2-(Het)aryl-substituted 7-azabicyclo[2.2.1]heptane systems

Article abstract of DOI:10.1002/(SICI)1099-0690(199809)1998:9<1997::AID-EJOC1997>3.0.CO;2-A

Epibatidine (1) is a recently discovered trace alkaloid found in the skin of a Latin-Amencan poisonous frog. Its remarkably high analgetic activity is accompanied by high toxicity. Therefore, in order to tune its biological activity, a convergent and effi

Full text of DOI:10.1002/(SICI)1099-0690(199809)1998:9<1997::AID-EJOC1997>3.0.CO;2-A

FULL PAPER
Chemistry in the Ambient Field of the Alkaloid Epibatidine, 1
2-(Het)aryl-Substituted 7-Azabicyclo[2.2.1]heptane Systems
Albert Otten, Jan Christoph Namyslo, Martin Stoermer, and Dieter E. Kaufmann*
Institut für Organische Chemie der Technischen Universität Clausthal,
Leibnizstr. 6, D-38678 Clausthal-Zellerfeld, Germany
Fax: (internat.) ϩ 49(0)5323/72-2834
E-mail: dieter.kaufmann@tu-clausthal.de
Received January 17, 1998
Keywords: Alkaloids / Acetylcholine receptor / Palladium / C-C coupling / Heterocycles
Epibatidine (1) is a recently discovered trace alkaloid found
in the skin of Latin-American poisonous frog. Its
pyrrole (7) with ethynyl p-tolyl sulfone (6) and subsequent
steps has been optimized. The crucial last step, the reductive
a
remarkably high analgetic activity is accompanied by high cleavage of the vinyl sulfone 9, has been replaced by a high-
toxicity. Therefore, in order to tune its biological activity, a
convergent and efficient synthetic pathway was sought to
synthesize epibatidine derivatives with different (het)aryl
yield fluoride-induced degradation of the β-silylated sulfone
12 to give 10. A number of structurally different racemic
epibatidine analogs (16b–e) can be prepared by palladium-
substituents. The hydro(het)arylation of the key intermediate catalyzed hydro(het)arylation of 10 with iodo(het)arenes
7-azabicycloheptene (10) represents such an approach. The 15b–e in good yields.
synthesis of 10 by a Diels–Alder reaction of an N-activated
The isolation[1] and complete spectroscopic characteri- port a general synthesis of (het)arylated epibatidine anal-
zation[2] of the the novel, structurally simple trace alkaloid ogs.
epibatidine (1), which is obtained from the skin of the La-
Results and Discussion
tin-American poisonous frog epipedobates tricolor, was re-
ported by Daly in 1992. This work has given rise to numer-
ous pharmaceutical investigations and great hopes after the
extremely high analgetic activity of this compound in the
“hot-plate test“ had been discovered. This was especially
important as epibatidine seemed to work in a different way
to current painkillers, thus binding to hitherto unknown
nonopiodic receptors in the brain[3]. From a chemical point
of view it is remarkable that, for the first time, an azabicy-
clo[2.2.1]heptane system has been found in nature and that,
to date, only the second time that a 2-chloropyridyl system
has been detected as part of a natural product, an anti-
tumor antibiotic[4]. A structural similarity to the natural
product nicotine (2) is evident. Indeed, up to now epibatid-
ine is the most effective of all known agonists of nico-
tinergic acetylcholine receptors. A pharmaceutical appli-
cation of epibatidine in human medicine is not feasible due
to its high toxicity, which exceeds that of nicotine.
Among the published syntheses of racemic epibatidine[5]
that proceed in a convergent manner, the synthesis by Clay-
ton and Regan[6] appeared most interesting. The key step
of that synthesis is a hydroarylation of an N-protected 7-
azabicycloheptene 10 with 2-chloro-5-iodopyridine (15a)
(Scheme 3). This reaction type should also allow the hy-
droarylation by other (het)arenes; our own hydroarylation
experiments with norbornene[7] gave us confidence to try
this synthetic procedure, although due to the presence of
a second donor center, there is always the problem of a
competitive complexation of the palladium catalyst. The
difficult synthetic access to the key compound 10 proved to
be a serious problem for the general applicability of the
hydroarylation reaction. In particular, the reductive cleav-
age of the sulfonyl group in the heterogenous phase led to
a distinct decrease in yield and low reproducibility in the
last step. Therefore, the whole synthesis was improved in
such a manner that the synthesis of 10 is now possible in
gram quantities without problems.
Scheme 1
Synthesis of N-Methoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (10)
The aluminum trichloride mediated reaction of bis(tri-
methylsilyl)acetylene[8] (3) with p-toluenesulfonyl chloride
Variations of the epibatidine structure are feasible in gave 2-(trimethylsilyl)ethynyl p-tolyl sulfone (5) in 97% yield
terms of the (het)arene substituent, the ring size of the bi- (ref.[9] 80%). The direct [4 ϩ 2] cycloaddition of N-(meth-
cyclic system, and the position and nature of the hetero oxycarbonyl)pyrrole (7) with 5 did not succeed, even under
atom. In this first publication of a series of articles we re- high-pressure conditions (13 kbar). Therefore, in order to en-
Eur. J. Org. Chem. 1998, 1997Ϫ2001
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
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1997

A. Otten, J. C. Namyslo, M. Stoermer, D. E. Kaufmann
FULL PAPER
hance the activity of 5 the silyl group had to be split off first. than with a heterogenous catalyst (palladium on charcoal).
The best desilylation method towards proved to The use of a Pd/C hydrogenation catalyst, which had not
6
be the reaction with a methanol/water solution of sodium been washed acid-free with triethylamine before use, gave
fluoride[10] (99% yield; ref.[9] 83%). The subsequent DielsϪ rise to a 2,3-bis-exo/endo,exo/exo,endo mixture of 12 in the
Alder reaction with 7 to give the azabicyclic vinyl sulfone[11] ratio 2:1:1. It also proved possible to add a tri-n-butylstan-
8 is strongly dependent on the reaction conditions. By careful nyl anion to obtain the β-stannylated sulfone 13 (yield 99%)
control of the reaction temperature over a small range in a Michael-analogous reaction by using a mixture of tri-
(85Ϫ87 oC, yield 74%) or under high-pressure conditions (12 n-butylstannane/lithium diisopropylamide. A number of
kbar, yield 81%) the reported yield[6] (36%) could be in- synthetic methods were tried for the subsequent β-elimin-
creased markedly. The subsequent catalytic hydrogenation of ation. In the case of the silylated sulfone, cleavage with
the less hindered double bond[12] proceeded almost quanti- TBAF (tetra-n-butylammonium fluoride) proved to be the
tatively (99%). A number of literature methods are known best method. For the bis-exo isomer 12, cleavage of the silyl
for the reductive degradation of vinyl sulfones[13]. However, and the sulfonyl group to give 10 was achieved with TBAF
employment of aluminum amalgam[14], potassium/graph- trihydrate (yield 86%), whereas the cis/trans mixture of 12
ite[15], lithium/ethylamine[16] (ring opening of the bicycle), could be degraded completely with anhydrous TBAF[22]
samarium iodide[17], tri-n-butyltin hydride[18] or sodium di- only. This synthetic methodology is distinctly superior to
thionite[19] all proved to be unsuccessful. Only in the hetero- the reductive cleavage, with a total yield of 83%. In con-
genous reaction with sodium amalgam[12] could 10 be ob- trast, degradation of the stannylated sulfone 13 with anhy-
tained in a yield ranging from 20 to 39%.
drous TBAF proceeded only in a low yield (up to 16%).
Therefore, an alternative synthetic approach was re- Another problem encountered in the synthesis of the pure
quired. The β-elimination of a saturated silylated or stanny- azabicycloheptene 10 on a preparative scale using the stan-
lated sulfone[20] looked promising. The formal hydrosilyl- nyl route was the difficulty in completely separating the tri-
ation of 9 was achieved in a two-step reaction: the anion in n-butylstannyl fluoride by column chromatography. The use
the β-position to the sulfonyl group was formed selectively of inorganic fluorides, like potassium fluoride on silica gel
by reaction of 9 with lithium diisopropylamide, followed by in methanol, led to ring opening of the bicyclic system to
almost quantitative silylation to 11 (yield 97%). The sub- give the substituted cyclohexene system 14. In conclusion,
sequent hydrogenation to 12 proceeded in a more reproduc- the synthetic pathway using the silylated sulfone is well
ible way (yield 99%) and with complete endo selectivity with suited to the generation of adequate amounts of 10 for a
diimide, generated from dipotassium azodicarboxylate[21]
,
subsequent chemical study.
Scheme 2
1998
Eur. J. Org. Chem. 1998, 1997Ϫ2001

Chemistry in the Ambient Field of the Alkaloid Epibatidine, 1
FULL PAPER
Palladium-Catalyzed Hydroarylation of N-Methoxycarbonyl-7-
azabicyclo[2.2.1]hept-2-ene (10)
cedures. Amines were dried with calcium hydride. Other reagents
are commercially available and were used as received. Ϫ NMR:
Bruker AMX 400 (1H: 400 MHz, 13C: 100 MHz) with CDCl3 as
solvent and TMS as internal standard. Ϫ Bis(trimethylsilyl)ace-
tylene[8] (BTMSA) (3), 2-(trimethylsilyl)ethynyl p-tolyl sulfone[9]
(5), N-(methoxycarbonyl)pyrrole[23] (7), and 2-chloro-5-iodopyrid-
ine[24] (15a) were synthesized as described in the literature.
The palladium-catalyzed reductive hydroarylation reac-
tion opens up a valuable way for the CϪC coupling of (het)
aromatic compounds with bicyclic alkenes, in cases where a
Heck reaction is not feasible, as the rigid bicyclic system
cannot rotate around the newly formed CϪC bond, to form
a conformation required for the subsequent syn elimination
of the hydridopalladium species.
All hydroarylation reactions were performed in dimeth-
ylformamide with 10 mol-% of bis(triphenylphosphane)pal-
ladium diacetate as catalyst and piperidinium formate as a
reducing agent.
Ethynyl p-Tolyl Sulfone (6): A solution of 3.72 g (88.6 mmol) of
sodium fluoride in degassed water (60 ml) was added dropwise to
a solution of 14.9 g (59.7 mmol) of 5 in degassed methanol (120
ml) at 10°C. After complete addition, the resulting suspension was
stirred for another 15 min. Water was added and the mixture was
extracted with ether (3 ϫ 100 ml). The combined ether layers were
treated with sodium hydrogen carbonate, washed with brine, and
then dried with anhydrous MgSO4. After concentration to dryness,
a white product was obtained. In most cases purification by flash
column chromatography was unnecessary. Yield: 10.5 g (99%) 6,
m.p. 74°C. Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ 2.47 (s, 3 H, CH3),
3.45 (s, 1 H, Halkynyl), 7.39 (d, J ϭ 8.3 Hz, 2 H, 3,5-Haryl), 7.89 (d,
J ϭ 8.3 Hz, 2 H, 2,6-Haryl). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ
21.8 (ϩ, Ar-CH3), 80.4 (ϩ, HCalkynyl), 81.0 (Cquat., CSO2), 127.7
(ϩ, Caryl-2,6), 130.1 (ϩ, Caryl-3,5), 137.8 (Cquat., Caryl-4), 146.0
(Cquat., Caryl-1). Ϫ GC-MS (70eV); m/z (%): 180 (42) [Mϩ], 139
(48), 115 (100).
Scheme 3
N-(Methoxycarbonyl)-2-(p-tolylsulfonyl)-7-azabicyclo[2.2.1]-
hepta-2,5-diene (8): This compound was obtained by cycloaddition
of 6 to 7 (4.0 equiv. used) during 24 h keeping the reaction tempera-
ture between 85 and 87°C. After concentration of the excess diene
under mild conditions, column chromatography on silica gel with
petroleum ether/AcOEt (2:1) (Rf ϭ 0.20) as the eluent afforded the
desired DielsϪAlder product on a 10-g scale (yield: 74%): white
1
solid, m.p. 95°C. Ϫ H NMR (400 MHz, CDCl3): δ ϭ 2.44 (s, 3
H, Ar-CH3), 3.42 (br. s, 3 H, OCH3), 5.21 (s, 1 H, 4-H), 5.42 (s, 1
H, 1-H), 6.85Ϫ7.05 (m, 2 H, 5,6-H), 7.35 (d, J ϭ 8.0 Hz, 2 H, 3Ј,5Ј-
Haryl), 7.59 (br. s, 1 H, 3-H), 7.74 (d, J ϭ 8.0 Hz, 2 H, 2Ј,6Ј-Haryl).
The reaction temperature was optimized in the case of
the epibatidine precursor 16a. This optimization is impor-
tant as reduction of the leaving group of the aromatic sys-
tem[7], which always occurs in parallel with the hydroaryl-
ation reaction, shows a different temperature dependence.
In this way an increase in the yield of 16a from 35%[6] to
77% was achieved mainly by lowering the reaction tempera-
ture from 75 to 50°C. Under identical reaction conditions
iodobenzene (15b), 3-iodopyridine (15c), 2-iodothiophene
(15d) and 4-chloro-3-fluoro-1-iodobenzene (15e) were al-
lowed to react with 10. In all cases CϪC coupling proceded
exclusively with formation of the exo-aryl-substituted aza-
bicyclic systems 16aϪe. The isolated yields varied between
44% in the case of the thienyl compound 16d and 85% in
the case of the phenyl-substituted system 16b. The amino
group, deactivated by the methoxycarbonyl group, did not
strongly inhibit the reaction rate or influence the yield.
These new alkaloid analogs are currently being tested for
their biological effects.
7-(Methoxycarbonyl)-2-(p-tolylsulfonyl)-7-azabicyclo[2.2.1]-
hept-2-ene (9): This compound was prepared from the correspond-
ing diene in almost quantitative yield (99%) by hydrogenation of a
solution of the bicyclic diene 8 in ethyl acetate or methanol, with
the calculated volume of hydrogen (catalyst: 10% palladium on
charcoal). All data were in accordance with the literature. Ϫ 1H
NMR (400 MHz, CDCl3): δ ϭ 1.32 (m, 2 H), 2.00 (m, 2 H), 2.44
(s, 3 H, Ar-CH3), 3.45 (br. s, 3 H, OCH3), 4.82 (d, J ϭ 3.5 Hz, 1
H, 1-H), 4.88 (m, 1 H, 4-H), 7.02 (d, 1 H, 3-Holefin.), 7.35 (d, J ϭ
8.3 Hz, 2 H, 3Ј,5Ј-Haryl), 7.78 (d, J ϭ 8.3 Hz, 2 H, 2Ј,6Ј-Haryl).
N-(Methoxycarbonyl)-3-(p-tolylsulfonyl)-2-trimethylsilyl-7-
azabicyclo[2.2.1]hept-2-ene (11): To an ice-cold solution of 1.19 ml
(8.40 mmol) of diisopropylamine in anhydrous THF (28 ml) was
added dropwise 5.25 ml (8.40 mmol) of 1.6  n-butyllithium in
hexane and the solution was stirred for an additional 15 min at
0°C. The resulting solution of lithium diisopropylamide was then
added at Ϫ78°C to 2.46 g (8.00 mmol) of the vinyl sulfone 9, dis-
solved in 150 ml of anhydrous THF, during 90 min by syringe. The
mixture was stirred for 2 h and the anion formed was quenched at
Ϫ78°C with 1.11 ml (8.80 mmol) of freshly distilled chlorotri-
methylsilane. The reaction mixture was allowed to warm up to
room temperature overnight and a saturated solution of am-
monium chloride was added. After addition of ether (200 ml) and
separation, the aqueous layer was extracted twice with ether. The
organic extract was treated with sodium hydrogen carbonate,
washed twice with brine and was then dried with anhydrous
MgSO4. The solid product obtained after evaporation of the sol-
We gratefully acknowledge the support of this work by the Bayer
AG, Leverkusen, the Fonds der Chemischen Industrie, the Degussa
AG, Frankfurt, and the Chemetall GmbH, Langelsheim. We are in-
debted to Dr. G. Remberg (Universität Göttingen) for MS measure-
ments.
Experimental Section
All reactions were carried out under dry nitrogen using Schlenk
techniques. All solvents were carefully dried by standard pro-
Eur. J. Org. Chem. 1998, 1997Ϫ2001
1999

A. Otten, J. C. Namyslo, M. Stoermer, D. E. Kaufmann
FULL PAPER
vent and finally drying in vacuo (2.95 g, 97%) was slightly yellow
N-(Methoxycarbonyl)-3-(p-tolylsulfonyl)-2-exo-tributylstannyl-
(100% pure by GC; mp. 83°C). An analytical sample was obtained 7-azabicyclo[2.2.1]heptane (13): To a solution of lithium diisopro-
by further purification by short column chromatography with
pylamide (4.15 mmol in 15 ml of anhydrous THF) was added drop-
petroleum ether/ethyl acetate (2:1; Rf ϭ 0.53). White solid, m.p.
86°C. Ϫ H NMR (400 MHz, CDCl3): δ ϭ 0.35 (s, 9 H, SiMe3), plete addition, the mixture was stirred at 0°C for another 15 min
wise 1.10 ml (4.15 mmol) of tributyltin hydride at 0°C. After com-
1
1.07 and 1.28 (ddd, J ϭ 11.7, 8.7, 3.0 Hz, 2 H, 5,6-Hendo),
and then cooled to Ϫ78°C. A solution of 1.16 g (3.77 mmol) of 9
1.83Ϫ1.92 (m, 1 H), 1.93Ϫ2.02 (m, 1 H), 2.44 (s, 3 H, Ar-CH3), in anhydrous THF (5 ml) was added by syringe. The mixture was
3.37 (br. s, 3 H, CO2CH3), 4.71 (d, J ϭ 3.8 Hz, 1 H, 1-H), 4.92 (d, allowed to warm up to room temperature overnight. 20 ml of water
J ϭ 3.8 Hz, 1 H, 4-H), 7.34 (d, J ϭ 8.1 Hz, 2 H, 3Ј,5Ј-Haryl), 7.76
was added and the aqueous layer was extracted with ether (3 ϫ 30
(d, J ϭ 8.1 Hz, 2 H, 2Ј,6Ј-Haryl). Ϫ 13C NMR (100 MHz, CDCl3): ml). The combined ether layers were washed with brine (2 ϫ 10
δ ϭ Ϫ0.5 (ϩ, SiMe3), 21.6 (ϩ, CH3), 24.0 (Ϫ), 52.5 (ϩ, OCH3), ml), dried (MgSO4), and the solvent evaporated under reduced
62.3 (ϩ), 66.5 (ϩ), 127.8 (ϩ, Caryl-2Ј,6Ј), 129.8 (ϩ, Caryl-3Ј,5Ј), pressure to yield crude 13 as a brown oil, 2.24 g (99%). As the
137.1 (Cquat., Caryl-4Ј), 144.5 (Cquat., Caryl-1Ј), 153.3 (Cquat.), 155.7 product is unstable to column chromatography it was used without
(Cquat., CϭO), 160.3 (Cquat.). Ϫ GC-MS (70eV); m/z (%): 351 (1) further purification [Rf ϭ 0.42 (SiO2; petroleum ether/AcOEt, 2:1)].
[Mϩ Ϫ C2H4], 336 (100) [Mϩ Ϫ C2H4 Ϫ CH3], 304 (10). Ϫ
Ϫ
1H NMR (400 MHz, CDCl3): δ ϭ 0.70Ϫ1.10 {m, 15 H,
C18H25NO4SSi (379.55): calcd. C 56.96, H 6.64, N 3.69, S 8.45; Sn(CH2[CH2]2CH3)3 }, 1.18Ϫ1.95 {m, 18 H, Sn(CH2[CH2]2CH3)3
found C 56.89, H 6.65, N 3.38, S 8.48.
and 2,3,5,6-H}, 2.41 (s, 3 H, Ar-CH3), 3.60 (s, 3 H, CO2CH3),
4.25Ϫ4.52 (m, 2 H, 1,4-H), 7.36 (d, J ϭ 8.0 Hz, 2 H, 3Ј,5Ј-Haryl),
7.70Ϫ7.80 (m, 2 H, 2Ј,6Ј-Haryl). Ϫ 13C NMR (100 MHz, CDCl3):
δ ϭ 9.8 (Ϫ, SnCH2CH2), 13.5Ϫ13.6 (ϩ, C-2,3 and Sn[CH2]3CH3),
21.4 (ϩ, CH3), 24.4 and 27.3 (Ϫ, Sn[CH2]2CH2CH3 and C-5,6),
29.0 (Ϫ), 30.5 (Ϫ, SnCH2CH2), 52.5 (ϩ, OCH3), 57.0 (ϩ), 58.0
N-(Methoxycarbonyl)-3-exo-(p-tolylsulfonyl)-2-exo-trimethyl-
silyl-7-azabicyclo[2.2.1]heptane (12) by Diimide Reduction: 3.55 g
(18.3 mmol) of dipotassium azodicarboxylate, freshly prepared by
saponification of azodicarboxamide with 40% aqueous potassium
hydroxide,[20] was added to a stirred solution of 2.32 g (6.10 mmol)
of the silylated bicyclic vinyl sulfone 11 in anhydrous methanol (60
ml) at 0°C. The reduction was initiated by adding sufficient acetic
acid (50% in water) to neutralize the solution (pH ϭ 6Ϫ7). The ice
bath was removed and the suspension stirred at room temperature
overnight. After 12 h, the bright yellow color of the azodicarboxylic
acid salt had disappeared. Water was added and the mixture ex-
tracted three times with ether (150 ml). GLC indicated complete
conversion (100%). The combined ether layers were washed with
brine (2 ϫ 10 ml) and dried (anhydrous MgSO4). The solvent was
evaporated under reduced pressure to yield the desired sulfone as
a pale yellow solid, 2.30 g (99%). An analytical sample was purified
by short column chromatography with petroleum ether/ethyl ace-
(ϩ), 127.9 (ϩ, Caryl-2Ј,6Ј), 130.0 (ϩ, Caryl-3Ј,5Ј), 137.0 (Cquat., Caryl
-
4Ј), 144.7 (Cquat., Caryl-1Ј), 155.3 (Cquat., CϭO). Ϫ MS (DIP, 70eV);
m/z (%): 542 (100) [Mϩ ϩ 1 Ϫ C4H9].
The destannylation was performed with 10 equiv. of dried
TBAF[22]. Yield: 16% of 10. Reaction of 13 with potassium fluoride
on silica gel in anhydrous methanol led, under ring opening, to
5-(methoxycarbonylamino)-1-(p-tolylsulfonyl)-6-tri-n-butyl-
tincyclohex-1-ene (14) (yield 75%) [Rf ϭ 0.48 (SiO2, petroleum
ether/AcOEt, 3:1)]. The structure of 14 was confirmed by H/D ex-
change at the carbamate, NOE and 2D-NMR experiments, includ-
ing HMBC and HMQC techniques. Ϫ 1H NMR (400 MHz,
CDCl3): δ ϭ 0.91 {t, J ϭ 7.3 Hz, 9 H, Sn[(CH2)3CH3]3}, 0.95Ϫ1.10
{m,
6
H, Sn[CH2(CH2)2CH3]3}, 1.28Ϫ1.39 {m,
7
H,
1
tate (3:1) (Rf ϭ 0.35). Ϫ H NMR (400 MHz, CDCl3): δ ϭ 0.30
Sn[(CH2)2CH2CH3]3 and 4-Hax.}, 1.86 (m, 1 H, 4-Heq.), 2.41 (s, 3
H, Ar-CH3), 2.45 (m, 2 H, 3-H), 2.64 (m, 1 H, 6-H), 3.60 (s, 3 H,
OCH3), 3.81 (m, 1 H, NCH), 4.59 (m, 1 H, NH), 6.63 (m, 1 H, 1-
Holefin.), 7.30 (d, J ϭ 8.1 Hz, 2 H, 3Ј,5Ј-Haryl), 7.68 (d, J ϭ 8.1 Hz,
2 H, 2Ј,6Ј-Haryl). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 11.8 [Ϫ,
1J(119Sn, CH2) ϭ 315 Hz, SnCH2CH2], 13.7 (ϩ, Sn[CH2]3CH3),
21.6 (ϩ, CH3), 25.4 (Ϫ, C-3), 27.4 (Ϫ, Sn[CH2]2CH2CH3), 28.9 (Ϫ,
(s, 9 H, SiMe3), 1.20 (t, J ϭ 7.0 Hz, 1 H, 2-Hendo), 1.55Ϫ1.90 (m,
4 H), 2.45 (s, 3 H, Ar-CH3), 2.65Ϫ2.78 (m, 1 H), 3.62 (s, 3 H,
CO2CH3), 3.74Ϫ3.91 (m, 1 H, 1-H), 4.31Ϫ4.43 (m, 1 H, 4-H), 7.36
(d, J ϭ 8.3 Hz, 2 H, 3Ј,5Ј-Haryl), 7.73 (d, J ϭ 8.3 Hz, 2 H, 2Ј,6Ј-
H
aryl). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 0.5 (ϩ, SiMe3), 13.8
(ϩ), 14.2 (ϩ), 21.6 (ϩ, CH3), 23.7 (Ϫ), 27.3 (Ϫ), 52.6 (ϩ, OCH3),
59.0 (ϩ), 62.0 (ϩ), 127.8 (ϩ, Caryl-2Ј,6Ј), 130.1 (ϩ, Caryl-3Ј,5Ј),
137.1 (Cquat., Caryl-4Ј), 144.7 (Cquat., Caryl-1Ј), 155.2 (Cquat., CϭO).
Ϫ GC-MS (70eV); m/z (%): 366 (30) [Mϩ Ϫ CH3], 226 (100) [Mϩ
Ϫ SO2Ar]. Ϫ C18H27NO4SSi (381.56): calcd. C 56.66, H 7.13, N
3.67, S 8.40; found C 56.26, H 6.93, N 3.51, S 8.49.
1
SnCH2CH2), 29.2 (Ϫ, C-4), 32.6 [ϩ, J(119Sn, CH) ϭ 240 Hz, C-
6], 50.7 (ϩ, NHCH), 52.0 (ϩ, OCH3), 127.6 (ϩ, Caryl-2Ј,6Ј), 129.8
(ϩ, Caryl-3Ј,5Ј), 131.3 (ϩ, SO2CϭCH), 136.6 (Cquat., Caryl-1Ј), 143.7
(Cquat., SnCCSO2), 144.0 (Cquat., Caryl-4Ј), 155.9 (Cquat., CϭO). Ϫ
MS (DIP, 70eV); m/z (%): 599 (3) [Mϩ ϩ 1], 542 (100) [Mϩ ϩ 1
Ϫ C4H9].
N-(Methoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene (10) by De-
silylation/Detosylation of 12: The fluoride-induced degradation of
the silyl compound 12 to the bicyclic alkene 10 was performed with
5Ϫ7 equiv. of tetra-n-butylammonium fluoride trihydrate in anhy-
drous THF at room temperature during 16 h. GLC indicated com-
plete conversion without the formation of any byproducts. After
the usual work up with water and extraction with ether/pentane,
the solvents were removed from the resulting alkene, which was
then purified by rapid filtration through a short column (basic alu-
mina, activity 1) with ether/pentane (1:1) [Rf ϭ 0.53 (SiO2; ether/
pentane, 1:1)]. Yield: 237 mg (86%). Ϫ 1H NMR (400 MHz,
CDCl3): δ ϭ 1.10 (dd, J ϭ 10.9, 3.4 Hz, 2 H, 5,6-Hendo), 1.77Ϫ1.90
(m, 2 H, 5,6-Hexo), 3.62 (s, 3 H, OCH3), 4.72 (s, 2 H, 1,4-H), 6.22
(s, 2 H, 2,3-H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 23.9 (Ϫ, C-
5,6), 52.4 (ϩ, OCH3), 59.5 (ϩ, C-1,4), 134.7 (ϩ, C-2,3), 154.9
(Cquat., CϭO). Ϫ MS (CI, CH4); m/z (%): 154 (100) [Mϩ ϩ 1].
Heck-Type Hydroarylation Reactions to Racemic Epibatidine
Analogs. Ϫ General Procedure: 0.05 equiv. of bis(triphenylphos-
phane)palladium(II) acetate was dissolved in 1.5 ml of anhydrous
dimethylformamide and 1.5 equiv. of the alkene, 1.0 equiv. of the
aryl compound, and 3.5 equiv. of piperidine were added. Finally,
3.0 equiv. of formic acid was added rapidly in one portion. After
stirring until conversion was complete (usually 16 h), the reaction
mixture was partitioned between water and ethyl acetate. The aque-
ous layer was extracted three times with ethyl acetate and then the
combined organic layers were washed with brine. After drying with
anhydrous MgSO4 and evaporation of the volatile components, the
crude products were purified by flash column chromatography
(SiO2, 40Ϫ63 µm; Macherey-Nagel, Düren, Germany).
2-(6Ј-Chloro-3Ј-pyridyl)-N-methoxycarbonyl-7-azabicyclo-
[2.2.1]heptane (16a): Colorless oil, 800 mg (77%) [Rf ϭ 0.29 (SiO2;
2000
Eur. J. Org. Chem. 1998, 1997Ϫ2001

Chemistry in the Ambient Field of the Alkaloid Epibatidine, 1
FULL PAPER
petroleum ether/AcOEt, 2:1)]. Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ
(m, 1 H, Haryl), 7.27 (m, 1 H, Haryl). Ϫ HRMS: C14H15ClFNO2:
1.48Ϫ1.66 (m, 2 H), 1.75Ϫ1.84 (m, 3 H), 1.99 (dd, J ϭ 12.7, 9.1 calcd. 283.0776; found 283.0776. Ϫ C14H15ClFNO2 (282.79): calcd.
Hz, 1 H, 3-Hendo), 2.87 (dd, J ϭ 9.1, 4.6 Hz, 1 H, 2-Hendo), 3.64 (s, C 59.46, H 5.35, N 4.95; found C 58.92, H 5.29, N 4.88.
3 H, CO2CH3), 4.18 (br. s, 1 H, 1-H), 4.42 (br. s, 1 H, 4-H), 7.22
(d, J ϭ 8.4 Hz, 1 H, 5Ј-Hpyridyl), 7.58 (dd, J ϭ 8.4, 2.3 Hz, 1 H,
[1]
J. W. Daly, T. Tokuyama, T. Fujiwara, R. J. Highet, I. L. Karle,
4Ј-Hpyridyl), 8.20 (d, J ϭ 2.3 Hz, 1 H, 2Ј-Hpyridyl). Ϫ 13C NMR (100
J. Am. Chem. Soc. 1980, 102, 830Ϫ836.
[2] [2a]
MHz, CDCl3): δ ϭ 28.7 (Ϫ, C-5 or C-6), 29.6 (Ϫ, C-5 or C-6),
40.2 (Ϫ, C-3), 44.7 (ϩ, C-2), 52.4 (ϩ, OCH3), 56.1 (ϩ, C-4), 62.0
T. F. Spande, H. M. Garaffo, M. W. Edwards, H. J. C. Yeh,
L. Pannell, J. W. Daly, J. Am. Chem. Soc. 1992, 114,
[2b]
3475Ϫ3478. Ϫ
C. Szantay, Z. Kardos-Balogh, I. Moldvai,
(ϩ, C-1), 124.1 (ϩ, Cpyridyl-5Ј), 137.1 (ϩ, Cpyridyl-4Ј), 139.8 (Cquat.
,
C. Szantay, Jr., E. Temesvari-Major, G. Blasko, Tetrahedron
Lett. 1994, 35, 3171Ϫ3174.
Cpyridyl-3Ј), 148.6 (ϩ, Cpyridyl-2Ј), 149.3 (Cquat., Cpyridyl-6Ј), 156.0
(CϭO). Ϫ MS (70eV); m/z (%): 266 (28) [Mϩ], 237 (7) [M Ϫ C2H5],
192 (8), 140 (28) [ClϪC5NH3ϪCHϭCH2ϩ], 127 (100). Ϫ HRMS:
C13H15ClN2O2: calcd. 266.0822; found 266.0822. Ϫ C13H15ClN2O2
(266.72): calcd. C 58.54, H 5.67, Cl 13.29, N 10.50; found C 58.08,
H 5.60, Cl 13.15, N 10.37.
[3]
[4]
T. Li, C. Qian, J. Eckman, D. F. Huang, T. Y. Shen, Bioorg.
Med. Chem. Lett. 1993, 3, 2759Ϫ2764.
J. E. Leet, D. R. Schroeder, S. J. Hofstead, J. Golik, K. L. Col-
son, S. Huang, S. E. Klohr, T. W. Doyle, J. A. Matson, J. Am.
Chem. Soc. 1992, 114, 7946Ϫ7948.
[5] [5a]
[5b]
[5c]
C. A. Broka, Med. Chem. Res. 1994, 4, 449Ϫ460. Ϫ
E.
C.
V. Dehmlow, J. Prakt. Chem. 1995, 337, 167Ϫ174. Ϫ
N-Methoxycarbonyl-2-phenyl-7-azabicyclo[2.2.1]heptane (16b):
Szantay, Z. Kardos-Balogh, C. Szantay, Jr., The Alkaloids 1995,
1
[5d]
Colorless oil, 786 mg (85%). Ϫ H NMR (400 MHz, CDCl3): δ ϭ
46, 95Ϫ125. Ϫ
Z. Chen, M. L. Trudell, Chem. Rev. 1996,
[5e]
96, 1179Ϫ1193. Ϫ
M. L. Trudell, C. Zhang, J. Org. Chem.
1.41 (d, J ϭ 7.1 Hz, 1 H), 1.50Ϫ1.65 (m, 1 H), 1.70Ϫ2.05 (m, 4
H), 2.89 (dd, J ϭ 8.2, 5.7 Hz, 1 H, 2-Hendo), 3.64 (s, 3 H, CO2CH3),
4.26 (br. s, 1 H, 1-H), 4.43 (br. s, 1 H, 4-H), 7.15Ϫ7.30 (m, 5 H,
Haryl) . Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 28.8 (Ϫ, C-5 or C-
6), 29.6 (Ϫ, C-5 or C-6), 40.0 (Ϫ, C-3), 48.3 (ϩ, C-2), 52.3 (ϩ,
OCH3), 56.1 (ϩ, C-4), 62.2 (ϩ, C-1), 126.2 (ϩ, Caryl-4Ј), 127.0 (ϩ,
Caryl-2Ј,6Ј), 128.4 (ϩ, Caryl-3Ј,5Ј), 145.5 (Cquat., Caryl-1Ј), 156.0 (Cϭ
O). Ϫ MS (70eV); m/z (%): 231 (24) [Mϩ], 127 (100). Ϫ HRMS:
C14H17NO2: calcd. 231.1259; found 231.1259. Ϫ C14H17NO2
(231.29): calcd. C 72.70, H 7.41, N 6.06; found C 72.09, H 7.42,
N 5.98.
[5f]
1996, 61, 7189Ϫ7191. Ϫ
G. M. P. Giblin, C. D. Jones, N. S.
[5g]
Simpkins, Synlett 1997, 589Ϫ590. Ϫ
G. M. P. Giblin, C. D.
Jones, N. S. Simpkins, Tetrahedron Lett. 1998, 39, 1023Ϫ1024.
S. C. Clayton, A. C. Regan, Tetrahedron Lett. 1993, 34,
7493Ϫ7496.
[6]
[7]
[8]
J. C. Namyslo, D. E. Kaufmann, Chem. Ber. 1997, 130,
1327Ϫ1331.
D. R. M. Walton, F. Waugh, J. Organomet. Chem. 1972, 37,
45Ϫ56.
[9] [9a]
R. V. Williams, K. Chauhan, V. R. Gadgil, J. Chem. Soc.,
Chem. Commun. 1994, 15, 1739Ϫ1740. Ϫ [9b] L. Waykole, L. A.
Paquette, D. A. Heerding, L. E. Overman, Org. Synth. 1988,
67, 149Ϫ155 and 1951Ϫ1954.
[10]
[11]
C. S. Kraihanzel, J. E. Poist, J. Organomet. Chem. 1967, 8,
239Ϫ243.
N-Methoxycarbonyl-2-(3Ј-pyridyl)-7-azabicyclo[2.2.1]heptane
(16c): Colorless oil, 743 mg (80%). Ϫ 1H NMR (400 MHz, CDCl3):
δ ϭ 1.48Ϫ2.10 (m, 6 H), 2.92 (dd, J ϭ 9.1, 4.2 Hz, 1 H, 2-Hendo),
3.67 (s, 3 H, CO2CH3), 4.25 (br. s, 1 H, 1-H), 4.46 (br. s, 1 H, 4-
H), 7.40Ϫ7.80 (m, 4 H, Haryl). Ϫ 13C NMR (100 MHz, CDCl3):
δ ϭ 28.6 (Ϫ, C-5 or C-6), 29.5 (Ϫ, C-5 or C-6), 40.3 (Ϫ, C-3), 45.5
(ϩ, C-2), 52.2 (ϩ, OCH3), 56.0 (ϩ, C-4), 61.9 (ϩ, C-1), 123.3 (ϩ,
Cpyridyl-5Ј), 133.9 (ϩ, Cpyridyl-4Ј), 140.6 (Cquat., Cpyridyl-3Ј), 147.6
(ϩ, Cpyridyl-6Ј), 148.8 (ϩ, Cpyridyl-2Ј), 155.8 (CϭO). Ϫ MS (70eV);
m/z (%): 232 (19) [Mϩ], 127 (100). Ϫ HRMS: C13H16N2O2: calcd.
232.1212; found 232.1212. Ϫ C13H16N2O2 (232.27): calcd. C 67.22,
H 6.94, N 12.06; found C 66.73, H 6.84, N 11.88.
H. J. Altenbach, B. Blech, J. A. Marco, E. Vogel, Angew. Chem.
1982, 94, 789Ϫ790; Angew. Chem. Suppl. 1982, 1614Ϫ1621; An-
gew. Chem. Int. Ed. Engl. 1982, 21, 772.
[12]
[13]
H. J. Altenbach, D. Constant, H.-D. Martin, B. Mayer, M.
Müller, E. Vogel, Chem. Ber. 1991, 124, 791Ϫ801.
`
P. Caubere, P. Coutrot in Comprehensive Organic Syntheses, vol.
8 (Reductions) (Eds.: B. M. Trost, I. Fleming), Pergamon Press,
Oxford 1991, p. 835Ϫ847 and 865Ϫ867.
[14]
[15]
[16]
[17]
[18]
V. Pascali, A. Umani-Ronchi, J. Chem. Soc., Chem. Commun.
1973, 351.
D. Savoia, C. Trombini, A. Umani-Ronchi, J. Chem. Soc., Per-
kin. Trans. 1 1977, 123Ϫ125.
B. M. Trost, L. Weber, P. Strege, T. J. Fullerton, T. J. Dietsche,
J. Am. Chem. Soc. 1978, 100, 3426Ϫ3435.
N-Methoxycarbonyl-2-(2Ј-thienyl)-7-azabicyclo[2.2.1]heptane
(16d): Colorless oil, 209 mg (44%). Ϫ 1H NMR (400 MHz, CDCl3):
δ ϭ 1.32Ϫ2.05 (m, 6 H), 3.19 (dd, J ϭ 7.9, 5.5 Hz, 1 H, 2-Hendo),
3.66 (s, 3 H, CO2CH3), 4.25 (br. s, 1 H, 1-H), 4.41 (br. s, 1 H, 4-
H), 6.82 (d, J ϭ 3.2 Hz, 1 H, 3Ј-Hthienyl), 6.88 (dd, J ϭ 5.1, 3.2 Hz,
1 H, 4Ј-Hthienyl), 7.11 (d, J ϭ 5.1 Hz, 1 H, 5Ј-Hthienyl). Ϫ MS (70eV);
m/z (%): 237 (26) [Mϩ], 162 (7), 139 (9), 127 (100). Ϫ HRMS:
C12H15NO2S: calcd. 237.0823; found 237.0823. Ϫ C12H15NO2S
(221.32): calcd. C 65.12, H 6.83, N 6.33; found C 64.92, H 6.85,
N 6.23.
G. E. Keck, K. A. Savin, M. A. Weglarz, J. Org. Chem. 1995,
60, 3194Ϫ3204.
D. H. R. Barton, G. Bringmann, G. Lamotte, W. B. Mo-
therwell, R. S. H. Motherwell, A. E. A. Porter, J. Chem. Soc.,
Perkin Trans. 1 1980, 2657Ϫ2664.
[19]
J. Bremner, M. Julia, M. Launay, J.-P. Stacino, Tetrahedron Lett.
1982, 23, 3265Ϫ3266.
[20] [20a] M. Ochiai, T. Ukita, E. Fujita, J. Chem. Soc., Chem. Com-
mun. 1983, 619Ϫ620. Ϫ [20b] R. V. Williams, K. Chauhan, V. R.
Gadgil, J. Chem. Soc., Chem. Commun. 1994, 1739Ϫ1740.
[21]
J. T. Groves, K. W. Ma, J. Am. Chem. Soc. 1977, 99,
4076Ϫ4082.
[22]
A. Kirschning, F. Narjes, E. Schaumann, Liebigs Ann. Chem.
2-(4Ј-Chloro-3Ј-fluorophenyl)-N-methoxycarbonyl-7-aza-
bicyclo[2.2.1]heptane (16e): Colorless oil, 345 mg (61%). Ϫ 1H
NMR (400 MHz, CDCl3): δ ϭ 1.30Ϫ2.05 (m, 6 H), 2.85 (dd, J ϭ
8.2, 5.7 Hz, 1 H, 2-Hendo), 3.67 (s, 3 H, CO2CH3), 4.22 (br. s, 1 H,
1-H), 4.42 (br. s, 1 H, 4-H), 6.96 (d, J ϭ 8.3 Hz, 1 H, Haryl), 7.06
1991, 933Ϫ936.
[23]
N.-C. Wang, H. J. Anderson, Can. J. Chem. 1977, 55,
4103Ϫ4111.
[24]
O. Magidson, G. Menschikoff, Ber. Dtsch. Chem. Ges. 1925,
58, 113Ϫ118.
[98020]
Eur. J. Org. Chem. 1998, 1997Ϫ2001
2001