Complete structural and spectral assignment of oxoisoaporphines by HMQC and HMBC experiments

Article abstract of DOI:10.1002/mrc.1177

The oxoisoaporphines 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one, 2,3-dihydro-5-methoxy-7H-dibenzo [de,h] quinolin-7-one, 5-methoxy-6-hydroxy-2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one, 5,6-dimethoxy-2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one and 5,6-methy

Full text of DOI:10.1002/mrc.1177

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2003; 41: 296–300
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1177
Spectral Assignments and Reference Data
additional three- or two-spin system or a singlet depending on
Complete structural and spectral assignment
of oxoisoaporphines by HMQC and HMBC
experiments
the substitution pattern on ring B. These signals can be assigned
unequivocally on the basis of the 1H–1H COSY spectra. The isolation
of these systems by a nitrogen heteroatom and the carbonyl group
makes the assignment of the 1H and 13C RMN spectra relatively
straightforward.
1∗
Eduardo Sobarzo-Sanchez, Bruce K. Cassels,1
´
Carolina Jullian2 and Luis Castedo3
RESULTS AND DISCUSSION
1
Department of Chemistry, Faculty of Sciences, and Millennium Institute
The dihydrooxoisoaporphines 4–7 were obtained starting from
the condensation products of 3,4-dimethoxyphenylethylamine
(homoveratrylamine) (1) or 3,4-methylenedioxyphenylethylamine
(homopiperonylamine) (2) with phthalaldehydic acid (3). The
intermediates were subsequently treated with polyphosphoric acid
to give the final products. On the other hand, 11 was obtained via N-
phenethylphthalimide (8), which was partially reduced and cyclized
to 5,6,8,12b-tetrahydro-8-isoindolo[1,2-a]isoquinolone (9) and
this converted into 1-(2-carboxyphenyl)-3,4-dihydroisoquinoline
(10), which was finally cyclized with sulfuric acid. The synthetic
routes and the molecular structures of the different 2,3-dihydro-7H-
dibenzo[de,h]quinolin-7-ones are shown in Scheme 1.
for Advanced Studies in Cell Biology and Biotechnology, University of
Chile, Casilla 653, Santiago, Chile
Department of Organic and Physical Chemistry, Faculty of Chemical
2
and Pharmaceutical Sciences, University of Chile, Casilla 233, Santiago
1, Chile
3
Department of Organic Chemistry and CSIC Associated Unit, Faculty
of Chemistry, University of Santiago, 15706 Santiago de Compostela,
Spain
Received 12 November 2002; accepted 7 January 2003
The 1H NMR spectra of 4–7 and 11 (Table 1), analyzed with
the aid of 1H–1H COSY and HMQC, displayed signals of aliphatic
protons coupled mutually at υ 4.05–4.20 (t, J D 7.5–7.9 Hz) and
2.78–2.96 (t, J D 7.7–8.3 Hz) assigned to C-2 and C-3, respectively,
the former strongly deshielded by the neighboring imine group,
and four aromatic protons at υ 8.22–8.32 (d, J D 7.5–7.6 Hz), 7.59
(ddd, J D 7.3–8.5, 1.1 Hz), 7.6–7.7 (ddd, J D 7.2–7.4, 1.3 Hz) and
8.31–8.41 (d, J D 7.1–7.3 Hz) attributed to C-8, C-9, C-10 and C-11,
respectively, in the D ring. Also, analyzing the 1H, 1H–1H COSY
and HMQC NMR spectra of 4, the methoxyl group at C-5 can
be easily assigned. The strong deshielding of the proton at C-11,
which resonates at υ 8.31–8.41 in all the studied oxoisoaporphines
due to the anisotropic effect of the attached quinolone unit, was
the starting point for the assignments of the quinoline system.
The 13C NMR spectra of all five dihydrooxoisoaporphines showed
13 common carbon resonances corresponding to two methylenes,
four methines and seven quaternary carbon atoms. The remaining
resonances for ring B varied according to the substitution level,
from three methines for 11, to two methines and an additional
quaternary carbon for 4, and one methine and two additional
quaternary carbons for 5, 6 and 7. Important correlations revealed
by the HMBC experiment are shown in Table 2. The imine carbon
atom, C-11b, and the carbonyl C-7 were the starting points for
assignment of the protons of the methine carbon atoms C-8 and
C-11, similarly affected by the deshielding moieties, C N and
The oxoisoaporphines 2,3-dihydro-7H-dibenzo[de,h]qu-
inolin-7-one, 2,3-dihydro-5-methoxy-7H-dibenzo [de,h]
quinolin-7-one, 5-methoxy-6-hydroxy-2,3-dihydro-7H-
dibenzo[de,h]quinolin-7-one, 5,6-dimethoxy-2,3-dihydro-
7H-dibenzo[de,h]quinolin-7-one and 5,6-methylenedi-
oxy-2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one were
prepared by cyclization of phenylethylaminophthalides
with polyphosphoric acid or by treating 1-(2-carboxyph-
enyl)-3,4-dihydroisoquinoline hydrochloride with sulfu-
ric acid at 0 ◦C. The structures were confirmed and 1H and
13C NMR spectra were completely assigned using a com-
bination of one- and two-dimensional NMR techniques.
Copyright  2003 John Wiley & Sons, Ltd.
KEYWORDS: NMR; 1H NMR; 13C NMR; 1H–1H COSY; HMBC;
HMQC; oxoisoaporphines;
2,3-dihydro-7H-dibenzo[de,h]quinolin-7-ones
INTRODUCTION
The oxoisoaporphine alkaloids isolated since the early 1980s from
the rhizomes of Menispermum dauricum DC (Menispermaceae)
are an unusual type of isoquinoline structure with a dubious
biogenesis having a 7H-dibenzo[de,h]quinolin-7-one skeleton con-
firmed through total synthesis and spectroscopic assignment.1–4
Some 2,3-dihydrooxoisoaporphines have been synthesized previ-
ously, together with a number of side-products, by cyclization of
phenylethylaminophthalides with polyphosphoric acid, although
their spectral characterization is poor by present-day standards.5
The unsubstituted 2,3-dihydrooxoisoaporphine had been syn-
thetized by a different route by heating 1-(2-carboxyphenyl)-3,4-
dihydroisoquinoline hydrochloride in sulfuric acid, and the relevant
spectroscopic information is also incomplete.6
C
O. For the former, the carbon resonates at almost the same
frequency in all five dihydrooxoisoaporphines, between υ 154.8 and
156.1 ppm. However, C-7 resonates close to 184 ppm in 4, 6, 7 and
11, but at 189 ppm in 5 owing to hydrogen bonding of the carbonyl
oxygen, evidenced by the chelated OH-6 proton resonance at υ
12.94 ppm.
EXPERIMENTAL
Synthesis of alkoxy-substituted
2,3-dihydro-7H-dibenzo[de,h]quinolin-7-ones (4–7)
A solution of phthalaldehydic acid in toluene was treated with
homoveratrylamine or homopiperonylamine and refluxed with
stirring under a Dean–Stark trap for 2 h. Each resulting mix-
In this paper, we describe the structure confirmation, conducted
entirely by the use of NMR spectroscopy, and the complete
chemical shift assignments of the 1H and 13C NMR spectra of
several 2,3-dihydrooxoisoaporphine derivatives. This was achieved
through the concerted application of a variety of one- and two-
dimensional techniques such as COSY7, HMQC8 and HMBC9 and
the incorporation of the well-documented10 pulsed field gradients
(PFG).11
°
ture was treated with polyphosphoric acid and kept at 100 C
for 10 min. The red mixtures were taken up in water, neutralized
with aqueous ammonia and extracted with CHCl3. The chloroform
extracts were then dried over anhydrous Na2SO4, concentrated
and the residues subjected to silica gel flash chromatography,
eluting with hexane–ethyl acetate (95 : 5, v/v) to give, among
other side-products, the 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-
ones 4–7. Their yields and melting-points are reported in
Table 3.
These compounds have a structure consisting of two four-spin
1H systems (two methylenes and four aromatic protons) and an
ŁCorrespondence to: Eduardo Sobarzo-Sa´nchez, Department of Chemistry,
Faculty of Sciences, and Millennium Institute for Advanced Studies in Cell
Biology and Biotechnology, University of Chile, Casilla 653, Santiago, Chile.
E-mail: esobarzo@usc.es
Synthesis of 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one (11)
N-Phenethylphthalimide (8) was reduced partially with sodium
borohydride in MeOH at room temperature and cyclized with
Contract/grant sponsor: FONDECYT; Contract/grant number: 2010056.
Copyright  2003 John Wiley & Sons, Ltd.

297
Spectral Assignments and Reference Data
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298
Spectral Assignments and Reference Data
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 296–300

299
Spectral Assignments and Reference Data
4
3
3a
3b
5
O
R5
R6
2
R3
R4
a
1
N
11b
O
6
+
6a
NH2
7
7a
8
11a
H
HO
(3)
11
10
O
(1) R3 = R4 = OMe
9
(2) R3, R4 = -OCH2O-
(4) R5 = OMe; R6 = H
(5) R5 = OMe; R6 = OH
(6) R5 = R6 = OMe
(7) R5, R6 = -OCH2O-
4
3
3a
5
2
O
N
3b A
B
d
c
b
1
N
N
6
N
6a
11b
O
7 C
11a
HOOC
11
10
O
7a
8
O
D
9
(8)
(9)
(10)
(11)
a = APF/100˚C/10 min., b = NaBH4/MeOH-HCl reflux, c = air/MeOH-dimethyl sulphate/heating, d = H2SO4/SO3
Scheme 1. Syntheses of 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one (11) and derivatives (4-7).
90 pulse was 10 µs. The homonuclear 1H–1H shift-correlated 2D
spectra were obtained using standard Bruker software (cosygs).
The spectral widths were 5000 Hz. The spectra were collected as
512 ð 512 blocks of data and were processed by sinusoidal multipli-
cation in each dimension. Other parameters were as follows: number
of increments in t1, 256; number of scans, 4; and relaxation delay,
2 s.
Table 3. Yields and melting-points of the 2,3-dihydrooxoisoaporphine
°
derivatives
°
Compound
Melting-point ( C)
Yield (%)
4
5
164–165
156–157
154–155
175 (d)a
163–164
30
9
The HMQC spectra were recorded using standard Bruker
software (inv4gstp). These spectra were collected with 512 ð 512
data points, a data acquisition of four scans ðF2 and 256 increments
in t1. Spectral widths of 5000 and 15 000 Hz were employed in the
6
4
7
7
F2 (1H) and F1 13C) domains, respectively. Data were processed
(
11
69
using Qsine functions for weighting in both dimensions. The HMBC
spectra were obtained using the inv4gslplrnd pulse sequence in the
Bruker software and collected with 512 ð 512 data points, a data
acquisition of 10 scans ðF2 and 256 increments in t1. The spectral
widths were 5000 Hz (F2) and 18 000 Hz (F1) and the delays 1
and2 were set to 3.45 and 65 ms, respectively. Data were processed
using an exponential window in F2 with lb D 0.3 Hz and Qsine
window in F1.
a Decomposition.
hydrochloric acid to give 5,6,8,12b-tetrahydro-8-isoindolo[1, 2 ꢀ
a]isoquinolone (9) (90%). Compound 9 was then oxidized with air
in the presence of NaOH–MeOH and dimethyl sulfate to afford
by heating 1-(2-methoxycarbonylphenyl)-3,4-dihydroisoquinoline,
which was not isolated, but directly hydrolyzed to (10) with
hydrochloric acid. Using fuming sulfuric acid at 0–5 C, 11 was
obtained as yellowish needles crystallized from MeOH.
°
Acknowledgements
E.S.-S. thanks Fundacio´n Andes for a scholarship. This work was
supported in part by FONDECYT grant No. 2010056.
NMR studies
Proton and 13C NMR spectra were acquired using a Bruker Avance
DRX 300 spectrometer operating at 300.13 and 75.47 MHz, respec-
tively. All measurements were performed at a probe temperature
of 300 K, using solutions of 4, 5, 6, 7 and 11 in CDCl3 contain-
ing tetramethylsilane (TMS) as an internal standard. All one- and
two-dimensional spectra were acquired with a Bruker inverse 5 mm
Z gradient probe. 1H spectra were obtained with a spectral width
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Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 296–300