Convenient preparation of aryl-substituted nortropanes by Suzuki-Miyaura methodology

Article abstract of DOI:10.1139/V06-045

The synthesis of a new bicyclic vinyl boronate (5) was accomplished from N-Boc-nortropinone (6) in two steps. The Suzuki-Miyaura coupling of 5 to a variety of aryl bromides and triflates afforded 3-aryl-8-azabicyclo[3.2.1]oct-2- enes in good yields by adj

Full text of DOI:10.1139/V06-045

555
Convenient preparation of aryl-substituted
nortropanes by Suzuki–Miyaura methodology1
Shyamali Ghosh, William A. Kinney, Diane A. Gauthier, Edward C. Lawson,
Tomas Hudlicky, and Bruce E. Maryanoff
Abstract: The synthesis of a new bicyclic vinyl boronate (5) was accomplished from N-Boc-nortropinone (6) in two
steps. The Suzuki–Miyaura coupling of 5 to a variety of aryl bromides and triflates afforded 3-aryl-8-
azabicyclo[3.2.1]oct-2-enes in good yields by adjusting the substrate and (or) reaction conditions. Reduction to the 3-
aryl-8-azabicyclo[3.2.1]octanes was achieved by hydrogenation. Interestingly, the coupling was also successful with
benzyl bromides, providing entry into another group of intermediates.
Key words: nortropane, Suzuki–Miyaura, boronate, piperidine, GPCR, benzyl bromide.
Résumé : La synthèse d’un nouveau boronate de vinyle cyclique (5) a été réalisée en deux étapes à partir de la N-
Boc-tropinone (6). Le couplage du composé 5 avec des bromures et des triflates d’aryles en faisant appel à la méthode
de Suzuki–Miyaura et en ajustant le substrat et les conditions réactionnelles conduit à la formation de 3-aryl-8-
azabicyclo[3.2.1]oct-2-ènes avec de bons rendements. La réduction des 3-aryl-8-azabicyclo[3.2.1]octanes a été réalisée
par hydrogénation. Il est intéressant de noter que la réaction de couplage a été réalisée avec succès avec des bromures
de benzyle, ce qui permet d’accéder à un autre groupe d’intermédiaires.
Mots clés : nortropane, Suzuki–Miyaura, boronate, pipéridine, GPCR, bromure de benzyle.
[Traduit par la Rédaction] Ghosh et al. 560
Introduction
ious aryl halides (Scheme 1). This approach was useful in
the preparation of a variety of 4-phenyl tetrahydropyridines
from an N-Boc-piperid-3-en-4-yl boronate (7b). The
palladium/copper(I)-catalyzed Negishi coupling of 4-
piperidinylzinc iodide with aryl halides and the piperid-3-en-
4-ol phosphate coupling with aryl boronic acids are also
noteworthy methods to prepare 4-arylpiperidines (8, 9).
Recently, a Stille coupling of a bicyclic vinyl tin reagent
provided access to phenyl-substituted 8-azabicyclo[3.2.1]oct-
2-enes (nortropene) and nortropanes (5). The coupling of a
bicyclic vinyl boronate with aryl halides might provide a
less toxic alternative to a variety of interesting nortropenes
and nortropanes. Besides investigating an alternative approach,
we also wanted to determine whether a greater variety of
aryl and benzyl halide coupling partners could be used in
combination with 5 than had been demonstrated with the
Suzuki couplings of the N-Boc-piperid-3-en-4-yl boronate
(7b).
Phenyl piperidines have proven to be valuable templates
for the construction of modulators of G-protein coupled re-
ceptors (GPCRs), which are the target of the largest group of
marketed drugs (~50%). Of the 38 GPCR-targeted drugs on
the market, listed in a recent review (1), five are aryl pipe-
ridines (Allegra, Claritin, Duragesic, Risperdal) or aryl-
substituted bicyclic piperidines (Atrovent, Combivent).
Several others are aryl piperazines or morphine-related
polycyclic aryl piperidines. To illustrate the structural diver-
sity of piperidine-containing GPCR ligands, some examples
are illustrated in the following: µ-opioid agonist loperamide
(1) (2), selective δ-opioid agonist 2 (3), urotensin-II receptor
antagonist palosuran (3) (4), and nonpeptidyl growth hor-
mone secretagogue 4 (5). These compounds demonstrate the
importance of aryl piperidines and how selectivity can be al-
tered by making changes in the aryl piperidine architecture
and pendant groups. We were interested in preparing aryl-
substituted 8-azabicyclo[3.2.1]octane (nortropane) systems
related to 2 and 4 in pursuit of novel GPCR ligands.
Results and discussion
We envisioned accessing aryl nortropanes by a Suzuki–
Miyaura (6) coupling of bicyclic vinyl boronate (5) with var-
The synthesis of 5 was accomplished by the methods out-
lined for the preparation of other pinacolato boronates (7).
Received 16 September 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 5 May 2006.
Dedicated to Professor Walter Szarek on the occasion of his 65th birthday.
S. Ghosh, W.A. Kinney,2 D.A. Gauthier, E.C. Lawson, and B.E. Maryanoff. Johnson & Johnson P.R.D., L.L.C., Spring House,
PA 19477, USA.
T. Hudlicky. Brock University, St. Catharines, ON L2S 3A1, Canada.
1This article is part of a Special Issue dedicated to Professor Walter Szarek.
2Corresponding author (e-mail: wkinney1@prdus.jnj.com).
Can. J. Chem. 84: 555–560 (2006)
doi:10.1139/V06-045
© 2006 NRC Canada

556
Can. J. Chem. Vol. 84, 2006
Cl
tional chlorine substituent was added to the aryl ring (8f,
8g), the triflate (10) was a much better substrate than the
bromo derivative, giving an excellent yield of 9f. The nitro
substituent in 8h did not significantly affect the coupling
yield with the arylbromide. The disubstituted nitro ester (9h)
is a useful intermediate for adding a variety of groups at the
2- and 4-phenyl positions.
O
NEt2
OH
N
The fully reduced 3-aryl-8-azabicyclo[3.2.1]octanes (10,
Scheme 1) could be achieved by reduction of the double
bond in 9. For example, 9d was treated with hydrogen and
10% palladium on carbon to afford a quantitative yield of
10d as a mixture of isomers. The same two isomers of 10d
were obtained when 9f was reduced because of the addi-
tional reduction of the chlorine substituent. The isomers of
10d (from 9f) were separated by column chromatography
and analyzed by 1D and 2D NMR to assign protons and dis-
tinguish the two isomers. For example, an expected NOE
was observed between the Ha and Hb protons in the cis iso-
mer (vide infra). The cis isomer is defined as having the aryl
and the amine on the same side of the bicycle. Once the two
N
Ph
Ph
O
NMe2
1
2
1
isomers were distinguished, the H NMR spectrum on the
HO
NHEt
product 10d derived from 9d was analyzed to determine the
ratio of isomers. There was a predominance of the cis iso-
mer (cis:trans, 1.65:1), as determined by ratios of the Ha and
CH3O- integrations of the two isomers, which are clearly
separated (e.g., Ha-cis δ 4.10 ppm, Ha-trans δ 3.29 ppm).
O
N
N
Me
Me
H
N
H2N
O
H
CH
O
NH
b
O
3
H
H
H
b
H
b
c
H
ar
O
O
H
c
H
H
d
b
c
H
a
NH
H
c
O
N
H
Ph
d
O
N
H
N
e
H
O
a
H
O
e
O
O
Me
CH
3
3
4
trans isomer
of 10d
cis isomer
of 10d
N-Boc-nortropinone (6) was deprotonated with potassium-
hexamethyldisilazide at low temperature and reacted with
Comins’ reagent (2-(N,N-bistriflouromethanesulfonyl)amino-
5-chloropyridine) to yield the vinyl triflate 7 in 92% yield.
The triflate 7 was coupled with bis(pinacolato)diboron, using
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (PdCl2-dppf, 2 mol%) as the cata-
lyst, to afford bicyclic boronate (5) in good yield (77%–
84%). This optimized yield was obtained by using only
1 equiv. of the diboron reagent and by carefully monitoring
the reaction progress by 1H NMR (vinyl proton of 5 vs. 7).
The coupling of bicyclic boronate (5) with a variety of
substituted benzene derivatives (8) was initially investigated
(Table 1). Reaction of 1-bromo-4-methoxybenzene (8a) with
5 using PdCl2-dppf as the catalyst (10 mol%) and potassium
carbonate as the base (Method A) gave a low yield of the de-
sired coupling. This poor result was overcome by instead
utilizing triflate 8b, which gave a quantitative yield of 9a. In
other cases the aryl bromides performed satisfactorily. For
example, 1-bromo-4-methylbenzene (8c) and 2-bromoben-
zoic acid methyl ester (8d) gave a reasonable yield of the
coupled products 9c and 9d (65% in each case). The exam-
ple of 2-bromobenzoic acid ethyl ester (8e) was added to
provide a direct comparison to the Stille approach, which
gave a low yield (42%) of 9e (5). In contrast, coupling of 8e
with 5 afforded 9e more efficiently (72%). When an addi-
The nitrophenyl olefin (9h) was also efficiently (91%) re-
duced under the above conditions to yield the aminophenyl
nortorpane (10h). In this case, the ratio of isomers was re-
versed (trans:cis, 1.27:1) based on the same comparison of
Ha and CH3O- integrations. Chlorophenyl tropane (10f) was
available, albeit in low yield (29%, unoptimized), by a
Sandmeyer reaction (11) with 10h.
A variety of aryl and benzyl halides were evaluated as
coupling partners for bicyclic boronate (5) (Table 1). The
electron-deficient aryl bromide, 2-bromopyridine (11), cou-
pled in good yield with 5 to give 2-pyridyl nortropene (9i).
Electron-rich 3-bromoindole (12) did not couple efficiently
under the usual conditions (Method A), but 9j was obtained
in good yield by using the same catalyst with aqueous so-
dium carbonate and dimethoxyethane (Method B) (12).
While the reaction of benzyl bromides with aryl boronic ac-
ids has been seen in recent years (13), their reaction with vi-
nyl boronic acids is less common (13d, 13e). Although the
yield was only moderate (47%), boronate 5 coupled success-
fully with 13 using tetrakis(triphenylphoshine)palladium(0)
as the catalyst (13b) to give benzyl-substituted 8-
azabicyclo[3.2.1]oct-2-ene (9k). In the case of benzyl bro-
mide (14), the coupling product 9l and its isomer 15l were
isolated (9l:15l, 77:23) in similar yield to 9k. The exocyclic
© 2006 NRC Canada

Ghosh et al.
557
Scheme 1.
O
N
OTf
N
O
O
B
N
O
O
O
O
O
O
6
7
5
O
R
N
R
N
10d, R =
10f, R =
10h, R =
O
R-X
Cl
8
O
O
O
O
O
O
O
O
NH2
10
9
Table 1. Examples of coupling of 5 with aryl and benzyl groups.
O
Z
R
R
H
O
O
N
O
N
Br
Y
N
Boc
N
Boc
Br
X
Br
Br
11
12
13
14
9
15
8
Isolated
yield (%)
Ar-X or
Bz-X
Isolated
yield (%)
Ar-X
X, Y, Z
Product
X, Y, Z
Product
8a
8b
8c
8d
8e
8f
Br, H, OMe
OTf, H, OMe
Br, H, Me
Br, CO2Me, H
Br, CO2Et, H
Br, CO2Me, Cl
31a
100a
65a
65a
72a
35a
9a
9a
9c
9d
9e
9f
8g
8h
11
12
13
14
OTf, CO2Me, Cl
Br, CO2Me, NO2
96a
9f
9h
9i
9j
9k
63a
65a
16a, 83b
47c
54c
9l, 15l (77:23)
aMethod A: Isolated yield using 0.1 equiv. PdCl2-dppf, 3 equiv. K2CO3, DMF–EtOH (4:1), 100 °C, 3–16 h.
bMethod B: Isolated yield using 0.1 equiv. PdCl2-dppf, 4 equiv. 2 mol/L Na2CO3, DME, 100 °C, 10 h.
cMethod C: Isolated yield using 0.1 equiv. [Pd(PPh)3]4, 2 equiv. 2 mol/L Na2CO3, DME, 100 °C, 16 h.
double bond product 15k was also observed in the crude
NMR spectrum of 9k (9k:15k, 85:15), but it was not iso-
lated.
In summary, the synthesis of new bicyclic boronate 5 was
accomplished from N-Boc-nortropinone in two steps. The
Suzuki–Miyaura coupling of 5 to a variety of aryl bromides
and triflates afforded 3-aryl-8-azabicyclo[3.2.1]oct-2-enes in
good yields by adjusting the substrate and (or) reaction con-
ditions. Reduction to the 3-aryl-8-azabicyclo[3.2.1]octanes
was achieved in good yields in cases in which the substrate
had compatible functionality. Interestingly, the coupling of 5
also was successful with benzyl bromides, providing entry
into another group of intermediates. The methodology de-
scribed by Eastwood (7b) has been extended to an elabo-
rated piperidine fragment, as well as to a greater variety of
coupling partners. The chemistry demonstrated in this report
should be applicable to other piperidine and bicyclic
piperidine systems.
© 2006 NRC Canada

558
Can. J. Chem. Vol. 84, 2006
argon for 20 min. The reddish mixture was heated with stir-
ring at 80 °C for 8–10 h, with the color turning a dark brown
within the first 2 h. The product to starting material ratio
was monitored by removing aliquots, evaporating the sol-
Experimental
1H NMR spectra were acquired at 300 MHz on a Bruker
Avance-300 spectrometer in CDCl3 unless indicated other-
wise, using Me4Si as an internal standard. Normal-phase
preparative chromatography was performed on an Isco
Combiflash separation system Sg 100c equipped with a
Redisep normal-phase disposable columns for flash chroma-
tography containing 12 g of silica gel (optimal flow rate
30 mL/min, column volume 16.8 mL, normal-phase silica
part no. 68-2203-026) with detection at 254 nm. Reverse-
phase preparative chromatography was performed on a
Gilson HPLC with a reversed-phase Kromasil column (10 µ,
100 Å, C18, column size 250 mm × 50 mm). Electrospray
(ES) mass spectra were obtained on a Micromass platform
LC single quadruple mass spectrometer in the positive mode.
LC–MS analyses were performed on a Hewlett Packard
series 1100 HPLC instrument eluting with a gradient of
water/MeCN/CF3COOH (10:90:0.2 to 90:10:0.2) over 6 min
with a flow rate of 0.75mL/min on a Supelco ABZ + PLUS
column (50 mm × 2.1 mm; 3.0 µ particle size) at 32 °C. Ac-
1
vent, and examining the sample by H NMR spectroscopy
(ratio of vinyl H of the boronate 5 vs. the triflate 7). The re-
action mixture was cooled, filtered through Celite®, and ad-
sorbed on silica gel (40 g). Chromatography (gradient
elution with 5%–10% ethyl acetate in pentane) yielded the
pure boronate 5 as a white solid (14.7 g, 77%, mp 98 °C).
The fractions that showed an integration ratio of at least
10:14 (Boc-group : pinacol-group Hs) were combined to af-
ford pure 5. Crude boronate 5 of 41% purity (3.1 g, 7%),
contaminated with diboron byproducts, was also obtained as
a waxy solid. The purity of crude 5 was determined by cou-
pling this crude material with 8b affording a 41% yield of
9a vs. 100% yield with pure 5 (1). 1H NMR (CDCl3,
300 MHz) δ: 6.71 (br s, 1H), 4.31–4.23 (m, 2H), 2.76–2.71
(m, 1H), 2.08 (m, 1H), 1.90–1.84 (m, 2H), 1.63–1.55 (m,
2H), 1.40 (s, 9H), 1.20 (s, 12H). HRMS (EI+) m/z calcd. for
C18H30BNO4: 335.2268; found: 335.2278. Anal. calcd. for
C18H30BNO4: C 64.49, H 9.02; found: C 64.46, H 9.00.
curate mass measurements were performed using
a
Micromass (Manchester, UK) Autospec E OA-TOF high-
resolution magnetic sector mass spectrometer tuned to a res-
olution of 6000 using the 10% valley definition. The ions
were produced in a fast atom bombardment ion source at an
accelerating voltage of 8 kV. Linear voltage scans at 33 Da/s
were collected to include the protonated sample ion and two
polyethylene glycol ions which were used as internal refer-
ence standards. The molecular mass was calculated using a
linear extrapolation method. Reported mass values are aver-
ages over 100 s. Elemental analyses were determined by
Quantitative Technologies, Inc., Whitehouse, New Jersey.
Method A (ref. 7b): 3-(4-Methoxyphenyl)-8-azabicyclo-
[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (9a)
To a mixture of 4-methoxy phenyl triflate (8b) (80 mg,
0.31 mmol), the bicyclic boronate 5 (100 mg, 0.30 mmol),
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (PdCl2-dppf, 24 mg, 0.03 mmol),
and K2CO3 (123 mg, 0.89 mmol) in a sealable tube (thick
walled) was added DMF and EtOH (4:1, 2.5 mL). The mix-
ture was stirred under argon at rt for 5–10 min and the tube
was then sealed and heated at 100 °C for 3 h (3–16 h). The
mixture was cooled to rt then filtered thru a pad of Celite®,
washing with EtOAc. The combined organic layer was con-
centrated and purified by flash chromatography using a gra-
dient system of 5%–50% ethyl acetate (0.1% TEA) in
heptane. The desired product 9a was isolated as a white
3-Trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-
ene-8-carboxylic acid tert-butyl ester (7)
A solution of N-Boc-nortropinone (6, 15.0 g, 67 mmol) in
THF (80 mL) was added over 30 min to a cooled (–78 °C)
0.5 mol/L solution of potassium hexamethyldisilazide
(162 mL, 81 mmol) in toluene under argon. More THF
(20 mL) was added to the reaction mixture, which was
stirred for 3.5 h and then treated with 2-(N,N-bistrifluoro-
methanesulfonyl)amino-5-chloropyridine (32.0 g, 81 mmol).
The reaction mixture was stirred at –78 °C for 4 h and then
allowed to warm to room temperature (rt) overnight (final
temp: –30 °C). The reaction mixture was adsorbed onto sil-
ica gel (40 g) and purified by careful flash chromatography
(elution with 10% ethyl acetate in pentane) to provide
1
solid (0.11 g, 100%). H NMR (CDCl3, 300 MHz) δ: 7.29
(d, J = 9 Hz, 2H), 6.85 (d, J = 9 Hz, 2H), 6.33 (br s, 1H),
4.6–4.4 (m, 2H), 3.80 (s, 3H), 3.1 (m, 1H), 2.3–1.6 (m, 5H),
1.45 (s, 9H). MS (ES+, M – Boc + 1) m/z: 216.1. Anal.
calcd. for C19H25NO3: C 72.35, H 7.99, N 4.44; found: C
72.56, H 7.96, N 4.36.
3-p-Tolyl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid
tert-butyl ester (9c)
1
Aryl bromide 8c was combined with 5 by Method A to
triflate 7 as a waxy solid (22 g, 92%). H NMR (CDCl3,
1
yield 9c as an oil (65%). H NMR (CDCl3, 300 MHz) δ:
300 MHz) δ: 5.89 (br s, 1H), 4.25 (br m, 2H), 2.86 (br m,
1H), 2.15–1.59 (m, 5H), 1.30 (s, 9H).
7.25 (d, J = 8 Hz, 2H), 7.11 (d, J = 8 Hz, 2H), 6.39 (br s,
1H), 4.6–4.4 (m, 2H), 3.2–3.0 (m, 1H), 2.33 (s, 3H), 2.3–1.6
(m, 5H), 1.44 (s, 9H). MS (ES+, M – Boc + 1) m/z: 200.1.
HRMS (FAB+) m/z calcd. for C19H25NO2: 299.1885; found:
299.1893.
3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-8-
azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl
ester (5)
The triflate 7 (20.5 g, 57 mmol) was dissolved in dioxane
(200 mL) and potassium acetate (16.8 g, 171 mmol),
bis(pinacolato)diboron (15.0 g, 59 mmol), [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) di-
chloromethane complex (PdCl2-dppf, 1.0 g, 1.2 mmol), and
3-(2-Methoxycarbonylphenyl)-8-azabicyclo[3.2.1]oct-2-
ene-8-carboxylic acid tert-butyl ester (9d)
Aryl bromide 8d was combined with 5 by Method A to
1
yield 9d as an oil (65%). H NMR (CDCl3, 300 MHz) δ:
1,1′-bis(diphenylphosphino)ferrocene
(0.7
g,
mmol,
7.76 (d of d, J = 7.7, 1.3 Hz, 1H), 7.42 (m, 1H), 7.30 (m,
1H), 7.12 (d, J = 7.5 Hz, 1H), 5.83 (br s, 1H), 4.5–4.3 (m,
1.3 mmol) were added and the mixture was degassed with
© 2006 NRC Canada

Ghosh et al.
559
1
2H), 3.85 (s, 3H), 3.1–2.8 (m, 1H), 2.3–1.9 (m, 5H), 1.49 (s,
9H). MS (ES+, M – Boc + 1) m/z: 244.2. HRMS (FAB+) m/z
calcd. for C20H25NO4: 343.1784; found: 343.1788.
isolated as a white solid (113 mg, 83%). H NMR (CDCl3,
300 MHz) δ: 8.78 (br s, NH), 7.61 (m, 1H), 7.4–7.2 (m, 2H),
7.13 (m, 1H), 6.09 (br s, 1H), 4.6–4.4 (m, 2H), 4.41 (q, J =
7 Hz, 2H), 3.6–3.4 (m, 1H), 3.2–2.9 (m, 1H), 2.4–2.0 (m,
4H), 1.50 (s, 9H), 1.42 (t, J = 7 Hz, 3H). MS (ES+, M + Na)
m/z: 419.2. Anal. calcd. for C23H28N2O4: C 69.67, H 7.12, N
7.07; found: C 69.86, H 7.25, N 6.90.
3-(2-Ethoxycarbonylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-
8-carboxylic acid tert-butyl ester (9e)
Aryl bromide 8e was combined with 5 by Method A to
1
yield 9e as an oil (72%). H NMR (CDCl3, 300 MHz) δ:
7.74 (d, J = 7.6 Hz, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 7.12 (d
of d, J = 7.5, 0.8 Hz, 1H), 5.83 (br s, 1H), 4.6–4.2 (m, 4H),
3.1–2.8 (m, 1H), 2.3–1.9 (m, 5H), 1.49 (s, 9H), 1.36 (t, J =
7 Hz, 3H). MS (ES+, M – Boc + 1) m/z: 258.1. HRMS
(FAB+) m/z calcd. for C21H27NO4: 357.1940; found:
357.1935.
Method C (ref. 13b): 3-(3-Methoxycarbonyl-benzyl)-8-
azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl
ester (9k)
To a mixture of benzyl bromide (13) (72 mg, 0.31 mmol),
boronate 5 (100 mg, 0.30 mmol), tetrakis(triphenylphos-
hine)palladium(0) (34 mg, 0.03 mmol), and 2 mol/L Na2CO3
(0.30 mL, 0.60 mmol) in a sealable tube (thick walled) was
added DME (3 mL). The mixture was stirred under argon for
5 min. The tube was then sealed and the reaction mixture
was heated at 100 °C for 16 h. The reaction mixture was
cooled to rt and then filtered through a pad of Celite®, wash-
ing with ethyl acetate. The filtrate was diluted with water
and extracted with ethyl acetate. The organic layer was sepa-
rated, dried (sodium sulfate), concentrated, and purified by
flash chromatography using a gradient system of 5%–50%
ethyl acetate (0.1% TEA) in heptane. Desired product 9k
was isolated as a white solid (53 mg, 47%). 1H NMR
(CDCl3, 300 MHz) δ: 7.9–7.8 (m, 2H), 7.3 (m, 2H), 5.8 (br
d, 1H), 4.4–4.1 (m, 2H), 3.91 (s, 3H), 3.24 (AB q, 2H), 2.8–
1.8 (m, 4H), 1.6–1.3 (m, 2H), 1.4 (br s, 9H). MS (ES+, M +
Na) m/z: 380.1. HRMS (FAB+) m/z calcd. for C21H27NO4 +
H: 358.2018; found: 358.2005.
3-(4-Chloro-2-methoxycarbonylphenyl)-8-azabicyclo-
[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (9f)
Aryl triflate 8g (10), prepared from the corresponding
phenol, was combined with 5 by Method A to yield 9f as an
oil (96%). 1H NMR (CDCl3, 300 MHz) δ: 7.75 (d, J =
2.2 Hz, 1H), 7.38 (d of d, J = 8.2, 2.2 Hz, 1H), 7.05 (d, J =
8.2 Hz, 1H), 5.83 (br s, 1H), 4.5–4.3 (m, 2H), 3.86 (s, 3H),
3.0–2.8 (m, 1H), 2.3–1.9 (m, 5H), 1.49 (s, 9H). MS (ES+,
M – Boc + 1) m/z: 278.1.
3-(2-Methoxycarbonyl-4-nitro-phenyl)-8-azabicyclo-
[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (9h)
Aryl bromide 8h was combined with 5 by Method A to
1
yield 9h as an oil (63%). H NMR (CDCl3, 300 MHz) δ:
8.63 (d, J = 2.4 Hz, 1H), 8.26 (d of d, J = 8.4, 2.4 Hz, 1H),
7.30 (d, J = 8.4 Hz, 1H), 5.91 (br s, 1H), 4.5–4.3 (m, 2H),
3.92 (s, 3H), 3.1–2.8 (m, 1H), 2.3–1.9 (m, 5H), 1.50 (s, 9H).
MS (ES, M + Na) m/z: 411.1. HRMS (FAB+) m/z calcd. for
C20H24N2O6 + H: 389.1713; found: 389.1706.
3-Benzyl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid
tert-butyl ester (9l) and 3-benzylidene-8-azabicyclo-
[3.2.1]octane-8-carboxylic acid tert-butyl ester (15l)
Benzyl bromide (14) was combined with 5 according to
Method C to yield a mixture of 9l and 15l as a colorless oil
3-Pyridin-2-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic
acid tert-butyl ester (9i)
1
(54%, 9l:15l, 77:23, the exocyclic double bond isomer). H
NMR (CDCl3, 300 MHz) δ: 7.39–7.15 (m, 5H), 6.45 (br s,
0.23H), 5.84 (br d, 0.77H), 4.4–4.1 (m, 2H), 3.5–2.5 (m,
4H), 2.2–1.5 (m, 4H), 1.40 (m, 9H). MS (ES+, M + Na) m/z:
321.9. HRMS (FAB+) m/z calcd. for C19H25NO2 – H:
298.1807; found: 298.1799.
2-Bromopyridine (11) was combined with 5 by Method A,
but purified by reverse-phase HPLC (10%–90% MeCN–H2O
containing 0.2% TFA), to yield the TFA salt of 9i as an oil
1
(65%). H NMR (CDCl3, 300 MHz) δ: 8.9 (m, 1H), 8.1 (m,
1H), 7.6 (m, 2H), 7.04 (br m, 1H), 4.7–4.5 (m, 2H), 3.5–1.7
(m, 5H), 1.45 (s, 9H). MS (ES+, M + 1) m/z: 287.3. HRMS
(FAB+) m/z calcd. for C17H22N2O2 + H: 287.1760; found:
287.1760.
3-(2-Methoxycarbonylphenyl)-8-azabicyclo[3.2.1]octane-
8-carboxylic acid tert-butyl ester (10d)
Compound 9d (40 mg, 0.12 mmol), MeOH (15 mL), and
10% Pd-C (15 mg) were shaken in a Parr apparatus (40 psig
of hydrogen, 3.7 atm) for 16 h. The reaction mixture was fil-
tered through Celite® and concentrated to give 10d as an oil
(41 mg, mixture of two isomers, 100%). The ratio of iso-
mers in the reaction mixture was determined to be 1.65:1
cis:trans. The isomers of 10d were initially formed in the
hydrogenation of 9f and separated by flash chromatography
using a gradient system of 5%–25% ethyl acetate (0.1%
TEA) in heptane over 20 min (flow rate 40 mL/min) and
their structures were determined. Analysis by 1H, 13C, and 2-
D NMR determined that the faster eluting, major isomer was
Method B (ref. 12): 3-(8-tert-Butoxycarbonyl-8-
azabicyclo[3.2.1]oct-2-en-3-yl)-1H-indole-2-carboxylic
acid ethyl ester (9j)
To
a mixture of the 3-bromoindole (12, 80 mg,
0.30 mmol), compound 5 (100 mg, 0.30 mmol), [1,1′-bis(di-
phenylphosphino)ferrocene]dichloropalladium(II) dichloro-
methane complex (PdCl2-dppf, 30 mg, 0.04 mmol), and
2 mol/L aq. Na2CO3 (0.6 mL, 1.2 mmol) in a sealable tube
(thick walled) was added DME (3 mL). After stirring under
argon for 5 min, the tube was sealed and heated at 100 °C
for 10 h. The reaction mixture was cooled to rt and then fil-
tered through a pad of Celite®, washing with EtOAc. The or-
ganic layer was concentrated and purified by flash
chromatography using a gradient system of 5%–50% ethyl
acetate (0.1% TEA) in heptane. The desired product 9j was
1
the cis isomer. Analysis of 10d mixture from 9d: H NMR
(CDCl3, 300 MHz) δ: 7.78 (m, 0.62H), 7.65 (m, 0.38H),
7.44 (m, 1H), 7.34 (m, 1H), 7.24 (m, 1H), 4.4–4.2 (m, 2H),
4.10 (m, 0.62Ha-cis), 3.91 (s, 1.9Hcis), 3.87 (s, 1.1Htrans), 3.29
© 2006 NRC Canada

560
Can. J. Chem. Vol. 84, 2006
(m, 0.38Ha-trans), 2.54 (m, 1H), 2.1–1.3 (m, 7H), 1.51 (s,
9H). MS (ES+, M + Na) m/z: 368.0. HRMS (FAB+) m/z
calcd. for C20H27NO4: 345.1940; found: 345.1940.3
ment, L.L.C. and TDC Research Inc., Department of Chem-
istry, Brock University, St. Catharines, Ontario. The authors
thank William Jones for obtaining extensive accurate mass
data, and Hank Breslin and Mark McDonnell for important
scientific discussions.
3-(4-Chloro-2-methoxycarbonylphenyl)-8-azabicyclo-
[3.2.1]octane-8-carboxylic acid tert-butyl ester (10f)
To a stirred mixture (11) of copper(II) chloride (58 mg,
0.43 mmol) in dry acetonitrile (1.5 mL) was added tert-butyl
nitrite (0.064 mL, 0.54 mmol) via syringe at rt under a nitro-
gen atmosphere. The resulting dark green suspension was
then heated (65 °C) with vigorous stirring. To the warm re-
action mixture was added a solution of 10h (130 mg,
0.36 mmol) in dry acetonitrile (4 mL) via syringe (5 min).
The resulting black solution was stirred at 65 °C for 1 h then
allowed to cool to rt. The reaction was diluted with ether
(10 mL), washed with aq. 1 N HCl (10 mL), washed with
brine (10 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude mixture was purified
by flash chromatography using a gradient system of 5%–
50% ethyl acetate (0.1% TEA) in heptane. The desired prod-
uct 10f was isolated as a clear colorless oil (40 mg, 29%)
with the same mixture of isomers as 10h (trans:cis, 1.3:1).
1H NMR (CDCl3, 300 MHz) δ: 7.77 (d, J = 2.3 Hz, 0.44H),
7.64 (d, J = 2.3 Hz, 0.56H), 7.38 (m, 1H), 7.3–7.2 (m, 1H),
4.4–4.2 (m, 2H), 4.09 (m, 0.44H), 3.91 (s, 1.3H), 3.88 (s,
1.7H), 3.26 (m, 0.56H), 2.5 (m, 1H), 2.1–1.3 (m, 7H), 1.51
(s, 9H), 1.36 (m, 2H). MS (ES+, M + 1) m/z: 380.0.
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Acknowledgements
This project was performed as a collaboration between
Johnson & Johnson Pharmaceutical Research and Develop-
3 Supplementary data (the 1H NMR structural assignments and NOE data for the cis and trans isomers of 10d) for this article are available on
the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI,
National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5023. For more information on obtaining material refer to
http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
© 2006 NRC Canada