Unexpected isomerization of new naphth[1,3]oxazino[2,3-a]isoquinolines in solution, studied by dynamic NMR and supported by theoretical DFT computations

Article abstract of DOI:10.1016/j.tet.2013.06.094

Through the reactions of 1-aminomethyl-2-naphthol and substituted 1-aminobenzyl-2-naphthols with 3,4-dihydroisoquinoline or 6,7-dimethoxy-3,4- dihydroisoquinoline under microwave conditions, naphth-[1,2-e][1,3]oxazino[2,3- a]-isoquinoline derivatives were prepared in good yields. The latter reaction was extended by using 2-aminoarylmethyl-1-naphthols, leading to isomeric naphth-[2,1-e][1,3]oxazino[2,3-a]isoquinolines. Beside the detailed NMR spectroscopic and theoretical study of both stereochemistry and dynamic behaviour of these new conformational flexible heterocyclic ring systems an unexpected dynamic process between two diastereomers was observed in solution, studied by variable temperature ¹H NMR spectroscopy and the mechanism proved by theoretical DFT computations.

Full text of DOI:10.1016/j.tet.2013.06.094

Tetrahedron 69 (2013) 7455e7465
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unexpected isomerization of new naphth[1,3]oxazino[2,3-a]
isoquinolines in solution, studied by dynamic NMR and supported
by theoretical DFT computations
a
b
b
a,
*
ꢀ
ꢀ
€ €
Istvan Szatmari , Matthias Heydenreich , Andreas Koch , Ferenc Fulop
,
Erich Kleinpeter b
,
*
a Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged,
€
€
Eotvos u. 6, Hungary
b Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam (Golm), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Through the reactions of 1-aminomethyl-2-naphthol and substituted 1-aminobenzyl-2-naphthols with
3,4-dihydroisoquinoline or 6,7-dimethoxy-3,4-dihydroisoquinoline under microwave conditions, naphth-
[1,2-e][1,3]oxazino[2,3-a]-isoquinoline derivatives were prepared in good yields. The latter reaction was
extended by using 2-aminoarylmethyl-1-naphthols, leading to isomeric naphth-[2,1-e][1,3]oxazino[2,3-a]
isoquinolines. Beside the detailed NMR spectroscopic and theoretical study of both stereochemistry and
dynamic behaviour of these new conformational flexible heterocyclic ring systems an unexpected dy-
namic process between two diastereomers was observed in solution, studied by variable temperature 1H
NMR spectroscopy and the mechanism proved by theoretical DFT computations.
Received 26 April 2013
Received in revised form 5 June 2013
Accepted 11 June 2013
Available online 1 July 2013
Keywords:
3,4-Dihydroisoquinoline
Aminonaphthol
Dynamic NMR spectroscopy
DFT calculations
Ó 2013 Elsevier Ltd. All rights reserved.
Conformational analysis
1. Introduction
We recently reported unexpected transformations between
1-a-aminobenzyl-2-naphthol or 1-aminomethyl-2-naphthol
The Mannich reaction1 is an important CeC bond formation
reaction that is widely used in the syntheses of secondary and
tertiary amine derivatives and as a key step in the syntheses of
many bioactive molecules and complex natural products.2 One of
its special variations is the modified Mannich reaction, in which
electron-rich aromatic compounds such as 1- or 2-naphthol are
applied.3 In consequence of the two or more functional groups in
the structure of the Mannich bases prepared via such modified
reactions, one of the most important areas of application of these
aminonaphthol derivatives is the synthesis of new heterocycles.3
In previous papers, we reported on the synthesis and conforma-
tional studies of naphth[1,2-e][1,3]oxazino[3,4-c][1,3]benzoxazine,4,5
naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline6 and naphth[1,2-e]
[1,3]oxazino[3,2-c]quinazolin-13-one.7 Through the cyclization of
1-hydroxynaphthyl-1,2,3,4-tetrahydroisoquinolines, 8-substituted
naphth[1,2-e][1,3]oxazino[4,3-a]isoquinoline derivatives were pre-
pared and their conformational behaviour was examined.8
and 6,7-dimethoxy-3,4-dihydroisoquinoline to furnish 9,10-
dimethoxynaphth[1,2-e][1,3]oxazino[2,3-a]isoquinolines under
microwave (MW) irradiation.9 A Russian research group later
synthesized this compound and a couple of 15-aryl derivatives
from the corresponding 1-dimethylaminomethyl-2-naphthols and
6,7-dimethoxy-3,4-dihydroisoquinoline.10
It is the major aim of this paper to extend this recent reaction
but starting from 3,4-dihydroisoquinoline, to examine the scope
and limitations when starting from 3,4-dihydroisoquinolines and
2-aminomethyl-1-naphthol analogues11 (reverse Betti bases), and
to study the obtained conformationally flexible ring system by
means of NMR spectroscopy and accompanying theoretical calcu-
lations at the DFT level of theory.
2. Results and discussion
2.1. Syntheses
For the synthesis of the model compounds 3 and 7 (cf. Table 1),
the previously published synthetic method9 was applied, starting
from 1-aminomethyl-2-naphthol (1a) or 1-aminobenzyl-2-naphthol
* Corresponding authors. Fax: þ36 62545705 (F.F.); þ49 331977 5064 (E.K.);
€ €
e-mail addresses: fulop@pharm.u-szeged.hu (F. Fulop), ekleinp@uni-potsdam.de
(E. Kleinpeter).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.094

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I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7456
Table 1
Reaction conditions for the preparation of naphth[1,2-e][1,3]oxazino[2,3-a]isoquinolines 3e12
R1
NH2 HCl
OH
R2
R2
R2
R2
R1
N
i
+
N
Et3N
O
R2 = MeO: 2a, H: 2b
1a-e
1
a
b
c
R = H: ; Me: ; Ph:
;
3-12
d
e
4-Cl-C6H4: ; 4-MeO-C6H4:
Entry
Product
R1
R2
Conditions (i)
Diastereomeric ratioa
trans/cis
Yield (%)
1
2
3
4
5
6
7
8
9
3
4
5
6
7
8
9
10
11
12
H
H
Me
Me
Ph
Ph
MeO
H
MeO
H
MeO
H
MeO
H
100 ꢀC, 90 min
90 ꢀC, 70 min
80 ꢀC, 60 min
80 ꢀC, 45 min
100 ꢀC, 90 min
90 ꢀC, 75 min
100 ꢀC, 90 min
100 ꢀC, 60 min
100 ꢀC, 100 min
100 ꢀC, 60 min
d
73
75
67
74
82
87
72
68
85
77
d
b
98:2
99.7:0.3
99.6:0.4
99.6:0.4
99.6:0.4
99.6:0.4
99.7:0.3
4-CleC6H4
4-CleC6H4
4-MeOeC6H4
4-MeOeC6H4
MeO
H
10
a
Determined from the 1H NMR spectrum of the crude product.
Not detected due to strong overlapping.
b
(1c) and 6,7-dimethoxy-3,4-dihydroisoquinoline (2a). To examine
the possibility of extending the reaction, 2a as starting material was
replaced by 3,4-dihydroisoquinoline (2b). The reaction led to the
formation of naphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline 4 and
15-phenylnaphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline 8 (Table 1,
entries 2 and 6). The scope of the reaction was further tested by using
different substituted 1-aminobenzyl-2-naphthol derivatives, such
as 1-(1-aminoethyl)-2-naphthol (1b), 1-amino-(4-chlorophenyl)
methyl-2-naphthol (1d) and 1-amino-(4-methoxyphenyl)methyl-2-
naphthol (1e). Their reaction either with 2a or with 2b yielded the
desired naphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline derivatives in
good yields (Table 1). It should be mentioned that the syntheses of
9,10-dimethoxy derivatives 3, 5, 7, 9 and 11 usually required longer
reaction times than those for the 9,10-unsubstituted analogues 4, 6,
8, 10 and 12 (Table 1).
Scope and limitations of the reaction were additionally tested by
using substituted 2-aminobenzyl-1-naphthol analogues (reverse
Betti bases: 13aed). It could be concluded that somewhat lower
temperatures (70 ꢀC) were adequate for the syntheses of 15-alkyl-
substituted naphth[2,1-e][1,3]oxazino[2,3-a]isoquinolines (Table 2,
entries 1 and 2) than for their 15-aryl analogues (Table 2, entries
3e10).
The conformational search protocol involved PM3 geometry
minimization, followed by geometry optimization without re-
strictions. All calculations were carried out by using the Gaussian
09 program package.12 Different conformations of the studied
compounds were preoptimized by using the PM3 Hamiltonian.
Density functional theory calculations were carried out at the
B3LYP/6-311G** level of theory.13,14
For the 15-substituted naphth[1,2-e][1,3]oxazino[2,3-a]iso-
quinoline derivatives (5e12), the diastereomeric ratios obtained
experimentally (Table 1) agreed excellently with the energy dif-
ferences calculated for the two diastereomers (Tables 3 and 4): the
energy difference between the diastereomers was ca. 3.8 kcal/mol
and 0e2% of the minor (cis) form was detected experimentally.
For the 15-substituted naphth[2,1-e][1,3]oxazino[2,3-a]iso-
quinolines (14e21), with the exception of the isopropyl derivative
(where the presence of the minor diastereomer could not be
detected experimentally and the calculated energy differences
were found to be 3.88 kcal/mol and 3.91 kcal/mol, respectively),
a more significant amount of the minor diastereomer(s) was ob-
served (7e21% for 14e17, 20 and 21: Table 2) and relative low en-
ergy differences (1.33e1.51 kcal/mol: Tables
5 and 6) were
computed. The 1-naphthyl substituent in 18 and 19 is restricted in
its rotation and, because of this additional chiral axis, atropisomers
result. Thus, the latter two compounds are expected to give four
diastereomers. Actually, for 18 and for 19 three components were
detected by NMR (Table 2). This is in accordance with theoretical
calculations, performed for 19, where four isomers were found to
have low energies: (15(S),14(R),7a(R),15(P), 15(R),14(S),7a(R),15(P),
15(R),14(S),7a(R),15(M), and 15(R),14(R),7a(R),15(P); see Fig. 1),
whereas the latter two differ only in their configuration at the ni-
trogen atom, which can rapidly invert (see below) to give only one
set of signals in the NMR spectrum.
To identify the configurations of the minor components of 19
found by NMR in solution, the chemical shift differences of some se-
lected nuclei between the major trans component (15(S),7a(R),15(P)-
19) and the minor components were calculated theoretically and
compared with the experimental data (see Table 7). The results were
in good agreement with the computations, and it could be concluded
that the minor component in an amount of 8.2% has the configuration
2.2. Structural analysis
The comparison of the diastereomeric ratios (trans and cis: as
concerns the relative intensity of the H-7a and H-15 proton NMR
signals) for the two sets of compounds indicates that the diaster-
eoselectivity of the latter reaction seems to differ depending on the
annelation type of the naphthyl ring (5e12 vs 14e21) and the
substituent R1 at position 15. To explain the different ratios in the
two naphth[1,3]oxazino[2,3-a]isoquinoline ring systems, full ge-
ometry optimization of the compounds studied was performed by
using DFT calculations. The ring systems of 3e12 and 14e21, re-
spectively, contain invertible N atoms. As regards both the R and the
S configurations of N-14, C-7a and C-15, all the isomers/enantio-
mers were considered in the DFT calculations; the energy differ-
ences (DE) obtained for the lowest-energy conformers for each
configuration are listed in Tables 3e6.

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I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7457
Table 2
Reaction conditions for the preparation of naphth[2,1-e][1,3]oxazino[2,3-a]isoquinolines 14e21
R2
R2
R1
NH2 HCl
OH
R1
N
R2
R2
i
O
+
N
Et3N
R2 = MeO: 2a, H: 2b
13a-d
R1 = i-Pr: ; Ph:
;
d
a
b
14-21
c
1-Nph: ; 2-Nph:
Entry
Product
R1
R2
Conditions (i)
Diastereomeric ratioa
trans/cis
Yield (%)
1
2
3
4
5
6
7
10
14
15
16
17
18
19
20
21
i-Pr
i-Pr
Ph
OMe
H
OMe
H
OMe
H
OMe
H
70 ꢀC, 40 min
70 ꢀC, 40 min
90 ꢀC, 60 min
90 ꢀC, 60 min
85 ꢀC, 75 min
85 ꢀC, 60 min
85 ꢀC, 75 min
85 ꢀC, 60 min
100:0
100:0
82:18
67
72
75
83
65
77
70
74
Ph
79:21
b
1-Nph
1-Nph
2-Nph
2-Nph
b
83:17
79:21
a
Determined from the 1H NMR spectrum of the crude product.
More than two diastereomers; 18: 92.9:5.8:1.3; 19: 89.4:8.2:2.4.
b
Table 3
Calculated energy differences for 3, 5, 7, 9 and 11 in kcal/mol
12
11
11a
7b
OMe
OMe
10
9
13
R
14N
15a
15
7a
8
1
4
15b
O7
2
3
6a
6
4a
5
3
5
7
9
11
R¼H
R¼Me
R¼Ph
R¼4-CleC6H4
R¼4eMeOeC6H4
d
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
G1a
0.0
G2b
1.26
Gct1
0.0
Gdt2
3.26
Gec1
3.84
Gfc2
5.83
Gct1
0.0
Gdt2
3.44
Gec1
3.68
Gfc2
4.90
Gct1
0.0
Gdt2
3.67
Gec1
3.78
Gfc2
5.11
Gct1
0.0
Gdt2
3.35
Gec1
3.58
Gfc2
4.78
Corresponding to the following configurations: a14(R),7a(R), b14(S),7a(R), c15(S),14(R),7a(R), d15(S),14(S),7a(R), e15(S),14(R),7a(S) and f15(S),14(S),7a(S).
Table 4
Calculated energy differences for 4, 6, 8, 10, and 12 in kcal/mol
12
11
8
11a
7b
10
9
13
R
14N
15a
15
7a
1
4
15b
O
7
2
3
6a
6
4a
5
4
6
8
10
12
R¼H
R¼Me
R¼Ph
R¼4-CleC6H4
R¼4-MeOeC6H4
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
G1a
0.0
G2b
1.42
Gct1
0.0
Gdt2
3.41
Gec1
3.87
Gfc2
5.81
Gct1
0.0
Gdt2
3.51
Gec1
3.79
Gfc2
4.85
Gct1
0.0
Gdt2
3.76
Gec1
3.85
Gfc2
5.11
Gct1
0.0
Gdt2
3.72
Gec1
3.98
Gfc2
5.03
Corresponding to the following configurations: a14(R),7a(R), b14(S),7a(R), c15(S),14(R),7a(R), d15(S),14(S),7a(R), e15(S),14(R),7a(S) and f15(S),14(S),7a(S).
15(R),7a(R),15(P), while the component in an amount of 2.4% has the
configuration 15(R),7a(R),15(M). Thus, both minor components are cis
isomers.
In the NMR spectra of 3 and 4, line broadenings due to dynamic
interconversion (mutual exchange of the two diastereotopic protons
H-15) were observed. The experimentally estimated free energies of
this dynamic process were found to be
D
G# (at 343 K)¼16.2 kcal/mol
for 3 and
DG
# (at 368 K)¼17.4 kcal/mol for 4. Our first assumption
was that the appropriate dynamic process may have involved
combined N-inversion/ring inversion processes and the reaction

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I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
Table 5
Calculated energy differences for 14, 16, 18 and 20 in kcal/mol
14
16
18
20
R¼i-Pr
R¼Ph
R¼1-Nph
R¼2-Nph
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
Gat1
0.0
Gbt2
3.89
Gcc1
3.88
Gdc2
4.87
Gat1
0.0
Gbt2
3.27
Gcc1
1.33
Gdc2
2.84
Gat1
Gbt2
Gcc1
Gdc2
Gat1
0.0
Gbt2
3.90
Gcc1
1.43
Gdc2
3.39
0.0e
4.78f
1.46e
2.55f
Corresponding to the following configurations: a15(S),14(R),7a(R), b15(S),14(S),7a(R), c15(S),14(R),7a(S) and d15(S),14(S),7a(S), e15P rotamer and f15M rotamer.
Table 6
Calculated energy differences for 15, 17, 19 and 21 in kcal/mol
15
17
19
21
R¼i-Pr
R¼Ph
R¼1-Nph
R¼2-Nph
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
trans (B)
cis (C)
Gat1
0.0
Gbt2
3.38
Gcc1
3.91
Gdc2
4.86
Gat1
0.0
Gbt2
3.29
Gcc1
1.42
Gdc2
2.77
Gat1
Gbt2
Gcc1
Gdc2
Gat1
0.0
Gbt2
3.91
Gcc1
1.51
Gdc2
3.25
0.0e
4.89f
4.85f
7.01e
1.50e
2.51f
2.53f
4.99e
f
Corresponding to the following configurations: a15(S),14(R),7a(R), b15(S),14(S),7a(R), c15(R),14(S),7a(R), d15(R),14(R),7a(R), e15P rotamer and 15M rotamer.
coordinate of this dynamic process was searched for employing
theoretical calculations. The transition state energies of 3 and 4 were
computed at the MP2/6311G** level,15 including solvent effects16 of
DMF. For this purpose the Self-Consistent Reaction Field with the
Polarized Continuum Model using the Integral Equation Formalism
(SCRF IEF-PCM) approach was used. The molecular modelling soft-
ware package SYBYL 7.317 was used to display results and geome-
tries. Theoretical calculations of solely the nitrogen inversion as the
dynamic process gave a difference between the ground and transi-
tion states of only 8.2 kcal/mol for 3 and 8.1 kcal/mol for 4 (Fig. 2).
These values are much too small to explain the dynamic behaviour
observed experimentally.
the studied compounds. This led us to further questions: (i) Is there
an exchange process between the diastereomers in 5e12 as well,
(ii) is it the same dynamic process that occurs in 14e21 and (iii)
what is the mechanism (reaction coordinate) of the exchange
process between the diastereomers? As a start, the careful exami-
nation of the NOESY spectra of 5e12 revealed several exchange
peaks. Thus, the diastereomers, though with very different ratios
than those for 16e21 (see Table 2), should be included in the ex-
change process as observed for 14e21.
For 16, 17, 20 and 21 the dynamic process (mutual exchange of
the two isomers) at elevated temperatures could be studied in
detail (cf. Table 8). The structures of the exchanging isomers were
investigated by stereochemical analysis of two compounds as ex-
amples (vide supra). For 15, which was found to be not a mixture of
diastereomers, the NOESY signals were integrated and related.
From a comparison of the volume integrals, with the assumption of
The literature values of
inversion are in fact higher than our calculated values, e.g., for cis-
D
G# for nitrogen inversion and/or ring
decalin (
D
G# (at 255 K)¼12.85 kcal/mol)18 and azabicycles (qui-
nolizidine derivatives) with a bridgehead nitrogen such as buta-
G# (at 200 K)¼9.6 kcal/mol),19 or the synthetic alkaloid
a distance of 2.5 A between two neighbouring aromatic protons,
ꢁ
clamol (
D
14-(R)-hydroxymarcfortine A (
they are still too small in comparison with the observed dynamic
process.
D
G
# (at 228 K)¼11.5 kcal/mol),20 but
rough distances between other protons can be estimated. These
ꢁ
ꢁ
were found to be 3.8 A between H-7a and H-15, 2.3 A between H-7a
0
ꢁ
and the isopropyl proton H-1 , and 2.2 A between H-15 and the
pseudoequatorial H-13. This is in good agreement with quantum
theoretically calculated distances for the trans isomer (3.6, 2.1 and
In continuation of our investigations with the naphth[2,1-e]
[1,3]-oxazino[2,3-a]isoquinolines 14e21, it was of special interest
that the room temperature NOESY spectra showed not only the
expected NOE signals, but also several others, probably exchange
peaks between the different isomers in 16e21. Especially H-7a and
H-15 are involved in this potential dynamic process and this in all of
ꢁ
2.2 A, respectively). Thus, the trans diastereomer is the preferred
configuration for 15 as suggested previously (cf. Table 2). The same
procedure was carried out for 17 at low temperature (193 K) to
avoid rapid chemical exchange, which can distort the integration.

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I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7459
Fig. 1. Four isomers of 19 with lowest energies: (a) 15(S),14(R),7a(R),15(P)d0.00 kcal molꢁ1; (b) 15(R),14(S),7a(R),15(P)d1.50 kcal molꢁ1; (c) 15(R),14(S),7a(R),15(M)d2.51 kcal molꢁ1
and (d) 15(R),14(R),7a(R),15(M)d2.53 kcal molꢁ1
.
Table 7
and C-15), which can only occur via an open-chain intermediate (A)
according to Scheme 1.
From the comparison of the experimentally determined di-
astereomeric ratios for naphth[1,2-e][1,3]oxazino[2,3-a]isoquino-
lines (5e12: Table 1) and naphth[2,1-e][1,3]oxazino[2,3-a]
isoquinolines (14e21: Table 2), it can be concluded that the free or
Selected chemical shift differences (calculation vs experiment) between the two
observed minor cis components and the major trans component of 19
Dd H7a (ppm) Dd H15 (ppm) Dd C7a (ppm) Dd C15 (ppm)
Exp.
-19 ꢁ0.01 ꢁ0.13 ꢁ0.47 ꢁ0.32 7.5
-19 0.16 0.12 0.37 0.84 6.7
Calcd Exp.
Calcd Exp. Calcd Exp. Calcd
15R
15R
*
,7aR
*
*
,15P
*
6.6
5.7
9.2
ꢁ0.8 ꢁ2.4
8.5
hindered rotation around the
s bond C-15aeC-15 in form A is
*
,7aR
,15M
*
crucial for the diastereomeric composition (B and C) after equili-
bration during the dynamic process. It should also be noted that the
ratios of B and C differ within the series 14e21, depending on the
steric bulkiness of the substituent at position 15 (Table 2). Less
hindered rotation occurs with phenyl (16 and 17) or 2-naphthyl (20
and 21), resulting in the presence of around 20% of form C, while
for the bulkier isopropyl (14 and 15), form C cannot be detected
(Table 2).
Table 8
Experimental dynamic NMR measurement data for 16, 17, 20 and 21a
Compound
Temperature (K)
D
G#(1)b (kcal/mol)
D
G#(2)c (kcal/mol)
16
17
20
21
318
368
328
378
17.8
20.1
17.6
20.2
16.8
19.1
16.7
19.5
The dynamic process for 17 was computed at the B3LYP/6-
311G** level, including SCRF IEF-PCM (dichloromethane) geometry
optimization, to find transition states between the ground states
(B and C) and the intermediate chain form A (Fig. 2). The transition
state search protocol was as follows: set the trans form (17B with
the geometry Gt1), ring opening (breaking bond OeC15), set the
CH]N bond in-plane and rotation around C15eN/TS1 (19.28 kcal/
mol); simultaneously, rotation around C15aeC15, C15ePh and
C15eN/metastable chain conformation (17A, 14.67 kcal/mol);
back-rotation around C15aeC15 and C15ePh/TS2 (16.24 kcal/
mol); ring closure/cis form (17C, 1.46 kcal/mol). The computed
a
Solvent: C2D2Cl4; mutual exchange of H-15, calculated by iteration with the
DNMR module of TopSpin 3.0.
b
Trans/cis.
Cis/trans.
c
ꢁ
ꢁ
Here, a distance of 3.8 A (theoretically calculated 3.6 A) was found
ꢁ
between H-7a and H-15 for the major component, and 3.1 A (calcd
ꢁ
2.6 A) for the minor component. This is again enough experimental
evidence that the major component is the trans and the minor
component is the cis isomer (cf. Table 2) and it is in agreement with
the theoretical calculations.
The investigation of the dynamic exchange process for 16, 17, 20
and 21 revealed good agreement with the free energy of activation
of the already studied dynamic process observed for 3 and 4 (Table
8). Furthermore, the dynamic process ought to involve a configu-
rational isomerization (change of the relative configuration of C-7a
free energies of activation (D
G#) were found to be slightly lower
than the experimental values: 19.3 versus 20.1 kcal/mol for
trans/cis, and 17.8 versus 19.1 kcal/mol for cis/trans (Fig. 3).
Finally, it should be mentioned that the p-chlorophenyl (9) and
p-methoxyphenyl (11) derivatives exhibited another dynamic
process (a mutual exchange of the corresponding o-protons): a re-
stricted rotation about the aryleC-15 single bond.
D
G# for these

ꢀ
7460
I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
Scheme 1.
Fig. 2. Ground and transition states of the nitrogen inversion process of 4.
processes was found to be unusually high for o- and m-unsub-
stituted phenyl rings (10.5 kcal/mol at 223 K for 9, and 11.2 kcal/mol
at 238 K for 11, respectively, Table 9), but in the same range as for
sterically hindered bridgehead p-chlorophenyl groups in bulky
substituted tetrahydro-2H-pyrrolo[2,1-b][1,3]oxazin-6(7H)-ones.21
the trans (B) and cis (C) forms was observed in solution. The latter
processwasexplained withtheaid ofanisomerizationprotocolviaan
open-chain form (A). The energies of the transition states for this
process were determined through dynamic NMR measurements,
and those calculated by theoretical DFT computation were in good
agreement.
3. Conclusions
4. Experimental section
A series of novel unsubstituted and substituted napth[1,2-e][1,3]-
oxazino[2,3-a]isoquinolines (3e12) were prepared by the reaction
of 1-aminomethyl-2-naphthol or substituted 1-aminobenzyl-2-
naphthol derivatives with 3,4-dihydroisoquinolines. This process
was extended to the reaction of 2-aminomethyl-1-naphthol ana-
logues with 3,4-dihydroisoquinolines, leading to the annelation
analogue, substituted napth[2,1-e][1,3]oxazino[2,3-a]isoquinoline
derivatives (14e21). The stereochemistry was studied by NMR spec-
troscopy and accompanying molecular modelling. It was found that
for all the compounds the most stable diastereomer displayed the
trans (B) arrangement of H-15 and H-7a, which was also indicated by
the DFT geometry optimization. Furthermore, for substituted napth-
[2,1-e][1,3]oxazino[2,3-a]isoquinolines, a dynamic process between
Melting points were determined on a Hinotek-X4 micro melting
apparatus and are uncorrected. Elemental analyses were performed
with a PerkineElmer 2400 CHNS elemental analyser. Merck Kie-
selgel 60F254 plates were used for TLC.
The 1H and 13C NMR spectra were recorded in CD2Cl2 solutions in
5 mm tubes, at room temperature, on a Bruker Avance III spectrom-
eterat600.24 (1H)and 150.93 (13C) MHz, with the deuterium signalof
the solvent as the lock and TMS (for 1H) or the solvent (53.7 ppm for
13C)asinternalstandard.Allspectra(1H,13C,gs-H, HeCOSY, gs-HMQC,
gs-HMBC andNOESY)wereacquiredand processedwiththestandard
BRUKER22 software. The PERCH program was used for iterational
analysis of some higher-order spin systems.23

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I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7461
Fig. 3. Ground and transition states of the isomerization process of 17 via the chain form (17A).
Table 9
(60 mg, 0.6 mmol) in 1,4-dioxane (5 mL) was placed in a 10 mL
reaction vial and heated in a CEM LabMate microwave reactor
under the microwave conditions given depicted in Tables 1 and 2.
The solvent was then evaporated off and the crude product was
crystallized with cold EtOH (8e12 mL), filtered off and recrystal-
lized from EtOH (11e15 mL).
Experimental dynamic NMR data for 3, 4, 9 and 11a
Compound Solvent Position Tc (K) Dnc (Hz) k (Hz)
DG
# (kcal/mol)
3
4
9
11
C2D2Cl4 H-15
343
368
223
238
122
106
641
617
285
252
1423
1370
16.2
17.4
10.5
11.2
DMF-d7 H-15
CD2Cl2
CD2Cl2
H-20
H-20
a
Calculated using the coalescence method.
4.2. 9,10-Dimethoxynaphth[1,2-e][1,3]oxazino[2,3-a]iso-
quinoline (3)
Mp: 191e194 ꢀC (lit.:10 186e187 ꢀC). 1H NMR (600 MHz):
d 7.78
For dynamic NMR spectroscopy, the probe temperature was
calibrated by means of a PT 100 thermocouple inserted into
a dummy tube. The temperature measurements were estimated to
be accurate to ꢂ2 K. The chemical shift difference Dnc (in Hz) was
determined by extrapolation from lower temperatures to Tc used to
(dt, J¼8.1, 1.2 Hz, 1H, H-4), 7.67 (dq, J¼8.4, 0.9 Hz, 1H, H-1), 7.65 (d,
J¼8.8 Hz, 1H, H-5), 7.50 (ddd, J¼8.3, 6.9, 1.2 Hz, 1H, H-2), 7.36 (ddd,
J¼8.1, 6.9, 0.9 Hz, 1H, H-3), 7.03 (d, J¼8.8 Hz, 1H, H-6), 6.93 (s, 1H,
H-8), 6.69 (s, 1H, H-11), 5.70 (s, 1H, H-7a), 4.73 (d, J¼15.4 Hz, 1H,
H-15), 4.26 (d, J¼15.5 Hz, 1H, H-15), 3.86 (s, 3H, 9-OMe), 3.84 (s, 3H,
10-OMe), 3.32 (m, 1H, H-13), 3.03 (m, 1H, H-12), 2.85 (m, 1H, H-13),
calculate kc and the
D
G# by the Eyring equation at Tc. To calculate
DG
# for the dynamic process in 16, 17, 20 and 21, the DNMR module
2.81 (m, 1H, H-12); 13C NMR (150 MHz):
d 151.8 (C-6a), 149.8 (C-10),
in TopSpin 3.022 was used. Variable temperature measurements
were made on a Bruker AVANCE spectrometer at 300.13 MHz or on
a Bruker AVANCE III spectrometer at 600.24 MHz.
147.9 (C-9),131.8 (C-15b),129.1 (C-4a),128.7 (C-4),128.2 (C-5),127.7
(C-11a), 126.7 (C-2), 125.4 (C-7b), 123.6 (C-3), 121.4 (C-1), 118.8
(C-6), 111.5 (C-15a), 111.4 (C-11), 111.3 (C-8), 87.1 (C-7a), 56.2
(9-OMe), 56.0 (10-OMe), 51.5 (C-15), 45.4 (C-13), 28.9 (C-12). Anal.
Calcd for C22H21NO3 (347.41): C, 76.06; H, 6.09; N, 4.03. Found: C,
76.15; H, 6.02; N, 4.07.
The following starting aminonaphthol derivatives were pre-
pared by literature methods:
1-Aminomethyl-2-naphthol (1a),24 1-(1-aminoethyl)-2-naphthol
(1b),25 1-aminobenzyl-2-naphthol (1c),24 1-amino-(4-chlorophenyl)
methyl-2-naphthol (1d),22 1-amino-(4-methoxyphenyl)methyl-2-
naphthol (1e),24 2-amino-(isopropyl)methyl-1-naphthol (13a),26 2-
aminobenzyl-1-naphthol (13b),11 2-amino-(naphth-1-yl)methyl-1-
naphthol (13c)27 and 2-amino-(naphth-2-yl)methyl-1-naphthol
(13d).27
4.3. Naphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline (4)
Mp: 176e178 ꢀC. 1H NMR (600 MHz):
d
7.77 (dt, J¼8.1, 1.1 Hz, 1H,
H-4), 7.67 (dq, J¼8.4, 1.1 Hz, 1H, H-1), 7.64 (d, J¼8.8 Hz, 1H, H-5),
7.50 (ddd, J¼8.3, 6.9, 1.2 Hz, 1H, H-2), 7.43 (dd, J¼7.7, 1.2 Hz, 1H,
H-8), 7.36 (ddd, J¼8.1, 6.9, 1.2 Hz, 1H, H-3), 7.32 (td, J¼7.6, 1.3 Hz, 1H,
H-10), 7.28 (tt, J¼7.6, 0.7 Hz, 1H, H-9), 7.21 (br d, J¼7.7 Hz, 1H, H-11),
7.02 (d, J¼8.8 Hz, 1H, H-6), 5.77 (s, 1H, H-7a), 4.74 (d, J¼14.7 Hz, 1H,
H-15), 4.27 (d, J¼14.7 Hz, 1H, H-15), 3.35 (m, 1H, H-13), 3.12 (m, 1H,
4.1. General procedure for the synthesis of naphth[1,2-e][1,3]
oxazino[2,3-a]isoquinolines and naphth[2,1-e][1,3]oxazino
[2,3-a]isoquinolines
H-12), 2.88 (m, 2H, H-12 and H-13); 13C NMR (150 MHz):
d 151.8
The mixture of the appropriate aminonaphtholhydrochloride
(C-6a), 135.4 (C-11a), 133.4 (C-7b), 131.8 (C-15b), 129.2 (C-4a), 128.9
(C-10), 128.9 (C-11), 128.8 (C-4), 128.5 (C-8), 128.2 (C-5), 126.7 (C-2),
126.3 (C-9), 123.6 (C-3), 121.4 (C-1), 118.9 (C-6), 111.5 (C-15a), 87.1
(0.44
mmol),
6,7-dimethoxy-3,4-dihydroisoquinoline
(2a,
0.4 mmol) or 3,4-dihydroisoquinoline (2b, 0.4 mmol) and Et3N

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I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7462
(C-7a), 51.4 (C-15), 45.3 (C-13), 29.3 (C-12). Anal. Calcd for
20H17NO (287.36): C, 83.59; H, 5.96; N, 4.87. Found: C, 83.65; H,
5.91; N, 4.81.
(10-OMe), 45.6 (C-13), 29.1 (C-12). Anal. Calcd for C28H25NO3
(423.50): C, 79.41; H, 5.95; N, 3.31. Found: C, 79.49; H, 5.91; N, 3.37.
C
4.9. (7aR
*
,15R )-9,10-Dimethoxy-15-phenylnaphth[1,2-e][1,3]
*
oxazino[2,3-a]isoquinoline (7C)
4.4. (7aR
*
,15S )-9,10-Dimethoxy-15-methylnaphth[1,2-e][1,3]
*
oxazino[2,3-a]isoquinoline (5B)
1H NMR (600 MHz):
d 5.44 (from EXSY, H-7a), 5.23 (s, H-15).
Mp: 179e181 ꢀC. 1H NMR (600 MHz):
d
7.78 (d, J¼8.5 Hz, 1H,
4.10. (7aR ,15S )-15-Phenylnaphth[1,2-e][1,3]oxazino[2,3-a]
*
*
H-1), 7.75 (d, J¼8.0 Hz, 1H, H-4), 7.62 (d, J¼8.9 Hz, 1H, H-5), 7.49
(br t, J¼7.9 Hz, 1H, H-2), 7.32 (t, J¼7.8 Hz, 1H, H-3), 6.98 (d, J¼8.8 Hz,
1H, H-6), 6.95 (s, 1H, H-8), 6.68 (s, 1H, H-11), 5.99 (s, 1H, H-7a), 4.42
(q, J¼6.9 Hz, 1H, H-15), 3.88 (s, 3H, 9-OMe), 3.84 (s, 3H, 10-OMe),
3.16 (from PERCH, ddd, J¼ꢁ11.3, 12.4, 4.1, 1H, H-13ax), 3.08 (from
PERCH, ddd, J¼ꢁ16.1, 12.4, 6.4, 1H, H-12ax), 2.82 (from PERCH, ddd,
J¼ꢁ11.3, 6.4, 1.4, 1H, H-13eq), 2.70 (from PERCH, ddd, J¼ꢁ16.1, 4.1,
1.4, 1H, H-12eq), 1.73 (d, J¼7.0 Hz, 3H, Me); 13C NMR (150 MHz):
isoquinoline (8B)
Mp: 231e234 ꢀC. 1H NMR (600 MHz):
d
7.78 (d, J¼7.7 Hz, 1H,
H-4), 7.75 (d, J¼8.9 Hz, 1H, H-5), 7.41 (d, J¼8.9 Hz, 1H, H-1),
7.34e7.18 (m, 10H, H-2, H-3, H-8, H-10, H-11, H-20, H-30 and H-40),
7.20 (t, J¼7.9 Hz, 1H, H-9), 7.08 (d, J¼8.9 Hz, 1H, H-6), 5.63 (s, 1H,
H-7a), 5.45 (s, 1H, H-15), 3.29 (m, 2H, H-12ax and H-13ax), 3.11 (m,
1H, H-13eq), 2.85 (m, 1H, H-12eq); 13C NMR (150 MHz):
d 152.2
d
150.8 (C-6a), 150.0 (C-10), 147.9 (C-9), 132.0 (C-15b), 129.4 (C-4a),
(C-6a), 142.8 (C-10), 135.4 (C-11a), 133.3 (C-7b), 132.6 (C-15b), 129.6
(C-20), 129.3 (C-5), 129.2 (C-4a), 129.0, 128.9, 128.9 (C-8, C-10 and
C-11), 128.8 (C-4), 128.4 (C-30), 127.7 (C-40), 126.7 (C-2), 126.2 (C-9),
123.4 (C-3), 122.9 (C-1), 119.0 (C-6), 111.2 (C-15a), 82.4 (C-7a), 62.9
(C-15), 45.6 (C-13), 29.5 (C-12). Anal. Calcd for C26H21NO (363.45):
C, 85.92; H, 5.82; N, 3.85. Found: C, 85.88; H, 5.87; N, 3.81.
128.9 (C-4), 128.4 (C-5), 127.9 (C-11a), 126.6 (C-2), 125.5 (C-7b),
123.2 (C-3), 122.0 (C-1), 118.9 (C-6), 115.8 (C-15a), 112.0 (C-8), 111.6
(C-11), 82.0 (C-7a), 56.2 (9-OMe), 56.1 (10-OMe), 54.8 (C-15), 45.5
(C-13), 29.1 (C-12), 22.9 (Me). Anal. Calcd for C23H23NO3 (361.43): C,
76.43; H, 6.41; N, 3.88. Found: C, 76.37; H, 6.45; N, 3.92.
4.5. (7aR
*
,15R )-9,10-Dimethoxy-15-methylnaphth[1,2-e][1,3]
*
4.11. (7aR
*
,15S )-15-Phenylnaphth[1,2-e][1,3]oxazino[2,3-a]
*
oxazino[2,3-a]isoquinoline (5C)
isoquinoline (8C)
1H NMR (600 MHz):
d 5.99 (s, H-7a), 4.27 (from EXSY, H-15).
1H NMR (600 MHz):
d 5.53 (s, H-7a), 5.25 (s, H-15).
4.6. (7aR ,15S )-15-Methylnaphth[1,2-e][1,3]oxazino[2,3-a]
*
*
4.12. (7aR
*
,15S )-9,10-Dimethoxy-15-(4-chlorophenyl)naphth
*
isoquinoline (6B)
[1,2-e][1,3]oxazino[2,3-a]isoquinoline (9B)
Mp: 178e180 ꢀC. 1H NMR (600 MHz):
d
7.70 (d, J¼8.5 Hz, 1H,
Mp: 154e156 ꢀC. 1H NMR (600 MHz):
d
7.79 (d, J¼7.8 Hz, 1H,
H-1), 7.66 (d, J¼8.1 Hz,1H, H-4), 7.54 (d, J¼8.9 Hz,1H, H-5), 7.40 (dd,
J¼8.4, 6.9 Hz, 1H, H-2), 7.36 (dd, J¼7.4, 1.5 Hz, 1H, H-8), 7.24 (br t,
J¼7.5 Hz, 1H, H-3), 7.24 (td, J¼7.5, 1.4 Hz, 1H, H-10), 7.20 (t, J¼7.3 Hz,
br, 1H, H-9), 7.12 (d, J¼7.4 Hz, 1H, H-11), 6.88 (d, J¼8.9 Hz, 1H, H-6),
5.98 (s, 1H, H-7a), 4.34 (q, J¼6.9 Hz, 1H, H-15), 3.09 (m, 2H, H-12
and H-13), 2.74 (m, 2H, H-12 and H-13), 1.65 (d, J¼6.9 Hz, 3H, Me);
H-4), 7.76 (d, J¼8.9 Hz, 1H, H-5), 7.37 (d, J¼8.0 Hz, 1H, H-1), 7.33
(br t, J¼7.5 Hz, 1H, H-2), 7.30 (br t, J¼7.4 Hz, 1H, H-3), 7.25 (m, 4H,
H-20 and H-30), 7.08 (d, J¼8.9 Hz, 1H, H-6), 6.77 (s, 1H, H-8), 6.67 (s,
1H, H-11), 5.49 (s, 1H, H-7a), 5.40 (s, 1H, H-15), 3.82 (s, 3H, 10-OMe),
3.79 (s, 3H, 9-OMe), 3.27 (m, 1H, H-13ax), 3.18 (ddd, J¼15.7, 12.3,
6.1 Hz, 1H, H-12ax), 3.08 (dd, J¼10.8, 6.1 Hz, 1H, H-13eq), 2.76 (dd,
13C NMR (150 MHz):
d 150.7 (C-6a), 135.6 (C-11a), 133.5 (C-7b),
J¼15.8, 3.4 Hz, 1H, H-12eq); 13C NMR (150 MHz):
d 152.3 (C-6a),
132.0 (C-15b), 129.4 (C-4a), 129.1 (C-8), 129.1 (C-10), 129.0 (2C, C-4
and C-11), 128.5 (C-5), 126.6 (C-2), 126.3 (C-9), 123.3 (C-3), 122.0
(C-1), 119.0 (C-6), 115.9 (C-15a), 82.1 (C-7a), 54.8 (C-15), 45.4 (C-13),
29.4 (C-12), 22.9 (Me). Anal. Calcd for C21H19NO (301.38): C, 83.69;
H, 6.35; N, 4.65. Found: C, 83.75; H, 6.31; N, 4.67.
149.9 (C-10), 147.8 (C-9), 141.5 (C-10), 133.3 (C-40), 132.5 (C-15b),
131.0 (C-20), 129.6 (C-5), 129.2 (C-4a), 128.8 (C-4), 128.5 (C-30), 127.6
(C-11a), 126.9 (C-2), 125.1 (C-7b), 123.5 (C-3), 122.7 (C-1), 119.0
(C-6), 111.6 (C-8), 111.5 (C-11), 110.6 (C-15a), 82.3 (C-7a), 62.1 (C-15),
56.1 (9-OMe), 56.0 (10-OMe), 45.5 (C-13), 29.1 (C-12). Anal. Calcd
for C28H24ClNO3 (457.95): C, 73.44; H, 5.28; N, 3.06. Found: C, 73.52;
H, 5.33; N, 3.08.
4.7. (7aR
*
,15R )-15-Methylnaphth[1,2-e][1,3]oxazino[2,3-a]
*
isoquinoline (6C)
4.13. (7aR
*
,15R )-9,10-Dimethoxy-15-(4-chlorophenyl)naphth
*
1H NMR (600 MHz):
d 5.11 (s, H-7a), 4.25 (from EXSY, H-15).
[1,2-e][1,3]oxazino[2,3-a]isoquinoline (9C)
4.8. (7aR
*
*
,15S )-9,10-Dimethoxy-15-phenylnaphth[1,2-e][1,3]
1H NMR (600 MHz):
d 5.39 (from EXSY, H-7a), 5.22 (s, H-15).
oxazino[2,3-a]isoquinoline (7B)
4.14. (7aR ,15S )-15-(4-Chlorophenyl)naphth[1,2-e][1,3]ox-
*
*
Mp: 182e184 ꢀC (Lit.:10 155e156 ꢀC). 1H NMR (600 MHz):
d
7.78
azino[2,3-a]isoquinoline (10B)
(d, J¼7.5 Hz, 1H, H-4), 7.75 (d, J¼8.9 Hz, 1H, H-5), 7.40 (d, J¼8.0 Hz,
1H, H-1), 7.33e7.22 (m, 7H, H-2, H-3, H-20, H-30, and H-40), 7.09 (d,
J¼8.9 Hz,1H, H-6), 6.78 (s,1H, H-8), 6.67 (s,1H, H-11), 5.55 (s,1H, H-
7a), 5.44 (s, 1H, H-15), 3.81 (s, 3H, 10-OMe), 3.78 (s, 3H, 9-OMe),
3.28 (m, 1H, H-13ax), 3.18 (ddd, J¼15.7, 12.3, 6.2 Hz, 1H, H-12ax),
3.09 (dd, J¼10.8, 6.2 Hz, 1H, H-13eq), 2.76 (dd, J¼15.8, 3.5 Hz, 1H, H-
Mp: 186e189 ꢀC. 1H NMR (600 MHz):
d
7.79 (d, J¼8.0 Hz, 1H,
H-4), 7.75 (d, J¼8.9 Hz, 1H, H-5), 7.36 (m, 1H, H-1), 7.32 (m, 2H, H-2
and H-3), 7.30e7.22 (m, 7H, H-8, H-10, H-11, H-20 and H-30), 7.21
(m, 1H, H-9), 7.07 (d, J¼8.9 Hz, 1H, H-6), 5.57 (s, 1H, H-7a), 5.41
(s, 1H, H-15), 3.28 (m, 2H, H-12 and H-13), 3.10 (m, 1H, H-13), 2.85
12eq); 13C NMR (150 MHz):
d
152.3 (C-6a), 149.8 (C-10), 147.8 (C-9),
(m,1H, H-12); 13C NMR (150 MHz): 152.2 (C-6a),141.4 (C-10),135.3
d
142.9 (C-10), 132.6 (C-15b), 129.6 (C-20), 129.3 (C-5), 129.2 (C-4a),
128.8 (C-4), 128.4 (C-30), 127.6 (2C, C-11a and C-40), 126.7 (C-2),
125.2 (C-7b), 123.4 (C-3), 122.8 (C-1), 118.9 (C-6), 111.7 (C-8), 111.5
(C-11), 111.1 (C-15a), 82.3 (C-7a), 62.9 (C-15), 56.1 (9-OMe), 56.0
(C-11a), 133.4 (C-7b), 133.1 (C-40), 132.5 (C-15b), 131.1 (C-20), 129.6
(C-5), 129.2 (C-4a), 129.1, 129.0, 128.9 (C-8, C-10 and C-11), 128.8
(C-4), 128.5 (C-30), 126.9 (C-2), 126.3 (C-9), 123.5 (C-3), 122.7 (C-1),
119.0 (C-6), 110.7 (C-15a), 82.3 (C-7a), 62.1 (C-15), 45.5 (C-13), 29.5

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(C-12). Anal. Calcd for C26H20ClNO (397.90): C, 78.48; H, 5.07; N,
3.52. Found: C, 78.55; H, 5.13; N, 3.47.
(m,1H, H-10),1.14 (d, J¼6.7 Hz, 3H, H-20),1.05 (d, J¼6.7 Hz, 3H, H-20);
13C NMR (150 MHz):
d 149.8 (C-10), 149.4 (C-6b), 147.9 (C-9), 133.5
(C-2a), 128.3 (C-11a), 127.5 (C-3), 127.1 (C-1), 126.0 (C-4), 125.7
(C-7b), 125.2 (C-5), 125.0 (C-6a), 121.9 (C-6), 118.6 (C-2), 116.2
(C-15a), 112.2 (C-8), 111.3 (C-11), 84.5 (C-7a), 67.8 (C-15), 56.3
(9-OMe), 56.0 (10-OMe), 46.2 (C-13), 34.4 (C-10), 29.2 (C-12), 20.2
(C-20), 19.3 (C-20). Anal. Calcd for C25H27NO3 (389.49): C, 77.09; H,
6.99; N, 3.60. Found: C, 77.17; H, 6.91; N, 3.62.
4.15. (7aR
*
,15R )-15-(4-Chlorophenyl)naphth[1,2-e][1,3]ox-
*
azino[2,3-a]isoquinoline (10C)
1H NMR (600 MHz):
d 5.23 (s, H-15).
4.16. (7aR ,15S )-9,10-Dimethoxy-15-(4-methoxyphenyl)
*
*
naphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline (11B)
4.21. (7aR
*
,15S )-15-Isopropylnaphth[2,1-e][1,3]oxazino[2,3-a]
*
isoquinoline (15B)
Mp: 137e140 ꢀC (Lit.:10 182e184 ꢀC). 1H NMR (600 MHz):
d
7.78
(dd, J¼8.1, 1.3 Hz, 1H, H-4), 7.73 (d, J¼8.9 Hz, 1H, H-5),
7.42 (d, J¼8.2 Hz, 1H, H-1), 7.32 (ddd, J¼8.3, 6.8, 1.4 Hz, 1H, H-2),
7.28 (dd, J¼8.0, 6.8 Hz, 1H, H-3), 7.20 (br, 2H, H-20), 7.08 (d,
J¼8.9 Hz, 1H, H-6), 6.80 (d, J¼8.8 Hz, 2H, H-30), 6.78 (s, 1H, H-8),
6.67 (s, 1H, H-11), 5.56 (s, 1H, H-7a), 5.38 (s, 1H, H-15), 3.81 (s, 3H,
10-OMe), 3.79 (s, 3H, 9-OMe), 3.73 (s, 3H, 40-OMe), 3.25 (from
PERCH, ddd, J¼ꢁ11.3, 12.5, 4.1 Hz, 1H, H-13ax), 3.16 (from PERCH,
ddd, J¼ꢁ16.1, 12.5, 6.4 Hz, 1H, H-12ax), 3.07 (from PERCH, ddd,
J¼ꢁ11.3, 6.4, 1.3 Hz, 1H, H-13eq), 2.75 (from PERCH, ddd, J¼ꢁ16.1,
Mp: 119e120 ꢀC. 1H NMR (600 MHz):
d
8.08 (d, J¼8.2 Hz, 1H,
H-6), 7.75 (d, J¼8.0 Hz, 1H, H-3), 7.54 (d, J¼6.6 Hz, 1H, H-8), 7.42
(br t, J¼7.6 Hz, 1H, H-4), 7.35 (m, 4H, H-2, H-5, H-9, H-10), 7.25
(d, J¼8.5 Hz, 1H, H-1), 7.22 (d, J¼6.9 Hz,1H, H-11), 5.93 (s, 1H, H-7a),
3.43 (d, J¼7.4 Hz, 1H, H-15), 3.19 (m, 2H, H-12, H-13), 2.75 (m, 2H,
H-12, H-13), 2.20 (m, 1H, H-10), 1.14 (d, J¼6.7 Hz, 3H, H-20), 1.06 (d,
J¼6.7 Hz, 3H, H-20); 13C NMR (150 MHz):
d 128.9 (C-10 or C-11),
128.8 (C-10 or C-11), 149.4 (C-6b), 136.0 (C-11a), 133.7 (C-7b), 133.5
(C-2a), 129.4 (C-8), 127.5 (C-3), 127.2 (C-1), 126.3 (C-9), 126.1 (C-4),
125.2 (C-5), 125.0 (C-6a), 121.9 (C-6), 118.7 (C-2), 116.2 (C-15a), 84.5
(C-7a), 67.8 (C-15), 46.1 (C-13), 34.4 (C-10), 29.6 (C-12), 20.2 (C-20),
19.3 (C-20). Anal. Calcd for C23H23NO (329.43): C, 83.85; H, 7.04; N,
4.25. Found: C, 83.67; H, 7.09; N, 4.27.
4.1, 1.3 Hz, 1H, H-12eq); 13C NMR (150 MHz):
d
159.2 (C-40), 152.2
(C-6a), 149.8 (C-10), 147.8 (C-9), 135.1 (C-10), 132.6 (C-15b), 130.6
(C-20), 129.2 (C-4), 129.2 (C-4a), 128.7 (C-5), 127.7 (C-11a), 126.7
(C-2), 125.3 (C-7b), 123.3 (C-3), 122.9 (C-1), 118.9 (C-6), 113.7 (C-30),
111.7 (C-8), 111.5 (C-11), 111.4 (C-15a), 82.2 (C-7a), 62.3 (C-15), 56.1,
56.0 (9- and 10-OMe), 55.4 (40OMe), 45.4 (C-13), 29.1 (C-12). Anal.
Calcd for C29H27NO4 (453.53): C, 76.80; H, 6.00; N, 3.09. Found: C,
76.87; H, 5.92; N, 3.13.
4.22. (7aR
*
,15S )-9,10-Dimethoxy-15-phenylnaphth[2,1-e][1,3]
*
oxazino[2,3-a]isoquinoline (16B)
Mp: 138e140 ꢀC. 1H NMR (600 MHz):
d
8.13 (d, J¼8.2 Hz, 1H,
4.17. (7aR
*
,15R
*
)-9,10-Dimethoxy-15-(4-methoxyphenyl)
H-6), 7.79 (d, J¼8.0 Hz, 1H, H-3), 7.47 (br t, J¼7.8 Hz, 1H, H-5), 7.43
(br t, J¼7.7 Hz, 1H, H-4), 7.39 (d, J¼8.4 Hz, 1H, H-2), 7.30 (m, 5H,
H-20, H-30, H-40), 7.13 (d, J¼8.4 Hz, 1H, H-1), 6.89 (s, 1H, H-8), 6.68
(s, 1H, H-11), 5.61 (s, 1H, H-7a), 5.05 (s, 1H, H-15), 3.82 (s, 3H,
10-OMe), 3.81 (s, 3H, 9-OMe), 3.30 (ddd, J¼12.4, 11.3, 3.3 Hz, 1H,
H-13), 3.17 (ddd, J¼14.8, 12.3, 6.1 Hz, 1H, H-12), 3.09 (dd, J¼12.4,
6.2 Hz, 1H, H-13), 2.76 (dd, J¼14.7, 3.2 Hz, 1H, H-12); 13C NMR
naphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline (11C)
1H NMR (600 MHz):
d 5.44 (s, H-7a), 5.19 (s, H-15).
4.18. (7aR ,15S )-15-(4-Methoxyphenyl)naphth[1,2-e][1,3]ox-
*
*
azino[2,3-a]isoquinoline (12B)
(150 MHz):d
150.0 (C-10), 149.7 (C-6b), 147.9 (C-9), 143.8 (C-10),
Mp: 169e172 ꢀC. 1H NMR (600 MHz):
d
7.78 (d, J¼7.7 Hz, 1H,
134.0 (C-2a), 129.5 (C-20), 128.4 (C-30), 127.9 (C-11a), 127.8 (C-3),
127.8 (C-40), 127.3 (C-1), 126.5 (C-5), 125.5 (C-7b), 125.4 (C-4), 125.1
(C-6a), 122.0 (C-6), 119.3 (C-2), 113.3 (C-15a), 112.1 (C-8), 111.6
(C-11), 83.0 (C-7a), 65.2 (C-15), 56.2 (9-OMe), 56.1 (10-OMe), 45.7
(C-13), 29.3 (C-12). Anal. Calcd for C28H25NO3 (423.50): C, 79.41; H,
5.95; N, 3.31. Found: C, 79.37; H, 5.92; N, 3.36.
H-4), 7.73 (d, J¼8.9 Hz, 1H, H-5), 7.42 (d, J¼8.2 Hz, 1H, H-1), 7.32 (br
t, J¼7.6 Hz, 1H, H-2), 7.28 (m, 3H, H-3, H-8 and H-10), 7.20 (m, 4H,
H-9, H-11 and H-20), 7.06 (d, J¼8.9 Hz, 1H, H-6), 6.79 (d, J¼8.7 Hz,
2H, H-30), 5.63 (s, 1H, H-7a), 5.39 (s, 1H, H-15), 3.73 (s, 3H, OMe),
3.28 (m, 1H, H-13), 3.24 (m, 1H, H-12), 3.08 (m, 1H, H-13), 2.85 (m,
1H, H-12); 13C NMR (150 MHz):
d
159.2 (C-40), 152.1 (C-6a), 135.4
(C-11a), 135.0 (C-10), 133.3 (C-7b), 132.6 (C-15b), 130.7 (C-20), 129.2
(C-4), 129.2 (C-4a), 129.0, 128.9, 128.8 (C-8, C-10 and C-11), 128.8
(C-5), 126.7 (C-2), 126.2 (C-9), 123.4 (C-3), 122.9 (C-1), 118.9 (C-6),
113.7 (C-30), 111.5 (C-15a), 82.3 (C-7a), 62.3 (C-15), 55.4 (OMe), 45.4
(C-13), 29.5 (C-12). Anal. Calcd for C27H23NO2 (393.48): C, 82.42; H,
5.89; N, 3.56. Found: C, 82.57; H, 5.81; N, 3.59.
4.23. (7aR
*
,15R )-9,10-Dimethoxy-15-phenylnaphth[2,1-e][1,3]
*
oxazino[2,3-a]isoquinoline (16C)
1H NMR (600 MHz):
d 8.29 (br, 1H, H-6), 7.73 (br, 1H, H-3), 7.52
(m, 1H, H-4), 7.47 (m, 1H, H-5), 7.30 (m, 7H, H-2, H-8, H-20, H-30, H-
40), 6.76 (d, J¼8.4 Hz, 1H, H-1), 6.64 (br, 1H, H-11), 5.62 (s, 1H, H-7a),
4.90 (s, 1H, H-15), 3.94 (s, 3H, 9-OMe), 3.82 (s, 3H,10-OMe), 3.01 (m,
1H, H-13), 2.93 (m, 1H, H-12), 2.63 (m, 1H, H-13), 2.57 (m, 1H, H-
4.19. (7aR
*
,15R )-15-(4-Methoxyphenyl)naphth[1,2-e][1,3]ox-
*
azino[2,3-a]isoquinoline (12C)
12); 13C NMR (150 MHz):
d 150.0 (C-10), 149.0 (C-6b), 148.3 (C-9),
142.7 (C-10), 133.4 (C-2a), 129.9 (C-20), 128.9 (C-30), 128.2 (C-40),
127.7 (C-11a), 119.7 (C-15a), 127.8 (C-3), 126.2 (C-1), 125.9 (C-5),
125.9 (C-7b), 125.9 (C-4), 125.1 (C-6a), 121.7 (C-6), 120.5 (C-2), 111.2
(C-11), 110.4 (C-8), 89.4 (C-7a), 68.7 (C-15), 56.4 (9-OMe), 56.1 (10-
OMe), 46.3 (C-13), 28.6 (C-12).
1H NMR (600 MHz):
d 5.52 (s, H-7a), 5.21 (s, H-15).
4.20. (7aR ,15S )-9,10-Dimethoxy-15-isopropylnaphth[2,1-e]
*
*
[1,3]oxazino[2,3-a]isoquinoline (14B)
Mp: 134e136 ꢀC. 1H NMR (600 MHz):
d
8.11 (d, J¼8.2 Hz, 1H,
4.24. (7aR
*
,15S )-15-Phenylnaphth[2,1-e][1,3]oxazino[2,3-a]
*
H-6), 7.75 (d, J¼8.1 Hz, 1H, H-3), 7.43 (br t, J¼7.6 Hz, 1H, H-4), 7.40
(br t, J¼7.7 Hz,1H, H-5), 7.35 (d, J¼8.5 Hz,1H, H-2), 7.24 (d, J¼8.5 Hz,
1H, H-1), 7.04 (s, 1H, H-8), 6.70 (s, 1H, H-11), 5.86 (s, 1H, H-7a), 3.43
(d, J¼7.4 Hz, 1H, H-15), 3.90 (s, 3H, 9-OMe), 3.85 (s, 3H, 10-OMe),
3.13 (m, 1H, H-13), 3.13 (m, 1H, H-12), 2.72 (m, 2H, H-12, H-13), 2.20
isoquinoline (17B)
Mp: 151e153 ꢀC. 1H NMR (600 MHz):
d
8.10 (d, J¼8.3 Hz, 1H,
H-6), 7.80 (d, J¼8.1 Hz, 1H, H-3), 7.47 (br t, J¼7.7 Hz, 1H, H-4), 7.40
(m, 4H, H-2, H-5, H-8, H-9), 7.31 (m, 5H, H-10, H-20, H-30), 7.25

ꢀ
I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7464
(m, 1H, H-40), 7.21 (d, J¼7.6 Hz, 1H, H-11), 7.14 (d, J¼8.3 Hz, 1H, H-
1), 5.68 (s, 1H, H-7a), 5.06 (s, 1H, H-15), 3.34 (m, 1H, H-13), 3.25
(m, 1H, H-12), 3.11 (m, 1H, H-13), 2.87 (m, 1H, H-12); 13C NMR
(s, 1H, H-15), 5.89 (s, 1H, H-7a); 13C NMR (150 MHz):
126.5 (C-1), 123.0 (C-80), 121.7 (C-6), 89.5 (C-7a), 61.4 (C-15).
d 127.5 (C-3),
(150 MHz):
d
149.6 (C-6b), 142.5 (C-10), 135.6 (C-11a), 134.0 (C-2a),
4.29. (7aR
*
,15S
*
,15P )-15-(Naphth-1-yl)naphth[2,1-e][1,3]ox-
*
133.4 (C-7b), 129.5 (C-20), 129.1, 129.0, 128.9 (C-8, C-10, C-11), 128.4
(C-30), 127.7 (C-9), 127.6 (C-3), 127.2 (C-1), 126.4 (C-4), 126.4 (C-40),
125.4 (C-5), 125.1 (C-6a), 121.9 (C-6), 119.4 (C-2), 113.3 (C-15a), 83.0
(C-7a), 65.1 (C-15), 45.5 (C-13), 29.6 (C-12). Anal. Calcd for
azino[2,3-a]isoquinoline (19B)
Mp: 162e164 ꢀC. 1H NMR (600 MHz):
d
8.33 (d, J¼8.5 Hz, 1H,
H-80), 8.14 (d, J¼8.3 Hz, 1H, H-6), 7.88 (d, J¼8.1 Hz, 1H, H-50), 7.82
(d, J¼8.1 Hz, 1H, H-3), 7.77 (d, J¼8.2 Hz, 1H, H-40), 7.61 (dd, J¼8.4,
7.0 Hz, 1H, H-70), 7.51 (m, 2H, H-4, H-60), 7.45 (dd, J¼8.2, 6.9 Hz,
1H, H-5), 7.42 (d, J¼8.3 Hz, 1H, H-2), 7.34 (d, J¼7.4 Hz, 1H, H-8),
7.30 (br t, J¼7.9 Hz, 1H, H-30), 7.27 (t, J¼7.5 Hz, 1H, H-10), 7.20 (t,
J¼7.5 Hz, 1H, H-9), 7.17 (d, J¼7.6 Hz, 1H, H-11), 7.10 (d, J¼8.3 Hz,
1H, H-1), 6.96 (d, J¼7.8 Hz, 1H, H-20), 5.79 (s, 1H, H-7a), 5.77 (s,
1H, H-15), 3.48 (dt, J¼12.3, 3.8 Hz, 1H, H-13), 3.36 (dd, J¼12.2,
6.4 Hz, 1H, H-13), 3.25 (ddd, J¼16.3, 12.4, 6.3 Hz, 1H, H-12), 2.90
C
26H21NO (363.45): C, 85.92; H, 5.82; N, 3.85. Found: C, 85.96; H,
5.81; N, 3.82.
4.25. (7aR
*
,15R )-15-Phenylnaphth[2,1-e][1,3]oxazino[2,3-a]
*
isoquinoline (17C)
1H NMR (600 MHz):
d
8.32 (d, J¼8.2 Hz, 1H, H-6), 7.84
(d, J¼7.6 Hz, 1H, H-8), 7.74 (d, J¼7.9 Hz, 1H, H-3), 7.52 (br t,
J¼7.8 Hz, 1H, H-5), 7.47 (m, 1H, H-4), 7.38 (m, 1H, H-9), 7.31 (m, 5H,
H-10, H-20, H-30), 7.26 (m, 2H, H-2, H-40), 7.17 (d, J¼7.5 Hz, 1H, H-
11), 6.77 (d, J¼8.6 Hz, 1H, H-1), 5.70 (s, 1H, H-7a), 4.91 (s, 1H, H-
15), 3.02 (m, 1H, H-13), 3.02 (m, 1H, H-12), 2.66 (m, 1H, H-13), 2.66
(dd, J¼16.3, 3.7 Hz, 1H, H-12); 13C NMR (150 MHz):
d 150.1 (C-6b),
138.9 (C-10), 135.4 (C-11a), 134.4 (C-4a0), 134.1 (C-2a), 133.3 (C-7b),
132.2 (C-8a0), 130.0 (C-50), 129.1 (C-8), 129.0 (C-10), 128.9 (C-20),
128.8 (C-11), 128.6 (C-40), 127.8 (C-3), 127.3 (C-1), 126.5 (C-4),
126.5 (C-70), 126.2 (C-9), 125.9 (C-60), 125.5 (C-5), 125.0 (C-6a),
124.9 (C-30), 124.4 (C-80), 121.9 (C-6), 119.6 (C-2), 113.1 (C-15a),
83.0 (C-7a), 62.3 (C-159), 45.2 (C-13), 29.6 (C-12). Anal. Calcd for
(m, 1H, H-12); 13C NMR (150 MHz):
d
148.9 (C-6b), 143.6 (C-10),
135.9 (C-11a), 133.8 (C-7b), 133.3 (C-2a), 129.9 (C-20), 128.8 (C-10),
128.6 (C-11), 128.4 (C-30), 128.1 (C-9), 127.6 (C-3), 127.4 (C-8), 126.5
(C-4), 126.5 (C-40), 126.1 (C-1), 125.8 (C-5), 125.1 (C-6a), 121.8 (C-6),
120.5 (C-2), 119.6 (C-15a), 89.4 (C-7a), 68.7 (C-15), 46.1 (C-13), 28.9
(C-12).
C30H23NO (413.51): C, 87.14; H, 5.61; N, 3.39. Found: C, 87.22; H,
5.65; N, 3.42.
4.30. (7aR
*
,15R
*
,15P )-15-(Naphth-1-yl)naphth[2,1-e][1,3]ox-
*
azino[2,3-a]isoquinoline (19C1)
4.26. (7aR
*
,15S
*
,15P )-9,10-Dimethoxy-15-(naphth-1-yl)
*
naphth[2,1-e][1,3]oxazino[2,3-a]isoquinoline (18B)
1H NMR (600 MHz):
d
8.46 (d, J¼8.7 Hz, 1H, H-80), 8.40 (d,
J¼8.4 Hz, 1H, H-6), 7.81 (m, 1H, H-8), 7.65 (m, 1H, H-20), 7.19 (m, 1H,
Mp: 194e196 ꢀC. 1H NMR (600 MHz):
d
8.33 (d, J¼8.5 Hz, 1H, H-
H-2), 6.68 (d, J¼8.6 Hz, 1H, H-1), 5.78 (s, H-7a), 5.30 (s, 1H, H-15);
80), 8.17 (d, J¼8.2 Hz, 1H, H-6), 7.89 (d, J¼7.9 Hz, 1H, H-50), 7.82 (d,
J¼8.0 Hz, 1H, H-3), 7.77 (d, J¼8.2 Hz, 1H, H-40), 7.62 (br t, J¼7.9, Hz,
1H, H-70), 7.52 (m, 2H, H-4, H-60), 7.46 (dd, J¼8.3, 7.0, Hz, 1H, H-5),
7.41 (d, J¼8.3 Hz, 1H, H-2), 7.30 (dd, J¼8.1, 7.3 Hz, 1H, H-30), 7.10 (d,
J¼8.4 Hz, 1H, H-1), 6.94 (d, J¼7.2 Hz, 1H, H-20), 6.84 (s, 1H, H-8),
6.64 (s, 1H, H-11), 5.76 (s, 1H, H-15), 5.72 (s, 1H, H-7a), 3.79 (s, 3H,
10-OMe), 3.78 (s, 3H, 9-OMe), 3.44 (ddd, J¼12.1, 11.5, 3.7 Hz, 1H, H-
13), 3.34 (dd, J¼11.4, 6.3 Hz, 1H, H-13), 3.17 (ddd, J¼16.1, 12.2,
6.3 Hz, 1H, H-12), 2.80 (dd, J¼16.1, 3.5 Hz, 1H, H-12); 13C NMR
13C NMR (150 MHz):
d
130.7 (C-20), 128.9 (C-8), 126.9 (C-80), 124.9
(C-1), 121.9 (C-6), 120.2 (C-2), 90.5 (C-7a), 71.5 (C-15).
4.31. (7aR
*
,15R
*
,15M )-15-(Naphth-1-yl)naphth[2,1-e][1,3]ox-
*
azino[2,3-a]isoquinoline (19C2)
1H NMR (600 MHz):
d
8.48 (d, J¼8.7 Hz,1H, H-80), 8.31 (m,1H, H-
6), 6.75 (d, J¼8.6 Hz, 1H, H-1), 6.14 (s, 1H, H-15), 5.95 (s, 1H, H-7a);
13C NMR (150 MHz):
7a), 61.5 (C-15).
d
125.9 (C-1), 122.9 (C-80), 121.9 (C-6), 89.7 (C-
(150 MHz):
d
150.1 (C-6b), 149.8 (C-10), 147.8 (C-9), 139.0 (C-10),
134.4 (C-4a0), 134.1 (C-2a), 132.2 (C-8a0), 129.0 (C-50), 128.8 (C-20),
128.6 (C-40), 127.8 (C-3), 127.7 (C-11a), 127.3 (C-1), 126.5 (C-4),
126.5 (C-70), 126.0 (C-60), 125.5 (C-5), 125.3 (C-7b), 124.9 (C-6a),
124.9 (C-30), 124.4 (C-80), 121.9 (C-6), 119.5 (C-2), 113.0 (C-15a),
111.9 (C-8), 111.4 (C-11), 82.9 (C-7a), 62.3 (C-15), 56.1 (9-OMe), 56.0
(10-OMe), 45.3 (C-13), 29.2 (C-12). Anal. Calcd for C32H27NO3
(473.56): C, 81.16; H, 5.75; N, 2.96. Found: C, 81.27; H, 5.77; N,
2.92.
4.32. (7aR
*
,15S )-9,10-Dimethoxy-15-(naphth-2-yl)naphth
*
[2,1-e][1,3]oxazino[2,3-a]isoquinoline (20B)
Mp: 183e184 ꢀC. 1H NMR (600 MHz):
d
8.16 (d, J¼8.2 Hz, 1H,
H-6), 7.83 (m, 3H, H-3, H-40, H-50), 7.69 (d, J¼8.6 Hz, 1H, H-30), 7.66
(d, J¼8.0 Hz, 1H, H-80), 7.50 (t, J¼7.3 Hz, 1H, H-4), 7.44 (m, 5H, H-2,
H-5, H-10, H-60, H-70), 7.21 (d, J¼8.3 Hz, 1H, H-1), 6.83 (s, 1H, H-8),
6.69 (s, 1H, H-11), 5.63 (s, 1H, H-7a), 5.19 (s, 1H, H-15), 3.82 (s, 3H,
10-OMe), 3.77 (s, 3H, 9-OMe), 3.35 (ddd, J¼11.3, 10.6, 3.4 Hz, 1H, H-
13), 3.21 (m, 1H, H-12), 3.15 (dd, J¼10.5, 6.4 Hz, 1H, H-13), 2.79 (dd,
4.27. (7aR
*
,15R
*
,15P )-9,10-Dimethoxy-15-(naphth-1-yl)
*
naphth[2,1-e][1,3]oxazino[2,3-a]isoquinoline (18C1)
J¼15.8, 3.2 Hz, 1H, H-12); 13C NMR (150 MHz):
d 149.9, 149.8 (C-6b,
1H NMR (600 MHz):
d
8.44 (d, J¼8.5 Hz, 1H, H-80), 8.38 (d,
C-10), 147.8 (C-9), 141.3 (C-20), 134.1 (C-2a), 133.1 (C-8a0), 133.0 (C-
4a0), 128.5 (C-10), 128.2 (C-80), 127.8 (3C, C-30, C-40, C-50), 127.7 (2C,
C-3, C-11a), 127.3 (C-1), 126.5 (C-4), 126.3 (2C, C-60, C-70), 125.4 (2C,
C-5, C-7b), 125.1 (C-6a), 122.0 (C-6), 119.3 (C-2), 113.0 (C-15a), 111.9
(C-8), 111.4 (C-11), 82.9 (C-7a), 65.2 (C-15), 56.1 (9-OMe), 56.0
(10-OMe), 45.6 (C-13), 29.2 (C-12).
J¼8.4 Hz, 1H, H-6), 7.69 (d, J¼8.1 Hz, 1H, H-3), 7.65 (m, 1H, H-20),
7.39 (m, 1H, H-8), 7.08 (m, 1H, H-70), 6.68 (d, J¼8.7 Hz, 1H, H-1), 5.72
(s, 1H, H-7a), 5.30 (s, 1H, H-15); 13C NMR (150 MHz): 130.6 (C-20),
d
127.6 (C-3), 126.8 (C-809), 125.4 (C-70), 125.0 (C-1), 121.7 (C-6), 110.1
(C-8), 90.5 (C-7a), 71.4 (C-15).
4.28. (7aR
*
,15R
*
,15M
*
)-9,10-Dimethoxy-15-(naphth-1-yl)
4.33. (7aR
*
,15R )-9,10-Dimethoxy-15-(naphth-2-yl)naphth
*
naphth[2,1-e][1,3]oxazino[2,3-a]isoquinoline (18C2)
[2,1-e][1,3]oxazino[2,3-a]isoquinoline (20C)
1H NMR (600 MHz):
J¼8.5 Hz, 1H, H-6), 7.72 (d, J¼8.1 Hz, 1H, H-3), 6.71 (m, 1H, H-1), 6.13
d
8.48 (d, J¼8.4 Hz, 1H, H-80), 8.30 (d,
1H NMR (600 MHz): 8.33 (br, 1H, H-6), 7.95 (br, 1H, H-10), 7.88
d
(br, 1H, H-80), 7.83 (m, 2H, H-40, H-50), 7.73 (d, J¼8.0 Hz, 1H, H-3),

ꢀ
I. Szatmari et al. / Tetrahedron 69 (2013) 7455e7465
7465
7.53 (m, 1H, H-5), 7.48 (m, 1H, H-4), 7.42 (m, 3H, H-30, H-60, H-70),
Acknowledgements
7.33 (s, 1H, H-8), 7.23 (br, 1H, H-2), 6.79 (br, 1H, H-1), 6.63 (s, 1H,
H-11), 5.68 (s, 1H, H-7a), 5.05 (s, 1H, H-15), 3.96 (s, 3H, 9-OMe), 3.82
(s, 3H, 10-OMe), 3.05 (br d, J¼10.0 Hz, H-13), 2.92 (br t, J¼15.3 Hz,
H-12), 2.68 (t, J¼10.1 Hz, H-13), 2.55 (d, J¼15.5 Hz, H-12); 13C NMR
The authors’ thanks are due to the Hungarian Research Foun-
dation (OTKA No. K-75433) and TAMOP-4.2.2.A-11/1/KONV-2012-
ꢀ
ꢀ
0052. I.S. acknowledges the award of a Bolyai Janos Fellowship.
(150 MHz):
d
149.2, 149.1 (C-6b, C-10), 148.1 (C-9), 142.4 (C-20),
133.4 (C-8a0), 133.4 (C-4a0), 133.0 (C-2a), 129.3 (C-10), 127.9 (C-80),
127.8 (C-40), 127.7 (C-3), 127.3 (C-11a), 126.3 (C-30),126.3 (C-1), 126.3
(C-4), 125.8 (C-5), 125.8 (C-7b), 125.1 (C-6a), 121.7 (C-6), 120.5 (C-2),
119.8 (C-15a), 111.0 (C-11), 110.2 (C-8), 89.3 (C-7a), 68.8 (C-15), 56.3
(9-OMe), 56.0 (10-OMe), 46.4 (C-13), 28.5 (C-12). Anal. Calcd for
References and notes
1. (a) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221; (b) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817; (c) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045.
2. (a) Liras, S.; Davoren, J. E.; Bordner, J. Org. Lett. 2001, 3, 703; (b) Ito, M.; Clark, C.
W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003.
C
32H27NO3 (473.56): C, 81.16; H, 5.75; N, 2.96. Found: C, 81.21; H,
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€ €
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€ €
3. (a) Szatmari, I.; Fulop, F. Curr. Org. Synth. 2004, 1, 155; (b) Szatmari, I.; Fulop, F.
Tetrahedron 2013, 69, 1255.
5.73; N, 2.95.
ꢀ
ꢀ
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€ €
4. Szatmari, I.; Hetenyi, A.; Lazar, L.; Fulop, F. J. Heterocycl. Chem. 2004, 41, 367.
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€ €
5. Heydenreich, M.; Koch, A.; Klod, S.; Szatmari, I.; Fulop, F.; Kleinpeter, E. Tetra-
hedron 2006, 62, 11081.
4.34. (7aR
*
,15S )-15-(Naphth-2-yl)naphth[2,1-e][1,3]oxazino
*
[2,3-a]isoquinoline (21B)
€ €
€
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€ €
6. Csutortoki, R.; Szatmari, I.; Koch, A.; Heydenreich, M.; Kleinpeter, E.; Fulop, F.
Tetrahedron 2011, 67, 8564.
7. Csutortoki, R.; Szatmari, I.; Heydenreich, M.; Koch, A.; Starke, I.; Fulop, F.;
Kleinpeter, E. Tetrahedron 2012, 68, 4600.
8. Heydenreich, M.; Koch, A.; Szatmari, I.; Fulop, F.; Kleinpeter, E. Tetrahedron
€ €
€
ꢀ
€ €
Mp: 166e168 ꢀC. 1H NMR (600 MHz):
d
8.13 (d, J¼8.2 Hz, 1H, H-
6), 7.83 (m, 3H, H-3, H-40, H-50), 7.69 (d, J¼8.6 Hz, 1H, H-30), 7.67 (d,
J¼8.0 Hz, 1H, H-80), 7.50 (m, 2H, H-4, H-60), 7.45 (m, 5H, H-2, H-5, H-
8, H-10, H-70), 7.31 (m, 2H, H-9, H-10), 7.23 (m, 2H, H-1, H-11), 5.71
(s,1H, H-7a), 5.21 (s,1H, H-15), 3.40 (ddd, J¼11.5, 10.4, 3.0 Hz,1H, H-
13), 3.30 (ddd, J¼16.3, 11.6, 5.9 Hz, 1H, H-12), 3.18 (dd, J¼10.5,
6.0 Hz, 1H, H-13), 2.90 (dd, J¼16.4, 2.9 Hz, 1H, H-12); 13C NMR
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€ €
2008, 64, 7378.
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€ €
9. Szatmari, I.; Fulop, F. Tetrahedron Lett. 2011, 52, 4440.
10. Osyanin, V. A.; Ivleva, E. A.; Osipov, D. V.; Klimochkin, Y. N. Chem. Heterocycl.
Compd 2011, 47, 845.
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€ €
11. Szatmari, I.; Martinek, T. A.; Lazar, L.; Fulop, F. Eur. J. Org. Chem. 2004, 2231.
12. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
T. A.; Peralta, J. E., Jr.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K.
N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene,
M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
nenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian: Wallingford, CT,
2009.
(150 MHz):
d
149.8 (C-6b), 141.2 (C-20), 135.6 (C-11a), 134.1 (C-2a),
133.4 (C-7b), 133.1 (C-8a0), 133.0 (C-4a0), 129.1 (C-10), 129.0 (C-9),
128.9 (C-11), 128.5 (C-8), 128.3 (C-80), 128.2 (C-10), 127.7 (C-3), 127.7
(C-30), 127.6 (C-40), 127.3 (C-50), 126.5 (C-60), 126.3 (C-1), 126.3 (C-4),
126.2 (C-70), 125.5 (C-5), 125.1 (C-6a), 121.9 (C-6), 119.4 (C-2), 113.1
(C-15a), 83.0 (C-7a), 65.2 (C-15), 45.6 (C-13), 29.6 (C-12). Anal. Calcd
for C30H23NO (413.51): C, 87.14; H, 5.61; N, 3.39. Found: C, 87.18; H,
5.65; N, 3.41.
4.35. (7aR
*
,15R
*
)-15-(Naphth-2-yl)naphth[2,1-e][1,3]oxazino
13. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. Ab Initio Molecular Orbital
Theory; Wiley: New York, NY, 1986.
14. Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
[2,3-a]isoquinoline (21C)
15. Møller, C.; Plesset, M. S. Physiol. Rev. 1934, 46, 618.
16. Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999.
17. SYBYL 7.3; Tripos: 1699 South Hanley Rd., St. Louis, MO.
1H NMR (600 MHz):
d
8.35 (d, J¼8.2 Hz, 1H, H-6), 7.97 (s, 1H, H-
10), 7.88 (m, 2H, H-8, H-80), 7.79 (m, 2H, H-40, H-50), 7.73 (d, J¼8.0 Hz,
1H, H-3), 7.53e7.41 (m, 5H, H-4, H-5, H-30, H-60, H-70), 7.31 (m, 2H,
H-9, H-10), 7.24 (m, 1H, H-2), 7.17 (d, J¼7.3 Hz, 1H, H-11), 6.80 (d,
J¼8.5 Hz, 1H, H-1), 5.75 (s, 1H, H-7a), 5.07 (s, 1H, H-15), 3.08 (dd,
J¼11.0, 4.2 Hz, 1H, H-13), 3.01 (ddd, J¼15.9, 11.1, 4.4 Hz, 1H, H-12),
2.71 (dt, J¼11.1, 3.1 Hz, 1H, H-13), 2.65 (br d, J¼16.0 Hz, 1H, H-12);
18. Jensen, F. R.; Beck, B. H. Tetrahedron Lett. 1966, 7, 4523.
19. Casarotto, M. G.; Craik, D. J.; Lloyd, E. J. J. Med. Chem. 1991, 34, 2043.
20. Slough, G. A.; Han, F.; Lee, B. H. Tetrahedron Lett. 1999, 40, 3851.
€
€€
ꢀ
ꢀ
21. Tahtinen, P.; Sillanpaa, R.; Stajer, G.; Szabo, A. E.; Pihlaja, K. J. Chem. Soc., Perkin
Trans 2 1999, 2011.
22. TopSpin 3.0; Bruker Biospin GmbH: Rheinstetten, 2010.
23. PERCH Solutions Ltd. Kuopio, Finland Laatikainen, R. J. Magn. Reson. 1991, 92, 1;
Laatikainen, R. QCMP100. MLDC8 QCPE Bull. 1992, 12, 23; Laatikainen, R.;
13C NMR (150 MHz): 149.0 (C-6b),139.9 (C-20),136.0 (C-11a),133.5
d
€ €
Niemitz, M.; Weber, U.; Sundelin, J.; Hassinen, T.; Vepsalainen, J. J. Magn. Reson.
1996, A120, 1; Laatikainen, R.; Niemitz, M.; Malaisse, W. J.; Biesemans, M.;
Willem, R. A. Magn. Reson. Med. 1996, 36, 359.
(C-8a0), 133.4 (C-7b), 133.4 (C-4a0), 133.1 (C-2a), 129.3 (C-10), 128.8
(C-40), 128.6 (C-11), 128.4 (C-9), 128.3 (C-10), 128.0 (C-80), 127.7 (C-
3), 127.6 (C-8), 127.4 (C-50), 127.3 (C-30), 126.4 (C-60), 126.3 (C-1),
126.3 (C-4), 126.2 (C-70), 125.9 (C-5), 125.1 (C-6a), 121.8 (C-6), 120.6
(C-2), 119.3 (C-15a), 89.4 (C-7a), 68.8 (C-15), 46.2 (C-13), 28.9
(C-12).
ꢀ
ꢀ ꢀ
€ €
24. Szatmari, I.; Martinek, T. A.; Lazar, L.; Fulop, F. Tetrahedron 2003, 59, 2877.
ꢀ
ꢀ
€ €
25. Toth, D.; Szatmari, I.; Fulop, F. Eur. J. Org. Chem. 2006, 4664.
ꢀ
€ €
26. Szatmari, I.; Fulop, F. Synthesis 2009, 775.
ꢀ
ꢀ
€ €
27. Toth, D.; Szatmari, I.; Heydenreich, M.; Koch, A.; Kleinpeter, E.; Fulop, F. J. Mol.
Struct. 2009, 929, 58.