Visualization and quantification of anisotropic effects on the 1H NMR spectra of 1,3-oxazino[4,3-a]isoquinolines-indirect estimates of steric compression

Article abstract of DOI:10.1016/j.tet.2009.07.038

The anisotropic effects of the phenyl, α- and β-naphthyl moieties in four series of 1,3-oxazino[4,3-a]isoquinolines on the ¹H chemical shifts of the isoquinoline protons were calculated by employing the Nucleus Independent Chemical Shift (NICS)

Full text of DOI:10.1016/j.tet.2009.07.038

Tetrahedron 65 (2009) 8021–8027
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1
Visualization and quantification of anisotropic effects on the H NMR spectra
of 1,3-oxazino[4,3-a]isoquinolinesdindirect estimates of steric compression
,
b
b
a
a
Erich Kleinpeter a , Istvan Szatmari , Laszlo Lazar , Andreas Koch , Matthias Heydenreich ,
*
´
´
´
´
´ ´
Ferenc Fu¨lo¨p b
a Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam(Golm), Germany
b Research Group for Stereochemistry, Hungarian Academy of SciencesdInstitute of Pharmaceutical Chemistry, University of Szeged, Eo¨tvo¨s u. 6., H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2009
Received in revised form 9 July 2009
Accepted 17 July 2009
Available online 22 July 2009
The anisotropic effects of the phenyl, a- and b-naphthyl moieties in four series of 1,3-oxazino[4,3-a]-
isoquinolines on the 1H chemical shifts of the isoquinoline protons were calculated by employing the
Nucleus Independent Chemical Shift (NICS) concept and visualized as anisotropic cones by a through-
space NMR shielding grid. The signs and extents of these spatial effects on the 1H chemical shifts of the
isoquinoline protons were compared with the experimental 1H NMR spectra. The differences between
the experimental
discussed in terms of the steric compression that occurs in the compounds studied.
Ó 2009 Elsevier Ltd. All rights reserved.
d
(1H)/ppm values and the calculated anisotropic effects of the aromatic moieties are
Keywords:
Anisotropic effect
1,3-Oxazino[4,3-a]isoquinoline derivatives
NMR spectroscopy
Theoretical calculations
GIAO
Steric compression
1H chemical shifts
1. Introduction
Of significant note though, there have been some recent de-
velopments of the NICS index30 showing that not the average NICS
but only the NICS(1)zz component could rigorously be used to quan-
tify aromaticity31 and average NICS have proven to be not generally
suitable for the quantitative evaluation of aromaticity.32–34 For ex-
ample, NICS analysis was shown to lead to an incorrect prediction of
aromaticity,33 e.g., for cyclopropane34 and the cyclopropenyl anion.35
During the conformational analysis of several series of 1,3-
oxazino[4,3-a]isoquinolines 1–4 (cf. Scheme 1),36,37 the proton
chemical shifts of the isoquinoline moiety proved to be strongly
dependent on the oxazine part of the molecules. Besides the con-
formations of these compounds, therefore, both the anisotropic
The shielding constant at or above the center of aromatic ring
systems (a nucleus independent chemical shiftdNICS)1 can be used
to characterize the aromaticity of organic compounds. NICS values
on a grid around molecules can be calculated to locate the diatropic
and paratropic regions of the molecules involved.2 These through-
space NMR shieldings (TSNMRSs) have been visualized3 as iso-
chemical-shielding surfaces (ICSSs) and employed to quantify the
anisotropic effects of functional groups (to determine the stereo-
chemistry of nuclei proximal to the functional group),3–18 to sep-
arate the anisotropic effect of the C]C double bond from the
influence of steric hindrance on the same protons,19 and to visualize
and quantify planar20,21 and spherical (anti)aromaticity.22–24
Similar approaches to estimate TSNMRS have been published by
Alkorta and Elguero,25 and Martin et al.26 In both cases, shieldings
of similar size and direction, comparable with the results of our
model and the classical model of Bovey and Johnson27 and Haigh
and Mallion,28,29 were obtained.
effect of the phenyl group (in 2), and the a- (in 3) and b-naphthyl
group (in 4) and the steric compression (the stronger the steric
hindrance, the more the protons involved are shifted to low field)
came into question. As we have considerable experience in
employing TSNMRS grids for the visualization and quantification of
anisotropic effects,3–18 and hence separating these effects from
competitive steric compression effects on the same proton chem-
ical shifts,10,19 our earlier approach3 was applied and the aniso-
tropic effects of the above aromatic moieties on the isoquinoline
protons were quantified. A critical comparison of the experimental
1H chemical shift variations in 1–4 with the anisotropic effects of
the aromatic moieties in 2–4 should answer the given question.
* Corresponding author. Tel.: þ49 331 977 5210; fax: þ49 331 977 5064.
E-mail address: kp@chem.uni-potsdam.de (E. Kleinpeter).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.038

8022
E. Kleinpeter et al. / Tetrahedron 65 (2009) 8021–8027
10
12
15
11
O
O
O
O
9
13
15b NH
15a
N
N
O
O
14
O
O
OH
O
O
O
1c
1b
1a
O
O
O
O
O
N
N
NH
OH
O
O
2c
2b
2a
O
O
O
O
O
N
O
N
NH
OH
O
O
O
3c
3b
3a
O
O
O
O
O
N
O
N
NH
OH
O
O
O
4c
4b
4a
Scheme 1. Compounds studied. For a better comparison, the atoms in 1a–c, 2a–c, 3a, and 4a are denoted by using the numbering of the naphth[1,2-e]- and naphth[2,1-e]-
[1,3]oxazino[4,3-a]isoquinoline ring systems (3b,c and 4b,c).
2. Results and discussion
respectively) and only H-9(ax) reveals NOE to H-15b. Further
NOEs of H-15b to H-9 and H-10 could not be detected, but the
NOEs of H-15b to H-9(ax) and of H-12 to the two H-10 protons
2.1. Synthesis and conformational analysis of the compounds
studied
prove the unequivocal assignment of H-9(ax). Moreover, d(OH)
was found at 11–12 ppm (broadened at room temperature), which
is characteristic for intramolecular hydrogen-bonding, as
computed.
With respect to the conformations of the two methoxy groups
in 1–4, both in-plane (0ꢁ) and out-of plane conformations (90ꢁ)
were obtained, which increased the number of conformers for
the various diastereomers; in each case, however, the in-plane/
in-plane conformers41 were found to be the most stable and
were used as basis structures for the forthcoming anisotropy
study.
The synthesis and conformational analysis of naphth[1,2-e]-
(3b,c) and naphth[2,1-e][1,3]oxazino[4,3-a]isoquinolines (4b,c),
and the preparation of 1-(6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolin-1-yl)-2-naphthol (3a) and 2-(6,7-dimethoxy-1,2,3,4-tet-
rahydroisoquinolin-1-yl)-1-naphthol (4a) were reported
previously.37 2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-
ethanol (1a) and 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-
1-yl)phenol (2a) were synthesized according to literature
procedures.38,39 During the conformational analysis of 2b,c, as
expected, the same minimum-energy structures as obtained for
4b,c37 were computed: a twisted chair conformer for 2b and
a twisted-boat conformation for 2c (cf. Fig. 1), in agreement with
the experimental findings.40
Experimental and computational conformational analysis of
1a–4a, starting materials for 2b,c–4b,c, has not been carried out
earlier. The results of the theoretical calculations were un-
equivocal: the same minimum energy structure was obtained for
each derivative (given in Fig. 2): the 15bS,9S isomers involving the
intramolecular hydrogen bond between the hydroxy group and
the nitrogen lone pair (cf. Fig. 2). Experimental proof comes from
the proton NMR spectra of 2a–4a: the protons at C-9 and C-10 are
positioned in gauche fragments [C(11)–C(10)–C(9)–N] and exhibit
characteristic H,H coupling constants (Jgem¼ꢀ11.7 and ꢀ15.8 Hz,
respectively; Jax,ax¼8.6 Hz, Jax,eq and Jeq,eq¼5.3 and 4.6 Hz,
Figure 1. Minimum-energy structures of 2b (left), a twisted chair conformer, and 2c
(right), a twisted-boat conformation, as obtained at the B3LYP/6-31G level of theory.
*

E. Kleinpeter et al. / Tetrahedron 65 (2009) 8021–8027
8023
Figure 2. Minimum-energy structures of 1a–4a (from left to right), as obtained at the B3LYP/6-31G
*
level of theory.
2.2. 1H chemical shifts
8
The protons in 1–4 whose chemical shifts are compared in the
following study are the isoquinoline protons H-15 and H-12 and the
methoxy protons 13-OMe and 14-OMe. The chemical shifts of these
ring and methyl protons are given in Table 1 together with the
computed values and the data are correlated with each other (cf.
Fig. 3). The agreement between the theoretically calculated and
y = 1.1347x - 0.2394
R2 = 0.9974
7
6
5
4
3
2
experimental values is excellent
[
dexp.¼1.1347dcalcdꢀ0.2394
(R2¼0.9974)], particularly with regard to the fact that the theoret-
ical
d values were computed for molecules in the gas phase, but
3-7ppm
those measured experimentally36,37,42 related to solution. Besides
the additional fact that the ring interconversion of 1–4 at room
temperature is fast on the NMR time-scale, the theoretically cal-
culated geometries of these isoquinoline derivatives obviously
dominate over the magnetic properties and the medium proves to
be of only minor influence. Furthermore, this agreement between
the computed and experimental 1H chemical shifts strongly sup-
port the geometries calculated for the molecules.
2
4
6
8
δ comp.
The strongest variation of the proton resonances in the 1H NMR
spectra of 1–4 was observed for H-15b (Dd¼1.00 ppm), followed by
Figure 3. Correlation of the experimental chemical shifts of H-12, the 13-OMe, and
14-OMe protons and H-15 in 1a–c to 4a–c versus the computed values.
d
Table 1
Experimental chemical shifts (d) of H-12, H-15, 12-OMe, and 14-OMe, chemical shift differences Dd of these protons in 1a–c with respect to 2a–c, 3a–c, and 4a–c, respectively,
and the corresponding anisotropic effects/ppm of the aromatic moieties in 2–4 on these protons
1a
1b
1c
/ppm
/ppm /ppm
/ppm
Anisotropic
Steric
/ppm
Anisotropic Steric
effect/ppm compression
/ppm
Anisotropic Steric
effect/ppm compression
effect/ppm
compression
H-12
6.57
-
-
-
-
6.61
-
-
-
-
6.64
-
-
-
-
13-
3.85*
3.85*
3.87*
OMe
14-
3.83*
-
-
-
3.84*
-
-
-
-
3.86*
-
-
-
-
OMe
H-15
-
6.53
2a
6.52
2b
6.60
2c
H-12
13-
6.61
3.85
+0.04
-
-0.03
6.65
3.86
+0.04
+0.01
-0.02
-0.02
6.70
3.87
+0.06
-
-0.04
+0.01
+0.01
OMe
14-
3.66
-0.17
-0.16
+0.33
+0.76
+0.16
+0.60
3.94
+0.10
+0.28
-0.09
-0.32
3.74
-0.12
-0.01
+0.20
+0.37
+0.08
+0.36
OMe
H-15
6.37
3a
6.80
3b
6.59
3c
H-12
13-
6.70
3.80
+0.13
-0.05
-0.07
6.67
3.86
+0.06
+0.01
-0.09
-0.01
6.72
3.85
+0.08
+0.02
-0.08
+0.01
+0.01
OMe
14-
3.26
-0.57
-0.39
+0.66
+0.95
+0.09
+0.56
3.35
-0.49
-
+0.59
+0.71
+0.10
+0.71
3.30
-0.56
-0.41
+0.68
+0.76
+0.12
+0.35
OMe
H-15
6.14
4a
6.52
4b
6.18
4c
H-12
13-
6.62
3.84
+0.05
+0.01
-0.06
0.01
6.66
3.87
+0.05
+0.02
-0.04
-0.03
6.70
3.86
+0.04
-0.01
-0.06
+0.01
OMe
14-
3.61
6.40
-0.22
-0.13
+0.39
+0.71
+0.17
+0.59
3.98
6.90
+0.14
+0.38
-0.14
-0.43
3.67
6.61
-0.19
+0.22
+0.30
+0.03
+0.31
OMe
H-15
+0.01
*Or reversed.

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E. Kleinpeter et al. / Tetrahedron 65 (2009) 8021–8027
Figure 4. Visualization of the TSNMRSs (ICSSs: blue represents 5 ppm shielding, cyan 2 ppm shielding, green-blue 1 ppm shielding, green 0.5 ppm shielding, yellow 0.1 ppm
shielding, red ꢀ0.1 ppm deshielding and magenta ꢀ0.01 ppm deshielding) of the minimum-energy structures of 3b (left) and 4b (right).
H-15 (0.58 ppm) and 14-OMe (0.72 ppm); smaller changes were
observed for H-12 (0.15 ppm) and 13-OMe (0.07 ppm). Especially
the broad range of chemical shifts of the 14-OMe protons in these
isoquinoline derivatives encouraged us to study this phenomenon
in more detail. While H-15b is too proximal3 to the aromatic moi-
eties in 2–4 to be included on the anisotropy study (vide infra), the
other four should be suitable; further, H-15b and 14-OMe should be
proximal enough to be additionally influenced by steric compres-
sion and a competition can be expected. A detailed study of this is
another topic of this paper.
effect¼ꢀ0.02 to ꢀ0.04 ppm]. Obviously, H-12 is excellently suited to
reveal quantitatively the anisotropic effect of the aromatic moiety in
2–4 on the isoquinoline moieties.
13-OMe: These methoxy groups in 2–4 are turned away from the
aromatic moieties, which cause the anisotropic substituent effects;
therefore, the effect is almost negligible. However, even though
small, both the experimental Dd values and the anisotropic effects
are generally parallel in sign and size [Dd¼ꢀ0.05 to 0.02 ppm; an-
isotropic effect¼0.01 to ꢀ0.03 ppm].
14-OMe: In contrast, 14-OMe in 2–4 are turned toward the ar-
omatic moieties and show the strongest effects of all [Ddexp.¼ꢀ0.57
to 0.14 ppm; anisotropic effect¼0.68 to ꢀ0.14 ppm]. These chemical
shift ranges are comparable and generally point in the same di-
rection, but the anisotropic effects are up to 0.17 ppm smaller than
the experimental Dd values (cf. Table 1). There must be an addi-
tional influence on the proton chemical shifts of 14-OMe, which
was identified to be the steric compression43 of these protons
subject to the proximal aromatic moieties in 2–4 (vide infra).
However, in spite of this peculiarity, the anisotropic effects of the
2.3. Anisotropic effects of aromatic moieties in 2–4 on the 1H
chemical shifts of the isoquinoline protons
TSNMRs for 2–4 were calculated as described above, and can be
easily visualized by different ICSSs.3 Figure 4 depicts the corre-
sponding illustrations for 3b and 4b; similar representations for the
other compounds studied (2–4) can readily be drawn. These two
compounds were selected for presentation because of the different
aromatic moieties in 2–4 on d(14-OMe) are correctly (in direction to
signs of the anisotropic effects of the a-naphthyl moieties in the
high or low field, but reduced in size) indicated by the experimental
Dd values and prove that not only H-12 and 13-OMe, but also 14-
OMe is a useful indication of the anisotropic substituent influences
in 2–4.
H-15: For H-15, which are positioned nearest to the aromatic
moieties in 2–4, (as expected and inherent) the largest anisotropic
effects were computed (ꢀ0.32 to 0.95 ppm). The experimental Dd
values, however, follow the sequences even less than the Dd values
of the 14-OMe protons, for the same reason as discussed previously
(vide supra).
two compounds on the chemical shifts of 14-OMe and H-15. In 3b,
both the 14-OMe protons and H-15 are positioned in the shielding
ICSS¼þ0.5 ppm (green) [cf. Table 1: anisotropic effect Dd (14-
OMe)¼0.59 ppm; Dd (H-15)¼0.71 ppm], while in 4b the corre-
sponding protons are no longer shielded by the anisotropic effect of
a
-naphthyl, but are deshielded [cf. Table 1: anisotropic effect Dd
(14-OMe)¼ꢀ0.14 ppm; Dd (H-15)¼ꢀ0.43 ppm], due to the position
in the deshielding belt (red) of this aromatic moiety. In this way, all
anisotropic effects on the certain protons were taken from the
corresponding TSNMRS grids and are given in Table 1 together with
When the experimental Dd values are compared with the cor-
responding anisotropic effects in 2–4, an agreement in signs (to
high/low field) of the two parameters is found, but the extents of
the experimental deshielding (up to 0.38 ppm) and shielding Dd
values (ꢀ0.01 to ꢀ0.41 ppm) are smaller than the corresponding
deshielding (ꢀ0.32 to ꢀ0.43 ppm) and shielding anisotropic effects
(0.30–0.95 ppm) (cf. Table 1). This is in agreement with the effects
observed for the chemical shift of the 14-OMe protons (vide supra)
and points to the competing activity of steric compression on the
chemical shifts of H-15. In the latter case, the competition will be
studied in some detail.
(i) First, the experimental Dd values were subtracted from the
anisotropic effect computed (cf. Table 1; values in magenta).
These differences, which should arise mainly from steric com-
pression, are distinct for the various types of compounds studied.
In 2c, 3c, and 4c, they are 0.31–0.36 ppm, in 2a, 3a, and 4a they
are 0.56–0.60 ppm and in 2b, 3b, and 4b they are even equivocal:
the experimental d values and the differences in the d values (Dd) of
the isoquinoline protons H-12, 13-OMe, 14-OMe and H-15 in 1a–c
and 2a–c, 3a–c and 4a–c, respectively.
A critical comparison of the experimental chemical shift differ-
ences Dd with the anisotropic effect thus obtained appears equiv-
ocal. If only this anisotropic effect is responsible for the
experimental Dd values a complete (within the margin of error of
the DFT study) agreement between the pairs of values can be
expected. However, this is not generally the case: it depends on the
proton inspected.
H-12: The anisotropic effect on H-12 was found to be minor and
generally in the low field direction (Dd¼ꢀ0.02 to ꢀ0.09 ppm), in
total agreement with the sign of the experimental Dd (¼0.04–
0.13 ppm). Additionally, the relative size of Dd and the anisotropic
effect proved consistent: the strongest effects were observed in 3
[
Dd¼0.06–0.13 ppm; anisotropic effect¼ꢀ0.07 to ꢀ0.09 ppm] and
the smallest ones in
2
[
Dd¼0.04–0.06 ppm; anisotropic

E. Kleinpeter et al. / Tetrahedron 65 (2009) 8021–8027
8025
there are no such effects in 2b and 4c, but the strongest effect is
observed in 3b.
was identified, in agreement with the parallel structural changes
of the geometries.
(ii) In search for the origin of these results, the geometries of 2–4
were carefully studied. Robust references to differences in steric
compression could readily be found, e.g., the bond lengths rC(15)–H
This approach for the quantitative separation of the anisotropic
effects and the steric compression of the functional groups on the
1H chemical shifts allowed a re-appraisal of some assertions in NMR
textbooks (e.g., deshielding by 1.57 ppm of H-4 in 11-ethynyl-
phenanthrene relative to its counterpart in phenanthrene was not
found to be due to the anisotropy of the C^C triple bond)10 and the
identification of a steric strain in a highly congested hydrocar-
bons,19 and can be recommended as a generally applicable method.
should parallel the steric hindrance, the shorter rC(15)–H
:
Compound
rC(15)–H
Steric compression 0.31 to 0.36 ppm
2c, 3c, 4c
ꢀ0.001 to ꢀ0.002 Å ꢀ0.002 Å
2a, 3a, 4a
2b, 4b
ꢂ0
3b
ꢀ0.004 Å
0.56 to 0.60 ppm 0.04 ppm 0.71 ppm
The sequence of bond length shortening is in line with the in-
creasing steric compression in these structural fragments:
3b[2a,3a,4a>2c,3c,4c>2b,4b. The strongest shortening of rC(15)–H
is observed for 3b, with almost no effect in the analogs 2b and 4b. If
the bond angles :C(15a)–C(15)–H(15) and :H(15)–C(15)–C(14) are com-
pared, which are similarly influenced by steric compression, the
same activity is considered: :C(15a)–C(15)–H(15) is widened and
4. Experimental
4.1. General
Melting points were determined on a Kofler micro melting ap-
paratus and are uncorrected. Merck Kieselgel 60F254 plates were
used for TLC.
:
is diminished.
H(15)–C(15)–C(14)
Compound
:
2b,4b
118.82–118.83ꢁ
119.60–119.62ꢁ
3b
118.93ꢁ
118.93ꢁ
1H and 13C NMR spectra were recorded in CDCl3 (unless speci-
fied as CD2Cl2 or DMSO-d6) solution in 5 mm tubes, at room tem-
perature, on a 500 MHz NMR spectrometer at 500.17 (1H) and
125.78 (13C) MHz, with the deuterium signal of the solvent as the
lock and TMS as the internal standard for 1H, or the solvent as the
internal standard for 13C. All spectra (1H, 13C, gs-H,H-COSY, gs-
HMQC, gs-1D-HMQC, gs-HMBC and NOESY) were acquired and
processed with the standard software.
C(15a)–C(15)–H(15)
:
H(15)–C(15)–C14)
To illustrate the difference in steric compression, the energy-
minimum structures of 3b and 4b are compared in Figure 5; the
hard steric compression in 3b, but the strainless position of H-15 (in
magenta) in 4b is immediately visible, leading to the conclusions
drawn from the geometry of the compounds studied.
Figure 5. Minimum-energy structures of 3b (left) and 4b (right) as obtained at the B3LYP/6-31G level of theory.
*
The same conclusion can be drawn for the other compounds
from the changes in geometry (cf. Supplementary data).
The quantum-chemical calculations were carried out with the
Gaussian 03 program package.44 Geometry optimizations were
performed at the B3LYP/6-31G
level of theory45 without re-
*
strictions. For 1–4, the four 9,15b diastereomers were energy-op-
timized with respect to the preferred conformers and their relative
energies were calculated; the predominant conformer of the most
stable diastereomer was considered further.
3. Conclusions
For the series of 1,3-oxazino[4,3-a]isoquinolines 1–4, the
minimum-energy isomers/conformers were determined by NMR
spectroscopy and theoretical calculations at the DFT level of
theory. On the basis of these structures, the anisotropic effects of
The spatial magnetic properties (TSNMRS) were constructed,3
using the NICS concept; the NICS values2 were computed on the
basis of the B3LYP/6-31G
*
geometries of 1–4 via the GIAO
the aromatic moieties (phenyl in 2,
a-naphthyl in 3 and
method46,47 at the HF/6-31G
*
level of theory.48 To calculate spatial
b
-naphthyl in 4) on the isoquinoline protons H-12 and H-15 and
NICS, ghost atoms were placed on a lattice of ꢀ10 Å to þ10 Å with
a step size of 0.5 Å in the three directions of the Cartesian co-
ordinate system. The resulting 68,921 NICS values thus obtained
were analyzed and visualized by means of the SYBYL 7.3 molec-
ular modeling software;49 different ICSSs of ꢀ0.01 ppm (magenta)
and ꢀ0.1 ppm (red) deshielding, and 5 ppm (blue), 2 ppm (cyan),
1 ppm (green-blue), 0.5 ppm (green), and 0.1 ppm (yellow)
the methoxy protons 13-OMe and 14-OMe were computed via
TSNMRS grids around the aromatic substituents. While H-12 and
13-OMe proved to be excellent indicators of the anisotropic ef-
fects in 2–4, the values for H-15 and 14-OMe in these com-
pounds were found to be smaller than the experimental Dd
values. As the reason for the differences between Dd and the
anisotropic effects of the aromatic moieties, steric compression43

8026
E. Kleinpeter et al. / Tetrahedron 65 (2009) 8021–8027
shielding are used to visualize the TSNMRS of 3b and 4b in
Figure 4.
evaporated, resulting in an oil, which became crystalline on treat-
ment with Et2O. The crystals were filtered off and recrystallized
from EtOH. Yield: 0.67 g (54%), mp: 189–190 ꢁC.
NMR chemical shifts were calculated by the GIAO method46,47 at
the B3LYP/6-31G level of theory (the reference compound TMS
*
was calculated at the same level). All calculations were carried out
on SGI workstations and LINUX clusters.
Supplementary data
The synthesis of naphth[1,2-e]- (3b,c) and naphth[2,1-e]-
[1,3]oxazino[4,3-a]isoquinolines (4b,c), and the preparation of 1-
(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-2-naphthol (3a)
and 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-naphthol
(4a) were reported previously.37 2-(6,7-Dimethoxy-1,2,3,4-tetrahy-
droisoquinolin-1-yl)ethanol (1a) and 2-(6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-1-yl)phenol (2a) were synthesized according
to literature procedures.38,39
Absolute energies, bond angles and bond distances, and x,y,z-
coordinates at the B3LYP/6-31G level of theory for 1–4. Supple-
*
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2009.07.038.
References and notes
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´
2. von Rague Schleyer, P.; Manoharan, M.; Wang, Z. X.; Kiran, B.; Jiao, Y.; Puchta,
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oxazino[4,3-a]isoquinoline (1b)
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To a solution of amino alcohol 1a (0.71 g, 3 mmol) in MeOH
(10 mL), 36% formaldehyde solution (0.5 mL) was added. The
mixture was allowed to stand at room temperature for 1 h, then
poured into H2O (50 mL) and extracted with CH2Cl2 (3ꢃ25 mL). The
combined organic extracts were dried (Na2SO4) and evaporated.
The oily product crystallized on treatment with Et2O. The crystals
were filtered off and recrystallized from i-Pr2O. Yield: 0.61 g (82%),
mp 102–103 ꢁC.
´
´ ´
12. Kleinpeter, E.; Klod, S. J. Mol. Struct. 2004, 704, 79.
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4.3. 9,10-Dimethoxy-1,6,7,11b-tetrahydro-2H,4H-1,3-
oxazino[4,3-a]isoquinolin-4-one (1c)
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hedron 2006, 62, 11081.
To a stirred mixture of amino alcohol 1a (1.19 g, 5 mmol), tolu-
ene (30 mL), NaHCO3 (0.63 g, 7.5 mmol), and H2O (30 mL), ethyl
chloroformate (0.60 g, 5.5 mmol) was added and the mixture was
stirred at room temperature for 1 h. The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc (3ꢃ30 mL).
The combined extracts were dried (Na2SO4) and evaporated to yield
1.50 g (97%) of ethyl 1-(20-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-2-carboxylate as an oily product, which
was used in the next step without further purification.
The previous urethane derivative (1.00 g, 3.2 mmol) was thor-
oughly mixed with NaOMe (0.18 g, 3.3 mmol) and the mixture was
kept under N2 at 130 ꢁC for 45 min. The melt was extracted with hot
EtOAc (5ꢃ30 mL), and the combined organic phases were washed
with 5% HCl (2ꢃ30 mL) and H2O (2ꢃ30 mL), dried (Na2SO4), and
evaporated. The oily residue crystallized on treatment with Et2O.
The crystals were filtered off and recrystallized from i-Pr2O. Yield:
0.44 g (52%), mp 119–121 ꢁC.
ˇ
´
´
17. Rasovic, A.; Steel, P. J.; Kleinpeter, E.; Markovic, R. Tetrahedron 2007, 63, 1937.
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observed in the NOESY spectrum because of identical proton chemical shifts. In

E. Kleinpeter et al. / Tetrahedron 65 (2009) 8021–8027
8027
2c, as in 4c, a short distance between H-15b and H-9(syn) corroborates the
experimentally found NOE enhancement.
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