Microwave-assisted iridium-catalyzed synthesis of nicotine and anabasine derivatives

Article abstract of DOI:10.1055/s-0032-1316859

Various functionalized nicotine and anabasine analogues are synthesized via a three-step sequence that exploits a microwave-assisted iridium-catalyzed N-heterocyclization of 1,4- and 1,5-diols for the construction of the pyrrolidine and piperidine ring systems. The microwave-assisted N-heterocyclization furnishes derivatives of nicotine and anabasine in good yields (50-75%) with overall yields ranging from 30-50%. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0032-1316859

2120▌
SPECIAL TOPIC
special topic
Microwave-Assisted Iridium-Catalyzed Synthesis of Nicotine and Anabasine
Derivatives
Synthesis of Nicotine and Anabasine Derivatives
Tushar Dattu Apsunde, Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-mail: mtrudell@uno.edu
Received: 20.12.2012; Accepted after revision: 31.01.2013
the preparation of cyclic amines via N-alkylation of diols
Abstract: Various functionalized nicotine and anabasine analogues
by primary amines.9 This methodology allowed for the
are synthesized via a three-step sequence that exploits a microwave-
synthesis of N-heterocyclic products without generation
of harmful by-products (H2O is the only by-product), and
assisted iridium-catalyzed N-heterocyclization of 1,4- and 1,5-diols
for the construction of the pyrrolidine and piperidine ring systems.
The microwave-assisted N-heterocyclization furnishes derivatives thus is an attractive green chemistry process. Previously,
of nicotine and anabasine in good yields (50–75%) with overall
yields ranging from 30–50%.
we were the first to describe the application of the iridium-
catalyzed N-heterocyclization reaction for the synthesis
Key words: pyridine alkaloids, iridium, microwave, green chemis-
try, N-heterocyclization
of nicotine-related compounds, and the first total synthe-
sis of the alkaloid, noranabasamine.10,11 Further studies by
Zhao and co-workers showed that N-heterocyclization of
simple amine/alcohol systems proceeded under solvent-
Nicotine (1) and anabasine (2) (Figure 1) are pyridine al- free, base-free microwave-assisted conditions (Scheme
kaloids commonly found in species of the Solanaceae 1).12
plant family (e.g. Nicotiana tabacum and Nicotiana rusti-
ca).1 These pyridine alkaloids can modulate neuronal nic-
NH2R
[Cp*IrCl2]2
n
otinic acetylcholine receptors (nAChRs), which affect the
central nervous system (CNS).2 The pharmacological ac-
tions of pyridine alkaloids and related derivatives on the
central nervous system has attracted considerable atten-
tion as potential therapeutic targets for a variety of dis-
ease-states and pathological conditions mediated by
nicotinic acetylcholine receptors.2–5 Nevertheless, toxicity
and abuse potential has limited the use of nicotine-related
drugs for central nervous system disorders.2 Therefore,
new analogues of nicotine with unique nicotinic acetyl-
choline receptor subtype selectivity remain important
pharmacological targets for the development of novel
therapeutics with improved safety profiles. To this end,
considerable effort has been focused on the development
of new synthetic methods for the construction nicotine de-
rivatives.6–8 Although a variety of methods have been re-
ported, there is still a need for versatile and practical
methods for the synthesis of nicotine-related derivatives.
n
HO
OH
N
R
Scheme 1 The iridium-catalyzed N-heterocyclization reaction
Based on these findings, it was of interest to explore fur-
ther the application of these conditions for a green synthe-
sis of nicotine and anabasine-related analogues. Herein,
we report the efficient three-step synthesis of nicotine and
anabasine analogues employing a microwave-assisted
iridium-catalyzed N-heterocyclization of 1,4- and 1,5-di-
ols.
Our approach relied upon the initial synthesis of the 1-(3-
pyridinyl)diols using methodology previously developed
in our laboratory.11 As illustrated in Scheme 2, 3-bro-
mopyridine (3a), or 5-bromo-2-methoxypyridine (3b)
was treated initially with n-butyllithium at –78 °C in di-
ethyl ether. γ-Butyrolactone or δ-valerolactone was then
added to the resulting lithiated pyridine derivative to af-
ford the corresponding hydroxy ketones 4 or 5, in high
yields.
N
H
N
Me
Subsequent reduction with sodium borohydride in metha-
nol afforded the required intermediate diols 6 and 7 in
good overall yields. 1-(Quinolin-3-yl)butane-1,4-diol (9)
was prepared in similar fashion from 3-bromoquinoline
(3c) and γ-butyrolactone (Scheme 2).
N
N
1
2
Figure 1 Pyridine alkaloids from Nicotiana species
Fujita and co-workers reported the use of (pentamethylcy-
clopentadienyl)iridium dichloride dimer ([Cp*IrCl2])2 for
Initially, we explored and optimized the reaction condi-
tions for the synthesis of N-benzylnornicotine (10a) (Ta-
ble 1). The reaction of the diol 6a and benzylamine was
performed under normal reflux and microwave-assisted
conditions. When the reaction was performed in the ab-
sence of a base and solvent (Table 1, entries 1 and 2),
SYNTHESIS 2013, 45, 2120–2124
Advanced online publication: 27.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316859; Art ID: SS-2012-M0987-ST
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Nicotine and Anabasine Derivatives
2121
O
Table 1 Optimization of the N-Heterocyclization Reaction
1) n-BuLi, Et2O, –78 °C
Br
OH
2) γ-butyrolactone or
OH
BnNH2
δ-valerolactone
n
[Cp*IrCl2]2
base, solvent
OH
N
R
N
R
N
Bn
N
N
3a R = H
3b R = OMe
4a n = 1, R = H
4b n = 1, R = OMe
n = 2, R = H
6a
10a
5
Entry Solvent
Base
Conditions
Yield (%)a
OH
OH
1
2
3
4
5
6
7
8
9
–
–
reflux, 17 h
MW, 2 h
reflux, 17 h
MW, 2 h
reflux, 17 h
MW, 2 h
MW, 2 h
MW, 2 h
MW, 2 h
10
15
NaBH4
MeOH
0 °C
n
–
–
R
N
toluene
toluene
H2O
H2O
H2O
H2O
H2O
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaOAc
Na2CO3
K2CO3
<10
20
6a n = 1, R = H
6b n = 1, R = OMe
7
n = 2, R = H
50
O
60
Br
OH
1) n-BuLi, Et2O, –78 °C
2) γ-butyrolactone
65
N
N
75
3c
8
35
a Yield of isolated product. MW = microwave.
OH
OH
NaBH4
MeOH
0 °C
N
Table 2 Synthesis of Nicotine and Anabasine Analogues
9
NH2R2
[Cp*IrCl2]2
Na2CO3, H2O
OH
n
Scheme 2 Synthesis of 1,4- and 1,5-diols
OH
N
R2
n
MW, 2 h
R1
N
R1
N
compound 10a was formed in low yields. Even using a
base (NaHCO3) and toluene as the solvent did not im-
prove substantially the yields of 10a (Table 1, entries 3
and 4). The highly polar nature and poor solubility of the
diol in toluene encouraged us to explore water as a solvent
for this transformation. The yield of the reaction was im-
proved considerably (50%, Table 1, entry 5) when water
was used as the solvent under reflux conditions. More-
over, the use of water as the solvent in the heterocycliza-
tion facilitated by microwave irradiation resulted in both
an increased yield and a shorter reaction time (Table 1, en-
try 6). Further evaluation of the base determined that so-
dium carbonate was superior to sodium bicarbonate,
sodium acetate and potassium carbonate (Table 1, entries
6–9), and led to an optimized yield of 75%.
Diol
R1
n
R2
Product Yield
(%)a
6a
6a
6b
6a
6b
7
H
1
1
1
1
1
2
2
–
Me
Bn
Bn
1
50
75
78
73
75
70
75
78
H
10a
10b
11a
11b
12a
12b
13
OMe
H
4-MeOC6H4CH2
4-MeOC6H4CH2
Bn
OMe
H
7
H
4-MeOC6H4CH2
Bn
9
–
The microwave-assisted N-heterocyclization of 1,4-bu-
tanediols and 1,5-pentanediols was performed under opti-
mized aqueous conditions to prepare a series nicotine and
anabasine derivatives. As summarized in Table 2, the re-
action of 1,4-diol 6a with methylamine gave a modest
yield (50%) of nicotine. The lower than expected yield is
believed to be due to the high volatility of methylamine in
water at the elevated temperatures of the microwave con-
ditions. Alternatively, the reaction of benzylamine or 4-
methoxybenzylamine with the 1,4- and 1,5-diols provided
good yields of the corresponding cyclization products. In
addition, the N-heterocyclization of diol 9 afforded the
a Yield of isolated product.
corresponding quinoline derivative 13 in 78% yield (Fig-
ure 2).
N
Bn
N
13
Figure 2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2120–2124

2122
T. D. Apsunde, M. L. Trudell
SPECIAL TOPIC
1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 8.61 (d, J = 3.6 Hz,
1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.34–7.30 (m, 1 H), 3.91 (br s, 1 H),
3.63 (t, J = 6.0 Hz, 2 H), 3.04 (t, J = 7.2 Hz, 2 H), 1.92–1.89 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 199.3, 153.3, 149.5, 135.8, 132.4,
124.0, 61.5, 35.6, 26.8.
To further demonstrate the utility of this approach, we
converted the N-benzylnornicotine analogue 10b into the
corresponding nornicotine derivative 14. Hydrogenolysis
(1 atm) of 10b over palladium on carbon (Pd/C) at 55 °C
afforded 14 in 75% yield (Scheme 3).
4-Hydroxy-1-(6-methoxypyridin-3-yl)butan-1-one (4b)
The title product was prepared from 5-bromo-2-methoxypyridine
(3b) (2.0 g, 10.6 mmol), γ-butyrolactone (1.0 g, 11.7 mmol) and n-
BuLi (5.1 mL, 12.7 mmol, 2.5 M in hexane) in anhyd Et2O (30 mL).
Purification by flash chromatography afforded the product as a yel-
low oil; yield: 1.5 g (70%). The spectroscopic data were consistent
with those reported previously for this compound.11
H2 (1 atm)
Pd/C, MeOH
55 °C
N
N
H
Bn
MeO
N
MeO
N
10b
14
Scheme 3 Hydrogenolysis of N-benzylnornicotine analogue 10b
1H NMR (400 MHz, CDCl3): δ = 8.80 (d, J = 2.4 Hz, 1 H), 8.13 (dd,
J = 8.8, 2.4 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.74–
3.73 (m, 2 H), 3.07 (t, J = 7.2 Hz, 2 H), 2.02–1.97 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 198.4, 166.4, 149.1, 138.3, 126.7,
111.1, 61.7, 54.1, 35.0, 27.0.
In summary, we have developed an efficient three-step
synthesis of nicotine and anabasine derivatives from read-
ily available starting materials. The key step involves the
aqueous microwave-assisted, iridium-catalyzed N-hetero-
cyclization reaction of pyridinylbutane-1,4-diols and pyr-
idinylpentane-1,5-diols with various amines. The
application of this versatile and green chemistry process
toward the synthesis of novel nicotinic acetylcholine re-
ceptor ligands is currently under investigation and will be
reported elsewhere.
5-Hydroxy-1-(pyridin-3-yl)pentan-1-one (5)
The title product was prepared from 3-bromopyridine (3a) (2.0 g,
12.5 mmol), δ-valerolactone (1.4 g, 13.9 mmol) and n-BuLi (6.0
mL, 15 mmol, 2.5 M in hexane) in anhyd Et2O (30 mL). Purification
by flash chromatography afforded the product as a yellow oil; yield:
1.7 g (65%). The spectroscopic data were consistent with those re-
ported previously for this compound.11
1H NMR (400 MHz, CDCl3): δ = 9.14 (d, J = 4.0 Hz, 1 H), 8.73 (dd,
J = 8.0, 4.0 Hz, 1 H), 8.22 (dd, J = 8.0, 4.0 Hz, 1 H), 7.41–7.39 (m,
1 H), 3.67 (t, J = 4.8 Hz, 2 H), 3.05–3.01 (m, 2 H), 1.87–1.82 (m, 2
H), 1.67–1.63 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 199.2, 153.2, 149.4, 135.7, 132.3,
123.9, 61.9, 38.6, 32.1, 20.3.
All chemicals were purchased from Aldrich Chemical Company
and used as received unless otherwise noted. Microwave-assisted
N-heterocyclization reactions were carried out using a StartSYNTH
multicavity instrument with start rotor from Milestone. The maxi-
mum microwave power was 1200 W and the reaction temperature
was monitored by an internal infrared sensor. All the reactions were
performed in glass reactor tubes with a maximum working pressure
of 15 bars and maximum temperature of 230 °C. Thin-layer chro-
matography (TLC) was performed on silica gel plates (250 mm)
purchased from Sorbent Technologies. Compounds were made vi-
sual with UV light, iodine or phosphomolybdic acid. Chromatogra-
phy was accomplished with silica gel 60 Å (230–400 mesh)
Diols 6a,b and 7; General Procedure
Powdered NaBH4 (1.5 equiv) was added to a well stirred soln of hy-
droxy ketone 4a,b or 5 (1 equiv) in anhyd MeOH at 0 °C. After 2 h,
NaHCO3 was added to the reaction mixture and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography to afford the diols 6a,b or 7 as viscous oils.
purchased from Sorbent Technologies. 1H NMR (400 MHz) and 13
C
1-(Pyridin-3-yl)butane-1,4-diol (6a)
NMR (100 MHz) spectra were recorded on a Varian 400 MHz
1
The title product was prepared from 4a (1.0 g, 6.0 mmol) and
NaBH4 (0.34 g, 9.0 mmol) in anhyd MeOH (20 mL). Purification by
flash chromatography (CH2Cl2–MeOH, 92:8) afforded a colorless
oil; yield: 0.96 g (95%). The spectroscopic data were consistent
with those reported previously for this compound.13
NMR spectrometer at ambient temperature in CDCl3. H NMR
chemical shifts are reported as δ values (ppm) relative to tetrameth-
ylsilane. 13C NMR chemical shifts are reported as δ values (ppm)
relative to CDCl3 (77.0 ppm). Atlantic Microlab, Inc., Norcross, GA
performed all CHN microanalyses.
1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 4.0 Hz, 1 H), 8.38 (dd,
J = 8.0, 4.0 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.24 (dd, J = 8.0, 4.0
Hz, 1 H), 4.95 (br s, 1 H), 4.73 (t, J = 6.4 Hz, 1 H), 3.69 (br s, 1 H),
3.68–3.64 (m, 2 H), 1.87–1.82 (m, 2 H), 1.68–1.62 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 147.6, 140.8, 134.2, 123.8,
71.8, 62.6, 36.7, 29.1.
Hydroxy Ketones 4a,b and 5; General Procedure
Under an N2 atm, bromopyridine 3 (1 equiv) was added to anhyd
Et2O (20 mL) and cooled to –78 °C. A soln of n-BuLi (2.5 M in hex-
ane, 1.2 equiv) was added dropwise, and the mixture was stirred for
15 min. A soln of γ-butyrolactone or δ-valerolactone (1.1 equiv) in
Et2O (5 mL) was added and the mixture was stirred for 2 h. The mix-
ture was allowed to warm to r.t. and brine (20 mL) was added. The
mixture was extracted with Et2O (3 × 20 mL) and the combined or-
ganic layers dried over Na2SO4, filtered and concentrated under re-
duced pressure. The residue was purified by flash chromatography
(CH2Cl2–MeOH, 92:8) to afford the hydroxy ketones 4a,b and 5 as
oils.
1-(6-Methoxypyridin-3-yl)butane-1,4-diol (6b)
The title product was prepared from 4b (1.0 g, 5.2 mmol) and
NaBH4 (0.30 g, 7.77 mmol) in anhyd MeOH (20 mL). Purification
by flash chromatography afforded a colorless oil; yield: 0.90 g
(90%).
1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.46 (d, J = 0.8 Hz,
1 H), 6.59 (d, J = 8.4 Hz, 1 H), 5.06 (br s, 1 H), 4.48 (t, J = 6.4 Hz,
1 H), 4.43 (br s, 1 H), 3.76 (s, 3 H), 3.47–3.43 (m, 2 H), 1.70–1.61
(m, 2 H), 1.52–1.43 (m, 2 H).
4-Hydroxy-1-(pyridine-3-yl)butan-1-one (4a)
The title product was prepared from 3-bromopyridine (3a) (2.0 g,
12.5 mmol), γ-butyrolactone (1.2 g, 13.9 mmol) and n-BuLi (6.0
mL, 15.0 mmol, 2.5 M in hexane) in anhyd Et2O (30 mL). Purifica-
tion by flash chromatography afforded the product as a yellow oil;
yield: 1.4 g (65%). The spectroscopic data were consistent with
those reported previously for this compound.11
13C NMR (100 MHz, CDCl3): δ = 163.7, 144.5, 137.1, 133.3, 110.8,
71.4, 62.2, 53.7, 36.0, 29.0.
Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C,
60.75; H, 7.55; N, 6.99.
Synthesis 2013, 45, 2120–2124
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Nicotine and Anabasine Derivatives
2123
1-(Pyridin-3-yl)pentane-1,5-diol (7)
(75%). The spectroscopic data were consistent with those reported
previously for this compound.15
1H NMR (400 MHz, CDCl3): δ = 8.63 (s, 1 H), 8.48 (d, J = 3.6 Hz,
1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.33–7.18 (m, 6 H), 3.81 (d, J = 13.2
Hz, 1 H), 3.44–3.40 (m, 1 H), 3.13–3.09 (m, 2 H), 2.28–2.18 (m, 2
H), 1.89–1.68 (m, 3 H).
The title product was prepared from 5 (1.0 g, 5.2 mmol) and NaBH4
(0.30 g, 7.8 mmol) in anhyd MeOH (20 mL). Purification by flash
chromatography afforded a colorless oil; yield: 0.90 g (95%).
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 1.6 Hz, 1 H), 8.38 (dd,
J = 6.4, 1.2 Hz, 1 H), 7.70–7.69 (m, 1 H), 7.26–7.23 (m, 1 H), 4.68
(t, J = 5.6 Hz, 1 H), 3.58 (t, J = 6.4 Hz, 2 H), 1.82–1.70 (m, 2 H),
1.71–1.65 (m, 2 H), 1.45–1.36 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 147.6, 141.0, 134.27,
123.8, 71.8, 62.6, 38.8, 32.4, 22.1.
13C NMR (100 MHz, CDCl3): δ = 149.9, 148.8, 135.2, 128.8, 128.7,
128.4, 127.2, 123.9, 67.2, 58.3, 53.7, 35.5, 22.7.
5-(1-Benzylpyrrolidin-2-yl)-2-methoxypyridine (10b)
The title product was prepared from 6b (100 mg, 0.50 mmol),
[Cp2*IrCl2]2 (12 mg, 0.012 mmol), Na2CO3 (1.1 mg, 0.012 mmol)
and BnNH2 (0.053 g, 0.50 mmol). Purification by flash chromatog-
raphy afforded a colorless oil; yield: 100 mg (78%).
1H NMR (400 MHz, CDCl3): δ = 8.15–8.14 (d, J = 2.4 Hz, 1 H),
7.75 (dd, J = 8.8, 2.4 Hz, 1 H), 7.29–7.20 (m, 5 H), 6.76 (d, J = 8.8
Hz, 1 H), 3.94 (s, 3 H), 3.80 (d, J = 12.0 Hz, 1 H), 3.33–3.31 (m, 1
H), 3.08–3.06 (m, 2 H), 2.19–2.14 (m, 2 H), 1.89–1.86 (m, 1 H),
1.80–1.69 (m, 2 H).
Anal. Calcd for C10H15NO2: C, 66.27; H, 8.34; N, 7.73. Found: C,
66.22; H, 8.45; N, 7.67.
1-(Quinolin-3-yl)butane-1,4-diol (9)
Under an N2 atm, 3-bromoquinoline (3c) (2.0 g, 9.6 mmol) was add-
ed to anhyd Et2O (30 mL) and the resulting soln cooled to –78 °C.
A soln of n-BuLi (4.6 mL, 11.4 mmol, 2.5 M in hexane) was added
dropwise and the mixture stirred for 15 min. A soln of γ-butyrolac-
tone (0.95 g, 10.5 mmol) in Et2O (5 mL) was added and the mixture
was stirred for 2 h. The mixture was allowed to warm to r.t. and
brine (20 mL) was added. The mixture was extracted with Et2O (3
× 20 mL) and the combined organic layers were dried over Na2SO4,
filtered and concentrated under reduced pressure to furnish ketone
8 as a light yellow oil. The crude ketone 8 was dissolved in anhyd
MeOH (20 mL) and cooled to 0 °C. Powdered NaBH4 (0.52 g,
14.22 mmol) was added in one portion and the mixture was stirred
for 2 h. Purification by flash chromatography (10% MeOH–
CH2Cl2) afforded 9 as a yellow oil; overall yield over two steps: 1.1
g (50%).
13C NMR (100 MHz, CDCl3): δ = 163.9, 146.3, 139.7, 138.2, 132.0,
128.4, 127.0, 111.3, 66.6, 58.1, 53.5, 35.1, 22.5.
Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C,
76.00; H, 7.73; N, 10.28.
3-[1-(4-Methoxybenzyl)pyrrolidin-2-yl]pyridine (11a)
The title product was prepared from 6a (100 mg, 0.60 mmol),
[Cp2*IrCl2]2 (12 mg, 0.015 mmol), Na2CO3 (1.3 mg, 0.015 mmol)
and 4-methoxybenzylamine (82 mg, 0.60 mmol). Purification by
flash chromatography afforded a colorless oil; yield: 110 mg (73%).
The spectroscopic data were consistent with those reported previ-
ously for this compound.15
1H NMR (400 MHz, CDCl3): δ = 8.63 (d, J = 1.6 Hz, 1 H), 8.49 (dd,
J = 4.4, 1.6 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.25 (dd, J = 8.0,
4.4 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 6.81 (d, J = 8.0 Hz, 2 H),
3.78 (s, 3 H), 3.73 (d, J = 12.8 Hz, 2 H), 3.38 (t, J = 8.0 Hz, 1 H),
3.10–3.02 (m, 2 H), 2.64–2.19 (m, 2 H), 1.77–1.67 (m, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.77 (d, J = 2.0 Hz, 1 H), 8.06 (s,
1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.63–7.57
(m, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 4.87 (t, J = 6.0 Hz, 1 H), 3.69–
3.60 (m, 3 H), 1.92–1.87 (m, 2 H), 1.71–1.01 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 149.5, 147.2, 138.0, 133.1, 129.6,
128.7, 128.1, 127.1, 110.5, 72.0, 62.5, 36.7, 29.2.
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.59; H, 7.03; N, 6.11.
13C NMR (100 MHz, CDCl3): δ = 158.8, 149.8, 148.8, 139.7, 135.2,
129.6, 123.8, 114.0, 113.8, 67.0, 57.6, 55.4, 53.5, 35.5, 22.7.
Microwave-Assisted N-Heterocyclization; General Procedure
The diol (1 equiv) was added to a well stirred soln of [Cp*IrCl2]2 (5
mol%) and Na2CO3 (1.1 equiv), in H2O (5 mL), in a microwave re-
actor tube under an N2 atm. The amine (1 equiv) was added to the
soln and the mixture was irradiated at 110 °C for 2 h. The mixture
was extracted with EtOAc (3 × 10 mL) and the combined organic
layers were dried over Na2SO4, filtered and concentrated under re-
duced pressure. The residue was purified by flash chromatography
(3% MeOH–CH2Cl2) to afford the cyclic amine.
2-Methoxy-5–[1-(4-methoxybenzyl)pyrrolidin-2-yl]pyridine
(11b)
The title product was prepared from 6b (100 mg, 0.50 mmol),
[Cp2*IrCl2]2 (12 mg, 0.012 mmol), Na2CO3 (1.1 mg, 0.012 mmol)
and 4-methoxybenzylamine (69 mg, 0.50 mmol). Purification by
flash chromatography afforded a colorless oil; yield: 110 mg (75%).
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 1.6 Hz, 1 H), 7.72 (dd,
J = 8.0, 1.6 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.82 (d, J = 8.0 Hz,
2 H), 6.76 (d, J = 8.4 Hz, 1 H), 3.93 (s, 3 H), 3.77 (s, 3 H), 3.73 (d,
J = 12.8 Hz, 1 H), 3.28 (t, J = 8.0 Hz, 1 H), 3.05 (t, J = 8.0 Hz, 1 H),
2.98 (d, J = 12.8 Hz, 1 H), 2.22–2.10 (m, 2 H), 1.89–1.65 (m, 3 H).
(±)-Nicotine (1)
The title product was prepared from 6a (100 mg, 0.60 mmol),
[Cp*IrCl2]2 (12 mg, 0.015 mmol), Na2CO3 (1.3 mg, 0.015 mmol)
and 40% aq MeNH2 soln (0.050 mL, 0.60 mmol). Purification by
flash chromatography afforded a brown oil; yield: 48 mg (50%).
The spectroscopic data were consistent with a commercial sample
and those reported previously for this compound.14
13C NMR (100 MHz, CDCl3): δ = 163.9, 158.7, 146.2, 138.2, 132.0,
131.7, 130.0, 113.7, 111.3, 66.4, 57.3, 55.4, 53.6, 53.4, 35.1, 22.4.
Anal. Calcd for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C,
72.40; H, 7.52; N, 9.11.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 2.0 Hz, 1 H), 8.49 (dd,
J = 4.8, 1.6 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.26 (t, J = 6.8 Hz,
1 H), 3.25 (t, J = 7.6 Hz, 1 H), 3.09 (t, J = 8.0 Hz, 1 H), 2.35–2.29
(m, 1 H), 2.24–2.16 (m, 4 H), 2.00–1.74 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.5, 149.7, 135.8, 124.0, 75.8,
61.9, 35.7, 29.9, 26.8.
3-(1-Benzylpiperidin-2-yl)pyridine (12a)16
The title product was prepared from 7 (100 mg, 0.55 mmol),
[Cp*IrCl2]2 (14 mg, 0.013 mmol), Na2CO3 (1.2 mg, 0.013 mmol)
and BnNH2 (55 mg, 0.55 mmol). Purification by flash chromatog-
raphy afforded a colorless oil; yield: 100 mg, (70%).
1H NMR (400 MHz, CDCl3): δ = 8.65 (d, J = 1.6 Hz, 1 H), 8.48 (dd,
J = 4.8, 1.6 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.34–7.18 (m, 6 H),
3.70 (d, J = 13.6 Hz, 1 H), 3.16 (dd, J = 11.2, 2.8 Hz, 1 H), 2.99 (d,
J = 11.6 Hz, 1 H), 2.85 (d, J = 13.6 Hz, 1 H), 1.99–1.92 (m, 2 H),
1.81–1.75 (m, 2 H), 1.65–1.42 (m, 2 H), 1.42–1.37 (m, 1 H).
3-(1-Benzylpyrrolidin-2-yl)pyridine (10a)
The title product was prepared from 6a (100 mg, 0.60 mmol),
[Cp*IrCl2]2 (12 mg, 0.015 mmol), Na2CO3 (1.3 mg, 0.015 mmol)
and BnNH2 (64 mg, 0.60 mmol) in H2O (5 mL). Purification by
flash chromatography afforded a colorless oil; yield: 105 mg,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2120–2124

2124
T. D. Apsunde, M. L. Trudell
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): δ = 149.7, 148.9, 141.2, 139.5, 135.1,
128.8, 128.4, 127.1, 124.0, 66.7, 60.3, 53.5, 37.2, 26.0, 25.2.
13C NMR (100 MHz, CDCl3): δ = 164.8, 147.0, 138.4, 123.8, 111.5,
60.8, 53.8, 45.1, 31.6, 24.0.
Anal. Calcd for C17H20N2: C, 80.91; H, 7.99; N, 11.10. Found: C,
80.77; H, 8.21; N, 11.00.
Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C,
67.12; H, 8.15; N, 15.67.
3-[1-(4-Methoxybenzyl)piperidin-2-yl)pyridine (12b)
The title product was prepared from 7 (100 mg, 0.55 mmol),
[Cp*IrCl2]2 (14 mg, 0.013 mmol), Na2CO3 (1.2 mg, 0.013 mmol)
and 4-methoxybenzylamine (75 mg, 0.55 mmol). Purification by
flash chromatography afforded a colorless oil; yield: 129 mg (75%).
1H NMR (400 MHz, CDCl3): δ = 8.63 (s, 1 H), 8.48 (dd, J = 4.8, 1.6
Hz, 1 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.26–7.24 (m, 1 H), 7.12 (d,
J = 8.4 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H), 3.78 (s, 3 H), 3.61 (d,
J = 13.6 Hz, 1 H), 3.15 (dd, J = 7.2, 2.4 Hz, 1 H), 2.98 (d, J = 11.6
Hz, 1 H), 2.79 (d, J = 13.6 Hz, 1 H), 1.96–1.89 (m, 1 H), 1.80–1.72
(m, 2 H), 1.63–1.50 (m, 3 H), 1.41–1.30 (m, 1 H).
Acknowledgment
This research was funded by the National Institute on Drug Abuse
(DA023916), Louisiana Board of Regents through the Board of
Regents Support Fund [contract LEQSF (2009-12)-RD-A-26], and
the University of New Orleans.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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13C NMR (100 MHz, CDCl3): δ = 158.7, 149.7, 148.8, 141.3, 135.1,
131.3, 130.0, 123.9, 113.7, 66.6, 59.3, 55.4, 53.3, 37.3, 26.0, 25.2.
References
Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C,
76.50; H, 7.91; N, 9.78.
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3-(1-Benzylpyrrolidin-2-yl)quinoline (13)
The title product was prepared from 9 (100 mg, 0.50 mmol),
[Cp*IrCl2]2 (12 mg, 0.012 mmol), Na2CO3 (1.1 mg, 0.012 mmol)
and BnNH2 (53 mg, 0.50 mmol). Purification by flash chromatog-
raphy afforded a colorless oil; yield: 100 mg (78%).
1H NMR (400 MHz, CDCl3): δ = 9.05 (s, 1 H), 8.17 (s, 1 H), 8.12
(d, J = 8.8 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 7.2 Hz, 1
H), 7.56 (t, J = 7.2 Hz, 1 H), 7.34–7.19 (m, 5 H), 3.85 (d, J = 12.8
Hz, 1 H), 3.59 (t, J = 7.6 Hz, 1 H), 3.15 (d, J = 12.8 Hz, 1 H), 2.34–
2.27 (m, 2 H), 2.01–1.81 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 151.6, 148.1, 139.5, 137.0, 134.4,
129.5, 129.2, 129.0, 128.6, 128.4, 127.8, 127.1, 126.8, 67.5, 58.5,
53.7, 35.5, 22.9.
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2-Methoxy-5-(pyrrolidin-2-yl)pyridine (14)
5-(1-Benzylpyrrolidin-2-yl)-2-methoxypyridine (10b) (100 mg,
0.37 mmol),) and 10% Pd/C (10 mg) were stirred in EtOH under H2
(1 atm) for 2 h at 55 °C. After the reaction was complete (TLC), the
mixture was filtered through Celite. The solvent was removed under
reduced pressure to afford the nornicotine derivative as a light yel-
low oil; yield: 51 mg (75%).
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 4.0 Hz, 1 H), 7.79 (dd,
J = 4.8, 2.4 Hz, 1 H), 6.72 (d, J = 4.8 Hz, 1 H), 5.73 (br s, 1 H, NH),
4.37 (t, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 3.36–3.34 (m, 1 H), 3.21–
3.16 (m, 1 H), 2.16–2.14 (m, 1 H), 2.10–2.01 (m, 3 H).
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Synthesis 2013, 45, 2120–2124
© Georg Thieme Verlag Stuttgart · New York