Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2′-substituted 5′-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine analogues

Article abstract of DOI:10.1021/jm0100178

A convenient, high-yield synthesis of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (5), which involved the addition of tributyltin hydride to 7-tert-butoxycarbonyl-2-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-ene (4) followed by elimination of the tributyltin and p-tolylsulfonyl groups using tetrabutylammonium fluoride was developed. The addition of 2-amino-5-iodopyridine to 5 under reductive Heck conditions provided 7-tert-butoxycarbonyl-2-exo-(2′-amino-5′-pyridinyl)-7-azabicyclo [2.2.1]heptane (6). Compound 6 was the key intermediate used to prepare epibatidine analogues where the 2′-chloro group on the pyridine ring was replaced with a fluorine (1b), bromine (1c), iodine (1d), hydroxy (1e), amino (1f), dimethylamino (1g), trifluoromethanesulfonate (1h), and hydrogen (1i) group. (+)- and (-)-Epibatidine and compounds 1b-d and 1i all possess similar binding affinities at the (α₄β₂ nAChR receptors labeled by [³H]epibatidine. Compound 1f has affinity similar to nicotine, whereas compounds 1e, 1g, and 1h have much lower affinity. The binding affinity appears to be dependent upon the electronic nature of the substituent. However, other factors are also involved. None of the compounds possesses appreciable affinity for the α₇ nAChR labeled by [¹²⁵I] iodo-MLA. With the exception of 1f and 1g, all the epibatidine analogues are full agonists (tail flick test) in producing antinociception after intrathecal injection in mice.

Full text of DOI:10.1021/jm0100178

J . Med. Chem. 2001, 44, 2229-2237
2229
Syn th esis, Nicotin ic Acetylch olin e Recep tor Bin d in g, a n d An tin ocicep tive
P r op er ties of 2-exo-2-(2′-Su bstitu ted 5′-p yr id in yl)-7-a za bicyclo[2.2.1]h ep ta n es.
Ep iba tid in e An a logu es
F. Ivy Carroll,*,† Feng Liang,† Herna´n A. Navarro,† Lawrence E. Brieaddy,† Philip Abraham,† M. I. Damaj,‡ and
Billy R. Martin‡
Chemistry and Life Sciences, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, and
Department of Pharmacology and Toxicology, Medical College of Virginia Commonwealth University,
Richmond, Virginia 23298
Received J anuary 11, 2001
A convenient, high-yield synthesis of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (5),
which involved the addition of tributyltin hydride to 7-tert-butoxycarbonyl-2-p-toluenesulfonyl-
7-azabicyclo[2.2.1]hept-2-ene (4) followed by elimination of the tributyltin and p-tolylsulfonyl
groups using tetrabutylammonium fluoride was developed. The addition of 2-amino-5-
iodopyridine to 5 under reductive Heck conditions provided 7-tert-butoxycarbonyl-2-exo-(2′-
amino-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane (6). Compound 6 was the key intermediate used
to prepare epibatidine analogues where the 2′-chloro group on the pyridine ring was replaced
with a fluorine (1b), bromine (1c), iodine (1d ), hydroxy (1e), amino (1f), dimethylamino (1g),
trifluoromethanesulfonate (1h ), and hydrogen (1i) group. (+)- and (-)-Epibatidine and
compounds 1b-d and 1i all possess similar binding affinities at the R4â2 nAChR receptors
labeled by [3H]epibatidine. Compound 1f has affinity similar to nicotine, whereas compounds
1e, 1g, and 1h have much lower affinity. The binding affinity appears to be dependent upon
the electronic nature of the substituent. However, other factors are also involved. None of the
compounds possesses appreciable affinity for the R7 nAChR labeled by [125I]iodo-MLA. With
the exception of 1f and 1g, all the epibatidine analogues are full agonists (tail flick test) in
producing antinociception after intrathecal injection in mice.
In tr od u ction
been published.2 In addition, we have reported the
synthesis of [18F]-1b and described its mapping of the
nAChRs in baboons7-9 using positron emission tomog-
raphy (PET) and in rodent and human brain using in
vitro and ex vivo autoradiographic studies.10 We have
also reported the synthesis and in vivo binding proper-
ties of [3H]-2-exo-(3′-pyridinyl)-7-azabicyclo[2.2.1]heptane
([3H]-1i).11 Davila-Garcia and co-workers have reported
the synthesis and pharmacological characterization of
It is now well recognized that the natural alkaloid
epibatidine (1a, exo-2-(2′-chloro-5′-pyridinyl)-7-azabicyclo-
[2.2.1]heptane) binds to the R4â2 nicotinic acetylcholine
receptor (nAChR) with much greater affinity than
nicotine.1,2 Since the nAChRs have been targeted for the
development of drugs for Alzheimer’s disease, anxiety,
attention deficit hyperactivity disorder (ADHD), Par-
kinson’s disease, analgesia, inflammatory bowel disor-
der, schizophrenia, anxiety, depression, Tourette’s syn-
drome, and smoking cessation, there is current interest
in characterizing the pharmacophore for the R4â2
nAChR.1,3-6 In this study we report the synthesis,
nAChR binding properties, and antinociceptive effects
of the exo-2-(2′-substituted-5′-pyridinyl)-7-azabicyclo-
[2.2.1]heptanes (1a -i). A preliminary account on the
[
125I]-exo-2-(2-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-
heptane ([125I]-1d ).12
Ch em istr y
The routes used to synthesize epibatidine analogues
1a -i are outlined in Scheme 1. Heating a solution of
N-(tert-butoxycarbonyl)pyrrole13 and p-tolylsulfonylacet-
ylene14 at 80 °C yielded 65% of the diene 3. Selective
reduction of the 5,6-double bond using nickel boride15
in ethanol gave 86% of the monoolefin 4. Originally the
desulfonation of 4 to give 5 was carried out in 55% yield
using 2.5% sodium amalgam in a 1:1 mixture of ethyl
acetate and tert-butyl alcohol containing disodium hy-
drogen phosphate.2 Later we discovered that 4 could be
converted to 5 in higher yield and on larger scale by
adding tributyltin hydride to 4 in benzene containing
2,2′-azabisisobutyronitrile (AIBN) followed by treatment
of the resulting addition product with tetrabutylammo-
nium fluoride in tetrahydrofuran. A preliminary account
of this new synthesis of 5 has been reported.16 Coupling
of 5 with 2-amino-5-iodopyridine using palladium ac-
etate as catalyst in dimethylformamide containing
tetrabutylammonium chloride and potassium formate
at 100 °C for 12 h provided 68% of 7-tert-butoxycarbonyl-
synthesis and nAChR binding properties of exo-2-(2′-
fluoro-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane (1b) has
* Corresponding author. Tel: 919-541-6679. Fax: 919-541-8868.
E-mail: fic@rti.org.
† Research Triangle University.
‡ Medical College of Virginia Commonwealth University.
10.1021/jm0100178 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/23/2001

2230 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13
Carroll et al.
Sch em e 1a
a
Reagents: (a) HCtCSO2C6H5CH3, 80 °C; (b) Ni2B, EtOH; (c) NaHg (2.5%), Na2HPO4,EtOAc:t-BuOH (1:1); (d) (i) (C4H9)3SnH, AlBN,
benzene, (ii) (C4H9)4NF, THF; (e) 2-amino-5-iodopyridine, Pd(OAc)2, n-Bu4N+Cl-, KO2CH, DMF, 100 °C, 12 h; (f) NaNO2, HCl, CuCl; (g)
NaNO2, pyridine‚HF; (h) NaNO2, Br2, HBr; (i) 2-fluoro-5-iodopyride, Pd(OAc)2, n-Bu4N+Cl-, KO2CH, DMF, 100 °C, 4 days; (j) CF3CO2H;
(k) NaNO2, HOAc, K2CO3; (l) (CF3SO2)2O, pyridine; (m) isoamyl nitrite, CH2I2, HI; (n) 3-iodopyridine, Pd(OAc)2, n-Bu4N+Cl-, KO2CH,
DMF, 80 °C, 24 h; (o) NaBH3CN, H2CO, CH3OH; (p) resolution using p-toluoyl tartaric acid; (q) HCl, CH3OH.
exo-2-(2′-a m in o-5′-pyr idin yl)-7-a za bicyclo[2.2.1]-
heptane (6). The 2-exo stereochemistry assigned to 6 was
based on an analysis of the H NMR (CDCl3) spectrum.
sulfonic anhydride gave the 2′-triflate 8. Diazotization
of 6 with isoamyl nitrite in methylene iodide containing
hydrogen iodide afforded the N-tert-butoxycarbonyl 2′-
iodo compound 7c. Reduction Heck coupling of 5 with
3-iodopyridine yielded N-tert-butoxycarbonyl 2′-norchlo-
ro analogue 7d . Reductive methylation of 6 with form-
aldehyde using sodium cyanoborohydride yielded the
N-tert-butoxycarbonyl 2′-dimethylamino analogue 9.
Treatment of 7a -d , 8, and 9 with trifluoroacetic acid
yielded the 2′-substituted epibatidine analogues 1d -i.
We also attempted to synthesize the 2′-fluoro ana-
logue 1b by the route outlined in Scheme 2. Thus, the
additions of phenyltriflimide to a tetrahydrofuran solu-
tion of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-
one (10)18 provided the triflate 11. Reaction of 11 with
2-fluoro-5-pyridineboronic acid (17), prepared as shown
in Scheme 3, in refluxing dimethoxyethane using tet-
rakis(triphenylphosphine)palladium(O) yielded 7-tert-
butoxycarbonyl-2-(2′-fluoro-5′-pyridinyl)-7-azabicyclo-
[2.2.1]hept-2-ene (12). Since Fletcher et al.18 reported
that reduction of 7-tert-butoxycarbonyl-2-(2′-chloro-5-
pyridinyl)-7-azabicyclo[2.2.1]hept-2-ene (18) yielded a
1
The spectrum showed a doublet of doublets at 2.74 ppm
for the H-2 proton with J 2R,3â ) 5.0 Hz, J 2R,3R ) 8.8 Hz,
J 2R,1 ) 0 Hz, which is characteristic of the 2-exo
stereochemistry.15 Diazotization17 of 6 in pyridine con-
taining 70% hydrogen fluoride effected conversion of the
2-amino group to a fluoro group, and deprotection of the
N-Boc group to give 46% of 1b. Compound 1b could also
be obtained by direct reductive Heck coupling of 2-fluoro-
5-iodopyridine (obtained by diazotization of 2-amino-5-
iodopyridine14 in pyridine‚HF) with 5 to give interme-
diate 7a , which gave the desired 1b on removal of the
N-Boc-protecting group with trifluoroacetic acid. How-
ever, this route was less desirable since the overall yield
was 39% and the coupling of 2-fluoro-5-iodopyridine
with 5 took 4 days, whereas the coupling of 2-amino-5-
iodopyridine with 5 was complete in 12 h. We also found
that diazotization of 6 in hydrochloric acid in the
presence or absence of cuprous chloride gave a 76% yield
of epibatidine (1a ) which was identical to an authentic
sample.15 This provided additional support for the 2-exo
structural assignment of 6. Epibatidine (1a ) was re-
solved into (+)- and (-)-1a using di-p-toluyl-d-tartaric
acid.15 Diazotization of 6 using sodium nitrite in hydro-
bromic acid containing bromine or acetic acid containing
sodium carbonate gave the 2′-bromo analogues 1c and
the N-tert-butoxycarbonyl 2′-hydroxy compound 7b,
respectively. Treatment of 7b with trifluoromethane-
4:1 mixture of 2-endo- and 2-exo-7-tert-butoxycarbonyl-
2-(2′-chloro-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane (19),

Synthesis of Epibatidine Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13 2231
Sch em e 2a
Male ICR mice were tested for antinociception in the
tail-flick test after intrathecal (i.t.) injection, and the
results are listed in the table. Intrathecal injections
were performed free-hand between the L4 and L6
lumbar space in unanesthetized male mice according
to the method of Hylden and Wilcox.21 Antinociception
was assessed by the tail-flick method of D’Amour and
Smith.22 A control response (2-4 s) was determined for
each mouse before treatment, and a test latency was
determined after drug administration. The mice were
tested 5 min after i.t. injections of nicotinic ligands for
the dose-response evaluation. ED50 values with 95%
CL for behavioral data were calculated by unweighted
least-squares linear regression as described by Tallarida
and Murray.23
a
Reagents: (a) NaN[Si(CH3)3]2, C6H5N(Tf)2, THF, -78 °C, 1 h,
5 °C, 5 days; (b) 2-fluoro-5-pyridineboronic acid (17),
then
Pd[P(C6H5)3]4, LiCl, Na2CO3, DME reflux 1 h; (c) H2, PtO2, EtOAc,
25 °C, 48 h.
Resu lts a n d Discu ssion
A number of 2′-substituted epibatidine analogues
have been prepared and their nAChR binding properties
determined using various radioligands.1 In this study
we determined the nAChR binding properties of a set
of 2′-substituted epibatidine analogues using [3H]epi-
batidine and [125I]iodo-MLA. When appropriate, the
data are compared to previously reported results. The
set of compounds from this study possess both electron-
withdrawing and electron-releasing substituents as well
as substituents having variation in size and lipophilic-
ity, thus, revealing new structure-activity relationships
(SAR) information about the epibatidine class of nAChR
ligands.
Sch em e 3a
a
Reagents: (a) I2, aq HOAc, H2SO4, H5IO6, 80 °C, 4 h; (b)
In agreement with published results, both (+)-natural
and (-)-epibatidine (1a ) possess high affinity for the
R4â2 nAChR.1,24,25 In addition, we found that unnatural
(-)-1a with a Ki value of 18 pM is slightly more potent
than the natural isomer (+)-1a , which has a Ki value of
26 pM. This is in agreement with the reported 45 and
58 pM Ki values for (-)- and (+)-1a using [3H]nico-
tine.1,24 Houghtling has reported almost identical Ki
values of 61 and 62 pM for (+)- and (-)-1a .24,25 More
recently, Gna¨disch et al. reported Ki values of 7.2 and
7.5 pM for natural epibatidine using [3H]epibatidine and
(-)-[3H]cytisine, respectively.26 In our preliminary com-
munication,2 we reported a Kapp of 20 pM for the
2′-fluoro analogue 1b, which compares favorably with
the Ki value of 27 pM found in this study using [3H]-
epibatidine as well as a recently reported value by Horti
et al. of 37 pM.27 Ki values of 31 pM using [3H]nicotine19
and 45 pM using [3H]-1a have been reported for the
norchloroepibatidine analogue 1i and the 2′-bromo
analogue 1c, respectively. We find Ki values 20, 23, and
70 pM for 1i, 1c, and ld , respectively.
From an SAR point of view, it is interesting to note
that epibatidine (1a ), the 2′-fluoro, 2′-bromo, 2′-iodo, and
2′-norchloro analogues 1b, 1c, 1d , and 1i, respectively,
all possess essentially the same Ki values. These results
show that replacing the 2′-chloro group with a relatively
large iodo group or small hydrogen had no effect on
binding affinity. Compounds 1a -c, which have electron-
withdrawing halogen groups, all possess much higher
affinity than the compounds 1e-g containing the
electron-donating 2′-hydroxy, 2′-amino, and 2′-dimethy-
lamino groups, respectively. However, other factors
must be involved since compound 1h , which has a
strongly electron-withdrawing 2′-trifluoromethanesulfo-
pyridine-HF, NaNO2, 0 °C, 15 min, then 90 °C, 2 h; (c) nC4H9Li,
[(CH3)2CHO]3B, THF, -78 °C; (d) 3 N NaOH.
we expected that a similar reduction of 12 would lead
to
a
2-endo- and 2-exo-2-(2′-fluoro-5′-pyridinyl)-7-
azabicyclo[2.2.1]heptane. However, we found that a
similar reduction of 12 gave only the 2-endo-isomer 13.
Moreover, since reports from both our laboratory15 and
Merck Sharp and Dohme Research Laboratories18 showed
that 2-endo-19 could be isomerized to 2-exo-19, we
expected that 13 could be isomerized to the 2-exo isomer.
However, we were unable to successfully convert 13 to
the 2-exo-isomer. Any conditions strong enough to affect
isomerization resulted in decomposition. Apparently, the
2′-fluoro compound 13 is much more sensitive to alka-
line reagents than compound 19.
Biology
The Ki values for the inhibition of [3H]epibatidine
([3H]1a ) binding at the R4â2 nAChR in male rat cerebral
cortex for nicotine, (-)- and (+)-epibatidine [(-)- and
(+)-1a , respectively], and the 2-substituted epibatidine
analogues 1b-i are listed in Table 1. The cerebral cortex
homogenates were incubated with 0.5 nM [3H]epibati-
dine and 10-12 different concentrations of the test
compound. Nonspecific binding was determined in the
presence of 300 µM nicotine. The IC50 values were
determined from at least three independent experi-
ments, and the Ki values were calculated using the
Cheng-Prusoff equation.19 The compounds were also
evaluated once at 50 nM for inhibition of [125I]iodo-MLA
binding at the R7 nAChR using conditions previously
reported.20

2232 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13
Carroll et al.
Ta ble 1. Radioligand Binding Data and Antinociceptive Potencies of 2-Exo-(2′-Substituted 5′-pyridinyl)-7-azabicyclo[2.2.1]heptanes
d
R4â2
ED50
nmol/mouse
( CL
[3H]epibatidineb
(Ki, nM)
[3H]nicotinec
(Ki, nM)
compda
X
Hill slope
nicotine
(+)-1a e
(-)-1a
1b
1c
1d
1e
1f
1g
1h
1.50 ( 0.30
0.026 ( 0.002
0.018 ( 0.001
0.027 ( 0.001
0.023 ( 0.001
0.070 ( 0.004f
107 ( 0.5
0.90 ( 0.4
0.98 ( 0.05
1.02 ( 0.07
0.90 ( 0.02
0.90 ( 0.03
1.01
0.045
0.058
74 (37-137)
0.5 (0.11-5)
0.6 (0.49-0.82)
0.31 (0.26-0.98)
0.33 (0.29-0.37)
NTg
52.4 (30-87)
27% @ 112
10% @ 32.5
Cl
Cl
F
Br
I
OH
NH2
(CH3)2N
CF3SO3
H
0.48
1.0 ( 0.05
1.0 ( 0.01
1.0 ( 0.01
1.1 ( 0.02
0.80 ( 0.02
1.3 ( 0.1
26.4 ( 1.4
8.5 ( 0.2
19.2 (4.5-77)
0.2 (0.15-0.23)
1i
0.020 ( 0.001
0.031
a
b
d
All compounds were assayed as their hydrochloride salts. Kd ) 20 pM. c Taken from ref 22. Tail-flick test. e Compound (+)-1a is
natural epibatidine hydrochloride. It has an [R]2D5 value of +42.6 (0.31, CH3OH). Its enantiomer (-)-1b hydrochloride has an [R] value
25
D
of -42.9 (0.29, CH3OH). Kapp determined using [3H]norchloroepitadine (ref 2). Not tested.
f
g
site.20 The 2′-fluoro analogue 1b which showed only 20%
inhibition was the most potent analogue. Thus, none of
the compounds showed appreciable affinity for the R7
nAChR.
Ta ble 2. Radioligand Binding Data for the Nicotine
Analoguesa
Nicotine and epibatidines in vivo results in the tail-
flick test are similar to those previously reported. Most
compounds tested, except for 1f and 1g, are agonists in
producing antinociception after intrathecal injection in
mice. Furthermore, a good correlation (a coefficient of
0.96) exists between the Ki (nM) binding affinity values
to brain [3H]epibatidine sites and the ED50 (nmol/mouse)
values for antinociceptive potency for the 2-substituted
epibatidine analogues if 1e (which is 10 000 less potent
than epibatidine) was excluded. If 1e was included in
the correlation, a 0.75 coefficient was obtained. The
weak antinociceptive activity of compound 1f is unex-
pected, since its binding affinity was equal to that of
nicotine.
compd
X
(Ki, nM)
20a
20b
20c
20d
20e
20f
-H
-Br
-Cl
-F
-NH2
-OH
1.26
0.45
0.63
1.03
81.0
1072
a
Data taken from ref 28.
nyl group, has lower affinity than the 2′-halogenated
analogues and, as mentioned above, the norchloro
analogue 1i, which possesses an electronic neutral
hydrogen substituent, has an affinity almost identical
to that of epibatidine. Interestingly, the 2-amino ana-
logue 1f with a Ki value of 1.3 nM is considerably more
potent than the 2-hydroxy analogue 1e, which has a Ki
value of 107 nM. Changing the 2-amino compound to
the N,N-dimethyl analogue 1g also results in loss of
affinity.
Exp er im en ta l Section
7-ter t-Bu toxyca r bon yl-2-p-tolylsu lfon yl-7-a za bicyclo-
[2.2.1]h ep ta -2,5-d ien e (3). A stirred solution of 11.7 g (0.065
mol) of p-tolylsulfonylacetylene in 19.5 g (0.116 mol) of N-tert-
butoxycarbonylpyrrole (2) was heated to 80 °C under N2. After
6 days, the excess N-tert-butoxycarbonylpyrrole was distilled
from the resulting tarry reaction mixture under high vacuum
at 85 °C. The residue was recrystallized from an ethyl ether
and petroleum ether mixture. The mother liquor was concen-
trated under reduced pressure and filtered through a two-inch
pad of silica gel, eluting with 5% chloroform in 25% ethyl
acetate and hexane to give a total of 14.1 g (65%) of 3: 1H
NMR (CDCl3) δ 1.27 (br s, 9H), 2.45 (s, 3H), 5.18 (br s, 1H),
5.39 (br s, 1H), 6.88 (m, 2H), 7.34 (d, J ) 8.2, 2H), 7.58 (s,
1H), 7.76 (d, J ) 8.3, 2H). Anal. (C18H21NO4S) C, H, N, S.
7-ter t-Bu toxyca r bon yl-2-(p-tolylsu lfon yl)-7-a za bicyclo-
[2.2.1]h ep ta -2-en e (4). To a solution of 0.64 g (0.0025 mol) of
nickel tetraacetate in 2.5 mL of ethanol under N2 at 25 °C
was added dropwise 0.097 g (0.0025 mol) of sodium borohy-
dride in 2.5 mL of ethanol at room temperature. After 10 min,
0.174 g (0.0005 mol) of the cycloadduct 7 in 2.5 mL of THF
was added to the resulting black slurry followed by dropwise
addition of 0.42 mL (5 mmol) of concentrated hydrochloric acid.
After 1 h or until judged complete as evidenced by TLC
analysis [bright fluorescent spot above starting material (3:1
hexane/ethyl acetate)], the reaction mixture was filtered
through Celite, the slurry was washed with 10 mL of ethylene
chloride, and the filtrate was rendered basic (pH 8-9) using
In a previous study, the inhibition of [3H] nicotine
binding for several 6-substituted nicotine analogues was
studied.28 QSAR studies suggested that the affinities
were related to the lipophibicity of the 6-position sub-
stitutent and was further influenced by the size of the
substituents. The structure and Ki values of the nicotine
analogues which have 6-substituents identical to the
2-substituent epibatidine analogues in this study are
listed in Table 2. A correlation of 0.99 was found
between the binding affinity of 20a -f and the similarly
substituted epibatidine analogues 1a -f and 1e. This
provides additional evidence that 6-substituted nicotine
analogues and 2′-substituent epibatidine analogues are
binding to the nAChR in a similar fashion.
Since R7 nAChR receptors are thought to be involved
in learning, memory, and neuroprotection,1 the com-
pounds 1a -i were assayed at 50 nM concentration for
inhibition of [125I]iodo-MLA binding to determine if any
of the compounds possessed appreciable affinity at this

Synthesis of Epibatidine Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13 2233
saturated sodium bicarbonate solution. The organic layer was
dried (Na2SO4), filtered, and concentrated under vacuum to
give 0.28 g of crude product which was extracted in ether and
concentrated to obtain 0.15 g (86%) of 4 as a yellowish white
solid: 1H NMR (CDCl3) δ 1.21 (br s, 9H), 1.27-1.47 (m, 2H),
2.01 (m, 2H), 2.45 (s, 3H), 4.76 (m, 1H), 4.83 (br s, 1H), 7.06
J ) 8.5, 1H), 7.42 (d, J ) 8.5, 1H), 7.90 (s, 1H); 13C NMR
(CDCl3) δ (ppm) 28.31, 28.31, 29.52, 40.15, 44.62, 55.91, 62.29,
79.53, 108.68; 136.51, 146.50, 156.97; IR (neat, NaCl) υ 3485,
3000, 1686, 1618, 1499, 1409, 1384, 1360, 1151, 1094 cm-1
Anal. (C16H23N3O2) C, H, N.
.
2-exo-(2′-F lu o r o -5′-p y r id in y l)-7-a za b ic y c lo [2.2.1]-
h ep ta n e (1b) Hyd r och lor id e fr om 6. To 17 mg (0.058 mmol)
of 6 at room temperature under nitrogen in a plastic vessel
was added 0.02 mL (0.7 mmol, 70% HF in pyridine) of HF-Py
with stirring. After 1 h, a solution of 26 mg of NaNO2 (0.38
mmol) in 0.2 mL of H2O was added, followed by warming to
80 °C for 2 h. The reaction mixture was slowly poured into 25
mL of a 50% aqueous NH4OH solution. The water phase was
saturated with NaCl and extracted with three 25 mL portions
of Et2O. The combined organic phase was dried (MgSO4),
filtered, and concentrated under reduced pressure to give 5.6
mg of a brown oil. This material was purified by column
chromatography (silica gel), eluting with 30% Et3N in Et2O to
give 4.5 mg (46%) of 2-exo-(2′-fluoro-5′-pyridinyl)-7-azabicyclo-
[2.2.1]heptane (1b) as a colorless oil: 1H NMR (CDCl3) δ (ppm)
1.55-1.65 (m, 5H), 1.90 (dd, J ) 8.9, 12.2, 1H), 2.78 (dd, J )
5.0, 9.0, 1H), 3.55 (m, 1H), 3.78 (m, 1H), 6.83 (dd, J ) 3.0, 8.5,
(d, J ) 2.2 Hz, 1H), 7.35 (m, 2H), 7.81 (m, 2H). Anal. (C18H23
NO4S) C, H, N, S.
-
2-(p -Tolylsu lfon yl)-3-t r ib u t ylst a n n yl-7-(ter t-b u t oxy-
ca r bon yl)-7-a za bicyclo[2.2.1]h ep ta n e. To a stirred solution
of 4 (23.4 g, 0.067 mol) and AIBN (0.60 g, 0.0036 mol) in 250
mL of benzene was added tributyltin hydride (40.1 g, 0.138
mol) via a syringe. The reaction was refluxed for a period of 3
h and cooled to room temperature, and 70 g of silica gel was
added. The slurry was concentrated in vacuo to a paste and
chromatographed on silica gel using hexanes to remove the
excess tributyltin hydride (19.3 g). Using hexane/EtOAc (9:1)
mixtures as the eluent, 32.8 g of the addition product (78%)
was isolated as a thick, clear oil. Upon standing, the oil
solidified to waxy solid (mp 54-57 °C): 1H NMR (CDCl3) δ
(ppm) 0.79 (br s, 4H), 0.85-0.94 (t, 6H), 1.25-1.90 (m, 18H),
1.41 (s, 9H), 2.44 (s, 3H), 2.57-2.63 (m, 1H), 3.67-3.70 (m,
1H), 4.20-4.26 (m, 2H), 7.33-7.36 (d, 2H), 7.71-7.75 (d, 2H).
Anal. (C30H51NO4SSn) C, H, N.
7-ter t-Bu toxycar bon yl-7-azabicyclo[2.2.1]h ept-2-en e (5)
(Meth od A). To a solution of the above intermediate (52.3 g,
0.0832 mol) in 480 mL of tetrahydrofuran was added 166 mL
(0.166 mol) of 1 M tetrabutylammonium fluoride in THF. The
reaction mixture was stirred at reflux for 17 h, then cooled to
room temperature, and concentrated in vacuo. The oily residue
was chromatographed on silica gel using hexane/EtOAc (9:1)
mixtures as the eluent to afford 15.6 g (98%) of 5 as a light
yellow oil: 1H NMR (CDCl3) δ (ppm) 1.08-1.11 (d, 2H), 1.41
(s, 9H), 1.82-1.87 (br d, 2H), 4.65 (br s, 2H), 6.21 (br s, 2H).
Meth od B. To a stirred mixture of 337 g (0.288 mol) of 2.5%
sodium amalgam, 10 g (0.072 mol) of Na2HPO4, and 8.6 g
(0.072 mol) of NaH2PO4 at 0 °C under N2 was added 5.04 g
(0.0144 mol) of 4 in 200 mL of 1:1 ethyl acetate and tert-butyl
alcohol. The reaction mixture was warmed to room tempera-
ture over a 1 h period. After 24 h, the top layer was poured
into 500 mL of water and extracted with three 50 mL portions
of ethyl acetate. The bottom layer (Hg layer) was washed with
two 50 mL portions of ethyl acetate. The combined organic
phase was dried (MgSO4), filtered, and concentrated under
reduced pressure to give 4.6 g of a white oily solid. This
material was purified by filtration through a short pad of silica
gel, eluting with hexanes to give 1.56 g (55%) of 5 as a colorless
oil, which was dried by azeotropation with toluene and further
dried under high vacuum.
7-ter t-Bu toxyca r bon yl-2-exo-(2′-a m in o-5′-p yr id in yl)-7-
a za bicyclo[2.2.1]h ep ta n e (6). To a stirred mixture of 1.93 g
(0.00985 mol, dried by azeotropation with toluene and under
high vacuum) of 5, 4.3 g (0.0197 mol) of 2-amino-5-iodopyri-
dine, 700 mg (2.5 mmol) of n-Bu4NCl, 1.66 g (0.0197 mol) of
KO2CH in 40 mL of DMF at room temperature under nitrogen
was added 55 mg (0.25 mmol) of Pd(OAc)2. The reaction vessel
was inserted into a 100 °C oil bath. After 12 h, another 55 mg
(0.25 mmol) of Pd(OAc)2 was added. After 12 h, the reaction
mixture was diluted with 100 mL of ethyl acetate and filtered
through a Celite pad into 100 mL of 1:1 NH4OH and H2O. The
aqueous phase was extracted with two 50 mL portions of ethyl
acetate. The combined organic phase was dried (MgSO4),
filtered, and concentrated under reduced pressure. The result-
ing brown oil was redissolved into 50% of ethyl acetate in
hexanes, allowed to stand for 3 h (to precipitate all the white
solid), and filtered. The filtrate was concentrated under
reduced pressure to give a yellow solid. This material was
purified by recrystallization from acetone to give 1.56 g of 6
as colorless crystals. The mother liquor was purified by column
chromatography, eluting with 30% Et3N in Et2O to give an
additional 229 mg of the same product (68% total) as a white
solid (mp 135-136 °C): 1H NMR (CDCl3) δ (ppm) 1.43 (s, 9H),
1.43-1.59 (m, 3H), 1.81 (m, 2H), 1.93 (dd, J ) 8.8, 12.3, 1H),
2.74 (dd, J ) 5.0, 8.8, 1H), 4.10 (m, 1H), 4.36 (m, 3H), 6.46 (d,
1H), 7.87 (ddd, J ) 2.6, 8.3, 8.5, 1H), 8.07 (d, J ) 2.6, 1H); 13
C
NMR (CDCl3) δ (ppm) 30.18, 31.38, 40.49, 44.40, 56.43, 62.83,
109.03 (d, J ) 36.7 Hz), 140.04 (br d, J ) 7.7 Hz), 146.11 (d,
J ) 14.0 Hz), 160.48, 164.25; IR (neat, NaCl) υ 3335, 2945,
1590, 1473, 1394, 1243, 910, 837, 639 cm-1
.
The hydrochloride salt had a melting point of 177-179 °C:
1H NMR (DMSO-d6) δ (ppm) 1.61-1.95 (m, 4H), 2.22 (m, 1H),
2.37 (m, 1H), 3.25 (m, 1H), 4.13 (m, 1H), 4.34 (m, 1H), 7.09
(dd, J ) 2.5, 8.5, 1H), 8.05 (ddd, J ) 2.6, 8.5, 8.5, 1H), 8.17 (d,
J ) 2.6, 1H), 8.95 (s, 1H), 9.57 (s, 1H). Anal. (C11H14ClFN2) C,
H, N.
7-ter t-Bu toxyca r bon yl-2-exo-(2′-flu or o-5′-p yr id in yl)-7-
a za bicyclo[2.2.1]h ep ta n e (7a ). To a stirred mixture of 138
mg (0.70 mmol) of 5, 157 mg (0.704 mmol) of 2-fluoro-5-
iodopyridine, 196 mg (0.704 mmol) of n-Bu4NCl, and 89 mg
(1.06 mmol) of KO2CH in 1.0 mL of DMF at room temperature
under nitrogen was added 16 mg (0.07 mmol) of Pd(OAc)2.
After 4 days, the reaction mixture was diluted with 50 mL of
25% ethyl acetate in hexanes, filtered through a Celite pad,
and concentrated under reduced pressure to give 150 mg of a
yellow oil. This material was purified by radial PLC (silica gel)
eluting with a solvent mixture of CH2Cl2:CHCl3:CH3OH:NH4-
OH (450:40:9:1) to give 106 mg (51%) of 7a as a colorless oil:
1H NMR (CDCl3) δ (ppm) 1.34-1.71 (m, 3H), 1.36 (s, 9H), 1.93
(dd, J ) 9.0. 12.3, 1H), 2.81 (dd, J ) 5.0, 9.0, 1H), 4.08 (m,
1H), 4.30 (m, 1H), 6.78 (dd, J ) 3.0, 8.5, 1H), 7.70 (ddd, J )
2.2, 8.5, 8.5, 1H), 7.99 (d, J ) 2.2, 1H); 13C NMR (CDCl3) δ
(ppm) 28.24, 28.72, 29.60, 40.48, 44.71, 56.14, 62.02, 79.80,
109.22 (d, J ) 37.2 Hz), 139.25 (d, J ) 31.6 Hz), 146.06 (d, J
) 14.3 Hz), 155.24, 160.48, 164.25; IR (neat, NaCl) υ 2956,
1703, 1593, 1403, 1359, 1251, 1151, 1092 cm-1. Anal. (C16H21
FN2O2) C, H, N.
-
2-exo-(2′-F lu o r o -5′-p y r id in y l)-7-a za b ic y c lo [2.2.1]-
h ep ta n e (1b) fr om 7a . To a stirred solution of 60 mg (0.205
mmol) of 7-tert-butoxycarbonyl-2-exo-(2′-fluoro-5′-pyridinyl)-7-
azabicyclo[2.2.1]heptane (11) in 1 mL of CH2Cl2 at 0 °C under
nitrogen was added dropwise 1.0 mL of CF3CO2H. After 0.5
h, 25 mL of a saturated aqueous K2CO3 solution was added.
The reaction mixture was extracted with two 50 mL portions
of CH2Cl2. The combined organic phase was dried (Na2SO4),
filtered, and concentrated under reduced pressure to give 43
mg of a yellow oil. This material was purified with column
chromatography, eluting with a solvent mixture of CH2Cl2:
CHCl3:CH3OH:NH4OH (50:40:9:1) to give 30 mg (77%) of 1b
1
as a colorless oil. The H NMR spectrum was identical to the
sample of 1b prepared from compound 6.
2-exo-(2′-C h lo r o -5′-p y r id in y l)-7-a za b ic y c lo [2.2.1]-
h ep ta n e [1a , (()-Ep iba tid in e]. To 115 mg (0.358 mmol) of
6 at 0 °C was added 1.5 mL of a 36% hydrochloric acid with
stirring, and 500 mg of NaNO2 was added in three portions.
The reaction mixture was warmed to room temperature, and
1.5 g of CuCl was added as a solid. After 1 h, the reaction

2234 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13
Carroll et al.
mixture was poured into 25 mL of 3:1 NH4OH and H2O, and
it was extracted with three 50 mL portions of CHCl3. The
combined organic phase was dried (MgSO4), filtered, and
concentrated under reduced pressure to give 60 mg (72%) of
(m, 3H), 2.03 (dd, J ) 9.7, 13.4, 1H), 3.93 (dd, J ) 5.3, 9.8,
1H), 4.20 (m, 1H), 4.38 (m, 1H), 7.11 (d, J ) 9.1, 1H), 7.88
(dd, J ) 2.6, 9.1, 1H), 8.25 (d, J ) 2.7, 1H); 13C NMR (CDCl3)
δ (ppm) 155.69, 154.78, 147.78, 142.74, 139.76, 118.57 (q, J )
320), 115.37, 80.48, 61.88, 56.16, 44.79, 40.40, 30.01, 29.60,
28.73, 28.63.
1
pure (()-epibatidine (1a ) as a colorless oil. The H NMR and
Rf values are identical to the reported values.14,15
2-exo-(2′-B r o m o -5′-p y r id in y l)-7-a za b ic y c lo [2.2.1]-
h ep ta n e (1c). To 105 mg (0.358 mmol) of 6 at 0 °C was added
0.41 mL of a 48% HBr solution in acetic acid (3.58 mmol) with
stirring. After 0.5 h, 0.02 mL of Br2 was added dropwise
followed by a solution of NaNO2 in 0.5 mL of water. After 0.5
h, the resulting tarry reaction mixture was diluted with 25
mL of 1:1 NH4OH (concentrated) and H2O then extracted with
three 25 mL portions of 10% MeOH in CHCl3. The combined
organic phase was washed with a saturated aqueous Na2SO3
solution, dried over MgSO4, filtered, and concentrated under
reduced pressure to give 120 mg of a brown oil. This material
was purified by column chromatography, eluting with 20%
triethylamine in ether to give 35 mg (36%) of a colorless oil,
which was purified again with column chromatography, elut-
ing with a solution of 96:3:1 CHCl3:MeOH:NH4OH to give 31
mg of 2-exo-(2′-bromo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane
as a colorless oil. 1H NMR (CDCl3) δ (ppm) 1.55-1.73 (m, 3H),
1.82 (m, 2H), 1.93 (dd, J ) 8.8, 12.4, 1H), 2.78 (dd, J ) 5.0,
8.8, 1H), 3.64 (m, 1H), 4.88 (m, 1H), 7.40 (d, J ) 8.2, 1H), 7.71
(dd, J ) 2.4, 8.2, 1H), 8.27 (d, J ) 2.4, 1H); 13C NMR (CDCl3)
δ (ppm) 149.45, 140.15, 139.16, 137.53, 127.90. 62.77, 56.87,
44.24, 39.53, 30.76, 29.09.
To a stirred solution of 31 mg of 1c free base (0.114 mmol)
in 0.5 mL of 2:1 Et2O and MeOH at room temperature was
added dropwise 1.0 mL of a 1.0 M HCl solution in Et2O (1
mmol). After 2 h, the solvents were removed under reduced
pressure, and the resulting white solid was redissolved into
MeOH, filtered, and recrystallized from MeOH and Et2O to
give 31 mg of 2-exo-(2′-bromo-5′-pyridinyl)-7-azabicyclo[2.2.1]-
heptane (1c) dihydrochloride as a white solid (mp 183-185
°C). Anal. (C11H15BrCl2N2) C, H, N.
7-ter t-Bu toxyca r bon yl-2-exo-(2′-h yd r oxy-5′-p yr id in yl)-
7-a za bicyclo[2.2.1]h ep ta n e (7b). To a stirred solution of 52
mg (0.18 mmol) of 6 in 1 mL of AcOH at 0 °C was added 62
mg of NaNO2 (0.86 mmol) in 1.0 mL of water. After 2 h, 8 mL
of saturated aqueous solution of Na2CO3 was added (until pH
g 10), and the reaction mixture was warmed to room temper-
ature. After 1 h, the reaction mixture was poured into 25 mL
of 1:1 NH4OH and H2O and extracted with three 25 mL
portions of CHCl3. The combined organic phase was dried over
MgSO4, filtered, and concentrated under reduced pressure to
give 40 mg of pure 7b as a colorless oil. This material was
used without further purification.
2-exo-(2′-H yd r oxy-5′-p yr id in yl)-7-a za b icyclo[2.2.1]-
h ep ta n e (1e) Dih yd r och lor id e. Trifluoroacetic acid (2.0 mL,
0.026 mol) was added to compound 7b (0.45 g, 0.0015 mol) in
CH2Cl2 (5 mL). The reaction was stirred at room temperature
for 1 h then concentrated in vacuo. The residue was purified
by silica gel column chromatography using 80 CMA as eluent
to afford 1e (0.24 g, 84%) as an oil. The HCl salt was prepared
by dissolving the free base in ether and adding ethereal HCl
to give solids that were crystallized from MeOH/EtOAc
mixtures to afford a beige solid (mp 220-223 °C): 1H NMR
(MeOD, base) δ 1.89-2.16 (m, 5H), 2.43 (m, 1H), 3.48 (m, 1H),
4.36 (m, 1H), 4.54 (m, 1H), 7.19 (d, 1H), 8.13 (s, 1H), 8.27 (d,
1H). Anal. (C11H16C12N20) C, H, N.
2-exo-(2′-Tr iflu or om eth a n esu lfon yloxy-5′-p yr id in yl)-7-
a za bicyclo[2.2.1]h ep ta n e (1h ) Hyd r och lor id e. To a stirred
solution of 53 mg of 7-tert-butoxycarbonyl-2-exo-(2′-trifluo-
r om et h a n esu lfon yloxy-5′-pyr idin yl)-7-a za bicyclo[2.2.l]-
heptane (0.12 mmol) in 0.5 mL of CH2Cl2 at room temperature
was added 0.5 mL of TFA. After 1 h, the reaction mixture was
concentrated under reduced pressure. The residue was dis-
solved in 50 mL of CHCl3 and washed with 50 mL of 1:1 NH4-
OH (concentrated) and H2O. The aqueous phase was extracted
with two 25 mL portions of CHCl3. The combined organic
phase was dried over MgSO4, filtered, and concentrated under
reduced pressure to give 39 mg of 2-exo-(2′-trifluoromethane-
sulfonyloxy-5′-pyridyl)-7-azabicyclo[2.2.1]heptane as a yellow
oil (100%): 1H NMR (CDCl3) δ (ppm) 1.11-1.18 (m, 2H), 1.41-
1.59 (m, 3H), 1.85 (dd, J ) 9.7, 13.4, 1H), 2.73 (dd, J ) 5.3,
9.8, 1H), 3.51 (m, 1H), 3.74 (m, 1H), 7.01 (d, J ) 9.1, 1H), 7.97
(dd, J ) 2.6, 9.1, 1H), 8.21 (d, J ) 2.7, 1H); 13C NMR (CDCl3)
δ (ppm) 154.19, 147.46, 143.58, 139.86, 118.67 (q, J ) 320),
114.72, 62.69, 56.35, 44.42, 40.54, 31.47, 30.35.
To a stirred solution of 39 mg of 1h free base and 0.5 mL of
Et2O in MeOH at room temperature under N2 was added 1.0
mL of 1.0 M solution of HCl (1.0 mmol) in Et2O. After 2 h, the
stirrer was stopped, and the solvents were removed with a
pipet. The resulting white solid was washed with two 0.5 mL
portions of Et2O and dried under vacuum to give 39 mg of
2-exo-(2′-trifluoromethanesulfonyloxy-5′-pyridyl)-7-azabicyclo-
[2.2.l]heptane (1h ) hydrochloride as a white solid (mp 204-
205 °C). Anal. (C12H14ClF3N2SO3) C, H, N.
7-ter t-Bu t oxyca r b on yl-2-exo-(2′-iod o-5′-p yr id in yl)-7-
a za bicyclo[2.2.1]h ep ta n e (7c). To a stirred mixture of 50
mg (0.172 mmol) of 6 and 1 mL of CH2I2 under N2 at room
temperature was added 0.35 mL of isoamyl nitrite (3.43 mmol).
After 0.5 h, 0.005 mL of HI was added. After 12 h, the reaction
mixture was poured into 50 mL of 1:1 NH4OH and H2O and
extracted with two 25 mL portions of CHCl3. The combined
organic phase was dried over MgSO4, filtered, and concen-
trated under reduced pressure to give 202 mg of a brown oil.
This material was azeotroped with 10:1 MeOH and acetone
followed by column chromatography, eluting with 25% ethyl
acetate in hexanes to give 57 mg (79%) of 7c as a colorless oil.
1H NMR (CDCl3) δ (ppm) 1.43 (s, 9H), 1.55-1.73 (m, 3H), 1.82
(m, 2H), 1.99 (dd, J ) 9.6, 13.4, 1H), 2.81 (dd, J ) 5.3, 9.6,
1H), 4.15 (m, 1H), 4.37 (m, lH), 7.31 (dd, J ) 2.5, 8.8, 1H),
7.63 (d, J ) 8.8, 1H), 8.23 (d, J ) 2.5, 1H); 1C NMR (CDCl3) â
(ppm) 149.97, 140.88, 136.30, 134.65, 115.20, 79.90, 61.78,
56.35, 43.84, 39.92, 29.95, 28.41, 28.26.
2-exo-(2′-I o d o -5′-p y r i d i n y l)-7-a z a b i c y c lo [2.2.1]-
h ep ta n e (1d ) Hyd r och lor id e. To a stirred solution of 63 mg
(0.126 mmol) of 7c and 0.5 mL of CH2Cl2 under N2 at 0 °C
was added 0.5 mL of trifluoroacetic acid (6.49 mmol). The
reaction mixture was warmed to room temperature in a 4 h
period. After an additional 4 h, the reaction mixture was
poured into 20 mL of 1:1 NH4OH and H2O and extracted with
two 25 mL portions of CHCl3. The combined organic phase was
dried over MgSO4, filtered, and concentrated under reduced
pressure to give 44 mg of a brown oil. This material was
filtered through a 1 in. pad of silica gel, eluting with 50% ethyl
acetate in hexanes to give 38 mg (79%) of 1d as a colorless oil:
1H NMR (CDCl3) δ (ppm) 1.51-1.63 (m, 5H), 1.90 (dd, J )
9.6, 13.08, 1H), 2.71 (dd, J ) 5.4, 9.6, 1H), 3.55 (m, 1H), 3.78
(m, 1H), 7.45 (dd, J ) 2.6, 8.8, 1H), 7.62 (d, J ) 8.8, 1H), 8.26
(d, J ) 2.6, 1H); 13C NMR (CDCl3) â (ppm) 150.17, 141.92,
136.75, 134.47, 117.80, 62.70, 56.37, 44.58, 40.28, 31.39, 30.15.
7-ter t-Bu toxyca r bon yl-2-exo-(2′-tr iflu or om eth a n esu lfo-
n yloxy-5′-p yr id in yl)-7-a za bicyclo[2.2.1]h ep ta n e (8). To a
stirred solution of 40 mg (0.34 mmol) of 7b in 4.0 mL of
pyridine at room temperature was added 0.5 mL of (CF3SO2)2O
(3.4 mmol). After 8 h, the reaction mixture was poured into
25 mL of 1:1 NH4OH and H2O and extracted with three 25
mL portions of CHCl3. The combined organic phase was dried
over MgSO4, filtered, and concentrated under reduced pressure
to give 60 mg of a yellow oil. This material was filtered through
a 1 in. pad of silica gel, eluting with 25% ethyl acetate in
hexanes to give 53 mg (88%) of 8 as a colorless oil: 1H NMR
(CDCl3) δ (ppm) 1.44 (s, 9H), 1.52-1.69, (m, 2H), 1.79-1.86
To a stirred solution of 38 mg of 1d in 1 mL of 2.5% MeOH
in Et2O under N2 at room temperature was added dropwise
0.3 mL of 1 M HCl solution in Et2O. After an additional 0.5 h,
the solvent was removed, and the residue was recrystallized

Synthesis of Epibatidine Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13 2235
from MeOH and Et2O to give the hydrochloride salt as a light
yellow solid (mp 178-179 °C). Anal. (C11H14ClN2) C, H, N.
pressure. The residue was dissolved in 50 mL of CHCl3 and
washed with 50 mL of 1:1 of NH4OH and H2O. The aqueous
phase was extracted with two 25 mL portions of CHCl3. The
combined organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure to give 37 mg (95%) of
1g as a yellow oil. This material was converted into HCl salt
without further purification and recrystallized from MeOH and
Et2O to give 15 mg of 2-exo-(2′-N,N-dimethylamino-5′-pyridi-
nyl)-7-azabicyclo[2.2.1]heptane dihydrochloride monohydrate
as a light yellow solid (mp 222 °C dec): 1H NMR (CDCl3) δ
(ppm) 1.46-1.57, (m, 3H), 1.72-1.84 (m, 3H), 2.63 (dd, J )
5.5, 9.6, 1H), 2.95 (s, 6H), 3.39 (m, 1H), 3.63 (m, 1H), 6.38 (d,
J . ) 9.5, 1H), 7.36 (dd, J ) 2.7, 9.5, 1H), 7.92 (d, J ) 2.7, 1H):
13C NMR (CDCl3) δ (ppm) 158.14, 146.20, 136.11, 128.98,
105.80, 62.96, 56.37, 44.67, 39.81, 38.20, 30.67, 29.71. Anal.
(C13H23Cl2N3O) C, H, N.
2-exo-(2′-Am in o -5′-p y r id in y l)-7-a za b ic y c lo [2.2.1]-
h ep ta n e (1f) Dih yd r och lor id e. To a stirred solution of 23
mg (0.079 mmol) of 6 in 0.5 mL of MeOH at room temperature
under nitrogen was added dropwise 2 mL of 36% aqueous HCl
solution. After 8 h, the reaction mixture was concentrated
under reduced pressure to give 25 mg of a yellow oil. This
material was purified by recrystallization in MeOH and Et2O
to give 18 mg of 2-exo-(2′-amino-5′-pyridinyl)-7-azabicyclo-
[2.1.1]heptane (1f) dihydrochloride as a colorless crystal (mp
270 °C (dec)): 1H NMR (CD3OD) δ (ppm) 1.85-2.12 (m, 5H),
2.39 (dd, J ) 5.0, 8.8, 1H), 3.36 (m, 1H), 4.34 (m, 1H), 4.48
(m, 1H), 7.05 (d, J ) 8.5, 1H), 7.84 (s, 1H), 7.96 (d, J ) 8.5,
1H). Anal. (C11H17Cl2N3) C, H, N.
7-ter t-Bu toxycar bon yl-2-exo-(3′-pyr idin yl)]-7-azabicyclo-
[2.2.1]h ep ta n e (7d ). To a stirred mixture of 230 mg (1.17
mmol) of 5, 481 mg of 3-iodopyridine (2.34 mmol), 82 mg of
n-Bu4NCl (0.29 mmol), and 198 mg of KO2CH (2.34 mmol) in
2.0 mL of DMF at room temperature under nitrogen was added
26 mg of Pd(OAc)2 (0.12 mmol). The reaction mixture was
warmed to 80 °C. After 24 h, the reaction mixture was warmed
to 120 °C. After 1 h, the reaction mixture was diluted with 50
mL of 25% ethyl acetate in hexanes, filtered through a 1 in.
pad of Celite, and concentrated under reduced pressure to give
500 mg of a yellow oil. This material was purified by chro-
matatron, eluting with 25% followed by 50% ethyl acetate in
hexanes to give 306 mg (94%) of 7d as a colorless oil: 1H NMR
(CDCl3) δ (ppm) 1.43 (s, 9H), 1.45 (m, 1H), 1.57 (m, 1H), 1.86-
1.94 (m, 2H), 2.00 (dd, J ) 8.8, 12.4, 1H), 2.89 (dd, J ) 5.0,
8.8, 1H), 4.22 (m, 1H), 4.38 (m, 1H), 7.21 (dd, J ) 3.7, 7.9,
1H), 7.65 (d, J ) 7.9, 1H), 8.44 (dd, J ) 1.9, 3.7, 1H), 8.48 (d,
J ) 1.9, 1H); 13C NMR (CDCl3) δ (ppm) 155.12, 148.94, 147.60,
140.97, 134.21, 123.45, 79.64, 61.87, 55.74, 45.47, 39.64, 29.96,
28.59, 28.23.
2-exo-(3′-P yr id in yl)-7-a za bicyclo[2.2.1]h ep ta n e (1i) Di-
h yd r och lor id e. To a stirred solution of 45 mg of 7d in 2.5
mL of 5:1 Et2O and MeOH at room temperature under
nitrogen was added dropwise 2 mL of a 1 M solution of HCl in
ethyl ether (excess). After 8 h, the reaction mixture was
concentrated under reduced pressure to give 50 mg of a white
solid. This material was purified by recrystallization in MeOH
and Et2O to give 35 mg of the dihydrochloride salt as a white
solid (mp 239 °C (dec)): 1H NMR (CD3OD) δ (ppm) 1.84-2.54
(m, 6H), 3.66 (dd, J ) 5.0, 8.8, 1H), 4.43 (m, 1H), 4.68 (m, 1H),
7.39 (s, 1H), 8.04 (dd, J ) 3.7, 7.9, 1H), 8.66 (d, J ) 3.7, 1H),
8.69 (d, J ) 7.9, 1H), 9.08 (s, 1H). Anal. (C11H16Cl2N2‚0.25H2O)
C, H, N.
7-ter t-Bu toxyca r bon yl-2-exo-(2′-N,N-d im eth yla m in o-5′-
p yr id in yl)-7-a za -bicyclo-[2.2.1]h ep ta n e (9). To a stirred
solution of 102 mg (0.348 mmol) of 6 in MeCN at room
temperature under N2 was added 1.5 mL (20 mmol) of a 37%
polyformaldehyde solution in H2O followed by 450 mg (6.8
mmol) of NaBH3CN as a solid. After 2 h, 0.5 mL of HOAc was
added dropwise, and the reaction mixture was poured into 50
mL of a 10% aqueous NaOH solution and extracted with three
50 mL portions of CHCl3. The combined organic phase was
washed with a saturated aqueous NaCl solution, dried (Na2-
SO4), filtered, and concentrated under reduced pressure to give
130 mg of a white solid. This material was purified by column
chromatography, eluting with 50% ethyl acetate in hexanes
to give 97 mg (87%) of 9 as a white solid: mp 99.5-100 °C; 1H
NMR (CDCl3) δ (ppm) 1.43 (s, 9H), 1.49-1.60 (m, 2H), 1.77-
1.87 (m, 3H), 1.94 (m, 1H), 2.74 (m, 1H), 3.05 (s, 6H), 4.09 (m,
1H), 4.34 (m, 1H), 6.48 (d, J ) 8.8, 1H), 7.45 (dd, J ) 2.4, 8.8,
1H), 8.00 (d, J ) 2.4, 1H); 13C NMR (CDCl3) δ (ppm) 158.36,
155.42, 146.45, 135.80, 128.66, 105.96, 79.42, 67.89, 58.35,
48.20, 41.40, 38.28, 30.71, 28.34.
7-ter t-Bu toxyca r bon yl-7-a za bicyclo[2.2.1]h ep t-2-en e-2-
tr iflu or om eth ylsu lfon a te (11). To a stirred solution of 590
mg of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one
(16) (2.78 mmol) in 2.5 mL of THF at -78 °C under nitrogen
was added 4.2 mL of a 1.0 M solution of NaN[(SiCH3)]2 (4.2
mmol) in THF. After 3 h, 2.0 g of C6H5N(Tf)2 (5.6 mmol) was
added as a solid, and the reaction mixture was warmed to 0
°C. After 0.5 h, the reaction mixture was warmed to 5 °C. After
5 days, the reaction mixture was poured into 150 mL of a
saturated aqueous NH4Cl solution and extracted with three
100 mL portions of hexanes. The combined organic phase was
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give 1 g of a yellow solid. This material
was purified by column chromatography, eluting with 10%
ethyl acetate in hexanes to give 650 mg (68%) of 7-tert-
butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene-2-trifluorometh-
ylsulfonate (11) as a colorless oil. 1H NMR (CDCl3) δ (ppm)
1.32-1.55 (m, 2H), 1.43 (s, 9H), 2.05 (m, 2H), 4.69 (d, J ) 6.6,
1H), 4.75 (m, 1H), 5.96 (m, 1H); 13C NMR δ (ppm) 24.18, 25.23,
27.98, 60.25, 60.25, 80.96, 118.48 (q, J ) 321.2), 120.38, 153.69,
154.78; IR (neat, NaCl) υ 2975, 1719, 11619, 1427, 1361, 1289,
1246, 1216, 1150, 1083, 922, 817 cm-1; Anal. (C12H16F3N2O5S)
C, H, N.
7-ter t-Bu t oxyca r b on yl-2-[(2′-flu or o-5′-p yr id in yl)]-7-
a za b icyclo[2.2.1]h ep t en e (12). A mixture of 55 mg of 11
(0.218 mmol), 45 mg of 2-fluoro-5′-pyridineboronic acid (17)
(0.327 mmol), 15 mg of LiCl (0.65 mmol), 0.3 mL of a saturated
aqueous Na2CO3 solution, and 15 mg of Pd(PPh3)4 (0.01 mmol)
in 0.7 mL of DME under nitrogen was heated to reflux. After
0.5 h, the reaction mixture was cooled to room temperature,
diluted with 20 mL of Et2O, filtered through a 1 in. pad of
Celite into 50 mL of a 1:1 NH4OH and water solution. The
water phase was extracted with two 50 mL portions of Et2O.
The combined organic phase was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give 50
mg of a yellow wax. This material was purified by column
chromatography, eluting with 25% ethyl acetate in hexanes
to give 32 mg (69%) of 7-tert-butoxycarbonyl-2-[(2′-fluoro-5′-
1
pyridinyl)]heptene (12) as a colorless oil. H NMR (CDCl3) δ
(ppm) 1.17-1.33 (m, 2H), 1.41 (s, 9H), 1.47 (m, 1H), 1.96-
2.05 (m, 2H), 4.80 (m, 1H), 5.02 (d, J ) 3.6, 1H), 6.48 (d, J )
2.3, 1H), 6.91 (dd, J ) 3.0, 8.6, 1H), 7.78 (ddd, J ) 2.5, 7.6,
8.6, 1H), 8.23 (m, 1H).
7-ter t-Bu toxyca r bon yl-2-en d o-[(2′-flu or o-5′-p yr id in yl)]-
7-a za bicyclo[2.2.1]h ep ta n e (13). To a stirred solution of 16
mg of 12 (0.055 mmol) in 0.5 mL of ethyl acetate at room
temperature under nitrogen was added 2 mg of PtO2, and the
mixture was then exposed to H2. After 48 h, the reaction
mixture was diluted with 50 mL of ethyl acetate, filtered
through a one-inch pad of Celite, and concentrated under
reduced pressure to give 16 mg (95%) of 7-tert-butoxycarbonyl-
2-endo-[(2′-fluoro-5′-pyridinyl)]-7-azabicyclo[2.2.1]heptane (13)
a yellow oil: 1H NMR (CDCl3) δ (ppm) 1.41-1.51 (m, 3H), 1.49
(s, 9H), 1.55-1.62 (m, 2H), 1.84 (m, 1H), 2.32 (m, 1H), 3.46
(m, 1H), 4.32 (m, 1H), 6.91 (dd, J ) 3.0, 8.3, 1H), 7.62 (ddd, J
) 2.5, 8.3, 8.3, 1H), 8.07 (m, 1H).
2-exo-(2′-N,N-Dim eth ylam in o-5′-pyr idin yl)-7-azabicyclo-
[2.2.1]h ep ta n e (1g) Dih yd r och lor id e. To a stirred solution
of 66 mg of 7-tert-butoxycarbonyl-2-exo-(2′-(dimethylamino)-
5′-pyridinyl)-7-azabicyclo[2.2.1]heptane (0.21 mmol) in 0.5 mL
of CH2Cl2 at room temperature was added 0.5 mL of TFA. After
1 h, the reaction mixture was concentrated under reduced
2-F lu or o-5-iod op yr id in e (16). To a powder of 820 mg of
2-amino-5-iodopyridine2 (3.73 mmol) in a plastic vessel at room

2236 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13
Carroll et al.
temperature under nitrogen was added 5 mL of HF-pyridine
(70% HF in Py) with stirring. After 20 min, 775 mg of NaNO2
(11.2 mmol) was added in small portions in a 15 min period.
After 1 h, the resulting blue solution was warmed to 100 °C,
and the brown fume was led to a good vent. After 1 h, the
resulting yellow reaction mixture was slowly poured into 100
mL of a 1:1 NH4OH and water solution and extracted with
three 50 mL portions of 50% ethyl acetate in hexanes. The
combined organic phase was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to give 1 g
of a yellow oil. This material was sublimated from room
temperature to -78 °C, giving 500 mg (60%) of 2-fluoro-5-
iodopyridine (16) as a colorless solid (mp 31.2-31.7 °C): 1H
NMR (CDCl3) δ (ppm) 6.72 (dd, J ) 3.0, 8.6, 1H), 7.97 (ddd, J
) 2.5, 7.6, 8.6, 1H), 8.32 (m, 1H); 13C NMR δ (ppm) 119.97 (d,
J ) 38.1), 149.05 (d, J ) 7.8), 153.60 (d, J ) 14.5), 161.22,
165.04. Anal. (C5H3FIN) C, H, N.
°C until needed. Triplicate samples were run in 1.4-mL
polypropylene tubes (Matrix Technologies Corporation, Hud-
son, NH). Briefly, in a final volume of 0.5 mL, each assay
sample contained 3 mg of wet weight rat cerebral cortex (added
last), 40-50 pM [125I]MLA, and 50 nM final concentration of
test compound dissolved in buffer containing 10% DMSO,
giving a final DMSO concentration of 1%. Total and nonspecific
binding were determined in the presence of vehicle and 300
µM (-)-nicotine, respectively. After a 2 h incubation on ice,
the samples were vacuum-filtered using a Multimate 96-well
harvester (Packard Instruments, Meriden, CT) onto GF/B
filters presoaked for at least 30 min in assay buffer containing
0.15% bovine serum albumin. Each well was then washed with
approximately 3.0 mL of ice-cold buffer. The filter plates were
dried, and 30 µL of Microscint20 (Packard) was added to each
well. The amount of radioligand remaining on each filter was
determined using a TopCount 12-detector (Packard) microplate
scintillation counter at approximately 70% efficiency.
2-F lu or op yr id in e-5-bor on ic Acid (17). To a stirred solu-
tion of 700 mg of 16 (3.14 mmol) in 1.0 mL of THF at -78 °C
under nitrogen was added 1.9 mL of a 2.5 M solution of n-BuLi
(4.71 mmol) in hexanes dropwise down the side of the flask.
After 0.5 h, 1.1 mL of (I-PrO)3B (4.71 mmol) was added, and
the resulting brown slurry was warmed to 0 °C. After 1 h, the
reaction mixture was warmed to room temperature, and 50
mL of 10% hydrochloric acid was added. After 15 min, the
mixture was neutralized to pH ) 7 with 3 N aqueous NaOH
solution, saturated with NaCl, and extracted with three 70
mL portions of Et2O. The combined organic phase was dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to give 300 mg (68%) of 2-fluoropyridine-5-
boric acid (17) as a white solid. The analytical sample was
purified by recrystallization from ethyl acetate at room tem-
perature (mp 190-191 °C): 1H NMR (5 µL of CD3OD in CDCl3)
δ (ppm) 3.59 (s, 2H), 6.94 (ddd, J ) 1.9, 8.2, 1H), 8.22 (m, 1H),
8.50 (s, 1H). Anal. (C5H5BFO2N) C, H, N.
Ta il-F lick Test. Antinociception was assessed by the tail-
flick method of D’Amour and Smith.22 A control response (2-4
s) was determined for each mouse before treatment, and a test
latency was determined after drug administration. To mini-
mize tissue damage, a maximum latency of 10 s was imposed.
Antinociceptive response was calculated as percent maximum
possible effect (%MPE), where %MPE ) [(test - control)/(10
- control)] × 100. Groups of 8-12 animals were used for each
dose and for each treatment. The mice were tested 5 min after
i.t. injections of epibatidine analogues for the dose-response
evaluation. A total of 8-12 mice were treated per dose, and a
minimum of four doses was performed for dose-response curve
determination.
Ack n ow led gm en t. This research was supported by
the National Institute on Drug Abuse Grant DA12001.
Refer en ces
[3H]Ep iba tid in e Bin d in g Assa y. Adult male rat cerebral
cortices (Pelfreeze Biological, Rogers, AK) were homogenized
in 39 volumes of ice-cold 50 mM Tris buffer (pH 7.4 at 4 °C)
containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM
MgCl2 and sedimented at 37000g for 10 min at 4 °C. The
supernatant was discarded, the pellet resuspended in the
original volume of buffer, and the wash procedure repeated
twice more. After the last centrifugation, the pellet was
resuspended in 1/10 its original homogenization volume and
stored at -80 °C until needed. In a final volume of 0.5 mL,
each assay tube contained 3 mg of wet weight male rat cerebral
cortex homogenate (added last), 0.5 nM [3H]epibatidine (NEN
Life Science Products, Wilmington, DE), and one of 10-12
different concentrations of test compound dissolved in buffer
(pH 7.4 at room temperature) containing 10% DMSO resulting
in a final DMSO concentration of 1%. Total and nonspecific
binding were determined in the presence of vehicle and 300
µM (-)-nicotine, respectively. After a 4 h incubation at room
temperature, the samples were vacuum-filtered over GF/B
filter papers presoaked in 0.03% polyethylenimine using a
Brandel 48-well harvester and washed with 6 mL of ice-cold
buffer. The amount of radioactivity trapped on the filter was
determined by standard liquid scintillation techniques in a
TriCarb 2200 scintillation counter (Packard Instruments,
Meriden, CT) at approximately 50% efficiency. The binding
data were fit using the nonlinear regression analysis routines
in Prism (Graphpad, San Diego, CA). The Ki values for the
test compounds were calculated from their respective IC50
values using the Cheng-Prusoff equation.
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