Synthesis of Epibatidine Analogues Having a 2-Substituted 2-Azabicyclo[2.2.2]octane Skeleton

Article abstract of DOI:10.1002/ejoc.201301397

The synthesis of 1-cyano-2-aza-[2.2.2]bicyclooctanes has been studied using the dynamic cyanide addition to cyclohexanone derivatives. These compounds were further elaborated into a new class of epibatidine derivatives from which a number of examples were

Full text of DOI:10.1002/ejoc.201301397

FULL PAPER
DOI: 10.1002/ejoc.201301397
Synthesis of Epibatidine Analogues Having a 2-Substituted
2-Azabicyclo[2.2.2]octane Skeleton
Iris Wauters,[a][‡] Ann De Blieck,[a][‡] Koen Muylaert,[a] Thomas S. A. Heugebaert,[a] and
Christian V. Stevens*[a]
Keywords: Medicinal chemistry / Natural products / Nitrogen heterocycles / Cyanides / Cyclization / Biological activity
The synthesis of 1-cyano-2-aza-[2.2.2]bicyclooctanes has
a number of examples were fully deprotected to give the po-
been studied using the dynamic cyanide addition to cyclo- tentially active compounds. The highly hydrophilic character
hexanone derivatives. These compounds were further elabo-
rated into a new class of epibatidine derivatives from which
of the compounds resulted in a difficult isolation and purifica-
tion of the epibatidine analogues.
times higher than that of morphine (1). The high potency
of epibatidine (3) spurred interest in this field. However, the
toxicity of the natural product is too high for it to be used
clinically.[10] Many analogues have been synthesized, aiming
to reduce the toxicity, while maintaining or improving the
efficacy of the compound (the so-called therapeutic ratio).
Epiboxidine (4) and ABT-594 (5) are among the most suc-
cessful examples (Figure 1).[11]
Introduction
Chronic pain presents a major challenge to the citizens
and economy of Europe, as one in five Europeans is esti-
mated to suffer from chronic pain, and this burden is likely
to worsen with an ageing population and a greater pressure
for people to work longer.[1–3] Current pain management is
mostly reliant on pharmacological intervention, using anal-
gesics [(non)-opioids, e.g., morphine (1) and codeine (2)]
and NSAIDs (non-steroidal anti-inflammatory drugs), as
well as adjuvant therapies such as antidepressants and anti-
convulsants.
Given the complexity and unfavourable side-effects of
pain treatment, combined with a high cost, the develop-
ment of new drug candidates to counter chronic pain is still
of paramount value for the industry.[4] One strategy fo-
cusses on interaction with neuronal nicotinic acetylcholine
receptors (nAChRs),[5] pentameric ion channels structurally
composed of 17 subunits [α(1–10), β(1–4), γ, δ, and ε].[6]
The predominant receptor subtypes in the central nervous
system (CNS) are of the α4β2 and α7 varieties, whereas the
α3β4 receptor subtype predominates in the peripheral ner-
vous system.[7,8] Of these receptor subtypes, the first ac-
counts for approximately 90% of all nAChRs.[4] In 1974,
Figure 1. Morphine (1), codeine (2), epibatidine (3), epiboxidine
Daly et al. discovered that alkaloids extracted from the skin (4), and ABT-594 (5).
of the Ecuadorian tree frog Epipedobates tricolor produced
Moreover, the 2-azabicyclo[2.2.2]octane core or iso-
a Straub tail response in mice (a rigid, erect, S-shaped tail),
similar to that produced by opioids.[9] The alkaloid epibat-
idine (3) was shown to have an analgesic potency about 200
quinuclidine skeleton is omnipresent in nature. A series of
plant alkaloids with a variety of interesting properties have
been isolated. Ibogaine (6), isolated from the root of the
African plant Tabernanthe iboga, is a tricyclic secondary
plant metabolite that causes hallucinations. However, de-
spite these side-effects, it has been used in the treatment of
opiate, nicotine, and alcohol addiction.[12] Another interest-
ing alkaloid is dioscorine (7), the prototype molecule from
Dioscorea hispida, a tropical yam and edible tuber. This
toxic alkaloid shows insecticidal and antifeedant properties
[a] Research Group SynBioC, Department of Sustainable Organic
Chemistry and Technology, Faculty of Bioscience Engineering,
Ghent University,
Coupure links 653, 9000 Ghent, Belgium
E-mail: Chris.Stevens@Ugent.be
www.SynBioC.UGent.be
[‡] Equal contributions
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301397.
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Synthesis of Epibatidine Analogues
through interaction with the AChRs and suppression of the cyclization reaction.[16–18] The synthesis of the precursor 4-
central nervous system (Figure 2).[13] Several synthetic (methanesulfonyloxymethyl)cyclohexanone (11) was de-
routes towards the isoquinuclidine scaffold have been re- signed such that the bicyclic core would be formed in a
ported, the majority of which used a Diels–Alder cycload- single reaction step (Scheme 2).
dition[14] or an intramolecular ring closure.[15]
Scheme 2. Retrosynthetic analysis of 8.
Figure 2. Ibogaine (6) and dioscorine (7).
First, the envisaged precursor (i.e., 11) was prepared
from commercially available racemic ethyl 4-hydroxycyclo-
hexane-1-carboxylate (13) by reduction of the ester moiety
with lithium aluminium hydride to give the corresponding
By combining these two structural moieties, the azabicy-
clo[2.2.2]octane skeleton and the pyridyl side-chain, we
have developed a new series of epibatidine analogues. This
diol (i.e., 14) in nearly quantitative yield, followed by selec-
paper highlights the different synthetic strategies towards
tive oxidation of the secondary alcohol in the presence of
these epibatidine analogues, starting from the interesting 2-
sodium hypochlorite in glacial acetic acid to give ketone
15.[19] Final mesylation to transform the alcohol function-
ality into a good leaving group led to precursor 11 in an
overall yield of 90% (Scheme 3).
substituted 2-azabicyclo[2.2.2]octane-1-carbonitriles 8, as
presented in Scheme 1. To preserve epibatidine’s very im-
portant “internitrogen distance” of approximately 5.5 Å, an
extra carbon atom was introduced between the pyridine
substituent and the azabicycle.
Having synthesized precursor 11, several experiments
were carried out to construct the isoquinuclidine core, using
our cyanide-induced dynamic intramolecular cyclization re-
action with acetone cyanohydrin as a hydrogen cyanide
source.[17]
4-(Methanesulfonyloxymethyl)cyclohexanone
(11) in dry methanol was treated with a primary amine,
triethylamine, and acetone cyanohydrin in a sealed pressure
vial at 110 °C for 2 d (Scheme 4). The mechanism of ring
closure is illustrated below (Scheme 5). If the reaction was
stopped after a few hours of reflux, adduct 16 and/or 17
was the major component of the mixture, along with traces
of the bicyclic end product (i.e., 8). It is especially note-
worthy that only the cis isomer (i.e., 17) allows the ring
closure to give the envisaged isoquinuclidine skeleton (i.e.,
8) to take place. When the reaction time was prolonged to
2 d, azabicyclic compound 8 was isolated as the major
Scheme 1. Retrosynthetic approach (PMB = 4-methoxybenzyl;
DMB = 2,4-dimethoxybenzyl).
Results and Discussion
A new strategy towards scaffold 8 was pursued, im- product, but still some of adducts 16 and/or 17 could be
plementing our cyanide-induced dynamic intramolecular detected, depending on the R group.
Scheme 3. Precursor synthesis.
Scheme 4. Synthesis of azabicyclic core 8.
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C. V. Stevens et al.
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cleophilic attack of a pyridin-2-yl group onto the nitrile,
however, proved to be more efficient.
Scheme 5. Reaction mechanism.
Scheme 6. Synthesis of epibatidine analogues.
After extraction with sodium hydrogen carbonate, the
The imines formed by the nucleophilic attack of the pyr-
crude bicyclic products 8 could be purified by column idyl anion onto the nitrile functionality proved to be quite
chromatography or recrystallization from methanol, the lat- resistant to acidic hydrolysis, and intermediate ketimine
ter method being less time-consuming. Using a variety of 18dЈ could be isolated in 30% yield by column chromatog-
primary amines, a range of derivatives was successfully pre- raphy instead of the expected product, 18d (1H NMR spec-
pared in moderate to good yields, as shown in Table 1. The troscopic analysis, recorded in CDCl3; CqCHN at δ =
significant discrepancy in yield between entries 1 and 7 can 9.1 ppm instead of δ = 9.8 ppm for the ketone). Further
be attributed to a difficult isolation in the latter case.
hydrolysis of 18dЈ resulted in the formation of the desired
Because of the introduction of a chloropyridyl side-chain ketone (i.e., 18d; Scheme 7). However, when the reaction
and its subsequent deprotection were troublesome in a pre- was performed on a smaller scale, no imine was detected,
viously reported series of epibatidine analogues,[17] and be- and 18d was obtained directly (Table 2). Consequently, the
cause it is known that omitting the chlorine atom does not hydrolysis was found to be a critical step in obtaining the
greatly affect the binding affinity towards the nAChRs,[20] epibatidine analogues in good yields. It must be carried out
only 2- and 3-bromopyridine were evaluated as pyridyl nu- for 24 h to guarantee the transformation of the imine into
cleophiles for this series of epibatidine derivatives.
the ketone.
Avenoza et al. published a reaction sequence towards α-
To enhance the potential activity or binding affinity with
aminoketones using organolithium reagents derived from 3- the nAChRs, the nitrogen atom of the bicyclic core had to
bromopyridine.[21] Based on these published results, along be deprotected. Large groups, e.g., benzyl, p-meth-
with our own experience of introducing a 2- or 3-pyridyl oxybenzyl, or 2,4-dimethoxybenzyl, prevent efficient inter-
side-chain in previous series of compounds,[18] we devel- action, and thus reduce the activity of the analogues. Based
oped an analogous route starting from the 2-substituted 2- on our experience of removing the benzyl groups from our
azabicyclo[2.2.2]octane-1-carbonitriles (i.e., 8; Scheme 6). previous series of epibatidine analogues, the current series
An overview of the compounds synthesized and their yields were deprotected using a reductive deprotection strategy as
is presented in Table 2. In none of the cases could complete shown in Scheme 8. The use of ammonium formate and
consumption of the starting material be obtained. The nu- palladium on carbon (10 wt.-%) led to the complete re-
Table 1. , yields of 2-substituted 2-azabicyclo[2.2.2]octane-1-carbonitriles 8.
R
Compd.
Yield of 8
Compd.
16/17
Yield of 16/17
[%]
[%]
1
2
3
4
5
6
7
Bn
PMB
2,4-DMB
Et
pyridin-2-ylmethyl
pyridin-3-ylmethyl
pyridin-4-ylmethyl
8a
8b
8c
8d
8e
8f
83[a]
72[b]
59[b]
73[a,d]
68[c]
a
b
c
d
e
f
–
–
–
–
9[e]
17[e]
25[e]
55[c]
8g
25[a]
g
1
[a] Yield after column chromatography (SiO2). [b] Yield after recrystallization. [c] Determined from the H NMR spectrum of the crude
material, co-elution impeded further purification. [d] Given the volatile properties of EtNH2, 2 equiv. of RNH2 were used. [e] Determined
1
from the H NMR spectrum of the crude material.
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Synthesis of Epibatidine Analogues
Table 2. Synthesis of 2-substituted 1-pyridinylcarbonyl-2-azabicyclo[2.2.2]octanes using 2- or 3-bromopyridine.
Entry
R
Time/temp.
After adding 8
Compound 8
Compound 19
Compound 18 or 20
[%]
[%][a]
[%][a]
18 Using 3-bromopyridine
1
2
3
4
PMB
Bn
a
b
c
30 min, –78 °C; over- 36
night, room temp.
30 min, –78 °C; over- 45
night, room temp.
30 min, –78 °C; over- 49
night, room temp.
30 min, –78 °C; over- 15
night, room temp.
8
56[b]
37[b]
31[c]
38[b]
18
12
47
2,4-DMB
Et
d
20 Using 2-bromopyridine
5
6
7
PMB
a
b
c
30 min, –78 °C; over- 16
night, room temp.
30 min, –78 °C; over- 15
night, room temp.
30 min, –78 °C; over- 17
night, room temp.
20
18
21
64[b]
63[c]
62[b]
Bn
Et
[a] Determined from the 1H NMR spectrum of the crude material. [b] Yield after column chromatography (SiO2). [c] Yield after recrystalli-
zation.
Scheme 8. Deprotection of epibatidine analogues 18b and 20b.
Scheme 7. Synthesis of intermediate ketimine 18dЈ.
Given the difficulties associated with deprotection, and
since QSAR (quantitative structure–activity relationship)
studies of epibatidine analogues have shown that derivatives
moval of the benzyl group within 3 h. In the presence of with small alkyl groups on the nitrogen atom may still show
the palladium catalyst, ammonium formate decomposes to activity against the nAChRs,[22] ethyl-protected compounds
produce the reducing agent, hydrogen gas, along with car- were further derivatized by reducing the carbonyl moiety to
bon dioxide and ammonia. The reaction times are espe- the corresponding racemic alcohol with sodium boro-
cially noteworthy, and they varied depending on the sub- hydride in dry methanol. When necessary, an extra purifica-
strate, as shown in Scheme 8. Unnecessary extension of the tion step was implemented to isolate the racemic alcohol as
reaction time led only to decomposition of the final product its hydrochloride salt (i.e., 24b) in 65% yield, using a satu-
in the reaction medium.
rated solution of hydrochloric acid in ether. Two such deriv-
Scheme 9. Derivatisation of analogues 18d and 20c.
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C. V. Stevens et al.
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Table 3. Screening of ligand-gated ion channel and CNS-related receptor modulatory activity at 1 μm concentration. Values below 30%
are considered to be insignificant
Receptor
Inhibition [%]
18d
20b
20c
21
22
23a
24b
D1(h)[a]
4
2
4
–9
0
–11
7
–12
–2
–14
–6
–14
0
7
7
–65
–4
–13
–20
12
–3
–5
–10
2
6
11
7
–6
–13
–8
–2
6
–9
–5
–24
5
5
8
–14
–2
D3(h)[a]
D3(h)[b]
D5(h)[a]
D5(h)[b]
N neuronal α-BGTX-
insensitive (α4β2)[b]
N neuronal α-BGTX-
sensitive (α7)[a]
N muscle-type (h)[a]
7
–1
9
4
–15
7
–12
8
–11
6
–5
0
–7
–1
–2
1
[a] Antagonist radioligand. [b] Agonist radioligand.
NMR spectrometer. Peaks were assigned with the aid of DEPT,
2D-HSQC, and 2D-COSY spectra. The compounds were dissolved
in deuterated solvents, and the solvent used is indicated for each
compound. Multiplicities are indicated using the following abbrevi-
ations: s singlet, d doublet, t triplet, q quadruplet, quint quintuplet,
sext sextuplet, sept septuplet, oct octuplet, non nonuplet, m mul-
tiplet, br. broad, ~ resembles. Low-resolution mass spectra were
recorded with an Agilent 1100 Series VS (ES, 4000V) mass spec-
trometer. Infrared spectra were recorded with a Perkin–Elmer Spec-
trum BX FTIR spectrometer. Compounds were analyzed in neat
atives were prepared accordingly, and an overview of the
yields is given in Scheme 9.
Seven analogues containing the 2-azabicyclo[2.2.2]octane
skeleton were selected and evaluated for their biological ac-
tivity. To get a general idea of the activity profile of these
compounds, they were submitted to a series of competitive
binding assays. A series of neurotransmitter recognition
sites relevant to the pharmacology of nicotinic acetylchol-
ine receptors was chosen as a testing panel. Representatives
of the major classes, the ligand-gated ion channels (nicot- form with an ATR (Attenuated Total Reflectance) accessory. Only
selected absorbances (ν) are reported. Melting points of crystalline
˜
inic acetylcholine) and other CNS-related receptors relevant
to pain mechanisms such as the dopaminic receptors were
included.[23] The percentage inhibition was obtained from a
competitive binding assay using known radioligands, and
the results are shown in Table 3. Values are expressed as
the percentage decrease of control-specific binding in the
presence of the compounds, as determined by scintillation
counting. As can be seen from Table 3, no significant
(Ͼ30%) binding to any of these receptors could be detected
for the selected compounds.
compounds were measured with a Büchi 540 apparatus. The purifi-
cation of reaction mixtures was performed by flash chromatog-
raphy using a glass column with silica gel (Acros, particle size
0.035–0.070 mm, pore diameter ca. 6 nm).
4-(Hydroxymethyl)cyclohexanol (14):
A suspension of LiAlH4
(1.5 equiv., 3.31 g, 87.1 mmol) in dry THF (300 mL) was stirred at
0 °C under an inert nitrogen atmosphere. A solution of commer-
cially available ethyl 4-hydroxycyclohexane-1-carboxylate 13
(1 equiv., 10.00 g, 58.1 mmol) in dry THF (50 mL) was carefully
added dropwise to the solution, using a dropping funnel with a
bypass. After the addition was complete, the cooling equipment
was removed, and the reaction mixture was stirred at room tem-
perature for 4 h. Then, water was added carefully to neutralize the
excess lithium aluminium hydride. The solution was dried with
magnesium sulfate, and then the solids were removed by filtration.
Evaporation of the filtrate under reduced pressure gave pure diol
14 (7.60 g, 96%) as a translucent oil. The spectroscopic data were
consistent with literature data.[24]
Conclusions
The results described clearly show the utility of 4-(meth-
anesulfonyloxymethyl)cyclohexanone as a building block
for the construction of the 2-azabicyclo[2.2.2]octane skel-
eton, using our cyanide-induced dynamic intramolecular
cyclization reaction. This cyclohexanone forms the ideal
precursor for the synthesis in only four steps of the iso-
quinuclidine skeleton that is omnipresent in nature. Due to
the versatility of the interesting nitrile derivative, a new
series of epibatidine analogues could be synthesized, start-
4-(Hydroxymethyl)cyclohexanone (15): In
a 250 mL flask, 14
(1 equiv., 7.60 g, 58.1 mmol) was dissolved in glacial acetic acid
(40 mL), and then commercially sourced sodium hypochlorite solu-
tion (La Croix Traditional Bleach, 39.93 g/L; 1.17 equiv., 127 mL,
68 mmol) was carefully added at room temperature. The mixture
ing from 2-substituted 2-azabicyclo[2.2.2]octane-1-carbo- was stirred form 1 h, and then the solvent was removed in vacuo.
The oily residue was re-dissolved in dry diethyl ether (50 mL) to
precipitate the salts. The solids were removed by filtration, and the
filtrate was evaporated to give compound 15 (7.44 g; quantitative
nitriles. A lithium–halogen exchange to prepare a pyridyl
nucleophile plays a central role in the route towards these
interesting rigid skeletons. The azabicyclo[2.2.2]octane
epibatidine derivatives did not show significant activity as
potential analgesic compounds.
yield) as a colourless oil, with a purity of 94%. IR: ν = 1705 (C=O).
˜
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.45 (dq, J = 12.1, J =
5.5 Hz, 2 H, 2 CHCHaHb), 1.89–2.06 (m, 1 H, CH), 2.08–2.13 (m,
2 H, 2 CHCHaHb), 2.34–2.48 (m, 4 H, 2 COCH2), 3.58 (d, J =
6.6 Hz, 2 H, CH2OH), 5.27 (br. s, 1 H, OH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 29.12 (2 CHCHaHb), 38.51 (CH), 40.38 (2
COCH2), 66.54 (CH2OH), 212.88 (C=O) ppm. MS (ES): m/z (%)
= 129 (100) [M + H]+, 130 (20). HRMS (ESI): calcd. for C7H13O2
Experimental Section
General Remarks: High-resolution 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded with a Jeol JNM-EX 300
1300
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Synthesis of Epibatidine Analogues
[M + H]+ 129.0916; found 129.0919. Chromatography, 30:70,
EtOAc/petroleum ether; Rf = 0.10.
258 (15). C16H20N2O (256.35): calcd. C 75.0, H 7.9, N 10.9; found
C 74.7, H 8.3, N 10.5, m.p. 75.0 °C. Chromatography, 10:90,
EtOAc/petroleum ether; Rf = 0.26. Yellow crystals.
4-(Methanesulfonyloxymethyl)cyclohexanone (11): In an oven-dried
250 mL flask, compound 15 (1 equiv., 7.40 g, 58.1 mmol) was dis-
solved in dry dichloromethane (150 mL) together with triethyl-
amine (1.1 equiv., 6.47 g, 63.9 mmol). The mixture was cooled to
0 °C under an inert nitrogen atmosphere. A solution of mesyl chlor-
ide (1.1 equiv., 7.32 g, 63.9 mmol) in dry dichloromethane (50 mL)
was added dropwise, and then the reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was poured into a
saturated NaHCO3 solution, and then the mixture was extracted
with CH2Cl2 (2ϫ 50 mL). The combined organic extracts were
dried with MgSO4. The solvent was removed in vacuo, and the
residue was recrystallized from ethyl acetate to give compound 11
(11.4 g; 95%) as white crystals. The crystals needed to be stored at
2-(2,4-Dimethoxybenzyl)-2-azabicyclo[2.2.2]octane-1-carbonitrile
1
(8c): Yield 59%. IR: ν = 2238 (CϵN), 1611, 1586, 1504 (Ar). H
˜
NMR (300 MHz, CDCl3, 25 °C): δ = 1.56–1.80 (m, 5 H, 2 CHCH2,
CH), 1.98 (dt, J = 12.1, J = 4.4 Hz, 2 H, 2 CHaHb), 2.35–2.48 (m,
2 H, 2 CHaHb), 2.71 (br. s, 2 H, CHCH2N), 3.80 [s, 3 H, OCH3
(Ar)], 3.81 [s, 3 H, OCH3 (Ar)], 3.93 (s, 2 H, NCH2Ar), 6.43 [d, J
= 2.2 Hz, 1 H, CqCHCq (Ar)], 6.48 [dd, J = 8.3, J = 2.2 Hz, 1 H,
CqCHCH (Ar)], 7.33 [d, J = 8.3 Hz, 1 H, CqCHCH (Ar)] ppm. 13
C
NMR (75 MHz, CDCl3): δ = 24.21 (2 CHCH2), 25.13 (CH), 30.38
(2 CqCHaHb), 52.41 (Cq, NCH2Ar), 55.16 (CHCH2N), 55.46 [2
OCH3 (Ar)], 98.44 [CqCHCq (Ar)], 104.15 [CqCHCH (Ar)], 119.35
[Cq (Ar)], 122.40 (CϵN), 130.46 [CqCHCH (Ar)], 158.49 [Cq (Ar)],
159.87 [Cq (Ar)] ppm. MS (ES): m/z (%) = 151 (60), 152 (5), 287
(100) [M + H]+, 288 (20). C17H22N2O2 (286.37): calcd. C 71.3, H
7.7, N 9.8; found C 70.9, H 8.0, N 9.7, m.p. 72.7 °C. Chromatog-
raphy, 10:90, EtOAc/petroleum ether; Rf = 0.18. Orange crystals.
–18 °C, as they were unstable at room temperature. IR: ν = 1705
˜
(C=O), 1344, 1339 (S=O), 932 (S-O). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.54 (dq, J = 12.4, J = 5.2 Hz, 2 H, 2 CHCHaHb),
2.11–2.30 (m, 3 H, CH, 2 CHCHaHb), 2.31–2.48 (m, 4 H, 2
COCH2), 3.05 [s, 3 H, CH3 (Ms)], 4.16 (d, J = 6.6 Hz, 2 H, CH2O)
ppm. 13C NMR (75 MHz, CDCl3): δ = 28.67 (2 CHCHaHb), 35.86
(CH), 37.42 [CH3 (Ms)], 39.94 (2 COCH2), 72.70 (CH2O), 210.34
(C=O) ppm. MS (ES): m/z (%) = 224 (100) [M + NH4+]. HRMS
(ESI): calcd. for C8H17NO4S [M + NH4]+ 223.0878; found
223.0192, m.p. 66.2–68.3 °C.
2-Ethyl-2-azabicyclo[2.2.2]octane-1-carbonitrile (8d): Yield 73%.
IR: ν = 2241 (CϵN). 1H NMR (300 MHz, CDCl , 25 °C): δ = 1.12
˜
3
[t, J = 7.2 Hz, 3 H, CH3 (Et)], 1.56–1.77 (m, 5 H, 2 CHCH2, CH),
1.85–1.96 (m, 2 H, 2 CHaHb), 2.24–2.36 (m, 2 H, 2 CHaHb), 2.75–
2.78 (m, 2 H, CHCH2N), 2.81 [q, J = 7.2 Hz, 2 H, NCH2 (Et)]
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.34 [CH3 (Et)], 24.11 (2
CHCH2), 24.76 (CH), 29.93 (2 CqCHaHb), 48.75 [NCH2 (Et)],
52.40 (Cq), 54.61 (NCH2), 122.02 (CϵN) ppm. MS (ES): m/z (%)
= 165 (100) [M + H]+, 166 (11). HRMS (ESI): calcd. for C10H17N2
[M + H]+ 165.1392; found 165.1390. Chromatography, 40:60,
EtOAc/petroleum ether; Rf = 0.33. Yellow oil.
2-Substituted 2-Azabicyclo[2.2.2]octane-1-carbonitriles (8): In a dry,
pressure-resistant 150 mL vial, 4-(methanesulfonyloxymethyl)cy-
clohexanone (11; 1 equiv., 14.7 mmol, 3.00 g), a primary amine
(1 equiv., 14.7 mmol), acetone cyanohydrin (2 equiv., 2.50 g,
29.4 mmol), and triethylamine (2 equiv., 2.98 g, 29.4 mmol) were
dissolved in dry methanol (100 mL). When using pure ethylamine,
the volatile amine (2 mL, 30 mmol) was used. The vessel was closed
and heated to 110 °C for 2 d. The reaction mixture was poured
into a saturated NaHCO3 solution, the mixture was extracted with
dichloromethane (3ϫ 50 mL), and the combined organic extracts
were dried with MgSO4. The crude 2-substituted 2-azabicy-
clo[2.2.2]octane-1-carbonitriles 8 could be further purified by col-
umn chromatography or by recrystallization from methanol.
2-(Pyridin-4-ylmethyl)-2-azabicyclo[2.2.2]octane-1-carbonitrile (8g):
Yield 25%. IR: ν = 2240 (CϵN), 1602, 1561, 1493 (pyr.). 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 1.59–1.80 (m, 5 H, m, 2 CHCH2,
CH), 1.95–2.07 (m, 2 H, 2 CHaHb), 2.33–2.45 (m, 2 H, 2 CHaHb),
2.64 (br. s, 2 H, CHCH2N), 3.98 (s, 2 H, NCH2pyr.), 7.32 [d, J =
5.5 Hz, 2 H, 2 CH (pyr.)], 8.56 [d, J = 5.5 Hz, 2 H, 2 CH (pyr.)]
ppm. 13C NMR (75 MHz, CDCl3): δ = 23.91 (2 CHCH2), 24.78
(CH), 30.09 (2 CqCHaHb), 52.23 (Cq), 55.48 (CHCH2N), 58.02
(NCH2pyr.), 121.73 (CϵN), 123.50 [2 CH (pyr.)], 147.95 [Cq (pyr.)],
149.69 [2 CH (pyr.)] ppm. MS (ES): m/z (%) = 228 (100)
[M + H]+, 229 (15). HRMS (ESI): calcd. for C14H18N3 [M + H]+
2-Benzyl-2-azabicyclo[2.2.2]octane-1-carbonitrile (8a): Yield 83%.
IR: ν = 2237 (CϵN), 1494, 1454 (Ph). 1H NMR (300 MHz, CDCl ,
˜
3
25 °C): δ = 1.56–1.78 (m, 5 H, 2 CHCH2, CH), 1.99 (dt, J = 12.0,
J = 4.4 Hz, 2 H, 2 CHaHb), 2.33–2.45 (m, 2 H, 2 CHaHb), 2.62 (br. 228.1501; found 228.1497. C14H17N3 (227.31): calcd. C 74.0, H 7.5,
s, 2 H, CHCH2N), 3.96 (s, 2 H, NCH2Ph), 7.22–7.39 [m, 5 H, 5 N 18.5; found C 73.9, H 7.6, N 18.3, m.p. 43.3 °C. Chromatog-
CH (Ph)] ppm. 13C NMR (75 MHz, CDCl3): δ = 24.21 (2 CHCH2),
25.00 (CH), 30.27 (2 CqCHaHb), 52.42 (Cq), 55.11 (CHCH2N),
59.02 (NCH2Ph), 122.19 (CϵN), 127.18 [CH (Ph)], 128.38 [2 CH
(Ph)], 128.81 [2 CH (Ph)], 138.67 [Cq (Ph)] ppm. MS (ES): m/z (%)
= 227 (100) [M + H]+, 228 (15). C15H18N2 (226.32): calcd. C 79.6,
H 8.0, N 12.4; found C 79.2, H 7.9, N 12.1, m.p. 99.3 °C.
Chromatography, 10:90, EtOAc/petroleum ether; Rf = 0.30. Yellow
crystals.
raphy, 30:70, EtOAc/petroleum ether; Rf = 0.19. Orange crystals.
2-Substituted 1-(Pyridin-3-ylcarbonyl)-2-azabicyclo[2.2.2]octanes
(18): In a dry 50 mL flask, a 2-substituted 2-azabicyclo[2.2.2]-
octane-1-carbonitrile 8 (1 equiv., 5.7 mmol) and 3-bromopyridine
(1.1 equiv., 0.99 g, 6.3 mmol) were dissolved in dry diethyl ether
(35 mL). The flask was placed under an inert N2 atmosphere and
cooled to –78 °C. Using a syringe, BuLi (2.5 m solution; 1.1 equiv.,
2.5 mL, 6.3 mmol) was added over a period of 10 min. The reaction
2-(4-Methoxybenzyl)-2-azabicyclo[2.2.2]octane-1-carbonitrile (8b): mixture was stirred for 30 min at –78 °C, and then it was allowed
1
Yield 72%. IR: ν = 2234 (CϵN), 1610, 1586, 1510 (Ar). H NMR
to slowly warm up to room temperature. The mixture was left stir-
˜
(300 MHz, CDCl3, 25 °C): δ = 1.56–1.77 (m, 5 H, 2 CHCH2, CH), ring for 24 h. Methanol was added to neutralize the excess BuLi,
1.97 (dt, J = 12.1, J = 4.4 Hz, 2 H, 2 CHaHb), 2.31–2.44 (m, 2 H, and the volatile components were removed in vacuo. The reaction
2 CHaHb), 2.60 (br. s, 2 H, CHCH2N), 3.79 [s, 3 H, OCH3 (Ar)],
mixture was redissolved in a 1:1 mixture of methanol and HCl (1 m)
3.89 (s, 2 H, NCH2Ar), 6.86 [d, J = 8.3 Hz, 2 H, 2 CH (Ar)], 7.28 (30 mL). Silica gel (0.5 g) was added to improve the hydrolysis, and
[d, J = 8.3 Hz, 2 H, 2 CH (Ar)] ppm. 13C NMR (75 MHz, CDCl3): the mixture was stirred for 24 h at room temperature. The pH of
δ = 24.22 (2 CHCH2), 25.00 (CH), 30.26 (2 CqCHaHb), 52.33 (Cq),
54.90 (CHCH2N), 55.36 [OCH3 (Ar)], 58.30 (NCH2Ar), 113.76 [2
the solution was adjusted to 8 by the addition of a concentrated
NaHCO3 solution. Compound 18 was extracted using dichloro-
CH (Ar)], 122.26 (CϵN), 129.94 [2 CH (Ar)], 130.66 [Cq (Ar)], methane (3ϫ 50 mL), and the combined organic extracts were
158.83 [Cq (Ar)] ppm. MS (ES): m/z (%) = 257 (100) [M + H]+, dried with MgSO4. The solids were removed by filtration, and the
Eur. J. Org. Chem. 2014, 1296–1304
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1301

C. V. Stevens et al.
FULL PAPER
volatile components were evaporated. The residue was purified by
column chromatography to give compound 18. Crystalline materi-
als were recrystallized from methanol.
formed after nucleophilic attack of the pyridyllithium onto the
nitrile moiety towards hydrolysis, was proved by isolation of com-
pound 18dЈ after column chromatography in 30% yield as a repre-
sentative example. IR: ν = 1676 (C=N), 1607, 1582, 1448 (pyr.). 1H
˜
2-(4-Methoxybenzyl)-1-(pyridin-3-ylcarbonyl)-2-azabicyclo[2.2.2]-
NMR (300 MHz, CDCl3, 25 °C): δ = 1.00 [t, J = 7.2 Hz, 3 H, CH3
(Et)], 1.58–1.81 (m, 7 H, 2 CHCH2, CH, 2 CHaHb), 2.05–2.19 (m,
2 H, 2 CHaHb), 2.48 [q, J = 7.2 Hz, 2 H, NCH2 (Et)], 2.93 (br. s,
2 H, CHCH2N), 7.28 [dd, J = 8.0, J = 5.0 Hz, 1 H, CqCHCH
(pyr.)], 8.20 [dt, J = 8.0, J = 1.7 Hz, 1 H, CqCHCH (pyr.)], 8.60
[dd, J = 5.0, J = 1.7 Hz, 1 H, NCHCH (pyr.)], 9.10 [s, 1 H, CqCHN
(pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 13.61 [CH3 (Et)],
24.85 (2 CHCH2), 26.41 (CH), 28.55 (2 CqCHaHb), 47.91 [NCH2
(Et)], 54.33 (CHCH2N), 61.51 (Cq), 122.70 [CqCHCH (pyr.)],
135.32 [Cq (pyr.)], 135.84 [CqCHCH (pyr.)], 149.47 [CqCHN (pyr.)],
150.10 [NCHCH (pyr.)], 181.78 (C=N) ppm. MS (ES): m/z (%) =
244 (100) [M + H]+, 245 (15). HRMS (ESI): calcd. for C15H22N3
[M + H]+ 244.1814; found 244.1817. Chromatography, 98:2,
CH2Cl2/MeOH; Rf = 0.05. Yellow oil.
octane (18a): Yield 56%. IR: ν = 1674 (C=O), 1611, 1582, 1511
(Ar, pyr.). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.62–1.85 (m,
˜
1
7 H, 2 CHCH2, CH, 2 CHaHb), 2.42–2.54 (m, 2 H, 2 CHaHb), 2.82
(br. s, 2 H, CHCH2N), 3.54 (s, 2 H, NCH2Ar), 3.75 [s, 3 H, OCH3
(Ar)], 6.79 [d, J = 8.3 Hz, 2 H, 2 CH (Ar)], 7.12 [d, J = 8.3 Hz, 2
H, 2 CH (Ar)], 7.37 [dd, J = 8.3, J = 5.0 Hz, 1 H, CqCHCH (pyr.)],
8.71 [~dd, J = 5.0, J = 1.7 Hz, 1 H, NCHCH (pyr.)], 8.76 [~dt, J
= 8.3, J = 1.7 Hz, 1 H, CqCHCH (pyr.)], 9.97 [d, J = 1.7 Hz, 1 H,
CqCHN (pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 24.64 (2
CHCH2), 26.67 (CH), 27.93 (2 CqCHaHb), 54.75 (CHCH2N), 55.25
[OCH3 (Ar)], 57.98 (NCH2Ar), 65.28 (Cq), 113.71 [2 CH (Ar)],
123.15 [CqCHCH (pyr.)], 129.54 [2 CH (Ar)], 130.64 [Cq (Ar)],
130.89 [Cq (pyr.)], 137.61 [CqCHCH (pyr.)], 151.96 [CqCHN (pyr.)],
152.84 [NCHCH (pyr.)], 158.63 [Cq (Ar)], 202.59 (C=O) ppm. MS
(ES): m/z (%) = 337 (100) [M + H]+, 338 (28). HRMS (ESI): calcd.
for C21H25N2O2 [M + H]+ 337.1916; found 337.1909. Chromatog-
raphy, 30:70, EtOAc/petroleum ether; Rf = 0.29. Yellow oil.
2-Ethyl-1-(pyridin-3-ylcarbonyl)-2-azabicyclo[2.2.2]octane (18d):
Yield 38%. IR: ν = 1675 (C=O), 1580, 1448, 1412 (pyr.). 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 0.92 [t, J = 7.2 Hz, 3 H, CH3 (Et)],
1.62–1.77 (m, 6 H, 2 CHCH2, 2 CHaHb), 1.79–1.84 (m, 1 H, CH);
2.25–2.35 (m, 2 H, 2 CHaHb), 2.39 [q, J = 7.2 Hz, 2 H, NCH2 (Et)],
2.94 (br. s, 2 H, CHCH2N), 7.36 [dd, J = 7.7, J = 5.0 Hz, 1 H,
CqCHCH (pyr.)], 8.71 [dd, J = 5.0, J = 1.7 Hz, 1 H, NCHCH
(pyr.)], 8.78 [dt, J = 7.7, J = 1.7 Hz, 1 H, CqCHCH (pyr.)], 9.84 [s,
1 H, CqCHN (pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 13.25
[CH3 (Et)], 24.74 (2 CHCH2, CqCHaHb), 26.65 (CH), 27.95
(CqCHaHb), 49.45 [NCH2 (Et)], 54.87 (CHCH2N), 65.59 (Cq),
123.04 [CqCHCH (pyr.)], 131.32 [Cq (pyr.)], 137.73 [CqCHCH
(pyr.)], 152.14 [CqCHN (pyr.)], 152.77 [NCHCH (pyr.)], 202.97
(C=O) ppm. MS (ES): m/z (%) = 196 (40), 245 (100) [M + H]+,
246 (15). HRMS (ESI): calcd. for C15H21N2O [M + H]+ 245.1654;
found 245.1646. Chromatography, 30:70, EtOAc/petroleum ether;
Rf = 0.20. Yellow oil.
2-Benzyl-1-(pyridin-3-ylcarbonyl)-2-azabicyclo[2.2.2]octane (18b):
Yield 37%. IR: ν = 1666 (C=O), 1580, 1494, 1476 (Ph, pyr.). 1H
˜
NMR (300 MHz, CDCl3, 25 °C): δ = 1.64–1.87 (m, 7 H, 2 CHCH2,
CH, 2 CHaHb), 2.45–2.56 (m, 2 H, 2 CHaHb), 2.85 (br. s, 2 H,
CHCH2N), 3.61 (s, 2 H, NCH2Ph), 7.16–7.29 [m, 5 H, 5 CH (Ph)],
7.36 [dd, J = 7.7 Hz, J = 5.0 Hz, 1 H, CqCHCH (pyr.)], 8.70 [d, J
= 5.0 Hz, 1 H, NCHCH (pyr.)], 8.76 [~dt, J = 7.7, J = 1.7 Hz, 1
H, CqCHCH (pyr.)], 9.97 [s, 1 H, CqCHN (pyr.)] ppm. 13C NMR
(75 MHz, CDCl3): δ = 24.64 (2 CHCH2), 26.68 (CH), 28.00 (2
CqCHaHb), 55.07 (CHCH2N), 58.70 (NCH2Ph), 65.33 (Cq), 123.16
[CqCHCH (pyr.)], 126.98 [CH (Ph)], 128.39 [2 CH (Ph)], 128.41 [2
CH (Ph)], 130.90 [Cq (pyr.)], 137.61 [CqCHCH (pyr.)], 138.70 [Cq
(Ph)], 152.03 [CqCHN (pyr.)], 152.93 [NCHCH (pyr.)], 202.66
(C=O) ppm. MS (ES): m/z (%) = 307 (100) [M + H]+, 308 (24).
HRMS (ESI): calcd. for C20H23N2O [M + H]+ 307.1810; found
307.1803. C20H22N2O (306.41): calcd. C 78.4, H 7.2, N 9.1; found
C 78.3, H 7.6, N 9.1, m.p. 91.4 °C. Chromatography, 30:70, EtOAc/
petroleum ether; Rf = 0.16. Yellow crystals.
2-Substituted 1-(Pyridin-2-ylcarbonyl)-2-azabicyclo[2.2.2]octanes
(20): The protocol for the preparation of 2-substituted 1-(pyridin-
2-ylcarbonyl)-2-azabicyclo[2.2.2]octanes 20 is similar to that for the
synthesis of 2-substituted 1-(pyridin-3-ylcarbonyl)-2-azabicyclo
[2.2.2]octanes 18, except that 3-bromopyridine was replaced by 2-
bromopyridine.
2-(2,4-Dimethoxybenzyl)-1-(pyridin-3-ylcarbonyl)-2-azabicyclo-
[2.2.2]octane (18c): Yield 31%. IR: ν = 1670 (C=O), 1613, 1591,
˜
1
1581, 1504, 1457 (Ar, pyr.). H NMR (300 MHz, CDCl3, 25 °C): δ
2-(4-Methoxybenzyl)-1-(pyridin-2-ylcarbonyl)-2-azabicyclo[2.2.2]-
= 1.63–1.86 (m, 7 H, 2 CHCH2, CH, 2 CHaHb), 2.43–2.57 (m, 2 octane (20a): Yield 64%. IR: ν = 1685 (C=O), 1610, 1583, 1568,
˜
H, 2 CHaHb), 2.92 (br. s, 2 H, CHCH2N), 3.57 (s, 2 H, NCH2Ar), 1509, 1463 (Ar, pyr.). 1H NMR (300 MHz, CDCl3, 25 °C): δ =
3.64 [s, 3 H, OCH3 (Ar)], 3.77 [s, 3 H, OCH3 (Ar)], 6.32 [d, J =
2.2 Hz, 1 H, CqCHCq (Ar)], 6.44 [dd, J = 8.3, J = 2.2 Hz, 1 H,
1.62–1.83 (m, 5 H, 2 CHCH2, CH), 1.96 (td, J = 12.0, J = 5.0 Hz,
2 H, 2 CHaHb), 2.61–2.73 (m, 2 H, 2 CHaHb), 2.77 (br. s, 2 H,
CqCHCH (Ar)], 7.27 [d, J = 8.3 Hz, 1 H, CqCHCH (Ar)], 7.29 [dd, CHCH2N), 3.52 (s, 2 H, NCH2Ar), 3.75 [s, 3 H, OCH3 (Ar)], 6.73
J = 7.7, J = 5.0 Hz, 1 H, CqCHCH (pyr.)], 8.64 [d, J = 5.0 Hz, 1 [d, J = 8.8 Hz, 2 H, 2 CH (Ar)], 6.98 [d, J = 8.8 Hz, 2 H, 2 CH
H, NCHCH (pyr.)]; 8.71 [~dt, J = 7.7, J = 1.7 Hz, 1 H, CqCHCH (Ar)], 7.37 [ddd, J = 7.7, J = 5.0, J = 1.1 Hz, 1 H, CqCHCHCH
(pyr.)], 9.87 [s, 1 H, CqCHN (pyr.)] ppm. 13C NMR (75 MHz,
(pyr.)], 7.75 [td, J = 7.7, J = 1.1 Hz, 1 H, CqCHCH (pyr.)], 8.25
CDCl3): δ = 24.61 (2 CHCH2), 26.79 (CH), 28.13 (2 CqCHaHb), [dd, J = 7.7, J = 1.1 Hz, 1 H, CqCH (pyr.)], 8.74 [d, J = 5.0 Hz, 1
52.50 (NCH2Ar), 55.05 [OCH3 (Ar)], 55.37 (CHCH2N), 55.40 H, NCH (pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 24.84 (2
[OCH3 (Ar)], 65.39 (Cq), 98.14 [CqCHCq (Ar)], 103.74 [CqCHCH CHCH2), 26.88 (CH), 27.95 (2 CqCHaHb), 55.07 (CHCH2N), 55.34
(Ar)], 119.19 [Cq (Ar)], 122.92 [CqCHCH (pyr.)], 129.74 [CqCHCH [OCH3 (Ar)], 58.42 (NCH2Ar), 65.14 (Cq), 113.57 [2 CH (Ar)],
(Ar)], 131.12 [Cq (pyr.)], 137.64 [CqCHCH (pyr.)], 152.05 [CqCHN
124.78 [CqCH (pyr.)], 125.74 [CqCHCHCH (pyr.)], 129.59 [2 CH
(pyr.)], 152.52 [NCHCH (pyr.)], 158.22 [Cq (Ar)], 159.64 [Cq (Ar)], (Ar)], 131.62 [Cq (Ar)], 136.39 [CqCHCH (pyr.)], 149.04 [NCH
202.80 (C=O) ppm. MS (ES): m/z (%) = 367 (100) [M + H]+. 368,
(pyr.)], 155.00 [Cq (pyr.)], 158.58 [Cq (Ar)], 204.94 (C=O) ppm. MS
(30). C22H26N2O3 (366.46): calcd. C 72.1, H 7.15, N 7.6; found C
(ES): m/z (%) = 337 (100) [M + H]+, 338 (25). HRMS (ESI): calcd.
72.1, H 7.3, N 7.4, m.p. 83.7 °C. Chromatography, 30:70, EtOAc/ for C21H25N2O2 [M + H]+ 337.1916; found 337.1910. Chromatog-
petroleum ether; Rf = 0.14. Orange crystals.
raphy, 30:70, EtOAc/petroleum ether; Rf = 0.12. Yellow oil.
2-Ethyl-1-(pyridin-3-ylimino)-2-azabicyclo[2.2.2]octane (18dЈ): The
2-Benzyl-1-(pyridin-2-ylcarbonyl)-2-azabicyclo[2.2.2]octane (20b):
importance of sufficient hydrolysis, and the resistance of the imine
Yield 63%. IR: ν = 1681 (C=O), 1581, 1567, 1493, 1450 (Ph, pyr.).
˜
1302
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Eur. J. Org. Chem. 2014, 1296–1304

Synthesis of Epibatidine Analogues
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.63–1.83 (m, 5 H, 2 148.92 [NCHCH (pyr.)], 149.24 [CqCHN (pyr.)] ppm. MS (ES):
CHCH2, CH), 1.91–2.03 (m, 2 H, 2 CHaHb), 2.62–2.74 (m, 2 H, 2
m/z (%) = 219 (100) [M + H]+, 220 (15). HRMS (ESI): calcd. for
CHaHb), 2.79 (br. s, 2 H, CHCH2N), 3.60 (s, 2 H, NCH2Ar), 7.05– C13H19N2O [M + H]+ 219.1497; found 219.1495. C13H18N2O
7.10 [m, 2 H, 2 CH (Ph)], 7.13–7.22 [m, 3 H, 3 CH (Ph)], 7.35 [ddd,
J = 7.7, J = 5.0, J = 1.1 Hz, 1 H, CqCHCHCH (pyr.)], 7.73 [td, J
= 7.7, J = 1.7 Hz, 1 H, CqCHCH (pyr.)], 8.25 [dd, J = 7.7, J =
1.1 Hz, 1 H, CqCH (pyr.)], 8.73 [dd, J = 5.0, J = 1.7 Hz, 1 H, NCH
(pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 24.76 (2 CHCH2),
26.82 (CH), 27.91 (2 CqCHaHb), 55.27 (CHCH2N), 59.05
(NCH2Ar), 65.10 (Cq), 124.70 [CqCH (pyr.)], 125.71 [CqCHCHCH
(pyr.)], 126.74 [CH (Ph)], 128.09 [2 CH (Ph)], 128.46 [2 CH (Ph)],
136.34 [CqCHCH (pyr.)], 139.53 [Cq (Ph)], 148.98 [NCH (pyr.)],
154.89 [Cq (pyr.)], 204.82 (C=O) ppm. MS (ES): m/z (%) = 307
(100) [M + H]+, 308 (29). HRMS (ESI): calcd. for C20H23N2O [M
+ H]+ 307.1810; found 307.1803. C20H22N2O (306.41): calcd. C
78.4, H 7.2, N 9.1; found C 78.4, H 7.4, N 9.1, m.p. 74.4–74.8 °C.
Chromatography, 30:70, EtOAc/petroleum ether; Rf = 0.25. Yellow
crystals.
(218.30): calcd. C 71.5, H 8.3, N 12.8; found C 71.3, H 8.2, N 12.7,
m.p. 103.3 °C. White crystals.
1-(Pyridin-2-ylhydroxymethyl)-2-azabicyclo[2.2.2]octane (22): Yield
39%. IR: ν = 3276 (NH), 3049 (br., OH), 1588, 1567, 1470, 1454
˜
(pyr.); 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.37–1.43 (m, 2 H,
2 CHCHaHb), 1.43–1.86 (m, 7 H, 2 CHCHaHb, CH, 2 CHaHb),
2.97 (br. s, 1 H, OH), 3.02 (br. s, 2 H, CHCH2N), 4.37 (s, 1 H,
CHOH), 7.19 [dd, J = 7.7, J = 5.0 Hz, 1 H, CqCHCHCH (pyr.)],
7.30 [d, J = 7.7 Hz, 1 H, CqCH (pyr.)], 7.65 [td, J = 7.7, J = 1.7 Hz,
1 H, CqCHCH (pyr.)], 8.55 [dd, J = 5.0, J = 1.7 Hz, 1 H, NCH
(pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 24.97 (CH2), 25.10
(CH2), 25.61 (CH), 27.17 (CH2), 29.40 (CH2), 48.07 (CHCH2N),
53.83 (Cq), 78.76 (CHOH), 122.58 [CqCHCHCH (pyr.)], 122.90
[CqCH (pyr.)], 136.08 [CqCHCH (pyr.)], 148.42 [NCH (pyr.)],
159.65 [Cq (pyr.)] ppm. MS (ES): m/z (%) = 219 (100) [M + H]+,
220 (20). HRMS (ESI): calcd. for C13H19N2O [M + H]+ 219.1497;
found 219.1495. C13H18N2O (218.30): calcd. C 71.5, H 8.3, N 12.8;
found C 71.6, H 8.5, N 12.8, m.p. 144.1–144.9 °C. White crystals.
2-Ethyl-1-(pyridin-2-ylcarbonyl)-2-azabicyclo[2.2.2]octane (20c):
Yield 62%. IR: ν = 1686 (C=O), 1581, 1567, 1462 (pyr.). 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 0.89 [t, J = 7.2 Hz, 3 H, CH3 (Et)],
1.58–1.82 (m, 5 H, 2 CHCH2, CH), 1.90 (td, J = 12.1, J = 5.0 Hz,
2 H, 2 CHaHb), 2.34–2.44 (m, 2 H, 2 CHaHb), 2.43 [q, J = 7.2 Hz,
2 H, NCH2 (Et)], 2.93 (br. s, 2 H, CHCH2N), 7.37 [dd, J = 7.7, J
= 5.0 Hz, 1 H, CqCHCHCH (pyr.)], 7.78 [td, J = 7.7, J = 1.1 Hz,
1 H, CqCHCH (pyr.)], 8.47 [dd, J = 7.7, J = 1.1 Hz, 1 H, CqCH
(pyr.)], 8.73 [dd, J = 5.0, J = 1.1 Hz, 1 H, NCH (pyr.)] ppm. 13C
NMR (75 MHz, CDCl3): δ = 13.39 [CH3 (Et)], 24.68 (2 CHCH2),
26.50 (CH), 27.65 (2 CqCHaHb), 49.40 [NCH2 (Et)], 56.11
(CHCH2 N), 65.19 (Cq ), 125.15 [Cq CH (pyr.)], 125.64
[CqCHCHCH (pyr.)], 136.17 [CqCHCH (pyr.)], 149.24 [NCH
(pyr.)], 154.16 [Cq (pyr.)], 203.70 (C=O) ppm. MS (ES): m/z (%) =
245 (100) [M + H]+, 246 (20). HRMS (ESI): calcd. for C15H21N2O
[M + H]+ 245.1654; found 245.1650. Chromatography, 98:2,
CH2Cl2/MeOH; Rf = 0.08. Yellow oil.
Reduction of Epibatidine Analogues: In a dry 25 mL flask, com-
pound 18d or 20c (1 equiv., 1 mmol) was dissolved in dry methanol
(15 mL). The flask was placed under an inert N2 atmosphere at
–78 °C. NaBH4 (1.2 equiv., 45.4 mg, 1.2 mmol) was added. The re-
action mixture was stirred for 4 h at room temperature, and then
water was carefully added to neutralize the excess NaBH4. The mix-
ture was extracted with dichloromethane (3ϫ 15 mL). The com-
bined organic extracts were dried with MgSO4 and, after filtration
of the solids and removal of the volatile components in vacuo, race-
mic alcohol 23a was obtained in good yield.
When necessary the crude alcohol could be further purified. The
residue was redissolved in dry diethyl ether and bubbled through
with hydrogen chloride. Compound 24b was isolated as the hydro-
chloric salt in 65% yield. The melting point could not be recorded,
due to degradation upon heating.
Removal of the N-Protecting Group: As a representative example,
the synthesis of 1-(pyridin-3-ylhydroxymethyl)-2-azabicyclo[2.2.2]-
octane (21) is described here. In a 25 mL flask, 2-benzyl-1-(pyridin-
3-ylcarbonyl)-2-azabicyclo[2.2.2]octane (18b; 1 equiv., 0.18 g,
0.59 mmol) and ammonium formate (4 equiv., 0.15 g, 2.36 mmol)
were dissolved in dry methanol (15 mL). Palladium on activated
carbon (10 wt.-%; 0.05 g) was added, and the suspension was
heated at reflux under an inert nitrogen atmosphere for 3 h. The
heterogeneous mixture was filtered through Celite®, and the meth-
anol was evaporated. Dichloromethane (5 mL) was added, and the
excess of ammonium formate was removed by filtration. The
dichloromethane was evaporated, and te residue was further puri-
fied by recrystallization from diethyl ether to give compound 21.
When 2-benzyl-1-(pyridin-2-ylcarbonyl)-2-azabicyclo[2.2.2]octane
(20b) was used as a substrate for the reductive deprotection, the
reaction was already complete after 2 h of reflux.
2-Ethyl-1-(pyridin-3-ylhydroxymethyl)-2-azabicyclo[2.2.2]octane
1
(23a): Yield 79%. IR: ν = 3355 (OH), 1590, 1577, 1447 (pyr.). H
˜
NMR (300 MHz, CDCl3, 25 °C): δ = 1.05–1.15 (m, 1 H, CHaHb),
1.15 [t, J = 7.2 Hz, 3 H, CH3 (Et)], 1.24–1.36 (m, 2 H, CHaHb,
CqCHaHb), 1.42–1.95 (m, 6 H, CH, 2 CHaHb, CqCHaHb,
CqCHaHb), 2.42 [dq, J = 11.6, J = 7.2 Hz, 1 H, NCHaHb (Et)],
2.67 (dt, J = 11.6, J = 3.0 Hz, 1 H, NCHaHb), 3.08–3.17 [m, 2 H,
NCHaHb, NCHaHb (Et)], 4.40 (br. s, 1 H, OH), 4.76 (s, 1 H,
CHOH), 7.25 [dd, J = 7.7, J = 4.6 Hz, 1 H, CqCHCH (pyr.)], 7.68
[d, J = 7.7 Hz, 1 H, CqCHCH (pyr.)], 8.47 [br. s, 2 H, NCHCH,
CqCHN (pyr.)] ppm. 13C NMR (75 MHz, CDCl3): δ = 14.35 [CH3
(Et)], 23.11 (CHaHb), 24.30 (CqCHaHb), 24.33 (CqCHaHb), 25.66
(CHaHb), 26.39 (CH), 44.43 [NCH2 (Et)], 55.04 (CHCH2N), 57.19
(Cq), 73.51 (CHOH), 122.77 [CqCHCH (pyr.)], 135.42 [CqCHCH
(pyr.)], 136.46 [Cq (pyr.)], 148.43 [NCHCH or CqCHN (pyr.)],
148.12 [NCHCH or CqCHN (pyr.)] ppm. MS (ES): m/z (%) = 247
(100) [M + H]+, 248 (20). HRMS (ESI): calcd. for C15H23N2O [M
+ H]+ 247.1810; found 247.1806. C15H22N2O (246.35): calcd. C
73.1, H 9.0, N 11.4; found C 72.9, H 8.7, N 11.3, m.p. 79.0 °C.
Yellow crystals.
1-(Pyridin-3-ylhydroxymethyl)-2-azabicyclo[2.2.2]octane (21): Yield
34%. IR: ν = 3254 (NH), 3047 (br., OH), 1575, 1472, 1420 (pyr.).
˜
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.22–1.34 (m, 2 H, 2
CHCHaHb), 1.34–1.84 (m, 7 H, 2 CHCHaHb, CH, 2 CHaHb), 3.03
(br. s, 2 H, CHCH2N), 3.48 (br. s, 1 H, OH), 4.44 (s, 1 H, CHOH),
7.25 [dd, J = 7.7, J = 5.0 Hz, 1 H, CqCHCH (pyr.)], 7.65 [dt, J =
2-Ethyl-1-(pyridin-2-ylhydroxymethyl)-2-azabicyclo[2.2.2]octane
7.7, J = 2.8 Hz, 1 H, CqCHCH (pyr.)], 8.49 [dd, J = 5.0, J = 2.8 Hz, Hydrochloride (24b): Yield 65%. IR: ν = 3198 (OH), 1589, 1570,
˜
2 H, NCHCH, CqCHN (pyr.)] ppm. 13C NMR (75 MHz, CDCl3): 1470, 1453 (pyr.). 1H NMR (300 MHz, D2O, 25 °C): δ = 1.27–1.39
δ = 24.41 (CH2), 24.68 (CH2), 24.78 (CH2), 25.29 (CH), 29.33 (m, 1 H, CHaHb), 1.45 [t, J = 7.2 Hz, 3 H, CH3 (Et)], 1.57–1.87
(CH2), 47.81 (CHCH2N), 54.44 (Cq), 77.04 (CHOH), 123.07 (m, 5 H, CHaHb, 2 CqCHaHb), 2.02–2.29 (m, 3 H, CH, 2 CHaHb),
[CqCHCH (pyr.)], 135.33 [CqCHCH (pyr.)], 136.09 [Cq (pyr.)],
3.20–3.35 [m, 2 H, NCHaHb, NCHaHb (Et)], 3.65 (d, J = 12.1 Hz,
Eur. J. Org. Chem. 2014, 1296–1304
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1303

C. V. Stevens et al.
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Acknowledgments
Financial support of this research by the Research Fund Ghent,
University (BOF, Bijzonder Onderzoeksfonds Universiteit Gent; to
A. D. B.) and the Fund for Scientific Research Flanders (FWO
Vlaanderen), grant to I. W. and T. H., is gratefully acknowledged.
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Received: September 13, 2013
Published Online: December 17, 2013
1304
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Eur. J. Org. Chem. 2014, 1296–1304