Epibatidine alkaloid chemistry: 5. Domino-heck reactions of azabicyclic and tricyclic systems

Article abstract of DOI:10.3390/11080603

Palladium-catalyzed hydroarylations and additional domino reactions of azabicyclic and tricyclic norbornene derivatives were investigated and a series of new epibatidine analogues were synthesized.

Full text of DOI:10.3390/11080603

Molecules 2006, 11, 603-614
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Epibatidine Alkaloid Chemistry: 5. Domino-Heck Reactions of
Azabicyclic and Tricyclic Systems †
Çigdem Yolacan 1, Emine Bagdatli 1, Nüket Öcal 1,* and Dieter E. Kaufmann 2,*
1 Yıldız Technical University, Faculty of Art and Sciences, Department of Chemistry, Davutpasa
Campus, 34210, Istanbul, Turkey
2 Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstr. 6, D-38678
Clausthal-Zellerfeld, Germany
†
For the preceding paper in this series, see ref. [4]
* Authors to whom correspondence may be addressed; e-mails: nocal@yildiz.edu.tr;
dieter.kaufmann@tu-clausthal.de
Received: 26 July 2006; in revised form: 11 August 2006 / Accepted: 12 August 2006 / Published: 16
August 2006
Abstract: Palladium-catalyzed hydroarylations and additional domino reactions of aza-
bicyclic and tricyclic norbornene derivatives were investigated and a series of new
epibatidine analogues were synthesized.
Keywords: Epibatidine, Palladium, Hydroarylation, Domino Reactions, Heck Reactions,
Alkynes, Heterocycles.
Introduction
Epibatidine (1), a novel class of amphibian alkaloid, was first isolated by Daly in trace amounts
from the skin of the Ecuadorian poison frog Epipedobates tricolor [1]. The very high analgesic activity
of 1 is a consequence of its high potency as an agonist towards nicotinic acetylcholine receptors
(nAChRs) in the central and autonomic nervous systems [2]. The exciting biological properties and
unique structure of 1, combined with its scarcity in Nature (ca. 1 mg were obtained from some 750
frogs) have aroused the interest of synthetic chemists [3].

Molecules 2006, 11
604
N
H
Cl
N
1
Despite the large number of syntheses of epibatidine published to date [4, 5], only a few analogues
with modified pyridine rings have been prepared by reductive Heck reactions [6, 7]. In conjuction with
this work we became interested in the possibility of synthesizing epibatidine analogues with modified
bicyclic ring systems in a single synthetic operation via reductive Heck and additional domino-Heck
reactions employing aryl(heteroaryl) iodides.
Results and Discussion
Our synthesis started with the Hetero-Diels-Alder reaction of cyclopentadiene and the iminium ion
generated from formaldehyde and ammonium chloride [8]. The reaction occurred smoothly in aqueous
methanol at room temperature to give the bicyclic amine 2. Because of its unstable nature, this
secondary amine was protected with benzoyl chloride to provide 3 in good yield (Scheme 1).
Scheme 1
H
MeOH
H
NH4Cl
+
O
+
N
rt
H
2
O
PhCOCl
N
Ph
3
Due to the presence of rotamers, all the signals in the NMR spectra of 3 appear in pairs. Malpass
and co-workers have previously prepared and protected compound 2 using both the
benzyloxycarbonyl- (Cbz) and t-butoxycarbonyl (BOC) groups. They only worked with 2-chloro-5-
iodopyridine under reductive Heck conditions using triphenylphosphine (PPh3) as the ligand [6]. In our
work excellent yields were obtained using triphenylarsine (AsPh3) instead of PPh3. Treatment of 3
with iodobenzene, 2-iodothiophene, 2-iodonaphthalene and 2-chloro-5-iodopyridine under reductive
Heck conditions gave new compounds 4a-d and 5b, 5d as regioisomers after chromatographic
separation. The reactions with iodobenzene and 2-iodonaphthalene gave only 5-exo- products. The use
of trimethylsilylacetylene under domino-Heck conditions provided alkynic bicyclic systems 6e and 6f
(Scheme 2). The reactivity of the bicyclic double bond in 3 is dependent on the nature of the
N-
protecting group.

Molecules 2006, 11
605
Scheme 2
O
N
Ar(Het)
Ar(Het)
Ph
Pd(OAc)2,
AsPh3,
O
4a-d
+
Ar(Het)-I
N
+
Ph
HCOOH,
O
Et3N, 65 °C
3
N
Ph
5b,5d
Ar(Het)- =
,
,
,
S
N
Cl
a
c
b
d
O
O
Me3Si
Ph
N
N
Ph
Ph
Pd(OAc)2,
AsPh3,
O
6e
+
Ph-I
Me3Si
+
+
N
Me3Si
Ph
Et3N, 40 °C
3
Ph
6f
1
The regiochemistry of new compounds was inferred from their H-NMR and HH-COSY spectra.
For example, observation of the H1 proton at 4.15 ppm in the 1H-NMR spectra of 4b (red spectrum in
Figure 1), while it appeared at 4.04 ppm for 5b (blue spectrum in Figure 1) was the first evidence for
determining both exo-regioisomers. In the HH-COSY spectra of 4b, an interaction between H6x and H1
was seen clearly, but the spectrum of 5b did not show the same coupling due to the 6-exo- substituent.
Figure 1

Molecules 2006, 11
606
The structures of the regioisomers 6e and 6f resulting from the domino-Heck reactions were also
identified from the HMBC spectra. In the spectrum of 6f, the interaction of the acetylene carbon (at
103.5 ppm) with the H1 proton (at 4.24 ppm) was obvious; in the isomer 6e, an interaction between the
phenyl group quaternary carbon (at 139.0 ppm) with the H1 proton (at 4.40 ppm) was apparent, but in
both cases similar effects were not seen in the other isomers. This provided good evidence for the
assignment of the positions of the phenyl and trimethlysilylacetylene substituents on the bicyclic ring.
In the second part of this work we prepared compound 7 by the reaction of
with
N
-carbomethoxypyrrole
N
-phenylmaleimide, using the literature procedure [9], to explore tricyclic epibatidine analogues
in order to find the most active members of the class (Scheme 3).
Scheme 3
MeO2C
O
N
O
25 °C, 14 kbar
N CO2Me
N Ph
+
CH2Cl2
N
Ph
O
O
7
Due to the strain in substituted norbornenes and their derivatives such as 7, the C=C double bond
reacts readily with many transition metal catalysts. Under typical reductive Heck coupling reaction
conditions, and using aryl(heteroaryl) iodides such as iodobenzene, 2-iodothiophene and 4-
chloroiodobenzene, we obtained a series of bicyclic imides 8a-c as single regioisomers due to the
symmetry of 7. We also synthesized a new diazatricylic compound 9 using domino-Heck conditions.
Not surprisingly, the attachments of phenyl and silylethynyl groups was observed to have taken place
exclusively from the exo-side of the bicylic alkene 7 (Scheme 4). The structures of 8a-c and 9 were
also assigned by analysis of their HH-COSY and HMBC spectra in CDCl3.
Scheme 4
MeO2C
MeO2C
Pd(OAc)2,
AsPh3,
N
N
Ar(Het)
O
O
+ Ar(Het)-I
HCOOH,
Et3N, 65 °C
N
N
Ph
Ph
O
O
7
8a-c
Ar(Het)- =
,
,
S
Cl
a
b
c

Molecules 2006, 11
607
Scheme 4. Cont.
Pd(OAc)2,
MeO2C
N
MeO2C
Ph
N
Me3Si
O
O
AsPh3,
Ph-I
Me3Si
+
+
N
N
Et3N,
40 °C
Ph
Ph
O
O
7
9
Conclusions
The palladium-catalyzed hydroarylation of the easily accessible
N-benzoylated 2-aza-
bicyclo[2.2.1]heptene (3) in the presence of triphenylarsine as a ligand has been proven to be an
excellent, versatile and high-yield approach to aryl- and heteroaryl analogues 4 and 5 of the bioactive
alkaloid epibatidine (1); in case of aryl groups the reaction proceeds regioselectively. Reductive
arylations of a diazatricyclic alkene 7, synthesized by cycloaddition of a pyrrole carboxylic ester with
N-phenylmaleimide, also succeeded under comparable reaction conditions. Domino-Heck sequential
C-C couplings with aryl halides have been shown to be feasible in the presence of
trimethylsilylacetylene. All Heck-type reactions proceed exo-selectively, leading to the same
stereochemistry as found in 1.
Experimental
General
NMR spectra (CDCl3 solvent) were recorded on Bruker Digital FT-NMR Avance 400 and Varian
Inova 500 MHz NMR spectrometers, with TMS as internal reference. In the 13C-NMR spectra
quaternary, methylene and methyl carbons were identified using DEPT experiments. FTIR spectra
(KBr) were recorded on a Perkin Elmer FT-IR spectrometer. GC-EIMS spectra were measured on a
Varian SAT2100T/GC3900 spectrometer using ionisation by FAB. Reactions were performed under
dry nitrogen. Melting points were measured on a Gallenkamp melting point apparatus. Silicagel 60
(Merck) was used for column chromatography separations. TLC was conducted on standard
aluminium sheets pre-coated with a 0.2 mm layer of silica gel.
Heck Reactions General procedure
–
A solution of palladium(II) acetate [Pd(OAc)2] (5.6 mg, 25 µmol) and AsPh3 (33.7 mg, 11 µmol) in
anhydrous DMF or DMSO (3 mL) was stirred under nitrogen at 65 oC for 15 min. Then, compounds 3
or 7 (1.0 mmol), Et3N (488 µL, 3.5 mmol), the appropriate aryl(heteroaryl) iodide (1.5 mmol) and
HCOOH (138 mg, 3.0 mmol) were added. The reaction mixture was stirred for 8-24 h. After cooling to
r.t. EtOAc and brine added, the organic layer was separated, dried (MgSO4), filtered and the solvent
evaporated. The residue was purified by column chromatography.

Molecules 2006, 11
608
Domino-Heck Reactions – General Procedure
Pd(OAc)2 (5.6 mg, 25 µmol) and the arsine ligand (55
µmol) were dissolved in dry DMF (3 mL)
o
and the solution was stirred at 40 C for 15 min. Then, 3 or 7 (1.0 mmol), the aryl compound (1.5
mmol), triethylamine (488 µL, 3.50 mmol) and trimethylsilylacetylene (3.00 mmol) were added
rapidly in one portion. The mixture was heated at the same temperature for 24 h. After cooling down
to r.t. brine (50 mL) was added, the reaction mixture was extracted with ethyl acetate and dried over
MgSO4. The solvent was evaporated and the residue purified by column chromatography.
N-Benzoyl-2-azabicyclo[2.2.1]hept-5-ene (3)
H7a
H6
H7s
H1
O
N
Ph
H3x
H5
H4
H3n
Freshly distilled cyclopentadiene (4 mL, 50 mmol) was added to a solution of NH4Cl (1.325 g, 25
mmol), 36% aqueous formaldehyde (2.6 mL, 35 mmol) and MeOH (5 mL). The reaction mixture was
stirred overnight at r.t. The resulting light yellow solution was diluted with an equal volume of water
and washed with diethyl ether (2x15 mL). To a mixture of this extract and 10% NaOH (5 mL) benzoyl
chloride (2.10 g, 10 mmol) was added over 10 min at r.t. and the mixture was allowed to stir for 2 h.
The organic layer was separated, dried over Na2SO4, filtered and the solvent removed under reduced
pressure to give a yellow oil that was separated by column chromatography (1:1 ethyl acetate-n-
hexane) to give 3 in 83% yield; colorless crystals; Rf: 0.57; mp 49-51 oC; IR: 3060, 1622, 1575, 1495,
1
1426, 1176, 710, 659 cm-1; H-NMR (rotamer ratio= 1:0.6)
δ: 1.56-1.62 (dd, J=8.0, 6.5 Hz, 4H, H7a
and H7s),
rotamer), 2H, H3n
major and minor rotamers, 2H, H3x),
[6.18-6.20 (dd, J=2.0, 2.0 Hz, minor rotamer) and 6.20-6.22 (dd, J=2.0, 2.0 Hz, major rotamer, 2H,
H6)], 6.34-6.36 (dd, J=2.0, 2.0 Hz, major rotamer) and 6.48-6.50 (dd, J=2.0, 2.0 Hz, minor rotamer),
2H, H5 : 42.8, 45.9, 49.2, 64.0, 127.3, 128.5, 128.6,
, 7.30-7.45 (m, 10H, aromatic protons); 13C-NMR
[
2.54-2.56 (dd, J=1.5, 1.5 Hz, minor rotamer) and 2.90-2.92 (dd, J=1.5, 1.5 Hz, major
, [3.14 (bs, minor rotamer) and 3.24 (bs, major rotamer), 2H, H4], 3.49-3.55 (m,
4.46 (bs, major rotamer) and 5.14 (bs, minor rotamer), 2H, H1
]
[
],
[
]
δ
133.4, 137.3, 138.5, 171.3 (major rotamer); 44.0, 47.6, 49.8, 60.5, 127.6, 128.4, 130.3, 133.2, 135.9,
136.6, 169.5 (minor rotamer); MS: m/z 199 [M+], C13H13NO.
H7a
H6x
Ar(Het)
H7s
H1
H7a
Ar(Het)
H5x
H7s
H1
O
O
N
N
Ph
Ph
H3x
H3x
H4
H6n
H4
H6n
H5n
H3n
H5n
H3n
4a-d
5a, 5d

Molecules 2006, 11
609
N-Benzoyl-5-exo-phenyl-2-azabicyclo[2.2.1]heptane (4a).
Purified by column chromatography (1:1 ethyl acetate-
n
-hexane) as colorless crystals in 91% yield;
1
Rf: 0.42; mp 81-83 oC; IR: 3030, 1622, 1575, 1494, 1423, 1195, 710, 653 cm-1; H-NMR (rotamer
ratio=1:0.5)
rotamer) and 1.92-2.20 (m, minor rotamer), 2H, H6x
and 2.38-2.45 (ddt, J=2.5, 2.5 Hz, minor rotamer), 2H, H6n
major rotamer), 2H, H4 2.90-2.96 (m, minor rotamer) and 3.06-3.14 (m, major rotamer), 2H, H5n
[3.24-3.28 (m, minor rotamer) and 3.32-3.36 (m, major rotamer), 2H, H3n], 3.40-3.48 (m, minor
rotamer) and 3.54-3.64 (m, major rotamer), 2H, H3x 4.08 (bs, major rotamer) and 4.74 (bs, minor
rotamer), 2H, H1 7.08-7.27 (m, major and minor rotamers), 10H, aromatic protons 7.30-7.51 (m,
major and minor rotamers), 10H, aromatic protons : 35.2, 36.4, 40.6, 42.6, 53.5, 57.4,
13C-NMR
δ
: 1.51-1.70 (m, major and minor rotamers, 4H, H7a and H7s),
2.26-2.32 (ddt, J=2.0, 2.5 Hz, major rotamer)
2.60 (bs, minor rotamer) and 2.74 (bs,
[1.76-1.86 (m, major
], [
], [
]
,
[
],
[
], [
]
,
[
], [
]
;
δ
126.6, 126.9, 127.2, 127.4, 128.6, 128.8, 130.1, 137.1, 144.9, 169.2 (major rotamer); 35.0, 35.7, 39.0,
44.1, 52.4, 56.9, 126.4, 127.0, 127.1, 127.4, 128.5, 128.8, 130.1, 135.4, 142.5, 169.6 (minor rotamer);
MS: m/z 277 [M+], C19H19NO.
N-Benzoyl-5-exo-(2-thienyl)-2-azabicyclo[2.2.1]heptane (4b).
Separated by column chromatography (4:1 ethyl acetate-
n
-hexane) as a yellow oil, yield 57%; Rf:
: 1.58-1.74
1
0.67; IR: 3028, 1624, 1575, 1424, 1197, 798, 700 cm-1; H-NMR (rotamer ratio=1:0.4)
δ
(m, major and minor rotamers, 4H, H7a and H7s), 1.80-1.89 (m, major and minor rotamers, 2H, H6x),
2.30-2.36 (ddt, J=2.5, 2.5 Hz, major rotamer) and 2.42-2.48 (ddt, J=2.0, 2.0 Hz, minor rotamer), 2H,
H6n 2.58 (bs, minor rotamer) and 2.72 (bs, major rotamer), 2H, H4 , 3.13-3.19 (m, major and minor
rotamers, 2H, H5n), 3.23-3.34 (m, major and minor rotamers, 2H, H3n 3.41-3.46 (dd, J=3.5, 3.0 Hz
minor rotamer) and 3.59-3.62 (dd, J=3.5, 3.5 Hz, major rotamer), 2H, H3x 4.15 (bs, major rotamer)
and 4.74 (bs, minor rotamer), 2H, H1 , 6.72-6.75 (m, major and minor rotamers, 2H, thienyl protons),
[
]
,
[
]
], [
], [
]
6.83-6.88 (m, major and minor rotamers, 2H, thienyl protons), 7.04-7.08 (m, major and minor rotamers,
13
2H, thienyl protons), 7.30-7.46 (m, major and minor rotamers, 10H, aromatic protons); C-NMR
δ:
36.2, 41.3, 41.8, 44.4, 52.5, 59.8, 123.1, 123.3, 126.8, 127.1, 128.4, 130.o, 136.6, 149.3, 169.0 (major
rotamer); 34.8, 40.3, 41.1, 45.7, 54.5, 56.7, 123.1, 123.3, 126.8, 127.2, 128.3, 130.1, 136.5, 149.5,
169.7 (minor rotamer); MS: m/z 283 [M+], C17H17NOS.
N-Benzoyl-5-exo-(2-naphthyl)-2-azabicyclo[2.2.1]heptane (4c).
Separated by column chromatography (1:1 ethyl acetate-
0.42; mp 56-58 oC; IR: 3034, 1625, 1574, 1508, 1260, 779, 701 cm-1; 1H-NMR (rotamer ratio=1:0.8)
1.71-1.92 (m, major and minor rotamers, 4H, H7a and H7s), 1.93-2.01 (m, major rotamer) and 2.03-
2.12 (m, minor rotamer), 2H, H6x 2.29-2.35 (dddd, J=1.5, 2.0, 2.0, 3.0 Hz, major rotamer) and 2.57-
2.64 (dddd, J=2.0, 2.5, 2.5, 3.0 Hz, minor rotamer), 2H, H6n 2.83 (bs, minor rotamer) and 2.90 (bs,
major rotamer), 2H, H4 3.18-3.22 (d, J=9.5 Hz, minor rotamer) and 3.34-3.38 (d, J=9.0 Hz, major
rotamer), 2H, H5n 3.48-3.52 (dd, J=1.0, 1.0 Hz, minor rotamer) and 3.56-3.60 (dd, J=1.0, 1.5 Hz
major rotamer) 2H, H3n 3.65-3.72 (m, minor rotamer) and 3.76-3.82 (m, major rotamer), 2H, H3x
n-hexane) as white crystals, yield 96%; Rf:
δ:
[
], [
], [
], [
], [
]
,
[
],

Molecules 2006, 11
4.55 (bs, major rotamer) and 5.01 (bs, minor rotamer), 2H, H1
610
[
]
, 7.11-7.20 (d, J=7.0 Hz, major rotamer,
1H, aromatic proton), 7.28-7.47 (m, major and minor rotamers, 13H, aromatic protons), 7.48-7.62 (m,
major and minor rotamers, 4H aromatic protons), 7.66-7.70 (d, J=9.5 Hz, minor rotamer, 1H, aromatic
proton), 7.71-7.74 (d, J=8.0 Hz, major rotamer, 1H, aromatic proton), 7.80-7.83 (d, J=8.5 Hz, minor
rotamer, 1H, aromatic proton), 7.84-7.88 (d, J=8.0 Hz, major rotamer, 1H, aromatic proton), 7.98-8.02
(d, J=7.5 Hz, minor rotamer, 1H, aromatic proton), 8.04-8.08 (d, J=9.0 Hz, major rotamer, 1H,
aromatic proton); 13C-NMR
δ: 35.1, 37.0, 39.4, 41.4, 53.5, 60.5, 121.4, 124.0, 125.5, 125.9, 126.3,
127.3, 127.5, 128.7, 129.2, 130.2, 131.8, 134.2, 137.0, 140.6, 169.2 (major rotamer); 34.7, 37.0, 39.7,
41.3, 52.9, 60.9, 122.1, 123.7, 125.3, 125.9, 126.3, 127.2, 127.4, 128.6, 129.0, 130.2, 131.7, 134.4,
136.9, 141.0, 169.0 (minor rotamer); MS: m/z 327 [M+], C23H21NO.
N-Benzoyl-5-exo-(2-chloro-5-pyridinyl)-2-azabicyclo[2.2.1]heptane (4d).
Separated by column chromatography (1:1 ethyl acetate-
0.45; IR: 3065, 1627, 1574, 1508, 1260, 780, 714 cm-1; 1H-NMR (rotamer ratio=1:0.6)
major and minor rotamers, 4H, H7a and H7s), 1.78-2.20 (m, major and minor rotamers), 2H, H6x
2.28-2.32 (dddd, J=2.0, 2.0, 2.5, 2.5 Hz, major rotamer) and 2.38-2.44 (dddd, J=2.0, 2.0, 2.5, 2.5 Hz,
minor rotamer), 2H, H6n 2.62 (bs, minor rotamer) and 2.74 (bs, major rotamer), 2H, H4 2.90-3.00
(m, minor rotamer) and 3.06-3.15 (m, major rotamer), 2H, H5n 3.22-3.28 (m, minor rotamer) and
3.33-3.38 (m, major rotamer) 2H, H3n 3.43-3.48 (m, minor rotamer) and 3.52-3.62 (m, major
rotamer), 2H, H3x 4.14 (bs, major rotamer) and 4.78 (bs, minor rotamer), 2H, H1 , 7.26-7.28 (d,
n
-hexane) as a colorless oil, yield 54%; Rf:
δ: 1.52-1.70 (m,
[
],
[
]
,
[
], [
], [
], [
]
,
[
]
J=8.0 Hz, major and minor rotamers, 2H, aromatic protons), 7.30-7.47 (m, major and minor rotamers,
10H, aromatic protons), 7.47-7.49 (dd, J= 8.0, 3.0 Hz, 2H, major and minor rotamers, aromatic
protons), 8.22-8.24 (d, J=3.0 Hz, 2H, major and minor rotamers, aromatic protons); 13C-NMR
δ: 35.1,
36.4, 40.5, 42.7, 53.4, 57.5, 126.6, 126.9, 127.1, 128.5, 128.7, 130.0, 136.7, 139.2, 148.4, 169.1 (major
rotamer), 35.0, 36.2, 40.8, 42.9, 54.0, 57.9, 127.0, 127.2, 128.9, 129.0, 130.5, 137.0, 139.8, 148.7,
170.2 (minor rotamer); MS: m/z 312 [M+], C18H17ClN2O.
N-Benzoyl-6-exo-(2-thienyl)-2-azabicyclo[2.2.1]heptane (5b).
Separated by column chromatography (4:1 ethyl acetate-
n
-hexane) as yellow crystals, yield 40%;
o
1
Rf: 0.60; mp 98-100 C, IR: 3025, 1613, 1571, 1430, 1074, 789, 716 cm-1; H-NMR (rotamer ratio=
1:0.3) δ: 1.52-1.66 (m, major and minor rotamers, 4H, H7a and H7s), 1.92-1.98 (m, major and minor
rotamers, 2H, H5x), 2.08-2.14 (m, major and minor rotamers, 2H, H5n), [2.60 (bs, minor rotamer) and
2.72 (bs, major rotamer), 2H, H4], [3.08-3.11 (dd, J=1.0, 1.0 Hz, minor rotamer) and 3.20-3.23 (dd,
J=1.5, 1.5 Hz major rotamer), 2H, H3n], [3.40-3.43 (tt, minor rotamer) and 3.49-3.52 (m, major
rotamer), 2H, H3x], 3.54-3.60 (m, major and minor rotamers, 2H, H6n),
4.70 (bs, minor rotamer), 2H, H1 , 6.82-6.90 (dd, J=1.0, 1.0 Hz, major and minor rotamers, 2H, thienyl
protons), 7.04-7.10 (dd, J=1.0, 1.0 Hz, major and minor rotamers, 4H, thienyl protons), 7.28-7.52 (m,
major and minor rotamers, 10H, aromatic protons); 13C-NMR
: 35.7, 37.1, 39.2, 45.0, 52.1, 65.8,
123.4, 123.6, 127.0, 127.1, 128.4, 130.2, 136.2, 146.6, 168.9 (major rotamer), 36.2, 37.5, 39.5, 43.1,
[4.04 (bs, major rotamer) and
]
δ

Molecules 2006, 11
611
56.9, 62.2, 123.3, 123.8, 126.9, 127.3, 128.3, 130.2, 136.6, 147.6, 169.5 (minor rotamer); MS: m/z
283 [M+], C17H17NOS.
N-Benzoyl-6-exo-(2-chloro-5-pyridinyl)-2-azabicyclo[2.2.1]heptane (5d).
Separated by column chromatography (1:1 ethyl acetate-
0.39; IR: 3065, 1625, 1575, 1510, 1260, 781, 712 cm-1; 1H-NMR (rotamer ratio=1:0.55)
(m, major and minor rotamers, 4H, H7a and H7s), 1.92-2.00 (m, major rotamer and minor rotamers),
2H, H5x 2.02-2.12 (m, major rotamer and minor rotamers), 2H, H5n 2.60 (bs, minor rotamer) and
2.74 (bs, major rotamer), 2H, H4 3.08-3.13 (dd, J= 1.0, 1.0 Hz, minor rotamer) and 3.19-3.24 (dd,
J=1.5, 1.5 Hz, major rotamer), 2H, H3n 3.40-3.45 (tt, minor rotamer) and 3.48-3.52 (tt, major
rotamer) 2H, H3x , 3.54-3.58 (m, major rotamer and minor rotamers), 2H, H6n 4.16 (bs, major
rotamer) and 4.72 (bs, minor rotamer), 2H, H1 , 7.20-7.40 (m, major and minor rotamers, 12H,
aromatic protons), 7.41-7.50 (dd, J=8.5, 2.5 Hz, major and minor rotamers, 2H, aromatic protons),
8.16-8.18 (d, J=2.5 Hz, major and minor rotamers, 2H, aromatic protons); 13C-NMR
: 35.2, 36.5,
n
-hexane) as a colorless oil, yield 40%; Rf:
δ: 1.52-1.68
[
]
,
[
], [
], [
], [
]
], [
]
δ
37.2, 45.1, 52.0, 62.0, 126.8, 127.8, 128.1, 128.6, 130.1, 136.9, 145.3, 149.4, 169.7 (major rotamer),
35.4, 36.8, 37.8, 45.7, 52.3, 61.8, 127.0, 128.0, 128.2, 128.9, 131.0, 137.4, 145.6, 149.8, 170.0 (minor
rotamer); MS: m/z 312 [M+], C18H17ClN2O.
N-Benzoyl-5-exo-(trimethylsilylethynyl)-6-exo-phenyl-2-azabicyclo[2.2.1]heptane (6e).
Separated by column chromatography (2:3 ethyl acetate-
n
-hexane) as yellow crystals, yield 60%;
o
Rf: 0.38; mp 113-115 C; IR: 3025, 2177, 1629, 1574, 1427, 1085, 840, 696 cm-1; 1H-NMR (rotamer
ratio=1:0.4)
1.89 (m, major and minor rotamers, 4H, H7a and H7s),
2.29-2.31 (d, J=10.8 Hz, minor rotamer), 2H, H6n
rotamer), 2H, H4 , [3.11-3.13 (m, minor rotamer) and 3.24-3.31 (m, major rotamer), 2H, H5n], 3.46-
3.50 (dd, J=4.0, 3.6 Hz, minor rotamer, 1H, H3n), [3.69-3.72 (dd, J=4.0, 4.0 Hz, major rotamer) and
3.51-3.53 (d, J=9.6, minor rotamer), 2H, H3x , 3.55-3.57 (d, J=9.2 Hz, major rotamer, 1H, H3n), 4.40
(bs, major rotamer) and 5.05 (bs, minor rotamer), 2H, H1 , 7.06-7.28 (m, major and minor rotamers,
10H, aromatic protons), 7.29-7.54 (m, major and minor rotamers, 10H, aromatic protons); 13C-NMR
δ
: -0.154 (s, major rotamer, 9H, Si(CH3)3), -0.145 (s, minor rotamer, 9H, Si(CH3)3), 1.81-
2.19-2.22 (d, J=10.4 Hz, major rotamer) and
2.78 (bs, minor rotamer) and 2.89 (bs, major
[
], [
]
]
[
]
δ:
-0.42, 36.4, 40.9, 43.6, 50.9, 53.5, 62.6, 89.6, 106.0, 126.4, 127.1, 127.9, 128.0, 128.4, 130.0, 136.0,
139.0, 168.3 (major rotamer), -0.51, 34.9, 40.6, 44.9, 51.9, 54.5, 58.8, 89.6, 106.3, 126.2, 127.2, 127.7,
128.3, 128.4, 130.1, 136.1, 139.8, 169.2 (minor rotamer); MS: m/z 373[M+], C24H27SiNO.
N-Benzoyl-6-exo-(trimethylsilylethynyl)-exo-5-phenyl-2-azabicyclo[2.2.1]heptane (6f).
Separated by column chromatography (2:3 ethyl acetate-
n
-hexane) as yellow crystals, yield 35%;
o
Rf: 0.43; mp 128-130 C; IR: 3026, 2171, 1626, 1573, 1418, 1072, 835, 695 cm-1; 1H-NMR (rotamer
ratio=1:0.4)
1.86 (m, major rotamer) and 1.90-1.93 (m, minor rotamer), 4H, H7a and H7s),
major rotamer) and 2.37-2.39 (d, J=10.4 Hz, minor rotamer), 2H, H6n 2.83 (bs, minor rotamer) and
δ: -0.199 (s, major rotamer, 9H, Si(CH3)3), -0.147 (s, minor rotamer, 9H, Si(CH3)3), [1.84-
[
2.26-2.29 (d, J=10.0 Hz,
], [

Molecules 2006, 11
612
2.98 (bs, major rotamer), 2H, H4
]
, 3.13-3.16 (m, major and minor rotamers, 2H, H5n), 3.37-3.41 (m,
major and minor rotamers, 2H, H3n),
J=3.6, 3.2 Hz, major rotamer), 2H, H3x
H1 , 7.15-7.25 (m, major and minor rotamers, 5H, aromatic protons), 7.26-7.31 (m, major and minor
[
3.56-3.59 (dd, J=3.6, 3.2 Hz, minor rotamer) and 3.64-3.68 (dd,
], [
4.24 (bs, major rotamer) and 4.78 (bs, minor rotamer), 2H,
]
rotamers, 4H, aromatics), 7.40-7.48 (m, major and minor rotamers, 5H, aromatic protons), 7.52-7.56
13
(m, major and minor rotamer, 6H, aromatic protons); C-NMR
δ: -0.51, 36.9, 40.2, 44.7, 50.2, 54.0,
64.4, 91.2, 103.5, 126.3, 127.1, 127.9, 128.0, 128.5, 130.1, 136.1, 140.9, 169.3 (major rotamer), -0.43,
34.8, 41.8, 43.0, 49.6, 57.8, 61.1, 90.6, 104.1, 126.2, 127.2, 127.8, 128.0, 128.3, 130.2, 136.1, 141.1,
169.8 (minor rotamer); MS: m/z 373 [M+], C24H27SiNO.
endo-Methyl 3,5-dioxo-4-phenyl-4,10-diazatricyclo[5.2.1.02,6]dec-8-ene-10-carboxylate (7).
MeO2C
N H7
H8
H6
O
N
H9
H
1H2
Ph
O
1
IR: 3065, 1774, 1713, 1697 cm-1; H-NMR
δ
: 2.96 (s, 2H, H2 and H6), 3.62 (s, 3H, -OCH3), 5.21
13
(s, 2H, H1 and H7), 6.58 (s, 2H, H8 and H9), 7.24-7.48 (m, 5H, aromatic protons); C-NMR
63.5, 126.3, 128.8, 129.1, 131.5, 156.0, 174.5,175.1; MS: m/z 298 [M+], C16H14N2O4.
δ: 53.1,
MeO2C
N H7
Ar(Het)
H9x
H6
O
N
H
H8n
Ph
H9n
1H2
O
endo-Methyl 3,5-dioxo-4,8exo-diphenyl-4,10-diazatricyclo[5.2.1.02,6]decane-10-carboxylate (8a)
Separated by column chromatography (2:1 ethyl acetate-
Rf: 0.49; mp 220-222 oC; IR: 3061, 1777, 1713, 1698 cm-1; 1H-NMR
3.09-3.26 (m, 2H, H2 and H6), 3.46 (s, 3H, -OCH3), 3.57 (s, 1H, H8n), 4.75 (bs, 1H, H1), 5.06 (bs, 1H,
H7), 7.21-7.33 (m, 5H, aromatic protons); 7.36-7.48 (m, 5H, aromatic protons); 13C-NMR
: 37.9, 47.7,
n
-hexane) as colorless crystals, yield 55%;
δ: 2.12-2.23 (m, 2H, H9x and H9n),
δ
49.3, 50.7, 52.9, 60.6, 65.3, 126.3, 127.2, 128.8, 129.3, 131.9, 142.9, 155.3, 175.2, 175.4; MS: m/z 375
[M+], C22H20N2O4.
endo-Methyl 8-exo-(4-chlorophenyl)-3,5-dioxo-4-phenyl-4,10-diazatricyclo[5.2.1.02,6]decane-10-
carboxylate (8b).
Separated by column chromatography (1:1 ethyl acetate-
n
-hexane) as colorless crystals, yield 72%;
: 2.07-2.21 (m, 2H, H9x and H9n),
Rf: 0.40; mp 182-84 oC; IR: 3058, 1776, 1716, 1695 cm-1; 1H-NMR (
δ

Molecules 2006, 11
613
3.07-3.24 (m, 2H, H2 and H6), 3.47 (s, 3H, -OCH3), 3.57 (s, 1H, H8n), 4.70 (bs, 1H, H1), 5.06 (bs, 1H,
H7), 7.23-7.29 (m, 5H, aromatic protons), 7.36-7.41 (m, 2H, aromatic protons), 7.46-7.48 (m, 2H,
aromatic protons); 13C-NMR
δ: 37.8, 46.8, 49.0, 50.3, 52.9, 59.2, 65.0, 126.4, 128.3, 128.6, 128.8,
129.1, 131.4, 132.9, 141.2, 155.2, 174.9, 175.0; MS: m/z 410 [M+], C22H19ClN2O4.
endo-Methyl 3,5-dioxo-4-phenyl-8-exo-(2-thienyl)-4,10-diazatricyclo[5.2.1.02,6]decane-10-carboxyl-
ate (8c).
Separated by column chromatography (1:1 ethyl acetate-
n
-hexane) as colorless crystals, yield 58%;
1
Rf: 0.43; mp 224-226 oC; IR: 3112, 3064, 1778, 1713, 1691 cm-1; H-NMR
δ: 2.22-2.24 (m, 2H, H9x
and H9n), 3.10-3.12 (dd, J=7.5, 4.0 Hz, 1H, H6), 3.21-3.24 (d, J=9.0 Hz, 1H, H2), 3.45 (s, 3H, -OCH3),
3.57 (s, 1H, H8n), 4.75 (bs, 1H, H1), 5.04 (bs, 1H, H7), 6.92-6.94 (dd, J=4.5, 4.5 Hz, 2H, thienyl
13
protons), 7.24-7.26 (m, 1H, thienyl proton), 7.37-7.49 (m, 5H, aromatic protons); C-NMR
δ: 38.7,
48.7, 49.6, 52.7, 58.9, 65.8, 124.0, 124.4, 126.0, 126.4, 126.6, 128.8, 129.1, 131.4, 146.2, 155.4, 174.9,
175.0; MS: m/z 382 [M+], C20H18N2O4S.
endo-Methyl 3,5-dioxo-9-exo-(trimethylsilylethynyl)-4,8-exo-diphenyl-4,10-diazatricyclo-[5.2.1.02,6]-
decane-10-carboxylate (9).
Separated by column chromatography (1:1 ethyl acetate-n-hexane) as yellow crystals, yield 42%;
1
Rf: 0.52; mp 196-198 oC; IR: 3033, 1781, 1717, 1693 cm-1; H-NMR
δ: 0.0 (s, 9H, Si(CH3)3), 3.31-
3.48 (m, 4H, H9n, H8n, H2 and H6), 3.78 (s, 3H, -OCH3), 5.08 (bs, 1H, H1), 5.31 (bs, 1H, H7), 7.36-7.45
13
(m, 5H, aromatic protons), 7.47-7.64 (m, 5H, aromatic protons); C-NMR
δ: 0.52, 42.9, 49.0, 49.9,
51.6, 53.0, 63.1, 64.5, 91.6, 102,7, 125.9, 126.0, 127.0, 128.0, 128.3, 128.8, 129.2, 134.2, 139.0, 154.4,
174.3, 174.5; MS: m/z 472 [M+], C27H28SiN2O4.
Acknowledgements
This research has been supported by the Yıldız Technical University Scientific Research Projects
Coordination Department, Project Numbers; 24-01-02-04 and 26-01-02-04. We also thank Marko
Spillner and Dr. Jan C. Namyslo, both from the Clausthal University of Technology, for preparing the
tricyclic starting material 7 (M.S.) and for some spectroscopic results and fruitful discussions (J.C.N.).
References and Notes
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3. Evans, D. A.; Scheidt, K. A.; Downey, C. W. Synthesis of (-)-Epibatidine. Org. Lett. 2001, 3,
3009-3012.

Molecules 2006, 11
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4. Stuhlmann, F.; Kaufmann, D. E. 2-Nitro derivatives of the alkaloid Epibatidine. J. Prakt. Chem
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azabicyclo[2.2.1]hept-5-ene derivatives. Tetrahedron 1999, 55, 11879-11888.
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conformational properties of some derivatives of 7-azabicyclo[2.2.1]heptane. X-ray determination
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1284.
Sample Availability: Samples of the compounds are available from the authors.
© 2006 by MDPI (http:www.mdpi.org). Reproduction is permitted for non commercial purposes.