MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2006; 44: 1131–1134
Published online 12 October 2006 in Wiley InterScience
(
www.interscience.wiley.com) DOI: 10.1002/mrc.1911
Spectral Assignments and Reference Data
Complete assignments 1H and 13C NMR
spectral data of four anabaseine derivatives
chemical shift assignments of the 1H and 13C NMR spectra of
four anabaseine derivatives afforded from 6,7-dimethoxy-1-(pyridin-
7
3
-yl)-3,4-dihydroisoquinoline (2) as potential nicotinic agonists.
This was achieved through the concerted application of gradient-
enhanced experiments such as HMQC and HMBC.
8
9,10
1
∗
2
Eduardo Sobarzo-S a´ nchez, Julio De la Fuente,
El ´ı as Quezada and Luis Castedo1
The investigated alkaloids can be separated into three groups
see Scheme 1): (i) two 1-(pyridine-3-yl)-3,4-dihydroisoquinoline (2,
1
(
3
); (ii) one 1,2,3,4-tetrahydro-1-(pyridine-3-yl)isoquinoline (4); and
1
Department of Organic Chemistry and C.S.I.C. Associated Unit, Faculty
of Chemistry, University of Santiago de Compostela, 15782, Santiago
de Compostela, Spain
(
iii) 1,2,3,4-tetrahydro-6,7-dimethoxy-1-(piperidin-3-yl)isoquinoline
1
(5). All H signals could be assigned unequivocally on the basis
1
1
of the H- H COSY spectra. However, the complexity of the cou-
pling patterns in the H NMR spectra owing to the presence of
several neighboring methylenes and methines made it necessary
to apply HMQC and HMBC techniques for the direct unequivocal
assignment of the heteronuclear correlations.
2
Department of Organic and Physical Chemistry, Faculty of Chemical
1
and Pharmaceutical Sciences, University of Chile, Casilla 233, Santi-
ago 1, Chile
Received 27 March 2006; revised 21 August 2006; accepted 4 September 2006
The anabaseine derivatives 6-methoxy-7-hydroxy-1-
(
pyridin-3-yl)-3,4-dihydroisoquinoline, 6,7-dimethoxy-
RESULTS AND DISCUSSION
1
-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline and 6,7-
dimethoxy-1-(piperidin-3-yl)-1,2,3,4-tetrahydroisoquino-
line were prepared either by demethylation with
HBr or by reduction with different reagents, NaBH4
and H2/PtO2 from 6,7-dimethoxy-1-(pyridin-3-yl)-3,4-
dihydroisoquinoline, as starting material. The structures
have been fully assigned by the combination of one- and
two-dimensional experiments. Copyright 2006 John
Wiley & Sons, Ltd.
The anabaseine derivatives were prepared by using 6,7-dimethoxy-
1-(pyridin-3-yl)-3,4-dihydroisoquinoline (2) as starting material.
Demethylation of the O-7-CH3 group of 2 by heating with
HBr/AcOH should give a catechol derivative. However, an expected
product was characterized as 6-methoxy-7-hydroxy-1-(pyridin-3-yl)-
3
,4-dihydroisoquinoline (3).
Several reduction methods were used in order to explore the
reactivity of the substituted isoquinoline derivatives with a pyridine
ring at C-1. By using NaBH4 in MeOH as solvent, 6,7-dimethoxy-
1
KEYWORDS: H NMR; 13C NMR; HMQC; HMBC; anabaseine;
1-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (4) was obtained in
1
-(pyridin-3-yl)-3,4-dihydroisoquinoline
high yield, and the mild catalytic hydrogenation under PtO2 as
catalyst led to the complete reduction of both the pyridine ring
and the imine bond; the product obtained was 6,7-dimethoxy-
1
-(piperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (5). The complete
INTRODUCTION
assignments of the NMR spectra of 2–5 are summarized in Tables 1
and 2. The synthetic route of the different anabaseine derivatives are
shown in Scheme 1.
Neuronal nicotinic receptors have attracted much interest during the
past few years, largely due to the discovery that the Alzheimer’s
1
,2
1
brain loses many of its nicotinic receptors by the time of death.
The H NMR spectra of compounds 2–4 were analyzed with
Anabaseine (3-(3,4,5,6-tetrahydropyridin-2-yl)pyridine) (1) (Fig. 1)
1
1
the aid of H, H COSY and HMQC. For 2, the signals of aromatic
protons were easily assigned to C-5 and C-8 with values of υ D 6.70
and 6.79 ppm, respectively. The methine proton H-8 of 4 at υ D 6.15
ppm shows a significant shielding as compared to 2, 3 and 5 owing to
the loss of planarity of the imine-pyridine system. The protons at the
pyridine ring for the compounds 2–4 were assigned unequivocally
with the aid of HMBC; the correlations are given in Table 2. The
was initially isolated from a marine worm, but has subsequently
3
,4
been found in certain species of ants. As with nicotine, anabaseine
enhances passive avoidance behavior in nucleus basalis-lesioned
5
rats and has been extensively studied for its potential activity on
nicotinic acetylcholine receptors (nAChR).6
In this paper, we describe the structure determination, conducted
entirely by the use of NMR spectroscopy, and the complete
0
aromatic H-6 of 4 with υ D 8.51 (dd, J D 4.1 Hz) is moderately
shielded with respect to 2 and 3; this may be due to the larger
basicity of the secondary amine nitrogen atom. The methoxyl groups
at C-6 and C-7 are differently influenced by the neighboring aromatic
systems. Thus, the O-6-CH3 protons show no major change in all
compounds, while the O-7-CH3 protons of 4 are somewhat shielded
5
4
3
6
(
υ D υ 3.61 ppm). This fact may be attributed to the lack of conjugation
N 1
due to the reduction of the imine group (sp carbon at C-1). The
methylene protons of the dihydroisoquinoline framework of 2 and 3,
as well as the methine H-1 in the tetrahydroisoquinoline derivatives
3
2
3
'
4
and 5 were easily assigned by analyzing the HMBC spectra. So, the
methylene group at C-4 of 2 and 3, and the methine proton at C-1 in
4
'
2'
4
and 5 were identified by long-range correlation with H-3, H-5 and
0
H-8. Likewise, H-3 of 5 was assigned unequivocally by correlation
with H-2 and H-5 as well as with H-1.
The C NMR spectra of all anabaseine derivatives revealed
eight carbon resonances; two methylenes, two aromatic methines
and four quaternary carbon atoms in the isoquinoline moiety.
The remaining resonances for all derivatives varied according
5
'
N
1'
0
1
0
3
6
'
1
1
13
to the degree of hydrogenation. Thus, H, C correlations were
useful starting points for the assignment of each carbon (Table 2).
For instance, C-3 of 2 and 3 resonate at υ D 47.61–47.74 ppm
while for 4 and 5 the signals are at υ D 41.70–42.23 ppm being
affected by the strong shielding of the tetrahydro-system. Once the
signals were identified, the four additional methylene carbons of 1-
(piperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (5) were assigned by
HMBC.
Figure 1. Structure of (3-(3,4,5,6-tetrahydropyridin-2-yl)pyridine) –
anabaseine (1).
Ł
Correspondence to: Eduardo Sobarzo-S a´ nchez, Department of Organic
Chemistry and C.S.I.C. Associated Unit, Faculty of Chemistry, University of
Santiago de Compostela, 15782, Santiago de Compostela, Spain.
E-mail: esobarzo@usc.es
Copyright 2006 John Wiley & Sons, Ltd.
Sobarzo-Sanchez, Eduardo
