Synthesis of anabaseine and anabasine derivatives: Structural modifications of possible nicotinic agonists

Article abstract of DOI:10.1080/00397910701227168

Coupling nicotinoyl chloride with 3,4-dimetoxyphenethylamine under Bischler-Napieralski cyclization afforded the isoquinoline (4) in good yield. This latter was used as starting material to obtain with only hydrobromic acid a product with demethylation at

Full text of DOI:10.1080/00397910701227168

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Synthesis of Anabaseine and Anabasine
Derivatives: Structural Modifications of
Possible Nicotinic Agonists
Eduardo Sobarzo‐Sánchez a , Luis Castedo a & Julio R. De la Fuente b
a Department of Organic Chemistry and C.S.I.C. Associated Unit, Faculty of
Chemistry , University of Santiago de Compostela , Santiago de Compostela,
Spain
b Department of Organic and Physical Chemistry, Faculty of Chemical and
Pharmaceutical Sciences , University of Chile , Casilla, Santiago, Chile
Published online: 12 Apr 2007.
To cite this article: Eduardo Sobarzo‐Sánchez , Luis Castedo & Julio R. De la Fuente (2007) Synthesis of
Anabaseine and Anabasine Derivatives: Structural Modifications of Possible Nicotinic Agonists, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:8,
1331-1338, DOI: 10.1080/00397910701227168
To link to this article: http://dx.doi.org/10.1080/00397910701227168
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Synthetic Communicationsw, 37: 1331–1338, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701227168
Synthesis of Anabaseine and Anabasine
Derivatives: Structural Modifications of
Possible Nicotinic Agonists
´
Eduardo Sobarzo-Sanchez and Luis Castedo
Department of Organic Chemistry and C.S.I.C. Associated Unit, Faculty
of Chemistry, University of Santiago de Compostela, Santiago de
Compostela, Spain
Julio R. De la Fuente
Department of Organic and Physical Chemistry, Faculty of Chemical and
Pharmaceutical Sciences, University of Chile, Casilla, Santiago, Chile
Abstract: Coupling nicotinoyl chloride with 3,4-dimetoxyphenethylamine under
Bischler-Napieralski cyclization afforded the isoquinoline (4) in good yield. This latter
was used as starting material to obtain with only hydrobromic acid a product with
demethylation at the position 7 (5). In addition, treatment of (4) with NaBH4/MeOH
gave 6,7-dimetoxy-1-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (6) and unexpectedly,
under mild reduction of the pyridine moiety with H2/PtO2/AcOH/, gave 6,7-dimetoxy-
1-(piperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (7) as the title compound. The unusual
chemical reactivity of 4 onto acidic conditions and catalytic hydrogenation allowed us to
obtain anabaseine and anabasine derivatives under mild conditions.
Keywords: anabaseine, anabasine, 1-(pyridin-3-yl)isoquinoline, nicotinic acetyl-
choline receptor
INTRODUCTION
Nicotine (1), as a main component of cigarette smoke, affects organisms
through nicotinic acetylcholine receptors. In addition to the central nervous
Received in Poland June 12, 2006
Address correspondence to Eduardo Sobarzo-Sanchez, Department of Organic
´
Chemistry and C.S.I.C. Associated Unit, Faculty of Chemistry, University of
Santiago de Compostela, Santiago de Compostela 15782, Spain. Fax: þ34 981
595012; E-mail: esobarzo@usc.es
1331

´
E. Sobarzo-Sanchez, L. Castedo, and J. R. De la Fuente
1332
system, nicotine is known to affect many other tissues such as the respiratory
tract, skin, hematological cells, and vascular and immune tissues.[1,2] Thus,
nicotinic acetylcholine receptors (nAChRs) play an important role in the
mediation of synaptic signals in the nervous systems of animals.[3] At the
molecular level, anabaseine (2) differs from nicotine and anabasine (3) by
having a tetrahydropyridyl ring whose imine double bond is electronically
conjugated with the 3-pyridyl ring (Fig. 1). This causes its two rings to be
approximately coplanar in their relative orientation, whereas the two rings
in the tobacco alkaloids nicotine and anabasine are almost perpendicular to
each other.[4,5]
The syntheses of anabaseine consist of CsF on CaO-catalyzed cycliza-
tion of aromatic amides,[6] from 2-piperidone aminal and a nicotinic acid
derivatives via acid-catalyzed rearrangement of a nicotinoylpiperidone
salt,[7] and by a-alkylation of (E)-N-(1-(pyridin-3-yl)ethylidene)propan-
2-amine with ethylenetetramethyldisilyl-protected v-bromoamines,
followed by ring closure.[8] On the other hand, anabasine derivatives
have been synthesized from racemic 2-hydroxymethyl–piperidine,
racemic pipecolic acid, or (S)-(-)-piperidine-1,2-dicarboxylic-acid-1-tert-
Bu ester,[9] and recently through the cyclodehydration of achiral or racemic
aryl-d-oxoacids with (R)-phenylglycinol to give (-)-anabasine.[10] Theoreti-
cal and molecular modeling studies have been conducted among anabaseine
analogues to provide valuable tools for nAChR drug-receptor structure–
function relationships.[11] The position of a benzylidene moiety attachment
to anabaseine analogues has effects on the potency of this class of agonists in
practical drug design against Alzheimer’s disease.[12] The annulation of a
rigid system into the tetrahydropyridyl ring such as substituted benzene
ring with electron-donating groups would help to improve the pharmacologi-
cal properties of this type of alkaloid with simple structural modifications.
In this communication, we describe the formation of 6-methoxy-
7-hydroxy-1-(pyridin-3-yl)-3,4-dihydroisoquinoline (5), 6,7-dimethoxy-1-
(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (6), and 6,7-dimethoxy-1-
(piperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline
6,7-dimethoxy-1-(pyridine-3-yl)-3,4-dihydroisoquinoline (4) (Scheme 1).
(7)
starting
from
Figure 1. Nicotine (1), Anabaseine (2), Anabasine (3).

Anabaseine and Anabasine Derivatives
1333
Scheme 1. Reagents and experimental conditions.
RESULTS AND DISCUSSION
The reaction between 3,4-dimethoxyphenethylamine and nicotinoyl chloride
afforded the corresponding amide that, without further purification, was used
through the standard Bischler–Napieralski reaction to give (4) in good
yield.[13] Because this precursor can be obtained in an efficient way, the
synthesis of anabaseine derivatives was carried out to study the reactivity of
this type of heterocycle under acidic and reductive conditions. Thus, the
demethylation of the methoxyl groups by heating with HBr/AcOH should
give a catechol derivative as the main compound. This reaction induced by
HCl or HI has been described in isoquinoline derivatives, for instance, as
potential antidepressant drugs.[14] However, (4) unexpectedly afforded a
product characterized as 6-methoxy-7-hydroxy-1-(pyridin-3-yl)-3,4-dihydroi-
soquinoline (5). The partial hydrolysis of the methoxyl group at C-7 was
observed in the hydrolysis of the methoxyl group at C-1 in aporphines as nor-
nuciferina,[15] being possibly attributable to steric hindrance between the

´
E. Sobarzo-Sanchez, L. Castedo, and J. R. De la Fuente
1334
pyridine ring and the isoquinoline framework. In this sense, the chemical shifts
of the O-7-CH3 and O-6-CH3 groups at d 3.73 and 3.94 ppm, respectively,
indicated to us a shield evident for the first one. This could be attributed to
the loss of the anisotropic effect from the aromatic ring on the methoxyl
group at C-7, probably due to the lack of coplanarity between both, and the
proximity and rotation of the pyridine ring at C-1. On the other hand, several
reduction methods were used to explore the reactivity of (4) under reductive
conditions. Using NaBH4 in MeOH as solvent afforded 6,7-dimethoxy-1-
(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (6) in high yield, and this was an
effective way to obtain anabasine derivatives. However, the mild catalytic
hydrogenation under PtO2 as catalyst to gave a product characterized as 6,7-
dimethoxy-1-(piperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline
(7),
which
presented the complete reduction of both the pyridine ring and the imine
bond. This unusual hydrogenation has been described by us in a small group
of isoquinoline alkaloids called “oxoisoaporphines,” whose reactivity has
been determined either by the partial or total unsaturation of the isoquinoline
skeleton.[16] Therefore, the formation of a single product under mild hydrogen-
ation conditions using the Adam’s catalyst would be useful for the preparation
of piperidine derivatives attached to substituted isoquinolines at C-1.
EXPERIMENTAL
Melting points were determined on a Reichert-Jung Galen III Kofler hot stage
and are uncorrected. Column chromatography was performed on Merck silica
gel 60, 230–400 mesh, and thin-layer chromatography (TLC) was performed
on Merck silica gel G. Mass spectra of high and low resolution were carried
out on the Micromass Autospec-Q and HP-5988A spectrometers, respectively.
The infrared spectra were recorded on a Perkin-Elmer Paragon 1000 FT-IR
spectrophotometer. NMR spectra were recorded in CDCl3 using a Bruker
AMX 300 instrument operating at 300.13 MHz (1H) or 75.48 MHz (13C).
All solvents and reagents were obtained from either Aldrich Chemical Co.
or Merck. Methanol, dichloromethane, tetrahydrofuran, and diethyl ether were
dried using standard procedures.
Synthesis of N-(3,4-dimethoxyphenethyl)nicotinamide (A)
Nicotinoyl chloride (1 g, 5.51 mmol) was added into a mixture of THF
(40 mL) and 40 mL of 10% aqueous NaOH solution in an ice bath with
stirring. Later on, 3,4-dimethoxyphenethylamine (0.92 mL, 5.51 mmol)
dissolved in 20 mL of THF was added dropwise to the mixture during 1 h.
The formed white precipitate was filtered off, and the ether layer of the
filtrate was evaporated to leave the residue. The precipitates and the residue
were combined and dissolved in CH2Cl2. The organic solution was washed

Anabaseine and Anabasine Derivatives
1335
successively with 10% aqueous HCl solution, 10% aqueous NaOH solution,
and water and dried over Na2SO4. Removal of the solvent by evaporation
left the residue, which was purified by column chromatography on silica gel
(eluted by CH2Cl2 containing 5% MeOH) to give the corresponding
benzamide derivative A (1.33 g, 85%) as brownish oil.
1HNMR d (CDCl3, ppm): 2.88 (t, J ¼ 8.4 Hz, 2H, CH2), 3.71
(t, J ¼ 8.1 Hz, 2H, CH2), 3.83 (s, 3H, O-4-CH3), 3.85 (s, 3H, O-3-CH3),
6.39 (bs, 1H, N-H), 6.73–6.83 (m, 3H, H-1, H-4, H-5), 7.36 [dd, J
(4,5) ¼ J (5,6) ¼ 6.0 Hz, 1H, H-50], 8.06 [dd, J (4,5) ¼ 11.7 Hz; J
(4,6) ¼ 2.7 Hz, 1H, H-40], 8.67 [dd, J (6,5) ¼ 5.7 Hz; J (6,4) ¼ 2.0 Hz, 1H,
H-60], 8.87 [d, J (2,4) ¼ 1.2 Hz, 1H, H-20]. 13C-NMR d (CDCl3, ppm):
35.08, 41.27, 55.81, 55.86, 111.36, 111.79, 120.64, 123.53, 130.29, 130.99,
135.14, 147.51, 147.77, 149.10, 152.01, 165.45. IR (KBr, n, cm21): 3055
(N-H), 1653 (NC55O). EI-MS (m/z): 286.25 (Mþ, 100). EI-HRMS calcd.
for C16H18N2O3 286.1317; found 286.1317.
Synthesis of 6,7-Dimethoxy-1-(pyridin-3-yl)-3,4-
dihydroisoquinoline (4)
N-(3,4-Dimethoxyphenethyl)nicotinamide (A) (6.7 g, 23.4 mmol) was dissolved
in 30 mL of toluene and heated with POCl3 (30 mL) at 1308C for 3 h. The
solvent and the excess reagent were removed by evaporation in vacuum, and
the residual reagent was decomposed by adding MeOH and 10% HCl aq. The
acidic solution was washed once with Et2O, made alkaline with 10% NH4OH
aq., and extracted with CH2Cl2. The extract was washed with H2O and dried,
and the solvent was evaporated. The residue was purified by column chromato-
graphy on silica gel (eluted by CH2Cl2 containing 10% MeOH). Recrystalliza-
tion from cyclohexane gave 4.74 g (75%) of 4 as brownish needles.
1H-NMR d (CDCl3, ppm): 2.74 (t, J ¼ 7.4 Hz, 2H, H-4), 3.73 (s, 3H, O-7-
CH3), 3.83 (t, J ¼ 7.4 Hz, 2H, H-3), 3.94 (s, 3H, O-6-CH3), 6.70 (s, 1H, H-8),
6.79 (s, 1H, H-5), 7.37 [dd, J (4,5) ¼ 7.3 Hz; J (5,6) ¼ 4.9 Hz, 1H, H-50], 7.94
[dd, J (4,5) ¼ 7.8 Hz; J (4,6) ¼ 1.8 Hz, 1H, H-40], 8.68 [dd, J (6,5) ¼ 4.8 Hz;
J (6,4) ¼ 1.5 Hz, 1H, H-60], 8.83 [d, J (2,4) ¼ 1.3 Hz, 1H, H-20]. 13C-NMR d
(CDCl3, ppm): 25.82, 47.74, 56.04, 56.16, 110.48, 110.87, 120.97, 123.16,
132.50, 134.77, 136.17, 147.31, 149.78, 150.29, 151.28, 164.36. IR (KBr, n,
cm21): 1636 (C55N). Mp 117–1188C. EI-MS (m/z): 268.20 (Mþ, 100). EI-
HRMS calcd. for C16H16N2O2 268.1211; found 268.1208.
Synthesis of 6-Methoxy-7-hydroxy-1-(pyridin-3-yl)-3,4-
dihydroisoquinoline (5)
A solution of 4 (1.2 g, 4.48 mmol) was dissolved over a 50% AcOH/HBr
mixture and heated with stirring at 100 8C for 1 h under an Ar atmosphere.

´
E. Sobarzo-Sanchez, L. Castedo, and J. R. De la Fuente
1336
Later on, the organic residue was washed with a 20% NaHSO3 solution, the
pH was adjusted at 8 with NH4OH, and the residue was extracted with
CH2Cl2. The extracts were then dried with Na2SO4 and concentrated in
vacuum to be subjected to silica-gel flash chromatography eluted with dichlor-
omethane–methanol 9:1 (v/v) to afford (5) (0.680 g, 67%) as yellow needles.
1HNMR d (CDCl3, ppm): 2.67 (t, J ¼ 7.6 Hz, 2H, H-4), 3.71
(t, J ¼ 7.6 Hz, 2H, H-3), 3.85 (s, 3H, O-6-CH3), 6.59 (s, 1H, H-8), 6.95
(s, 1H, H-5), 7.50 [dd, J (4,5) ¼ 7.9 Hz; J (5,6) ¼ 4.9 Hz, 1H, H-50], 7.90
[dd,
J
(4,5) ¼ 8.1 Hz;
J
(4,6) ¼ 2.0 Hz, 1H, H-40], 8.66 [dd,
J
(6,5) ¼ 4.8 Hz; J (6,4) ¼ 1.6 Hz, 1H, H-60], 8.68 [d, J (2,4) ¼ 1.6 Hz, 1H,
H-20], 9.20 (bs, 1H, OH). 13C NMR d (CDCl3, ppm): 25.53, 47.61, 56.16,
111.77, 114.77, 120.89, 123.66, 130.63, 134.64, 136.51, 145.14, 149.61,
150.50, 150.54, 164.07. IR (KBr, n, cm21): 3427, 1297 (OH), 1639 (C55N).
Mp 114–1158C. EI-MS (m/z): 254.25 (Mþ, 100). EI-HRMS calcd. for
C15H14N2O2 254.1055; found 254.1128.
Synthesis of 6,7-Dimethoxy-1-(pyridin-3-yl)-1,2,3,4-
tetrahydroisoquinoline (6)
A suspension of (4) (0.375 g, 1.39 mmol) in methanol (50 mL) was carried out
in an ice-water bath at 08C. After 5 min, NaBH4 (2 g, 52.6 mmol) was added in
portions, resulting in effervescence and solution of the material. This suspen-
sion was stirring for 20 min and diluted with water. After adjusting the pH at
8–9 with AcOH solution, the mixture was extracted with CH2Cl2. The organic
layer was dried with Na2SO4 and concentrated in vacuum. The residue was
purified by column chromatography on silica gel (eluted by CH2Cl2 contain-
ing 10% MeOH) to give 0.310 g (83%) of (6) as brownish oil.
1H NMR d (CDCl3, ppm): 2.74–2.91 (m, 2H, H-4), 3.06–3.17 (m, 2H,
H-3), 3.61 (s, 3H, O-7-CH3), 3.85 (s, 3H, O-6-CH3), 5.07 (s, 1H, H-1), 6.15
(s, 1H, H-8), 6.62 (s, 1H, H-5), 7.22 [dd, J (4,5) ¼ 7.7 Hz; J (5,6) ¼ 4.9 Hz,
1H, H-50], 7.53 [d, J (4,5) ¼ 7.8 Hz, 1H, H-40], 8.51 [d, J (6,5) ¼ 4.1 Hz,
1H, H-60], 8.54 [d, J (2,4) ¼ 1.1 Hz, 1H, H-20]. 13C NMR d (CDCl3, ppm):
29.00, 41.70, 55.86, 55.89, 58.80, 110.60, 111.60, 123.50, 127.70, 128.40,
136.40, 140.00, 147.30, 147.90, 149.00, 150.30. IR (KBr, n, cm21): 3384,
1520 (NH). EI-MS (m/z): 270.25 (Mþ, 100). EI-HRMS calcd. for
C16H18N2O2 270.0429; found 270.0433.
Synthesis of 6,7-Dimethoxy-1-(piperidin-3-yl)-1,2,3,4-
tetrahydroisoquinoline (7)
A solution of (4) (0.3 g, 1.12 mmol) dissolved in AcOH (50 mL) was hydro-
genated at 80 psi over PtO2 (100 mg) as catalyst at room temperature for 24 h.
The colorless solution was diluted with 100 mL of water, neutralized with

Anabaseine and Anabasine Derivatives
1337
NH4OH, and extracted with CH2Cl2 (200 mL). The organic extract was dried
over Na2SO4 and concentrated to dryness, and the residue was subjected to
flash column chromatography on silica gel and eluted with 90:10 CH2Cl2–
MeOH (v/v) to give 7 (0.102 g, 33% yield) as a brownish amorphous solid.
1H NMR d (CDCl3, ppm): 1.81 (m, 4H, H-40/H-50), 2.35 (m, 2H, H-30),
2.57 (m, 4H, H-20/H-60), 2.57–2.72 (m, 2H, H-4), 2.86–3.13 (m, 2H, H-3),
3.80 (s, 3H, O-7-CH3), 3.87 (s, 3H, O-6-CH3), 3.99 (m, 1H, H-1), 6.52
(s, 1H, H-5), 6.70 (s, 1H, H-8). 13CNMR d (CDCl3, ppm): 24.63, 27.82,
29.45, 40.16, 42.23, 45.39, 45.98, 55.77, 56.05, 58.26, 109.05, 111.70,
128.11, 128.40, 2 ꢀ 147.30. IR (KBr, n, cm21): 3437, 1521 (NH). Mp
112–113 8C. EI-MS (m/z): 276.20 (Mþ, 100). EI-HRMS calcd. for
C16H24N2O2 276.1837; found 276.1911.
ACKNOWLEDGMENTS
E. S. S. thanks FONDECYT Grant No. 1030963 for financial support and
B. Cassels for his invaluable help with this research.
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