Stereoselective synthesis of conformationally constrained tropane analogues: 6-Chloro-2,5-diazatetracyclo[8.5.0.02,13.0 4,9]pentadeca-4,6,8-triene-11-one and 6-chloro-2,7-diazatetracyclo- [8.5.0.02,13.04,9]pentadeca-4,6,8-triene-11-one

Article abstract of DOI:10.1002/jhet.5570410414

Two conformationally constrained tropane derivatives were prepared as rigid nicotinic acetylcholine receptor ligands. A palladium catalyzed intramolecular α-arylation reaction was employed to generate the tricyclic compounds in good yields from N-(bromo-chloropyridylmethyl)-8-azabicyclo[3.2.1]octan-3-ones.

Full text of DOI:10.1002/jhet.5570410414

Jul-Aug 2004
569
Stereoselective Synthesis of Conformationally Constrained Tropane
Analogues: 6-Chloro-2,5-diazatetracyclo[8.5.0.0 .0 ]pentadeca-
2,13 4,9
4,6,8-triene-11-one and 6-Chloro-2,7-diazatetracyclo-
2,13 4,9
[8.5.0.0 .0 ]pentadeca-4,6,8-triene-11-one
Jie Cheng, Liang Xu, Edwin D. Stevens and Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148
Sari Izenwasser and Dean Wade
Department of Psychiatry and Behavioral Sciences, University of Miami, School of Medicine,
Miami, FL 33136
Received March 11, 2004
Two conformationally constrained tropane derivatives were prepared as rigid nicotinic acetylcholine
receptor ligands. A palladium catalyzed intramolecular α-arylation reaction was employed to generate the
tricyclic compounds in good yields from N-(bromo-chloropyridylmethyl)-8-azabicyclo[3.2.1]octan-3-ones.
J. Heterocyclic Chem., 41, 569 (2004).
The alkaloid (-)-epibatidine (1), isolated from the skin of
system. Therefore it was of interest to conformationally
constrain the tropane analogues to determine if the potency
could be improved. Herein we wish to report the synthesis
of two conformationally constrained homologues of epiba-
tidine, 6-chloro-2,5-diazatetracyclo[8.5.0.02,13 .04,9] p e n-
tadeca-4,6,8-triene-11-one (5) and 6-chloro-2,7-diazatetra-
cyclo[8.5.0.02,13.04,9]pentadeca-4,6,8-triene-11-one (6).
As illustrated in Scheme 1, the synthesis of the first of
tricyclic homoepibatidines was envisaged to proceed from
tropinone (7). Demethylation of 7 by treatment with
methyl chloroformate in the presence of a catalytic amount
of potassium carbonate afforded the methyl carbamate 8
[16] in 95% yield. The carbamate 8 was then heated at
reflux with trimethylsilyliodide in chloroform. This fur-
nished nortropinone (9) [17] in 86% yield. The required
pyridine derivative 12 was synthesized by diazotization
and chlorination of commercially available 2-amino-5-
bromo-6-methylpyridine (10) to a provide the intermediate
2-chloro-5-bromo-6-methylpyridine (11) [18] in 60 %
yield. Subsequent bromination of 11 with N-bromosuccin-
imide and benzoyl peroxide in carbon tetrachloride at
reflux afforded 12 [19] in 73 % yield. The bromide 12 was
then heated at reflux with nortropinone (9) in toluene and
triethylamine to furnish the pyridyl-tethered tropinone
derivative 1 3 in 60% yield. A palladium-catalyzed
intramolecular α-arylation was then employed to affect the
coupling of the two ring systems and generate the desired
rigid tricyclic skeleton. Treatment of 13 with 10% trans-
dichloro-bis(triphenylphosphine) palladium (II) and
cesium carbonate in toluene at 100-110 °C catalyzed the
intramolecular α-arylation reaction and furnished the
desired diazatetracyclo[8.5.0.02,13 .04,9]pentadeca-4,6,8-
triene-11-one (5) in 82% isolated yield.
the Ecuadorian poison dart frog Epipedobates tricolor by
Daly and co-workers[1], has been reported to be an excep-
tionally potent non-opioid analgesic and a nicotinic acetyl-
choline receptor agonist. Its uncommon 7-azabicy-
clo[2.2.1]heptane ring system and remarkable biological
activity [2-4] has inspired numerous syntheses of epibati-
dine and related analogues [5-7]. Recent investigations
have focused on the synthesis and biological screening of
structurally similar analogues of 1 and nicotine (2) to dis-
cover compounds that possess low toxicity and greater
selectivity at various nicotinic acetylcholine receptor sub-
types [8-13]. Earlier studies in our laboratories reported a
series of epibatidine homologues 3 and 4 as novel nicotinic
acetylcholine receptor ligands [14,15]. The stimulant
activity in vivo of 3 and 4 was found to be 30-100 fold less
potent than 1. The reduced potency of 3 and 4 relative to
epibatidine was believed to be due to the increased confor-
mational flexibility of the 8-azabicyclo[3.2.1]octane ring
The structure of 5 was unequivocally established by X-
ray crystallography and the ORTEP diagram is shown in

570
J. Cheng, L. Xu, E. D. Stevens, M. L. Trudell, S. Izenwasser and D. Wade
Vol. 41
Scheme 1
Figure 1 [20]. The regioselectivity of the α-arylation reac-
tion of 13 is noteworthy, since it has been shown that the
reaction of 2,5-dihalopyridines in cross-coupling reactions
typically yield 2-substituted coupling products as the
major regioisomer [21-23]. In addition, earlier studies in
our laboratories demonstrated that the palladium catalyzed
C-N cross-coupling reaction of 7-azabicyclo[2.2.1]hep-
tane with 2-chloro-5-iodopyridine predominantly gave
coupling products at the 2-position of the pyridine ring
[24]. It is believed that the reversed regioselectivity
observed for 13 in the intramolecular C-C coupling reac-
tion is due to the thermodynamic preference of the system
to form the 6-member ring of 5 over the less stable 7-
member ring product that would result from coupling at
the 2-chloro substitution.
The other structural isomer 6 was synthesized in similar
fashion from nortopinone (9) and the trihalogenated pyri-
dine derivative 17. As illustrated in Scheme 2, bromina-
tion of 2-amino-4-methylpyridine 14 at room temperature
selectively gave 5-bromo-2-amino-4-methylpyridine (15)
[25] in 70% yield. Diazotization and concomitant chlori-
nation of 1 5 furnished the 5-bromo-2-chloro-4-
methylpyridine 16 in 56% yield. Subsequent bromination
of 16 with N-bromosuccinimide and a catalytic amount of
benzoyl peroxide in refluxing carbon tetrachloride fur-
nished the desired 5-bromo-4-bromomethyl-2-chloropyri-
dine 17 in 47% yield. The reaction of nortropinone (9)
with 17 in refluxing toluene gave the pyridyl-tethered
tropinone derivative 18 in 52% yield. Palladium catalyzed
α-arylation of 18 furnished the 6-chloro-2,7-diazatetracy-
clo[8.5.0.02,13.04,9 ]pentadeca-4,6,8-triene-11-one (6) in
53% yield. The regioselectivity of the arylation reaction
was confirmed by X-ray crystallographic analysis. As
illustrated in Figure 2, the ORTEP diagram of 6 confirms
the orientation of the pyridyl nitrogen atom relative to the
trisubstituted nitrogen atom [20].
The binding affinities of the rigid epibatidine homo-
logues 5 and 6 at nicotinic acetylcholine receptors were
determined by the inhibition of [3H]cytisine binding in
homogenates of rat striatum. There are a variety of
nACHRs subtypes that exist in the central nervous system;
however, the α4β2-subtype is the predominant nicotinic
acetylcholine receptor in rat striatum tissue. Therefore, the
binding affinities most likely correspond to the neuronal
Scheme 2

Jul-Aug 2004
Stereoselective Synthesis of Conformationally Constrained Tropane Analogues
571
the basic nitrogen of the saturated ring system contributes
significantly to the binding affinity of compounds such as
1, 2 and 3. To this end, the constrained geometry of 5 and 6
appears to place the pyridyl ring in an unfavorable orienta-
tion relative to the basic nitrogen of the cyclic system for
high affinity binding. As a result the constrained deriva-
tives 5 and 6 exhibit very poor binding affinity for neu-
ronal nicotinic acetylcholine receptors. It should also be
noted that the poor binding affinities of 5 and 6 may be due
to the conformational or substituent effects introduced by
the carbonyl group. While the effects of carbonyl group
incorporated into the 7-azabicyclo[2.2.1]heptane ring sys-
tem epibatidine are not known, the poor affinities of 5 and
6 may be due to functional group intolerance at this posi-
tion by the receptor. Further studies directed toward the
elucidation of the nicotinic acetylcholine receptor pharma-
cophore are under investigation and will be reported else-
where.
α4β2-subtype receptors.[26] Upon comparison with the
tropane analogue 3 (Ki = 1 nM) the conformationally con-
strained compounds 5 (37% inhibition @ 100 µM
[3H]cytisine) and 6 (14% inhibition @ 100 µM [3H]cyti-
sine) exhibited very little affinity for the nicotinic acetyl-
choline receptor. Similarly constrained analogues of epiba-
tidine were also reported to be less potent than 1 at nico-
tinic acetylcholine receptors [27].
It was not surprising that the binding affinity of 5 was
significantly less than epibatidine, nicotine or 3, since the
intramolecular nitrogen-nitrogen distance of 5 was consid-
erably shorter than the optimum distances predicted by
various pharmacophore models for high affinity receptor
binding [28]. From the X-ray structure of 5 (Figure 1) the
nitrogen-nitrogen distance was determined to be 3.74 Å as
compared to 5.1 Å and 5.5 Å determined for the different
rotational conformations of epibatidine [28,29].
Alternatively the nitrogen-nitrogen distance determined
from the X-ray structure of 6 (Figure 2) was 5.12 Å and
was comparable to nitrogen-nitrogen distances of epibati-
dine. From these results it is apparent that despite the sim-
ilar structural features there appears to be a well-defined
pharmacophore that is not met by the rigid homologues.
Presumably the orientation of the pyridyl ring relative to
EXPERIMENTAL
All chemicals were purchased from Aldrich Chemical Co.,
Milwaukee, WI, unless otherwise noted. Anhydrous tetrahydro-
furan, dichloromethane and methanol was purchased from Baker
Chemical Company and stored under argon. Chromatography
refers to chromatography on silica gel (Silica Gel 60, 230-400
mesh, E. M. Science). Petroleum ether refers to pentanes with a
boiling point range of 30-60°. Reported melting points are
uncorrected. All spectra were recorded for the free base. All nmr
specta were recorded on a Varian Gemini 400 MHz multiprobe
spectrometer. Chemical shifts are reported as δ values from
tetramethylsilane in deuteriochloroform. Mass spectra were
recorded on a Micromass Autospec Mass Spectrometer fitted
with a Fisson GC 8060. Elemental analyses were obtained from
Atlantic Microlabs, Inc., Norcross, GA. Existence of fractional
moles of water in some analytical samples persisted despite vig-
orous drying (110°, 24 h) under vacuum (0.01 mm Hg). All com-
pounds were homogeneous by thin layer chromatography.
N-Ethoxycarbonyl-8-azabicyclo[3.2.1]octan-3-one (8) [16].
A solution of 1.8 g (13 mmol) of tropinone (7) and a catalytic
amount of potassium carbonate (100 mg) in 25 mL of toluene
was heated at reflux under nitrogen. Methyl chloroformate (4
mL, 41.8 mmol) was added via syringe and the solution was
heated at reflux overnight. The mixture was allowed to cool to
room temperature and the solvent was removed under reduced
pressure. The residue was dissolved in 50 mL of dichloromethane
and washed with water. The organic layer was separated, and the
aqueous layer was extracted with dichlormethane (2 x 50 mL).
The organic layers were combined, dried (sodium sulfate) and
evaporated under reduced pressure. The residue was purified by
flash chromatography (silica gel-hexane:ethyl acetate, 9:1) to
furnish a colorless liquid and yield 2.4 g (95%) of 8; ir (neat):
Figure 1. ORTEP Drawing of 5.
-1
1
1699, 1194, 1107 cm ; H nmr (deuteriochloroform): δ 4.51
(brs, 2H), 4.16 (quartet, J = 7.2 Hz, 2H), 2.63 (brs, 2H), 2.31 (dd,
J = 17.4, 1.6 Hz, 2H), 2.07-2.03 (m, 2H), 1.65 (d, J = 7.6 Hz, 2H),
13
1.25 (t, J = 7.2 Hz, 3H); C NMR (CDCl ): δ 208.3, 154.1, 61.6,
3
53.2, 49.1, 29.5, 28.8, 14.9.
Figure 2. ORTEP Drawing of 6.

572
J. Cheng, L. Xu, E. D. Stevens, M. L. Trudell, S. Izenwasser and D. Wade
Vol. 41
8-Azabicyclo[3.2.1]octan-3-one (9)[17].
was extracted with ether (2 x 20 mL). The organic layers were
combined, dried (sodium sulfate) and evaporated to give a crude
solid, which was purified by flash chromatography (silica gel-
hexane: ethyl acetate, 10:1, v/v) to yield 1.0 g (60%) of a yellow
solid 13, mp 100-102°. This compound was converted into the
oxalate salt affording a white powder, mp 162° (decomp.); ir
To a solution of 2.7 g (14 mmol), of N-ethoxycarbonyl-8-
azabicyclo[3.2.1]octan-3-one (8) in 50 mL of dry chloroform at
reflux was added 5.9 mL (41 mmol) of trimethylsilyl iodide
slowly over 10 minutes. The solution was heated at reflux for five
hours then allowed cool to room temperature. Methanol (50 mL)
was added slowly to destroy the excess any excess trimethylsilyl
iodide. The solvent was removed under reduced pressure and the
residue was dissolved in 50 mL of saturated sodium thiosulfate
solution and extracted with dichloromethane (3 x 50 mL). The
aqueous layer was made basic with 10% sodium hydroxide solu-
tion to pH 11 and extracted with chloroform (3 x 50 mL). The
organic layers were combined, dried (sodium sulfate) and evapo-
rated under reduced pressure to yield 1.45 g (84%) of the crude 8-
azabicyclo[3.2.1]octan-3-one (9) that was of sufficient purity to
–1
1
(NaCl): 1713, 1423, 1152,1044 cm ; H nmr (deuteriochloro-
form): δ 7.77 (d, J = 8 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 2.58 (brs,
2H). 2.68 (dd, J = 16, 4.4 Hz, 2H), 2.16 (d, J = 15.6 Hz, 2H),
13
2.14-2.07 (m, 2H), 1.62-1.56 (m, 2H); C nmr (deuteriochloro-
form): δ 210.1, 158.0, 149.4, 143.1, 124.3, 120.3, 59.5, 55.9,
+
48.3, 28.0. MS (CI) m/z 330 (MH , 100), 249 (85).
Anal. Calcd. for C
H N BrClO•C H O : C, 42.93; H, 3.84;
13 14 2 2 2 4
N, 6.68. Found: C, 43.08; H, 3.97; N, 6.59.
2,13 4,9
6-Chloro-2,5-diazatetracyclo[8.5.0.0 .0 ]pentadeca-4,6,8-
triene-11-one (5).
-1
be employed in subsequent reactions; ir (NaCl) 3350, 1775 cm ;
1
H nmr (deuteriochloroform): δ 3.74 (brs, 2H), 2.51 (dd, J = 16.4,
4.4 Hz, 2H), 2.20 (d, J = 16 Hz, 2H), 1.78-1.74 (m, 2H), 1.61-
1.53 (m, 2H).
A Schlenk tube, flame-dried in vacuo, was placed under an
argon atmosphere on a vacuum line. The tube was charged with
70 mg (10 mol%, 0.1 mmol) of trans-dichloro-bis(triphenylphos-
phine) palladium, 980 mg (3 mmol) cesium carbonate, 330 mg (1
mmol) N- ( 3 - b r o m o - 6 - c h l o r o - 2 - p y r i d y l m e t h y l ) - 8 - a z a b i c y-
clo[3.2.1]octan-3-one (13) and 5 mL of dry toluene. The Schlenk
tube was sealed and heated in a oil bath (100-110°) for10 hours.
The mixture was allowed to cool to room temperature and diluted
with 10 mL of water. The mixture was then extracted with diethyl
ether (3 x 20 mL) and the combined organic phases were washed
with brine, and dried (magnesium sulfate). The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography (silica gel-hexane:ethyl acetate, 1:1, v/v).
This afforded 180 mg (71%) of a white solid to give 5, mp 166-
5-Bromo-2-chloro-6-methylpyridine (11)[18].
Sodium nitrite (1.4 g, 20 mmol) was added slowly to a solution
of 6-amino-3-bromo-2-methylpyridine (10) (1.9 g, 10 mmol) in
25 mL of concentrated hydrochloric acid at –20°. After 1 hour,
the reaction was allowed to warm to room temperature and then
stirred for 2 h. Ice-cold 10 N sodium hydroxide solution was then
added to the reaction mixture until pH 11 was reached while
keeping the temperature below 5°. The aqueous solution was
extracted with ether (3 × 50 mL). The organic layers were com-
bined, washed with brine, dried (sodium sulfate), and evaporated
to give a white solid to yield 1 g (48%) of 5-bromo-2-chloro-6-
methylpyridine (11), mp 46-47° (lit. [18] mp 43 – 45°); ir (NaCl):
-1
1
1566, 1420, 819 cm ; H nmr (deuteriochloroform): δ 7.71 (d, J
13
= 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 2.60 (s, 3H). C nmr
Table 1
Crystal Data and Structure Refinement for 5
(deuteriochloroform): δ 158.1, 149.1, 142.1, 122.9, 119.7, 24.7.
3-Bromo-2-bromomethyl-6-chloropyridine (12)[19].
Empirical formula
Formula weight
Temperature
C H ClN O
13 13 2
248.70
150(2) K
A solution of 3.2 (16 mmol) of 5-bromo-2-chloro-6-
methylpyridine (11), 3.4 g (19 mmol) of N-bromosuccinimide
and 10 mol% benzoyl peroxide (380 mg, 1.6 mmol) in 35 mL of
dried carbon tetrachloride were heated at reflux for over 28
hours. The succinimide was removed by filtration, and then the
solution was washed successively with water, brine, and dried
(sodium sulfate). The solution was evaporated under reduced
pressure and the residue was distilled under reduced pressure (3
mmHg, 95°-100°) to give 2.3 g (50%), of 12 as a colorless oil; ir
Wavelength
Crystal system
Space group
0.71073 Å
Triclinic
P-1
Unit cell dimensions
a = 6.6270(2) Å
b = 8.6521(3) Å
c = 10.2975(4) Å
α = 74.4830(10)°
β= 81.9170(10)°
γ = 85.9910(10)°
3
Volume
562.94(3) Å
Z
2
3
Density (calculated)
Absorption coefficient
F(000)
1.467 Mg/m
0.322 mm
260
-1
1
(neat): 1558, 1419, 829 cm ; H nmr (deuteriochloroform): δ
7.81 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H);
13
C nmr (deuteriochloroform): δ 155.6, 149.9, 143.6, 125.6,
-1
3
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
0.4 x 0.7 x 0.7 mm
2.07 to 34.44°.
119.6, 32.3.
-10 ≤ h ≤ 10, -13 ≤ k ≤ 13, -16 ≤ l ≤ 16
11505
4516 [R(int) = 0.0185]
N-(3-Bromo-6-chloro-2-pyridylmethyl)-8-azabicyclo[3. 2. 1]-
octan-3-one (13).
Completeness to theta = 34.44° 94.8 %
Absorption correction
Max. and min. transmission
Refinement method
Empirical
A solution of 2.3 g (7.8 mmol) of 3-bromo-2-bromomethyl-6-
chloropyridine (12), 0.66 g (5.3 mmol) of 8-azabicyclo[3.2.1]-
octan-3-one (9) and 1.1 mL (7.8 mmol) of triethylamine in 20
mL of dried toluene (20 mL) was heated at reflux for 4 hours.
After the solution was allowed to cool to room temperature, satu-
rated sodium carbonate solution (20 mL) and ether (20 mL) were
added. The organic layer was separated and the aqueous layer
1.000000 and 0.713709
Full-matrix least-squares on F
4516 / 0 / 206
2
Data / restraints / parameters
2
Goodness-of-fit on F
1.067
Final R indices [I>2sigma(I)]
R indices (all data)
L a rgest diff. peak and hole
R1 = 0.0316, wR2 = 0.0935
R1 = 0.0385, wR2 = 0.0961
0.444 and -0.336 e.Å
-3

Jul-Aug 2004
Stereoselective Synthesis of Conformationally Constrained Tropane Analogues
573
168°. This compound was converted into the oxalate salt afford-
ing a white powder, mp 196 °(decomp.); ir (NaCl): 1717, 1542,
Anal. Calcd. for C H NBr Cl: C, 25.25; H, 1.41; N, 4.91.
6
Found: C, 25.00; H, 1.51; N, 5.00.
4
2
-1
1
1458, 1135 cm ; H nmr (deuteriochloroform): δ 7.33 (d, J = 8
Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 4.59 (d, J = 20 Hz, 1H), 4.28 (d,
J = 20 Hz, 1H), 3.82 (t, J = 5.4 Hz, 1H), 3.56 (d, J = 6.4 Hz, 1H),
3.50 (s, 1H), 2.39 (ddd, J = 15, 5.0, 2.2 Hz, 1H), 2.19-2.04 (m,
N-(5-Bromo-2-chloro-4-pyridylmethyl)-8-azabicyclo[3. 2. 1]-
octan-3-one (18).
A solution of 3.8 g (13 mmol) of 5-bromo-4-bromomethyl-2-
chloropyridine (1 7), 1.1 g (8.8 mmol) of 8-azabicyclo[3.2.1]-
octan-3-one (9) and 2.5 mL (18 mmol) of triethylamine in 40 mL
of dry toluene were heated at reflux for 18 hours. The reaction
mixture was allowed to cool to room temperature and 40 mL of
saturated sodium carbonate solution and 40 mL of ether were
added. The organic layer was separated and the aqueous layer
was extracted by ether (2 x 40 mL). The organic layers were com-
bined, dried (sodium sulfate) and evaporated to give a crude
solid, which was purified by flash chromatography (silica gel-
hexane: ethyl acetate, 10:1, v/v) to yield 1.5 g (52%) of a yellow
solid. This compound was converted into the oxalate salt afford-
ing a white powder, mp 159 °(decomp.); ir (KBr): 2955, 1713,
13
3H), 1.78-1.71 (m, 1H), 1.62-1.56 (m, 1H); C nmr (deuteri-
ochloroform): δ 206.8, 156.8, 150.5, 139.1, 127.4, 122.5, 62.5,
+
58.1, 57.6, 51.0, 42.9, 28.5, 27.0. MS (CI) m/z 249 (MH , 100),
215 (14), 79 (15).
Anal. Calcd. for C
8.27. Found: C, 53.25; H, 4.68; N, 8.06.
H N ClO•C H O : C, 53.18; H, 4.46; N,
13 13 2 2 2 4
2-Amino-5-bromo-4-methylpyridine (15) [25].
To a solution of 2-amino-4-methylpyridine 14 (1.1 g, 10
mmol) in 3 mL of acetic acid, was added a solution of 1.6 g (10
mmol) of bromine in 1 mL of acetic acid with vigorous stirring
over 30 minutes. The mixture was heated at 50° for 3 hours then
allowed to cool to room temperature. The mixture was diluted
with 5 mL of water, and basified to pH 11 by slow addition of 5 N
sodium hydroxide solution. The white precipitate was collected
by vacuum filtration and washed with water. The solid was sus-
pended in 5 mL of hexane and heated at reflux for 10 minutes
and then collected by vacuum filtration. The filtrate was washed
with hot hexane three times to yield 1.3 g (70%) a pale-yellow
powder, mp 134-135°(Lit. mp 134 °[25]). ir (KBr): 3436, 1541,
-1
1
1570, 1331, 1090, 893 cm ; H nmr (deuteriochloroform): δ
8.38 (s, 1H), 7.64 (s, 1H), 3.72 (s, 2H), 3.45 (s, 2H), 2.68 (dd, J =
16.4, 4.4 Hz, 2H), 2.24 (d, J = 16 Hz, 2H), 2.14-2.10 (m, 2H),
13
1.70-1.64 (m, 2H); C nmr (deuteriochloroform): δ 209. 1,
151.7, 151.3, 128.8, 125.0, 120.5, 60.0, 54.7, 48.8, 28.1. MS (EI)
+
m/z 329 (M , 70), 273 (100), 191 (61).
Anal. Calcd for C
H, 4.00; N, 6.53. Found: C, 41.76; H, 3.84; N, 6.26.
H N BrClO•C H O •0.5H O: C, 42.03;
13 14 2 2 2 4 2
-1
1
1476, 1440, 854 cm ; H nmr (deuteriochloroform): δ 8.09 (s,
2,13 4,9
6-Chloro-2,7-diazatetracyclo[8.5.0.0 .0 ]pentadeca-4,6,8-
triene-11-one (6).
13
1H), 6.41 (s, 1H), 4.36 (brs, 2H), 2.29 (s, 3H); C nmr (deuteri-
ochloroform): δ 157.7, 148.9, 148.4, 112.0, 110.7, 22.5. MS
A Schlenk tube, flame-dried in vacuo, was placed under an Ar
atmosphere on a vacuum line. The tube was charged with 70 mg
(10 mol%, 0.1 mmol) of trans-dichloro-bis(triphenylphosphine)
palladium, 980 mg (3 mmol) cesium carbonate, 330 mg (1 mmol)
N-(5-bromo-2-chloro-4-pyridylmethyl)-8-azabicyclo[3. 2. 1]-
+
(ESI) m/z 187 (MH ).
5-Bromo-2-chloro-4-methylpyridine (16).
Sodium nitrite (1.4 g, 20 mmol) was added slowly to a solution
of 1.9 g (10 mmol) of 2-amino-5-bromo-4-methylpyridine (15) in
20 mL concentrated hydrochloric acid at –20°. After 1 hour, the
reaction mixture was allowed to warm to room temperature and
stirred for 2 hours. A cold 10 N sodium hydroxide solution was
added slowly to adjust the reaction mixture to pH 11 while keep-
ing the temperature below 5°. The aqueous mixture was extracted
with dichloromethane (3 x 50 mL) and the combined org a n i c
phases were washed with brine, dried (sodium sulfate) and evap-
orated to give 1.0 g (48%) of a yellow liquid, 16; ir (NaCl): 1577,
Table 2
Crystal Data and Structure Refinement for 6
Empirical formula
Formula weight
C H ClN O
13 13 2
248.70
Temperature
150(2)K
Wavelength
0.71073 Å
-1
1
Crystal system, space group
Unit cell dimensions
Orthorhombic, Pbca
a = 6.9021(4)Å
b = 14.6333(9)Å
c = 22.7108(14)Å
1451, 1030, 886 cm ; H nmr (deuteriochloroform): δ 8.32 (s,
13
1H), 7.12 (s, 1H), 2.30 (s, 3H); C nmr (deuteriochloroform): δ
α = 90°
β = 90°
γ = 90°
151.0, 150.3, 150.1, 126.1, 122.1, 22.4. An analytically pure
sample was obtained for the hydrochloride salt.
Anal. Calcd. for C H NBrCl•HCl: C, 29.67; H, 2.49; N, 5.77.
3
Volume
2293.8(2) Å
6
5
3
Z, Calculated density
Absorption coefficient
F(000)
8, 1.440 Mg/m
0.316 mm
1040
Found: C, 29.62; H, 2.33; N, 5.80.
-1
5-Bromo-4-bromomethyl-2-chloropyridine (17).
Crystal size
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta = 28.89
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
0.15 x 0.30 x 0.45 mm
2.78 to 28.89 deg.
-9<=h<=9, -19<=k<=19, -30<=l<=29
19131 / 2911 [R(int) = 0.0629]
96.4 %
Empirical
1.000000 and 0.576179
Full-matrix least-squares on F
2911 / 165 / 206
A solution of 2.1 g (10 mmol) of 5-bromo-2-chloro-4-
methylpyridine (16), 2.0 g (11 mmol) of N-bromosuccinimide
and 242 mg of benzoyl peroxide (10 mol%,) in 60 mL of dry car-
bon tetrachloride was heated at reflux overnight. The succinimide
was removed by filtration and the solution was washed succes-
sively with water and brine, and dried (sodium sulfate). The solu-
tion was evaporated under reduced pressure and the residue was
purified by vacuum distillation to yield 0.80 g (47% based on
recovered starting material) of a colorless oil 17, bp 125-130° at
2
2
Goodness-of-fit on F
0.998
Final R indices [I>2sigma(I)]
R indices (all data)
Largest diff. peak and hole
R1 = 0.0410, wR2 = 0.1049
R1 = 0.0576, wR2 = 0.1120
0.400 and -0.260 e. Å
-1
1
0.3 mmHg; ir (NaCl): 1571, 1447, 1111 cm ; H nmr (deuterio-
chloroform): δ 4.44 (s, 2H), 8.50 (s, 1H), 7.45 (s, 1H).
-3

574
J. Cheng, L. Xu, E. D. Stevens, M. L. Trudell, S. Izenwasser and D. Wade
Vol. 41
Chem., 64, 4966 (1999).
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Org. Chem., 64, 4069 (1999).
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N. Liu, K. T. Nguyen, S. Uhrich, J. Yuan, Y. Xiao, D. M. Wypij, F. Zuo
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octan-3-one (18) and 5 mL of dry toluene. The Schlenk tube was
sealed and heated in an oil bath (100-110 °C) for10 hours. The
mixture was allowed to cool to room temperature and diluted
with 10 mL of water. The mixture was then extracted with diethyl
ether (3 x 20 mL) and the combined organic phases were washed
with brine, and dried (magnesium sulfate). The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography (silica gel-hexane:ethyl acetate, 1:1, v/v).
This afforded 130 mg (53%) of a white solid to give 6, mp 142-
144°. This compound was converted into the oxalate salt afford-
1
ing a white powder, mp 188 °(decomp.). H nmr (deuteriochlo-
[16] R. Noyori, Y. Hayakawa, Y. Baba and S. Makino, J. Am.
Chem. Soc., 100, 1786 (1978).
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Commun. 20, 2971 (1990).
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E. A. O’Neil, C. D. Schwartz, C. M. Thompson, C. E. Fitzgerald, S. J.
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[20] The authors have deposited atomic coordinates for compounds
5 and 6 with the Cambridge Crystallographic Data Center. The coordinates
can be obtained upon request from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EB, U.K.
[21] Y. Hama, Y. Nobuhara, Y. Aso, T. Otsubo and F. Ogura, Bull.
Chem. Soc. Jpn., 61, 1683 (1988).
roform): δ 8.10 (s, 1H), 7.16 (s, 1H), 4.55 (d, J = 20 Hz, 1H), 4.26
(d, J = 19.6 Hz, 1H), 3.77 (t, J = 5.2 Hz, 1H), 3.54 (s, 1H), 3.48
(d, J = 7.2 Hz, 1H), 2.32 (ddd, J = 14.8, 4.8, 2 Hz, 1H), 2.19-2.01
(m, 3H), 1.81-1.74 (m, 1H), 1.63-1.57 (m, 1H); C nmr deuteri-
ochloroform): δ 206.2, 150, 149.2, 147.7, 128.5, 121.1, 62.2,
+
58.1, 54.6, 48.0, 42.8, 28.3, 27.0. MS (ESI) m/z 249 (MH ).
13
Anal. Calcd for C H N ClO•C H O •H O: C, 50.5; H, 4.80;
13 13 2 2 2 4 2
N, 7.85. Found: C, 50.82; H, 4.54; N, 7.44.
Acknowledgment.
We are grateful to the National Institute on Drug Abuse (DA
12703) for the financial support of this research.
[22]
R. W. Friesen, C. Brideau, C. C. Chan, S. Charleson, D.
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