1H), 4.59 (br s, 2H), 2.78 (dd, J ) 4.5, 8.7, 1H),
This product was used in the next step without further purification.
tert-Butyl 2-(6-Aminopyridin-3-yl)-1,2,3,4-tetrahydro-1,4-epi-
2
9
1
6
.15 (dt, J ) 4.5, 11.7, 1H), 1.91 (dd, J ) 8.7, 12 Hz, 1H), 1.29 (s,
13
3
H). C NMR (CDCl ) δ: 155.6, 155.1, 146.5, 146.3, 138.6, 137.3,
minonaphthalene-9-carboxylate (39). A solution of 38 (1.00 g,
.004 mol), 2-amino-5-iodopyridlne (1.08 g, 0.005 mol), potassium
30.7, 129.4, 129.1, 128.2, 127.0, 126.9, 122.3, 120.4, 120.1, 80.6,
7.9, 61.5, 43.3, 37.9, 28.6.
0
formate (691 mg, 8.22 mmol), tetrabutyl ammonium chloride (286
mg, 1.03 mmol), and palladium (II) chloride (152 mg) in 8.2 mL
of DMF was stirred for 18 h at 60 °C under nitrogen. Water was
added, and the mixture was extracted with ethyl acetate. The
combined ethyl acetate extracts were washed with brine, dried with
magnesium sulfate, filtered, and evaporated. Flash chromatography
This product was used in the next step without further purification.
2-(6-Fluoro-5-phenylpyridin-3-yl)-1,2,3,4-tetrahydro-1,4-epi-
minonaphthalene (8b). To a stirred, –9 °C solution of 41 (232
mg, 0.561 mmol) in 1.0 mL of anhydrous pyridine was added
dropwise 2.0 mL of hydrofluoric acid in pyridine (7:3). Sodium
nitrite (387 mg, 5.61 mmol) was added slowly to the solution. The
solution was stirred for 2 h while warming from 7 °C to room
temperature. The solution was neutralized with 50% ammonium
hydroxide in water and extracted with chloroform. The combined
chloroform extracts were washed with brine, dried with sodium
sulfate, filtered, and evaporated. Flash chromatography over silica
gel with 50% hexane in ethyl acetate afforded 43.8 mg (25%) of
over silica gel with 5% methanol in ethyl acetate afforded 500 mg
1
(
36%) of 39 as a white solid. H NMR (CDCl
3
) δ: 7.98 (s, 1H),
7
.55 (d, J ) 8.1 Hz, 1H), 7.29 (s, 2H), 7.16 (m, 2H), 6.50 (d, J )
8
.4 Hz, 1H), 5.23 (s, 1H), 4.95 (s, 1H), 4.42 (br s, 2H), 2.73 (dd,
J ) 4.2,8.4, 1H), 2.10 (dt, J ) 4.5, 11.7 Hz, 1H), 1.89 (d, J ) 9,
1
3
1
1
3
3
1.7, 1H) 1.32 (s, 9H). C NMR (CDCl ) δ: 157.5, 147.3, 146.0,
37.0, 130.0, 126.8; 126.7, 120.2, 109.0, 80.5, 67.8, 61.5, 43.2,
7.7, 28.4.
1
8b. H NMR (CDCl ) δ: 8.19 (m, 2H), 7.60 (m, 2H), 7.44 (m,
3
This product was used in the next step without further purification.
3H), 7.26 (m, 2H), 7.13 (m, 2H), 4.65 (d, J ) 6 Hz, 1H), 4.42 (s,
2-(6-Chloropyridin-3-yl)-1,2,3,4-tetrahydro-1,4-epiminonaph-
1H), 2.82 (dd, J ) 4.5, 8.7, 1H), 2.40 (br s, 1H), 2.04 (dt, J ) 4.5,
1
3
thalene (8a). To a stirred, 0 °C solution of 39 (200 mg, 0.593 mmol)
in 2.0 mL of concentrated hydrochloric acid was slowly added
sodium nitrite (736 mg, 10.7 mmol). The reaction mixture was
stirred for 1 h at 0 °C. A solution of 50% ammonium hydroxide in
water was added dropwise to the solution, and the solution was
extracted with chloroform. The combined chloroform extracts were
washed with brine, dried with magnesium sulfate, filtered, and
evaporated. Flash chromatography over silica gel with 50%
11.7, 1H), 1.94 (dd, J ) 8.7, 12 Hz, 1H). C NMR (CDCl ) δ:
3
159.4 (d, J ) 237 Hz), 149.3 (d, J ) 46.9 Hz), 145.3 (d, J ) 14.3
Hz), 140.3, 140.2, 139.7, 139.6, 134.4, 134.3′, 128.9, 128.8, 128.6,
128.5, 128.3, 126.4, 123.2 (d, J ) 28.3 Hz), 119.5 (d, J ) 27.0
Hz), 67.6, 61.3, 41.9, 37.7. To a stirred, –10 °C solution of the
free amine in 2 mL of methylene chloride was added 1 mL of
hydrochloric acid in ether (1 M). The solution was stirred for 3 h
while warming to 10 °C. The solution was evaporated and dried
on the vacuum pump overnight. Recrystallization from chlo-
roform-ether provided 45.2 mg (89.5%) of a white solid. Anal.
methanol in ethyl acetate afforded 40.0 mg (26%) of 8a as a light
yellow oil. H NMR (CDCl
1
3
) δ: 8.37 (d, J ) 2.4 Hz, 1H), 7.98
2
(
4
dd, J ) 2.4, 8.4 Hz, 1H), 7.20 (m, 4H), 4.66 (d, J ) 3.9 Hz, 1H),
Calcd (C H ClFN · / H O): C, H, N.
2
1
18
2
3
2
.37 (s, 1H), 2.76 (dd, J ) 4.5, 8.4 Hz, 1H), 2.35 (br s, 1H), 1.99
13
(
m, 2H). C NMR (CDCl
3
) δ: 149.8, 149.6, 149.1, 140.5, 138.4,
Acknowledgment. This research was supported by the
National Institute on Drug Abuse, Grant DA12002.
1
26.6, 126.4, 124.2, 119.9, 119.6, 67.7, 61.5, 42.2, 37.9. The free

Bridged and Fused Ring Analogues of Epibatidine
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6391
1
1
Supporting Information Available: Results from elemental
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
R. F. Synthesis and evaluation of N-[ C]methylated analogues of
epibatidine as tracers for positron emission tomographic studies of
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nient synthesis of (()-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-
hepten-5,10-imine (MK801). J. Chem. Soc., Chem. Commun. 1996,
(
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