A new and efficient approach to the synthesis of nicotine and anabasine analogues

Article abstract of DOI:10.1002/jhet.233

(Chemical Equation Presented) A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.

Full text of DOI:10.1002/jhet.233

1252
A New and Efficient Approach to the Synthesis of Nicotine and
Anabasine Analogues
Vol 46
´
Kun Huang, Margarita Ortiz-Marciales,* Melvin De Jesus,
and Viatcheslav Stepanenko
Department of Chemistry, University of Puerto Rico-Humacao, CUH Station, Humacao,
Puerto Rico 00791-4300, USA
*E-mail: ortiz@quimica.uprh.edu
Received May 7, 2009
DOI 10.1002/jhet.233
Published online 6 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A straightforward and practical approach was established for the synthesis of nicotine and anabasine
analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyr-
rolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity
using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which
was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester
derived from diphenyl prolinol and ethylene glycol.
J. Heterocyclic Chem., 46, 1252 (2009).
INTRODUCTION
four-member ring analogue, N-methyl-(3-pyridyl)azeti-
dine (4), produced a 10-fold increase in binding affinity
compared with nicotine [6]. Wang et al. demonstrated
that 6-methylnicotine (5) possess higher affinity in com-
petition studies for [3H]nicotine in rat brain membranes
[7]. Anabasine 6 has been established to be a selective
a7-nAChR agonist in an animal model and with low
toxicity for the potential treatment of schizophrenia [1e].
Recently, Bhatti et al. [8] evaluated the activity of bicy-
clic analogue 7, which displayed high affinity for the
a4b2 receptor.
As a group of ligand-gated ion channels, neuronal
nicotinic acetylcholine receptors (nAChRs) hold signifi-
cant promise as therapeutic targets for the treatment of
the central nervous system (CNS) and peripheral nerv-
ous disorders [1]. Recent studies have shown that nico-
tine 1 (Fig. 1) displays beneficial effects on patients suf-
fering from Parkinson’s disease, anxiety, schizophrenia,
Alzheimer’s disease, ulcerative colitis, and other CNS
disorders [2]. Furthermore, nicotine has been used on a
large scale as an insecticide [3].
In the past decade, much attention has been concen-
trated on the discovery of novel nicotine analogues (Fig.
1) that would display higher selectivity to particular
AChRs subtypes, targeting the beneficial actions of nico-
tine whereas reducing the toxicity effects [2–8]. SIB-
1508Y (2) was designed as a memory enhancer and
anti-Parkinson’s agent [4]. The nAChR agonist ABT-
418 (3), containing an isoxazole bioisostere of pyridine,
was promising for the treatment of Alzheimer’s patients
because this analogue not only have binding potencies
comparable with nicotine but also produce enhanced
cognitive activity with less adverse effects [5]. The
Consequently, considerable efforts had been focused
on the development of new syntheses of nicotine and
anabasine analogues, which have been recently reviewed
[9a]. Although various methods have been reported,
including asymmetric induction using chiral auxiliaries
[9b,c] and enantioselective stoichiometric allylboration
of the 3-pyridyl carboxaldehyde [9d], surprisingly, there
is a lack of a suitable direct synthetic routes for the pyr-
rolidine and piperidine ring construction of nicotine and
anabasine analogues, respectively. Furthermore, our
research program for the synthesis of potential biologi-
cal active amino derivatives as nicotinic receptor
C
V
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A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues
1253
azacyclization product was observed. As a result, the
desired nicotine and its derivatives were easily purified
and obtained in high yield (entries 1–7).
To further develop our methodology, the aza-annula-
tion of the 1,5- and 1,6-dimesylated 1-(6-methoxypyri-
dyl)diol to form six and seven member rings were inves-
tigated (Scheme 2). In general, the 1,5-dimesylated diol
was readily annulated to yield the desired anabasine
derivatives in moderate to good yield (Table 1, entries
8–11). On the other hand, as observed by GC-MS analy-
sis, the 1,6-dimesylate was found to be unsuitable for
the formation of azepanes under the previous conditions
due to the less favored seven membered ring closure.
Enantiomers of a given racemate often display differ-
ence on the basis of potency, selectivity, or efficacy at
biologic targets. (S)-Nicotine is more bioactive than the
(R)-enantiomer, as it is also observed for related ana-
logues [11]. The high yield and excellent enantionselec-
tivity achieved in the borane reduction of heterocyclic
ketones catalyzed by our spiroborate ester 13 derived
from diphenyl prolinol (Scheme 3) [12a], prompted us
to investigate the asymmetric synthesis of the nicotine
derivative (S)-15.
Figure 1. Nicotinic acetylcholine receptor agonists.
agonists, a practical synthesis of racemic and nonrace-
mic nicotine and anabasine analogues was required.
Herein, we report a new and efficient approach to pre-
pare these compounds in racemic form from inexpensive
commercial sources in good to excellent yields. In addi-
tion, an asymmetric synthesis of a representative nico-
tine derivative using our recently developed chiral spiro-
borate ester, as an environmentally friendly catalyst, is
also described.
Considering that borane can react with the hydroxyl
group of ketone 8, and that an intramolecular uncata-
lyzed reaction can take place, the hydroxyl group was
initially protected with an acetyl group. The acetylated
ketone was then reduced with borane employing 10%
and 30% mol of catalyst 13 obtaining 81% ee and
85.5% ee of the diacetylated product, respectively.
When the temperature was decreased at ꢀ10ꢁC using
30% of catalyst, the enantioselectivity decreased to 78%
ee. Therefore, the hydroxyl group was protected with
TIPSCl affording 12 in 95% yield. High yield and
excellent enantioselectivity (94% ee) was then achieved
by the borane-mediated reduction of 12 employing 50%
of catalyst 13. The absolute R configuration of the prod-
uct was assigned according to the catalyst 13 predicted
stereoselectivity. After deprotection of silylated ether
(R)-14 with Bu4F to yield the diol (R)-9, followed by
dimesylation according to our previous procedure, the
RESULTS AND DISCUSSION
As shown in Scheme 1, lithiation of 3-bromopyridine
with n-butyl lithium at ꢀ78ꢁC, followed by treatment
with c-butyrolactone at the same temperature, furnished
ketone [8] in good yield (81%) [10]. Diol 9 was readily
available from 8 by reduction with NaBH4 in excellent
yield (96%). Treatment of 9 with methanesulfonyl chlo-
ride in the presence of Et3N afforded dimesylate 10.
Attempts to purify this product by column chromatogra-
phy on silica gel failed because it decomposed during
the process. Accordingly, after a simple work-up and
solvents removal under reduced pressure, compound 10
was used directly for the next step. After stirring over-
night the crude dimesylated diol with neat benzylamine,
the benzyl substituted nornicotine (11) was obtained. Pu-
rification of this compound by flash column chromatog-
raphy provided the desired pure product in 83% overall
yield from 9. This facile and effective azacyclization
reaction opens a new way for the direct access to N-sub-
stituted nornicotine derivatives.
Scheme 1. Synthesis of N-10-benzyl nornicotine as a model method for
the preparation of nicotine analogues.
With an interest in developing compounds with poten-
tial biological activity and to demonstrate the synthetic
potential of our new methodology, we prepared nicotine
and a variety of analogues with N-substitution on the
pyrrolidine ring (Table 1). The corresponding primary
amines were allowed to react with dimesylate 10 under
the previous established reaction conditions. By TLC
and GC-MS analysis of the reaction mixture, only the
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K. Huang, M. Ortiz-Marciales, M. De Jesus, and V. Stepanenko
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Table 1
Aza-cyclization of dimesylated diols with representative primary amine.
Entry
n
R
R0
Producta
Yield (%)b
c
1
1
Py
CH3NH2
86
2
1
Py
PhCH2NH2
83
3
4
1
1
Py
Py
CH3(CH2)2NH2
88
81
CH3O(CH2)2NH2
5
6
7
8
9
1
1
1
2
2
Py
Py
CH3O(CH2)3NH2
83
82
82
78
76
Py
NH2OHꢂHCld
c
6-MeOPy
6-MeOPy
CH3NH2
PhCH2NH2
10
11
2
2
6-MeOPy
6-MeOPy
CH3O(CH2)2NH2
78
81
CH3O(CH2)3NH2
a The mixture of the corresponding dimesylate diol and the neat primary amine was stirred at 0ꢁC overnight.
b Purified by flash column chromatography.
c Methylamine solution (33 wt %) in absolute ethanol was employed and the reaction was conducted at room temperature.
d NH2OH.HCl and Et3N was used in ethanol and dichloromethane at room temperature.
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A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues
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Scheme 2. Pyperidine and azepane rings formation of pyridyl
analogues.
applications in academic research and in the pharmaceu-
tical industry.
EXPERIMENTAL
Air- and moisture-sensitive reactions were performed under
N2 atmosphere in flame-dried glassware. Common solvents
were dried and distilled by standard procedures. All reagents
were obtained commercially unless otherwise noted. Chro-
matographic purification of products was accomplished using
R
flash chromatography on a Merck silica gelV Si 60 A (70–230
˚
mesh). H and 13C spectra were recorded on a Bruker Avance
400 MHz spectrometer with standard pulse sequences operat-
1
azacyclization of (R)-10 was successfully achieved, pro-
viding the desired nicotine derivative (S)-15.
1
ing at 400.152 MHz and 100.627 MHz for H and 13C, respec-
Although some racemization took place at the ben-
zylic position during the cyclization step, even at
ꢀ10ꢁC, the desired nicotine derivative (S)-15 was
obtained in good enantiomeric excess (82% ee) and in
good overall yield (76%).
tively. Chiral GC analysis was processed with a Crompack
Chirasil-Dex-CB column (30 m ꢃ 0.25 mm ꢃ 0.25 lm).
High-resolution mass spectral analyses (HRMS) were per-
formed at the University of Florida.
General procedure for the synthesis of hydroxy ketones
[10]. To a stirred solution of 3-bromopyridine (10 g, 63.3
mmol) in anhydrous ether (100 mL) was added n-BuLi (40
mL, 1.6 M in hexane, 64 mmol) dropwise at ꢀ78ꢁC. The mix-
ture was stirred for 15 min and a solution of c-butyrolactone,
d-valerolactone, or e-caprolactone (63.6 mmol) in ether
(20 mL) was added dropwise. The solution was stirred 1 h and
then it was left overnight at room temperature. The mixture
was diluted with brine (100 mL). The product was extracted
with n-BuOH (3 ꢃ 150 mL) and the combined extracts were
washed with brine (100 mL) and dried over anhydrous
MgSO4. The solvents were evaporated under reduced pressure
and the residue was purified by column chromatography,
eluted by CH2Cl2/MeOH (10/1).
CONCLUSION
In summary, a direct, mild, and efficient methodology
for the synthesis of a variety of nicotine and anabasine
analogues from commercially available sources has been
described. Moreover, a catalytic asymmetric synthesis of
the nicotine derivative (S)-15 in good enantiomeric pu-
rity was established by the enantioselective reduction of
the TIPS protected ketone 12. Considering the readily
available starting materials, facile synthetic procedures,
easy purification and high yields, the present work con-
stitutes an excellent methodology for the rapid access to
important nicotinic receptor agonists, and will find
4-Hydroxy-1-(pyridin-3-yl)butan-1-one. Yellow oil, Lit
[10] mp 36–37ꢁC; yield 81% (6.45 g); 1H NMR (400 MHz,
CDCl3): d 2.06 (m, 2H, CH2), 2.22 (br s, 1H, OH), 3.19 (m,
2H, CH2), 3.80 (m, 2H, CH2), 7.46 (m, 1H, Py), 8.28 (m, 1H,
Scheme 3. Asymmetric synthesis of nicotine analogue (S)-15.
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K. Huang, M. Ortiz-Marciales, M. De Jesus, and V. Stepanenko
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Py), 8.81 (m, 1H, Py), 9.22 (m, 1H, Py); 13C NMR (100 MHz,
CDCl3): d 26.6, 35.5, 61.9, 123.7, 132.2, 135.4, 149.6, 153.5,
199.2.
ture was cooled to 0ꢁC and MsCl (2.3 mL, 30 mmol) was
added dropwise for 1 h by a syringe pump. The resulting solu-
tion was stirred until TLC indicated that the starting material
was consumed. Water (100 mL) was added to quench the reac-
tion and the aqueous phase was extracted with CH2Cl2 (3 ꢃ
50 mL). The combined organic phases were washed with
brine, dried over MgSO4, and concentrated under reduced pres-
5-Hydroxy-1-(6-methoxypyridin-3-yl)pentan-1-one. Colorless
oil, yield 85% (5.68 g); 1H NMR (400 MHz, CDCl3): d 1.66
(m, 2H, CH2), 1.87 (m, 2H, CH2), 2.05 (br s, 1H, OH), 2.99
(t, J ¼ 7.0 Hz, 2H, CH2), 3.70 (t, J ¼ 6.2 Hz 2H, CH2), 4.03
(s, 3H, OCH3), 6.80, d, J ¼ 9 Hz, 1H, Py), 8.18 (dd, J1 ¼ 2,4
Hz, J2 ¼ 8.7 Hz, 1H, Py), 8.83 (d, J ¼ 2.0 Hz, 1H, Py); 13C
NMR (100 MHz, CDCl3): d 203, 32.2, 38.0, 54.1, 62.3, 111.2,
126.7, 138.2, 149.0, 166.8, 198.1. EIS TOF HRMS calcd. for
[M þ H]þ C11H16NO3: 210.1125; found 210.1124.
1
sure at 25ꢁC to obtain the crude dimesylate 10: H NMR (400
MHz, CDCl3): d 1.90 (m, 2H), 2.10 (m, 1H), 2.19 (m, 1H),
2.96 (s, 3H, CH3SO2), 3.09 (s, 3H, CH3SO2), 4.35 (t, J ¼ 6.3
Hz 2H, OCH2), 5.80 (m, 1H, OCH), 7.59 (m, 1H, Py), 8.01
(dt, J1 ¼ 1.8 Hz, J2 ¼ 7.9 Hz, 1H, Py), 8.74 (m, 1H, Py), 8.82
(m, 1H, Py); 13C NMR (100 MHz, CDCl3): d 25.1, 33.1, 37.5,
39.0, 52.6, 68.7, 124.9, 135.7, 136.9, 145.8, 148.0.
6-Hydroxy-1-(pyridin-3-yl)hexan-1-one [10]. Light yellow
crystals, mp 27–29ꢁC; yield 68% (8.26 g); 1H NMR (400
MHz, CDCl3): d 1.47 (m, 2H, CH2), 1.67 (m, 2H, CH2), 1.85
(m, 2H, CH2), 2.18 (br s, 1H, OH), 3.03 (m, 2H, CH2), 3.70
(m, 2H, CH2), 7.44 (m, 1H, Py), 8.26 (m, 1H, Py), 8.78 (m,
1H, Py), 9.22 (m, 1H, Py); 13C NMR (100 MHz, CDCl3): d
23.6, 25.5, 32.5, 38.8, 62.5, 123.7, 132.2, 135.4, 149.6, 153.3,
199.1.
3-(1-Benzylpyrrolidin-2-yl)pyridine (11) [9c]. To the crude
dimesylate 10 (323 mg, 1 mmol), neat benzylamine (3 mL, 27
mmol) at 0ꢁC was added. The resulting mixture was stirred
overnight at the same temperature. The remaining benzylamine
was removed in a Kugelrohr at 80ꢁC under high vacuum and
the residue was mixed with 10 mL water. The aqueous phase
was extracted with CH2Cl2 (3 ꢃ 5 mL), and the combined or-
ganic phases were washed with brine (2 ꢃ 5 mL) solution and
dried over Na2SO4. The pure product was obtained after flash
column chromatography on silica gel eluted with hexane/
EtOAc (1:1): Colorless oil, yield 83% (197 mg); 1H NMR
(400 MHz, CDCl3): d 1.76–1.95 (m, 3H), 2.29 (m, 2H), 3.17
(m, 2H), 3.48 (m, 1H), 3.85 (m, 1H), 7.25–7.35 (m, 6H, Ar),
7.85 (m, 1H, Py), 8.54 (m, 1H, Py), 8.70 (m, 1H, Py; 13C
NMR (100 MHz, CDCl3): d 22.6, 35.3, 53.5, 58.1, 67.0,
123.6, 126.9, 128.2, 128.6, 135.0, 139.3, 139.5, 148.6, 149.7;
GC-MS m/z 238.1 (Mþ).
General procedure for the synthesis of diols. To a flask
was added the ketone (20 mmol) and MeOH (40 mL) at room
temperature. Then, neat NaBH4 (1.52 g, 40 mmol) was added
portion-wise to the solution at 0ꢁC. The resulting mixture was
stirred for 1 h and the solvent was evaporated under reduced
pressure. Distilled water was added (50 mL) and the mixture
was extracted with CH2Cl2 (3 ꢃ 100 mL) and the combined
organic phases were removed under reduced pressure. The res-
idue was directly submitted to the next step or recrystallized.
1-(Pyridin-3-yl)butane-1,4-diol (9) [13]. Light yellow oil;
yield 96% (4.38 g); 1H NMR (400 MHz, CDCl3): d 1.88 (m,
2H, CH2), 1.93 (m, 2H, CH2), 3.51 (br s, 1H, OH), 3.72 (m,
2H, CH2), 4.63 (br s, 1H, OH), 4.80 (m, 1H, OCH), 7.30 (m,
1H, Py), 7.76 (m, 1H, Py), 8.46 (m, 1H, Py), 8.54 (m, 1H,
Py); 13C NMR (100 MHz, CDCl3): d 29.0, 36.6, 62.5, 123.5,
133.9, 140.5, 147.5, 148.3.
1-(6-Methoxypyridin-3-yl)pentane-1,5-diol. Light yellow
oil; yield 93% (1.88 g); 1H NMR (400 MHz, CDCl3): d 1.38
(m, 1H, CH2), 1.45 (m, 1H, CH2), 1.62 (m, 2H, CH2), 1.75
(m, 1H, CH2), 1.85 (m, 1H, CH2), 1.95 (br s, 1H, OH), 2.63
(br s, 1H, OH), 3.66 (t, J ¼ 6.3 Hz, 2H, CH2), 3.96 (s, 3H,
CH3), 4.68 (t, J ¼ 6.6 Hz, 1H, OCH), 6.78 (d, J ¼ 8.6 Hz,
1H, Py), 7.63 (dd, J1 ¼ 2.4 Hz, J2 ¼ 8.6 Hz, 1H, Py), 8.01 (d,
J ¼ 2.2 Hz, 1H, Py); 13C NMR (100 MHz, CDCl3): d 22.0,
32.3, 38.4, 53.5, 62.5, 71.8, 110.9, 132.8, 136.7, 144.6, 163.8.
EIS TOF HRMS calcd. for [M þ H]þ C11H18NO3: 212.1281;
found 212.1288.
3-(1-Methylpyrrolidin-2-yl)pyridine (or 1-methyl-2-(3-
pyridyl)pyrrolidine) (rac-nicotine) [9c]. Colorless oil, yield
1
86% (139 mg); H NMR (400 MHz, CDCl3): d 1.74–1.84 (m,
2H, CH2), 1.96 (m, 1H, CH2), 2.18 (m, 4H, CH2), 2.34 (m,
1H, CH2), 3.12 (t, J ¼ 8.5 Hz, 1H, CH), 3.28 (t, J ¼ 8.5 Hz,
1H, CH), 7.26 (m, 1H, Py), 7.70 (m, 1H, Py), 8.51 (s, 1H, Py),
8.55 (m, 1H, Py); 13C NMR (100 MHz, CDCl3): d 22.6, 35.2,
40.4, 57.0, 68.9, 123.6, 134.8, 138.8, 148.6, 149.6; GC-MS m/
z 162.0 (Mþ).
3-(1-Propylpyrrolidin-2-yl)pyridine [14]. Colorless oil,
1
yield 88% (167 mg); H NMR (400 MHz, CDCl3): d 0.84 (t,
3H, J ¼ 7.2 Hz, CH3), 1.43–1.51 (m, 2H, CH2), 1.72 (m, 1H,
CH), 1.86 (m, 1H, CH), 1.98 (m, 1H, CH), 2.07 (m, 1H, CH),
2.21 (m, 2H, CH), 2.46 (m, 1H, CH), 3.36 (t, J ¼ 8.2 Hz, 1H,
CH), 3.40 (td, J1 ¼ 2.4 Hz, J2 ¼ 8.5 Hz, 1H, CH), 7.26 (dd,
J1 ¼ 4.8 Hz, J2 ¼ 7.8 Hz, 1H, Py), 7.75 (d, J ¼ 7.8 Hz, 1H,
Py), 8.52 (dd, J1 ¼ 0.8 Hz, J2 ¼ 4.7 Hz, 1H, Py), 8.59 (d, J ¼
1.9 Hz, 1H, Py); 13C NMR (100 MHz, CDCl3): d 11.9, 22.0,
22.7, 35.2, 53.6, 56.4, 67.6, 123.5, 134.9, 139.8, 148.4, 149.6;
GC-MS m/z 190.1 (Mþ).
1-(Pyridin-3-yl)hexane-1,6-diol. Colorless oil; yield 96%
(1.88 g); 1H NMR (400 MHz, CDCl3): d 1.34–1.59 (m, 4H,
CH2), 1.55–1.62 (m, 2H, CH2), 1.71–1.87 (m, 2H, CH2), 2.39
(br s, 1H, OH), 3.66 (t J ¼ 6.4 Hz, over s, 3H, CH2 and OH),
4.76 (m, 1H, OCH), 7.30 (t, J ¼ 3.8 Hz,, 1H, Py), 7.75 (dt, J1
¼ 1.8 Hz, J2 ¼ 7.8 Hz, 1H, Py), 8.47 (dd, J1 ¼ 1.6 Hz, J2 ¼
4.8 Hz, 1H, Py), 8.52 (d, J1 ¼ 2.0 Hz, 1H, Py); 13C NMR
(100 MHz, CDCl3): d 25.4, 25.6, 32.5, 39.0, 62.5, 71.9, 123.6,
133.8, 140.5, 147.6, 148.5. EIS TOF HRMS calcd. for [M þ
H]þ C11H18NO2: 196.1332; found 196.1344.
3-[1-(2-Methoxyethyl)pyrrolidin-2-yl]pyridine [9c]. Colorless
1
oil, yield 81% (167 mg); H NMR (400 MHz, CDCl3): d 1.73
(m, 1H, CH), 1.86 (m, 1H, CH), 2.01 (m, 1H, CH), 2.20 (m,
1H, CH), 2.36 (m, 2H, CH), 2.79 (m, 1H, CH), 3.29 (s, 3H,
OCH3), 3.34–3.47 (m, 4H, CH), 7.26 (dd, J1 ¼ 4.8 Hz, J2
¼
7.8 Hz, 1H, Py), 7.75 (d, J ¼ 7.8 Hz, 1H, Py), 8.52 (dd, J1 ¼
1.5 Hz, J2 ¼ 4.7 Hz, 1H, Py), 8.59 (d, J ¼ 2.0 Hz, 1H, Py);
13C NMR (100 MHz, CDCl3): d 22.8, 35.0, 53.7, 54.5, 58.7,
67.8, 71.5, 123.5, 134.9, 139.4, 148.5, 149.6; GC-MS m/z
206.0 (Mþ).
Typical procedure: Synthesis of rac-nicotine derivative
11 from diol 9. To a two-neck round bottom flask was added
a solution of diol 9 (1.67 mg, 10 mmol) in anhydrous CH2Cl2
(100 mL) and Et3N (7 mL, 50 mmol) under nitrogen. The mix-
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A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues
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7.94 (d, J ¼ 2.3 Hz, 1H, Py); 13C NMR (100 MHz, CDCl3): d
24.9, 26.0, 36.6, 53.4, 54.3, 54.4, 58.7, 65.7, 70.6, 110.9,
133.2, 137.9, 145.8, 163.5. EIS TOF HRMS calcd. for [M þ
H]þ C14H23N2O2: 251.1754; found 251.1762.
3-[1-(3-Methoxypropyl)pyrrolidin-2-yl]pyridine. Colorless
oil, yield 83% (183 mg); 1H NMR (400 MHz, CDCl3): d
1.68–1.74 (m, 3H, CH), 1.81–2.01 (m, 2H, CH), 2.17–2.27 (m,
3H, CH), 2.59 (m, 1H, CH), 3.28 (s, 3H, OCH3), 3.29–3.43
(m, 4H, CH), 7.26 (dd, J1 ¼ 4.8 Hz, J2 ¼ 7.8 Hz, 1H, Py),
60-Methoxy-1-(3-methoxypropyl)-1,2,3,4,5,6-hexahydro-
[2,30]bipyridinyl. Colorless oil, yield 81% (206 mg); 1H
NMR (400 MHz, CDCl3): d 1.27 (m, 1H, CH), 1.43 (m, 1H,
CH), 1.52–1.71 (m, 6H, CH), 1.86 (m, 1H, CH), 1.94 (m, 1H,
CH), 2.39 (m, 1H, CH), 2.91 (dd, J1 ¼ 2.7 Hz, J2 ¼ 11 Hz,
1H, CH), 3.05–3.21 (m, 6H, CH), 3.85 (s, 3H, OCH3), 3.34–
3.47 (m, 4H, CH), 6.62 (d, J ¼ 8.5 Hz, 1H, Py), 7.50 (dd, J1
¼ 2.0 Hz, J2 ¼ 8.4 Hz, 1H, Py), 7.93 (d, J ¼ 2.3 Hz, 1H, Py);
13C NMR (100 MHz, CDCl3): d 25.0, 26.1, 26.4, 36.7, 51.8,
53.2, 53.3, 58.4, 65.6, 71.1, 110.8, 133.4, 137.9, 145.7, 163.4.
EIS TOF HRMS calcd. for [M þ H]þ C15H25N2O2: 265.1911;
found 265.1929.
7.77 (dt, J1 ¼ 1.9 Hz, J2 ¼ 7.8 Hz, 1H, Py), 8.51 (dd, J1
¼
1.7 Hz, J2 ¼ 4.8 Hz, 1H, Py), 8.57 (d, J ¼ 2.0 Hz, 1H, Py);
13C NMR (100 MHz, CDCl3): d 22.7, 28.9, 35.3, 51.2, 53.6,
58.5, 67.6, 70.9, 123.4, 134.9, 139.7, 148.5, 149.5; GC-MS m/
z 220.1 (Mþ). EIS TOF HRMS calcd. for [M þ H]þ
C14H21N2O: 221.1654; found 221.1626.
3-[1-(Prop-2-ynyl)pyrrolidin-2-yl]pyridine [14]. Colorless
oil, yield 82% (152 mg); 1H NMR (400 MHz, CDCl3): d
d1.77 (m, 1H, CH), 1.85 (m, 1H, CH), 2.03 (m, 1H, CH), 2.24
(m, 2H, CH), 2.78 (q, J ¼ 8.8 Hz, 1H, CH), 3.22 (m, 2H,
CH), 3.47 (m, 1H, CH), 3.61 (t, J ¼ 8.2 Hz, 1H, CH), 7.26
(dd, J1 ¼ 4.8 Hz, J2 ¼ 7.7 Hz, 1H, Py), 7.71 (d, J ¼ 7.8 Hz,
1H, Py), 8.52 (d, J ¼ 3.5 Hz, 1H, Py), 8.59 (d, J ¼ 1.4 Hz,
Py); 13C NMR (100 MHz, CDCl3): d 22.6, 34.9, 40.1, 52.2,
63.7, 72.9, 78.5, 123.6, 135.0, 138.2, 148.8, 149.7; GC-MS m/
z 186.1 (Mþ).
2-(Pyridin-3-yl)pyrrolidin-1-ol [15]. Colorless oil, yield
82% (134 mg); 1H NMR (400 MHz, CDCl3): d 1.76 (m, 1H,
CH), 1.92 (m, 2H, CH), 2.26 (m, 1H, CH), 2.87 (q, J ¼ 9.5
Hz, 1H, CH), 3.38 (m, 1H, CH), 3.76 (m, 1H, CH), 7.18 (dd,
J1 ¼ 4.8 Hz, J2 ¼ 7.8 Hz, 1H, Py), 7.65 (dt, J1 ¼ 1.6 Hz, J2
¼ 7.8 Hz 1H, Py), 8.35 (dd, J1 ¼ 1.4 Hz, J2 ¼ 4.8 Hz, 1H,
Py), 8.54 (d, J ¼ 1.8 Hz, 1H, Py); 13C NMR (100 MHz,
CDCl3): d 19.9, 30.3, 57.5, 70.2, 123.2, 135.6, 137.5, 148.1,
149.3.
Asymmetric synthesis of (S)-3-[1-(2-methoxyethyl)pyrro-
lidin-2-yl]pyridine (S)-15 [9c]
Borane reduction of ketone 12. To a 25 mL round flask,
equipped with a septa and nitrogen flow, was added catalyst
13 (244 mg, 0.75 mmol). Then, dry THF (4 mL) and BH3.THF
(2.6 mL, 1 M, 2.6 mmol) were added to the flask and the
resulting mixture was stirred about 1 h at room temperature. A
solution of ketone 12 (482 mg, 1.5 mmol) in dry THF (3 mL)
was added dropwise by a syringe pump for 1 h. After addition,
the mixture was stirred for 1 h and then cooled by an ice bath.
MeOH (5 mL) was added slowly to quench the excess of bor-
ane and the mixture was refluxed overnight. The solvents were
removed under reduced pressure and the residue was purified
by column chromatography on silica gel, eluted with CH2Cl2/
MeOH (20/1).
(R)-1-(Pyridin-3-yl)-4-triisopropylsilyloxybutan-1-ol (R)-
14. This was obtained as a colorless oil; yield 85% (411 mg);
94% ee. 1H NMR (400 MHz, CDCl3): d 1.08–1.19 (m, 21H,
TIPS), 1.60–1.70 (m, 2H, CH2), 1.77 (m, 2H, CH2), 3.84 (m,
2H, CH2), 3.98 (br s, 1H, OH), 4.84 (m, 1H, CH), 7.32 (m,
1H, Py), 7.79 (m, 1H, Py), 8.53 (m, 1H, Py), 8.63 (s, 1H, Py);
13C NMR (100 MHz, CDCl3): d 11.9, 18.0, 29.4, 37.3,
63.7, 71.9, 123.4, 133.5, 140.4, 147.9, 148.6. Chiral-GC
analysis of acetyl derivate gave tR ¼ 121.479 min for major
enantiomer, tR ¼ 124.10 min for minor enantiomer under the
following gradient conditions: 80ꢁC, 1ꢁC/min up to 120ꢁC,
maintained for 40 min; then, 2ꢁC/min up to 150ꢁC,
maintained for 30 min; 2ꢁC/min up to 160ꢁC and maintained
for 15 min.
Azacyclization of (R)-14. To a solution of (R)-14 (323 mg,
1 mmol) in 15 mL THF was added Bu4NF (1.5 mL, 1.0 M in
THF) dropwise at 0ꢁC. The mixture was stirred until TLC
indicated that the starting material was consumed (about 1 h).
The solvents were removed under reduced pressure and the
residue was directly submitted to the cyclization at ꢀ10ꢁC fol-
lowing the general procedure given above. Compound (S)-15
was obtained as a colorless oil after purification by column
chromatography on silica gel, eluted with CH2Cl2/MeOH
(30:1); yield 76% (156 mg, three steps); 82% ee; [a]2D0 ¼ ꢀ82
(c 1.7, CHCl3); Chiral-GC analysis gave tR ¼ 110.67 min for
major enantiomer, tR ¼ 118.38 min for minor enantiomer
under the following gradient condition: 80ꢁC, 1ꢁC/min up to
110ꢁC, and maintained for 20 min; then 1ꢁC/min up to 120ꢁC,
then, maintained for 50 min; then, 1ꢁC/min up to 130ꢁC, and
maintained for 30 min.
6-Methoxy-3-(1-methylpiperidin-2-yl)pyridine. Colorless
1
oil, yield 78% (161 mg); H NMR (400 MHz, CDCl3): d 1.29
(m, 1H, CH), 1.48 (m, 1H, CH), 1.61 (m, 3H, OH), 1.73 (m,
1H, CH), 1.90 (s, 3H, CH3), 2.02 (m, 1H, CH), 2.65 (dd, J1 ¼
2.9 Hz, J2 ¼ 11 Hz, 1H, CH), 2.95 (m, 1H, CH), 3.85 (s, 3H,
OCH3), 6.63 (d, J ¼ 8.6 Hz, 1H, Py), 7.50 (dd, J1 ¼ 2.4 Hz,
J2 ¼ 8.5 Hz, 1H, Py), 7.93 (d, J ¼ 2.3 Hz, 1H, Py); 13C NMR
(100 MHz, CDCl3): d 24.9, 26.1, 35.8, 44.5, 53.4, 57.5, 67.5,
110.9, 132.9, 137.7, 145.7, 163.6; GC-MS m/z 206.1 (Mþ).
EIS TOF HRMS calcd. for [M þ H]þ C12H19N2O: 207.1492;
found 207.1500.
6-Methoxy-3-(1-benzylpiperidin-2-yl)pyridine. Colorless
1
oil, yield 76% (214 mg); H NMR (400 MHz, CDCl3): d 1.41
(m, 1H, CH), 1.63 (m, 3H, CH), 1.82 (m, 2H, CH), 1.99 (td,
J1 ¼ 3.5 Hz, J2 ¼ 11.5 Hz, 1H, CH), 2.86 (d, J ¼ 13.6 Hz,
1H, CH), 3.00 (m, 1H, CH), 3.17 (dd, J1 ¼ 2.8 Hz, J2 ¼ 11
Hz 1H, CH), 3.80 (d, J ¼ 13.5 Hz, 1H, CH), 3.98 (s, 3H,
OCH3), 6.78 (d, J ¼ 8.5 Hz, 1H, Py), 7.24–7.33 (m, 5H, Ph),
7.78 (dd, J1 ¼ 2.3 Hz, J2 ¼ 8.5 Hz, 1H, Py), 8.19 (d, J ¼ 2.2
Hz, 1H, Py); 13C NMR (100 MHz, CDCl3): d 25.1, 26.0, 36.9,
53.37, 53.4, 59.6, 65.7, 111.1, 126.6, 128.1, 128.6, 133.7,
137.8, 139.6, 145.8, 163.5; GC-MS m/z 282.1 (Mþ). EIS TOF
HRMS calcd. for [M þ H]þ C18H23N2O: 283.1805; found
283.1817.
6-Methoxy-3-[1-(2-methoxyethyl)piperidin-2-yl]pyrid-
ine. Colorless oil, yield 78% (195 mg); 1H NMR (400 MHz,
CDCl3): d 1.29 (m, 1H, CH), 1.48 (m, 1H, CH), 1.58 (m, 3H,
CH), 1.70 (m, 1H, CH), 2.01 (m, 2H, CH), 2.60 (m, 1H, CH),
2.97 (dd, J1 ¼ 2.7 Hz, J2 ¼ 11 Hz, 1H, CH), 3.11 (s, 3H,
OCH3), 3.30 (m, 2H, CH), 3.85 (s, 3H, CH3), 6.62 (d, J ¼ 8.5
Hz, 1H, Py), 7.52 (dd, J1 ¼ 2.2 Hz, J2 ¼ 8.5 Hz, 1H, Py),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´
K. Huang, M. Ortiz-Marciales, M. De Jesus, and V. Stepanenko
1258
Vol 46
M. W.; Anderson, D. J.; Cadman, E. D.; Raszkiewicz, J. L.; Sullivan,
J. P.; Aneric, S. P. J Med Chem 1994, 37, 4455.
Acknowledgments. Financial support by the National Institute
of Health through their MBRS (GM 08216) and NIH-AABRE
(NC P20 RR-016470) grants is greatly appreciated. We express
our special gratitude to the NSF-MRI (01–07) and NIH-MBRS
programs to have made possible the acquisition of a 400 MHz
NMR spectrometer. The NSF-PREM (DMR-03537730), NIH-
INBRE and NIH-RISE, NIH-MARC, NSF-AMP undergraduate
student’s support are also gratefully acknowledged.
[6] Abood, L. G.; Lerner-Marmarosh, N.; Wang, D.; Saraswati,
M. Med Chem Res 1993, 2, 552.
[7] Wang, D. X.; Booth, H.; Lerner-Marmarosh, N.; Osdene,
T. S.; Abood, L. G. Drug Dev Res 1998, 45, 10.
[8] Bhatti, B. S.; Strachan, J.-P.; Breining, S. R.; Miller, C. H.;
Tahiri, P.; Crooks, P. A.; Deo, N.; Day, C. S.; Caldwell, W. S. J Org
Chem 2008, 73, 3497.
[9] For other alternative methods see: (a) Wagner, F. F.; Com-
ins, D. L. Tetrahedron, 2007, 63, 8065; Extensive review: (b) Che-
lucci, G. Tetrahedron: Asymmetry 2005, 16, 2353; (c) Baxendale,
I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J Chem Soc Perkin Trans
1 2002, 143; (d) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet