Preparation of novel azabicyclic amines and α7 nicotinic acetylcholine receptor activity of derived aryl amides

Article abstract of DOI:10.1002/jhet.5570450131

(Chemical Equation Presented) Three new azabicyclic amines, namely exo-3-amino-1-azabicyclo[3.2.1]octane, 3-amino-1-azabicyclo-[3.2.2]nonane and exo-6-amino-8-azabicyclo[3.2.1]octane, have been designed and prepared as isosteres of 3-aminoquinuclidine. Ar

Full text of DOI:10.1002/jhet.5570450131

Jan-Feb 2008
247
Preparation of Novel Azabicyclic Amines and ꢀ7 Nicotinic
Acetylcholine Receptor Activity of Derived Aryl Amides
Daniel P. Walker,* Brad A. Acker, E. Jon Jacobsen and Donn G. Wishka
Pfizer Global Research and Development, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO
63017, e-mail: daniel.p.walker@pfizer.com
Received July 2, 2007
NH
H
Ar
N
H
N
O
Ar
NH
O
O
Ar
N
N
H
O
HN
N
H
Ar
Three new azabicyclic amines, namely exo-3-amino-1-azabicyclo[3.2.1]octane, 3-amino-1-azabicyclo-
[3.2.2]nonane and exo-6-amino-8-azabicyclo[3.2.1]octane, have been designed and prepared as isosteres of
3-aminoquinuclidine. Aryl amides derived from each series were prepared and tested in an ꢀ7 nicotinic
acetylcholine receptor assay as part of a drug discovery program to treat the cognitive deficits in
schizophrenia. All new amides showed significant ꢀ7 nAChR activity and one series displayed potent ꢀ7
activity equal to the quinuclidine series.
J. Heterocyclic Chem., 45, 247 (2008).
quinuclidine, such as PNU-282987 and PHA-543613, are
potent ꢀ7 nAChR agonists, whereas amides derived from
a conformationally more flexible diamine are, at best,
weak ꢀ7 nAChR agonists [8a,8b]. The rigid quinuclidine
framework locks the orientation of the bridgehead
nitrogen lone pair orthogonal to that of the amide
carbonyl oxygen lone pair. This orientation is presumably
important for optimal binding to the ꢀ7 nAChR. In a
prior study, we utilized this design element to prepare
new aryl amides as ꢀ7 nAChR agonists derived from
isosteres of 3-aminoquinuclidine, including 3-amino-1-
azabicyclo[2.2.1]heptane and 2-amino-7-azabicyclo-
[2.2.1]heptane [8c]. We detail below the synthesis and ꢀ7
nAChR activity of aryl amides derived from other rigid
aminoazabicyclic alkanes not disclosed in our previous
communication, including exo-3-amino-1-azabicyclo-
[3.2.1]octane, 3-amino-1-azabicyclo[3.2.2]-nonane and
exo-6-amino-8-azabicyclo[3.2.1]octane.
INTRODUCTION
Azabicyclic alkanes are important building blocks in
drug discovery. Several drug substances possessing an
azabicyclic alkane moiety, including sabcomeline [1],
varenicline [2], granisetron [3] and cevimeline [4] have
been launched (Chart 1). In addition, numerous reports on
biologically active substances containing an azabicyclic
alkane have appeared in the literature, with an emphasis
towards CNS-related targets, such as serotonin 5-HT3 and
5-HT4 [5], muscarinic [6] and nicotinic receptors [7].
Chart 1
CN
NH
OMe
N
N
N
N
sabcomeline
varenicline
Me
H
O
N
Cl
Me
O
N
O
S
N
H
N
H
N
NH
NMe
N
O
O
N
N
granisetron
cevimeline
PHA-543613
PNU-282987
As part of a drug discovery program, we have been
interested in the design and synthesis of novel azabicyclic
aryl amides as ꢀ7 nicotinic acetylcholine receptor
(nAChR) agonists for the potential treatment of cognitive
deficits in schizophrenia [8]. Early in our program, we
established that aryl amides derived from 3-amino-
RESULTS AND DISCUSSION
Modeling studies suggested that aryl amides derived
from 3-amino-1-azabicyclo[3.2.1]octane show similar
spatial orientation and distances between the key

248
D. P. Walker, B. A. Acker, E. J. Jacobsen and D. G. Wishka
Vol 45
pharmacophoric groups (i.e., the bridgehead nitrogen, the
amide carbonyl and the aryl ring) to that of the
corresponding quinuclidine amides. Also, a report from
the muscarinic literature suggested that 1-azabicyclo-
[3.2.1]octane can function as an effective isostere of
quinuclidine [9].
to PNU-282987, whereas enantiomer (+)-1 is significantly
less potent. The 40-fold potency difference between (-)-1
and (+)-1 is similar to the potency difference observed
between PNU-282987 and ent-PNU-282987. The absolute
configuration of enantiomer (-)-1 was found to possess the
(3R,5R)-stereochemistry [13], which is consistent with the
preferred (3R)-stereochemistry of the quinuclidine and
1-azabicyclo[2.2.1]heptane amides for this receptor
[8a,8c].
Chlorobenzamide (±)-1 was initially prepared in
racemic form (Scheme 1). Thus, treatment of the known
ketone (±)-2 [10] with hydroxylamine generated the
corresponding oxime as a mixture of geometric isomers.
Subjection of the oxime to dissolving metal conditions
[Na°, n-PrOH, reflux, 1 h] gave rise to exo-amine (±)-3 as
the only isolable product. Selective formation of the exo-
amine was not unexpected based on reductions of similar
systems [11]. Furthermore, the exo-configuration was
unambiguously established via X-ray crystallography on
amide (-)-1 (vide infra). Amide (±)-1 was prepared in
modest yield by coupling amine (±)-3 with 4-chloro-
benzoic acid in the presence of diphenyl phosphoryl azide
(DPPA), followed by subsequent exposure to para-
toluenesulfonic acid.
In order to efficiently prepare additional amides
possessing (3R,5R)-1-azabicyclo[3.2.1]octan-3-yl amine,
an asymmetric synthesis of bicyclic amine (±)-3 needed
to be developed. Our asymmetric route commenced with
enantiomerically pure carboxylic acid (-)-4 [14], which
was prepared in a single step by mixing (S)-ꢀ-methyl-
benzylamine and itaconic acid to give a 1:1 mixture of
diastereomeric pyrrolidonecarboxylic acids. Previously,
the diastereomers were separated by flash chromatography
as the corresponding methyl esters [14b]. However, we, as
well as others [14a], have found it more convenient,
especially on larger scale, to separate the carboxylic acid
diastereomers by trituration, taking advantage of the lower
solubility of diastereomer (-)-4. Treatment of compound
(-)-4 with lithium aluminum hydride effected smooth
reduction of the lactam and carboxylic acid moieties.
Activation of the resulting alcohol with thionyl chloride,
followed by SN2 displacement with cyanide afforded nitrile
(-)-5. Methanolysis of (-)-5 gave rise (77%) to ester (-)-6.
It should be mentioned that Orena has previously prepared
ester (-)-6 in 7-steps utilizing an oxidative cyclization of
N-(2-alkenyl-1-yl)amides mediated by manganese(III)
[15]. Transformation of (-)-6 into azabicyclic ketone (+)-7
was realized via a Kowalski carbon homologation [16],
followed by hydrogenolysis of the ꢀ-methylbenzyl group.
The initially formed ꢀ-chloro ketone was unstable and
cyclized during workup to form a quaternary ammonium
salt. While the ꢀ-chloro ketone could be detected by
LCMS (ESI) prior to workup, no attempts were made to
fully characterize this intermediate. Our initial efforts
toward utilizing the Kowalski sequence gave variable
yields of the corresponding quaternary ammonium salt.
After several attempts, we discovered that slow addition
of a lithium diisopropyl amide solution to a cold (-78 °C)
solution containing substrate and chloroiodomethane,
maintaining the reaction temperature below -75 °C,
consistently gave higher yields of the quaternary
ammonium salt, particularly on larger scale (24 g).
Ketone (+)-7 was transformed into amine (-)-3 using
identical conditions to that shown in Scheme 1. Amide
formation using HATU [17], followed by hydrochloride
salt formation, afforded amide (+)-8 [18]. The ꢀ7-5HT3
activity of (+)-8, prepared according to Scheme 2, was
identical to the biological activity of (-)-1 prepared
according to Scheme 1 (data not shown).
Scheme 1
H
H
i, ii, iii
iv, v
NH2
O
75%
2HCl
29%
N
N
(+/-)-3
(+/-)-2
H
H
H
5
vi
3
NH
HN
O
NH
O
+
Ar Ar
Ar
N
TsOH
N
N
O
TsOH
TsOH
(+/-)-1 Ar=4-chlorophenyl
(-)-1 (46%)
(+)-1 (48%)
Ar = 4-chlorophenyl
Reagents and conditions: (i) NH2OH•HCl, NaOAc•3H2O, EtOH, room
temperature, 17 h; (ii) Na°, n-PrOH, reflux, 1 h; (iii) HCl, MeOH;
(iv) 4-chlorobenzoic acid, DPPA, NEt3, room temperature, 15 h;
(v) TsOH, EtOH; (vi) chromatographic resolution of enantiomers
The biological activity of newly prepared amides is
detailed in Table 1. The compounds were evaluated in a
FLIPR-based functional assay that utilizes SH-EP1 cells
expressing the ꢀ7-5HT3 chimera [8a]. Compounds were
also evaluated in an ꢀ7 nAChR radio-ligand binding assay.
Quinuclidine amide, PNU-282987, and its enantiomer, ent-
PNU-282987, are shown for comparative purposes. We
were pleased to discover that amide (±)-1, possessing the
exo-configuration, shows similar ꢀ7-5HT3 functional
activity to PNU-282987 [12]. The racemate (±)-1 was
subsequently resolved by preparative chiral HPLC into its
individual enantiomers (Scheme 1). Biological testing
indicated that enantiomer (-)-1 shows very similar ꢀ7
nAChR functional activity and binding affinity compared

Jan-Feb 2008
Preparation of Novel Azabicyclic Amines
249
effectively utilized in subsequent steps, 12a and 12b were
carried forward as a mixture. Cleavage of the tert-butoxy
carbonyl group in 12a,b with trifluoroacetic acid provided
the corresponding piperidine, which was isolated as the
trifluoroacetate salt. Slow addition of a solution of the
piperidine trifluoroacetate salt to a dilute solution of
Hunig’s base in refluxing acetonitrile afforded azabicyclic
ketone 13 in good yield. While ketone 13 has been
prepared previously via Dieckmann condensation of
diester 14, the product was isolated in less than 1% yield
[20]. Conversion of ketone 13 into the corresponding
oxime followed by dissolving metal reduction and
treatment with para-toluenesulfonic acid afforded
diamine (±)-15 in good yield. HATU-mediated coupling
of (±)-15 with furo[2,3-c]pyridine-5-carboxylic acid [8b]
and subsequent exposure to fumaric acid led to racemic
amide (±)-10.
Scheme 2
CO2H
i
NH2
+
CO2H
HO2C
O
N
Ph
Me
36%
Ph
(-)-4
CO2Me
CN
v
ii, iii, iv
N
N
77%
61%
Ph
Ph
(-)-6
(-)-5
H
H
viii, ix, x
vi, vii
O
HCl
NH2
N
N
85%
46-61%
2HCl
Scheme 3
(+)-7
(-)-3
O
H
O
O
Cl
xi, xii
NH
iii
i, ii
HCl
N
81%
N
67%
52%
N
(+)-8
BOC
BOC
9
11
Reagents and conditions: (i) (a) 160 °C, 5 h; (b) MeOH-EtOH
trituration; (ii) LiAlH4, Et2O, reflux, 3 h; (iii) SOCl2, CHCl3, reflux, 1 h;
(iv) NaCN, DMSO, 95 °C, 1 h; (v) HCl, MeOH, 72 h; (vi) LDA,
ClCH2I, THF, -78 °C, 2 h; n-BuLi, THF, 0.5 h; NH4Cl; (vii) H2, 10%
Pd/C, MeOH, 45 psi, 60 h; (viii) NH2OH•HCl, NaOAc•3H2O, EtOH,
room temperature; (ix) Na°, n-PrOH, reflux, 1 h; (x) HCl, MeOH; (xi)
HATU, i-Pr2NEt, DMF, 0 °CꢀRT, 24 h; (xii) HCl, MeOH
O
X
iv, v
vi, vii, viii
O
N
80%
80%
N
BOC
13
12a, X = Br
12b, X = Cl
Based on the favorable biological activity of (+)-8, we
next considered amides derived from 3-amino-1-
azabicyclo[3.2.2]nonane, which can be considered a
hybrid of the 3-aminoquinuclidine and 3-amino-1-
azabicyclo[3.2.1]octane templates. The first amide to be
prepared in this series was furopyridine (±)-10 [19]. As
shown in Scheme 3, tert-butyl 4-oxo-1-piperidine-
carboxylate (9) served as the starting point for the
preparation of racemic amide (±)-10. Toward this end,
Horner-Emmons olefination of ketone 9, followed by
catalytic hydrogenation of the double bond afforded
ketone 11. Treatment of the lithium enolate of 11,
generated from the reaction of ketone 11 with lithium
bis(trimethylsilyl)amide at -78 °C, with trimethylsilyl
chloride gave the corresponding silyl enol ether. In situ
exposure of the silyl enol ether to phenyltrimethyl-
ammonium tribromide gave rise (52%) to a 1:2 mixture of
ꢀ-bromo ketone 12a and ꢀ-chloroketone 12b,
respectively. Presumably, a significant portion of the
initially formed bromide 12a underwent further reaction
with lithium chloride, which was generated during the
reaction, to give 12b. Since both ketones can be
ix, x
NH
O
NH2
O
N
N
40%
2TsOH
N
fumarate
(+/-)-15
(+/-)-10
Reagents and conditions: (i) NaH, diethyl (2-oxopropyl)phosphonate,
THF, 0 °C ꢀ room temperature, 18 h; (ii) H2, 10% Pd/C, EtOH, 50 psi,
5 h; (iii) LiHMDS, TMSCl, THF, -78 °C; PhMe3NBr3, -78 ꢀ 0 °C; (iv)
TFA, CH2Cl2 0 °C; (v) i-Pr2NEt, CH3CN, reflux, 17 h; (vi) NH2OH•HCl,
NaOAc•3H2O, EtOH; (vii) Na°, n-PrOH, reflux, 2 h; (viii) TsOH, EtOH;
(ix) furo[2,3-c]pyridine-5-carboxylic acid, HATU, i-Pr2NEt, DMF, 0 °C
ꢀ room temperature, 17 h; (x) fumaric acid, acetone, 45 °C
The biological activity of amide (±)-10 is detailed in
Table 1; PHA-543613 and its enantiomer are shown for
comparative purposes. Amide (±)-10 is 18-fold less active
than PHA-543613 and 5-fold less active than ent-PHA-
543613 in the ꢀ7-5HT3 assay. Consistent with the
functional data, the ꢀ7 nAChR Ki values for (±)-10 are
significantly higher than PHA-543613. The primary
binding interaction between the ꢀ7 nAChR and the
azabicyclic amides under study most likely involves a

250
D. P. Walker, B. A. Acker, E. J. Jacobsen and D. G. Wishka
Vol 45
cation-pi interaction between the bridgehead nitrogen of
the azabicycle and electron-rich aromatic residues in the
agonist binding pocket [21]. The lower affinity of (±)-10
suggests that this pocket is sensitive to modest changes in
steric bulk around the azabicyclic framework. Given the
lower potency of (±)-10, no attempts were made to
resolve this compound.
unexpected given the high endo-to-exo conversion
obtained on a similar system [25]. Additional support for
the exo-configuration of carboxylic acid (±)-21 was
provided by 1H NOE studies on amide (±)-17 (vide infra).
While our work was on-going, Pandey described an
asymmetric synthesis of carboxylic acid 21 (R = H),
which utilized piperidine 18 and Oppolzer’s chiral acrloyl
sultam [26]. Also concurrent with our work, Daly has
described a racemic synthesis of the corresponding methyl
ester of (±)-21 via a 1,3-dipolar cycloaddition reaction of
1-benzyl-3-oxidopyridinium chloride and methyl acrylate
(5-steps, 1.2% yield) [27]. Curtius rearrangement of
carboxylic acid (±)-21 and subsequent treatment with
benzyl alcohol led to carbamate (±)-22. Hydrogenolysis
of the CBZ-group, followed by amide coupling with
furo[2,3-c]pyridine-5-carboxylic acid and salt formation
gave rise (75%) to amide (±)-17. The stereochemistry of
N
EtO2C
CO2Et
14
In our previous communication, we identified amide 16
(Chart 2), containing the epibatidine-like 7-azabicyclo-
[2.2.1]heptane skeleton, as a potent ꢀ7 nAChR agonist
with affinity similar to that of PHA-543613 [8c].
Research by Bai [22a] on epibatidine analogs showed that
homoepibatidine possesses similar analgesic activity to
epibatidine, and another report by Malpass [22b]
established that homoepibatidine shows similar activity to
epibatidine in a nicotinic receptor radio-ligand binding
assay. The above results, together with the structural
similarities between epibatidine and amide 16, prompted
us to prepare a ring expanded version of amide 16 that
contains the 6-amino-8-azabicyclo[3.2.1]octane nucleus
present in homoepibatidine (i.e., (±)-17).
1
the C(6) amido group in (±)-17 was determined by H
NOE studies to possess the exo-orientation (Figure 1).
That is, when the C(6)-methine proton was irradiated,
signal enhancement was observed for the endo-protons at
C(3) and C(4), suggesting the C(6-endo)-H disposition.
Scheme 4
Ref. 23, 24
i
TMS
N
TMS
N
4-Steps, 42%
46%
Bn
18
Chart 2
BOC
19
H
H
H
H
HN
NH
iv
ii, iii
RN
RN
N
N
CO2H
CO2Me
77%
84%
Cl
Cl
(+/-)-homoepibatidine
(+/-)-21 R = BOC
(+/-)-epibatidine
(+/-)-20 R = Bn
H
H
H
O
O
O
HN
v, vi, vii
HN
RN
N
H
N
H
OBn
N
H
75%
N
N
O
O
2HCl
(+/-)-17
(+/-)-22 R = BOC
16
Amide (±)-17 was prepared as shown in Scheme 4. The
synthesis commenced with piperidine 18, recognized in
1998 as a logical starting point for the preparation of the
8-azabicyclo[3.2.1] framework [23]. Piperidine 18 was
prepared in 4-steps and 42% yield from N-BOC-
piperidine (19) [23,24]. Treatment of azomethine ylide
precursor 18 with silver(I) fluoride in the presence of
methyl propiolate provided in 46% yield azabicyclic ester
(±)-20. Hydrogenation of the olefin selectively generated
the corresponding endo-ester. Inversion of the ester
configuration with sodium methoxide, followed by
subsequent saponification gave rise to carboxylic acid
(±)-21. Complete conversion to the exo-isomer was not
Reagents and conditions: (i) methyl propiolate, AgF, CH3CN, 40 °C, 18
h; (ii) H2, 10% Pd/C, (BOC)2O, EtOH, 50 psi, 6 h; (iii) NaOMe, MeOH,
reflux, 4 h; H2O, 0 °C; (iv) (PhO)2P(O)N3, Et3N, toluene, room
temperature; BnOH, 60 °C, 17 h; (v) H2, 10% Pd/C, EtOH, 50 psi, 2 h;
(vi) furo[2,3-c]pyridine-5-carboxylic acid, HATU, i-Pr2NEt, DMF, room
temperature, 17 h; (vii) 3N aq. HCl, MeOH, 60 °C, 1 h
2HCl
NH
O
H4
H3
H6
N
H
N
O
(+/-)-17
Figure 1. Difference NOE Experiment of compound (±)-17 in DMSO-d6

Jan-Feb 2008
Preparation of Novel Azabicyclic Amines
251
Chemical shifts are reported in parts per million (ꢁ) relative to
tetramethylsilane (ꢁ 0.0). Infrared (IR) spectra, high-resolution
mass spectra and combustion analyses were performed in-house
by Analytical Chemistry Department personnel, Kalamazoo, MI.
Melting points were obtained on a Thomas-Hoover melting
point apparatus and are uncorrected. Reactions were monitored
by thin layer chromatography (TLC) using Analtech silica gel
GF 250 micron plates. The plates were visualized either by UV
inspection or I2 stain. Flash chromatography was performed as
described by Still [29] using EM Science silica gel 60 (230-400
mesh). All reagents were purchased from either the Aldrich
Chemical Co. or The Lancaster Synthesis Co. and used without
further purification unless otherwise stated. HATU [17] was
purchased from Biosystems, Warrington, UK. All solvents were
HPLC grade unless otherwise stated. Anhydrous solvents were
purchased from the Aldrich Chemical Co. and used without
further drying.
Biological results on exo-amide (±)-17 show that it is
nine-fold less potent than amide 16 in the ꢀ7-5HT3
functional assay and eight-fold less potent in the ꢀ7
nAChR binding assay. Due to the diminished activity of
(±)-17, no attempts were made to resolve this compound.
The corresponding racemic endo-isomer of (±)-17
conceivably could have been synthesized from ester
(±)-20. However, given the reduced affinity of racemic
endo-epibatidine toward nicotinic receptors [28] and the
lack of functional activity of the corresponding endo-
diastereomers of 16 (ꢀ7-5HT3 EC50 = 12.2 μM and >100
μM, absolute stereochemistry undetermined), preparation
of the endo-isomers of (±)-17 was not justified.
Table 1
In vitro ꢀ7 nAChR Functional and Binding Activity
1-Azabicyclo[3.2.1]octan-3-amine dihydrochloride [(±)-3].
To a stirred mixture of racemic 1-azabicyclo[3.2.1]octan-3-one
[10] ((±)-2, 4.30 g, 26.6 mmol) and sodium acetate trihydrate
(10.9 g, 79.8 mmol) in ethanol (150 mL) was added
hydroxylamine hydrochloride (2.40 g, 34.5 mmol). The mixture
stirred for 30 min., followed by the addition of chloroform. The
precipitate was filtered through Celite, and the filtrate was
concentrated in vacuo to afford a white solid. The solid was
taken up in n-propanol (130 mL), and sodium metal (17.6 g, 766
mmol) was added in small portions, which caused the mixture to
Cpd#
ꢀ7-5HT3 chimera EC50
(nM) ± SEM [a]
128 ± 31 (n = 16)
3400
ꢀ7 Ki (nM) ± SEM [b]
PNU-282987
ent-PNU-282987
(±)-1
24 ± 8 (n = 13)
NT
460, 790
190, 350
11,000
110, 290
18, 26
NT
(-)-1
(+)-1
PHA-543613
ent-PHA-543613
(±)-10
65 ± 11 (n = 12)
220, 240
1,200, 1200
69, 130
8.8 ± 1.1 (n = 5)
12, 18
110, 160
9 ± 1 (n =4)
NT
reflux. [CAUTION: reaction is very exothermic].
After
16
ent-16
(±)-17
complete addition, a refluxing temperature was maintained with
the aid of a 100 °C oil bath. Heating was maintained at that
temperature for an additional 40 minutes. The oil bath was
removed and n-propanol (50 mL) was added, which dissolved
the remaining sodium metal. The mixture was CAREFULLY
quenched through the drop wise addition of water (100 mL).
Brine (20 mL) was added, and the layers were separated. The
organic layer was dried over anhydrous magnesium sulfate,
filtered, treated with a freshly prepared hydrogen chloride in
methanol solution. The mixture was concentrated in vacuo, and
the remaining solid was triturated in ether-ethanol (180 mL,
5:1). The solid was filtered, washed with ethanol and dried in
vacuo to afford 3.96 g (75%) of (±)-3 as a white solid: IR
(diffuse reflectance) 3098, 3036, 3018, 2943, 2890, 2866, 2858,
4,700
880
60, 90
[a] Compounds tested in a cell-based FLIPR assay using SH-EP1 cells
expressing the ꢀ7-5HT3 chimera, which was previously established as
predictive of native ꢀ7 nAChR activity [8a,8b]. [b] Rat brain
homogenate binding assay, [3H]MLA.
CONCLUSION
We have designed and prepared three new azabicyclic
amines and evaluated a derived aryl amide in each series
as an ꢀ7 nAChR agonist. Of these, amide (±)-1, derived
from the exo-3-amino-1-azabicyclo[3.2.1]octane template,
shows the most promising ꢀ7 nAChsR activity.
Furthermore, it was found that enantiomer (-)-1,
possessing the (3R,5R)-stereochemistry, shows activity
equal to PNU-282987. While amides derived from the 3-
amino-1-azabicyclo[3.2.2]nonane and exo-6-amino-8-
azabyclo[3.2.1]octane templates are active in the ꢀ7-5HT3
assay, they are significantly less potent than PHA-543613
and amide 16, respectively. Additional amides derived
from azabicyclic amine (-)-3 are in progress. A full report
on the synthesis, structure-activity relationship and in vivo
activity of amides derived from amine (-)-3 will be
reported in due course.
1
2839, 2782, 2746, 2707, 2653, 2632, 2610, 2536 cm-1; H NMR
(400 MHz, meanthol-d4) ꢁ 4.00-3.85 (m, 1H), 3.80-3.70 (m,
1H), 3.70-3.55 (m, 2H), 3.45-3.30 (m, 3H), 2.95-2.85 (m, 1H),
2.40-2.15 (m, 2H), 2.10-2.00 (m, 1H), 1.95-1.85 (m, 1H); low
resolution MS (FAB) m/e 127 (M+H), 126, 125, 123, 110, 83;
high resolution MS (FAB) calcd for C7H14N2 (M+H) m/e
127.1235, found 127.1235. Anal. Calcd for C7H14N2•2HCl•
1/8H2O: C, 41.75; H, 8.13; N, 13.91. Found: C, 41.74; H, 7.97;
N, 13.89.
N-exo-1-Azabicyclo[3.2.1]oct-3-yl-4-chlorobenzamide•4-
methylbenzenesulfonate [(±)-1]. To a stirred solution of
4-chlorobenzoic acid (0.157 g, 1.00 mmol), triethylamine (0.14
mL, 1.0 mmol) and diphenylphosphoryl azide (0.19 mL, 0.88
mmol) in methylene chloride (5.0 mL) was added a solution of
(±)-3 (0.832 g, 0.832 mmol) in methylene chloride (5.0 mL).
The mixture was allowed to stir at room temperature over night.
The mixture was concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (Biotage 40S).
Elution with chloroform-methanol-ammonium hydroxide
(90:9:1) gave 64 mg of a white solid. The solid was dissolved in
EXPERIMENTAL
Proton (1H) and carbon (13C) nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker 400 spectrometer.

252
D. P. Walker, B. A. Acker, E. J. Jacobsen and D. G. Wishka
Vol 45
ethanol and treated with para-toluenesulfonic acid mono hydrate
(46 mg, 0.24 mmol). The mixture was concentrated in vacuo.
The remaining residue was triturated in ethyl acetate-ethanol
followed by acetone to afford 106 mg (29%) of (±)-1 as a white
solid: mp 236-238 °C; IR (diffuse reflectance) 3290, 1656, 1547,
1319, 1242, 1194, 1182, 1168, 1152, 1123, 1034, 1011, 853,
827, 683 cm-1; 1H NMR (400 MHz, DMSO-d6) ꢀ 9.95 (br s, 1H),
8.51 (d, 1H, J = 7.59 Hz), 7.85 (d, 2H, J = 8.54 Hz), 7.57 (d, 2H,
J = 8.52 Hz), 7.47 (d, 2H, J = 8.04 Hz), 7.11 (d, 2H, J = 7.97
Hz), 4.57-4.43 (m, 1H), 3.55-3.38 (m, 3H), 3.21-3.17 (m, 2H),
3.06 (t, 1H, J = 11.67 Hz), 2.75-2.71 (m, 1H), 2.29 (s, 3H), 2.20-
2.08 (m, 1H), 1.98-1.89 (m, 2H), 1.73 (t, 1H, J = 11.62 Hz);
high resolution MS (API) calcd for C14H18ClN2O [M+H] m/e
265.1107, found 265.1106. Anal. Calcd for C14H17ClN2O
•C7H8O3S: C, 57.72; H, 5.77; N, 6.41. Found: C, 57.55; H, 5.93;
N, 6.41.
3.15 (m, 1 H), 2.35-2.55 (m, 2 H), 2.25-2.35 (m, 2 H), 1.95-2.10
(m, 1 H), 1.75-1.90 (m, 1 H), 1.42 (d, 3H, J = 6.4 Hz); 13C NMR
(100 MHz, CDCl3) ꢀ 146.9, 130.3, 128.8, 128.7, 69.7, 67.4,
59.3, 54.0, 40.1, 28.7, 24.8; low resolution MS (EI) m/e 205
(M+), 191, 190, 128, 105, 91, 88, 86, 84, 77, 51. Anal. Calcd for
C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 76.11; H, 9.14;
N, 6.83.
A solution of the above alcohol (78.85 g, 384.1 mmol) in
chloroform (500 mL) was treated with a solution of thionyl
chloride (70.0 mL, 960 mmol) in chloroform (60 mL). The
mixture spontaneously warmed during the addition and was
heated under reflux for 40 min and cooled. The resulting
mixture was concentrated, and the resulting semi-solid was
partitioned between water and ethyl acetate. The pH of the
aqueous layer was adjusted to 9 using aqueous sodium
bicarbonate, and the layers were separated. The aqueous layer
was back extracted with ethyl acetate, and the combined
organics were washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo. Toluene
(ca. 50 mL) was added and the mixture was again concentrated
in vacuo to afford 89 g (99%) of the corresponding chloride as
The compound (±)-1 (520 mg) was resolved by preparative
chiral HPLC using closed-loop steady-state recycling [30], 5 x
50 cm Chiralcel OD column (30 °C column temperature, 84
mL/min flow rate, 249 nm detection). Elution with heptane-iso-
propyl alcohol-diethylamine (75:24.9:0.1, v/v/v) afforded 242
mg (46%) of enantiomer (-)-1 [retention time 8.5 min (>99%
1
an oil: H NMR (400 MHz, CDCl3) ꢀ 7.39-7.20 (m, 5H), 3.56-
ee); [ꢁ]25 -6 (c 0.96, DMSO)] and 252 mg (48%) of enantiomer
3.50 (m, 2H), 3.22 (q, 1H, J = 6.55 Hz), 2.79-2.63 (m, 2H),
2.63-2.50 (m, 1H), 2.50-2.33 (m, 2H), 2.13-2.03 (m, 1H), 1.59-
1.54 (m, 1H), 1.41 (d, 3H, J = 6.58 Hz).
D
(+)-1 [retention time 15.0 min (97% ee)].
(3S)-5-Oxo-1-[(1S)-1-phenylethyl]-3-Pyrrolidine carboxylic
acid [(-)-4]. Itaconic acid (123 g, 947 mmol) and (S)-ꢁ-
methylbenzylamine were heated in a 160 °C oil bath under N2.
After 4.25 h, the mixture was cooled and methanol (200 mL)
was added, which caused a solid precipitate to form. The
resulting solid was filtered and re-suspended in ethanol (~750
mL). The mixture was heated for 15 min, followed by
concentration in vacuo until ~450 mL of solvent remained. The
mixture was cooled to room temperature, and allowed to stand
overnight. The resulting solid was filtered and dried in vacuo to
afford (-)-4 (83.2 g, 36%) as a white solid: mp 203-206 °C (lit.
The above oil was dissolved in DMSO (350 mL) and the
solution was treated with sodium cyanide (32.9 g, 671 mmol).
The mixture was heated in a 95 °C oil bath for 1 h, followed by
cooling to room temperature. Water (400 mL) was added and
the solution extracted with tert-butyl methyl ether (MTBE). The
MTBE layer was washed with water (2x), and brine. The
organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo to afford (-)-5 (80.6 g, 98%)
as a red oil. An analytical sample was prepared via distillation
(110-120 °C, ~3 torr) to afford a clear oil: [ꢁ]25 -53° (c 1.03,
D
[14a] 202-204 °C); [ꢁ]25 -102 (c 1.1, MeOH) [lit. [14a] -100 (c
DMSO); IR (liq.) 3027, 2970, 2932, 2875, 2786, 1492, 1452,
1
D
1370, 1315, 1307, 1281, 1211, 1149, 765, 702 cm-1; H NMR
1.1, MeOH)]; IR (diffuse reflectance) 2980, 2322, 2243, 1977,
1955, 1904, 1737, 1653, 1450, 1225, 1216, 1194, 1185, 699, 677
(400 MHz, CDCl3) ꢀ 7.25-7.40 (m, 5 H), 3.26 (q, J = 6.6 Hz, 1
H), 2.70-2.85 (m, 2 H), 2.40-2.60 (m, 4 H), 2.27 (dd, J = 9.4, 5.1
Hz, 1 H), 2.10-2.20 (m, 1 H), 1.55-1.65 (m, 1 H), 1.31 (d, J =
6.4 Hz, 3 H); low resolution MS (CI) m/e 215 (M+H), 128, 120,
111, 109, 84, 70, 69, 61, 58; high resolution MS (FAB) calcd for
C14H19N2 (M+H) 215.1548, found 215.1543. Anal. Calcd for
C14H18N2: C, 78.46; H, 8.47; N, 13.07. Found: C, 78.14; H,
8.44; N, 12.87.
1
cm –1; H NMR (400 MHz, DMSO-d6) ꢀ 12.66 (s, 1 H), 7.40-
7.20 (m, 5H), 5.23 (q, 1H, J = 7.1 Hz), 3.55-3.40 (m, 1H), 3.25-
3.10 (m, 2H), 2.65-2.40 (m, 2H), 1.45 (d, 3H, J = 7.3 Hz); low
resolution MS (EI) m/e 233 (M+H) 218, 160, 105, 104, 103, 91,
79, 78, 77; high resolution MS (FAB) calcd for C13H16NO3
(M+H) m/e 234.1130, found 234.1118. Anal. Calcd for
C13H15NO3: C, 66.94; H, 6.48; N, 6.01. Found: C, 66.76; H,
6.54; N, 5.95.
(3R)-1-[(1S)-1-Phenylethyl]-3-pyrrolidineacetic acid
methyl ester [(-)-6]. To a stirred solution of (-)-5 (137.5 g, 641
mmol) in methanol (200 mL) was added to a solution of
hydrogen chloride in methanol, prepared by the slow addition of
acetyl chloride (900 mL, 12.7 mol) to a chilled (ice bath) flask
containing methanol (1.5 L). The mixture was stirred under a
nitrogen atmosphere for 72 h. Nitrogen was bubbled through the
suspension for 2.5 h, and the remaining mixture was
concentrated in vacuo. The remaining residue was partitioned
between 5% aqueous sodium hydroxide and ethyl acetate. The
pH of the aqueous layer was adjusted to 9 with additional
aqueous sodium hydroxide and sodium bicarbonate, and the
layers were separated. The aqueous layer was back extracted
with ethyl acetate, and the combined organics were dried over
anhydrous magnesium sulfate, filtered, concentrated in vacuo to
afford 132 g of an orange oil. The crude product was purified
by distillation (107-109 °C, ~3 torr) to afford (-)-6 (122.4 g,
(3R)-1-[(1S)-1-Phenylethyl]-3-Pyrrolidineacetonitrile [(-)-
5]. A suspension of (-)-4 (82.30 g, 352.8 mmol) in ether (200
mL) was added slowly (over ~45 min) to a slurry of lithium
aluminum hydride (17.41 g, 458.7 mmol) in ether (700 mL).
The mixture began to reflux during the addition. After complete
addition, the mixture was heated with a 40 °C oil bath for an
additional 2.5 h. The mixture was cooled to 0 °C and water (62
mL) was cautiously added. The resulting mixture was filtered
and concentrated to give a yellow oil, which was crystallized
(EtOAc/hexane) to afford 32.8 g (61%) of (3S)-1-[(1S)-1-
phenylethyl]-3-pyrrolidinemethanol as a white solid: mp 86-88
°C (lit. [31] 86-87 °C); [ꢁ]25D -67° (c 2.3, EtOAc) [lit. [31] -65.3
(c 1, EtOAc)]; IR (diffuse reflectance) 3187, 2976, 2970, 2962,
2955, 2926, 2870, 2823, 2806, 1450, 1368, 1141, 1058, 767, 706
1
cm-1; H NMR (400 MHz, CDCl3) ꢀ 7.20-7.45 (m, 5H), 3.60-
3.70 (m, 1H), 3.40-3.60 (m, 2H), 3.19 (q, 1H, J = 6.6 Hz), 3.05-

Jan-Feb 2008
Preparation of Novel Azabicyclic Amines
253
77%) as a clear oil: [ꢀ]25 -47° (c 0.98, DMSO); IR (liq.) 2970,
(3R,5R)-1-Azabicyclo[3.2.1]octan-3-amine dihydro-
chloride [(-)-3]. The compound (-)-3 (3.51 g, 78%) was
prepared from (+)-7 (3.64 g, 22.6 mmol), hydroxylamine
hydrochloride (2.04 g, 29.4 mmol) and sodium acetate trihydrate
(9.23 g, 67.8 mmol), followed by subsequent treatment with
sodium metal (13.6 g, 618 mmol) in n-propanol (100 mL) in a
manner similar to that described for the preparation of (±)-3.
White solid: mp >290 °C; [ꢀ]25D -3° (c 0.94, DMSO).
D
2954, 2932, 2781, 1738, 1492, 1452, 1436, 1370, 1281, 1253,
1200, 1156, 765, 702 cm-1; 1H NMR (400 MHz, CDCl3) ꢁ 7.20-
7.40 (m, 5 H), 3.69 (s, 3 H), 3.23 (q, J = 6.5 Hz, 1 H), 2.85-2.95
(m, 1 H), 2.55-2.70 (m, 2 H), 2.40-2.55 (m, 3 H), 2.00-2.15 (m,
2 H), 1.40-1.50 (m, 1 H), 1.40 (d, J = 6.6 Hz, 3 H); low
resolution MS (EI) m/e 247 (M+), 233, 232, 170, 105, 103, 91,
86, 84, 79, 77; high resolution MS (FAB) calcd for C15H22NO2
(M+H) 248.1650, found 248.1651. Anal. Calcd for C15H21NO2:
C, 72.84; H, 8.56; N, 5.66. Found: C, 72.89; H, 8.40; N, 5.69.
(5R)-1-Azabicyclo[3.2.1]octan-3-one•hydrochloride [(+)-
7]. A solution containing (-)-6 (24.0 g, 97.0 mmol) and tetra-
hydrofuran (270 mL) under argon atmosphere was cooled to -78
°C. To this solution was added chloro iodomethane (21.1 mL,
290 mmol). After complete addition, the mixture was stirred for
5 min before a freshly prepared lithium diisopropyl amide
solution (~1.5 M in THF, 290 mmol) was slowly added via
canula. After complete addition (ca. 1.25 h), the mixture was
stirred at -78 °C for an additional 25 min. n-BuLi (138 mL of a
2.1 M tetrahydrofuran solution, 290 mmol) was added over a 20
minute period. The mixture was stirred for an additional 15
min., followed by quenching via the addition of a saturated
aqueous ammonium chloride solution (ca. 50 mL). The mixture
was warmed to 0 °C, followed by the addition of water (100
mL). While still cold, the organic layer was separated, washed
with water (40 mL), brine (50 mL) and the combined aqueous
layers were back extracted with ethyl acetate (100 mL). The
combined organics were concentrated in vacuo, and the
remaining residue was diluted with ethanol (30 mL). The
mixture was concentrated in vacuo and the remaining residue
was diluted with methylene chloride. Concentration of the
mixture in vacuo gave a foam. The crude product was
purified by column chromatography (Biotage 40M).
Elution with methylene chloride-methanol (95:5ꢀ85:15)
N-(1R,3R,5R)-1-Azabicyclo[3.2.1]oct-3-yl-4-chlorobenz-
amide•hydrochloride [(+)-8]. To a stirred solution of p-chloro-
benzoic acid (0.221 g, 1.11 mmol), N,N-diisopropylethylamine
(0.62 mL, 3.6 mmol) and (-)-3 (0.221 g, 1.11 mmol) in tetrahydro-
furan-N,N-dimethylformamide (22 mL, 9:2) at 0 °C was added O-
(7-azabenzotriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate [17] (HATU, 0.422 g, 1.11 mmol). The mixture was
allowed to warm to room temperature and stir overnight. The
mixture was concentrated in vacuo, and the remaining residue was
partitioned between ethyl acetate and 1 N aqueous sodium
hydroxide solution. The organic layer was separated, washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (Biotage 40S). Elution with
chloroform-methanol-ammonium hydroxide (90:9:1), followed by
concentration of the fractions in vacuo gave an oil. The oil was
taken up in ethyl alcohol and re-concentrated in vacuo. The
remaining oil was treated with a solution of hydrogen chloride in
methanol, followed by concentration in vacuo. The crude product
was triturated in a mixture of isopropyl alcohol-ethanol-ether. The
solid precipitate was filtered and dried in vacuo to afford 0.272 g
(81%) of (+)-8 as a white solid: mp 284-287 °C (dec.); [ꢀ]25D 3 (c
0.44, MeOH); IR (diffuse reflectance) 2599, 2578, 2555, 2535,
2516, 2501, 2488, 1658, 1592, 1538, 1485, 1319, 1302, 1091, 851
1
cm-1; H NMR (400 MHz, DMSO-d6) ꢁ 10.48 (br s, 1 H), 8.55-
8.65 (m, 1 H), 7.87 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H),
4.40-4.55 (m, 1 H), 3.00-3.55 (m, 6 H), 2.65-2.75 (m, 1 H), 2.05-
2.20 (m, 1 H), 1.85-2.00 (m, 2 H), 1.65-1.80 (m, 1 H); low
resolution MS (EI ) m/e 264 (M+), 264, 141, 139, 111, 109, 96, 94,
83, 82, 75; high resolution MS (FAB) calcd for C14H18ClN2O
(M+H) 265.1107, found 265.1120. Anal. Calcd for C14H17ClN2O•
HCl•1/8H2O: C, 55.41; H, 6.06; N, 9.23. Found: C, 55.41; H,
6.09; N, 9.16.
gave 17.3
g (67%) of (5R)-3-oxo-1-[(1S)-1-phenyl-
ethyl]-1-azoniabicyclo[3.2.1]octane chloride as an off-
white foam: 1H NMR (400 MHz, DMSO-d6) ꢁ 7.60-7.75 (m, 2
H), 7.45-7.55 (m, 3 H), 5.02 (q, J = 7.1 Hz, 1 H), 4.05-4.20 (m, 1
H), 3.80-4.05 (m, 4 H), 3.25-3.35 (m, 1 H), 2.85-3.00 (m, 1 H),
2.65-2.80 (m, 1 H), 2.35-2.50 (m, 2 H), 1.85-1.95 (m, 1 H), 1.74
(d, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6) ꢁ 201.5,
134.5, 131.3, 131.2, 129.9, 73.0, 65.4, 64.5, 62.5, 46.2, 32.4,
29.6, 15.5; MS (ESI+) m/e (M+H) 230.
tert-Butyl 4-(2-oxopropyl)piperidine-1-carboxylate (11).
Sodium hydride (60% oil dispersion, 4.2 g, 105 mmol) was
washed with pentane (3X) and suspended in dry tetrahydrofuran
(100 mL). The solution was cooled to 0 °C before diethyl (2-
oxopropyl)phosphonate (20.5 g, 105 mmol) was added drop-
wise. After complete addition, the solution was warmed to room
temperature and stirred for 30 min. tert-Butyl 4-oxo-1-
piperidinecarboxylate (9, 20.0 g, 100.0 mmol) was added in
portions over 10 min., followed by stirring at room temperature
for 2 h. A saturated aqueous solution of ammonium chloride
was added, followed by dilution with ether. The organic layer
was extracted with water. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated to a
yellow oil. The crude product was purified by flash chromato-
graphy on silica gel. Elution with hexanes-ether (60:40) gave
15.0 g (62%) of tert-butyl 4-(2-oxopropylidene)piperidine-1-
carboxylate as a white solid: mp 71-72 °C; Rf 0.50 (ether-
hexanes, 1:1); IR (diffuse reflectance) 1676, 1620, 1428, 1364,
1353, 1306, 1277, 1248, 1166, 1119, 955, 864, 767, 696, 640
cm-1; 1H NMR (CDCl3) ꢁ 6.12 (s, 1H), 3.53 (t, 2H, J = 5.81 Hz),
3.47 (t, 2H, J = 5.80 Hz), 2.93 (t, 2H, J = 5.50 Hz), 2.28 (t, 2H, J
A mixture of the above foam (38.4 g, 144 mmol) and 10%
Pd/C (9.5 g) in methanol (400 mL) in a Parr bottle was shaken
under an atmosphere of hydrogen (45 psi) for 60 h. The mixture
was filtered through Celite, and the filter cake was washed with
methanol. The filtrate was concentrated in vacuo. The remaining
residue was suspended in ether-ethanol and sonicated. The solid
was filtered and dried in vacuo to afford 17.1 g (73%) of (+)-7
as a white solid: mp 281-283 (dec.); [ꢀ]25D 33° (c 0.97, DMSO);
IR (diffuse reflectance) 2958, 2904, 2803, 2738, 2717, 2683,
1
2605, 2580, 2550, 2498, 2443, 1730, 1359, 1221, 874 cm-1; H
NMR (400 MHz, methanol-d4) ꢁ 4.15-4.25 (m, 1 H), 3.85-3.95
(m, 1 H), 3.65-3.85 (m, 2 H), 3.50-3.65 (m, 3 H), 3.00-3.10 (m,
1 H), 2.80-2.95 (m, 1 H), 2.55-2.65 (m, 1 H), 2.35-2.50 (m, 1
H), 2.00-2.10 (m, 1 H); 13C NMR (100 MHz, methanol-d4) ꢁ
201.4, 65.2, 58.4, 55.2, 47.9, 34.3, 29.6; low resolution MS (EI)
m/e 125 (M+), 97, 96, 82, 69, 68, 56, 55, 54, 51; high resolution
MS (FAB) calcd for C7H12NO (M+H) m/e 126.0919, found
126.0937. Anal. Calcd for C7H11NO•HCl: C, 52.02; H, 7.48; N,
8.67. Found: C, 51.89; H, 7.53; N, 8.63.

254
D. P. Walker, B. A. Acker, E. J. Jacobsen and D. G. Wishka
Vol 45
1H
= 5.73 Hz), 2.22 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) ꢀ 199.6, 156.8, 155.2, 123.6, 80.03, 36.93, 32.53, 30.14,
28.99. Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84; N, 5.85.
Found: C, 65.03; H, 8.82; N, 5.85.
1-Chloro-3-piperidin-4-ylacetone
trifluoroacetate:
NMR (400 MHz, CDCl3) ꢀ 8.63-8.52 (br s, 1H), 8.22-8.09 (br s,
1H), 4.10 (s, 2H), 3.52 (br d, 2H, J = 12.63 Hz), 3.02 (q, 2H, J =
12.41 Hz), 2.68 (d, 2H, J = 6.60 Hz), 2.31-2.19 (m, 1H), 2.01 (br
d, 2H, J = 13.84 Hz), 1.60 (qd, 2H, J = 15.55, 3.88 Hz); low
resolution MS (ESI) m/e 176 [M+H].
A mixture of the above solid (8.15 g, 34.3 mmol) and 10%
palladium on activated carbon (1.0 g) in ethyl alcohol (200 mL)
was placed in a Parr bottle and hydrogenated for 5 h at 50 psi.
The mixture was filtered through Celite, and the filtrate was
concentrated in vacuo to afford 8.1 g (99%) of 11 as a clear oil:
Rf 0.52 (ether-hexanes, 1:1); IR (neat) 2966, 2921, 1708, 1691,
To a stirred solution of diisopropylethylamine (30 mL) in
acetonitrile (1.3 L) at reflux temperature was added a solution of
the above oil (4.7 g, 14.1 mmol) in acetonitrile (250 mL) over a
6 h period via syringe pump. The mixture was kept at reflux
temperature overnight. The mixture was concentrated in vacuo,
and the remaining residue was partitioned between half saturated
aqueous potassium carbonate solution and chloroform-methanol
(90:10). The aqueous layer was extracted with chloroform-
methanol (90:10), and the combined organic layers were dried
over magnesium sulfate, filtered and concentrated in vacuo to a
brown oil. The crude product was purified by flash chromato-
graphy on silica gel. Elution with chloroform-methanol-
ammonium hydroxide (95:4.5:0.5) gave 1.59 g (81%) of 13 as a
clear solid: mp 129-131 °C (lit. [20] 128.5-131.5 °C); Rf 0.55
(chloroform-methanol-ammonium hydroxide, 81:15:1); IR
(chloroform) 2931, 2867, 1701, 1455, 1404, 1198, 1092 cm-1; 1H
NMR (400 MHz, CDCl3) ꢀ 3.63 (s, 2H), 3.27-3.18 (m, 2H),
3.07-2.95 (m, 2H), 2.72 (d, 2H, J = 4.11 Hz), 2.25-2.20 (m, 1H),
1.96-1.79 (m, 4H); 13C NMR (100 MHz, CDCl3) ꢀ 224.1, 70.20,
51.72, 47.35, 27.54, 24.20; low resolution MS (ESI) m/e 140
[M+H].
1241, 1162, 1081, 965, 861, 764 cm-1; H NMR (400 MHz,
1
CDCl3) ꢀ 4.07 (br d, 2H, J = 13.00 Hz), 2.73 (td, 2H, J = 14.43,
2.10 Hz), 2.37 (d, 2H, J = 6.76 Hz), 2.30 (s, 3H), 1.99 (m, 1H),
1.65 (br d, 2H, J = 13.56 Hz), 1.46 (s, 9H), 1.10 (qd, 2H, J =
12.49, 4.39 Hz); 13C NMR (100 MHz, CDCl3) ꢀ 208.3, 155.2,
79.70, 50.54, 43.97, 32.28, 32.13, 31.06, 28.84.
4-(3-Bromo-2-oxo-propyl)-piperidine-1-carboxylic acid tert-
butyl ester [12a] and 4-(3-chloro-2-oxo-propyl)-piperidine-1-
carboxylic acid tert-butyl ester [12b]. To a dry flask was
added a solution of lithium bis(trimethylsilyl)amide (14.6 mL of
a 1.0 M solution in tetrahydrofuran, 14.6 mmol). The solution
was cooled to -78 °C, followed by sequential dropwise addition
of trimethylsilyl chloride (1.86 mL, 14.6 mmol) and 11 (3.21 g,
13.3 mmol) in tetrahydrofuran (50 mL). The mixture was stirred
at -78 °C for 30 min. The mixture was warmed to 0 °C and
phenyltrimethylammonium tribromide (5.31 g, 14.0 mmol) was
added at once. The mixture was stirred at 0 °C for 1 h. The
mixture was diluted with ether and water, and the layers were
separated. The aqueous layer was extracted with ether. The
organic layer was washed with saturated aqueous sodium
thiosulfate and brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated in
vacuo to an oil. The crude product was purified by flash
chromatography on silica gel. Elution with hexanes-ether
(60:40) gave 2.2 g (52%) of an inseparable 1:2 mixture of 12a
and 12b, respectively as a clear oil.
1-Azabicyclo[3.2.2]nonan-3-aminebis(4-methylbenzene
sulfonate) [(±)-15]. To a stirred mixture of 13 (1.51 g, 10.8
mmol) and sodium acetate trihydrate (2.94 g, 21.6 mmol) in
ethyl alcohol (27 mL) was added hydroxylamine•hydrochloride
(905 mg, 13.0 mmol). The mixture was stirred at room
temperature for 16 h. The mixture was diluted with chloroform,
filtered, and the mother liquor was concentrated in vacuo to
afford 1.66 g (99%) of a mixture (2.4:1) of oximes as a white
solid.
ꢁ-Bromoketone 12a: Rf 0.41 (hexanes-ether, 20:80); 1H
NMR (400 MHz, CDCl3) ꢀ 4.11 (br d, 2H, J = 13.56 Hz), 3.89
(s, 2H), 2.77 (td, 2H, J = 13.32, 2.60 Hz), 2.63 (d, 2H, J = 6.78
Hz), 2.13-2.03 (m, 1H), 1.70 (br d, 2H, J = 13.05 Hz), 1.49 (s,
9H), 1.17 (qd, 2H, J = 12.44, 4.28 Hz); low resolution MS (ESI)
m/e 220 [M-BOC+2H].
ꢁ-Chloroketone 12b: Rf 0.41 (hexanes-ether, 20:80); 1H
NMR (400 MHz, CDCl3) ꢀ 4.11 (br d, 2H, J = 13.56 Hz), 4.09
(s, 2H), 2.77 (td, 2H, J = 13.32, 2.60 Hz), 2.56 (d, 2H, J = 6.74
Hz), 2.13-2.03 (m, 1H), 1.70 (br d, 2H, J = 13.05 Hz), 1.49 (s,
9H), 1.17 (qd, 2H, J = 12.44, 4.28 Hz); low resolution MS (ESI)
m/e 176 [M-BOC+2H].
First eluting oxime: Rf 0.62 (chloroform-methanol-
ammonium hydroxide, 80:19:1); 1H NMR (400 MHz, methanol-
d4) ꢀ 4.17 (s, 2H), 3.30-3.10 (m, 4H), 2.76 (d, 2H, J = 4.40 Hz),
2.40-2.35 (m, 1H), 2.10-2.00 (m, 4H).
Second eluting oxime: Rf 0.53 (chloroform-methanol-
ammonium hydroxide, 80:19:1); 1H NMR (400 MHz, methanol-
d4) ꢀ 3.97 (s, 2H), 3.25-3.05 (m, 4H), 2.88 (d, 2H, J = 4.00 Hz),
2.40-2.35 (m, 1H), 2.00-1.85 (m, 4H).
To a stirred solution of the above mixture of oximes (1.67 g,
10.8 mmol) in n-propanol (150 mL) at reflux temperature was
added sodium metal (3.7 g, 162 mmol) in small portions over 30
minutes. Heating at reflux was continued for 2 h. The solution
was cooled to RT and diluted with ethyl acetate and brine. The
organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo to a white solid. The solid is
taken up in ethyl alcohol (20 mL) and p-toluenesulfonic acid
monohydrate (4.3 g, 21.6 mmol) was added. The solution was
warmed in a water bath to 50 °C for 30 minutes, followed by
cooling in a freezer (–10 °C) overnight. The solid precipitate
was collected by filtration, washed with acetone and dried in
vacuo to afford 4.21 g (80%) of (±)-15 as a white solid: mp
231-233 °C; IR (diffuse reflectance) 3023, 2990, 2943, 2886,
2733, 2672, 1498, 1493, 1217, 1175, 1124, 1035, 1011, 814, 684
1-azabicyclo[3.2.2]nonan-3-one [13]. To a stirred mixture of
12a and 12b (1:2 mixture, 4.5 g, 14.1 mmol) in methylene
chloride (60 mL) in an ice-water bath was added trifluoroacetic
acid (15 mL, 190 mmol). The mixture was stirred at 0 °C for 30
min. The volatiles were removed in vacuo to afford 4.7 g (99%)
of 1:2 mixture of 1-bromo-3-piperidin-4-ylacetone trifluoro-
acetate and 1-chloro-3-piperidin-4-ylacetone trifluoroacetate as
an oil.
1-Bromo-3-piperidin-4-ylacetone
trifluoroacetate: 1H
NMR (400 MHz, CDCl3) ꢀ 8.63-8.52 (br s, 1H), 8.22-8.09 (br s,
1H), 3.90 (s, 2H), 3.52 (br d, 2H, J = 12.63 Hz), 3.02 (q, 2H, J =
12.41 Hz), 2.74 (d, 2H, J = 6.62 Hz), 2.31-2.19 (m, 1H), 2.01 (br
d, 2H, J = 13.84 Hz), 1.60 (qd, 2H, J = 15.55, 3.88 Hz); low
resolution MS (ESI) m/e 220 [M+H].
1
cm-1; H NMR (400 MHz, MeOH-d4) ꢀ 7.73 (d, 4H, J = 8.16
Hz), 7.27 (d, 4H, J = 7.99 Hz), 4.05-3.90 (m, 2H), 3.55-3.35 (m,
5H), 2.53-2.40 (m, 2H), 2.39 (s, 6H), 2.20-2.10 (m, 1H), 2.08-

Jan-Feb 2008
Preparation of Novel Azabicyclic Amines
255
1.98 (m, 3H), 1.87 (t, 1H, J = 12.55 Hz); 13C NMR (100 MHz,
MeOH-d4) ꢀ 143.7, 142.4, 130.4, 127.3, 57.15, 50.99, 46.48,
45.41, 38.71, 25.78, 24.54, 22.12, 21.73; high-resolution MS
(FAB) calcd for C8H17N2 [M+H] m/e 141.1392, found 141.1388.
Anal. Calcd C8H16N2•2C7H8O3S: C, 54.53; H, 6.66; N, 5.78.
Found: C, 54.34; H, 6.67; N, 5.79.
65.54, 57.90, 51.59, 25.04, 24.57, 16.66; low resolution MS (EI)
m/e (rel intensity): 257 (M+, 8), 257 (8), 228 (14), 198 (37), 106
(6), 92 (10), 91 (99), 86 (23), 84 (33), 65 (17), 51 (19); high
resolution MS (ESI) calcd for C16H20NO2 [M+H] m/e 258.1494,
found 258.1496.
exo-8-Azabicyclo[3.2.1]octane-6,8-dicarboxylic acid 8-
tert-butyl ester [(±)-21]. Methyl ester (±)-20 was combined
with 300 mg of 10% palladium on activated carbon and di-
tert-butyl dicarbonate (3.8 g, 17.3 mmol) and 50 mL of ethyl
alcohol in a 250 mL Parr shaker flask. The mixture was
hydrogenated at 50 psi for 6 h at room temperature. The
catalyst was removed by filtration, and the volatiles were
removed in vacuo. The crude product was purified by flash
chromatography on silica gel. Elution with hexanes-ethyl
acetate (85:15) gave 2.69 g (87%) of methyl endo-8-tert-
butoxycarbonyl-8-aza-bicyclo[3.2.1]octane-6-carboxylate as
a pale yellow solid: mp 81-83 °C; IR (diffuse reflectance)
2980, 2950, 2430, 2395, 2332, 2285, 2237, 1735, 1682,
1409, 1315, 1307, 1212, 1197, 1186 cm-1; 1H NMR (400
MHz, CDCl3) ꢀ 4.39-4.17 (m, 2H), 3.73 (s, 3H), 3.23-3.17 (m,
1H), 2.26-2.18 (m, 2H), 1.76-1.49 (m, 6H), 1.49 (s, 9H); low
resolution MS (CI) m/e (rel intensity): 270 (MH+,58), 271
(9), 270 (58), 231 (25), 214 (4), 187 (3), 171 (9), 170 (99),
169 (3), 83 (6), 58 (5). Anal. Calcd for C14H23NO4: C, 62.43;
H, 8.61; N, 5.20. Found: C, 62.54; H, 8.50; N, 5.20.
N-(1-Azabicyclo[3.2.2]non-3-yl)furo[2,3-c]pyridine-5-car-
boxamide•fumarate [(±)-10]. To a stirred solution of (±)-15
(310 mg, 0.64 mmol) in N,N-dimethylformamide (8.0 mL) in a 0
°C ice bath were added sequentially diisopropylethylamine (334
μL, 1.92 mmol), furo[2,3-c]pyridine-5-carboxylic acid [8b] (130
mg, 0.67 mmol) and HATU (243 mg, 0.64 mmol). The mixture
was stirred at 0 °C for 15 min., followed by warming to room
temperature and stirring overnight. The mixture was concen-
trated in vacuo to a brown residue. The residue was partitioned
between saturated aqueous potassium carbonate solution and
chloroform-methanol (90:10). The aqueous layer was extracted
with chloroform-methanol (90:10), and the combined organic
layers were washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel. Elution with
chloroform-methanol-ammonium hydroxide (95:4.5:0.5) gave
85 mg (47%) of a solid.
To a stirred solution of the above solid (76 mg, 0.27 mmol) in
acetone was added fumaric acid (31 mg, 0.27 mmol). The
solution was heated in a water bath at 45 °C for 30 min.,
followed by concentration of the solvent in vacuo. Ethyl acetate
(3.0 mL) was added to the residue, which caused a solid to
precipitate. The precipitate was filtered and dried in vacuo to
afford 100 mg (93%) of (±)-10 as a white solid: mp 199-200 °C;
IR (diffuse reflectance) 3260, 3105, 2938, 2877, 2579, 1693,
1667, 1601, 1524, 1454, 1351, 1337, 1314, 1294, 1281 cm-1; 1H
NMR (400 MHz, methanol-d4) ꢀ 8.91 (s, 1H), 8.47 (s, 1H), 8.12
(d, 1H, J = 2.00 Hz), 7.12 (d, 1H, J = 1.52 Hz), 6.70 (s, 2H),
4.81-4.72 (m, 1H), 3.77 (dd, 1H, J = 12.98, 5.69 Hz), 3.67-3.57
(m, 1H), 3.50-3.29 (m, 4H), 2.42-2.37 (m, 2H), 2.22-1.98 (m,
5H); 13C NMR (100 MHz, methanol-d4) ꢀ 171.7, 167.0, 155.5,
151.9, 144.6, 137.0, 136.6, 134.0, 117.6, 108.4, 58.69, 50.56,
46.13, 44.09, 40.58, 26.30, 25.15, 22.70; high-resolution MS
(FAB) calcd for C16H20N3O2 [M+H] m/e 286.1555, found
286.1559. Anal. Calcd for C16H19N3O2•C4H4O4•0.25H2O: C,
59.18; H, 5.83; N, 10.35. Found: C, 59.13; H, 5.90; N, 10.15.
8-Benzyl-8-aza-bicyclo[3.2.1]oct-6-ene-6-carboxylic acid
methyl ester [(±)-20]. Methyl propiolate (3.4 mL, 38 mmol)
was combined with anhydrous silver fluoride (6.98 g, 55 mmol)
in dry acetonitrile (175 mL) in a 200 mL one neck round bottom
flask under nitrogen atmosphere. To this mixture was added 1-
benzyl-2,6-bis(trimethylsilyl)piperidine [23] (18, 8.0 g, 25
mmol). After 3 h of stirring at room temperature, a silver mirror
formed on the inside wall of the flask. The mixture was warmed
to 40 °C and stirring was maintained overnight. The mixture
was cooled, filtered through Celite, and the filter cake was
thoroughly washed with dichloromethane. The filtrate was
concentrated in vacuo to give a brown oil. The crude product
was purified by flash chromatography on silica gel. Elution with
hexanes-ethyl acetate (83:17) afforded 2.96 g (46%) of (±)-20
as a pale amber oil: IR (liq.) 2948, 2920, 2243, 1950, 1717,
1436, 1333, 1314, 1248, 1220, 1096, 1056, 746, 731, 698 cm-1;
1H NMR (400 MHz, CDCl3) ꢀ 7.38-7.22 (m, 5H), 6.94 (m, 1H),
3.79 (s, 3H), 3.76 (m, 1H), 3.60 (m, 1H), 3.58-3.48 (m, 2H),
1.84-1.75 (m, 2H), 1.56-135 (m, 4H); 13C NMR (100 MHz,
CDCl3) ꢀ 165.4, 142.5, 139.6, 135.2, 128.6, 128.3, 126.8, 66.09,
The above yellow solid (1.68 g, 6.57 mmol) was combined
with sodium methoxide (886 mg, 16.4 mmol) in 30 mL of
anhydrous methyl alcohol in an oven dried 100 mL two-neck
round bottom flask under nitrogen. The reaction was heated to
reflux for 4 h, followed by cooling to 0 °C. Water (8 mL) was
added, and the mixture was stirred overnight at room
temperature. The volatiles were removed in vacuo and the
remaining residue was dissolved in water (15 mL). The pH of
the mixture was adjusted to 3 with concentrated hydrochloric
acid, followed by extraction with ethyl acetate (4 x 25 mL). The
organic layer was dried over anhydrous magnesium sulfate and
concentrated in vacuo to provide 1.48 g (88%) of (±)-21, as a
white solid: mp 119-120 °C; IR (diffuse reflectance) 3007, 2975,
2965, 2950, 2930, 2878, 2351, 2338, 1691, 1397, 1360, 1324,
1239, 1188, 1096 cm-1; 1H NMR (400 MHz, CDCl3) ꢀ 4.58-4.25
(m, 2H), 2.69 (m, 1H), 2.40 (m, 1H), 1.99-1.27 (m, 8H), 1.46 (s,
9H); low resolution MS (EI) m/e (rel. intensity): 255 (M+, 38),
255 (38), 182 (67), 155 (69), 138 (36), 112 (57), 110 (78), 83
(99), 82 (80), 68 (57), 57 (95). Anal. Calcd for C13H21NO4: C,
61.16; H, 8.29; N, 5.49. Found: C, 61.14; H, 8.27; N, 5.43.
exo-6-Benzyloxycarbonylamino-8-azabicyclo[3.2.1]-
octane-8-carboxylic acid tert-butyl ester [(±)-22]. To a
stirred solution of (±)-21 (1.48 g, 5.94 mmol) and triethyl-
amine (0.808 ml, 5.8 mmol) in dry toluene (25 mL) in a 100 ml
two neck round bottom flask under nitrogen was added
diphenylphosphoryl azide (1.25 ml, 5.8 mmol). The mixture
was stirred at room temperature for 1 h. Benzyl alcohol (0.642
ml, 6.2 mmol) was added, and the mixture was warmed at 60
°C overnight. The mixture was cooled to room temperature
and was diluted with ethyl acetate (75 mL). The mixture was
washed with 100 mL of saturated aqueous sodium bicar-
bonate solution. The organic layer was dried over anhydrous
magnesium sulfate, and the volatiles were removed in vacuo.
The crude material was purified by flash chromatography on
silica gel. Elution with hexanes-ethyl acetate (75:25) gave
1.75 g (84%) of (±)-22 as a pale oil: IR (liq.) 2141, 1996,
1956, 1693, 1680, 1531, 1405, 1393, 1367, 1334, 1252,

256
D. P. Walker, B. A. Acker, E. J. Jacobsen and D. G. Wishka
Vol 45
1
1233, 1173, 1097, 1040 cm-1; H NMR (400 MHz, CDCl3) ꢀ
7.37 (m, 5H), 5.10-4.71 (m, 3H), 4.25 (m, 1H), 4.17-4.10 (m,
1H), 3.96 (m, 1H), 2.24 (m, 1H), 1.65 (m, 6H), 1.48 (s, 9H),
1.41 (m, 1H); low resolution MS (EI) m/e (rel. intensity): 360
(M+, 8), 260 (99), 183 (31), 127 (82), 92 (28), 91(86), 86
(61), 84 (77), 83 (87), 82 (80), 57 (57). Anal. Calcd for
C20H28N2O4: C, 66.64; H, 7.83; N, 7.77, Found: C, 66.29; H,
7.81; N, 8.09.
Acknowledgement. The authors thank Mark Wolfe and Dr.
Vince Groppi for generating ꢁ7-5HT3 functional data, Luz
Cortes-Burgos and Dr. Erik Wong for generating ꢁ7 nAChR
binding data, Randy Jensen for 1H NOE studies, Shahidur
Rahman for synthetic support and the Kalamazoo SAM-Chem
group for analytical data and chromatography support.
REFERENCES AND NOTES
exo-N-(8-Azabicyclo[3.2.1]oct-6-yl)furo[2,3-c]pyridine-
5-carboxamide•dihydrochloride [(±)-17]. Carbamate (±)-22
(812 mg, 2.25 mmol) was combined with 80 mg of 10%
palladium on activated carbon in 25 mL of ethyl alcohol in a
250 mL Parr shaker flask. The mixture was hydrogenated at
50 psi for 2h at room temperature. The catalyst was removed
by filtration and the filtrate was concentrated in vacuo to
provide a pale oil. The crude product was purified by flash
chromatography on silica gel. Elution with methylene
chloride-methanol-ammonium hydroxide (93:6:1) gave 508
mg (99%) of exo-6-amino-8-tert-butoxycarbonyl-8-aza-
bicyclo[3.2.1]octane as a pale oil: 1H NMR (400 MHz,
CDCl3) ꢀ 4.76 (m, 1H), 4.25 (m, 1H), 3.77 (m, 1H), 3.36 (m,
1H), 2.15 (m, 1H), 1.58 (m, 7H), 1.48 (s, 9H), 1.37 (m, 1H);
low resolution MS (API) m/e 227 [M+H].
[1] Bromidge, S.M.; Brown, F.; Cassidy, F.; Clark, M.S.; Dabbs,
S.; Hadley, M.S.; Hawkins, J.; Loudon, J.M.; Naylor, C.B.; Orlek, B.S.;
Riley, G.J. J. Med. Chem. 1997, 40, 4265.
[2] Coe, J.W.; Brooks, P.R.; Vetelino, M.G.; Wirtz, M.C.;
Arnold, E.P.; Huang, J.; Sands, S.B.; Davis, T.I.; Lebel, L.A.; Fox, C.B.;
Shrikhande, A.; Heym, J.H.; Schaeffer, E.; Rollema, H.; Lu, Y.;
Mansbach, R.S.; Chambers, L.K.; Rovetti, C.C.; Schulz, D.W.; Tingley,
F.D.; O’Neill, B.T. J. Med. Chem. 2005, 48, 3474.
[3] Bermudez, J.; Fake, C.S.; Joiner, G.F.; Joiner, K.A.; King,
F.D.; Miner, W.D.; Sanger, G.J. J. Med. Chem. 1990, 33, 1924.
[4] Sorbera, L.A.; Castaner, J. Drugs Future 2000, 25, 558.
[5] Gaster, L.M.; King, F.D. Med. Res. Rev. 1997, 17, 163.
[6] Jaen, J.C.; Davis, R.E. In Annu. Rep. Med. Chem., Bristol,
J.A. Ed, Academic Press, San Diego, 1994, Vol 29, pp. 23-32.
[7] Schmitt, J.D.; Bencherif, M In Annu. Rep. Med. Chem.,
Doherty, A.M. Ed, Academic Press, San Diego, 2000, Vol 35, pp. 41-51.
[8] [a] Bodnar, A.L.; Cortes-Burgos, L.A.; Cook, K.K.; Dinh,
D.M.; Groppi, V.E.; Hajos, M. Higdon, N.R.; Hoffmann, W.E.; Hurst,
R.S.; Myers, J.K.; Rogers, B.N.; Wall, T.M.; Wolfe, M.L. Wong, E.H. J.
Med. Chem. 2005, 48, 905; [b] Wishka, D.G.; Walker, D.P.; Yates,
K.M.; Reitz, S.C.; Jia, S.; Myers, J.K.; Olson, K.L.; Jacobsen, E.J.;
Wolfe, M.L.; Groppi, V.E.; Hanchar, A.J.; Thornburgh, B.A.; Cortes-
Burgos, L.A.; Wong, E.H.; Staton, B.A.; Raub, T.J.; Higdon, N.R.; Wall,
T.M.; Hurst, R.S.; Walters, R.R.; Hoffman, W.E.; Hajos, M.; Franklin,
S.; Carey, G.; Gold, L.H.; Cook, K.K.; Sands, S.B.; Zhao, S.X.; Soglia,
J.R.; Kalgutkar, A.S.; Arneric, S.P.; Rogers, B.N. J. Med. Chem. 2006,
49, 4425; [c] Walker, D.P.; Wishka, D.G.; Piotrowski, D.W.; Jia, S.;
Reitz, S.C.; Yates, K.M.; Myers, J.K.; Vetman, T.N.; Margolis, B.J.;
Jacobsen, E.J.; Acker, B.A.; Groppi, V.E.; Wolfe, M.L.; Thornburgh,
B.A.; Tinholt, P.M.; Cortes-Burgos, L.A.; Walters, R.R.; Hester, M.R.;
Seest, E.P.; Dolak, L.A.; Han, F.; Olson, B.A.; Fitzgerald, L.; Staton,
B.A.; Raub, T.J.; Hajos, M.; Hoffmann, W.E.; Li, K.S.; Higdon, N.R.;
Wall, T.M.; Hurst, R.S.; Wong, H.F.; Rogers, B.N. Bioorg. Med. Chem.
2006, 14, 8219.
To a stirred solution of the above oil (508 mg, 2.25 mmol),
furo[2,3-c]pyridine-5-carboxylic acid [8b] (474 mg, 2.37
mmol) and diisopropylethylamine (1.12 mL, 9.02 mmol) in
N,N-dimethylformamide (6 mL) under nitrogen atmosphere
was added HATU (890 mg, 2.37 mmol). The mixture was
stirred for 48 h at room temperature. The volatiles were
removed in vacuo, and the remaining residue was partitioned
between chloroform (25 mL) and brine-ammonium hydroxide
(25 mL, 1:1). The aqueous layer was back-extracted with 25
mL of chloroform, and the combined organic layer was dried
over anhydrous K2CO3, filtered and concentrated in vacuo.
The crude product was purified by flash chromatography on
silica gel. Elution with hexanes-ethyl acetate (1:1) gave 670
mg (80%) of tert-butyl exo-6-(furo[2,3-c]pyridine-5-yl-
carbonyl)amino-8-azabicyclo[3.2.1]octane-8-carboxylate as a
1
white solid: H NMR (400 MHz, DMSO-d6 ) ꢀ 8.98 (s, 1H),
8.46 (br s, 1H), 8.40 (s, 1H), 8.35 (d, 1H, J = 2 Hz), 7.22 (d,
1H, J = 2 Hz), 4.31 (m, 1H), 4.18 (m, 1H), 3.91 (m, 1H), 2.18
(m, 2H), 1.61 (m, 6H), 1.37 (m, 9H).
[9] Orlek, B.S.; Blaney, F.E.; Brown, F.; Clark, M.S.; Hadley,
M.S.; Hatcher, J.; Riley, G.J.; Rosenberg, H.E.; Wadsworth, H.J.;
Wyman, P. J. Med. Chem. 1991, 34, 2726.
To the above solid (497 mg, 1.39 mmol) was added
methanolic hydrogen chloride (5 mL of a 3.0 N solution). The
solution was stirred 1 h at 60 °C, which resulted in a white
precipitate. The mixture was cooled to room temperature and
diluted with ether (2 mL). The mixture was further cooled to 0
°C. The white precipitate was collected by filtration and washed
with ether. The precipitate was dried in vacuo to afford 455 mg
(95%) of (±)-17: mp 200-202 °C; IR (diffuse reflectance) 3029,
3022, 2987, 2943, 2924, 2895, 2462, 2351, 2339, 2288, 2224,
1668, 1635, 1601, 1339 cm-1; 1H NMR (400 MHz, D2O) ꢀ 10.01
(m, 1H), 8.49 (s, 1H), 8.26 (m, 1H), 7.22 (m, 1H), 4.44 (dd, 1H,
J = 9.2, 4.5), 4.22 (d, 1H, J = 7.2 Hz), 4.04 (m, 1H), 2.53 (dd,
1H, J = 14.7, 9.2 Hz), 2.25 (m, 1H), 1.88-1.75 (m, 3H), 1.68-
1.64 (m, 3H); low resolution MS (EI) m/e (rel. intensity): 271
(M+,23), 189 (99), 146 (81), 119 (54), 118 (85), 83 (91), 82
(74), 80 (42), 68 (66), 63 (41), 55 (33); high resolution MS (ESI)
calcd for C15H18N3O2 [M+H] m/e 272.1399, found 272.1399. %
Water (KF titration): 5.34. Anal. Calcd for C15H19Cl2N3O2•
5.34% H2O: C, 49.54; H, 5.86; N, 11.55. Found: C, 49.53; H,
6.00; N, 11.41.
[10] Thill, B.P.; Aaron, H.S. J. Org. Chem. 1968, 33, 4376.
[11] Cf: [a] Lewin, A.H.; Sun, G.; Fudala, L.; Navarro, H.; Zhou,
L.-M.; Popik, P.; Faynsteyn, A.; Skolnick, P. J. Med. Chem. 1998, 41,
988; [b] Maskill, H.; Wilson, A.A. J. Chem. Soc., Perkin Trans. 2 1984,
1369.
[12] The corresponding racemic endo-chlorobenzamide of (±)-1
was not prepared. However, the corresponding endo-chlorobenzamide of
(+)-8, prepared via treatment of ketone (+)-7 (Scheme 2) with
hydroxylamine, followed by subsequent hydrogenation [H2, PtO2,
AcOH, 45 psi, 17 h, 99%; endo:exo, 6:1] and amide coupling [HATU,
i-Pr2NEt, 4-chlorobenzoic acid, DMF, 17 h, 50%], shows significantly
diminished activity [ꢁ7-5HT3 EC50 = 28 μM] compared to the exo-
isomer.
[13] The absolute configuration of amide (-)-1 was
unambiguously established via single crystal X-ray crystallography (data
not shown).
[14] For the preparation of (-)-4, see: [a] Arvanitis, E.; Motevalli,
M.; Wyatt, P.B. Tetrahedron Lett. 1996, 4277. For the preparation of
(+)-4, see: [b] Culbertson, T.P.; Domagala, J.M.; Nichols, J.B.; Priebe,
S.; Skeean, R.W. J. Med. Chem. 1987, 30, 1711.
[15] Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1996, 52,

Jan-Feb 2008
Preparation of Novel Azabicyclic Amines
257
1069.
Chem. Lett. 1996, 279; [b] Malpass, J.R.; Hemmings, D.A.; Wallis,
A.L.; Fletcher, S.R.; Patel, S. J. Chem. Soc., Perkin Trans. 1 2001, 1044.
[23] Pandey, G.; Bagul, T.D.; Sahoo, A.K. J. Org. Chem. 1998,
63, 760.
[24] Beak, P.; Lee, W.-K. Tetrahedron Lett. 1989, 1197.
[25] Cf: Funk, R.L.; Bolton, G.L.; Daggett, J.U.; Hansen, M.M.;
Horcher, L.H. Tetrahedron 1985, 41, 3479.
[16] [a] Kowalski, C.J.; Haque J. Org. Chem. 1985, 50, 5140; [b]
Kowalski, C.J.; Reddy, R.E. J. Org. Chem. 1992, 57, 7194.
[17] Carpino, L.A. J. Am. Chem. Soc. 1993, 115, 4397-4398.
[18] Compound (+)-8 is the same absolute configuration as
compound (-)-1 but different salt form.
[19] Early in our program, PNU-282987 was used as a standard to
bench-mark the ꢀ7 activity of newly prepared compounds. However,
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